(Recent Results in Cancer Research 203) Florian Otto, Manfred P. Lutz (Eds.) - Early Gastrointestinal Cancer

Recent Results in Cancer Research
Series Editors: P. M. Schlag · H.-J. Senn
Florian Otto
Manfred P. Lutz Editors
Early
Gastrointestinal
Cancers II:
Rectal Cancer
Recent Results in Cancer Research
Volume 203
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H.-J. Senn, St. Gallen, Switzerland
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Florian Otto Manfred P. Lutz
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Early Gastrointestinal
Cancers II: Rectal Cancer
123
Editors
Florian Otto Manfred P. Lutz
Department of Medical Oncology Caritasklinik St. Theresia
Tumor- und Brustzentrum ZeTuP Saarbrücken
St. Gallen Germany
Switzerland
ISSN 0080-0015 ISSN 2197-6767 (electronic)

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DOI 10.1007/978-3-319-08060-4
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Preface
At the second St. Gallen EORTC Gastrointestinal Cancer Conference held in St.
Gallen, Switzerland on March 6–8, 2014, a group of renowned international
experts came together to discuss the developments in diagnosis and treatment of
early, potentially curable gastrointestinal malignancies. Nearly 300 participants
from 43 countries took part in the 3-day conference that was organized by St.
Gallen Oncology Conferences (SONK) and co-sponsored by the European Orga-
nization for Research and Treatment of Cancer (EORTC) and SONK with con-
tribution of the European School of Oncology (ESO).
The focus of this second conference lay on rectal cancer. The experts discussed
molecular and pathologic characteristics of rectal cancer, preferred methods for
initial staging, novel endoscopic and surgical techniques, multimodal therapeutic
approaches including radiation and medical oncology as well as quality-of-life
aspects. The concluding day of the conference was dedicated to an attempt on a
consensus on diagnosis and treatment of potentially curable rectal cancer. The
consensus statement will be published separately in a major oncology journal. The
majority of the invited expert contributions to the conference, however, are pub-
lished in this volume of the internationally well-known series, Recent Results in
Cancer Research, by Springer. We very much hope you will enjoy reading its
content.
The organizers of the conference invite interested clinicians and scientists
involved in the field of gastrointestinal malignancies to the next international St.
Gallen EORTC Cancer Conference that will be held in St. Gallen/Switzerland,
10–12 March 2016.
St. Gallen, Switzerland Florian Otto

Saarbrücken, Germany Manfred P. Lutz
v
Contents
Part I Staging of Rectal Cancer
Imaging Assessment of Early Rectal Cancer. . . . . . . . . . . . . . . . . . . . 3

Jo Waage, Fiona Taylor, James Read and Gina Brown
Predicting Lymph Node Metastases in pT1 Rectal Cancer . . . . . . . . . 15

S. L. Bosch and I. D. Nagtegaal
Part II Treatment of Early Rectal Cancer
Endoscopic Resection: When Is EMR/ESD Sufficient? . . . . . . . . . . . . 25

H. Messmann
Transanal Endoscopic Microsurgery . . . . . . . . . . . . . . . . . . . . . . . . . 31

Chris Cunningham
Part III Surgical Treatment of Rectal Cancer
What Is ‘‘Good Quality’’ in Rectal Cancer Surgery?

The Pathologist’s Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Total Mesorectal Excision: Open, Laparoscopic or Robotic. . . . . . . . . 47

Monica Young and Alessio Pigazzi
Ultra Low Resection Versus Abdomino-Perineal Excision

in Low Rectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Torbjörn Holm
vii
viii Contents
T4 Rectal Cancer: Do We Always Need an Exenteration? . . . . . . . . . 69

Thomas A. Vermeer, Miranda Kusters and Harm J. T. Rutten
Do T3 Rectal Cancers Always Need Radiochemotherapy?. . . . . . . . . . 95

Rob Glynne-Jones
Quality of Life After Surgery for Rectal Cancer. . . . . . . . . . . . . . . . . 117

Teresa Gavaruzzi, Francesca Giandomenico, Paola Del Bianco,
Lorella Lotto, Alessandro Perin and Salvatore Pucciarelli
Part IV Combined Modality Therapy in Rectal Cancer
Aims of Combined Modality Therapy in Rectal Cancer (M0) . . . . . . . 153

J. P. Gerard, K. Benezery, J. Doyen and E. Francois
Neoadjuvant Radiotherapy (5 3 5 Gy): Immediate Versus

Delayed Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Krzysztof Bujko, Maciej Partycki and Lucyna Pietrzak
Early and Late Toxicity of Radiotherapy for Rectal Cancer . . . . . . . . 189

Ines Joye and Karin Haustermans
Immediate Surgery or Clinical Follow-Up After

a Complete Clinical Response? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Angelita Habr-Gama and Rodrigo Oliva Perez
Part V Rectal Cancer with Synchronous Liver Metastases
Limits of Colorectal Liver Metastases Resectability:

How and Why to Overcome Them? . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Serge Evrard
Rectal Cancer with Synchronous Liver Metastases:

Leave It All in? When (not) to Resect the Primary? . . . . . . . . . . . . . . 231
Florian Lordick
Recurrence Patterns After Resection of Liver Metastases

from Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Halfdan Sorbye
Part I
Staging of Rectal Cancer
Imaging Assessment of Early Rectal
Cancer
Jo Waage, Fiona Taylor, James Read and Gina Brown
Abstract
Early rectal cancer (ERC) is defined as invasive adenocarcinoma spreading
into, but not beyond, the submucosa or muscularis propria—that is a Dukes’A:
T1N0 or T2N0 tumour in the tumour node metastasis (TNM) classification
(Taylor et al. 2008). Among these tumours it is suggested that the most
superficial T1 tumours least likely to metastasize to local lymph nodes than
adenocarcinoma invading deeper where the rich lymphatic and venous plexuses
within the submucosa provide a mechanism for tumour spread beyond the
rectum. Currently, only about 10 % of patients presenting symptomatically with
rectal cancer are diagnosed with early disease; however, up to 30 % of screen
detected cancers are being identified as Dukes’A. Thus, the overall detection of
early stage tumours is likely to increase following greater implementation in
screening programs. The goal of this invited review is to provide recommen-
dations based on the consensus discussion on the information from preoperative
imaging that is of relevance for clinical decision-making for patients with early
rectal cancer.
J. Waage G. Brown (&)

Haukeland University Hospital, Surgical Clinic, Bergen, Norway
e-mail: [email protected]
F. Taylor J. Read
Department of Surgery and Academic Radiology, Croydon University
and Royal Marsden NIHR BRC, Sutton, Surrey, UK
G. Brown
Department of Academic Radiology, Royal Marsden NIHR BRC, Sutton, Surrey, UK
F. Otto and M. P. Lutz (eds.), Early Gastrointestinal Cancers II: Rectal Cancer, 3
Recent Results in Cancer Research 203, DOI: 10.1007/978-3-319-08060-4_1,
Springer International Publishing Switzerland 2014
4 J. Waage et al.
1 Assessment and Rationale for Treatment Decisions

in Early Rectal Cancer
Total mesorectal excision for invasive rectal cancer guarantees removal of the
primary tumour and its draining lymph nodes in an enclosed package and is
associated with \3 % risk of local recurrence if no preoperative adverse features
are identified and is regarded as a standard of care for malignant lesions arising at a
height of 6 cm or more. For low rectal polyps, the additional morbidity and loss of
quality of life associated with an ultralow anastomosis or permanent stoma for-
mation means that the options of alternative approaches to enable sphincter
preservation while not compromising oncological outcomes increases in impor-
tance from the patient’s perspective. Precise preoperative staging by imaging and
histopathology is essential to enable a balanced risk assessment if more radical
surgery is to be avoided.
If local excision or TEM is being considered—preoperative staging of early
rectal cancer should enable surgical planning that avoids the risk of subsequent
recurrence caused either by tumour perforation beyond the mesorectal envelope or
of leaving viable metastatic disease within the mesorectum. In assessing early rectal
cancer it is important for radiologists to recognise early stage rectal cancer that is
potentially amenable to local excision. Equally, it is important for lesions detected
at endoscopy to be staged prior to removal to ensure definitive treatment of high risk
early stage rectal cancers for avoidance of piecemeal removal of polyp cancers.
MRI or endorectal ultrasound performed prior to a biopsy is likely to be more
accurate as oedema/inflammation may distort the submucosal and muscularis
propria layer interfaces resulting in potential overstaging.
2 Staging Classification of Early Rectal Cancers
Early rectal cancer can manifest as either a polyp characterised by a rounded or

polypoidal mass associated with a fibromuscular stalk or a sessile (flat) lesion. In
polyp cancers, tumour spread extends into the stalk and then into the submucosa
and beyond.
The principle of staging polyps and sessile lesions is based on knowledge that
the deeper and more extensive the tumour spread is into the rich lymphatic and
vascular plexuses of the mid and lower thirds of the submucosa, with a higher risk
of spread into the lymphatic and venous channels beyond the confines of the rectal
wall and into mesorectum.
Pedunculated polyps were originally classified by Haggitt (2008) on a 1–5 point
scale to describe the level of polyp invasion and associated risk of metastatic spread
to lymph nodes or vessels within the mesorectum. For sessile or flat lesions—the
Kikuchi classification describes the depth of submucosal invasion. The Kikuchi
classification divides the submucosa into thirds to classify T1 spread as sm1, sm2
and sm3. The upper third of the submucosa is relatively devoid of venous and
lymphatic channels and the risk of nodal metastatic disease for sm1 tumours was
Imaging Assessment of Early Rectal Cancer 5
originally reported by Kikuchi as 0 %. For increasing submucosal invasion, a higher

rate of nodal metastatic disease is seen—rising to 10 % for sm2 and 25 % for sm3
and sm3 is considered equivalent to Haggitt level 4 in terms of nodal risk spread.
Further risk factors for nodal spread have since been identified: resection margin
\1 mm (high risk), 1–2 mm (risk factor), poor differentiation, mucinous or signet
ring morphology, tumour budding, intramural lymphatic or vascular invasion.
These factors, when incorporated into histological staging of polyps form the basis
of a risk stratification that enables counselling of patients with regard to the need
for definitive surgery or to consider adjuvant therapy following the local excision
of an early rectal cancer.
3 Endorectal Ultrasonography
Since Dragsted et al. (1983) introduced ERUS as a method for rectal tumour
evaluation, the method has been increasingly accepted as an essential part of the
preoperative evaluation regime. Reviews and meta-analyses have indicated that the
overall accuracy of ERUS rectal tumour staging is in the range of 80–90 % (Bipat
et al. 2004; Puli et al. 2009; Hunerbein 2003). However, a number of papers
evaluating the method have been published over the last two decades (see Table 1),
demonstrating accuracies ranging from 55 to 97 %. This relatively wide range can,
at least in part, be explained by heterogeneity in methods, study design, prevalence
of different pT-stages and degree of observer experience. Multi-centre studies tend
to report lower accuracies than single-centre studies from high-volume institutions.
Studies have also shown that the accuracy of ERUS can be improved from low as
50 % to as high as 90 % with training (Orrom et al. 1990; Badger et al. 2007; Kav
and Bayraktar 2010; Li et al. 2010; Morris et al. 2011). Development in ultrasound
technology, such as strain elastography, may also contribute to improved staging of
ERC (Waage et al. 2011)
4 MRI Technique and Quality
The accuracy of MRI in assessing depth of spread into or beyond the rectal wall,
its ability to precisely assess the risk of CRM involvement and local recurrence on
baseline and post treatment scans—was based on high quality MRI scans per-
formed according to standardised protocol and images interpreted according to
agreed diagnostic criteria, which were standardised through 1 day training work-
shops. When applied in the multi-centre setting at non-specialised and tertiary
referral institutions alike the results were found to be reproducible and consistent.
The key to improvements in diagnostic and prognostic accuracy from preoperative
MRI assessment of rectal cancers was specialist gastrointestinal radiologists who
worked closely with their surgeons, oncologists and pathologists in the MDT
setting. The participating radiologists were responsible for reviewing and reporting
all newly diagnosed rectal cancers in the MDT meetings at their respective
6 J. Waage et al.
Table 1 Accuracy is either the reported overall uT-stage accuracy, or the accuracy computed
based on information given in the papers
First author (ref.) Year Patients (n) Reported overall uT-stage accuracy
Akahoshi (2000) 2000 39 0.83
Akasu (2009) 1997 150 0.96
Ashraf (2012) 2012 165 0.55
Bali (2004) 2004 29 0.79
Doornebosch et al. (2008) 2008
Beynon et al. (1986) 1986 33 0.91
Fedyaev et al. (1995) 1995 132 0.91
Garcia-Aguilar et al. (2002) 2002 545 0.69
Giovanniniet al. (2006) 2006 35 0.89
Glaser et al. (1990) 1990 110 0.90
Herzog et al. (1993) 1993 118 0.89
Katsura et al. (1992) 1992 112 0.96
Kulig et al. (2006) 2006 29 0.89
Manger and Stroh (2004) 2004 357 0.77
Nielsen et al. (1996) 1996 100 0.96
Ptok et al. (2006) 2006 3501 0.66
Rafaelsen et al. (1994) 1994 107 0.92
Rifkin 1989 101 0.67
Sailer 1997 162 0.97
Santoro 2001 – 0.82
Yamashita 1988 122 0.96
institutions. Participation in the MERCURY studies showed that with only a

minimal investment in training and support development of radiologists—it was
possible to harmonise the standards of cancer staging preoperatively.
5 Assessing Nodal Spread Preoperatively
It is now well understood that nodal metastatic spread cannot be reliably excluded
using preoperative imaging since a significant majority of metastases measure
\0.3 mm in diameter and well beyond the resolution of modern imaging tech-
niques (Landmann et al. 2007). It is also understood that measuring the size of
nodes is futile since benign reactive nodes are seen in many patients with and
without nodal metastatic disease and reactive nodes can enlarge to any size
(Dworak 1991). Therefore, measuring lymph nodes as a means of assessing the
Table 2 Criteria of tumour measured the following characteristics were included when examining the tumours on MRI
MRI characteristic
Tumour height from anal verge Measured in the sagittal plane from the lower most fibres of the external
Tumour height from the puborectalis sling sphincter
Measured in the sagtittal plane from the uppermost border of the puborectalis
muscle, verified using axial plane to cross reference anatomic location of
puborectalis muscle at point of insertion into symphysis pubis
Morphology
Sessile/Ulcerating
Imaging Assessment of Early Rectal Cancer
Polypoid
Diameter of the tumour (D)
Diameter of the advancing edge (A) Depth of extension into the submucosa
(E) thickness of preserved submucosa at the advancing edge of the tumour
(SM)
Quadrant of the advancing edge or fibromuscular stalk within the rectal wall Anterior quadrant (10–2 o’clock)
Right lateral quadrant (2–4 o’clock)
Posterior quadrant (6–8 o’clock)
Left lateral quadrant (8–10 o’clock)
(continued)
7
8
Table 2 (continued)
MRI characteristic
Advancing edge Nodular/irregular
Smooth bordered
Venous invasion Tumour signal expanding course of 1–2 mm extramural vein outside rectal
wall
Tumour signal expanding course of medium sized vein 3–5 mm vein
Tumour expanding anatomic large vessels: superior rectal vein, lateral rectal
vein and inferior rectal vein
Nodes No visible nodes
Smooth bordered uniform signal intensity
Mixed signal or irregular bordered nodes
J. Waage et al.
likelihood of malignancy is highly inaccurate and is not recommended as good

practice in the preoperative assessment of rectal cancer (Brown et al. 2003). The
positive identification of nodal or extramural disease relies on resolving tumour
signal within a node and its effect on the node, which can manifest as nodal
heterogeneity or penetration of the nodal capsule by tumour resulting in nodal
border irregularity; this is best seen on high resolution imaging with a minimal
voxel resolution of 1.1 mm3 (Brown et al. 2004).
6 MRI Technique
A 1.5T or 3T system is used with phase array coils. The first series is the sagittal
T2-weighted fast spin echo sequence to identify the primary tumour. The second
series is the large field of view axial sections of the whole pelvis and the third and
subsequent series consists of the high resolution images through the rectal cancer
and adjacent tissues. For patients with low tumours, high spatial resolution coronal
imaging will optimally show the levator muscles, the sphincter complex, the in-
tersphincteric plane and the relationship to the rectal wall. A sagittal high reso-
lution series will also enable multiplanar assessment of anteriorly located polyps or
sessile lesions. Finally, the examination is completed by undertaking further high
resolution axial imaging from the upper most border of the tumour to the L5/S1
junction to enable assessment of mesorectal nodes, venous deposits and pelvic
sidewall nodes at high resolution.
7 Assessment of Pelvic Lymph Nodes
Nodal assessment with imaging takes place in two settings:

1. The initial assessment of the mesorectum prior to resection/local excision/
TEM or preoperative therapy.
2. Following preoperative therapy.
3. During follow up surveillance of the mesorectum if primary radical surgery has
been avoided.
In all three scenarios—it is important that the entire mesorectum above the
primary tumour is imaged at high resolution, and that this covers the mesorectum
to the L5/S1 sacral junction.
The absence of any visible nodes within the mesorectum is strong reassurance
that there is an absence of nodal metastatic disease. The natural history of nodes
containing micrometastatic disease is unpredictable and is not necessarily asso-
ciated with adverse outcomes. Clearly, the absence of nodal recurrence in many
patients on long-term follow up suggests that the patient’s own immune system
with and without the use of adjuvant chemoradiotherapy in some high risk cases
results in long-term cures. The precise mechanisms for this are poorly under-
stood—however, this favours the possibility that nodal micrometastatic disease—
10 J. Waage et al.
at least in some patients does not necessarily equate to viable metastatic disease in
the long term. Thus, surveillance of nodes is relevant and the lack of progressive
change in the morphology of a node is reassuring. On the other hand, a node that
changes from smooth bordered and uniform signal to a mixed signal or irregular
node should be diagnosed as malignant and such patients can be successfully
salvaged by surgery.
8 The Anatomy of the Rectum and Mesorectum at High

Resolution
The first demonstration of the layers of the rectal wall using a high resolution MRI
technique was achieved by Schnall et al. in a study of 12 patients undergoing
endorectal MRI. In this paper, the authors elegantly showed how high resolution
imaging depicts the layers of the rectal wall. This has been reproduced using the
high resolution pelvic phased array MRI (Fig. 3).
9 Preoperative Evaluation of Primary Early Rectal Cancer
Assessment of polypoidal and sessile lesions

Preoperative evaluation of polypoidal lesions is aimed at firstly determining the
site of the stalk and then assessing the extension of tumour into the fibromuscular
stalk and beyond. Sessile or flat lesions are characterised by lateral raised rolled
edges, which are the non-invasive portions of the lesions, and the central depressed
portion, which forms the advancing edge of the tumour. Preoperative assessment
of sessile lesions requires detailed evaluation of the central depressed portion of
the tumour and the degree of preservation identifiable in the submucosa and
muscularis propria at the advancing edge. Multiplanar assessment is essential and
if submucosa is evident on any single view at the base of the stalk or at the central
invasive base of a sessile tumour—then this enables the confident diagnosis of a
T1 lesion amenable to a local excision approach. Assessment of the depth of T
stage tumour depth within and beyond the rectal wall is achieved by assessing the
extent of the intermediate signal intensity tumour and its extent of spread into the
submucosa, muscularis and beyond. The precise depth of extension into submu-
cosa should be attempted, but crucially a measurement of the thickness of pre-
served submucosa is relevant with a thickness of[1 mm in any plane increases the
likelihood of detection of an Sm1 or Sm2 lesion, which could be cured by a local
excision approach. The lack of any measurable high signal intensity layer on any
plane imaged between the advancing edge of the tumour and the low signal
intensity of the muscularis suggests a high probability of a T1sm3 or early T2
tumour. It should be emphasised that the distinction between a T1sm3 and an early
T2 is prognostically and clinically irrelevant since it means that a local excision
without removal of the full thickness of the underlying muscularis propria will
result in a positive deep margin of \1 mm.
In selecting patients for local excision, it is currently understood that T1 sm1

can be safely removed without further therapy since the likelihood of local relapse
and tumour recurrence is low in these patients. The current gold standard for
patients with T1 tumours sm2 or greater is TME surgery. This is considered a good
and safe option for patients amenable to TME surgery with sphincter conservation.
However, for low rectal polyps and early stage tumours within 10 mm of the
puborectalis sling, surgery most often requires either an abdominoperineal exci-
sion or an ultralow intersphincteric anastomosis—both result in significant impact
on patient’s quality of life due to impairment or loss of sphincter function. Thus,
despite the ideal recommendation being definitive surgery many patients opt for
the alternative of chemoradiotherapy and surveillance following local excision or
TEM of an early stage lesion. Thus, identification of patients with low lying
tumours amenable to sphincter preserving approaches is becoming increasingly
important.
In order to judge the safety of TEM preoperatively careful documentation of the
advancing edge of the tumour is needed, and therefore precise documentation of
both the quadrant (clock position) and height of tumour. Certain interfaces may
limit the extent for TEM excision: the anterior rectal wall and the prostate, the
tumour height and the relationship to levators, distal TME plane and the peritoneal
reflection.
Algorithm for staging using MRI and ERUS in early stage rectal cancer
The goal of preoperative imaging in early stage rectal cancer, whether by EUS
or MRI, is to determine the safety and feasibility of potentially less radical options
such as local excision and TEM. A policy of assessing lesions prior to attempted
removal would appear justified if high rates of piecemeal excision or unexpected
cancers in locally excised lesions are to be avoided. It is crucial that for both MRI
and EUS that appropriately trained expertise and equipment is used to optimally
assess early rectal cancer. In this way, patients can be presented with a compre-
hensive assessment of staging findings and options for treatment, which could
12 J. Waage et al.
range from local exicision, TEM, or primary TME surgery with and without
sphincter preservation and with or without preoperative therapy.
In future studies will need to assess ongoing controversies
What are the documented patterns of recurrence? When do patients relapse after
local excision, defining an ideal follow-up schedule and imaging appearances of
early relapse. What is the long-term prognostic importance of nodal micrometa-
static disease. What is the role of adjuvant chemoradiotherapy and chemotherapy
in high risk T1 disease following local excision.
Summary indications for MRI assessment of early rectal cancer lesions
• To assess bulky polyps [5 mm thick.
• Initial assessment of disease remote from the lumen within entire mesorectum.
• Identification of pelvic sidewall disease.
• Road-mapping for surgical planning—identify site location of stalk or invasive
border and relationship to puborectalis sling, peritoneal reflection, mesorectal
or intersphincteric border.
• Identification of high risk patients with extramural venous invasion.
• Ongoing surveillance of high risk cancer patients opting for conservative
approach.
Summary Indications for ERUS
• High frequency EUS to assess flat or depressed lesions \5 mm thick.
• Limited assessment of disease remote from the lumen—therefore for low risk
polyp assessment.
• Assisting with planned ESR—identify site location of invasive border.
10 Conclusion
Early stage tumours can be usefully evaluated using high resolution MRI and high
frequency ultrasound for superficial lesions.
Technique is important.
Options to consider especially for low lying early stage tumours: results from
current trials awaited.
Follow up if less radical therapy is given: MRI surveillance is also important to
enable early detection of salvageable regrowth/recurrence (Table 2).
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Predicting Lymph Node Metastases
in pT1 Rectal Cancer
Abstract
With the widespread introduction of population screening for colorectal cancer in
Europe, the number of early rectal cancers is expected to increase. In the past,
approximately 25 % of rectal cancers presented with early disease, defined as
stage I disease. First, results from population screening in the UK demonstrate an
increase to approximately 50 % stage I for screen-detected carcinomas. In the
absence of lymph node metastases, local excision of the tumor might be an
attractive option, with considerably less morbidity due to surgery and a lower
mortality. This option demonstrates the need for a reliable method of lymph
node metastasis prediction in early rectal cancer. The overall risk of lymph node
metastasis in pT1 tumors is still considerable, 11.4 %. In order to avoid both
under—and overtreatment, we need adequate risk factors.
1 Increase in Early Rectal Cancer
Following Council Recommendations of the European Union, many countries

have been installing national bowel cancer screening programs. Different screen-
ing modalities have been applied, aimed at both a high participation rate and high
detection rates. The use of (immunochemical) fecal occult blood testing and
(partial) colonoscopy will both result in increased numbers of colorectal
S. L. Bosch I. D. Nagtegaal (&)

Department of Pathology, Radboud UMC, Nijmegen, The Netherlands
16 S. L. Bosch and I. D. Nagtegaal
carcinomas (CRC). However, as already observed in the early screening trials

(Hardcastle et al. 1996), screen-detected CRC are detected at an early stage.
Recent data from the current UK program show an increase from 14.7 % stage I
tumors in the unscreened population (Steele et al. 2012) to 49.9 % in the screen-
detected tumors. Patients with these early tumors have an excellent prognosis.
Local excision is an attractive option, especially in the pT1 tumors, since it is
associated with less morbidity and mortality (Wu et al. 2011). From the onco-
logical point of view, this can be a safe procedure, provided that there are no
lymph node metastases (LNM). Local recurrence might be an issue, when resec-
tion margins are not free, but this is outside the scope of the current paper.
2 Risk on Lymph Node Metastasis
LNM have since long been recognized as an important risk factor in CRC. The
presence of LNM is associated with a poor prognosis, and, as a consequence,
adjuvant therapy is indicated after surgery. In tumor staging, the number of
involved lymph nodes is important, with a pN1 stage for 1–3 positive nodes, and a
pN2 stage for 4 or more LNM. More recent, the number of lymph nodes removed
and examined has received considerable attention as an important issue in lymph
node staging (Shia et al. 2012). Not only is the number of examined lymph nodes
considered an independent prognostic factor (Swanson et al. 2003), but it is also
thought that a larger number of lymph nodes is associated with an increased
likelihood of detecting LNM. However, there is some debate on the latter, since in
general LNM are larger and easier to detect than negative lymph nodes. Whether
increasing numbers of lymph nodes also lead to increased numbers of nodes with
micrometastases remain to be investigated. The presence of micrometastases is
associated with disease recurrence in stage I and II CRC (Sloothaak et al. 2014),
and these are hard to detect on preoperative imaging.
In general, the risk on LNM increases with increasing tumor invasion depth and
increasing tumor size (Mekenkamp et al. 2009). In pT1 tumors, the overall risk on
LNM is 11.4 %, as has been analyzed in a systemic review of 3,621 patients
(Bosch et al. 2013). However, there are histological factors that allow for a more
individualized risk estimation.
3 What Can We Measure?
As mentioned above, the risk on LNM increases with increasing size and invasion
depth of the tumor. Within the pT1 group, this still holds true. Submucosal invasion
depth can be subclassified applying a qualitative or a quantitative definition on
sessile carcinomas. The qualitative or semiquantitative definition of Kudo (1993)
uses the relative submucosal levels: sm1 (uppermost 1/3), sm2 (middle 1/3), and
sm3 (deepest 1/3 of the submucosa) (Fig. 1). Indeed, an increasing frequency of
lymph nodes are observed: 3.4 % (sm1), 8.5 % (sm2), 22.6 % (sm3) (Bosch et al.
Predicting Lymph Node Metastases in pT1 Rectal Cancer 17
Fig. 1 Kudo classification
2013). However, this method is hard to apply when the muscularis propria is not
present in the resection. Alternatively, exact measurements can be used to predict
LNM: cut-off levels of 1 and 2 mm have been suggested. Risk on LNM is extremely
low in case of an invasion depth less than 1 mm (1.5 %), however, this is a small
group of patients (Bosch et al. 2013). Invasion over 1 mm is associated with 12.3 %
LNM, and invasion depth over 2 mm is associated with 13.3 % LNM (Bosch et al.
2013). It should be noted that these percentages are only slightly increased com-
pared to the average risk for a pT1 tumor, and as such, these findings in itself do not
warrant a radical resection.
For cancers developing in polyps, the measurements of invasion depth are more
difficult. A semiquantitative measurement has been introduced by Haggitt et al.
(1985) (Fig. 2). A limited number of studies apply this classification, and the
increased risk on LNM seems only present in level 4 CRC.
Fig. 2 Haggitt classification
An alternative for tumor size is submucosal width, which is investigated in

three studies with a total number of 620 patients (Bosch et al. 2013). Larger tumors
with a submucosal width of over 5 mm showed LNM in 17 % compared to 5.6 %
in the smaller tumors.
4 Monitoring Tumor Behavior
Risk on LNM is also dependent on tumor biology. Molecular biomarkers are cur-
rently being investigated, but none are ready for diagnostic routine. However, growth
pattern and interactions with the tumor microenvironment have been investigated in
more detail and add relevant information for the risk estimation. Many studies have
examined the role of differentiation grade in early adenocarcinomas. Grading is
based on the percentage of gland formation in the tumor (World Health Organization.
2010), with a well-differentiated tumor entirely consisting of relatively well-defined
glands, and poorly differentiated tumors that consist of areas with a solid growth
pattern. For clinical use, the terms low grade (i.e., well and moderately differentiated)
and high grade are preferred. Other tumor types, such as mucinous carcinoma en
signet ring cell carcinoma, are in most studies grouped with high-grade tumors.
The presence of high grade is associated with an increased risk of LNM, 24.5 versus
8.9 % in low-grade lesions (Bosch et al. 2013).
Separately, the differentiation at the invasive front of the tumor is considered to
be important. Sometimes poorly differentiated clusters are observed here (Ueno
et al. 2013), that are strongly correlated with the process of budding. Not all
studies distinguish these two factors, there might be significant overlap. Budding is
sprouting of the tumor, and small groups or single cells infiltrate the microenvi-
ronment. While definitions of budding differ per study, tumor buds are in general
defined as less single cells or clusters of less than five cells. Poorly differentiated
clusters are defined as five cells or more, clustered without evidence of gland
formation (Ueno et al. 2013). In the systemic review, the impact of budding on
LNM was more pronounced than the effect of the poorly-differentiated clusters
(5 vs. 21.3 % and 10.2 vs. 19.2 %, respectively) (Bosch et al. 2013).
In the development of LNM, invasion of the lymphatics play a key role, which
is reflected by the high percentage of LNM in the presence of lymphatic invasion
(26.7 %) (Bosch et al. 2013). Not all studies report lymphatic invasion as a sep-
arate entity, but use lymphovascular invasion as an alternative, grouping lymphatic
and vascular invasion. While vascular invasion in itself is associated with a poor
prognosis, it is not directly related to the development of LNM and thus not such
an adequate risk factor.
5 Overview of Relevant Factors
In a recent meta-analysis, we have studied most of the histological factors that are
associated with LNM in pT1 tumors (Bosch et al. 2013). Figure 3 gives an overview
of all relevant factors and their impact on the prediction of LNM. In order to establish
the value of all factors, sensitivity, specificity, positive, and negative predictive value
should be taken into account. Sensitivity is especially high for submucosal invasion
depth (1 mm), with 96.7, however, this is accompanied by a low specificity, that
causes a high false-positive rate and many unnecessary radical resections. Specificity
is high for poor differentiation, which is associated with low sensitivity. Positive
predictive values are relatively low for all factors, but negative predictive values are
90 % or above. This illustrates the need for a comprehensive approach, in more
factors should be combined for optimal decision-making.
6 Future Considerations
With increasing numbers of patients potentially eligible for local excision of rectal
carcinoma, there is an obvious need for adequate risk estimation. Existing studies
have identified histological risk factors that can be applied in daily practice, but
need confirmation in large populations. We need to focus on combinations of
% positive nodes
budding
no budding
high grade
low grade
width > 5mm
width < 5mm
invasion > 2mm
invasion < 2mm
invasion > 1mm
invasion < 1mm
LVI+
no LVI
vascular invasion
no vascular invasion
lymphatic invasion
no lymphatic invasion
rectum
colon
0 5 10 15 20 25 30 35
Fig. 3 Histological risk factors for LNM. Source Based on the systematic review from Bosch
et al. LVI: lymphovascular invasion
factors to stratify patients according to LNM risk. Since the large studies in pT1
tumors originate from Asian countries, with a more extensive pathological
workup, we need to validate the risk factors in Western cohorts. In addition, we
need validation within screen-detected carcinomas. In breast cancer, it has been
suggested that screen-detected carcinomas have a biological distinct background
(Dawson et al. 2009), these tumors supposedly are less aggressive. The stan-
dardized data collection that is part of the screening programs will offer insights on
this issue within a couple of years.
Another issue that needs to be addressed is the application of neoadjuvant
therapy. In rectal cancer, this therapeutic strategy has been applied for years, in
various combinations of radiotherapy and chemotherapy. In a large number of
cases, significant downstaging as a result of treatment made less extensive surgery
a possibility. Tumors that decrease in size to ypT0 or ypT1 could potentially be
treated with local excisions. However, risk on LNM in these populations might be
very different. Even with a complete response of the primary tumor (ypT0), still
7 % of cases present with LNM (Nagtegaal and Marijnen 2008). In these cases,
there are no histological risk factors that can be examined. However, risk factors in
ypT1 and ypT2 tumors need to be identified, because adequate risk stratification
based on histological characteristics may prevent both over and undertreatment of
these patients.
References
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systematic review of risk factors providing rationale for therapy decisions. Endoscopy 45(10):
827–834
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adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology
89(2):328–336
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screening for colorectal cancer. Lancet 348(9040):1472–1477
Kudo S (1993) Endoscopic mucosal resection of flat and depressed types of early colorectal
cancer. Endoscopy 25(7):455–461
Mekenkamp LJ, van Krieken JH et al (2009) Lymph node retrieval in rectal cancer is dependent
on many factors–the role of the tumor, the patient, the surgeon, the radiotherapist, and the
pathologist. Am J Surg Pathol 33(10):1547–1553
Nagtegaal ID, Marijnen CAM (2008) The future of TNM staging in rectal cancer; the era of
neoadjuvant therapy. Curr Colorectal Cancer Rep 4:147–154
Shia J, Wang H et al (2012) Lymph node staging in colorectal cancer: revisiting the benchmark of
at least 12 lymph nodes in R0 resection. J Am Coll Surg 214(3):348–355
Sloothaak DA, Sahami S et al (2014) The prognostic value of micrometastases and isolated
tumour cells in histologically negative lymph nodes of patients with colorectal cancer: a
systematic review and meta-analysis. Eur J Surg Oncol 40(3):263–269
Steele RJ, McClements P et al (2012) Interval cancers in a FOBT-based colorectal cancer
population screening programme: implications for stage, gender and tumour site. Gut 61(4):
576–581
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number of lymph nodes examined. Ann Surg Oncol 10(1):65–71
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colorectal cancer: a multi-institution pathology review. J Gastroenterol.
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analysis. Hepatogastroenterology 58(106):364–368
Part II
Treatment of Early Rectal Cancer
Endoscopic Resection: When
Is EMR/ESD Sufficient?
H. Messmann
Abstract
Endoscopic treatment of malignant lesions in the gastrointestinal tract can be
treated curatively if the risk for lymph node metastasis is lower than 1%. In the
lower gi-tract (colon and rectum) the low risk criteria for this situaiton are well-
defined (G1/G2, LO, invasion depth B1000lm). However, en-bloc R0-
resection is also mandatory. Benign lesions such as lateral spreading tumors
(granular-type) can be also treated with piecemeal EMR, however, recurrence
rate is up to 30%. All other cases, regardless of size, such as non-granular type
lesions or mixed type lesions should be treated with endoscopic submucosal
dissection. The definitive histopathology of the resected specimen allows
further decision (e.g., surgery if invasion depth of tumor is [1000lm).
Curative endoscopic treatment of early gastrointestinal neoplasia may be possible

if the indications for endoscopic resection (ER) are clearly defined.
There is no doubt, that early neoplasia in the gastrointestinal tract invading the
submucosa have an increasing risk of lymph node metastasis.
The aim of endoscopic tumor therapy is a R0-resection similar to the approach
of surgical procedures. This means, that each early gastrointestinal neoplasia has to
be resected en-bloc in one piece. Piece meal resection is by definition not a R0-
resection and cannot be accepted as curative resection.
Nevertheless, endoscopic mucosal resection (EMR) is well established for
endoscopic removal of colorectal epithelial neoplasms. In lesions larger than
20 mm in diameter but also in smaller lesions with flat morphology EMR leads to
H. Messmann (&)
Department of Internal Medicine III, Klinikum Augsburg, Augsburg, Germany
26 H. Messmann
piecemeal resection. After piecemeal resection, histopathological assessment of

R0-resection is mostly impossible and the risk of incomplete resection and
recurrence is increased. Recently, published studies on piecemeal EMR of large
colorectal lesions (diameter [ 20 mm) have reported recurrence rates of 23.5 and
26.3 %, respectively (Hotta et al. 2009; Hochdörffer et al. 2010). ESD can over-
come this problem allowing en-bloc resection regardless of a lesions size.
Large studies from Japan showed the advantages of colorectal ESD (high en-
bloc resection rate even in large lesions, low recurrence rate) but also its disad-
vantages (time-consuming procedure, complication risk) (Saito et al. 2010).
Therefore, before starting the ER either with EMR or ESD it is important to
differentiate the type of colonic neoplasia. The Japanese classification describes
different types of flat polyps as ‘‘laterally spreading tumor (LST).’’ If the lesion
shows a homogenous granular surface, the lesion is described as ‘‘LST-granular
(LST-G) type’’ and by Paris classification it is a 0-IIa lesion. Lesions with a
combination of polypoid nodules and granular surface are so-called ‘‘nodular
mixed type lesions’’ (0-IIa, 0-Is + IIa, 0-IIa + Is). Besides LST-G type lesions,
we have to differentiate LST-nongranular lesions (LST-NG). This type of lesions
are either flat elevated (0-IIa) or pseudo-depressed (0-IIa + IIc, 0-IIc + IIa)
(Tanaka et al. 2008). Uraoka et al. showed, that 93 % of LST-G were adenoma or
mucosal cancer and submucosal cancer was present in 7 % respectively. In con-
trast, the LST-NG-type lesions were in 14 % submucosal cancer (Uraoka et al.
2006). Data from the National Cancer Center in Tokyo (personal communication)
had in 47 % of the LST-NG larger than 4 cm submucosal invasion.
The German guidelines for colorectal cancer define the polyps, which can be
resected endoscopically with a risk of positive lymph nodes \1 %. The low-risk
criteria are as follows: G1/2, no invasion of tumor in lymphatic or blood vessel,
submucosal infiltration \1,000 lm. In this situation, ER is an appropriate curative
treatment and no additional surgery is necessary. In all other cases—high risk
cancer (G3/4, L+/V+, sm-filtration [ 1,000 lm) the risk of lymph node metastases
is higher than 17 % and surgery is indicate (Schmiegel et al. 2005).
Diagnosis of submucosal infiltration is challenging. EUS cannot clearly dif-
ferentiate between sm-infiltration or not. An additional tool is the so-called
‘‘lifting-sign.’’ Those lesions with no lifting sign are not indicated for ER since in
the majority deep sm-invasion is present (Kobayash et al. 2007).
As mentioned, EMR has a high risk of recurrence even in lesions of 5–20 mm
as shown in a recent publication (Pohl et al. 2013).
ESD has the potential to overcome this problem. ESD is the only local ER
technique which allows independent from the size of the lesion an en-bloc resec-
tion. The technique consists of several steps: (1) exact location and demarcation of
the lesion; (2) injection of special fluid solutions (hyaluronic acid, glycerol, etc.) to
achieve lifting and a cushion; (3) circular incision of the lesion using special knives
(hook-knife, Dual knife, etc.); (4) submucosal dissection of the lesion.
Endoscopic Resection: When Is EMR/ESD Sufficient? 27
Fig. 1 Indications for colorectal ESD. EPMR endoscopic piecemeal mucosal resection, LST-NG
nongranular laterally spreading tumor (Tanaka et al. 2008)
By using this technique, the risk of recurrence is almost zero and the pathologist
has the chance to stage the whole lesions exactly. The Japanese Society for Cancer
of the Colon and Rectum has defined lesions which should be resected by ESD and
where surgery is indicated. Those lesions larger than 20 mm and difficult to resect
by snare in one piece should be resected by ESD. Especially those lesions sus-
picious for malignancy (LST-NG, pit-pattern Vi), fibrotic lesions, and local
recurrence after previous endoscopic treatment (Fig. 1).
Fujishiro et al. published (2006) the first data on ESD in rectal cancer. A total of
32 lesions were treated. The perforation rate was 5.7 % and during a mean follow-
up of 3 years 3.1 % recurrences were diagnosed (Tanaka et al. 2007).
Saito compared EMR and ESD in colorectal neoplasia. In both groups, 66 % of
the lesions were cancer. In the EMR group (228 lesions), the median size was
28 mm while the size of the lesions in the ESD group (n = 145) was 37 mm,
28 H. Messmann
respectively. Nevertheless, the en-bloc resection rate was 33 % in the EMR and
84 % in the ESD group, respectively. However, the procedure time was much
longer in the ESD group (108 min) compared to the EMR group (29 min). The
recurrence rate was 14% in the EMR and 2 % in the ESD group. Perforation rate
was 1.3 % in the EMR and 6.2 % in the ESD group, respectively (Saito et al. 2010).
Tanaka et al. demonstrated a learning curve depending on the number of cases
treatred over years. With increasing case load and changing the instruments the
perforation rate decreased from initially 18 to 0 % (Tanaka et al. 2007).
Own data confirm the learning curve of ESD. After 10 years performing more
than 500 procedures, we could increase the speed of performing ESD and achieved
nearly the same results compared to Saito et al. (Probst et al. 2012; Saito et al.
2013). We could increase our en-bloc resection rate from 60 to 96.2 % and the R0-
enbloc resection rate from 48 to 85 %, respectively.
A recent study from Japan evaluated EMR and ESD in 18 medium and high
volume endoscopy centers. A total of 1,845 patients were analyzed—220 patients
had submucosal cancer, 117 with a penetration depth of less than 1000 lm. 88 of
these lesions were treated by ESD. The en-bloc resection rate was independent of
lesion size between 94 and 96 %, however for EMR the en-bloc resection rate
varied between 66.5 (20–29 mm) and 12.3 % (40 mm), demonstrating again the
inadequate use of this technique for malignant lesions (Nakajima et al. 2013).
In a recent paper by Ikematsu et al., the long-term outcome for submucosal
invasive cancer was analysed. In group A, low-risk tumors were endoscopically
resected. The recurrence rate for rectal cancer was significant higher compared to
colon cancer group, with no difference in disease-free survival and overall sur-
vival. In group B (high risk group), ER was performed and if necessary additional
surgery was recommended. Again the recurrence rate was higher in the rectum
group, but also the disease free survival decreased in the rectal cancer group. No
difference for recurrence, disease free survival and overall survival was found
between colon cancer and rectal cancer group if surgery was performed as the only
treatment (Ikematsu et al. 2013).
1 Conclusion
Endoscopic treatment of colorectal cancer can be curative—however clear indi-

cations and techniques are necessary. Only low-risk colorectal cancer can be
treated endoscopically and en-bloc resection is mandatory. Therefore, EMR is in
most cases not adequate to treat malignant lesions, but ESD has the potential to
overcome this problem.
Endoscopic Resection: When Is EMR/ESD Sufficient? 29
Fig. 2 Therapeutic strategy for lesions diagnosed as M or SM carcinoma (JSCCR Guidelines

2010 for Treatment of Colorectal Cancer) (Ikematsu et al. 2013)
Therefore, the Japanese Society for Cancer of the Colon and Rectum suggested
a therapeutic strategy for mucosal and submucosal colorectal cancer (Fig. 2).
References
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Transanal Endoscopic Microsurgery
Chris Cunningham
Abstract
There is increasing interest in organ-preserving options in the management of
rectal cancer. Excision of small, early stage cancers by transanal endoscopic
microsurgery (TEM) is an important part of this approach. Carefully selected
cancers can be treated successfully by TEM with acceptably low risk of
recurrent disease and overall cancer outcomes similar to radical surgery. The
impact of recurrence can be mitigated by early detection of luminal or nodal
disease for which a robust surveillance programme is essential. However,
patients with high risk features on post-TEM pathology should be offered
completion radical surgery which is associated with good oncological results.
There may be an opportunity to expand the population of patients who can be
offered rectal preservation with the use of radiotherapy in either adjuvant or
neo-adjuvant context. Full thickness excision by TEM may be particularly
valuable in those demonstrating a clinical complete response to radiotherapy,
where diagnosis of complete pathological response can be confirmed. The use
of TEM in managing more advanced rectal cancers is exciting, but must be
tested within formal clinical trials before being adopted as routine practice.
1 Introduction
Transanal endoscopic microsurgery (TEM) was introduced by Gerhard Buess in

the 1980s, initially for use in benign disease (Buess et al. 1988). It became
apparent over the subsequent decade that it could play a role in the management of
C. Cunningham (&)
Oxford University Hospitals NHS Trust, Oxford, OX3 7LJ, UK
32 C. Cunningham
early stage rectal cancer (Buess et al. 1992). However, this role remains contro-
versial; local excision for rectal cancer is often perceived as a compromise
treatment, suitable only for those unfit for radical surgery (Paty et al. 2002).
Removal of the primary tumour by full thickness excision leaves occult nodal
disease in situ which, in addition to the risk of tumour re-growth at the TEM site,
leads to high rates of local recurrence of 20–40 % for T1-2 cancers. There is no
doubt that inappropriate use of local excision can have disastrous outcomes, as
highlighted by Paty et al. Delayed diagnosis of recurrent disease makes salvage
surgery difficult, highly morbid and associated with poor survival outcomes.
However, a proportion of patients with early stage disease, confined to the bowel
wall with no lymph node involvement, may be cured by local excision alone. This
avoids the short- and long-term morbidity and potential operative mortality of
radical surgery, be this total mesorectal excision (TME) or abdomino-perineal
excision (APE), while still offering cure for early stage disease. Organ preservation
in rectal cancer is gaining considerable momentum and local excision by TEM is
just one approach that can be used successfully.
2 Diagnosis and Treatment Selection in Early Rectal Cancer
Locally advanced rectal cancer is diagnosed on clinical suspicion, confirmed by

biopsy and staged locally by imaging, most commonly MRI. In early rectal cancer,
the pathway may be quite different; malignant polyps and small sessile cancers
may be diagnosed and treated simultaneously following removal by polypectomy,
endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).
This may be adequate treatment for very early cancers at low risk of recurrence or
lymph node involvement. However, risk of fragmentation and removal of these
cancers in the submucosal plane means that final pathology can be difficult to
interpret, and is more likely that margins will be involved if there is advanced T1
disease. Therefore, the use of EMR is best restricted to lesions when cancer is not
suspected or if the diagnosis of cancer will prompt treatment of the patient with
radical surgery or chemo-radiation, i.e., where there is no role for definitive local
excision. Incomplete excision by flexible endoscopic techniques can be treated by
re-excision with full thickness TEM.
Significant rectal neoplasms, which are confirmed on biopsy as cancer or for
which there is a suspicion of malignancy, should be staged completely before
considering local excision. Endorectal ultrasound and MRI give information in
tumour invasion (T-stage) and lymph node involvement (N-stage). CT scan should
exclude metastatic disease in the liver and lung. Cancers staged as cT1N0, may be
treated by full thickness excision obtaining a high quality intact specimen com-
prising all layers of the rectal wall, from mucosa to muscularis propria. This
allows accurate pathological assessment and prediction of risk of recurrence or
occult lymph node involvement.
Transanal Endoscopic Microsurgery 33
Full thickness rectal excision can be performed by traditional per-anal excision,

but there is good evidence that endoscopic excision by TEM, or similar platform
(Barendse et al. 2012), is superior in terms of specimen quality and overall cancer
outcome (Moore et al. 2008; Barendse et al. 2012). Full thickness rectal excision is
the safest when performed in the extra-peritoneal rectum where the muscle tube of
the rectum is usually covered in fatty mesorectum. Breaches into the peritoneal
cavity occur in 10 % of TEM cases and are often intentional, i.e., the lesion lies in the
intraperitoneal rectum. These can be repaired endoscopically with no apparent
increase in complications providing the surgeon has the required technical expertise.
There is evidence suggesting little impact on oncological outcome (Baatrup et al.
2009; Morino et al. 2013) when breach is performed during TEM for cancer, but
more outcome data are required before this practice can be recommended as the
theoretical risk of peritoneal spread of cancer is a concern. Peritoneal breach is more
likely in the anterior and lateral aspects of the rectum particularly in women, where
the pouch of Douglas may extend to the lower third anteriorly. MRI allows more
exact assessment of the location of the cancer, proximity to the peritoneal reflection
and the volume of underlying mesorectal fat. TEM in the lower third of the rectum
comes with additional complexity. The mesorectal fat is thin, particularly anteriorly,
meaning that TEM dissection may open onto the levator muscle, or the prostate or
vagina if the pathology is anterior. This has no immediate implications, however, if
the patient needs completion radical surgery directed by poor pathology, or indeed
develops recurrent disease, more extensive surgery (e.g., APE or even exenterative
surgery) may be required compared to that which would have been appropriate for
the primary pathology. This needs to be considered in planning suitability of a
cancer for TEM and potential compromise should be discussed with patients.
3 Staging
There is no ideal staging modality for early rectal cancer. Endorectal ultrasound
(ERUS) is highly accurate (Doornebosch et al. 2008) in assessing T stage but in
reality is less impressive in guiding clinical decision making (Ashraf et al. 2012).
The risk of over-staging with ERUS is significant, and this may direct a patient
unnecessarily to radical surgery. ERUS can provide the surgeon with additional
confidence over clinical assessment and decision-making but care must be taken
not to rely entirely on this modality. MRI staging is valuable in assessing lymph
node involvement and determining the proximity of tumour to peritoneal reflection
and adjacent pelvic organs. Assessment of early T-stage by MRI is challenging
although possible in expert hands (Taylor et al. 2011). A baseline MRI before
TEM surgery is important as a reference against which post-TEM imaging can be
compared to enable the early detection of nodal disease or tumour recurrence. Any
significant rectal lesion, even with benign histology should have MRI prior to
TEM surgery as 20–40 % of cancers have benign histology before TEM. Inter-
pretation of MRI immediately after TEM is largely unhelpful due to the disruption
from surgery and presence of reactive lymph nodes.
34 C. Cunningham
In the absence of definitive staging, the primary consideration in decision-

making in early rectal cancer is to determine if the lesion is safe to treat by TEM.
The term ‘TEM-able’ was coined and this encompasses the size and location of the
lesion and includes the individual’s skills and preference of the multidisciplinary
team over the application of this technique procedure. Careful and experienced
endoscopic and digital examination are critical, and this is best performed by the
surgeon undertaking the TEM surgery. Tumour morphology (polypoid or ulcer-
ated), location (quadrant and height from anal verge and anorectal junction) and
mobility should all be considered and will influence decision-making.
4 Neo-adjuvant Therapy and Local Excision
There is growing enthusiasm for organ preservation in treatment of rectal cancer

and the use of TEM is an important component of this. Some patients with more
advanced cancers (advanced T1-2) which are still small enough to consider for
local excision and do not appear to have involved nodes on MRI scan, may be
considered for neo-adjuvant radiotherapy (chemo-radiotherapy or short course
radiotherapy) followed by TEM. This approach depends heavily on preoperative
staging, which, as indicated above, is imperfect. In addition, because there is a
significant downsizing effect of this treatment in early stage disease, the underling
pathological stage and histological features may never be determined. The value of
this approach needs to be tested with clinical trials offering a non-radiotherapy arm
with either TEM and/or radical surgery. Despite this it is clear that the use of neo-
adjuvant radiotherapy with a view to considering local excision has leapt into the
treatment algorithm for many specialist centres dealing with rectal cancer. The
outcomes can be impressive, with studies suggesting no difference in disease-free
survival between radical surgery and local excision following radiotherapy for
early stage cancer (Lezoche et al. 2008). However, there is considerable selection
bias in these groups as a good response to chemo-radiation is itself a favourable
prognosticator, therefore, poorer prognostic early stage cancers showing little
effect or even progressing during neo-adjuvant treatment will be excluded. In this
way, the use of neo-adjuvant therapy may be a means of selecting those small
cancers, which can be managed by local excision and proponents of this approach
support the liberal use of radiotherapy as primary treatment. Up to 30 % of
tumours treated in this way may demonstrate a pathological complete response
prompting the question whether TEM surgery should be performed in those dis-
playing a complete clinical response. A cautionary note on the use of TEM after
chemo-radiotherapy is provided by the Sao Paolo group, who identify a incidence
of recurrent disease perhaps more in keeping with what we might expect from
ypT0-2 disease (Perez et al. 2013). Furthermore, the use of TEM after chemo-
radiotherapy is associated with increased complication rates over TEM in non-
irradiated patients. Wound dehiscence, pelvic sepsis and pain are reported in up to
40 % of patients, many requiring readmission (Perez et al. 2011; Marks et al.
2009). The combined approach of radiotherapy followed by TEM offers a chance

to expand the population who may benefit from organ preservation but it warrants
thorough and robust testing before being accepted as standard care.
5 Post-TEM Pathology, Risks of Recurrence and Decision-

Making
Against the obvious weaknesses in staging modalities before TEM surgery, one
benefit of primary treatment with TEM is that a high quality specimen is available
for post-TEM histological assessment. There are many factors which have been
used as predictors for lymph node involvement after local excision of colorectal
cancer (Bosch et al. 2013). A pragmatic approach is derived from analysis of the
UK TEM database which considers size of cancer, T-stage invasion and the
presence of lymphatic invasion as most important prognosticators (Bach et al.
2009). This work, supported by guidelines issued through the Association of
Coloproctology of UK and Ireland, advises restricting TEM as sole treatment to
those cancers of less than 3 cm, well or moderately differentiated, with clear
resection margins and lacking evidence of lymphatic invasion. With this careful
selection on histo-pathological grounds, the estimated local recurrence-free sur-
vival should be over 90 %, i.e., 10 % of patients will be expected to develop local
recurrence. The entire population treated by TEM for early stage cancer needs to
be surveyed effectively to detect recurrent cancer or evolving nodal disease at the
earliest stage. This is a high intensity programme that needs to be coordinated and
managed effectively through multidisciplinary teams. At present, there is little hard
data to guide this surveillance programme but expert opinion advocates 3 monthly
endoscopic and MRI assessment for the first 3 years with annual CT to exclude the
development of metastatic disease. There is evidence that effective surveillance
can detect recurrent cancer at an early stage when standard TME surgery can be
performed offering patients oncologically satisfactory outcomes in terms of local
control (De Graaf et al. 2009). Less-intensive surveillance for local recurrence
with 6–12 monthly MRI may need to continue for up to 10 years, particularly if
radiotherapy has been given.
In some patients, post-TEM pathology will convey a risk of recurrence which is
unacceptable for that individual. This is a complex assessment and many patients
are willing to accept a higher risk trading off oncological excellence in favour of
quality of life by avoiding major surgery (Solomon et al. 2003; Johnston et al.
2013). However, the message to patients must be clear; current standard of care for
high-risk pathology after local excision is completion surgery. There is good
evidence (Bach et al. 2009; Hahnloser et al. 2005) that immediate completion
surgery (TME or APER) after TEM with unfavourable pathology effectively
returns risk of recurrent cancer to that if radical surgery had been performed as the
primary treatment. This implies that a treatment strategy of TEM followed by
completion radical surgery does not compromise oncological outcome. This seems
36 C. Cunningham
extremely favourable but radical surgery after TEM can be technically challenging
and there is some evidence that a subgroup of patients do less well, particularly if
there is a poor quality TME specimen (Hompes et al. 2013). This may support the
selective use of chemo-radiotherapy prior to completion surgery for those with
unfavourable post-TEM pathology.
Many patients are treated by TEM as a compromise and, although post-TEM
pathology may be unfavourable, co-morbidity or life expectancy means comple-
tion radical surgery is not an option. Short course radiotherapy or chemo-radio-
therapy may be considered under these circumstances but there is little data to
guide practice. There is a suggestion from the pre-TEM era that local excision
followed by radiotherapy can be effective in reducing reduce local recurrence
(Minsky et al. 1989). In TEM surgery, Duek reported on 16 patients treated after
complete excision of T2 rectal cancer. In this small population, post-TEM
radiotherapy reduced local recurrence by 50 % compared to those kept under
surveillance (Duek et al. 2008). Post-TEM radiotherapy should be deferred until
the TEM site has healed and risks of sepsis are reduced. Radiotherapy fields may
be restricted relative to those in advanced disease as it is only the TEM surgical
bed and mesorectal lymph nodes that need to be targeted. There may also be a role
for brachytherapy techniques, further reducing the chances of radiotherapy-related
complications. As many as 40 % of cancers treated by TEM have no definitive
cancer diagnosis before surgery, and cannot be considered for primary treatment
with chemo-radiotherapy. Adjuvant radiotherapy may have an important role in
this population and further investigation defining the role and value of post-TEM
adjuvant therapy should be encouraged.
6 Conclusion
We have seen a dramatic improvement in the surgical management of rectal cancer

in the last 30 years with the adoption of TME surgery. Recurrence rates of less
than 5 % are reported and these may be reduced further with preoperative
radiotherapy. However, there is recognition that this may be over-treatment for a
group of patient with early stage disease where local excision is sufficient.
Approaches employing local excision and radiotherapy may increase the popula-
tion to benefit from organ-preserving treatments. These techniques will find a
place alongside non-operative management of rectal cancer with chemo-radio-
therapy alone (Habr-Gama et al. 2013). Efforts to avoid radical surgery in the
treatment of rectal cancer demand careful selection and considerable investment in
surveillance coupled with a defined plan of action should abnormalities be
detected on follow-up. The optimum system of surveillance and its duration have
yet to be determined, but it is likely to be continued for 5–10 years.
References
Ashraf S, Hompes R, Slater A, Lindsey I, Bach S, Mortensen NJ, Cunningham C, On behalf of
the Association of Coloproctology of Great B, Ireland Transanal Endoscopic Microsurgery C
(2012) A critical appraisal of endorectal ultrasound and transanal endoscopic microsurgery
and decision-making in early rectal cancer. Colorectal Dis 14:821–826
Baatrup G, Borschitz T, Cunningham C, Qvist N (2009) Perforation into the peritoneal cavity
during transanal endoscopic microsurgery for rectal cancer is not associated with major
complications or oncological compromise. Surg Endosc 23:2680–2683
Bach SP, Hill J, Monson JR, Simson JN, Lane L, Merrie A, Warren B, Mortensen NJ (2009) A
predictive model for local recurrence after transanal endoscopic microsurgery for rectal
cancer. Br J Surg 96:280–290
Barendse RM, Doornebosch PG, Bemelman WA, Fockens P, Dekker E, De Graaf EJ (2012)
Transanal employment of single access ports is feasible for rectal surgery. Ann Surg
256:1030–1033
Bosch SL, Teerenstra S, de Wilt JH, Cunningham C, Nagtegaal ID (2013) Predicting lymph node
metastasis in pT1 colorectal cancer: a systematic review of risk factors providing rationale for
therapy decisions. Endoscopy 45:827–841
Buess G, Kipfmuller K, Hack D, Grussner R, Heintz A, Junginger T (1988) Technique of
transanal endoscopic microsurgery. Surg Endosc 2:71–75
Buess G, Mentges B, Manncke K, Starlinger M, Becker HD (1992) Technique and results of
transanal endoscopic microsurgery in early rectal cancer. Am J Surg 163:63–69 (discussion
69–70)
De Graaf EJ, Doornebosch PG, Tollenaar RA, Meershoek-Klein Kranenbarg E, De Boer AC,
Bekkering FC, Van De Velde CJ (2009) Transanal endoscopic microsurgery versus total
mesorectal excision of T1 rectal adenocarcinomas with curative intention. Eur J Surg Oncol
35:1280–1285
Doornebosch P, Bronkhorst P, Hop W, Bode W, Sing A, de Graaf E (2008) The role of endorectal
ultrasound in therapeutic decision-making for local versus transabdominal resection of rectal
tumors. Dis Colon Rectum 51:38–42
Duek SD, Issa N, Hershko DD, Krausz MM (2008) Outcome of transanal endoscopic
microsurgery and adjuvant radiotherapy in patients with T2 rectal cancer. Dis Colon Rectum
51:379–384 (discussion 384)
Habr-Gama A, Sabbaga J, Gama-Rodrigues J, São Julião GP, Proscurshim I, Aguilar PB, Nadalin
W, Perez RO (2013) Watch and wait approach following extended neoadjuvant chemora-
diation for distal rectal cancer: are we getting closer to anal cancer management? Dis Colon
Rectum 56:1109–1117
Hahnloser D, Wolff BG, Larson DW, Ping J, Nivatvongs S (2005) Immediate radical resection after
local excision of rectal cancer: an oncologic compromise? Dis Colon Rectum 48:429–437
Hompes R, Mcdonald R, Buskens C, Lindsey I, Armitage N, Hill J, Scott A, Mortensen NJ,
Cunningham C, The Association of Coloproctology of Great B, Ireland Transanal Endoscopic
Microsurgery C (2013) Completion surgery following transanal endoscopic microsurgery:
assessment of quality and short- and long-term outcome. Colorectal Dis 15:e576–e581
Johnston CF, Tomlinson G, Temple LK, Baxter NN (2013) The management of patients with T1
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Lezoche G, Baldarelli M, Mario Paganini A, De Sanctis A, Bartolacci S, Lezoche E (2008) A
prospective randomized study with a 5-year minimum follow-up evaluation of transanal
endoscopic microsurgery versus laparoscopic total mesorectal excision after neoadjuvant
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Marks JH, Valsdottir EB, Denittis A, Yarandi SS, Newman DA, Nweze I, Mohiuddin M, Marks
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multicenter, European study. Ann Surg 253:711–719
Part III
Surgical Treatment of Rectal Cancer
What Is ‘‘Good Quality’’ in Rectal
Cancer Surgery? The Pathologist’s
Perspective
Abstract
High local recurrence rates were a major problem in rectal cancer treatment,
with between 30 and 50 % of patients affected, resulting in a very poor quality
of life and short survival of patients with rectal cancer. In recent years,
prognosis of rectal cancer has markedly improved, due to innovations in
surgical treatment in combination with neoadjuvant therapy. Quality evaluation
of surgical procedures has become the standard; constant high quality of
surgery is one of the major successes in rectal cancer over the last decade.
Continuous monitoring of surgical procedures is a new role for the pathologist.
Completeness of excision, resection margins, but also numbers of lymph nodes
have been firmly established as quality indicators.
1 Quality of Surgery: What Is Important?
Quality evaluation and continuous quality assurance are increasingly important in

health care, to ensure optimal treatment of patients. In the field of colorectal
cancer, surgical performance is one of the key factors for patient outcome. This is
illustrated by the large number of studies that have been published on quality of
surgery in colorectal cancer (Fig. 1). Numerous studies have shown that factors
such as specialisation and caseload are important prognostic factors. In order to
establish these factors, large studies with sufficient follow-up are required. Both
S. L. Bosch I. D. Nagtegaal (&)

Department of Pathology, Radboud Umc, Nijmegen, The Netherlands
400
350
300
250
200
150
100
50
0
2013
2011
2009
2007
2005
2003
2001
1999
1997
1995
1993
1991
1989
1987
1985
1983
1981
1979
1977
1975
1970
Fig. 1 The increase in publications categorised in PubMed that are retrieved using the
combination of ‘‘quality of surgery’’ and ‘‘colorectal cancer’’
short-term mortality and overall survival can be end-points of these studies, but the
bias that is created by case-mix complicates analysis. Moreover, these large studies
can provide data on quality evaluation, but are not suitable for continuous quality
assurance. In order to continuously improve surgical quality, every individual
operation should be evaluated using proven quality indicators. Pathological
evaluation can provide several of such quality indicators.
2 Quality Indicators Provided by the Pathologist:

Circumferential Resection Margin
The most important margin in rectal cancer surgery is the circumferential margin
(CRM); this is the resection margin the surgeon creates in the lateral plane, fol-
lowing Denonvillier’s fascia. By doing so, ideally a large fat column separates the
tumour and involved lymph nodes from the resection margin (alternatively called:
lateral, radial or mesorectal margin). However, in cases with locally advanced
tumours this is sometimes hard to achieve, and positive margins occur in various
frequencies, depending on the kind of neoadjuvant therapy, the quality of imaging
and the skills of the surgeon.
Circumferential margin (CRM) is strongly correlated not only to local recur-
rence, but also to distant recurrence and survival. With increasing free margins, the
risk on poor outcome decreases substantially (Nagtegaal et al. 2002a), therefore it
is recommended to provide adequate measurements of the CRM. The international
accepted cut-off for a positive resection margin is 1 mm. In a systematic review
(Nagtegaal and Quirke 2008) we proved that positive margins in the surgery only
setting are associated with a hazard ratio of 2.0 for local recurrence, however, after
What Is ‘ Good Quality’’ in Rectal Cancer Surgery? 43
neoadjuvant therapy, the hazard ratio is 6.3. This implies that the CRM is more
than a surgery quality indicator: it also defines the success of neoadjuvant therapy.
In addition, CRM involvement is a powerful prognostic factor. In the neoadjuvant
setting, CRM involvement is more important than invasion depth (Gosens et al.
2007; Nagtegaal et al. 2007).
It has been known for a long time that huge differences exist between surgeons in
local recurrence and survival rates. Indeed, when studying the CRM, these differences
can at least partially be explained (Birbeck et al. 2002). However, a positive CRM
might be a multifactorial problem, failure of neoadjuvant therapy, inadequate
imaging or incomplete mesorectal excision may all be responsible. Due to analysis of
the quality of surgery/completeness of excision as an independent factor, we can
investigate this matter and try to improve the future treatment of rectal cancer patients.
3 Quality Indicators Provided by the Pathologist: Distal

Resection Margin
The importance of the distal resection margin is less clear than that of the CRM.
Although this margin is routinely examined macroscopically, microscopic evalu-
ation is usually limited to those cases in which the tumour approaches the margin.
However, there are several ways in which this margin can become involved.
Continuous growth can occur either in the lumen of the bowel or intramural.
Intramural spread is often subclinical, but can occur in substantial numbers of
patients (Williams 1983). Initially, a 5 cm distal margin was advised. More
recently, a 1 cm rule was established. In a systematic review, Bujko et al. (2012)
demonstrated that, in a series of 948 patients with margins of less than 1 cm
compared to 4,626 patients with margins over 1 cm, differences in local recurrence
rates could not be substantiated. Alternatively, margins of 5 mm and 2 cm were
investigated, but there were no differences in local recurrence rates either.
Distal margins can also become involved by discontinuous growth, by distal
spread through lymph and blood vessels, or due to the presence of positive lymph
nodes and tumour deposits. When a large number of lymph node metastases occur
along the inferior mesenteric artery, lymphatic flow may change to a downward
direction, causing distal spread (Shirouzu et al. 1995). In 20 % of the lymph node
positive cases, lymphatic spread is observed distal to the primary tumour (in 6.4 %
of cases over 2 cm away from the tumour edge) (Morikawa et al. 1994).
For an adequate measurement of the distal margin, fixation induced shrinkage
of the bowel has to be recognised: unfixed colorectal segments can undergo
shrinkage up to 50 % (Goldstein et al. 1999).
Table 1 Grading system for quality of surgery

Plane of resection Definition Implication
TME Mesorectal fascia Smooth CRM, no defects deeper than 5 mm, Good prognosis
intact mesorectum
Intramesorectal Irregular mesorectal surface, moderate bulk to the Intermediate
mesorectum prognosis
Muscularis propria Defects down onto the muscularis propria, very Poor prognosis
irregular CRM
APR Outside levator Cylindrical specimen, with en bloc resection of Good prognosis
levators
Sphincter CRM on the surface of the intact sphincteric Intermediate
muscular tube prognosis
Intramuscular/ Perforation or missing areas of muscle Poor prognosis
submucosa
In case of an APR resection both gradings should be recorded
4 Quality Indicators Provided by the Pathologist: Quality

of the Mesorectum
The plane of surgery achieved after TME, which reflects the completeness of
mesorectal excision (Table 1), is a clinically relevant prognostic factor as well as
an indicator of quality of surgery (Nagtegaal et al. 2002b). As could be expected, it
is closely related to CRM, with a muscularis propria plane of resection automat-
ically leading to a high risk of positive CRM, even in small tumours. However, the
measurement of quality of surgery has prognostic value independent of the CRM.
In the first series, only 180 patients were included (Nagtegaal et al. 2002b), but
more recently these data have been confirmed in the CR07 with 1,117 patients
(Quirke et al. 2009) and a systematic review (Bosch and Nagtegaal 2012).
5 Quality Indicators Provided by the Pathologist: Quality

of the Sphincter Area
Rectal cancers in the lowest part of the rectum are frequently operated using the
abdominoperineal excision (APR), in which the anal sphincter is included in the
resection specimen. The surgical removal of this part of the rectum might be
difficult, due to the anatomical limitations of the lower pelvis, and consequently
perforations and positive margins are relatively common after this procedure. In
order to judge the APR surgical technique, a modification (Nagtegaal et al. 2005)
has been made to the original quality of surgery grading especially for the anal
canal area (Table 1).
What Is ‘ Good Quality’’ in Rectal Cancer Surgery? 45
6 Quality Indicators Provided by the Pathologist: Lymph

Node Counts
Lymph node sampling is an integral part of the pathological workup for resection
specimens. Low numbers of examined lymph nodes can be an argument for
adjuvant therapy (Benson et al. 2004). Numbers of nodes are dependent on several
factors (Mekenkamp et al. 2009), not in the least on the quality of pathology
examination. However, there is also a strong correlation with quality of surgery.
When the resection plane is on the mesorectal fascia, more lymph nodes can be
examined compared to the resection plane on the muscularis propria. In the Dutch
Colorectal Surgical Audit 10 or more examined lymph nodes is considered a
quality indicator, that is shown to be associated with both risk-adjusted morbidity
and risk-adjusted 30-day mortality (Gooiker et al. 2013).
7 What Is Next?
In the era of population screening, an increase in early rectal cancers is expected.

Radical treatment with total mesorectal excision might be replaced by local
excision in a substantial number of patients. Focus on quality of local excision is
important and urgent.
Analogous to the completeness of excision in rectal cancer, a scoring system
has been developed for colon cancer (West et al. 2008). In order to accomplish a
similar improvement of prognosis as observed in recent years in rectal cancer, we
need to implement pathological evaluation of quality of surgery for colon cancer.
References
Benson AB 3rd, Ajani JA et al (2004) Recommended guidelines for the treatment of cancer
treatment-induced diarrhea. J Clin Oncol 22(14):2918–2926
Birbeck KF, Macklin CP et al (2002) Rates of circumferential resection margin involvement vary
between surgeons and predict outcomes in rectal cancer surgery. Ann Surg 235(4):449–457
Bosch SL, Nagtegaal ID (2012) The importance of the pathologist’s role in assessment of the
quality of the mesorectum. Curr Colorectal Cancer Rep 8(2):90–98
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cancer based on clinical evidence? A systematic review. Ann Surg Oncol 19(3):801–808
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colorectal cancer care. J Surg Oncol 108(7):465–471
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cancer by the modified clearing method. Dis Colon Rectum 37:219–223
Nagtegaal ID, Gosens MJ et al (2007) Combinations of tumor and treatment parameters are more
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Total Mesorectal Excision: Open,
Laparoscopic or Robotic
Monica Young and Alessio Pigazzi
Abstract
Goals Total mesorectal excision (TME) is the gold standard technique for the
surgical treatment of rectal cancer. Despite the benefits of minimally invasive
surgery, laparoscopic TME (LTME) is a technically challenging procedure with
a long learning curve. Robotic TME (RTME) has been advocated as an
alternative to conventional LTME, but large studies supporting the efficacy or
RTME are scarce. This work will review the current literature on minimally
invasive surgery for rectal cancer and discuss future directions in the field.
Methods A review of recent large single and multicenter studies on minimally
invasive surgery for rectal cancer was conducted. Results Based on two large
randomized clinical studies (CLASICC (Green et al. 2013) and COLOR II (van
der Pas et al. 2013)). LTME is safe and feasible for the treatment of rectal
cancer. Compared to open surgery, LTME has been shown to result in superior
postoperative outcomes and similar oncologic results. However, the conversion
rate of LTME is around 17 %. The literature supporting RTME is more limited.
Robotic rectal resection appears to have similar postoperative and oncologic
outcomes compared to LTME. RTME results in higher costs and possibly lower
conversion rates. A large randomized clinical trial (ROLARR) comparing
robotic to laparoscopic surgery for rectal cancer is underway. Conclusions
Despite the technical challenges, current data supports the use of minimally
invasive technique for rectal cancer surgery with superior short-term outcomes
M. Young A. Pigazzi
Division of Colon and Rectal Surgery, University of California, Irvine, Orange, CA, USA
A. Pigazzi (&)
Department of Colon and Rectal Surgery, University of California Irvine Medical Center,
333 City Blvd West, Suite 850, Orange, CA 92868, USA
48 M. Young and A. Pigazzi
compared to an open approach. The use of robotic surgery is promising, but still
limited and awaiting the conclusion of randomized clinical trials.
Keywords

Total mesorectal excision Laparoscopic TME Minimally invasive rectal

surgery Robotic TME Robotic rectal surgery
1 Introduction
Since its introduction by Heald (1979), total mesorectal excision (TME) has been
found to reduce local recurrence rates and improve oncologic outcomes (Stewart
and Dietz 2007). A sharp, meticulous, en bloc resection of the cancer and sur-
rounding perirectal lymphatic tissue along fascial planes produced superior control
of local recurrence compared with nonstandardized surgery (Stewart and Dietz
2007). TME soon emerged as the gold standard technique for the surgical treat-
ment of rectal cancer. Advances in minimally invasive surgery have resulted in the
development of laparoscopic as well as robotic TME (RTME). Laparoscopic
techniques offer advantages, such as decreased length of hospital stay, reduced
postoperative pain, and improved cosmesis (D’Annibale et al. 2013; Jayne et al.
2007; Colon Cancer Laparoscopic or Open Resection Study Groupet al. 2009;
Fleshman et al. 2007). However, minimally invasive rectal surgery is technically
challenging with a steep learning curve. The pelvis is limited in space and width,
making retraction and rectal dissection difficult, especially with laparoscopic
instrumentation. Furthermore, concerns have been raised regarding the oncologic
outcomes associated with this approach. The advent of a robotic platform has
added even more alternatives to the minimally invasive rectal surgery armamen-
tarium. This chapter will review the current literature on minimally invasive
surgery for rectal cancer as well as discuss future directions in the field.
2 Open TME
The primary goal of surgical resection in rectal cancer is complete removal of the
primary tumor as well as radially spread cancer cells in the mesorectum (van der
Pas et al. 2013). The most important variables influencing local recurrence are the
presence of involved lymph nodes, lymphovascular invasion, and circumferential
resection margin positivity (Stewart and Dietz 2007; Chapuis et al. 2002; Bissett
and Hill 2000). While different methods of rectal mobilization have been descri-
bed, all share the common principle of removing the rectum with its perirectal fat
and mesorectal fascia intact (Enker et al. 1995; Heald et al. 1998; Tiret and Pocard
1999; Killingback et al. 2001). The retrorectal plane is key to correct surgical
Total Mesorectal Excision: Open, Laparoscopic or Robotic 49
technique during posterior mobilization of the rectum, as is the retroprostatic or

retrovaginal planes for the anterior dissection. Although this dissection historically
was done using a blunt or manual technique (Goligher 1960), sharp dissection is
now considered the standard operative approach (Beck and Steven 1998). When
TME is performed with the proper surgical techniques, local recurrence rates have
been reported in the range of less than 10 % (Enker et al. 1995; Aitken 1996). The
impact of this proper surgical technique compared to nonstandardized methods has
been well described in the literature. Kapiteijn et al. (2002) showed that local
recurrence was improved with the adoption of TME techniques and that TME,
when compared to conventional rectal resection, was an independent predictor of
overall survival.
One of the first large studies published on TME was by Heald and colleagues,
who reviewed their experience with 519 patients at North Hampshire Hospital in
Basingstoke, England from 1978 to 1997 (Heald et al. 1998). Local recurrence
rates were 6 % at 5 years and 8 % at 10 years. The clinically apparent anastomotic
leak rate for patients undergoing anterior resection with curative intent was 6.5 %.
Law et al. later published another large study on the outcomes of 622 patients with
rectal cancer who underwent anterior resection at Queen Mary Hospital in Hong
Kong from 1993 to 2002 (Law and Chu 2004). Patients with mid or low rectal
cancers were treated with TME (64 %), while rectosigmoid and upper rectal
cancers were treated with a partial mesorectal excision (PME, 36 %). The anas-
tomotic leak rate for patients undergoing TME was reported as 8.1 %. On mul-
tivariate analysis, TME, male gender, absence of a stoma, and blood loss[500 mL
were reported as independent risk factors for anastomotic leak. Local and distant
recurrent rates were reported together, and were 6.0 % at 2-year and 9.7 % at
5-year. Due to longer operative times, higher anastomotic leak rates, technically
challenging surgery and higher incidence of stoma formation, Law and colleagues
concluded that TME should be used selectively, but does produce a good onco-
logic outcome.
This dramatic improvement in local control due to TME sparked debate as to
whether neoadjuvant or adjuvant therapy was still significantly beneficial. As a
result, two prospective randomized trials were undertaken to investigate the effi-
cacy of radiation and chemotherapy in combination with TME for the treatment of
rectal cancer. The Dutch Colorectal Cancer Group studied 1,861 patients, 924 who
underwent preoperative radiotherapy followed by TME and 937 who underwent
surgery alone (Kapiteijn et al. 2001). Local recurrence rate was 2.4 % in the
radiation group and 8.2 % in the surgery alone group. However, overall survival at
2 years was not significantly different, with a rate of 82 % in the radiation group
and 81.8 % in the group treated with surgery alone. The German trial CAO/ARO/
AIO-94 examined the efficacy of neoadjuvant chemoradiation versus postoperative
radiation in patients undergoing TME for locally advanced (T3/T4) disease (Sauer
et al. 2001, 2003). A total of 805 patients were enrolled, with 355 in the neoad-
juvant group and 363 in the adjuvant group. Patients in the neoadjuvant group had
significantly lower rates of local recurrence, 6 % compared to 13 % local recur-
rence in the adjuvant group at 5 years. There was no difference in postoperative
morbidity or mortality between treatment groups. Neoadjuvant chemoradiation has

subsequently become the standard of care, largely due to the results of this trial.
3 Laparoscopic TME
The widespread adoption of TME in the 1990s to early 2000s was congruent with
the implementation of laparoscopy in colorectal operations. Laparoscopic colec-
tomy in the setting of colon cancer was first examined and proved to be safe with
less postoperative pain, earlier recovery, and comparable oncologic outcomes with
traditional open resection (Colon Cancer Laparoscopic or Open Resection Study
Group et al. 2009; Veldkamp et al. 2005; Leung et al. 2004). Although several
reports were published demonstrating the safety and feasibility of LTME (Zhou
et al. 2004; Scheidbach et al. 2002; Pasupathy et al. 2001), there was limited data
regarding long-term impact on oncologic outcomes. These results were summa-
rized in the Cochrane review of laparoscopic versus open TME for rectal cancer in
2006 (Breukink et al. 2006). A total of 48 studies met inclusion criteria, but 28
were case series and only one randomized controlled trial described primary
outcome, 3- and 5-year survival rates (Leung et al. 2004). Since this time, addi-
tional randomized controlled trials have been performed specifically comparing
laparoscopic versus open TME. In 2008, Anderson and colleagues reported a
meta-analysis on oncologic outcomes of laparoscopic surgery for rectal cancer
(Anderson et al. 2008). Their meta-analysis included 24 publications and exam-
ined 1,403 laparoscopic and 1,755 open rectal resections. Overall survival at
3 years was similar between treatment groups (76 % in laparoscopic and 69 % in
open cases), as was mean local recurrence rates (7 % for laparoscopic and 8 % for
open procedures). Another more recent meta-analysis by Qu et al. analyzed eight
randomized controlled trials reported in the Chinese and English literature (Qu
et al. 2013). The meta-analysis reviewed 863 patients with middle and low rectal
cancers, 438 who underwent LTME and 435 cases of open TME. LTME was
associated with significantly less intraoperative blood loss, earlier return of bowel
function, shorter hospital length of stay, lower wound infection and lower post-
operative bleeding rates compared to open TME. There were no significant dif-
ferences noted in operative time, number of resected lymph nodes, anastomotic
leak, ileus, or abscess formation.
Two large randomized clinical studies have recently been published assessing
outcomes of laparoscopic compared to open rectal resection. The COLOR II trial
included 30 medical centers across eight countries. A total of 1,044 patients with
rectal cancer within 15 cm from the anal verge and no evidence of distant
metastases were randomized, 739 in the laparoscopic, and 364 in the open surgery
group. The laparoscopic arm was found to have less blood loss, faster return of
bowel function, and shorter length of hospital stay, with longer operative time
compared to the open arm. The conversion rate was approximately 17 %. There
was no difference in oncologic resection margin between groups; the rate of
positive margins (defined as \2 mm) was 10 % in both cohorts. There were no

differences in morbidity and mortality.
The UK Medical Research Council recently published their long-term follow-up
of the CLASICC trial, which examined outcomes after conventional versus lapa-
roscopic resection in colorectal cancer (Green et al. 2013). A total of 794 patients
with colon and rectal cancer at 27 UK medical centers were randomized to laparo-
scopically assisted or open surgery from 1995 to 2002. For patients with rectal
cancer, no statistically significant differences were found between open and lapa-
roscopic groups in median overall survival (65.8 months open vs. 82.7 months
laparoscopic, respectively, p = 0.147) or median disease-free survival (67.1 months
open vs. 70.8 months laparoscopic, respectively, p = 0.925). Overall local recur-
rence was 10.9 % at 10 years and there was no significant difference found between
randomized groups.
These studies confirm that minimally invasive rectal surgery is oncologically
safe and a suitable alternative to open operations. In-hospital recovery after lap-
aroscopic surgery has been shown to be better than after open surgery. Therefore,
in selected patients treated by surgeons skilled in minimally invasive surgery,
laparoscopic resection of rectal cancer should be considered (van der Pas et al.
2013). Debate persists on the impact of conversion from laparoscopic to open, as
the CLASICC trial previously reported worse outcomes associated with conver-
sion (Green et al. 2013; Jayne et al. 2007). However, in the most recent analysis,
reduced disease free survival was only noted in converted patients with colon
cancer. Intraoperative conversion did not appear to affect overall survival or dis-
ease free survival in patients with rectal cancer. Furthermore, conversion rates
appear reduced in nonrandomized studies, ranging from 4.3 % (Yu et al. 2009) to
12 % (Morino et al. 2003).
4 Robotic TME
Robotic rectal resection appears to have similar postoperative and oncologic

outcomes compared to LTME; however, the literature supporting RTME is more
limited. Several studies have examined the short-term and long-term outcomes of
robotic rectal resection (D’Annibale et al. 2013; Baik et al. 2009; Baek et al.
2013a; Biffi et al. 2011; Du et al. 2013; Luca et al. 2013). For a completely
robotically performed TME mean operative times ranged from 220 to 270 min and
length of stay was reported as 7–8 days. Mean length of stay following hybrid
robotic-assisted laparoscopic rectal surgery is slightly lower at 6 days, with a range
of 3–9 days. One of the main perceived advantages of robotic-assisted rectal
resection is the lower conversion rate to open surgery. This finding was reported in
a meta-analysis by Trastulli et al. (2012) who identified eight nonrandomized
studies with a total of 854 patients comparing robotic and laparoscopic resection
for rectal cancer. The robotic group was found to have a lower conversion rate and
no significant differences in operative time, length of hospital stay, postoperative
morbidity, postoperative mortality, or oncologic outcomes. A meta-analysis by
Memon et al. (2012) found similar results. However, as large randomized con-
trolled trials are lacking, these lower conversion rates may be due to patient
selection or surgeon bias. The majority of the published studies to date are ret-
rospective or prospective nonrandomized trials. A systematic review of the liter-
ature published February 2014 by Kim and colleagues found 13 studies examining
various types of robotic-assisted rectal resection such as anterior resection, low
anterior resection, intersphincteric resection, or abdominoperineal resection (Kim
et al. 2014); however, the majority of these publications were comparative studies.
Although short-term outcomes appear to be acceptable, oncologic and long-term
outcomes of RTME remain unknown. Evidence suggests that robotics may allow
for better preservation of urinary and sexual function (Luca et al. 2013); however,
further studies are needed to definitely make this conclusion. Randomized clinical
trials and long-term follow-up are also needed to evaluate the influence of RTME
on recurrence and survival. The ROLARR trial, an international, randomized
controlled trial comparing robotic-assisted to laparoscopic resection for rectal
cancer is currently in progress. Results of this study should help assess the future
impact of RTME.
Key arguments against robotics are longer operative times and higher costs
compared to laparoscopic surgery (Baek et al. 2013b). Longer operative times are
attributed to setup, docking time of the robot, and time for surgeon to adapt to the
robotic system (Kim et al. 2014). Costs are elevated due to longer operative times,
robotic instruments, and the initial capital cost of the robotic platform itself. As
surgeons and operating room staff become more experienced with robotics,
operative times will likely decrease. Modifications have also been made to pre-
viously describe robotic techniques as a way to shorten operative time (Pigazzi
et al. 2006). Despite the drawback of higher costs, use of robotics is increasing, as
shown by Halabi et al. (2013) in his review of the Nationwide Inpatient Sample
database from 2009 to 2010. In this study, rectal cancer was the most common
indication for robotic-assisted colorectal surgery and increased from 1,188 cases in
2009 to 2,380 cases in 2010. These numbers are expected to be significantly higher
today.
5 Future Directions
Transanal TME is a new approach to performing minimally invasive surgery for

rectal cancer. Surgical access from the abdomen to the mid and low rectum can be
very technically challenging, even for surgeons skilled in laparoscopic techniques.
Patients with very distal tumors are particularly good candidates for this minimally
invasive approach (Atallah et al. 2013a). Literature published on the initial
experience with transanal TME has reported excellent exposure, even in male
patients with difficult body habitus and a narrow pelvis (Atallah et al. 2013b).
Although this early evidence appears promising, further studies are needed to
evaluate the oncological safety and surgical outcomes of this approach.
6 Conclusion
Despite the technical challenges, current data supports the use of minimally
invasive techniques for rectal cancer surgery. A review of the literature shows
superior short-term outcomes and equivalent oncologic outcomes with LTME
compared to an open approach. The use of robotics in rectal surgery is promising
but still limited. Further randomized clinical trials are necessary to fully under-
stand the outcomes of RTME. The ROLARR trial is currently in progress to assess
outcomes between laparoscopic and robotic surgery for rectal cancer.
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Ultra Low Resection Versus
Abdomino-Perineal Excision
in Low Rectal Cancer
Torbjörn Holm
Abstract
There have been several important improvements in the management of
patients with rectal cancer during the recent 20 years. For more accurate local
and distant tumour staging, introduction of neoadjuvant treatments, improved
surgery, a more precise macroscopic and microscopic evaluation of the
specimen and MDT discussions have all been crucial in improving local control
and survival. However, the most important factor has been the TME technique
with standardisation of the surgical procedure. For patients with low rectal
cancer, the decision making is complex with several treatment options,
including the choice between neoadjuvant treatment followed by surgery or
surgery alone, restorative procedures or APE. If an APE is necessary, this must
also be tailored to the individual patient based on patient’s characteristics and
the extent of local tumour growth.
1 Introduction
The earliest surgical approaches to rectal cancer were via the perineum and the
techniques used were exclusively extra-peritoneal. The mortality during and after
surgery was high, the postoperative functional results poor and the local recurrence
rate ranged up to 90 %. An important step in the development of surgery for rectal
cancer was taken by W. Ernest Miles, who on December 19, 1908 in The Lancet
T. Holm (&)
Department of Coloproctology, Center for Digestive Diseases,
Karolinska University Hospital, 171 76, Stockholm, Sweden
58 T. Holm
published a paper entitled ‘A method of performing abdomino-perineal excision

for carcinoma of the rectum and of the terminal portion of the pelvic colon’ (Miles
1908). In Miles original description of the procedure the rectum was bluntly
mobilised down to the sacro-coccygeal articulation posteriorly, to the prostate
anteriorly and to ‘the upper surface of the levatores ani’ laterally. A colostomy was
brought out and the abdominal wall was closed. The patient was then turned over
and placed in the right lateral and semi-prone position. The perineal part of the
operation included a wide excision of skin and fat and Miles emphasised that the
levator muscles should be divided ‘as far outwards as their origin from the white
line so as to include the lateral zone of spread’. The specimen was brought out
through the perineum and the skin was closed over two drains.
The Lancet paper had an enormous impact on the surgical community and
Miles operation became the gold standard procedure for all rectal carcinomas for
many decades. However, the concept of removing the entire rectum and the anus
in all patients with rectal cancer gradually changed with time, and the increasing
experience with bowel reconstruction, including the development of stapling
instruments, led to the new concept of anterior resection (AR) and low anterior
resection (LAR) which became the standard procedures for tumours in the upper
and middle rectum (Collins 1963; Fick et al. 1960; Groves and Harrison 1962;
Slanetz et al. 1972; Vandertoll and Beahrs 1965).
For tumours in the lower rectum, most surgeons continued to perform abdo-
mino-perineal excision (APE), although the extensive perineal approach described
by Miles was more or less forgotten and the synchronous combined APE was
introduced as a feasible procedure, which became popular and gained widespread
use in the treatment of low rectal cancer (Schmitz et al. 1958). During the syn-
chronous combined operation, the perineal part is carried out simultaneously with
the pelvic part of the abdominal procedure, with the patient in the supine lithotomy
or Lloyd Davis position; the rectum with its mesorectum is mobilised down to the
pelvic floor and the perineal surgeon then enters the pelvic cavity just in front of
the coccyx, the levator muscles are divided on both sides and finally the rectum is
dissected off the prostate or the vagina and the specimen is usually delivered
through the perineum.
Despite the gradual improvements in rectal cancer treatment during the twen-
tieth century, local control remained a major problem after surgery, with local
recurrence rates of up to 50 % after potentially curative resections (Påhlman and
Glimelius 1984). Therefore, preoperative radiotherapy was evaluated in several
large randomised trials during the 1980s and was shown to reduce the local
recurrence rate by 50 % and also to improve cancer-specific survival. Later, a
combination of radio- and chemotherapy was shown to further increase local
control and survival, especially in locally advanced tumours. Hence, preoperative
radio-chemotherapy is an established accessory treatment in rectal cancer.
Even with neoadjuvant treatment, the local recurrence rate was up to 15–20 %
and it was not until R. J. Heald described total mesorectal excision (TME) that the
picture changed dramatically (Heald et al. 1982; MacFarlane et al. 1993). After
extensive educational efforts by professor Heald and others, the TME technique for
Ultra Low Resection Versus Abdomino-Perineal Excision 59
rectal cancer resections has been introduced in many countries during the recent
15–20 years and is now considered the standard of care. Subsequently, the results
with regard to local control have improved significantly and local recurrence rates
are now reported to be less than 10 % in population-based studies (Kapiteijn et al.
2001; Martling et al. 2000; Wibe et al. 2004). The acknowledgement of TME as the
standard surgical technique in the treatment of rectal cancer has improved not only
local control but also increased the rates of sphincter saving procedures and survival.
2 Low Anterior Resection with Inter-sphincteric Resection
During the typical LAR with TME, the pelvic dissection is performed just outside
the mesorectal fascia in loose connective tissue, ‘the holy plane’, down to the pelvic
floor and the top of the puborectal muscle. Special attention is paid to preserve an
intact mesorectal fascia and also to identify and preserve autonomic nerves on the
pelvic sidewalls. Once the rectum and mesorectum are completely mobilised, the
bowel is sealed with a transverse stapler or with a right-angled clamp and the rectal
stump is rinsed with sterile water or some other mild cytotoxic agent. Another
transverse stapler is applied on the rinsed rectum, the bowel is divided and the
specimen removed. Subsequently, a circular stapler is introduced via the anus, the
transected proximal colon is connected to the stapler and the anastomosis is com-
pleted. Most surgeons advocate a small colonic pouch or an end to side anastomosis
in order to create a small reservoir, which improves short-term anorectal function, as
compared to a straight anastomosis (Hallböök et al. 1996).
With the development of LAR and TME there has been a constant refinement of
the concept of what represents a safe distal resection margin following the excision
of rectal cancer, which some consider to be as low as 1 cm in certain circumstances.
Therefore, restorative surgery for low rectal cancer, as defined by tumours within
6 cm from the anal verge, has evolved to include excision of all or part of the internal
anal sphincter, an adaptation of a technique initially described for use in inflam-
matory bowel disease. ISR and reconstruction with a hand sewn coloanal anasto-
mosis (CAA) is an attempt to extend the indications for rectal cancer excisions in
which the normal route of defecation can be preserved. During the last 10–15 years
and with the substantially improved results after TME and LAR, many surgeons
have advocated low or ultralow anterior resection for tumours in the lower rectum. It
has also been shown that these procedures are feasible and oncologically safe,
provided that the tumour can be removed with a clear distal and circumferential
margin (Schiessel et al. 2005). In dedicated and highly specialised centres, adopting
ISR for appropriate cases, the overall APE rate may be below 10 %.
Some surgeons even perform partial or complete ISR for tumours at or just
below the dentate line and the acceptable margin of distal clearance are usually
considered to be 1 cm. T1–T2 tumours are usually considered to be resectable by
ISR, while this procedure is contraindicated in tumours infiltrating the external
sphincter or pelvic floor. Therefore, local tumour staging by MRI, and sometimes
endoluminal ultrasound is crucial in patients with low rectal cancer. In addition to
60 T. Holm
the radiological local staging, digital rectal examination is vital to assess if the
tumour is mobile in relation to the external sphincter and pelvic floor.
The oncological results after ISR and CAA are acceptable and comparable to
those achieved with LAR and stapled anastomosis above the puborectal muscle,
with local recurrence rates usually in the range of 5–10 % and 5-year disease free
survival around 80 % (Martin et al. 2012).
Although feasible in selected patients, the functional results after ISR and CAA
is often poor with a high rate of low anterior resection syndrome (LARS), including
urgency, fragmentation of stools and incontinence. Major LARS at 1 year after
surgery has been reported in half of the patients after LAR and this proportion is
likely to be even higher after ISR and CAA. Patients with LARS also report poorer
quality of life (QoL) than patients without LARS (Emmertsen and Laurberg 2013).
Many patients with low rectal cancer will receive radio-chemotherapy before
surgery in order to shrink and downsize the tumour, which may make subsequent
surgery easier and prevent an involved circumferential resection margin (CRM).
However, several studies have shown that radiotherapy in rectal cancer leads to a
further deterioration of sexual and anorectal function which is persistent long term
after treatment.
The vast majority of patients undergoing ISR and CAA will have a defunc-
tioning ileostomy or transversostomy in order to prevent or diminish the severe
and sometimes fatal consequences of an anastomotic leak. Due to different post-
operative problems, such as persistent anastomotic leak with pelvic sepsis, other
complications and comorbidity, some patients will not have their stoma closed. In
other patients the functional results after ISR and CAA are so poor that a con-
version to a permanent colostomy is required. It has been reported from different
countries that the unintentional permanent stoma rate after LAR is around 20 %
after long-term follow-up.
Thus, it is important to realise that ISR and CAA in patients with low rectal
cancer should only be performed selectively; in those with early T1–T2 tumours
(before or after neoadjuvant treatment) and if the pre-operative anorectal function
is good, without any sign of incontinence. In addition, the patients have to be
carefully counselled about the risks of poor function and a permanent stoma,
despite the attempt to restore bowel continuity.
3 Abdomino-Perineal Excision
The majority of patients with low rectal cancer will need an APE, either because the
CRM will not be clear with a sphincter saving procedure or the patient, for different
reasons, is not suitable for restoration of bowel continuity. Traditionally, one
obvious problem associated with the conventional type of synchronous combined
APE was the lack of standardisation. Although the abdominal part of the operation
follows the standard TME principles, there has been no apparent agreement on the
surgical details of the perineal part of the operation. This probably explains the
significant variability in the reported rates of tumour involved margins, bowel
perforations, local recurrence and survival (Birbeck et al. 2002). Also, the results
in terms of bowel perforations, tumour involved CRM, local control and survival
have been significantly poorer after APE than after AR. In one study based on 561
patients from Leeds, UK, it was reported that patients undergoing APE had a higher
local failure rate (22.3 vs. 13.5 %) and a poorer survival (52.3 vs. 65.8 %) compared
with patients who had an AR during the same time period (Marr et al. 2005). In
another paper based on data from five different European trials it was reported that
the APE procedure was associated with an increased risk of circumferential resec-
tion margin (CRM) involvement, an increased local recurrence rate and a decreased
cancer specific survival (den Dulk et al. 2009).
The difference in oncological results between the two procedures may be
explained by several factors, including anatomical difficulties and the surgical
technique associated with standard APE surgery. In the lower rectum, the sur-
rounding mesorectum is reduced in size and disappears at the top of the sphincters.
Below this level, the sphincter muscle forms the circumferential resection margin
(CRM). As mentioned above, the abdominal dissection during a conventional
synchronous combined APE is often carried out along the mesorectum, all the way
down to the pelvic floor and the top of the puborectalis muscle, with the meso-
rectum being mobilised off the levator muscles. The perineal dissection then
follows the external sphincter to meet the pelvic dissection at the top of the anal
canal. With this technique the retrieved specimen often has a typical ‘waist’ at
3–5 cm from the distal end corresponding to the top of the external sphincter at the
level of the puborectalis muscle and the lowest part of the mesorectum.
This inwards coning at the pelvic floor carries the dissection close to the rectal
wall and several studies have reported higher rates of bowel perforation and
tumour involvement of CRM after APE as compared with AR. Nagtegaal et al.
assessed 846 AR specimens and 373 APE specimens from the Dutch TME trial
and found that the plane of resection was within the sphincter muscle, the sub-
mucosa or lumen in more than 1/3 of the APE cases, and in the remainder was on
the sphincter muscles. This resulted in a positive CRM rate of 30.4 % after APE
versus 10.7 % after AR and a perforation rate of 13.7 % after APE versus 2.5 %
after AR (Nagtegaal et al. 2005).
Due to this variability, and the suboptimal results after APE, there has been a call
for a different concept and a more standardised approach to APE (Radcliffe 2006).
In recent years, a new concept of APE has therefore evolved, which takes into
account the specific anatomical structures of the perineum and the pelvic floor and
which aims to adopt and standardise the procedure according to the characteristics
of the patient and the tumour. Basically, three types of APE can be described in
relation to the perineal approach and the extent of dissection; the inter-sphincteric
APE, the extra-levator APE and the ischio-anal APE. The mobilisation of the
rectum and the mesorectum during the pelvic dissection in the abdominal part of the
operation differs between the inter-sphincteric APE and the two other types. In
addition, the indications are different for the three procedures, as mentioned below.
62 T. Holm
3.1 Inter-Sphincteric APE
The abdominal and pelvic dissection in inter-sphincteric APE is identical to that

performed during LAR, which means that the mobilisation of the rectum with an
intact mesorectum is continued down to the pelvic floor and the puborectal muscle.
To perform the perineal phase of an inter-sphincteric APE the surgeon and
assistant move from the abdomen, the patient’s legs are elevated and the perineum
is exposed. An incision is made around the anus just distal to the inter-sphincteric
groove. A self-retaining retractor with hooks is recommended to optimise the view
and to facilitate the inter-sphincteric dissection. Once the skin incision is made the
anus is closed with a running suture. The dissection then follows the inter-
sphincteric plane between the internal and external sphincter, around the cir-
cumference of the anal canal, and all the way up to the puborectal sling and into
the pelvic cavity. The specimen is then gently removed either through the perineal
incision or, if the mesorectum is large and bulky, lifted up from the pelvis and
removed from the abdomen via the abdominal incision. The perineal incision is
then closed with a running or interrupted suture in the puborectal muscle, external
sphincter and skin.
3.2 Extra-Levator APE
The main objective of an extra-levator APE is to diminish the risk of inadvertent

bowel perforation and tumour involvement of the CRM. This is a consequence of
excision of the levator muscles en bloc with the mesorectum to protect the most
distal part of the bowel and thereby avoiding ‘the waist’ of the specimen, which
has been so common after the conventional type of synchronous combined APE.
Since the levator muscles should not be separated from the mesorectum, the pelvic
dissection during the abdominal part of an ELAPE differs notably from an anterior
resection or an inter-sphincteric APE (Holm et al. 2007).
3.2.1 The Pelvic Dissection in ELAPE

The initial abdominal and pelvic dissection is identical to that described above but
with one very important difference. In both anterior resection and inter-sphincteric
APE the dissection continues all the way down to the pelvic floor and the pubo-
rectal muscle and subsequently the mesorectum is lifted off the levator muscles. In
ELAPE it is crucial not to take the mobilisation of the rectum and mesorectum as
far down as the pelvic floor. Instead, the dissection should proceed only down to
the sacro-cocygeal junction dorsally, just beyond the inferior hypogastric plexus
antero-laterally, and anteriorly dissection should stop just below the seminal
vesicles in men or the cervix uteri in women. By terminating the mobilisation of
the rectum and mesorectum at this level, the mesorectum is still attached to the
levator muscles of the pelvic floor, which is a crucial feature of the ELAPE.
3.2.2 The Perineal Part of ELAPE

The perineal part of ELAPE differs considerably from the perineal part of the
inter-sphincteric APE or LAR with ISR. The perineal phase starts with closure of
the anus to avoid any spillage of faeces or mucus which could contain tumour
cells. The anal closure thus aims at reducing infection and also reducing the risk of
tumour contamination which may result in local recurrence. Closing the anus can
be done with a double purse string suture or with an inverting running suture after
the skin incision has been made around the anus. The latter technique is especially
valuable in very low, advanced tumours which may in fact protrude through the
anus. In the ELAPE less skin and ischio-anal fat is excised as compared with Miles
original description of the perineal part of the APE procedure. Instead, the skin is
incised around the anus with a margin of only about three centimetres anteriorly
and laterally, posteriorly the incision is carried up to the level of the lower sacrum
i.e. two to three centimetres cranial to the sacro-coccygeal junction.
With gentle traction and counter traction on the skin edges the dissection is now
continued in the subcutaneous fat and as dissection proceeds deeper it is important
to identify the subcutaneous extension of the external sphincter. These fibres of
striated muscle should be kept medially and the dissection follows a plane between
the external sphincter and the thin fascia covering the ischio-anal fat in the ischio-
anal compartment (also called ischio-rectal fossa) on both sides. At the top of the
external sphincter and puborectal muscle, the levator ani muscles are in direct
continuity and the dissection is carried along the surface of the levator muscles all
the way up to their insertion at the pelvic side wall, i.e. the obturator internus
muscle. Once the surface of the levator muscles are exposed all around the cir-
cumference the haemostasis must be controlled before entering the pelvic cavity.
In the midline the levator muscles are attached to the anterior surface of the
coccyx and continue as the presacral fascia on the anterior, lower aspect of the
sacrum. The dissection follows the proximal portion of the levator muscles on both
sides of the coccyx so that the coccyx is clearly exposed. Next, an incision is made
at the sacro-coccygeal junction, which is easily identified by gentle moving of the
coccyx. Once the cartilaginous connection between the sacrum and coccyx has
been opened the coccyx is pressed anteriorly to stretch the presacral fascia, which
is then divided and an entrance into the pelvic cavity is created. At this stage it is
important to identify the mesorectum in order not to injure the mesorectal fascia.
The pelvic floor, i.e. the levator muscle, is now divided from posterior to
anterior and as the division of the pelvic floor continues anteriorly it is important to
avoid a division of the levator muscles too far laterally and too close to the ischial
tuberosity as this may injure the main pudendal nerve and vessels in Alcock’s
canal. The division of the pelvic floor continues until the dorsolateral part of the
prostate or vagina can be palpated and visualised, or preferably one to two cen-
timetres posterior to this point. The specimen is now still attached to the anterior
aspect of the levator muscles and to the prostate or posterior wall of the vagina.
The dissection in the anterior plane during the perineal phase of the ELAPE is the
most difficult, and potentially most dangerous, part of the procedure because of the
64 T. Holm
close relationship between the anterior rectal wall and the prostate or posterior
vaginal wall. In addition, the neurovascular bundles derived from the inferior
hypogastric plexus run anterolaterally on each side of the prostate or vagina and
close to the rectum and can easily be damaged if they are not recognised at this stage
of the operation. The dissection along the anterior and lateral aspects of the lower
rectum must therefore be performed meticulously and with great care. If the dis-
section is performed close to the rectal wall there is a risk of inadvertent perforation
or tumour involved margin and if the dissection is carried out too laterally, or too
anteriorly, there is a risk of damage to the neurovascular bundles or to the prostate or
vagina. In anteriorly located tumours it may be necessary to include the posterior
vaginal wall or a slice of the posterior prostate with the specimen, and sometimes
even to sacrifice the neurovascular bundle on one side, to be able to achieve a
negative CRM. However, this extension of the procedure should ideally be planned
in advanced so that the surgeon is prepared for it and so that the patient is well
informed about the consequences which may be impairment of bladder and/or
sexual function. To facilitate the anterolateral dissection of the lower part of the
rectum it is recommended that the specimen is gently brought out of the pelvic cavity
so that the anterior aspect of the bowel can be seen. It is now easy to look into the
pelvic cavity and to recognise the seminal vesicles and upper part of the prostate in
men and the posterior vaginal wall in women. The plane between Denonvillers
fascia and the prostate or posterior vaginal wall is now carefully followed whilst the
surgeon should attempt to identify the neurovascular bundles on each side. Grad-
ually, these planes of dissection are developed anteriorly and alternately on the right
and left side and the remaining part of the levator muscles that are attached to the
lowest part of the rectum are divided. Finally, the puborectal muscle on each side and
the perineal body just posterior to the transverse perineal muscle is divided and the
specimen can be delivered. The excised specimen is ‘cylindrical’, usually without a
waist, due to the fact that the levator muscle is still attached to the mesorectum,
forming a cuff around the rectal muscle tube.
3.3 Ischio-Anal APE
In some patients the rectal tumour is locally advanced and may infiltrate or even
perforate the pelvic floor, i.e. the levator muscle. In other patients, a perianal
abscess may sometimes be the presenting feature of a perforated low rectal cancer,
and after drainage a fistula may persist between the low rectum and the perianal
skin. In a few very low tumours the growth may extend into the perianal skin. In
these instances an ELAPE may not be sufficient to achieve a safe, tumour free
CRM and an ischio-anal APE is usually required to obtain an oncologically secure
margin. In this situation the levator muscle must be removed and covered with
ischio-anal fat and the ischio-anal fat must be removed to include the perianal
fistula, which may contain tumour cells. Therefore, the ischio-anal APE is a valid
procedure in these special situations.
The abdominal part of the ischio-anal APE is exactly equivalent to the

abdominal part of the extra-levator APE. Thus, the dissection stops just above the
levator muscle, and leaves the mesorectum attached to the pelvic floor.
3.3.1 The Perineal Part of Ischio-Anal APE

The area of the skin incision in an ischio-anal APE depends on the extent of tumour
involvement of the skin. Any tumour infiltration or fistula opening must be included
in the excised skin area with a margin of at least 2–3 cm. As soon as the incision
deepens into the subcutaneous space the dissection should be directed laterally
towards the ischial tuberosity and progresses onto the fascia of the internal obtu-
rator muscle. Thus, contrary to an extra-levator APE, the dissection does not follow
the external sphincter and levator muscle but is instead carried along the fascia of
the internal obturator muscle. The dissection is performed along this plane up to
where the levator muscle is inserted onto the internal obturator muscle and hence
includes the entire fat compartment of the ischio-anal space. This dissection can be
performed unilaterally or bilaterally depending on the extent of tumour growth.
When the dissection up to this level is completed the sacro-coccygeal junction is
incised and the pelvic cavity is entered in the same fashion as with an ELAPE. The
subsequent dissection is also similar to that of the ELAPE, as the levator muscles
are divided along the fascia of the internal obturator muscle onto the prostate in men
or the vagina in women. Once the specimen has been brought out of the pelvic
cavity, the anterior and lateral dissection along the prostate or vagina is also carried
out as in an ELAPE. As mentioned above, the difference between an ELAPE and an
ischio-anal APE is that the fat in the ischio-anal space is resected en bloc and
attached to the levator muscle. This procedure is similar to what Miles described in
1908 in his original paper in The Lancet.
4 Restorative Procedure or APE in Low Rectal Cancer?
Every patient with low rectal cancer should have an appropriate clinical assess-
ment and radiological staging with MRI of the pelvis and CT of the thorax and
abdomen. The results of this work up should be presented a multidisciplinary team
(MDT) meeting and discussed in relation to current knowledge and the manage-
ment should be individualised to each patient with rectal cancer.
The choice between a restorative procedure, in terms of ISR and CAA, or APE
in low rectal cancer depends on the patient, the tumour and the surgeon. Important
patient related factors include comorbidity and anorectal function, tumour char-
acteristics include the height of the tumour from the anal verge and results of
preoperative radiological staging in terms of TNM stage, and surgeon-related
factors include experience, skill and technical resources.
66 T. Holm
Thus, ISR with CAA can be performed in patients with an early T1–T2 tumours
and good anal function. If the anal function is poor an inter-sphincteric APE is
probably a better choice. In patients with tumours threatening or involving the
external sphincter or pelvic floor an ELAPE is the procedure of choice and if the
tumour is even more advanced, an ischio-anal APE may be necessary.
5 Summary
There have been several important improvements in the management of patients

with rectal cancer during the recent 20 years. More accurate local and distant
tumour staging, introduction of neoadjuvant treatments, improved surgery, a more
precise macroscopic and microscopic evaluation of the specimen and MDT dis-
cussions have all been crucial in improving local control and survival. However,
the most important factor has been the TME technique with standardisation of the
surgical procedure. For patients with low rectal cancer the decision making is
complex with several treatment options, including the choice between neoadjuvant
treatment followed by surgery or surgery alone, restorative procedures or APE. If
an APE is necessary this must also be tailored to the individual patient, based on
patient characteristics and the extent of local tumour growth.
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T4 Rectal Cancer: Do We Always Need
an Exenteration?
Thomas A. Vermeer, Miranda Kusters and Harm J. T. Rutten
Abstract
The management of rectal cancer has changed dramatically over the last few
decades. Due to improvements in the multimodality treatment and the
introduction of neoadjuvant chemoradiation, previously irresectable tumours
can nowadays be cured by extensive multivisceral resections. These highly
complex operations are associated with significant morbidity and mortality.
Due to optimization of chemoradiotherapy, the introduction of IORT,
increasing knowledge of tumour pathology and patterns of recurrence the need
for extensive surgery diminishes. The question arises which patients with T4
rectal cancer really need extensive surgery and who can safely be considered
for an organ preserving approach.
T. A. Vermeer M. Kusters H. J. T. Rutten (&)

Department of Surgery, Catharina Hospital, Michelangelolaan 2,
5623, EJ, Eindhoven, The Netherlands
T. A. Vermeer
M. Kusters
70 T. A. Vermeer et al.
1 Introduction
Due to advances in multimodality rectal cancer treatment, previously untreatable

patients with locally advanced disease, now undergo curative multivisceral
resections with acceptable oncological outcome. Rectal cancer is a common dis-
ease with high incidence rate and a high cancer-related mortality rate. In 10 % of
patients present with primary rectal cancer, the tumour penetrates through the
mesorectal fascia and threatens the integrity of adjacent organs and structures and
an approach according to the TME principles would inevitably lead to an irradical
resection (Gebhardt et al. 1999). In these T4 rectal cancer patients, the surgical
peripheral margin has to be extended beyond the TME plane (Heald and Ryall
1986). The definition of advanced rectal cancer is very heterogeneous. In this
chapter, we discuss T4 rectal cancer, which can be identified better due to its
involvement of pelvic organs and structures, which can be easily diagnosed with
modern MRI techniques. T4a rectal cancer by definition invades the visceral
peritoneum; in upper rectal cancer adjacent organs are not involved (except bowel
loop which is located against the peritoneal surface of the upper rectum). T4b
rectal cancers always truly invade the adjacent organs. Both, T3+ and T4 tumours
are at high risk for local recurrence and worse oncological outcome, but this
chapter focuses on T4 tumours.
Despite the current multimodality treatment, the approach of rectal cancer
treatment is still based on the importance of the distance of the radial tumour boarder
to the MRF, as described by Quirke (1986). This radial margin, called the cir-
cumferential resection margin (CRM), is the strongest predictor of an unfavourable
oncological outcome; i.e. increase of local recurrence, distant metastasis and poor
survival (Nagtegaal and Quirke 2008; Kennelly et al. 2013). In order to fulfil the
main goal of rectal cancer surgery, achieving a radical resection, extension beyond
the circumferential resection margins will lead to a loss of pelvic structures and
organs and subsequent increased morbidity. In low rectal cancers, a T4 tumour will
often invade into the funnel-shaped pelvic floor or the anterior genital organs
(Fig. 1).
In mid-rectal cancer again the urogenital organs anteriorly, the lateral sidewalls
with the neural bundle, the piriformis muscles and the internal iliac vessels as well
as the posterior sacral fascia and sacrum are at risk. In high rectal cancer, the
uterus, ureters, bladder and major vessels pose a challenge. Therefore, T4 rectal
cancer is a very heterogeneous disease, depending on the level and orientation of
the tumour (Fig. 2).
The introduction of preoperative long-term radiotherapy with concomitant
chemotherapy, i.e. chemoradiotherapy (CRT), has improved oncological outcome
in locally advanced rectal cancer. In many cases, it results in downsizing and
downstaging of the tumour has been proven effective, but it is still unclear if the
oncological prognosis shifts parallel to the extent of the downstaging. More
concrete, does it mean when a T4 tumour becomes a T3 or even less, the prognosis
also change to that stage? Essentially, this is the controversy whether the tumour
T4 Rectal Cancer: Do We Always Need an Exenteration? 71
Fig. 1 Tumour invading the prostate and pelvic floor
Fig. 2 Large extended resections may be required to achieve a negative surgical margin
should be treated as it primary presented, or does downsizing and downstaging

also allow for a downscaled surgical approach meaning that a standard TME
resection might be sufficient?
In order to accurately assess whether downstaging has occurred, MRI is used
for restaging. But the question arises if it possible to accurately assess downstaging
on MRI and subsequently reliably downscale the surgical approach.
Besides neoadjuvant treatment and imaging, several issues will be discussed in
this article and two further questions remain to be answered. First, which margin
can be considered safe after CRT and does a close or even positive margin result in
a poor oncological outcome? Subsequent questions are about the optimal time
interval between neoadjuvant treatment and surgery. What is the optimal timing
for restaging, and does prolongation of this interval lead to further regression of
the tumour? The second question regards the advantage of intensification of the
neoadjuvant treatment. Is there a place for combining multiple drugs as part of the
concomitant CRT or would it be better to combine (chemo-) radiotherapy with
several courses of systemic chemotherapy? Does intensification of the radiother-
apy with additional brachytherapy or intraoperative radiotherapy compensate for
close or even affected margins?
2 Neoadjuvant Chemoradiotherapy
Neoadjuvant CRT became the standard treatment for locally advanced rectal
cancer, after several studies showed the improvement of downsizing and down-
staging of the tumour and its subsequent positive effect on oncological outcome,
i.e. increased local control (Frykholm et al. 2001; Valentini et al. 2002). The use of
concomitant continuous 5-FU administration as a radiation sensitizer resulted in
increased downstaging and local control compared to radiotherapy alone, and 5-
FU agents are now a part of the standard neoadjuvant treatment (Bosset et al. 2014;
Gerard et al. 2006; Saif et al. 2008). In order to further improve oncological
outcome, various chemoradiation schemes have been investigated over the last few
decades. Intensified CRT schemes, with additional chemotherapy to the above-
mentioned scheme, have been studied in locally advanced rectal cancer. The
addition of oxaliplatin showed promising results in different studies with an
increased effect on downstaging and even improved oncological outcome (Fakih
et al. 2008; Chau et al. 2006; Rutten et al. 2006; de Gramont et al. 2000).
Three randomised controlled multicentre phase III trials could not reproduce
these effects on downstaging, and oncological outcome did not improve by
intensifying CRT by adding oxaliplatin (Aschele et al. 2011; Rodel et al. 2012;
Gerard et al. 2010). In addition, increased toxicity rates were observed and the
administration of oxaliplatin was therefore discouraged. A recent update of the
ACCORD 12 trial, with a 3-year follow-up did not find any improvement on
clinical outcome for this intensified chemoradiation regimen (Gerard et al. 2012).
The randomised controlled multicentre CAO/ARO/AIO-04 trial shows contra-
dictory results, with increased pathological complete response without increased
acute toxicity rates (Rodel et al. 2012). Despite these results, no impact on R0
resection rate, positive CRM or overall survival was found (Sauer et al. 2012).
Especially in T4 rectal cancer downsizing and downstaging of the tumour is of
pivotal importance in order to perform a curative resection or even downscale the
surgical approach and prevent the patient form undergoing extensive multivisceral
resections. The multicentre phase II CORE study (Capecitabine, Oxaliplatin,
Radiotherapy follow by Excision), commenced in 2003 (Rutten et al. 2006). The
CORE regimen was significantly associated with tumour regression and high R0
resection rate. This subsequent positive effect of various chemoradiotherapy
schemes on R0 resection is confirmed by our data and is shown in Fig. 3 (data
presented during the St. Gallen Oncology Conference).
Fig. 3 Intensified
radiochemotherapy shows
better resection rates in T4
rectal cancer, but the clinical
relevance could not be
confirmed in several
randomised trials (be it that
these trials included mostly
T3 patients) (unpublished
data)
Grade 3 and 4 toxicity rates in the CORE group, 20 and 11 % respectively,

were comparable to the other regimens, 18 and 10 % respectively. This intensified
CRT scheme significantly improved cancer-specific survival (Martijnse et al.
2012). In this population with mainly T4 rectal cancer patients, the intensified
chemoradiation regimen appears effective. Oxaliplatin may only be effective, in
those patients with T4 rectal cancer in whom downstaging can induce a resectable
tumour. The systemic effects of oxaliplatin are encouraging, with a decrease in
distant metastases at the time of surgery (Aschele et al. 2011; Rodel et al. 2012;
Gerard et al. 2010) and increased relapse-free survival and cancer-specific survival
(Martijnse et al. 2012). Further effects on oncological outcome will be available in
the trial updates with increased follow-up.
The administration of additional 5FU-based chemotherapy in the rest period
proved to be save with acceptable toxicity and an increase in pCR rates and tumour
downstaging, achieving an overall complete response rate of 65 % (Habr-Gama
et al. 2009). The FOLFOX phase II trial, demonstrated an increased pCR rate,
25 % versus 16 %, after administration of two cycles of FOLFOX (folinic acid,
5-FU, oxaliplatin) in the rest period (Garcia-Aguilar et al. 2011). Since both
studies increased the timing interval compared to previous studies, the attribute of
additional chemotherapy cannot be conclusively determined.
3 Staging and Restaging Rectal Cancer
3.1 Staging Rectal Cancer
In order to accurately stage rectal cancer patients and assign them to neoadjuvant
treatment, Magnetic Resonance imaging (MRI) has evolved in the most important
diagnostic modality. MRI provides detailed images of dissection planes and pelvic
fascia’s, more specifically the mesorectal fascia (MRF) in rectal cancer, and is
therefore the diagnostic modality of choice. High-resolution MRI is superior to
Computed Tomography (CT) for imaging rectal tumours and assessment of a
threatened or involved MRF. A very good correlation of extramural spread of
tumours on MRI and in histopathology was reported by The Mercury study group,
confirming the reliability of MRI in predicting tumour invasion (Group MS 2007).
But the true value of MRI is its ability to predict a positive CRM or MRF
involvement. The best cut-off distance for predicting MRF involvement using MRI
is 1 mm between the tumour and the MRF. Using a cut-off point greater than
1 mm did not decrease local recurrence rates below 7 %, while patients with a
distance of less than 1 mm on MRI have a 20 % risk to develop a local recurrence
(Taylor et al. 2011). Besides local tumour staging, predicting lymph node
involvement is an important part of preoperative staging. The prediction of lymph
node involvement remains a diagnostic problem for the radiologist even on MRI.
Lateral lymph node disease can be assessed with MRI or PET-CT but the accuracy
remains insufficient. In order to accurately stage patients prior to treatment,
additional diagnostic modalities are used. Abdominal Computer tomography (CT)
is used to stage distant disease. Endorectal ultrasound (ERUS) is widely used in
staging early rectal cancer. EUS is accurate for the evaluation of the muscularis
propria, (Bipat et al. 2004; Kwok et al. 2000; Puli et al. 2009) but it cannot
visualise the MRF as reliably as an MRI scan, and the extend of organ involvement
cannot be accurately assessed (Bipat et al. 2004; Ref. 28). Therefore, ERUS has no
role in primary staging of T4 rectal cancer as a stand-alone diagnostic tool, but it
may have an application for determining specific organ involvement, particularly
the rectal-prostate interface (Beyond 2013) (Fig. 4).
3.2 Restaging Rectal Cancer
The response to preoperative CRT is evaluated by various diagnostic modalities;

i.e. ERUS, CT, MRI, diffusion weight (DW) MRI and FDG-PET/CT. Accurate
association between clinical stages predicted by the different diagnostic modalities
after CRT and pathological tumour stage is crucial. The question arises whether
the surgical strategy can be downscaled if partial or complete tumour response is
observed on the different imaging modalities. The tissue transformation induced by
chemoradiotherapy causing inflammation and fibrosis, has a major impact on post-
CRT radiological imaging and therefore assessment of these diagnostic modalities
is crucial (Fig. 5).
Fig. 4 Accurate delineation of structures and tumour with the help of MRI
Fig. 5 Restaging with MRI may lead to a new interpretation of the required extent of the
resection
The inability to differentiate between tumour and radiation-induced inflamma-

tion and fibrosis turns ERUS into an inaccurate diagnostic modality with sensitivity
rates between 38 and 48 % (Vanagunas et al. 2004; Mezzi et al. 2009; Huh et al.
2008; Dickman et al. 2013). Similar limitations are encountered using MRI since it
cannot completely differentiate between fibrosis and tumour residue and MRI tends
to overestimate CRM involvement. Introduction of Diffusion-Weighted (DW) MRI
enhanced the diagnostic accuracy compared to conventional MRI in evaluating
tumour response, including complete response. The sensitivity for predicting
Fig. 6 Left before and right after radiochemotherapy. No vital tumour cells were found
complete response increased from 55 to 91 % after addition of Diffusion-Weighted

Imaging in some series, with an increased inter-observer agreement (Lambregts
et al. 2011; Kim et al. 2009). A recent meta-analysis regarding restaging rectal
cancer using MRI, confirmed the added value of Diffusion-Weighted Imaging in
predicting tumour stage with a sensitivity increase from 50.4 to 83.6 %, with a
similar increase in specificity. The sensitivity for evaluation of a tumour-free CRM
was 76.3 %, with a specificity of 85.9 %.
In clinical practice, the true value of a diagnostic modality is based on its
possibility to modulate the surgical treatment. The identification of those tumours
that are confined to the rectal wall and are therefore suitable for downscaled
surgery is thus the major challenge in this specific group of patients; i.e. differ-
entiation between T0-3 versus T4 tumours. A specificity and positive predictive
value of 98 and 91 % respectively, was found for the prediction of tumour con-
fined to the rectum wall on MRI, T0-2 versus T3-4, by Dresden et al. (2009). These
results imply the possibility to downscale surgery based on restaging by MRI after
CRT. Evaluation of nodal status showed not to be reliable due to low specificity,
59.8 %, and the inability to differentiate benign from malignant lymphnodes,
especially in small nodes (van der Paardt et al. 2013) (Fig. 6).
Multiple recent studies have investigated the role of FDG-PET/CT in restaging
rectal cancer patients, with sensitivity ranging from 81 to 85 % and a specificity of
Fig. 7 Relation between 392 T4 rectal cancer patients between timing of surgery and magnitude
of T downstaging. Green, beige, purple and yellow line indicate 77 % T4 downstaged \= ypT3,
24 % \= ypT2, 13 % \=, 13 % \= ypT1 and 11 % ypT0, respectively (unpublished data)
80 % (Capirci et al. 2009; Kalff et al. 2009; Capirci et al. 2007). The results are
promising and suggest a future role for FDG-PET/CT in restaging rectal cancer.
Currently, FDG-PET is only able to discriminate responders from non-responders
but inaccurate in predicting T stage due to the inability to differentiate tumour
from fibrosis (Capirci et al. 2007, 2009; Kalff et al. 2009). In conclusion, none of
the currently available imaging modalities is able to 100 % reliably predict tumour
response and tumour-free CRM after CRT and surgical planning therefore remains
challenging. Overestimating tumour growth, due to the inability to differentiate
viable tumour from fibrosis, and poor specificity regarding nodal status are the
main drawbacks of the current imaging modalities.
4 Tumour Response and Timing Interval
Since the introduction of chemoradiotherapy as the standard neoadjuvant treatment

in advanced rectal cancer, new questions have arisen. The effects of chemora-
diotherapy on tumour tissue are well reported but are hardly predictable in clinical
practice for individual patients. The goal is to gain optimal tumour response after
neoadjuvant treatment without jeopardizing the patients’ safety or allowing local
tumour increase or distant tumour spread. Finding the optimal timing interval
between neoadjuvant treatment and surgery is therefore of pivotal importance
(Fig. 7).
Neoadjuvant chemoradiation leads to a pathological complete response (pCR)

in 15–20 % of patients with locally advanced rectal cancer. Many studies have
been published which have shown that pCR and pathological tumour regression
are associated with improved oncological outcome (Maas et al. 2010; Martin et al.
2012; Vecchio et al. 2005; Zorcolo et al. 2012). A recent systematic review by
Martin et al., reported a local recurrence rate of 0.7 % at a median follow-up of 55
moths in patients with pCR (Martin et al. 2012). This makes pCR an excellent
prognostic factor for local control with minimal risk of developing a local
recurrence. Despite a major influence on local control rates, distant failure is not
dramatically improved by pCR. Of the patients with pCR, 8.7 % developed
metastatic disease. The 5-year overall survival was 90.2 % for patients with pCR,
which is a 3.3-fold overall survival advantage over non-complete responders. In
addition to pCR, pathological tumour response, or downstaging, is a prognostic
factor for improved local failure rates, metastasis-free survival and overall survival
(Vecchio et al. 2005; Theodoropoulos et al. 2002). A close relationship between
pathological response and outcome has been observed; pT0-2 patients have
superior 5-year survival and local control rates regardless of cT stage compared to
non- or moderate responders (pT3/4 stage) (Valentini et al. 2002).
Increasing the timing interval, defined as the time between CRT and surgery,
has been associated with an increase in pCR rates and subsequent improved
oncological outcome (Wolthuis et al. 2012; de Campos-Lobato et al. 2011a, b;
Habr-Gama et al. 2008; Tulchinsky et al. 2008). A timing interval [7 weeks is
associated with increased pCR rates, 35 % versus 17 % (Tulchinsky et al. 2008)
and a timing interval [12 weeks is considered save without a negative influence
on oncological outcome (Habr-Gama et al. 2008; Tulchinsky et al. 2008). Based
on current literature, the optimal timing interval cannot be considered due to
insufficient quality evidence (Foster et al. 2013). However, if this time interval
effect also plays a significant role in T4 rectal cancer remains unclear. Therefore,
improving tumour response by altered neoadjuvant treatment schemes and opti-
mizing the timing interval should be the subject of additional studies to further
improve oncological outcome.
5 Extended Surgery
Despite the increasing effects of neoadjuvant treatment, surgery remains the cor-
nerstone of the current multimodality T4 rectal cancer treatment. The optimisation
of preoperative staging and neoadjuvant treatment has one important goal;
increasing the radicality rates of the resection and subsequently improving local
tumour control and oncological outcome. A radical resection is the most important
objective in any case of rectal cancer, and this includes this highly selected group
of patients. Since the treatment is associated with high morbidity and mortality
rates in these patients, the possibility of an irradical resection and subsequent poor
oncological outcome should be reduced by any mean. In T4 rectal cancer, in whom
Fig. 8 Resection of the sacrum, uterus, rectum and posterior vaginal wall
despite CRT and restaging, surgery cannot be downscaled and invasion of adjacent
organs indicates the need for extended surgery. Adequate preoperative staging
followed by a multidisciplinary team meeting in these patients is quintessential in
order to tailor the treatment to the individual patients’ need. The location of the
tumour influences the treatment strategy and oncological outcome. Dorsally
located locally advanced rectal tumours invade the pelvic floor muscles, ox coccyx
or sacrum when the MRF is breached. Central or anterior located rectal tumours
might invade the bladder, prostate or seminal vesicles in men or the vagina and
uterus in women. The lateral T4 tumours invade the neural bundle, the piriformis
muscles and the internal iliac vessels. Each tumour presents its specific challenges
in the treatment process. The location of the tumour itself influences oncological
outcome. The more dorsally the tumour is located, the higher the irradicality rate
and local recurrence rate is (Park et al. 2009).
5.1 Abdominosacral Resection
Infiltration of the tumour into the sacrum or coccyx typically requires an

abdominosacral resection (ASR) if curative surgery is intended. Tumour growth
into the lateral pelvic wall or pelvic floor muscles requires a wider dorsal resection
for optimisation of dorsal access in order to achieve a radical resection margin and
a sacral resection is required (Mannaerts et al. 2001). Sacral resection as high as
S1-S2 are described and expected feasible without muscoskeletal disability, but
bladder and anorectal dysfunction is inevitable due to nerve transaction at the
sacral nerve plexus (Ferenschild et al. 2009; Bhangu et al. 2012). Invasion of
the sciatic notch, involvement at the S1/S2 level or a tumour extending beyond
the sciatic foramen are usually excluded form surgery and are considered irre-
sectable as a radical resection will lead to unacceptable morbidity (Mannaerts et al.
2001; Ralph et al. 2012) (Fig. 8).
The oncological results for sacral resection in primary rectal cancer as

described in the literature are limited. Most studies report data on oncological
outcome in recurrent rectal cancer.
An irradical resection is the most important prognostic factor for poor survival,
disease-free survival and local recurrence in all series (Mannaerts et al. 2001;
Ferenschild et al. 2009; Bhangu et al. 2012; Ralph et al. 2012; Bebenek et al. 2007).
Ferenschild et al. and Dudink et al. reported a 5-year overall survival rate of 56 %
and local control rates of 88 and 79 % were reported in both series, respectively
(Ferenschild et al. 2009; Ralph et al. 2012). Five-year cancer specific survival is
reported to be 68 %. Bhangu et al. reported a 3-year local control rate and overall
survival rate of 100 % in eight patients after sacral resection for primary rectal
cancer (Bhangu et al. 2012). A larger series by Bebenek et al. reported a 60.3 and
73.2 % 5 year overall and relative survival rate respectively for primary rectal
cancer patients undergoing a ASR (Bebenek et al. 2007). In this series, similar
results were found for patients undergoing a standard abdominal resection, this
confirms the role of a radical resection as the most important indicator for onco-
logical outcome. Radical resection rates vary between 72 and 100 % (Mannaerts
et al. 2001; Bhangu et al. 2012; Ralph et al. 2012). If the use of IORT in R1
resections is considered a curative approach, the majority of patients with a dorsal
T4 tumour invading the sacrum can be treated (Mannaerts et al. 2001).
Overall postoperative complications after ASR are generally high, but mor-
bidity rates vary in literature between 14 and 82 % (Mannaerts et al. 2001;
Ferenschild et al. 2009; Bebenek et al. 2007). Sacral resection above S3 is
significantly associated with an increased rate of major complications, 60 % versus
27 % (Bhangu et al. 2012). Superficial perineal wound dehiscence, urinary tract
infection and urinary incontinence or retention are frequently diagnosed minor
complications. Anastomotic leakage, abscess formation and perineal wound
dehiscence are considered major complications, which in some series did not differ
significantly from complications in standard abdominal resection in primary rectal
cancer (Bebenek et al. 2007).
5.2 Multivisceral Resections
In T4 rectal cancer, different adjacent organs may be invaded by the tumour

depending on its location. Multivisceral resection (MVR) with en bloc resection of
the tumour and adjacent infiltrated organs is required to achieve a complete radical
resection. Adequate preoperative staging is crucial in the decision and planning of
a MVR. As described earlier, preoperative staging and diagnosing organ invasion
is challenging due to the inability of current diagnostic modalities to differentiate
fibrosis from tumour remnants. As MVR is associated with significant morbidity
and mortality, the decision to perform MVR can be hard. Peroperative distinction
of tumour and inflamed or fibrotic tissue is often impossible and therefore
preoperative staging is of paramount importance.
A recent meta-analysis for multivisceral resections in colorectal cancer was

performed by Mohan et al. A 5-year overall survival rate for MVR in primary
rectal cancer of 52.8 % (95 % CI, 52–53.8 %) was published. Survival rates in
recurrent rectal cancer are considerably worse, 19.5 % overall 5-year survival, and
recurrent rectal cancer should therefore be considered as a different entity (Mohan
et al. 2013). Acquisition of an R0 resection resulted in a significant better onco-
logical outcome compared to an R1/R2 resection. A weighed mean radicality rate
of 82.5 % was found for primary colorectal cancer.
The inability to peroperatively differentiate tumour residue from fibrosis is
confirmed by pathological findings. In more than 20 % of all patients included in
the systematic review adjacent organs were negative for tumour residue. A study
by Gezen et al., focussing solely on primary colorectal cancer, found a pT4 rate of
only 21.3 % for rectal cancer (Gezen et al. 2012). Nakafusa et al. found a 52.8 %
pT4 rate after multivisceral resection for combined primary colorectal cancer, with
a range in recent literature of 25–84 % (Nakafusa et al. 2004). True invasion did
not significantly affect survival in any of the included studies, which is an inter-
esting finding. However, an irradical resection is and downscaled surgery with the
risk of an R1 resection, which is the strongest predictor of oncological outcome, is
therefore unacceptable (Mohan et al. 2013). Preoperative staging and identifying
true tissue invasion therefore remains the biggest challenge. Significant morbidity
rates after MVR are reported, with a weighed mean complications rate of 41.5 %
and a perioperative mortality rate of 4.2 % (range 0–13 %). Infection, bowel
obstruction or ileus, urinary complications and abscess formation and anastomotic
leakage form the majority of complications (Gezen et al. 2012).
Morbidity rates after MVR are considerable but when an R0 resection can be
achieved, oncological outcome in primary rectal cancer is decent. Selecting those
patients in whom an R0 resection can be achieved is therefore crucial, subse-
quently saving patients from life long morbidity and poor oncological outcome in
case of an R1/R2 resection (Fig. 9).
6 Nonstandard Treatment Strategy
In highly selected patients, who are unfit for surgery or who are unwilling to
undergo invalidating surgery, a deviation from the usual treatment protocol is
sometimes required. A ‘‘wait-and-see’’ policy or local excision with intensive
follow-up has been proposed in some series. These treatment strategies are not part
of general patient care in our institute and should be taken with caution.
6.1 Wait-and-See
In patients with pCR, after CRT for LARC, no viable tumour residue is present in
the specimen, and the question arises whether these patients, in whom the tumour
has been sterilised, have to undergo extensive surgery. The superior oncological
Fig. 9 Multivisceral resections in 392 T4 rectal cancer patients demonstrating that R+ resections
carry a significant poorer prognosis (unpublished data)
results for patients with pCR might not be further improved by radical surgery,
therefore avoiding the sequel of TME or multivisceral surgery; e.g. surgical
morbidity and mortality; may be feasible in patients with clinical complete
response (cCR).
This ‘‘wait-and-see’’ policy has been described by various authors over the last
decade. Habr-Gama et al. reported a series of 265 patients, including 71 patients
(26.8 %) with a cCR after CRT who were treated with a non-operative approach
(Habr-Gama et al. 2004). A 5-year overall survival and disease-free survival were
100 and 92 % respectively, in the non-operative group, with a 2.8 % local
recurrence rate. A Dutch series by Maas et al., supported these results with a
2-year overall survival and disease-free survival of 91 and 93 %, respectively
(Maas et al. 2011). The recurrence rate was low, and could be salvaged by local
excision, and no metastatic disease developed during the relative short follow-up.
A more recent series by the Habr-Gama group, reported 50 % of patients with a
T2-4N0-2M0 treated successfully without undergoing surgery (Habr-Gama et al.
2013). A recent review, regarding the non-operative approach for LARC with cCR
after CRT, was not able to identify similar studies with comparable promising
results, and a pooled recurrence rate of 33.8 % was found (Glynne-Jones and
Hughes 2012).
The assessment of cCR is the first challenge in the ‘‘wait-and-see’’ approach.
No general definition is present in the literature and no single diagnostic modality
is available to confirm cCR. In a recent pooled analysis, cCR was associated with
pCR in 30 % of patients (Glynne-Jones et al. 2008). The superior results published
by Habr-Gama et al., are partly due to the extensive methods of defining cCR;
by clinical, endoscopic, radiological and metabolic imaging, confirmed by local

excision or biopsy; patient selection; and intensive follow-up (Glynne-Jones and
Hughes 2012). The second challenge is the detection of positive lymph nodes after
CRT. In pCR after CRT, there is no direct correlation with lymph node sterili-
sation and in 15–25 % of patients with cCR positive lymph nodes will be present
in the mesorectum (Glynne-Jones and Hughes 2012). These lymph nodes could
progress and cause a distant recurrence or metastasis. Especially in cT3 and cT4,
in whom the risk of nodal metastases is high, up to 50 % at diagnosis, a pelvic
recurrence might develop.
In conclusion, the major challenge in the ‘‘wait-and-see’’ approach is patient
selection, and the identification of patients with a cCR who also have a pCR.
Based on the current literature, no general consensus is present for a ‘‘wait-and-
see’’ policy in unselected patients. Patients with a low and small, i.e. non-bulky,
rectal tumour, without signs of positive lymph nodes may be selected for the
‘‘wait-and-see’’ approach if cCR is diagnosed using different modalities and follow
up is meticulous.
In Fig. 7 is demonstrated that only in 11 % of the presented T4 rectal cancer
patients a complete remission was achieved, irrespective of the interval between
RCT and surgery.
6.2 Local Excision
The local excision of cT2 tumours, at time of diagnosis, after CRT using TEM has
shown to give comparable oncological outcome compared to standard TME sur-
gery (Lezoche et al. 2012). cT4 tumours which are downscaled and downsized to
cT2 tumours are different biological tumours and data cannot be simply extrap-
olated. The inability of diagnostic modalities to restage nodal disease proposes
another challenge for selecting patients for local excision. The rate of node pos-
itivity in pathological studies with 235 specimens was 2 % for pT0, 15 % for pT1,
17 % for pT2, 38 % for pT3, and 33 % for pT4 cases (Pucciarelli et al. 2005).
A more conservative treatment, i.e. local excision, with intensive follow-up may
therefore be safe in patients with pCR after CRT for locally advanced rectal
cancer. Data regarding local excision in patients with cT1 or cT2 tumours without
nodal involvement after CRT is less clear. In a small series by Perez et al., patients
with initial LARC with cT0-2 rectal cancer after CRT, were treated with TEM.
This resulted in a 15 % local recurrence rate. Only lymphovascular invasion was a
prognostic factor for local recurrence; final ypT stage, CRM and tumour regression
were not significantly associated with local recurrence (Perez et al. 2013).
A multicentre phase II clinical trial, including stage T3N0-1 tumours at diagnosis
reported on 63 patients undergoing local excision after CRT. Patients underwent a
local excision in case of major tumour response. In case of ypT \ 2, negative
regional lymph nodes on MRI and negative resection margins patients were
considered adequate for follow-up. The authors concluded that patients with a
Fig. 10 Demonstrating the principles of an intraoperative electron boost at the area of risk
ypT2 tumour after local excision should undergo subsequent standard TME
surgery due to high local recurrence rates, as supported by earlier data (Lezoche
et al. 2012; Pucciarelli et al. 2013).
Data regarding local excision and follow-up is very scant and limited to cT B 3
tumours at time of diagnosis. Pathological studies with cT3/T4 tumours at time of
diagnosis show that in 17 % of pT0-2 tumours residual disease is present in the
rectal mesentery and nodes (Bedrosian et al. 2004). Local excision should there-
fore be recommended with caution. A highly selected group of patients may be
eligible for local excision and stringent follow-up. Additional pathological prog-
nostic factors, such as lymphovascular invasion, may be the key to predicting
lymph node metastases and local recurrence.
7 IORT
In order to improve oncological outcome in selected complex rectal cancer

patients, intraoperative radiation therapy (IORT) has been introduced in the 1990s.
The sterilisation of threatened or involved resection margins by high dose locally
administered radiation beams is hypothesised to improve local control in rectal
cancer patients. The required resection margin of [1 mm as is currently accepted
and associated with improved oncological outcome could possibly be reduced in
case of effective local radiotherapy. This strategy might lead to a decrease in
multivisceral and invalidating extensive resections (Fig. 10).
The administration of IORT as a radiotherapy boost of 10–15 Gy is debatable.

The safety of IORT has been established in several studies, without an increase of
morbidity and mortality after surgery has been observed (Avizonis et al. 1989;
Noyes et al. 1992; Harrison et al. 1998; Mannaerts et al. 2000; Azinovic et al.
2001; Gunderson 1996). Nerve tissue damage is the most important dose-limiting
factor, with a linear relationship between radiation dose and limb paralysis
(Kinsella et al. 1985). An IORT dose exceeding 12.5 Gy is associated with the
development of peripheral neuropathy (Gunderson et al. 1988). In theory IORT
reduces the risk of local recurrence in case of microscopic tumour residue (R1)
after resection by sterilizing the radiated area. The radiation boost should be
administered to this high-risk area. A high-risk area is indicated by a threatened
margin on preoperative MRI or perioperative positive frozen section. Some
institutes routinely administer the boost to the presacral area as high-risk area
(Calvo et al. 2002; Krempien et al. 2006). Studying the patterns of local recurrence
has revealed this is associated with development of a local recurrence outside the
presacral radiation field in 59–67 % (Calvo et al. 2002; Roeder et al. 2007). IORT
to the high-risk area results in less infield local recurrence than routine presacral
IORT (Kusters et al. 2009).
Many clinical studies have been published regarding the effect of IORT on
oncological outcome, with contradictory results. A positive impact on local control
and survival has been reported by several authors in earlier clinical studies
(Mannaerts et al. 2000; Calvo et al. 2002). Some series only show improved local
control rates without impact on survival (Kusters et al. 2010; Weinstein et al.
1995; Valentini et al. 2009). A recent pooled analysis of 605 European primary
rectal cancer patients undergoing IORT-containing multimodality treatment,
showed a local recurrence rate of only 12 % in a high-risk group of patients.
Furthermore, 55 % of patients with an R1 resection did not develop a local
recurrence, which suggests a positive effect of IORT on tumour residue (Kusters
et al. 2010). IORT could allow for a margin \1 mm. Our data show that a radical
resection is the most important factor in oncological outcome. The oncological
outcome after an R0 resection was not affected by the extent of the resection
margin. A resection margin \1 mm was not associated with poor oncological
outcome, as long as a R0 resection was obtained. This effect might be contributed
to the use of IORT. These data support the sterilising effect of IORT on threatened
resection margins. In the presence of IORT, surgery could be downscaled as long
as an R0 resection is obtained, without a decrease in oncological outcome.
These results are promising but IORT was not identified as a single prognostic
factor for local recurrence or survival in this analysis. Despite these promising
results, a recent RCT has not been able to find any benefit for the use of IORT in
primary rectal cancer (Dubois et al. 2011). Studying the quantitative effect of
IORT on oncological outcome remains a challenge and due to the heterogeneous
and complex patient population, the conduction of a prospective trial is difficult.
8 Discussion
Locally advanced rectal cancer treatment has evolved from a surgery alone, to a
multimodality treatment. Despite this shift in treatment strategy, a radical tumour
resection remains the cornerstone of rectal cancer treatment. The implementation
of this multimodality treatment has led to the establishment of multidisciplinary
teams (MDT’s) on a global level. The primary task of the MDT is preoperative
staging and planning the treatment strategy. The implementation of MDT’s is
significantly associated with an increase in R0 resections, decreased recurrent rates
and improved oncological outcome (Burton et al. 2006; Palmer et al. 2011;
MacDermid et al. 2009). Nowadays no single patient with colorectal cancer should
be treated without undergoing meticulous preoperative staging and treatment
planning in a MDT meeting. Due to the treatment complexity of locally advanced,
T4 stage in particular, and recurrent rectal cancer centralisation is the next step in
improving oncological outcome. Complex surgery, in which multivisceral resec-
tions including en bloc resection of gynaecological or urological organs are per-
formed, has improved oncological outcome in experienced hands and
postoperative morbidity and mortality decreases due to improved perioperative
care (de Gramont et al. 2000; Aschele et al. 2011).
The acquisition of pathological complete response (pCR) or downstaging is
associated with improved oncological outcome in T4 rectal cancer (Valentini et al.
2002; Maas et al. 2010, 2011; Martin et al. 2012; Vecchio et al. 2005; Zorcolo
et al. 2012; Theodoropoulos et al. 2002; Wolthuis et al. 2012; de Campos-Lobato
et al. 2011a, b; Habr-Gama et al. 2004, 2008; Tulchinsky et al. 2008) and in
selected patients with a major response to CRT a ‘‘wait-and-see’’ policy or local
excision may even be sufficient.
In order to achieve optimal tumour downstaging and pCR with subsequent
improved oncological outcome, neoadjuvant chemoradiotherapy (CRT) and tumour
restaging are of paramount importance. Intensifying standard CRT in T4 rectal
cancer by; adding oxaliplatin to 5FU-based chemotherapy; or by administration of
an additional cycle of 5-FU based chemotherapy or two cycles of FOLFOX during
the resting period; is associated with increased pCR and even improved oncological
outcome in some series (Fakih et al. 2008; Chau et al. 2006; Rutten et al. 2006;
de Gramont et al. 2000; Martijnse et al. 2012; Habr-Gama et al. 2009; Garcia-
Aguilar et al. 2011). Due to contradictory results from different studies or insufficient
follow-up in the latter studies, a general consensus regarding intensified CRT is not
present. Especially in T4 rectal cancer patients, in whom downstaging can induce a
resectable tumour and mean a chance of cure, intensified CRT may be effective.
Increasing the timing interval between CRT and surgery is significantly
associated with improved tumour response. The optimal timing interval
cannot be considered due to the lack of sufficient evidence, but a timing interval
[7 weeks is associated with improved tumour regression and pCR (Wolthuis
et al. 2012; de Campos-Lobato et al. 2011a, b; Habr-Gama et al. 2008;
Tulchinsky et al. 2008). Further increasing the timing interval beyond 12 weeks in
order to further allow tumour necrosis to occur is save and can be considered in
patients in whom downstaging of the tumour is insufficient after the standard
timing interval of 6 weeks (Habr-Gama et al. 2008).
Overestimating tumour growth, due to the inability to differentiate viable
tumour from fibrosis, and poor specificity regarding nodal status are the main
drawbacks of the current imaging modalities (Vanagunas et al. 2004; Mezzi et al.
2009; Huh et al. 2008; Dickman et al. 2013; Lambregts et al. 2011; Kim et al.
2009; Kalff et al. 2009; Capirci et al. 2007, 2009). Differentiating between pT0-2
and pT3-4 stage rectal cancer after CRT with DW-MRI can be done with sufficient
specificity and positive predictive value, allowing for less extensive, non-multi-
visceral resections, in selected patients (Dresen et al. 2009).
In patients in whom a multivisceral resection (MVR) or sacral resection is
inevitable due to tumour infiltration, oncological outcome is acceptable in case of
an R0 resection. Oncological outcome is even comparable to patients undergoing
standard abdominal resection for rectal cancer (Bebenek et al. 2007). An R1 or R2
resection is associated with worse oncological outcome and a major increase in
local recurrence. Oncological outcome for patients with locally recurrent rectal
cancer is even worse, this means that a radical resection in primary rectal cancer is
the patients’ best chance for cure and an R0 resection should always be the main
goal. Nevertheless, the definition and oncological outcome of a positive margin
has evolved over the last few decades. According to initial TME principles, a distal
tumour margin of 5 cm was required in order to avoid residual tumour deposits.
A recent systematic review concluded that a distal margin\1 cm and even\5 mm
in selected patients is save without jeopardizing local recurrence and survival
(Bujko et al. 2012). The selection criteria for these patients are unclear; well-
differentiated tumours, good response to CRT and short distal intramural tumour
spread might be associated with favourable outcome. A small Korean study, with
definite limitations, has recently published poor survival rates for patients under-
going a MVR in case of a distal margin B2 cm, due to the intramural spread which
is characteristic for T4 tumours (Kang et al. 2012). In T4 rectal cancer patient’s
sphincter preserving surgery is possible in an increasing number of patients, but
patient selection is important.
The initial TNM definition of a positive CRM and R1 resection is 0 mm. Over
the last decade, many pathological and clinical studies have been published
regarding tumour, surgical and patient-related factors influencing the CRM. On a
pathological level, a margin B1 mm is considered positive and has an accurate
correlation with local recurrence, distant metastasis and survival (Quirke et al.
1986; Nagtegaal and Quirke 2008; Smith et al. 2008). The prognostic value of
CRM status nowadays is less clear as the majority of these studies excluded
patients with neoadjuvant treatment. The use of CRT might allow for a narrower
margin. In a recent series of 563 patients with T3/T4 rectal cancer treated with
CRT followed by TME surgery, a CRM B1 was an independent risk factor for
local recurrence and is considered positive (Trakarnsanga et al. 2013). Based on
these results, a margin B1 mm is associated with poor oncological outcome and
therefore not acceptable, even in en era with highly optimised chemoradiotherapy.
Our data show that in patients treated with IORT the extend of the resection
margin becomes less important, as long as a R0 resection is obtained. These data
suggest IORT has a sterilising effect on these high-risk areas.
Poor tumour differentiation, vascular invasion and an ulcerative grow pattern
are associated with positive CRM. The increasing knowledge of pathological
prognostic factors has lead to optimisation of the surgical treatment of rectal
cancer. The introduction of IORT, administered to a high-risk area with threatened
margins, further decreased the need for extensive multivisceral resections.
More recent developments in rectal cancer treatment are the ‘‘wait-and-see’’
policy (Habr-Gama et al. 2004, 2013; Maas et al. 2011; Glynne-Jones and Hughes
2012) and local excision (Lezoche et al. 2012; Pucciarelli et al. 2005, 2013; Perez
et al. 2013) in patients with pCR or major tumour response after CRT. In highly
selected patients with pCR, without signs of nodal involvement, a wait-and-see
policy can be considered. Restaging has to be meticulous and follow-up has to be
intense in order to acquire sufficient oncological outcome. Especially in T4 rectal
cancer, with a high-risk of nodal involvement, and a poor association between pCR
and pCR, following a certain approach should be done with caution.
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Do T3 Rectal Cancers Always Need
Radiochemotherapy?
Rob Glynne-Jones
Abstract
The limitation of the traditional method of stratifying patients with rectal cancer
for prognosis using magnetic resonance imaging (MRI) and computerised
tomography (CT)—TNM staging—is that cT3 tumors comprise the vast majority
of rectal cancers. There is a wide variability in outcomes for cT3. Despite this
observation, many still advocate routine short course preoperative radiotherapy
(SCPRT) or chemoradiation (CRT) for all patients staged as cT3N0 regardless of
tumour location, proximity to other structures or extent, despite the fact that
advances in imaging with MRI now offer the ability to predict potential outcomes
in terms of the risk of local and metastatic recurrence for the individual.
Preoperative CRT is designed to reduce local recurrence. The majority of local
recurrences historically reflected inadequate quality of the mesorectal resection.
Currently, optimal quality-controlled surgery in terms of total mesorectal
excision (TME) in the trial setting can be associated with much lower local
recurrence rates of less than 10 % whether patients receive radiotherapy or not.
Because of the high risk of metastatic disease in selected patients, integrating
more active chemotherapy is now attractive. Chemoradiotherapy (CRT) achieves
shrinkage and sometimes eradication of tumour—i.e. a pathological complete
Conflict of interest statements: Rob Glynne-Jones has received honoraria for lectures and
advisory boards, and has been supported in attending international meetings in the last 5 years by
Eli Lilley, Merck, Pfizer, Sanofi-Aventis and Roche. He has also in the past received unrestricted
grants for research from Merck-Serono, Sanofi-Aventis and Roche. He is principal investigator of
a randomised phase II neoadjuvant chemotherapy study in the UK called ‘BACCHUS’
R. Glynne-Jones (&)
Radiotherapy Department, Mount Vernon Centre for Cancer Treatment, Rickmansworth Road,
Northwood, London, Middlesex HA6 2RN, UK
96 R. Glynne-Jones
response (pCR), and reduces local recurrence, but has no impact on overall
survival. CRT also increases surgical morbidity and impacts on anorectal, urinary
and sexual function with an increased risk of second malignancies. Hence, the
predominant aims of CRT have been to shrink/downstage a tumour to allow an R0
resection to be performed, or to increase the chances of performing sphincter-
sparing surgery. However, it remains unclear why shrinkage/downstaging is
meaningful to a patient unless the tumour is initially borderline resectable or
unresectable (i.e. the CRM is threatened) or the aim is to perform a lesser
operation (i.e. sphincter-sparing or local excision) or for organ-sparing, i.e. to
avoid surgery altogether. If it is important to shrink the cancer—ie there is a
predicted threat to the CRM, then CRT is currently the treatment of choice. If the
cancer is resectable and the aim is simply to lower the risk of local recurrence and
preoperative CRT does not impact on survival, can CRT be omitted in selected
cases? The answer is yes—with the proviso that we are using good quality MRI
and the surgeon is performing good quality TME surgery within the mesorectal
plane.
1 Introduction
Preoperative chemoradiation (CRT) has been the standard of care for patients with
clinical stage II and III rectal cancer because of the low rates of local recurrence
achieved, acceptable levels of toxicity, and the potential for sphincter preservation
compared with postoperative chemoradiation. In contrast, parts of Northern Eur-
ope have adopted a blanket approach to short course pre-operative radiotherapy
(SCPRT) using 25 Gy over 5 days followed by immediate surgery with the pre-
dominant aim of reducing the risk of pelvic recurrence. This strategy of preop-
erative CRT has been extrapolated from postoperative studies, mainly performed
in the US which showed a clear benefit for chemoradiation in terms of local
recurrence and survival. The GITSG 7175 trial randomly assigned patients to
surgery alone, adjuvant chemotherapy, adjuvant radiation therapy or combined
adjuvant chemotherapy and radiation. Since then, no large US phase III trial has
included a surgery-alone arm.
However, even with the advantage of accurate histopathogical staging
unmodified by neoadjuvant treatment, not all patients benefit from postoperative
chemoradiation. Data on 3791 patients within phase III US trials examining
postoperative adjuvant treatment in rectal cancer prior to the TME era (NCCTG
794751, NCCTG 864751, and US GI Intergroup 0114) (Douglas et al. 1986;
O’Connell et al. 1994; Tepper et al. 2002) using pooled analyses show a more
complex T and N combined classification can predict outcomes and risk of
recurrence: low (T1/2N0), intermediate (T1/2N1, T3N0), moderately high
(T1/2N2, T3N1, T4N0) and high (T3N2, T4N1/2). In 1060 patients with pT3N0
tumours classified as intermediate-risk, low rates of local recurrence were
Do T3 Rectal Cancers Always Need Radiochemotherapy? 97
associated recurrence (Gunderson 2004) and there was no improvement in disease-

free or overall survival when radiation was added to chemotherapy postopera-
tively. It should be noted that the majority of patients where radiation was omitted,
were treated with surgery and chemotherapy rather than surgery alone. This data
led to several prospective studies aimed at determining whether patients with T1/
2N1 and T3N0 disease could be treated with surgery and chemotherapy, but
without radiation therapy (NSABP R02) (Wolmark et al. 2000).
The low risk of local recurrence weakens the view that adjuvant radiotherapy
always offers added value to radical surgery and hence is a routine requirement for
patients with intermediate-risk tumours (T1/2N1 or T3N0). Many authors have
questioned whether selected patients with T1-2, N1-2 or T3N0 lesions have a
sufficiently low risk of local and distant relapse with surgery alone, that they could
avoid radiotherapy (Willett 1999).
Recent improvements in the quality of surgery, MRI and pathogical reporting of
the operative specimen, also mean the time has come to question both these
approaches (CRT or SCPRT).
The majority of the rectum lies below the peritoneal reflection and has no
serosa, allowing tumour growth to extend deeply into peri-rectal fat. Historically,
high rates of local pelvic recurrence following radical surgery were described.
However, surgical practice has evolved, and the technique of meticulous meso-
rectal dissection where the surgeon removes all of the surrounding mesorectal fat
using sharp dissection in a neat anatomical package is associated with much lower
rates of local recurrence and improved survival. With expert total mesorectal
excision (TME) consistently performed in specialist centres, metastatic disease is
now the predominant problem (Cecil et al. 2004), reflecting the likely presence of
distant micrometastases at diagnosis, rather than inadequate surgery. It is true that
old meta-analyses have shown that preoperative adjuvant radiotherapy reduces
local recurrence rates by almost 50 % and overall mortality by 2–10 %. However,
the local recurrence rates were very high in the region of 15–30 %, and impor-
tantly the trials included in these meta-analyses all use patient data from long
before the introduction of TME surgery, which questions their current relevance.
Conventional therapies for patients with locally advanced rectal cancer appear
to have reached a therapeutic plateau, as none of the recent phase III studies
investigating the use of radiotherapy or chemoradiation have improved overall
survival (OS). This may also reflect the difficulty of performing large scale mul-
ticentre studies, where the quality assurance is inevitably more variable.
In addition to the risk of a local recurrence, 10–40 % of patients require
extensive surgical procedures, which lead to a permanent stoma. Surgeons will
strive to preserve the anal sphincter, but it has been reported that in the United
Kingdom that there is a wide variation in the proportion of patients undergoing an
abdomino-perineal excision of the rectum (APER) (Morris et al. 2008)—which
may either reflect skills and training or the variability in the use of radiotherapy
and concerns regarding function after the combination of preoperative radiother-
apy and ultra low anterior resection.
98 R. Glynne-Jones
In general, we have focussed on avoiding local recurrence and facilitating

sphincter sparing in our phase III trials, hoping that improvements in survival
would automatically follow if the primary endpoints were achieved. Sadly this has
not been the case. Trials suggest that in resectable cancers, where the preoperative
MRI predicts the circumferential resection margin (CRM) is not potentially
involved, then SCPRT and CRT are equivalent in terms of outcomes such as local
recurrence, DFS and OS (Bujko et al. 2006; Ngan 2010). However, none of the
trials of radiotherapy alone (Peeters et al. 2007; Sebag-Montefiore et al. 2009) or
chemoradiation published in the last decade have impacted on DFS or OS (Sauer
et al. 2004; Bosset et al. 2006; Gerard et al. 2006; Roh et al. 2009). Local
recurrence is now sufficiently low that (unlike in breast cancer) it fails to impact on
overall survival. Alternatively, either the populations in these trials are too low risk
to benefit or the inadequacy of the systemic therapy within current chemoradiation
schedules may help to explain this finding.
Fluoropyrimidine-based CRT does not employ systemic doses of chemotherapy
and delays the integration of adjuvant chemotherapy. Enthusiasm has been stim-
ulated by the efficacy of oxaliplatin in dealing with distant micro-metastases in the
adjuvant setting in colon cancer (Kuebler et al. 2007; Andre et al. 2009). However,
results of trials using oxaliplatin as a radiosensitizer alone have not been shown to
change early outcome measures rate (Aschele et al. 2011; Gerard et al. 2010;
Gerard et al. 2012; Roh et al. 2011; Rödel et al. 2012; Schmoll et al. 2013) and
toxicity is substantial. The current therapeutic challenge is to optimize all our
available non-operative strategies by effective cytotoxic chemotherapy at systemic
doses. Incorporating new agents into current therapeutic regimens to reduce the
burden of metastases is a priority for research.
In contrast, for more locally advanced cases, where the CRM is breached or
threatened according to the MRI, the integration of more active chemotherapy and
biological agents into chemoradiation is an attractive strategy. There is an obvious
need to improve response to downsize the tumour to achieve a curative resection, and
there is a high risk of metastases. In patients where even technically optimised surgery
is unlikely to achieve a curative resection—5FU-based chemoradiation has been
shown to have a statistically significant effect on resectability and relapse free survival
(Frykholm et al. 2001; Braendengen et al. 2008). However, these trials have been
underpowered to show a benefit in terms of overall survival. At the time of diagnosis
between 20 and 25 % of patients with rectal cancer will be found to have overt
metastatic disease, and a further 30–40 % will subsequently develop metastases.
However, the rationale for CRT has been overcalled because of inflated
assessments of what is ‘locally advanced disease’, which is facilitated by ultra-
sound-based rather than MRI-based staging. Hence all cT3 are often considered
LARC. There is also a tendency to overstage patients radiologically if the CRM is
predicted to be threatened by 2 mm or even 3 mm where 1 mm is sufficient, and
the clinical stage migration of cT2 to cT3a engendered by a traditionally cautious
approach by radiologists. The delivery of CRT is perpetuated by the reluctance of
surgeons to risk a positive margin or the possibility of local recurrence without the
safety net of pelvic radiotherapy.
2 Imaging
Initial staging with MRI now offers a high degree of accuracy in predicting per-
itoneal involvement in upper rectal cancer above the peritoneal reflection, and the
depth of extramural spread and CRM involvement in mid and low rectal cancers.
In low rectal cancers, the mesorectum thins markedly at the level of levator ani—
especially anteriorly in relation to prostate, and predicting potential CRM
involvement becomes more difficult.
Recent advances in imaging particularly in terms of the precision available with
MRI offer the ability to predict potential outcomes in terms of the risk of local and
metastatic recurrence from a range of structural and other features (such as
extramural venous invasion, nodal involvement inside and outside the mesorectal
fascia, and depth of penetration through the muscularis propria).
The risk of local (pelvic) relapse reflects the degree of tumour extension beyond
the rectal wall and to nodal spread. T3c and T3d rectal cancers have markedly
worse progression-free and cancer-specific survival compared to T3a and T3b
(Pollheimer et al. 2010). This extension can be accurately assessed by MRI within
0.5 mm of tolerance (Mercury 2007).
High spatial resolution coronal imaging also defines the levator muscles, the
sphincter complex and intersphincteric plane with sufficient accuracy to allow us
to plan the most appropriate plane of surgery (standard TME surgery, inter-
sphincteric resection, APER, or Extralevator abdominoperineal resection, CRT
and local excision, TEM). If we can make decisions like this with widely different
impacts on QOL, based on MRI appearenaces, then we should also be taking into
account the features which predict the risk of local versus metastatic disease.
3 Local Recurrence
The majority of local recurrences historically reflected inadequate mesorectal

resection (Syk et al. 2008), which is a common finding on postoperative MRI after
partial mesorectal excision (Bondeven et al. 2013). Currently, optimal quality-
controlled surgery in terms of TME in the trial setting can be associated with local
recurrence rates of less than 10 % whether patients receive radiotherapy or not
(Quirke et al. 2009). Factors which compromise the performance of good quality
TME are well recognised and include patient and disease—related aspects and the
surgeon’s case volume (Garlipp et al. 2012).
One reason that local recurrence occurs after potentially curative resection is
explained by the work of Quirke and colleagues. The presence of microscopic
tumour cells within one millimetre of the radial or CRM is clearly demonstrated to
be associated with a very high rate of local recurrence and poor survival. High-
resolution pelvic MRI using surface phased array coils is now routinely applied in
the UK and much of Europe as a preoperative staging and selection tool for the use
of neoadjuvant radiation. MRI strongly predicts the likelihood of involvement of
100 R. Glynne-Jones
the CRM particularly in the mid-rectum, involvement of the levators in the low
rectum and the extramural depth of invasion. The risks of local failure are much
lower for cancers in the upper rectum. This MRI preoperative assessment can
identify patients at risk of the surgeon being unable to achieve an R0 resection
(MERCURY 2007). The accuracy of predicting tumour extent beyond the mus-
cularis propria was within 0.5 mm tolerance in the mid/upper rectum, and suggests
MRI can accurately predict ultimate outcome. MRI can also accurately measure
the distance between the anorectal junction and/or and the distal part of the tumour
and the luminal length of the tumour. However, MRI, multisclice CT and ERUS
all remain inadequately accurate to detect involved or uninvolved lymph nodes
despite specific imaging features such as size C8 mm/round/heterogenous/irreg-
ular in nodal border. Current studies have also failed to confirm that FDG-PET has
improved the accuracy of nodal staging.
Location of the primary tumor (anterior and low confer more risk) and site
within the rectum (upper, middle and lower) is also important. MRI is increasingly
influencing both the rationale for neoadjuvant radiotherapy, and the design of
current trials. Other pathological factors which increase the risk of recurrence
include T4 tumours, nodal involvement, extramural vascular invasion, perineural
invasion and extranodal deposits (Kusters et al. 2010). Some of these can be
identified also on preoperative MRI. Other recognised clinical, individual or social
factors that influence the development of recurrence include surgeon variability,
grade and sex, and BMI.
However, our sophistication in making decisions and our categorisation of risk
for these tumours has not kept pace, since about 65–70 % of rectal cancers are
classified as locally advanced rectal cancer (LARC).
The most recent update of the Dutch TME trial in rectal cancer (Van Gijn et al.
2011) reported a 10 year local recurrence cumulative incidence of 5 % in the
group assigned to short course preoperative radiotherapy (SCPRT) (5X5 Gy)
versus 11 % in the surgery alone group (P \ 0.001). This 50 % reduction in local
recurrence is maintained long-term, and in a non-protocolised subset analysis of
435 TNM stage III patients with a negative CRM, i.e. 23 % of the total population,
preoperative radiotherapy appears to improve 10 year OS from 40 to 50 %
(p = 0.032). However, this finding does not take into account the quality of the
mesorectal excision. Node positive patients with defects in the mesorectum are
likely to be at high risk of local recurrence, whereas complete mesorectal excision
will lead to local recurrence overall in the range 7–8 % (Quirke et al. 2009).
Yet, for all groups the results of the Dutch trial do not show a difference in OS
(Van Gijn et al. 2011), which implies that either the result has arisen by chance as
a type I error or some population groups within the trial (? node negative) are
disadvantaged in terms of survival by radiotherapy.
4 Late Effects of Radiotherapy
There are significant late-effects from pelvic radiotherapy on anorectal, urinary

and sexual function (Peeters et al. 2005; Lange et al. 2007), and a increased risk of
second malignancies after 10 years (Birgisson et al. 2005; Van Gijn et al. 2011).
Small bowel tolerance is a dose-limiting factor. A Cochrane review (Pachler et al.
2012) reported that CRT negatively affect the patient’s quality of life in rectal
cancer and prompts the need for larger and better designed future prospective
studies to examine whether a colostomy is associated with worse QOL.
Effects on sexual functioning (Marijnen et al. 2005), urinary incontinence
(Pollack et al. 2006), faecal incontinence (Lange et al. 2007), have been docu-
mented after SCPRT. These complications depend on the size of the radiation field,
shielding, the overall treatment time, the fraction size and total dose. Mature results
of the Swedish Rectal Cancer Trial confirm problems after RT particularly bowel
obstruction and abdominal pain (Birgisson et al. 2006). There are also unexplained
late cardiac effects (Pollack et al. 2006) and insufficiency fractures in the pelvis
(Herman et al. 2009). In addition, in the Dutch TME study deaths from second
malignancy were higher in the RT arm than the TME alone arm (13.7 vs. 9.4 %)
(Van Gijn et al. 2011). Given this finding is seen after only 11.6 years follow-up—
this difference may widen further after 15–25 years. As follow-up in the majority of
studies is generally short, the risks of these late effects are likely to be underesti-
mated. It is unclear how much these effects are highlighted in the consent process
for radiotherapy. In contrast to radiotherapy, the side effects of chemotherapy are
usually short-term, although the neuropathy from oxaliplatin may be permanent.
5 Postoperative Adjuvant Chemotherapy
Because of the high risk of metastatic disease, integrating more active chemo-
therapy is attractive, and enthusiasm has been stimulated by the efficacy of oxa-
liplatin in dealing with distant micro-metastases in the adjuvant setting in colon
cancer (Kuebler et al. 2007; Andre et al. 2009) although patients with rectal cancer
were excluded as ineligible. The possible options for systemic chemotherapy
option have expanded, but postoperative adjuvant chemotherapy remains only
partially effective, and toxicity (particularly with oxaliplatin) is substantial. The
current therapeutic challenge is to optimise all our available non-operative strat-
egies by effective cytotoxic chemotherapy at systemic doses. Incorporating new
agents into current therapeutic regimens to reduce the burden of metastases is a
priority for research.
Compliance to postoperative chemotherapy following chemoradiation is poor.
Neoadjuvant chemotherapy (NACT) offers an alternative strategy. At least
20–25 % of patients in whom chemotherapy with 5FU might be considered may
not be sufficiently fit or decline treatment (Sauer et al. 2004; Bosset et al. 2006;
Gerard et al. 2006). Compliance to additional postoperative oxaliplatin appears
even worse (Rödel et al. 2007).
102 R. Glynne-Jones
6 Does Chemotherapy Impact on Local Recurrence?
Systemic chemotherapy has been shown to enhance local control with radiation
(Bosset et al. 2006; Bosset et al. 2013; Gerard et al. 2006) after radiation (Bosset
et al. 2006; Bosset et al. 2013) or without radiation (Akasu et al. 2006).
In a study of patients with curatively resected stage III rectal cancer, who
underwent TME with selective lateral pelvic lymphadenectomy, patients were
randomised postoperatively to receive either oral uracil-tegafur (400 mg/m2
tegafur per day) for 12 months or no treatment. The rates of overall local recur-
rence were 5.8 % (8/139) for the uracil–tegafur group and 9.6 % (13/135) for the
surgery-alone group (Akasu et al. 2006). If radiation therapy does not improve
survival and systemic chemotherapy enhances local control with or without
radiation, and surgical salvage is possible in 50 % if sequential MRIs are per-
formed, then radiation may not always be required. Currently, although local
recurrence does increase the risk of distant metastases, local recurrence is reduced
to single figures and salvage surgery is effective in more than 50 %.
A recent small prospective trial at Memorial Sloan-Kettering Cancer Center
(Schrag et al. 2014) in 32 rectal cancer patients (22 with clinically staged node-
positive disease) evaluated the replacement of standard preoperative fluorouracil-
based chemoradiation with neoadjuvant FOLFOX (six cycles) and bevacizumab
(four cycles) and no radiation. In the 30 patients who completed this neoadjuvant
therapy and had a curative TME resection, eight patients (27 %) achieved a
pathologic complete response (PCR), and 0/32 patients suffered a local recurrence.
7 Are There Patients for Whom Neoadjuvant

Chemotherapy Is an Alternative?
There is clearly a high risk of metastatic disease in locally advanced rectal cancer,
yet systemically active doses of chemotherapy are not delivered in CRT schedules,
and compliance to postoperative adjuvant chemotherapy is generally poor.
Extrapolating from positive studies in colon cancer, many oncologists are
encouraged to use a FOLFOX regimen as postoperative chemotherapy for stage III
patients after chemoradiation. The optimal number of cycles of such treatment has
not been determined. Hence, some groups have extrapolated even further and
added chemotherapy either prior to CRT, when compliance to chemotherapy is
high (Fernandez-Martos et al. 2010; Fernandez-Martos et al. 2011), or following
chemoradiation to increase the response rate (Garcia-Aguilar et al. 2011). Some
groups have suggested that this strategy leads to excellent long-term results, but
raise concerns for a high early death rate (Chua et al. 2010). Others have proposed
NACT alone without radiation (Glynne-Jones et al. 2012).
8 The Importance of Good Surgery
Historically, the majority of local recurrences reflected inadequate mesorectal

resection (Syk et al. 2008) as in a series of 2,315 patients operated on by surgeons
trained to perform TME; on MRI there was evidence of residual mesorectal tissue
in 50/99 local recurrences. Also, unintentional persistent residual mesorectal tissue
(defined as mesorectum above the level of the anastomosis) perpendicular to the
bowel was observed in a study on postoperative MRI in 54 (40 %) of 136
patients—particularly after partial mesorectal excision in upper rectal cancers
(Bondeven et al. 2013). In the Dutch TME study only mobile tumours were
selected as eligible, and the local recurrence rates appear too high to validate the
claim that the whole series represents ‘standardised TME surgery’.
Some surgical authors have stressed the importance of careful dissection par-
ticularly in the posterior aspect of a TME specimen as there is a higher prevalence
of lymph nodes in this position (Perez et al. 2008), and it is easy to come out of the
appropriate surgical plane. It is acknowledged that the quality of TME can be
influenced both by the patient’s age, morphology and morbidity as well as disease-
related factors (site, position and stage) as well as the surgeon’s case volume
(Garlipp et al. 2012).
The quality of radical surgery has an independent prognostic factor, which may
impact on long-term outcomes. Hermanek, Quirke and Nagtegaal have promoted
the importance of assessing the quality of the mesorectum in the surgical specimen
and recording by means of a photograph. This classification derives from the
original findings from Hermanek and Quirke with three grades based on the
completeness of the removal of the mesorectum.
A TME specimen ideally should have a smooth surface, without incisions or
tearing, as an indication of successful surgery. ‘Coning’ is a tendency for the
surgeon to cut inwards towards the central tube of the rectum during distal dis-
section, rather than staying outside the visceral mesorectal fascia, which gives the
specimen a tapered, conical appearance. This observed feature is an indication of
suboptimal surgical quality (Hermanek and Heald Hermanek and Heald 2004).
Two trials—the CLASSICC study of the Medical Research Council in the
United Kingdom and the Dutch TME trial have originally defined a protocol to
assess the quality of surgery. This classification has been utilised in the MER-
CURY study and the CRO7 study (Quirke et al. 2009). Multivariate analysis will
need to be validated in future randomised studies.
9 Can Radiotherapy Be Omitted?
Several groups have explored omitting radiotherapy when MRI suggests the
tumour is easily resectable. This omission does not appear to have increased the
local recurrence rate (Taylor et al. 2011; Frasson et al. 2011; Mathis et al. 2012). It
seems clear that the surgeon needs to expect to be able to perform an optimal plane
104 R. Glynne-Jones
Table 1 Histopathological grading of the quality and completeness of the mesorectum in a total
mesorectal excision specimen
Mesorectum Defects Coning CRM
Complete Intact, smooth Not defects deeper None Smooth,
than 5 mm regular
Nearly complete Moderate bulk, No visible Moderate Irregular
but irregular muscularis propria
Incomplete Little bulk and Down to muscularis Moderate– Irregular
very irregular propria marked
of surgery i.e. to achieve a surgical specimen with an intact mesorectum displaying

only minor irregularities over a smooth mesorectal surface; with no defect deeper
than 5 mm; with no coning; and with a smooth CRM on slicing (Quirke et al.
2009) (Table 1).
Three feasibility/retrospective studies of NACT alone without radiation (Cercek
et al. 2010; Ishii et al. 2010; Fernandez-Martos et al. 2012; Schrag et al. 2014)
used FOLFOX plus/minus bevacizumab (Table 2). The pCR rate after chemo-
therapy alone varied from to 7–35 %, but as small non-randomised studies are
unable to show an impact on metastatic disease. The studies are too small and not
sufficiently mature to assess the local recurrence rate. However, the proof of
principle has given rise to many current studies exploring NACT (Table 3).
10 Are There Clearly Distinguishable Groups Who Do

not Need RT?
Accurate information on primary tumour local extension, precise location,

potential nodal-stage, potential CRM involvement and extra-mural venous inva-
sion is essential for defining the optimum treatment strategy on an individual basis.
Currently, the definition of locally advanced rectal cancer is variable from unit to
unit. Currently, in the UK many MDTS categorise patients into ‘The good, the bad
and the ugly’, which allows definition of three different settings where preopera-
tive neoadjuvant treatment may or may not be required. For clinically unresectable
cancers or where MRI shows a threatened/breached CRM (10–15 % of cases), or
in cancers which require surgical resection beyond the conventional TME plane,
then radiation as a component of CRT is clearly necessary. In contrast, early cT1/
T2 tumours are not usually treated with radiotherapy because of the low risk of
local recurrence. The problem with these above systems is that the intermediate
risk represents a wide spectrum, with variable behaviour and should be defined
more accurately with further risk groupings. Since in the trials about 50 % of
patients are low rectal cancer within 5 cms of the anal margin, probably more than
50 % are stage 2 and up to 30 % are T2 initially. A T3 subclassification has been
proposed in 2001 by Merkel from the Erlangen group, who suggested the
Table 2 Phase I/II studies of neoadjuvant chemotherapy without radiation
No of Eligibility Induction Toxicity PCR** T R0 Late outcome
pts* Mic***
Chemotherapy
Ishii 2010 26 cT3/T4 N0–2 Irinotecan (80 mg/m2), Not stated 1/15 (7 %) Not stated Not stated 5 year RFS
FUFA days 1, 8, and 74 % OS 84 %
15 for 4 weeks
Schrag 31 Clinical stage II–III FOLFOXbevacizumab 2 pts withdrawn 8/29 (27 %) Not stated 29/29 No data
2010 (but not T4) (6 cycles bev 1–4) (angina arrhythmia) (100 %)
Cercek 20 RT contraindicated 6 pts FOLFOX 14 pts Not stated 7/20 (35 %) Not stated Not stated No data
2010 or presence of FOLFOX + Bev 2/6 (33 %)
synchronous rectal cancer
Do T3 Rectal Cancers Always Need Radiochemotherapy?
metastases without
metastases
* number entering study
** number having had surgery
*** using regression grading not yp
105
Table 3 Trials of neoadjuvant chemotherapy in progress
106
Study (Reference) Pre-operative treatment Entry Criteria Status RT/CRT Comments

Phase III trials
GEMCAD Capecitabine/oxaliplatin + bevacizumab 3 MRI defined Recruiting Selective CRT according to Primary endpoint:
(Fernandez-Martos cycles then capox = total 4 cycles entry response response rate
2010) (RECIST)
41 patients
RAPIDO SCPRT (5 9 5 Gy) followed by Oxaliplatin/ MRI defined Yet to open CRT 50.4 Gy/28# with Primary endpoint:
Phase III capectabine 6 cycles versus entry capecitabine 3 year DFS
EudraCT number 2010- Control Capecitabine +CRT
023957-12 885 patients
Polish study EGBRJ SCPRT (5 9 5 Gy) followed by FOLFOX Unresectable Recruiting SCPRT versus CRT Primary endpoint: the
0109 (3 cycles) then surgery versus rectal cancer rate of R0 resection
NCT00833131 Versus 5FU/capecitabine CRT (50 Gy) as
540 patients control
Randomised phase II trials
BACCHUS FOLFOX +bevacizumab for 5 courses, then MRI defined Yet to open SCPRT or CRT only for Primary endpoint:
NCRI Randomised phase final FOLFOX then surgery entry progression/lack of response pCR
II Versus FOLFOXIRI bevacizumab for 5
60 patients courses, then final FOLFOXIRI then surgery
randomised phase II FOLFIRINOX 4–8 weeks then reassess/ MRI defined ?started If good cap 50 Gy versus Primary endpoint:
GRECCAR 4 randomised according to response entry surgery %R0
150 patients If good cap 50 Gy versus surgery If poor cap 50 Gy versus
If poor cap 50 Gy versus cap 60 Gy cap 60 Gy
(continued)
R. Glynne-Jones
Table 3 (continued)
Study (Reference) Pre-operative treatment Entry Criteria Status RT/CRT Comments
French phase II FOLFOX +bevacizumab Not MRI Ongoing Primary endpoint:
NCT00865189 for 6 courses then CRT(with bevacizumab/ not pCR
91 patients 5FU) versus CRT alone recruiting
Chinese Randomised FOLFOX (4 cycles) then surgery versus Not MRI Recruiting Primary endpoint
phase II FOLFOX CRT 3 year DFS
NCT01211210 Versus 5FU CRT (control)
495 patients
SWOG study Multiple regimens T4 rectal Ongoing CRT with cape Primary endpoint:
NCT00070434 cancer not response
Up to 65 patients recruiting
107
108 R. Glynne-Jones
subdivision of T3 into T3a \ 5 mm and T3b [ 5 mm (Merkel et al. 2001). The

Mercury Study Group extended this subclassification further into four groups: ‘a’
(\1 mm outside the wall), ‘b’ (1–5 mm), ‘c’ (5–15 mm) and ‘d’ ([15 mm)
(MERCURY 2007; Smith and Brown 2008). Distinction between cT2 and cT3a
remains difficult, but may be less relevant to outcome because the Erlangen data
suggests that prognosis is not significantly different for these two groups. MRI can
define macroscopic extramural vascular invasion (EMVI), which occurs in about
40 % of patients (Smith et al. 2008). This feature predicts for systemic failure with
good concordance between MRI EMVI and eventual pathology EMVI prognostic
outcome (Dirschmid et al. 1996; Sternberg et al. 2002), suggesting that patients
with macroscopic EMVI have only a 30 % 3 year disease free survival.
A structure which defines three risk groups within the broad intermediate risk
category, with low risk of local recurrence/low risk of metastatic disease, low risk
of local recurrence/high risk of metastatic disease, high risk of local recurrence/
low risk of metastatic disease, high risk of local recurrence/high risk of metastatic
disease is therefore proposed (Table 4).
Chemotherapy prior to CRT or SCPRT does not compromise the delivery CRT,
but has not increased pCR rates, R0-resection rate, improved DFS or reduced
metastases. There is significant late morbidity from pelvic radiotherapy and a
doubling of the risk of second malignancy. Hence, NACT alone without radio-
therapy could be explored compared with SCPRT or CRT in selected patients with
resectable rectal cancer showing adverse features (extramural vascular invasion
etc.) in a future research programme.
11 Biomarkers
There has also been a recent focus on predictive and prognostic molecular bio-
markers from the longstanding orthodoxy of carcinoembryonic antigen (CEA)
through Kras and Nras mutations, to insight regarding phosphoinositide 3-kinase
(PI3 K) mutations and wild type p53. Although none of these novel strategies have
been validated, they allow us to hope that we can select and stratify patients
according to their different molecular and imaging patterns. This knowledge select
patients for certain treatments and may also spare other patients from treatment,
which is unlikely to be effective. Criteria are therefore emerging, which suggest a
possible future role for individually tailored therapy.
12 The Future
A multi-institutional phase II/III randomised, prospective trial (NCCTG-N1048,

NCT01515787) currently compares neoadjuvant FOLFOX with selective use of
chemoradiation. The study randomises rectal cancer patients with low risk cT1/
2N1, cT3N0 and cT3N1 disease, with lesions located 5–12 cm from the anal verge
Table 4 Proposed mid rectal cancer risk categorisation based on MRI and clinical risk factors
Low risk Intermediate risk High risk
Low risk local Low risk local recurrence/ Moderate risk of local recurrence/ High risk of local recurrence/higher High risk local recurrence/
recurrence/low risk moderate risk metastases high risk metastases risk metastases high risk metastases
metastases
MRI cT2/T3a/ MRI cT3b [ 4 mm extension MRI cT3b [ 4 mm MRI cT3d, T4a (resectable) MRI cTany extension into
T3b \ 4 mm into muscularis propria cT3c, cN2, V2 CRM not threatened (predicted muscularis propria, T4b
extension into CRM not threatened (predicted CRM not threatened (predicted C2 mm) CRM breached or threatened
muscularis propria C2 mm) C2 mm) CT M0 (predicted \1 mm)
CRM not threatened cN1, CT M0 CT M0
(predicted C2 mm) CT M0 ? Mucinous
cN0
CT M0
Clinical factors Obesity
Male/with anterior tumours
Narrow pelvis
Previous pelvic surgery
Large bulky tumour
Sepsis/fistula/perforation
NICE guidelines low UK Nice guidelines intermediate risk NICE guidelines high risk a
risk +, but does not any cT3b or greater, in which the potential surgical margin is not threatened or threatened (\1 mm) or
include T3b \ 4 mm any suspicious lymph node not threatening the surgical resection margin or breached resection margin or
the presence of extramural vascular invasion low tumours encroaching
onto inter-sphincteric plane
or levator involvement
NICE Nice guidelines (UK) NICE
do not give RT SCPRT or CRT CRT recommended
Potential MRI directed recommendations
No requirement for If surgeon convinced able to SCPRT or CRT depending on SCPRT or CRT depending on Requires Chemoradiation
preop radiotherapy perform R0 resection and good whether shrinkage of tumour required whether shrinkage of tumour required (CRT)
Immediate surgery quality in mesorectal plane or Neoadjuvant chemotherapy alone or Neoadjuvant chemotherapy alone
could omit RT
109
110 R. Glynne-Jones
and amenable to sphincter-preserving surgery, to either the standard of preoper-

ative 5-fluorouracil /capecitabine-based chemoradiation, followed by TME and
FOLFOX (eight cycles) or to omot radiation and receive neoadjuvant FOLFOX
(six cycles). If clinical response ([20 %) is observed at restaging, then patients
undergo surgical resection followed by adjuvant FOLFOX (six cycles). Only those
patients with histologically CRM undergo chemoradiation, because of their
increased risk of local recurrence. In contrast, if clinical response is \20 %,
patients are administered standard combined modality therapy followed by surgery
and adjuvant FOLFOX (two additional cycles).
Similarly in the UK, the ongoing BACCHUS randomised phase II study
(registered at ClinicalTrials.gov as NCT01650428) evaluates the efficacy of
FOLFOXIRI and bevacizumab compared to FOLFOX and bevacizumab omitting
radiotherapy. The study aims to examine whether intensive NACT will deliver
pathological responses of the primary tumour at least equivalent to CRT as well as
reducing the risk of local recurrence and metastasis. If this triple regimen is
feasible, effective and tolerable, it would be suitable for testing as the novel arm
against the current standards of SCPRT (5 9 5 Gy) and/or 5FU-based CRT in a
future randomised phase III trial.
13 Conclusion
To achieve pelvic control the surgeon needs an R0 resection. Hence, preoperative

CRT is an important component of the multimodality treatment of rectal cancer if
the CRM is threatened. Pelvic failure gives rise to awful and debilitating symp-
toms, including intractable pain and intestinal obstruction, and a very poor quality
of life. However, for less advanced cases, an R0 resection may be more
straightforward, and the risk of metastatic disease now predominates over the risk
of local recurrence. It is difficult to understand how monolithic approaches,
established by studies conducted more than a decade ago, with none of the modern
amenities currently available still drive some to apply the same schedule of
SCPRT or CRT for all patients with cT3No resectable rectal cancer irrespective of
tumour position, extent and treatment goal (Sebag-Montefiore et al. 2009).
Modern MRI can define patients with a high risk of metastases (EMVI, T3c and
T3d)—particularly in the mid rectum. This high risk of metastatic disease means
that the use of chemotherapy at systemically-effective doses would seem essential
if we are to improve survival in patients with locally advanced rectal cancer. The
use of chemoradiation has compromised the integration of full systemic doses and
the uptake of postoperative chemotherapy. In contrast NACT has been shown to
allow full delivery of chemotherapy in systemic doses and an appropriate intensity
without compromising surgery.
The current term of ‘locally advanced rectal cancer’ or ‘T3 /T4’ rectal cancer
includes a large proportion of patients who either do not need radiotherapy or
equally are not going to benefit in a significant way from chemotherapy, using
analogies of the benefit of chemotherapy in low risk stage II colon cancer. We

need a new description /term for locally advanced rectal cancer, which provides an
effective risk categorisation. What is the predominant risk? Local recurrence or
metastatic disease? A proposal is tabled in this chapter.
All patients with cT3 rectal cancer should be discussed in a well functioning
MDT. Patients should be categorised according to clinical stage TNM, site in the
rectum, quadrant, and accurate localization in respect to the mesorectal fascia and
levators. Other factors, such as cN-stage, and vascular and nerve invasion are
important histologically although the prediction of nodal involvement is poor at
present and only macroscopic/gross vascular invasion can be imaged at present.
So, can we not do without radiotherapy if the CRM is not threatened? This may
be more easily accepted in the upper and mid rectal cancers than in low cancers.
But if we still cling to the notion that RT is needed in all cases in the modern TME
era, have we simply turned full circle and are back to advocating preoperative
radiotherapy to compensate for poor surgical technique? Or can we accept that if
we see the surgeon performing good quality surgery in 80–90 % of his specimens
within the mesorectal plane and the MRI suggests clear margins, that the benefit
from CRT is marginal.
112 R. Glynne-Jones
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Quality of Life After Surgery for Rectal
Cancer
Teresa Gavaruzzi, Francesca Giandomenico, Paola Del Bianco,
Lorella Lotto, Alessandro Perin and Salvatore Pucciarelli
Abstract
Patients’ health-related quality of life (HRQoL) is now considered a relevant
clinical outcome. This study systematically reviewed articles published in the
last 5 years, focusing on the impact of rectal cancer treatment on patients’
HRQoL. Of the 477 articles retrieved, 56 met the inclusion criteria. The most
frequently reported comparisons were between surgical procedures
(21 articles), especially between sphincter-preserving and non-sphincter
T. Gavaruzzi A. Perin S. Pucciarelli (&)

Department of Surgical Oncological and Gastroenterological
Sciences—First Surgical Clinic, University of Padova, Padua, Italy
T. Gavaruzzi
A. Perin
F. Giandomenico L. Lotto
Department of Developmental Psychology and Socialization,
University of Padova, Padua, Italy
L. Lotto
P. Del Bianco
Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto—IRCCS, Padua, Italy
118 T. Gavaruzzi et al.
preserving surgery or between stoma and stoma-free patients (13 articles), and
between multimodality therapies (11 articles). Additionally, twelve articles
compared patients’ and healthy controls’ HRQoL as primary or secondary aim.
The majority of the studies were observational (84 %), controlled (66 %),
cross-sectional (54 %), prospective (100 %), with a sample of more than 100
patients (59 %), and with more than 60 % of patients treated with neoadjuvant
therapy (50 %). The most frequently used instruments were the European
Organisation for Research and Treatment of Cancer Quality of Life Question-
naire Core 30 (QLQ-C30), its colorectal cancer specific module QLQ-CR38,
and the Medical Outcomes Study Short-Form 36 items questionnaire. Findings
from the included articles are summarised and commented, with a special focus
on the comparison between surgical treatments, between irradiated and not-
irradiated patients, and between patients and the general population.
Keywords
Rectal cancer Surgery Health-related quality of life (HRQoL) Systematic
review
1 Introduction
A milestone in the history of modern medicine has been the shift from a con-
ception of health as the opposite of illness to a multidimensional perspective of
health. This conception is reflected in the definition proposed in 1948 by the World
Health Organization (WHO) that describes health as ‘a state of complete physical,
mental and social well-being and not merely the absence of disease or infirmity’
(WHO 1946). The concept of Quality of Life (QoL) derives from this conception
of health. The WHO (WHOQoL Group 1993) defines QoL as ‘individuals’ per-
ception of their position in life in the context of the culture and value systems in
which they live and in relation to their goals, expectations, standards and concerns.
It is a broad ranging concept affected in a complex way by the person’s physical
health, psychological state, personal beliefs, social relationships and their rela-
tionship to salient features of their environment’.
In medical science, the more specific Health-Related Quality of Life (HRQoL)
concept has been introduced, that confines QoL to the health domain and refers to
how a disease or a medical condition affects the patient’s life (Guyatt et al. 1993).
This information is also used by health economics to inform policy making, for
example considering Quality-adjusted life-year in cost-effectiveness analyses
(Loomes and McKenzie 1989; Detsky 1990).
Quality of Life After Surgery for Rectal Cancer 119
While there is variation in how QoL and HRQoL are defined and measured,
there is a general agreement on several fundamental aspects of the concept of QoL,
as used in the medical science (Schumacher et al. 1991; Leplege and Hunt 1997).
In fact, it is accepted that QoL is: subjective, multidimensional, dynamic and
culturally correlated. The most important dimensions are: physical, psychological,
and social functioning and well-being, and physical symptoms that may be related
to the specific health condition and its treatment.
QoL can be assessed with generic and specific tools. Generic tools (e.g. Medical
Outcomes Study Short-Form 36 items, hereafter SF-36, (Ware 1992)) assess the
subjective health status and QoL of various types of patients. Specific tools assess
those aspects that can affect QoL of patients with a specific disease and/or a
specific treatment (e.g. European Organisation for Research and Treatment of
Cancer (EORTC) QoL Questionnaire Core 30, hereafter QLQ-C30 (Aaronson
et al. 1993) and its colorectal cancer specific module QLQ-CR38 (Sprangers et al.
1999)) or particular areas of QoL, independently of the disease (e.g. State-Trait
Anxiety Inventory (Spielberger et al. 1970)).
Rectal cancer is a common disease in Western countries. In the last decades, the
introduction of screening programs, allowing the early detection of the disease,
and the advances in surgery interventions and multimodality treatment have
improved clinical and oncological outcomes, reducing mortality rate. Presently,
the standard of care for locally advanced rectal cancer is neoadjuvant treatment,
either as preoperative radiotherapy (pRT) or chemoradiotherapy (pCRT), followed
by total mesorectal excision (TME) (National Comprehensive Cancer Network
updated). However, this approach is challenging, requiring skilled multidisci-
plinary teams and it may have severe functional consequences. Similarly to other
areas of medicine (Brundage et al. 2011), the shift of focus from assessing
exclusively objective oncological outcomes, such as overall and disease-free
survival, to subjective and self-reported evaluations of health status and HRQoL is
well established (Sprangers et al. 1995; Renner et al. 1999; Dunn et al. 2003).
The information obtained from HRQoL data and, more broadly, from patients’
reported outcomes (PROs, i.e. self-reported assessments from patients about how
they feel or function in relation to their health condition and therapy) are useful at
various levels of decision-making: for individual patients (micro level), for groups
of patients (meso level) and at the society level (macro level) (Sutherland and Till
1993; Stiggelbout and de Haes 2001). For example, they allow to monitor the
health status of individual patients and to start interventions to support their dif-
ficulties. They also represent a parameter for choosing between treatments with
similar clinical and oncological outcomes.
Although there is a growing number of studies assessing HRQoL in patients
with rectal cancer, findings are often limited by methodological flaws related to the
study design, the sample size, the use of non-validated questionnaires, the absence
of a baseline assessment, and statistical bias. Moreover, many questionnaires are
used to evaluate HRQoL, hindering the comparison of findings from different
studies (Brundage et al. 2011, 2013).
The aim of the present study was to review the articles published in the last five
years, focusing on HRQoL after surgery in patients with rectal cancer. In partic-
ular, we summarised the findings regarding the differences between patients and
the general population and the differences between different surgical treatments
and oncological approaches.
2 Methods
2.1 Search Strategy
A systematic literature search was performed on PubMed on December 1, 2013,

restricting the search to articles published in English from January 2009 to
November 2013. The specific terms searched were: (‘Rectal Neoplasms’[Mesh])
AND ((‘Quality of Life’[Mesh] OR (function*) OR (patient-reported)).
2.2 Inclusion and Exclusion Criteria
Studies were included if they measured patients’ reported HRQoL after surgery for
rectal cancer. QoL could be collected through self-report questionnaires or
structured interviews (by telephone or vis-à-vis).
Studies were excluded if: they did not report on primary data; HRQoL was not
evaluated; the focus was not on rectal cancer or findings did not distinguish
between rectal and colon cancer; the sample size was too small (\20), and other
reasons, such as studies performed to validate questionnaires, assessment during
neoadjuvant therapy, full text not accessible.
2.3 Coding and Classification
Similarly to our previous reviews (Gavaruzzi et al. 2013; Gavaruzzi et al. 2014),
the variables were coded according to the following criteria: comparison between
groups of patients, comparisons with general population, study design, sample
size, treatment characteristics and instruments used to assess QoL.
Studies were classified based on the comparison between surgical procedures,
multimodality therapies, other comparisons such as rectal versus colon cancer
patients and finally, no groups compared. It was also noted whether patients’ data
were compared with reference data or data from healthy controls. Anterior
resection (AR), low anterior resection (LAR), ultra low anterior resection (ULAR),
intersphincteric resection (ISR) and coloanal anastomosis (CAA) were considered
sphincter-preserving procedures. Abdominoperineal resection (APR) also named
abdominoperineal excision (APE), extralevator abdominoperineal excision (EL-
APE) and pelvic exenteration were considered as non-sphincter preserving
procedures.
Based on the statistical design, the studies were classified as: (a) observational
or experimental (randomised or not randomised); (b) controlled or not controlled;
(c) cross-sectional or longitudinal or before-and-after or longitudinal before-and-
after; (d) prospective cohort or retrospective cohort or case-control study.
2.4 Independent Reviewers and Discussion of Cases

of Disagreement
Titles and abstracts identified from the literature search were independently
reviewed for inclusion by two investigators (GF, GT). The coding of the included
articles was performed by one author (GF) and corroborated by a second author
(GT). The coding of the study design was performed by a statistician (PDB) and
corroborated by a second author (GF). Discrepancies were resolved by discussion
with all the authors.
With the exception of articles that compared patients with the general popu-
lation, when studies reported multiple comparisons between patients according to
different criteria (e.g. sex, surgery and stoma), they were classified based on their
primary aim and findings are summarised accordingly.
The findings from each included article were reviewed and summarised. For
instruments using a 0–100 score, differences of at least 10 points were considered
clinically significant (Osoba et al. 1998). When data were not reported numerically
but were depicted in figures, information about differences of at least 10 points was
extrapolated from the graphs. For instruments using other score ranges, statistical
significance was considered.
3 Results
Of 477 articles retrieved and considered for potential inclusion, 421 were exclu-
ded. Reasons for exclusion were: no primary (n = 113) or QoL data (n = 243)
reported, patients had no rectal cancer (n = 32), sample size \ 20 (n = 16), and
other reasons (n = 16).
The remaining 56 articles meet the inclusion criteria. Comparisons performed,
study design, sample size, patients who received neoadjuvant therapy and QoL
instruments used are summarised in Table 1.
3.1 Comparison Between Different Surgical Procedures
Out of 21 studies performed on this issue, nine compared sphincter-preserving

surgery (SPS) versus non-SPS (Campos-Lobato et al. 2011; Fischer et al. 2010;
Austin et al. 2010; Celasin et al. 2011; Varpe et al. 2011; Konanz et al. 2013; Mrak
et al. 2011; How et al. 2012; Kasparek et al. 2011), four compared stoma and
Table 1 Characteristics of the articles
122
Characteristics Number (%) References

of articles
Comparisons Between surgical 21 (37.5 %) Campos-Lobato et al. (2011), Fischer et al. (2010), Austin et al. (2010), Celasin et al.
between patients procedures (2011), Varpe et al. (2011), Konanz et al. (2013), Mrak et al. (2011), How et al. (2012),
Kasparek et al. (2011), Yau et al. (2009), Orsini et al. (2013), Bossema et al. (2011),
Krouse et al. (2009), Vaughan-Shaw et al. (2012), Kang et al. (2010), Andersson et al.
(2013), Li et al. (2010), Dumont et al. (2013), Doeksen et al. (2012), Barisic et al. (2011),
Gullà et al. (2011)
Between multimodality 11 (19.6 %) Canda et al. (2010), Peng et al. (2011), Thong et al. (2011), Bruheim et al. (2010),
therapies Kasparek et al. (2012), Parc et al. (2009), Braendengen et al. (2012), Tiv et al. (2010),
Kripp et al. (2012), Guckenberger et al. (2013), Stephens et al. (2010)
Other comparisons 5 (8.9 %) Ashburn et al. (2013), Riss et al. (2011), Ohigashi et al. (2011), You et al. (2011), Laforest
et al. (2012)
No comparisons 19 (33.9 %) Kilic et al. (2012), Bloemen et al. (2009), Pucciarelli et al. (2010), Mahjoubi et al. (2012),
Hoerske et al. (2010), Serpentini et al. (2011), Schmidt et al. (2010), Emmertsen (2013),
Zutshi et al. (2013), Neuman et al. (2011), Allaix et al. (2011), Pucciarelli et al. (2011),
Theodoropoulos et al. (2013), Hennies et al. (2012), Planting et al. (2013), Hirche et al.
(2010), Ristvedt and Trinkaus (2009), Carlsson et al. (2010), Caravati-Jouvenceaux et al.
(2011)
Comparisons with 12 (21.4 %) Austin et al. (2010), Konanz et al. (2013), Orsini et al. (2013), Thong et al. (2011),
general population Bruheim et al. (2010), Braendengen et al. (2012), Kripp et al. (2012), Guckenberger et al.
(2013), Pucciarelli et al.( 2010), Serpentini et al. (2011), Carlsson et al. (2010), Caravati-
Jouvenceaux et al. (2011)
(continued)
T. Gavaruzzi et al.
Table 1 (continued)
of articles
Design Observational 47 (83.9 %) Campos-Lobato et al. (2011), Fischer et al. (2010), Austin et al. (2010), Celasin et al.
(2011), Varpe et al. (2011), Konanz et al. (2013), Mrak et al. (2011), How et al. (2012),
Krouse et al. (2009), Vaughan-Shaw et al. (2012), Li et al. (2010), Dumont et al. (2013),
Barisic et al. (2011), Gullà et al. (2011), Canda et al. (2010), Peng et al. (2011), Thong
et al. (2011), Bruheim et al. (2010), Kasparek et al. (2012), Parc et al. (2009),
Guckenberger et al. (2013), Ashburn et al. (2013), Riss et al. (2011), You et al. (2011),
Kilic et al. (2012), Bloemen et al. (2009), Pucciarelli et al. (2010), Mahjoubi et al. (2012),
Hoerske et al. (2010), Serpentini et al. (2011), Schmidt et al. (2010), Emmertsen (2013),
Zutshi et al. (2013), Neuman et al. (2011), Allaix et al. (2011), Pucciarelli et al. (2011),
Theodoropoulos et al. (2013), Hennies et al. (2012), Planting et al. (2013), Hirche et al.
(2010), Ristvedt and Trinkaus (2009), Carlsson et al. (2010), Caravati-Jouvenceaux et al.
Quality of Life After Surgery for Rectal Cancer
(2011)
Experimental, 6 (10.7 %) Kang et al. (2010), Andersson et al. (2013), Doeksen et al. (2012), Braendengen et al.
randomised (2012), Tiv et al. (2010), Stephens et al. (2010)
Experimental, quasi- 1 (1.8 %) Kripp et al. (2012)
randomised
Experimental, not 2 (3.6 %) Ohigashi et al. (2011), Laforest et al. (2012)
randomised
(continued)
123
Table 1 (continued)
124

of articles
Controlled 37 (66.1 %) Campos-Lobato et al. (2011), Fischer et al. (2010), Austin et al. (2010), Celasin et al.
Gullà et al. (2011), Canda et al. (2010), Peng et al. (2011), Thong et al. (2011), Bruheim
et al. (2010), Kasparek et al. (2012), Parc et al. (2009), Braendengen et al. (2012), Tiv
et al. (2010), Kripp et al. (2012), Guckenberger et al. (2013), Stephens et al. (2010),
Ashburn et al. (2013), Riss et al. (2011), You et al. (2011), Laforest et al. (2012), Caravati-
Not controlled 19 (33.9 %) Ohigashi et al. (2011), Kilic et al. (2012), Bloemen et al. (2009), Pucciarelli et al. (2010),
Mahjoubi et al. (2012), Hoerske et al. (2010), Serpentini et al. (2011), Schmidt et al.
(2010), Emmertsen (2013), Zutshi et al. (2013), Neuman et al. (2011), Allaix et al. (2011),
Pucciarelli et al. (2011), Theodoropoulos et al. (2013), Hennies et al. (2012), Planting et al.
(2013), Hirche et al. (2010), Ristvedt and Trinkaus (2009), Carlsson et al. (2010)
Cross-sectional 30 (53.6 %) Fischer et al. (2010), Austin et al. (2010), Konanz et al. (2013), Mrak et al. (2011),
Kasparek et al. (2011), Orsini et al. (2013), Bossema et al. (2011), Krouse et al. (2009),
Vaughan-Shaw et al. (2012), Dumont et al. (2013), Barisic et al. (2011), Gullà et al.
(2011), Peng et al. (2011), Thong et al. (2011), Bruheim et al. (2010), Kasparek et al.
(2012), Tiv et al. (2010), Kripp et al. (2012), Guckenberger et al. (2013), Riss et al. (2011),
Laforest et al. (2012), Kilic et al. (2012), Bloemen et al. (2009), Pucciarelli et al. (2010),
Mahjoubi et al. (2012), Hoerske et al. (2010), Serpentini et al. (2011), Hirche et al. (2010),
Ristvedt and Trinkaus (2009), Caravati-Jouvenceaux et al. (2011)
(continued)
T. Gavaruzzi et al.
Table 1 (continued)
of articles
Longitudinal 2 (3.6 %) Ashburn et al. (2013), Zutshi et al. (2013)
Before-and-after 7 (12.5 %) Celasin et al. (2011), Varpe et al. (2011), Kang et al. (2010), Canda et al. (2010),
Braendengen et al. (2012), Hennies et al. (2012), Planting et al. (2013)
Longitudinal before-and- 16 (28.6 %) Campos-Lobato et al. (2011), How et al. (2012), Yau et al. (2009), Andersson et al. (2013),
after Li et al. (2010), Doeksen et al. (2012), Parc et al. (2009), Stephens et al. (2010), You et al.
(2011), Schmidt et al. (2010), Emmertsen (2013), Neuman et al. (2011), Allaix et al.
(2011), Pucciarelli et al. (2011), Theodoropoulos et al. (2013), Carlsson et al. (2010)
Mixed: cross sectional 1 (1.78 %) Ohigashi et al. (2011)
and before-and-after
Prospective cohort 56 (100 %) Campos-Lobato et al. (2011), Fischer et al. (2010), Austin et al. (2010), Celasin et al.
Gullà et al. (2011), Canda et al. (2010), Peng et al. (2011), Thong et al. (2011), Bruheim
et al. (2010), Kasparek et al. (2012), Parc et al. (2009), Braendengen et al. (2012), Tiv
et al. (2010), Kripp et al. (2012), Guckenberger et al. (2013), Stephens et al. (2010),
Ashburn et al. (2013), Riss et al. (2011), Ohigashi et al. (2011), You et al. (2011), Laforest
et al. (2012), Kilic et al. (2012), Bloemen et al. (2009), Pucciarelli et al. (2010), Mahjoubi
et al. (2012), Hoerske et al. (2010), Serpentini et al. (2011), Schmidt et al. (2010),
Emmertsen (2013), Zutshi et al. (2013), Neuman et al. (2011), Allaix et al. (2011),
Pucciarelli et al. (2011), Theodoropoulos et al. (2013), Hennies et al. (2012), Planting et al.
(2013), Hirche et al. (2010), Ristvedt and Trinkaus (2009), Carlsson et al. (2010),
Caravati-Jouvenceaux et al. (2011)
(continued)
125
Table 1 (continued)
126

of articles
Retrospective cohort 0 (0 %) no article
Case-control 0 (0 %) no article
Sample size \50 patients 11 (19.6 %) Austin et al. (2010), Vaughan-Shaw et al. (2012), Dumont et al. (2013), Barisic et al.
(2011), Gullà et al. (2011), Riss et al. (2011), Ohigashi et al. (2011), Laforest et al. (2012),
Theodoropoulos et al. (2013), Planting et al. (2013), Hirche et al. (2010)
50–100 patients 12 (21.4 %) Fischer et al. (2010), Celasin et al. (2011), Varpe et al. (2011), Mrak et al. (2011), How
et al. (2012), Canda et al. (2010), Mahjoubi et al. (2012), Neuman et al. (2011), Allaix
et al. (2011), Hennies et al. (2012), Ristvedt and Trinkaus (2009, Carlsson et al. (2010)
[100 patients 33 (58.9 %) Campos-Lobato et al. (2011), Konanz et al. (2013), Kasparek et al. (2011), Yau et al.
(2009), Orsini et al. (2013), Bossema et al. (2011), Krouse et al. (2009), Kang et al. (2010),
Andersson et al. (2013), Li et al. (2010), Doeksen et al. (2012), Peng et al. (2011), Thong
et al. (2011), Bruheim et al. (2010), Kasparek et al. (2012), Parc et al. (2009),
Braendengen et al. (2012), Tiv et al. (2010), Kripp et al. (2012), Guckenberger et al.
(2013), Stephens et al. (2010), Ashburn et al. (2013), You et al. (2011), Kilic et al. (2012),
Bloemen et al. (2009), Pucciarelli et al. (2010), Hoerske et al. (2010), Serpentini et al.
(2011), Schmidt et al. (2010), Emmertsen (2013), Zutshi et al. (2013), Pucciarelli et al.
(2011), Caravati-Jouvenceaux et al. (2011)
% of patients who 0 3 (5.4 %) Schmidt et al. (2010), Allaix et al. (2011), Ristvedt and Trinkaus (2009)
underwent
neoadjuvant therapy
\30 9 (16.1 %) Kasparek et al. (2011), Yau et al. (2009), Krouse et al. (2009), Peng et al. (2011), Kasparek
et al. (2012), Ashburn et al. (2013), Emmertsen (2013), Planting et al. (2013), Hirche et al.
(2010)
(continued)
T. Gavaruzzi et al.
Table 1 (continued)
of articles
30–60 10 (17.9 %) Fischer et al. (2010), Varpe et al. (2011), Konanz et al. (2013), How et al. (2012), Barisic
et al. (2011), Canda et al. (2010), Bruheim et al. (2010), Parc et al. (2009), Stephens et al.
(2010), Hoerske et al. (2010)
61–90 15 (26.8 %) Campos-Lobato et al. (2011), Celasin et al. (2011), Mrak et al. (2011), Orsini et al. (2013),
Vaughan-Shaw et al. (2012), Andersson et al. (2013), Li et al. (2010), Dumont et al.
(2013), Thong et al. (2011), Riss et al. (2011), You et al. (2011), Laforest et al. (2012),
Bloemen et al. (2009), Serpentini et al. (2011), Carlsson et al. (2010)
[90 13 (23.2 %) Kang et al. (2010), Doeksen et al. (2012), Gullà et al. (2011), Braendengen et al. (2012),
Tiv et al. (2010), Kripp et al. (2012), Guckenberger et al. (2013), Kilic et al. (2012),
Pucciarelli et al. (2010), Zutshi et al. (2013), Neuman et al. (2011), Pucciarelli et al.
(2011), Hennies et al. (2012)
Not specified 6 (10.7 %) Austin et al. (2010), Bossema et al. (2011), Ohigashi et al. (2011), Mahjoubi et al. (2012),
Theodoropoulos et al. (2013), Caravati-Jouvenceaux et al. (2011)
Questionnairesa EORTC QLQ-C30 36 (64.3 %) Fischer et al. (2010), Konanz et al. (2013), Mrak et al. (2011), How et al. (2012), Kasparek
(Aaronson et al. 1993) et al. (2011), Yau et al. (2009), Bossema et al. (2011), Vaughan-Shaw et al. (2012), Kang
et al. (2010), Andersson et al. (2013), Li et al. (2010), Dumont et al. (2013), Barisic et al.
(2011), Peng et al. (2011), Bruheim et al. (2010), Kasparek et al. (2012), Braendengen
et al. (2012), Tiv et al. (2010), Kripp et al. (2012), Guckenberger et al. (2013), Ohigashi
et al. (2011), Kilic et al. (2012), Bloemen et al. (2009), Pucciarelli et al. 2010, Mahjoubi
et al. (2012), Hoerske et al. (2010), Schmidt et al. (2010), Emmertsen (2013), Neuman
et al. (2011), Allaix et al. (2011), Pucciarelli et al. (2011), Theodoropoulos et al. (2013),
Hennies et al. (2012), Planting et al. (2013), Hirche et al. (2010), Caravati-Jouvenceaux
et al. (2011)
(continued)
127
Table 1 (continued)
128

of articles
EORTC QLQ-CR38 25 (44.6 %) Fischer et al. (2010), Konanz et al. (2013), How et al. (2012), Kasparek et al. (2011),
(Sprangers et al. 1999) Orsini et al. (2013), Kang et al. (2010), Andersson et al. (2013), Li et al. (2010), Dumont
et al. (2013), Doeksen et al. (2012), Thong et al. (2011), Kasparek et al. (2012), Tiv et al.
(2010), Stephens et al. (2010), Kilic et al. (2012), Bloemen et al. (2009), Pucciarelli et al.
(2010), Mahjoubi et al. (2012), Hoerske et al. (2010), Neuman et al. (2011), Allaix et al.
(2011), Pucciarelli et al. (2011), Hennies et al. (2012), Planting et al. (2013), Hirche et al.
(2010)
EORTC QLQ-CR29 6 (10.7 %) Mrak et al. (2011), Vaughan-Shaw et al. (2012, Peng et al. (2011), Kripp et al. (2012),
(Whistance et al. 2009) Guckenberger et al. (2013), Theodoropoulos et al. (2013)
MOS SF-36 (Ware 1992) 16 (28.6 %) Campos-Lobato et al. (2011), Austin et al. (2010), Celasin et al. (2011), Orsini et al.
(2013), Krouse et al. (2009), Doeksen et al. (2012), Thong et al. (2011), Parc et al. (2009),
Stephens et al. (2010), Ashburn et al. (2013), Ohigashi et al. (2011), Laforest et al. (2012),
Zutshi et al. (2013), Theodoropoulos et al. (2013), Carlsson et al. (2010), Caravati-
(continued)
T. Gavaruzzi et al.
Table 1 (continued)
of articles
FIQL (Rockwood et al. 5 (8.9 %) Barisic et al. (2011), Canda et al. (2010), Laforest et al. (2012), Allaix et al. (2011),
2000) Planting et al. (2013)
FACT-C (Ward et al. 3 (5.4 %) Austin et al. (2010), You et al. (2011), Ristvedt and Trinkaus (2009)
1999)
EQ-5D (Rabin and de 2 (3.6 %) Andersson et al. (2013) Allaix et al. (2011)
Charro 2001)
Other questionnairesb 10 (17.9 %) Varpe et al. (2011), How et al. (2012), Krouse et al. (2009), Gullà et al. (2011), Ashburn
et al. (2013), Riss et al. (2011), Serpentini et al. (2011), Zutshi et al. (2013), Neuman et al.
(2011), Theodoropoulos et al. (2013)
a
Several studies used multiple questionnaires
b
Other questionnaires used were: CGQL (Fazio et al. 1999); Coloplast stoma QOL questionnaire (Prieto et al. 2005); GIQLI (Eypasch et al. 1995); mCOH-
QOL-Ostomy (City of Hope/Beckman Research Institute Pain Resource Center Research Instruments); MOS SF-12 (Ware et al. 1996); PGWBI (Dupuy
1984); RAND 36-item (Hays et al. 1993); SQLI (Marquis et al. 2003); SQOL (Baxter et al. 2006)
List of acronyms CGQL: Cleveland Global Quality of Life; EORTC: European Organisation for Research and Treatment of Cancer; EQ-5D: EuroQoL 5-D;
FACT-C: Functional Assessment of Cancer Therapy-Colorectal; FIQL: Fecal Incontinence Quality of Life questionnaire; GIQLI: Gastrointestinal Quality of
Life Index; mCOH-QOL-Ostomy: modified City of Hope Quality of Life Ostomy-specific; MOS SF-36: Medical Outcomes Study Short-Form 36 item; MOS
SF-12: Medical Outcomes Study Short-Form 12 item; PGWBI: Psychological General Well-Being Index; QLQ-C30: Quality of Life Questionnaire Core 30;
QLQ-CR38: Quality of Life Questionnaire Colorectal 38; QLQ-CR29: Quality of Life Questionnaire Colorectal 29; RAND 36: RAND 36-Item Health
Survey; SQLI: Stoma care Quality of Life Index; SQOL: Stoma Quality of Life
129
non-stoma patients (Yau et al. 2009; Orsini et al. 2013; Bossema et al. 2011;
Krouse et al. 2009), four compared open versus laparoscopic surgery (Vaughan-
Shaw et al. 2012; Kang et al. 2010; Andersson et al. 2013; Li et al. 2010), two
compared different intestinal reconstructions after rectal resection (Dumont et al.
2013; Doeksen et al. 2012), one compared different ISRs (Barisic et al. 2011) and
one compared ghost versus standard ileostomy (Gullà et al. 2011).
3.1.1 Comparison Between Sphincter-Preserving

and Non-Sphincter-Preserving Surgery
Out of nine studies comparing SPS and non-SPS, in four there were no differences
between the two groups (Campos-Lobato et al. 2011; Fischer et al. 2010; Austin
et al. 2010; Celasin et al. 2011), in three the differences favoured SPS (Varpe et al.
2011; Konanz et al. 2013; Mrak et al. 2011), while mixed findings were found in
the remaining two studies (How et al. 2012; Kasparek et al. 2011).
Campos-Lobato et al. (Campos-Lobato et al. 2011) compared APR and LAR
patients overtime, from baseline up to 36 months from surgery, and found no dif-
ference in the summary scores of the SF-36. Fischer et al. (2010) compared a group
of APE patients with a group of ULAR patients without secondary stoma and a small
group of ULAR patients with a secondary stoma. APE patients reported worse
diarrhoea scores than ULAR patients without secondary stoma. At a median of
47 months, Austin et al. (2010) found no differences on the FACT-C scores between
patients who underwent pelvic exenteration and a control group of patients who
underwent either APE or LAR 3 months earlier. Again, no statistically significant
differences were found by Celasin et al. (2011), who longitudinally compared
Muslim patients treated with APE, LAR or AR, using the SF-36 questionnaire.
At 1 year after surgery, Varpe et al. (2011) found that AR patients had better
scores than APR patients on physical functioning and body pain, measured with
the RAND 36 questionnaire (Hays et al. 1993). Konanz et al. (2013) compared
three groups of patients who had undergone ISR, LAR or APR using the QLQ-C30
and QLQ-CR38. At a median time of 59 months form surgery, ISR and LAR
patients had better scores than APR patients on physical function, body image,
sexual functioning and lower male sexual dysfunction, but worse score on diar-
rhoea, especially for ISR patients. Additionally, LAR patients had better score than
APR on role function and future perspectives, but also had worse on constipation,
whereas ISR patients had lower female sexual dysfunction, but also more gas-
trointestinal problems than APR and more defecation problems than LAR patients.
At a median follow-up of 74 months, Mrak et al. (2011) reported that patients who
underwent ULAR with J-pouch anastomosis reported better HRQoL scores than
patients treated with APE. On the QLQ-C30, ULAR patients had higher global
health status/QoL, physical, role, emotional, cognitive and social function, and less
fatigue, diarrhoea and financial difficulties compared to APE patients. On the
QLQ-CR29 (Whistance et al. 2009), ULAR patients had better scores on body
pain, weight and sexual interest, and lower problems with urinary frequency,
embarrassment and impotence.
Mixed findings were found in two studies (How et al. 2012; Kasparek et al.
2011). How et al. (2012) compared 32 patients who underwent LAR and 30 who
underwent APE (19 of them were ELAPE). Using the QLQ-C30 and QLQ-CR38,
the authors found that, preoperatively, LAR patients had more symptoms than
APE patients, including fatigue, insomnia, defecation problem and male sexual
dysfunction, but also less diarrhoea and better scores on sexual functioning and
enjoyment and future perspectives. Two years after surgery, LAR patients showed
worse role and social function, and more fatigue, pain, insomnia, diarrhoea and
gastrointestinal problems, but also better sexual functioning and enjoyment and
better cognitive function. The authors’ conclusion was that global QoL ratings
were comparable in the two groups and that, compared with SPS, the APE should
not be regarded as an inferior option for patients with low rectal cancer as concern
as the QoL. Kasparek et al. (2011) compared APR patients with CAA patients with
or without stoma at a median follow-up of 73 months. On the QLQ-C30 and QLQ-
CR38, patients treated with CAA without a stoma had better body image and lower
male and female sexual dysfunction, although sexual functioning was also lower
than APR patients. In contrast, compared to APR patients, patients treated with
CAA and with a stoma had worse global health status/QoL, social function, body
image, sexual functioning and future perspectives, and experienced more symp-
toms related to fatigue, pain and male sexual dysfunction.
3.1.2 Comparison Between Patients With and Without Stoma

While patients treated with non-SPS always have a stoma, patients treated with
SPS are not always stoma-free. The primary end-point in the following articles
was the comparison between patients with and without stoma.
Yau et al. (2009) used the QLQ-C30 at baseline, during adjuvant therapy, and
3 years after surgery. Patients with either a temporary or a permanent stoma still
had worse social function than no-stoma patients at 3 years follow-up. Stoma
patients had less constipation at baseline, but this advantage was not found at
3 years. Orsini et al. (2013) compared the effects of having a stoma separately for
patients younger or older than 70 at diagnosis using the SF-36 and the QLQ-C30.
At a median time from surgery of 3.4 years, younger patients only showed a
difference in female sexual dysfunction, higher in stoma than no-stoma patients,
whereas older patients with a stoma had more role limitations due to physical and
emotional problems, worse body image and more male sexual dysfunction than
no-stoma patients. Bossema et al. (2011) used the QLQ-C30 functional scales at a
median time from surgery of about 8 years. Stoma patients reported worse
physical function, but also improved social function compared to no-stoma
patients. Krouse et al. (2009) compared the effects of having a stoma separately for
females and males, at a median time from surgery of 11.4 years, using the SF-36
and the modified m-COH-QoL-Ostomy (City of Hope/Beckman Research Institute
Pain Resource Center Research Instruments). For males, the only difference found
was on social functioning measured with the m-COH-QoL-Ostomy, with stoma
patients reporting worse social function. For females, several differences were
clinically meaningful. Female patients with stoma compared to no-stoma patients

had worse general health, physical function, social function, vitality, mental health
and more limitations due to physical and emotional problems, as measured with
the SF-36. Additionally, they had lower scores on the m-COH-QoL-Ostomy for
total QoL, social function, and psychological function.
3.1.3 Comparisons Between Laparoscopic and Open Resection

Four studies compared open and laparoscopic surgery, two of them were ran-
domised trials. Vaughan-Shaw et al. (2012) compared QoL of three small groups
of patients who underwent ELAPE, standard LAPE and OAPE. Be aware of the
bias of the study, the authors concluded that extended APE performed laparo-
scopically is not associated with deterioration of QoL. In the large randomised
COREAN trial comparing laparoscopic and open surgery for rectal cancer up to
9 cm from anal verge, Kang et al. (2010) used the QLQ-C30 and QLQ-CR38
preoperatively and at 3 months or after ileostomy closure. No clinically significant
differences were found at either time point between open and laparoscopic surgery
arms. In the Andersson et al.’s (2013) study, HRQOL was assessed in a subset of
patients enrolled in the COLOR II trial. The EQ-5D (Rabin and de Charro 2001),
QLQ-C30, and QLQ-CR38 questionnaires were administered preoperatively and
4 weeks, 6 and 12 months after surgery. There were no differences between groups
in any of the questionnaires administered and at any time point measured. Li
et al.’s (2010) study compared open and laparoscopic surgery in a prospective but
not randomised fashion. QoL assessment was performed preoperatively, and then
at 1 week, 3 and 12 months postoperatively using the Chinese version of the QLQ-
C30 and QLQ-CR38. The laparoscopic group had less pain 1 week after the
surgery, fewer financial difficulties at 1 week and 3 months, and better body image
at each time point following surgery, whereas there were no differences in the
global health status/QoL scale.
3.1.4 Comparison Between Intestinal Anastomoses Following

Rectal Resection
Dumont et al. (2013) compared two small groups of patients, who underwent
coloanal anastomosis after ISR or perineal pseudocontinent colostomy (PCC) after
APR. At a median of 57.7 months from surgery, using the QLQ-C30 and QLQ-
CR38 questionnaires, PCC patients had better functional scores (physical and
cognitive function, sexual functioning and enjoyment, and future perspectives), but
also more symptoms (fatigue, pain, insomnia, diarrhoea, chemotherapy side effects
and defecation problems) than those with ISR. Doeksen et al. (2012) randomised
patients to receive J-pouch or side-to-end reconstruction after TME. HRQoL was
assessed with the SF-36 and QLQ-CR38 preoperatively and 4 and 12 months
postoperatively. Of the 107 patients randomised, only data from 52 of them were
analysed. Of the subset of scales reported, there were no differences preopera-
tively, whereas at both follow-up times, J-pouch patients had better physical
function and social function, but also more micturition problems and more
gastrointestinal symptoms than side-to-end patients. General health, sexual func-

tioning and defecation problems did not differ between groups at either follow-up.
3.1.5 Comparison Between Sphincter-Preserving Surgery Procedures

Barisic et al. (2011) compared three small groups of patients who underwent
partial, subtotal and total ISR for distal third rectal cancer. At 12 months after
ileostomy reversal, no statistically significant differences were found on the QLQ-
C30 and only some differences on the FIQL scores (Rockwood et al. 2000)
regarding the scales of coping/behaviour and depression/self perception.
3.1.6 Comparison Between Ileostomies

Gullà et al. (2011) compared patients treated with ghost ileostomy or traditional
covering stoma, using the Stoma care Quality of Life Index (SQLI) (Marquis et al.
2003). While the authors themselves specified that this questionnaire is divided
into 13 subscales, their results reported a single score, whose interpretation is
unclear.
3.2 Comparison Between Multimodality Therapies
Of the 11 articles reporting on the effect of multimodality therapies, six included a

control group undergoing surgery-only (Canda et al. 2010; Peng et al. 2011; Thong
et al. 2011; Bruheim et al. 2010; Kasparek et al. 2012; Parc et al. 2009), whereas
five studies did not (Braendengen et al. 2012; Tiv et al. 2010; Kripp et al. 2012;
Guckenberger et al. 2013; Stephens et al. 2010).
3.2.1 Studies Including a Control Group

Canda et al. (2010) compared two small groups of patients, one treated with sur-
gery-only, one with pCRT followed by surgery. After a median of 14 months, the
two groups did not differ on FIQL scores. Peng et al. (Peng et al. 2011) evaluated
four groups of patients who underwent surgery-only, surgery plus adjuvant CT,
surgery plus adjuvant CRT and pCRT plus surgery plus adjuvant CT, using the
QLQ-C30 and QLQ-CR29 questionnaires. At a median follow-up of 10 months,
compared with non-irradiated patients, irradiated patients showed worse scores for
faecal incontinence and diarrhoea. Thong et al. (2011) compared SF-36 and QLQ-
C38 scores in patients treated with surgery-only or with preoperative radiotheraphy
(pRT) followed by surgery, at a median follow-up of 4 years. In patients with a
follow-up of less than 5 years, surgery-only patients reported less body pain, and
lower male and female sexual dysfunction than pRT patients. For patients with 5 or
more years of follow-up, surgery-only patients had better body image and sexual
enjoyment, and lower stoma related-problems and male sexual dysfunction than
pRT patients. At a median follow-up of 4.8 years, Bruheim et al. (2010) compared
irradiated and non-irradiated patients on the functional scales of the QLQ-C30. The
only difference was found for social function, which was better in non-irradiated
than in irradiated patients. Kasparek et al. (2012) compared HRQoL in patients who
underwent APR without pre or postoperative RT (n = 55), with pRT (n = 53), and
with postoperative RT (n = 35). Median follow-up was 52 months and HRQoL
was measured with the QLQ-C30 and QLQ-CR38. Apart from females’ sexual
functioning which scored better in both RT groups and sexual enjoyment which
scored better in the pRT group compared to the surgery-only group, the surgery-
only group scored better on role function, body image and future perspectives;
and showed less constipation, diarrhoea, and male and female sexual dysfunction
than pRT patients; and better future perspectives and less female sexual dysfunction
than postoperative RT patients. Parc et al. (2009) assessed HRQoL in 364 patients
who entered a randomised trial (Fazio et al. 2007) comparing colorectal and col-
oanal anastomoses after LAR. The SF-36 questionnaire was administered preop-
eratively, and 4, 12 and 24 months postoperatively. There were no statistically
significant differences at any time points between patients treated with or without
pRT. However, patients treated with pCRT compared to those treated with pRT had
lower physical and mental summary scores at 4 months, and lower mental summary
score at 12 months.
3.2.2 Studies not Including a Control Group

Braendengen et al. (2012) evaluated 76 out of 209 patients who were randomised to
pRT or pCRT followed by surgery for non-resectable rectal cancer (Brændengen
et al. 2008). At a median follow-up of 6 years, there were no differences in QLQ-
C30 scores. Tiv et al. (2010) evaluated HRQoL, using the QLQ-C30 and QLQ-
CR38 questionnaires, in 207 French patients entered in the 22921 EORTC trial
(Bosset et al. 2006). According to the original randomised trial, patients underwent:
pRT and surgery, pCRT and surgery, pRT plus surgery plus postoperative CT and
pCRT plus surgery plus postoperative CT. Median follow-up from randomisation to
HRQoL evaluation was 4.6 years, and results were reported comparing the pRT
group with all the other ones. Patients treated with CT had worse social function
and more diarrhoea than those treated with pRT only. Kripp et al. (2012) compared
99 locally advanced rectal cancer patients either treated within a phase III (Hofh-
einz et al. 2011) or Phase I/II trials (Willeke et al. 2007; Horisberger et al. 2009) and
randomised to intensified CRT (ICRT) or conventional CRT. The only differences
reported on the QLQ-C30 and QLQ-CR29 favoured the ICRT group for urinary
frequency and the conventional CRT group for anxiety and diarrhoea. Gucken-
berger et al. (2013) compared the effects of short-course pRT or long-course pCRT
using the QLQ-C30 and QLQ-CR29 questionnaires. At a median follow-up time of
67 months, pCRT patients reported more diarrhoea, financial difficulties and
embarrassment, but also less dyspareunia than pRT patients. Stephens et al. (2010)
compared SF-36 and QLQ-CR38 scores in patients randomised to short-course pRT
and surgery or surgery followed by postoperative CRT (postCRT) in selected
patients, i.e. those with positive circumferential margin. Clinical data of this trial
were reported elsewhere (Sebag-Montefiore et al. 2009). To note, only 63 out of
676 randomised in the second arm actually received postoperative CRT. HRQoL
was assessed before any treatment, and 3, 6, 12, 18, 24, 30 and 36 months post-
operatively. The authors compared the two groups only for the SF-36 general health
and physical function scales, and the QLQ-CR38 defection problems and male
sexual dysfunction scales. No clinically meaningful differences were found at any
time point.
3.3 Other Comparisons
Of the five articles reporting other comparisons, two compared patients with and
without anastomotic leakage (Ashburn et al. 2013; Riss et al. 2011), one compared
rectal and colon cancer patients (Ohigashi et al. 2011), one compared curative,
non-curative, and no surgery (You et al. 2011), and one examined the effect of an
anal sphincter training (Laforest et al. 2012).
3.3.1 Anastomotic Leak

Both Ashburn et al. (2013) and Riss et al. (2011) compared a group of patients who
experienced an anastomotic leakage with a group of controls. No clinically
meaningful differences were found one year from surgery on the two component
summary scores of the SF-36 (Ashburn et al. 2013) and after a median of 8.9 years
(Riss et al. 2011) on the two component summary scores of the SF-12 (Ware et al.
1996).
3.3.2 Rectal Versus Colon Cancer

No clinically meaningful differences were found on the SF-36 and QLQ-C30
between patients with rectal and colon cancer at a median of 878 days from
surgery by Ohigashi et al. (2011).
3.3.3 Other
You et al. (2011) longitudinally surveyed 52 locally recurrent rectal patients with
the FACT-C (Ward et al. 1999). No clinically meaningful differences were found
between patients treated with curative surgery, non-curative surgery or no surgery.
Laforest et al. (2012) assessed the effect of anal sphincter training on patients’
HRQoL at a median of 21.5 months after closure of the diverting stoma. The only
benefit was found for the depression/self perception scale of the FIQL question-
naire, whereas no differences were found on the SF-36.
3.4 Observational Studies Without Group Comparisons
Out of the 19 articles that did not compare groups, nine used uni- or multi-variate
analyses to compare the effect of one or more patients’ characteristics on HRQoL
(Kilic et al. 2012; Bloemen et al. 2009; Pucciarelli et al. 2010; Mahjoubi et al. 2012;
Hoerske et al. 2010; Serpentini et al. 2011; Schmidt et al. 2010; Emmertsen 2013;
Zutshi et al. 2013), six focused on the analysis of HRQoL overtime (Neuman et al.
2011; Allaix et al. 2011; Pucciarelli et al. 2011; Theodoropoulos et al. 2013;
Hennies et al. 2012; Planting et al. 2013) and four had a different focus (Hirche et al.
2010; Ristvedt and Trinkaus 2009; Carlsson et al. 2010; Caravati-Jouvenceaux
et al. 2011).
3.4.1 Univariate or Multivariate Analyses

Kilic et al. (2012) measured HRQoL with the QLQ-C30 and QLQ-CR38 ques-
tionnaires, at a median of 5 years from treatment in patients who underwent
adjuvant CRT. Multiple factors were considered, including: age, follow-up time,
gender and type of surgery, with a focus on the latter. Compared to APR patients,
LAR patients reported better global health status/QoL, emotional and social
function, body image and future perspective, and lower symptoms related to
fatigue, nausea and vomiting, pain, appetite loss, diarrhoea, financial difficulties,
CT side effects and sexual dysfunction. Bloemen et al. (2009) evaluated HRQoL
with the QLQ-C30 and QLQ-C38 in a consecutive series of patients, at a median
of 36 months form surgery. Patients who suffered postoperative complications had
slightly lower physical function, experienced more fatigue, pain and weight loss
than those who did not. Patients with a stoma had better future perspectives and
slightly less gastrointestinal symptoms, but also more male sexual dysfunction
than those without a stoma. In a sample of stoma-free patients, Pucciarelli et al.
(2010) assessed HRQoL with the QLQ-C30 and QLQ-CR38 questionnaires, at a
median of 43 months from surgery. Univariate analyses were used to assess the
impact of a series of clinical variables. The QLQ-C30 functional scales were
negatively affected by bowel function-related covariates, whereas clinical factors
were associated only with the future perspective and defecation problems scales of
the QLQ-CR38. In a sample of Iranian patients with a stoma, Mahjoubi et al.
(2012) compared males and females’ scores on the QLQ-C30 and QLQ-CR38 at a
median of 32 months from surgery. Compared to females, males had better
physical function, body image, future perspectives, and sexual functioning and
enjoyment, and less CT side effects, gastrointestinal symptoms and stoma-related
problems, but also more micturition problems and weight loss. Hoerske et al.
(2010) assessed QLQ-C30 functional scales and QLQ-CR38 scores at a median of
13 years from treatment, comparing patients depending on whether they under-
went CRT, the tumour site and the need for a permanent stoma. CRT patients had
worse role and social function, more defecation problems, stoma related problems,
and male and female sexual dysfunction, but also better body image than those
who did not undergo CRT. Compared with patients with a tumour in the upper or
middle third of the rectum, those with a tumour in lower third of the rectum had
worse role and social function, more defecation problems, and male sexual dys-
function, but also better body image and better future perspectives. Patients with a
stoma had worse physical, role and social function, worse sexual enjoyment and
more male sexual dysfunction, but also better body image, better future perspec-
tives and less female sexual dysfunction. Serpentini et al. (2011) used multivariate
analysis to ascertain clinical and socio-demographic factors independently asso-

ciated to well-being, measured with the PGWBI (Dupuy 1984), at a median of
68 months from surgery. General health was negatively affected by time from
diagnosis and fecal urgency. Positive well-being resulted independently affected
by time from diagnosis and occurrence of early major complications self-control
was negatively associated with primary education and fecal urgency. Schmidt
et al. (2010) measured HRQoL preoperatively, at 3, 6, 12 and 24 months, and
compared males and females, different age groups and different surgical proce-
dures (APR vs. AR). The QLQ-C30 was used; however, it is unclear what the
authors refer to when reporting results referring to ‘functional status’ score.
Emmertsen et al. (2013) grouped patients treated with sphincter preserving surgery
depending on whether they suffered major anterior resection syndrome (LARS).
The QLQ-C30 questionnaire was administered before treatment, and at 3 and
12 months after surgery or stoma closure. At 3 months, patients with major LARS
had worse global health status/QoL, role and social function; they also experienced
more fatigue and more constipation, but also less pain and less diarrhoea. On the
contrary, at 12 months, they had better global health status/QoL, role and emo-
tional function, less insomnia and less diarrhoea, while they also had worse social
function and more fatigue. Zutshi et al. (2013) compared male and female two
component summary scores of the SF-36 and found no differences.
3.4.2 HRQoL Change Overtime

HRQoL changes overtime were assessed by Neuman et al. (2011) in a sample of
patients undergoing SPS with a temporary diverting stoma, using the QLQ-C30 and
CR-38. Compared to preoperative scores, at stoma closure and at 6 months there
were no differences in global health status/QoL, physical, role and social function,
body image and gastrointestinal symptoms, whereas future perspectives increased.
The other scales were not reported. Allaix et al. (2011) measured HRQoL preop-
eratively, 3 months, 1 and 5 years after surgery in a sample of patients treated with
transanal endoscopic microsurgery (TEM) for extraperitoneal rectal cancer.
Compared to preoperative scores, there were no clinically meaningful changes in
QLQ-C30 and QLQL-CR38 scores. The mean general QoL score, measured with
the EQ-5D visual analogue scale increased significantly at 1 and 5 years compared
with preoperative values. Of the four domains of the FIQL questionnaire, no dif-
ferences were found at 3 months, whereas depression/self perception and embar-
rassment increased significantly at 1 year and remained higher at 5 years, with an
additional increase in the life style score. A series of pCRT patients were evaluated
before pCRT, 2/3 weeks after pCRT, and at 6 and 12 months postoperatively by
Pucciarelli et al. (2011). Relative to pre-treatment scores, no clinically meaningful
changes were observed in QLQ-C30 and QLQ-CR38 scores except for an increase
in male sexual dysfunction, which remained higher at each assessment time. The-
odoropoulos et al. (2013) prospectively assessed patients treated with laparoscopic
colectomy preoperatively, 1, 3, 6 and 12 months after surgery. Patients were per-
sonally interviewed using the SF-36, QLQ-C30, QLQ-CR29 and Gastrointestinal
QOL Index (GIQLI) (Eypasch et al. 1995). Compared to preoperative scores, at

1 month there was an improvement in emotional function and levels of anxiety, but
a worsening in the global health status/QoL, physical function and role limitation
due to physical problems. At 3 months, patients reported better general, emotional
and mental health. At 6 months only emotional and mental health was better than
preoperative scores, whereas at 12 months several differences were found. Patients
had better scores on role limitations due to emotional problems, emotional function,
(absence of) anxiety, emotional and mental health, physical function, and global
GIQLI score. In a study focusing on the effect of testicular radiation dose, Hennies
et al. (2012) assessed HRQoL with the QLQ-C30 and QLQ-CR38. Compared to
pre-treatment scores, at 1 year patients reported worse physical, role and social
function; worse body image, sexual functioning and enjoyment and increased
symptoms, including fatigue, pain, dyspnoea, diarrhoea, financial difficulties,
micturition problems, CT side effects, defecation problems and male sexual dys-
function, although future perspectives increased. Planting et al. (2013) used a
telephone interview to assess the impact of TEM on HRQoL, measured with the
QLQ-C30, QLQ-CR38 and FIQL. The overtime analysis, however, is unreliable, as
preoperative scores were assessed retrospectively and biases could have occurred.
3.4.3 Other Focus

Hirche et al. (2010) reported on long-term outcomes of patients with a specific
neosphincter reconstruction (perineal spiral cuff plasty) after APR for very low
rectal cancer. Ristvedt and Trinkaus (2009) focused on the influence of trait
anxiety, measured at the first follow-up visit after surgery, on HRQoL and post-
traumatic stress symptoms 2–5 years after surgery. Carlsson et al. (2010) focused
on the concerns expressed by stoma patients and how they change overtime.
Additionally, HRQoL was measured and results were compared with population
norms. Finally, the article by Caravati-Jouvenceaux et al. (2011) also focused on
the comparison with healthy controls.
3.5 Comparison with Reference Data from Healthy Population
Out of 56 articles selected for this review, 12 made comparison with healthy
subjects. Two articles compared patients’ HRQoL with data from the general
population at different time points. Carlson et al. (2010) used the 8 subscales of the
SF-36 preoperatively and 1, 3 and 6 months postoperatively to compare stoma
patients’ scores to population norms. Preoperatively, patients had worse scores for:
role limitations due to physical health and to emotional problems, social function
and mental health. This difference remained clinically significant at 6 months only
for role limitations due to physical health and social function. Caravati-Jovenceaux
et al. (2011), using the SF-36 and QLQ-C30 questionnaires, compared three
cohorts of rectal cancer patients (n = 198) with 5, 10 and 15 years of follow-up
with a random sample of the general population (n = 413). Clinically meaningful

differences were found only for diarrhoea, which was worse in all cohorts of
patients. Patients with 10 years of follow-up also showed more constipation and
lower social function than the general population.
Most of the other studies comparing patients with the general population
focussed on (neo)adjuvant therapies. Thong et al. (2011) compared a group of
patients undergoing surgery-only and a group of patients undergoing pRT followed
by surgery with the reference data for the SF-36 questionnaires. Additionally, data
concerning the sexuality subscale of the QLQ-CR38 were collected from the
general population to allow a comparison of sexual functioning as well. While no
clinically meaningful differences were found in the SF-36 scores, at a median of
4 years form surgery, both groups of patients showed impaired sexual functioning
and reduced sexual enjoyment. Bruheim et al. (2010) compared irradiated and non-
irradiated patients with the general population on the functional scales of the QLQ-
C30. At a median time of 4.8 years from surgery, the only difference was found for
irradiated patients who had worse social function than the general population.
Compared to the general population, at a median time from surgery of 5.6 years,
patients who underwent either long course pCRT or short course pRT had sig-
nificantly worse role and emotional functioning, more diarrhoea, more constipa-
tion, and more financial difficulties (Guckenbergen et al. 2013). Similarly, Kripp
et al. (2012) reported that both patients who underwent conventional or intensified
pCRT had worse role and social function and more diarrhoea relative to the
general population, and Braendengen et al. (2012) found that patients who
underwent pCRT or pRT had worse social functioning and more diarrhoea than the
general population at a median time from surgery of 6 years. pCRT patients
reported worse constipation and diarrhoea than the general population also in the
study by Pucciarelli et al. (2010), although no other differences were found on the
QLQ-C30. Konanz et al. (2013) compared three groups of patients with the general
population using the QLQ-C30 at a median time from surgery of 4.9 years. All
patients showed worse role and social functioning, more constipation, diarrhoea
and financial difficulties. Other clinically meaningful differences compared to the
general population were found for: global health status (reduced in patients who
underwent ISR or APR); physical function (reduced in patients who underwent
LAR or APR); cognitive function (reduced in ISR and LAR patients); dyspnoea
(increased in ISR and APR patients); fatigue and insomnia (both increased in LAR
and APR patients). Orsini et al. (2013) stratified patients with and without a stoma
in two age groups and compared their scores with the reference data for the SF-36
questionnaire and the sexuality subscale of the QLQ-CR38. For patients younger
than 70, no clinically meaningful differences were found in the SF-36 scores, at a
median of 3.4 years form surgery, but both stoma and non-stoma patients showed
impaired sexual functioning and reduced sexual enjoyment. Patients older than 70
reported worse sexual enjoyment, but no differences in sexual functioning relative
to healthy controls. Stoma patients showed a decreased physical function and non-
stoma patients showed increased role limitations due to physical problems. Austin
et al. (2010) compared patients who underwent pelvic exenteration to the general
population at a median time of 3.9 years from surgery. Of the two component
summary scores of the SF-36 questionnaire, the physical one was significantly
worse in patients, whereas the mental score did not differ. Using the PGWBI, after
a median time of 68 months, Serpentini et al. (2011) found that patients aged
between 65 and 74 years had statistically significant better scores on general
health, positive well-being, vitality, anxiety, depressed mood and global index
score.
4 Discussion and Conclusion
While the traditional outcomes in rectal cancer research have been overall, dis-
ease-free and local recurrence-free survival, in the last decades there has been
growing interest in the field of QoL, which is now considered a relevant outcome
in clinical trials (Sprangers et al. 1995; Renner et al. 1999; Dunn et al. 2003).
Because of the aggressiveness of multimodality approaches, the potentially severe
consequences on bowel function, faecal continence, and sexual function, and the
high rate of surgical morbidity, the diagnosis and the treatment of rectal cancer
may have a significant impact on patients’ HRQoL.
The aim of this review was to retrieve, classify and analyse the articles pub-
lished from January 2009 to November 2013, focusing on HRQoL after surgery in
patients with rectal cancer. Fifty-six articles met the inclusion criteria.
As summarised in the Table 1, the majority of the articles focused on the
comparison between surgical treatments (37.5 %) and, particularly, on the impact
of having a stoma on HRQoL, or on the impact of multimodality treatment on
HRQoL (19.6 %). The comparison between patients and the normal population
was a principal end point or a secondary aim in twelve (21.4 %) studies. From a
methodological point of view, the vast majority of studies (83.9 %) were obser-
vational, and only 10.7 % were performed within prospective randomised trials.
Two third of the articles were controlled, and more than 50 % were cross-sec-
tional. About 60 % of the studies included more than 100 patients, and in half of
the articles, the proportion of patients who had received a neoadjuvant treatment,
either pRT or pCRT, was more than 60 %. The most frequent instruments used
were the EORTC QLQ-C30, its colorectal module QLQ-CR38 and the MOS SF-
36, which were used in 64.3, 44.6 and 28.6 % of the studies, respectively.
Our review highlighted the heterogeneity of design characteristics, and caution
should be used in interpreting findings considering methodological limitations.
The ideal study on HRQoL should be: prospective, longitudinal, with a baseline
assessment prior to any treatment, randomised (when comparing two or
more treatments), controlled, with an adequate sample size, powered to detect the
expected changes on relevant HRQoL subscales, and HRQoL should be assessed
with validated and established questionnaires. Less than 10 % of the studies
included in this review presented these characteristics (Austin et al. 2010; Kang
et al. 2010; Andersson et al. 2013; Doeksen et al. 2012; Braendengen et al. 2012).
In addition to differences between topics, aims and methodology, the com-

parison of findings from different studies has also been limited by factors related to
the quality of the reporting of HRQoL. For instance, even when using the same
instruments, in some cases the authors did not fully report raw data making it
difficult to fully judge the presence of clinically meaningful differences or, albeit in
fewer cases, the findings from some instruments were not reported. This is in line
with previous work showing that the quality of reporting HRQoL data is poor and
needs improvement (Brundage et al. 2011). For example, only 14 % of randomised
controlled trials including HRQoL data met simultaneously four essential minimal
quality indicators, i.e. reporting evidence for the validity of the instrument, stating
HRQoL hypothesis, reporting how missing data were handled, and interpreting and
discussing HRQoL findings. This issue is especially relevant when considering
that findings from different studies have to be aggregated when informing deci-
sion-making at all levels (Sutherland and Till 1993; Stiggelbout and de Haes
2001).
Taking into consideration these concerns, we can summarise the main findings
in the area of the three most frequently investigated comparisons, namely between
surgical treatments, between irradiated and not-irradiated patients and between
patients and the general population.
The most frequent comparisons between surgical treatments were between SPSs
and non-restorative resections, and between stoma and stoma-free patients. Living
with a permanent stoma has for long time been thought to have a negative impact on
patients’ HRQoL. This conviction has been questioned by the findings of our
review, as well as by previous reviews (Pachler and Wille-Jørgensen 2005; Cornish
et al. 2007). The findings about the comparison between stoma and no-stoma and
between SPSs and non-restorative resections were often disparate and are difficult
to summarise. Out of the 13 articles on this topic included in our review (Campos-
Lobato et al. 2011; Fischer et al. 2010; Austin et al. 2010; Celasin et al. 2011; Varpe
et al. 2011; Konanz et al. 2013; Mrak et al. 2011; How et al. 2012; Kasparek et al.
2011; Yau et al. 2009; Orsini et al. 2013; Bossema et al. 2011; Krouse et al. 2009),
four did not find clinically meaningful differences (Campos-Lobato et al. 2011;
Fischer et al. 2010; Austin et al. 2010; Celasin et al. 2011). The most frequently
impacted HRQoL scales were: social function (8 articles), sexual functioning and
male sexual dysfunction (5 articles each), global health status, physical functioning,
body pain, diarrhoea and fatigue (4 articles each). Global health status and social
functioning were always found to be better in the group without stoma or in the
group treated with SPS. Additionally, four of the five studies reporting differences
on sexual functioning or male sexual dysfunction favoured stoma-free patients or
patients treated with sphincter-preserving interventions. In line with the Cochrane
review (Pachler and Wille-Jørgensen 2005) and a previous meta-analysis (Cornish
et al. 2007), these findings support the thesis that having a stoma has not a clear
negative impact on HRQoL, although none of the articles analysed was clearly in
favour of non-restorative surgeries or stoma creation. However, an important point
to consider is that the alternative to non-restorative surgery is ULAR or ISR with
low colorectal or CAA, often preceded by radiotherapy or chemoradiotherapy. It is
known that these procedures are associated with a high rate of morbidity, including
anastomotic leakage, and severe consequences on bowel function and faecal con-
tinence. Thus, it is not surprising that many HRQoL scores of stoma-free patients
are not dissimilar from those of patients with a permanent stoma.
Other factors that may contribute to the lack of a clear difference between the
two groups are related to the ethnic, cultural, economic, stoma care and educa-
tional factors (Pachler and Wille-Jørgensen 2005), as well as to proper informa-
tion, especially about patients’ adaptation to stoma and changing concerns
overtime (Carlsson et al. 2010). Therefore, when possible, the choice between
sphincter- or non-SPS should not be preconceived, should be individualised and
should take into account fully informed patient’s preferences.
Remaining in the surgical domain, the increasing use of laparoscopy also in the
treatment of rectal cancer calls for assessments of whether its use has advantages
over the use of open surgical approaches. On this topic, three of the four studies
included in this review assessed more than 100 patients. Two of them were ran-
domised, one included all patients randomised in the COREAN trial (Kang et al.
2010) and the other included a subgroup of patients enrolled in the COLOR II trial
(Andersson et al. 2013). Both randomised trials found no clinically meaningful
differences at any time point assessed. The other non-randomised study found
differences concerning body image, which was better in the laparoscopic group at
1 week, 3 months and 1 year after surgery. The sample size, design and ease of
comparison between studies using the same HRQoL instruments strongly support
the equivalence between the two techniques.
Another frequently addressed topic is the effect of multimodality therapies. The
comparison between irradiated and non-irradiated patients was reported in six
studies (Canda et al. 2010; Peng et al. 2011; Thong et al. 2011; Bruheim et al.
2010; Kasparek et al. 2012; Parc et al. 2009) and four studies assessed the effect of
adding chemotherapy to radiation therapy (Parc et al. 2009; Braendengen et al.
2012; Tiv et al. 2010; Guckenberger et al. 2013). Two studies found no differences
between irradiated and non-irradiated patients (Canda et al. 2010; Parc et al. 2009),
the others found some differences, favouring non-irradiated patients in the areas of
bowel function (2 studies), sexuality (2 studies) and role and social function
(1 study each). However, it should be noted that the two groups had often dif-
ferences in clinical characteristics at baseline. One of the studies assessing the
additional effect of CT found no differences (Braendengen et al. 2012), two studies
found a negative impact on bowel function (Tiv et al. 2010; Guckenberger et al.
2013), one on social function (Tiv et al. 2010) and one found an effect on mental
scores and a temporary effect on physical scores (Parc et al. 2009). These findings
are in line with our previous work, suggesting that the most impacted HRQoL
dimensions are role and social function and symptoms related to bowel and sexual
function (Gavaruzzi et al. 2013; Gavaruzzi et al. 2014).
In total, twelve articles reported on comparisons between patients’ and general
population’s HRQoL scores. The majority (9 out of 11) of the articles that reported
on scales assessing global or general health or QoL (QLQ-C30, SF-36, PGWBI)
found no differences between patients and the general population (Orsini et al.
2013; Thong et al. 2011; Bruheim et al. 2010; Braendengen et al. 2012; Kripp et al.
2012; Guckenberger et al. 2013; Pucciarelli et al. 2010; Carlsson et al. 2010;
Caravati-Jouvenceaux et al. 2011), whereas the other two articles reported con-
trasting findings, one favouring the general population (Konanz et al. 2013) and
one favouring patients (Serpentini et al. 2011). In terms of HRQoL functions,
patients were found to have worse scores that the general population on social
function (6 out of 10 articles), role function (5 out of 10 articles), physical function
(3 out of 11 articles) and emotional function (1 out of 7 articles). In terms of
symptoms scales, the most frequently reported differences concerned bowel
function (including diarrhoea and constipation, 6 out of 6 articles) and sexual
function (assessed with the two functional scales of the QLQ-CR38, 2 out of 2
articles). The finding that general HRQoL scores are similar between patients and
healthy controls is in line with previous reviews (Gavaruzzi et al. 2013; Gavaruzzi
et al. 2014). In terms of instruments used to assess HRQoL, most studies used the
SF-36 or QLQ-C30 questionnaire. While the former is a generic instrument, the
latter is a specific instrument designed for all cancer patients and includes also
symptoms scales. Given that the most consistent difference between patients and
the general population concerns bowel symptoms, our findings support the use of
the QLQ-C30 rather than the SF-36 questionnaire. Additionally, two studies also
compared patients and healthy controls on the sexual functional scales of the QLQ-
CR38, both finding a lower function in patients.
When planning studies comparing patients and the general population or
comparing different treatments, particular attention should be paid to the use of
instruments that are likely to detect potential differences and to the calculation of
sample size based on relevant subscales.
In conclusion, there is no clear evidence that HRQoL is better in stoma-free
patients compared with those with a permanent stoma. The choice between SSP or
non-SSP should be individualised, not preconceived and should take into account
the fully informed patient’s preferences. Laparoscopic and open surgery are
equivalent in terms of HRQoL. While there is no strong evidence that neoadjuvant
therapy has a negative impact on global QOL, our findings suggest that preoper-
ative irradiation do have a negative impact on some scales.
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Part IV
Combined Modality Therapy
in Rectal Cancer
Aims of Combined Modality Therapy
in Rectal Cancer (M0)
J. P. Gerard, K. Benezery, J. Doyen and E. Francois
Abstract
Optimizing the Cost/benefit ratio of treatment: Evidence Based The aim of a
cancer treatment is always to achieve the maximum of cure rate with a minimum
of toxicity and best quality of life at an acceptable cost for the society. It is
always a multifactorial challenge depending on the patient, the tumor, the
doctor, and the society cultural and financial backgrounds. The goal is to find the
best cost/benefit ratio between all possible strategies in agreement with a well-
informed patient. In rectal cancer (M0) surgery is the cornerstone of treatment.
Combined modality therapies aim at optimizing the cost/benefit ratio of possible
strategies and only randomized trials can bring strong evidence regarding their
results and recommendations. Lessons from randomized trials: quite modest
During the past decades many phase III trials have shown that: (1) neoadjuvant
treatment even with ‘‘TME’’ surgery was better than adjuvant, (2) chemoradio-
therapy (CRT) was better than RT alone, (3) long course CRT was probably
more efficient (in terms of ypCR) than short course (25/5), and (4) capecitabine
was as efficient as 5 FU but oxaliplatin was not adding benefit. Overall, the gains
of nCRT remain modest and it is mainly a reduction in local relapse not
exceeding 5 %, but no benefit in survival and neither in sphincter saving surgery
has been proven. The way forwards organ preservation in case of CCR. Local
Conflict of interest: JP Gérard is the medical advisor of the Ariane Medical Systems company
J. P. Gerard (&) K. Benezery J. Doyen

Departement of Radiation Oncology, Centre Antoine-Lacassagne, 33 Avenue de Valombrose,
01689, Nice Cedex 2, France
E. Francois
Departement of Medical Oncology, Centre Antoine Lacassagne, Nice, France
154 J. P. Gerard et al.
control: can probably be improved for T4 tumors by RT dose escalation.

Survival: can be increased by innovative medical treatment either before or after
surgery. Toxicity: may be reduced by a less aggressive treatment in elderly.
Conservative treatment: A new field of clinical research is to achieve ‘‘organ
preservation’’ (and not only sphincter saving). To modify the surgical approach
and preserve the whole rectum, neoadjuvant treatment must achieve safely a
clinical complete response. As rectal adenocarcinoma is a relatively radiore-
sistant tumor endocavitary irradiation (contact X-Ray) is a promising safe
approach and this hypothesis will be addressed by the OPERA randomized trial.
Keywords
Rectal cancer Multimodality therapy Organ preservation Conservative
treatment
1 Optimizing the Cost–Benefit Ratio of Treatment

According to Evidence-Based Medicine
Since Hippocrates the aim of a curative medical treatment is to achieve the most
efficient result against the disease and the less toxic effect for the patient. One the
first curative treatments for rectal cancer was introduced by Miles in 1908 using
‘‘a radical abdomino-perineal resection’’ (APR) with an acceptable (although high)
operative mortality. Since then surgery has been (and will remain) the cornerstone
of the treatment of rectal cancer. The modern era of rectal surgery started with the
introduction of the so-called ‘‘TME surgery’’ removing the mesorectum along the
‘‘holly plane’’ with sharp dissection under vision control (Heald and Ryall 1986).
To improve local control and survival radiotherapy and chemotherapy have been
used in association with surgery. Due to the many confounding factors, the results
of such combined treatments can be evaluated only using randomized control trial.
The ultimate aim is to reach 100 % cure with 0 % toxicity. Most of the new
treatments aiming at better local control or survival use radiation dose escalation
or more efficient multidrug medical treatments. The main limiting factor to this
intensification is the induced toxicity. It is the merit of the ‘‘TME surgery’’ to be at
the same time able to achieve a better local control by reducing the breaching of
the rectal fascia and a lower toxicity by sparing the latero-pelvic nerves. It is
probably the advantage of the laparoscopic approach to reach similar results by
reducing further the operative health constraint for the patient (Panis et al. 2011).
May be one of the most significant progress in the past decades impacting survival
was the dramatic reduction in the rate of operative mortality. Intensive care,
improved anesthesia, reduction of radiation toxicity with smaller irradiated vol-
ume, and better surgical bleeding and infection control have reduced the 60 days
postoperative mortality from 10 % to close to 1 %. Only in elderly, frail patients
surgery is remaining a significant trauma (Rutten et al. 2008).
Aims of Combined Modality Therapy in Rectal Cancer (M0) 155
When analyzing the benefits of the various combined multimodality treatments

associated to surgery it is crucial to take into consideration the two aspects of the
balance (benefit vs. cost) and to include in the cost all the sustainable aspects
relevant to the patient, the healthcare system, and the society. Most probably in
this subtle equilibrium between benefit and cost, toxicity is the main parameter
because it is, since Hippocrates again, the key ethical message of medicine:
‘‘Primum non nocere’’ which in modern language may be assimilated to the
‘‘Principe de précaution.’’ In such a complex situation and as the improvements are
generally (and unfortunately) small only RCT can bring reliable scientific evi-
dence, which remains the best way leading to changes of practice in the medical
community.
2 Recent Results Gained Through Randomized Trials
2.1 Quite Modest Even if Local Recurrence Rate

Is Now Below 7 %
Until the end of the twentieth century radical surgery followed by adjuvant che-
moradiotherapy (CRT) was the standard treatment for rectal cancer (stage M0)
(Conference 1990; Krook et al. 1991; O’Connell et al. 1994) (Table 1). It was the
merit of the Swedish and mainly German trials (Folkesson et al. 2005; Pahlman and
Glimelius 1990; Frykholm et al. 1993; Sauer et al. 2004, 2012) to demonstrate that
neoadjuvant CRT (nCRT) was more efficient and possibly less toxic than adjuvant
CRT (Park et al. 2011). As ‘‘TME surgery’’ was introduced in early 2000, it was one
of the main conclusion of the Dutch trial to show that even with a ‘‘TME surgery’’
preoperative radiotherapy (short course) was improving local control (Kapiteijn
et al. 2001; van Gijn et al. 2011). Other more recent trials demonstrated that nCRT
was more efficient for long-term local control than radiotherapy alone (Bosset et al.
2006, 2014; Gerard et al. 2006), that capecitabine was as efficient as Fluorouracile
(5FU) (Gerard et al. 2010, 2012; Aschele et al. 2011; Schmoll et al 2013; Roh et al.
2011) that radiation dose escalation using external beam radiotherapy (EBRT) from
45 Gy/5 weeks up to 50 Gy/5w was producing more pathologic sterilization of the
tumor (ypCR) without increase in 3-year toxicity, but without other clinical sig-
nificant benefits (Gerard et al. 2012) and that oxaliplatine was not to be given
concurrently with EBRT and Capecitabine (or 5FU) (Schmoll et al. 2013; Roh et al.
2011). As local control is at the present time close to 95 % in T2-3 M0 tumors the
only way to improve survival is to find an efficient (and not too toxic) medical
treatment. First-line chemotherapy has been proven possible without compromising
nRT and surgery (Fernandez-Martos et al. 2010; Chua et al. 2010). With increasing
knowledge about the molecular abnormalities driving cell growth, immune reac-
tion, and tumor proliferation various molecular targeted drugs (MTD) have been
tested. So far the results have not been totally convincing using as neoadjuvant
Table 1 Overview of some of the main messages and conclusion derived from recent randomized control trials
156
Study Regimen 5-year local 5-year Sphincter Comments

recurrence overall preservation
(%) survival (%)
(%)
Krook et al. (1991) Postoperative radiotherapy (45 Gy) versus 25 versus 48 versus 50 versus 50 Postoperative concurrent
(1980–1986) n = 204 postoperative concurrent 13.5 58 chemoradiotherapy improves local control
chemoradiotherapy (45 Gy and 5-FU) and survival; becomes standard treatment
(P = 0.03)
Pahlman and Surgery alone versus preoperative 25 versus 8 55 versus 44 versus 40 Postoperative death in experimental arm
Glimelius (1990), radiotherapy (25 Gy in 5 fractions) 63 was reduced from 15 to 4 % by reducing
Frykholm et al. the radiation volume
(1993) (1987–1990)
(P = 0.001) (P = 0.008) (P = 0.001)
n = 908
Marsh et al. (1994) Surgery alone versus preoperative 36.5 versus 50 versus 48 versus 46 4 MV linear accelerator and small fields in
(1982–1986) n = 284 radiotherapy (20 Gy in 4 fractions) small 12.8 56 the posterior pelvis reduce local recurrence
field (10 9 10 cm) without toxicity
(P = 0.0001)
Kapiteijn et al. Total mesorectal excision versus 11 versus 6 63 versus 67 versus 65 Short course preoperative radiotherapy
(Pettersson et al. preoperative radiotherapy (25 Gy in 5 64 improves local control even with total
(P = 0.001)
2010) (1996–1999) fractions) mesorectal excision surgery
n = 1,861
Lyon R96–02 (Gerard Preoperative radiotherapy versus 11 versus 8 67 versus 44 versus 76 Safe high-dose RT escalation with CBX
et al. 2004; Ortholan preoperative radiotherapy and CBX (85 Gy 67 enables improved sphincter and rectal
(P = 0.004)
et al. 2012) in 3 fractions) preservation
(1996–2001) n = 88
CAO/ARO/AIO Postoperative concurrent 13 versus 6 74 versus 71 versus 69 Preoperative concurrent
(Sauer et al. 2004, chemoradiotherapy (45 Gy in 25 fractions 76 chemoradiotherapy superior in terms of
(P = 0.006)
2012) (1995–2002) and 5-FU) versus preoperative concurrent local control and early toxicity; becomes
n = 823 chemoradiotherapy (45 Gy in 25 fractions standard treatment
and 5-FU)
J. P. Gerard et al.
(continued)
Table 1 (continued)
(%) survival (%)
(%)
FFCD 9203 (Géard Preoperative radiotherapy (45 Gy in 25 16 versus 8 67 versus 50 versus 50 Properative concurrent chemoradiotherapy
2006) (1993–2003) fractions) versus preoperative concurrent 67 is superior to radiotherapy alone in terms
n = 762 chemoradiotherapy (45 Gy in 25 fractions of local control
and 5-FU)
MRC CRO7 (Sebag Preoperative radiotherapy (25 Gy in 5 10.6 versus 70 versus 63 versus 65 Confirmation of Kapiteijn et al. (Pettersson
2009) (1998–2005) fractions) versus selective postoperative 4.4 68 et al. 2010) with minimal radiation
n = 1,350 concurrent chemoradiotherapy (45 Gy and toxicity; local control improved with
5–FU) preoperative radiotherapy versus
postoperative concurrent
chemoradiotherapy
ACCORD 12 (Gerard Preoperative concurrent chemoradiotherapy 6.1 versus 85 versus 74 versus 76 A sterilized operative specimen was
et al. 2003) (45 Gy and capecitabine) versus 4.7§ 83§ observed in 13 % of cases in first arm and
(2005–2008) n = 598 preoperative concurrent chemoradiotherapy 19 % in second
(50 Gy and capecitabine and oxaliplatin) Local relapse at 3 years \5 % with 50 Gy
Aims of Combined Modality Therapy in Rectal Cancer (M0)
radiotherapy
STAR 01 (Aschele Preoperative concurrent chemoradiotherapy NR NR 79 versus 81 A sterilized operative specimen was
2011) (2003–2008) (50.4 Gy in 28 fractions and 5-FU) versus observed in 16 % of cases in both arms.
n = 747 preoperative concurrent chemoradiotherapy Oxaliplatin associated with higher early
(50.4 Gy in 28 fractions and oxaliplatin) grade 3 toxic events and does not increase
tumor sterilization
(continued)
157
Table 1 (continued)
158

(%) survival (%)
(%)
KOREA (Park et al. Preoperative versus postoperative 4 % versus 77 % versus 80 % versus Despite more ypCR in preop group no
2011) N = 220 chemoradiotherapy (CAP50) 6% 73 % 72 % significant difference in sphincter
preservation. Post op less toxic than preop
(4 year) (3y DFS) (NS)
CAO/ARO04 (Rodel Preop RT (46 Gy + 5Fu ± oxaliplatin) NR NR 88 % (no FU+ oxalipt give a higher reate of ypCR
et al. 2012) 1236 pts different) without excessive toxicity. Waiting for
endpoints 3y DFS
PETTAC6 (Schmoll Néoadjuvant and adjuvant treatment using NR NR 68 % (no Oxaliplatin does not increase tumor
et al. 2013) N = 1094 capecitabine + oxaliplatin versus difference) response or local control or survival but
capecitabine alone gives more toxicity
NSABP R04 (Roh 2 9 2 format 5FU versus capecitabine with NR NR 62 % (no Capecitabine is equivalent to 5FU.
et al. 2011) N = 1608 or without oxaliplatin néoadjuvants difference) Oxaliplatin no benefit more early toxicity
J. P. Gerard et al.
treatment either anti EGFR MDT (Dewdney et al. 2012) or anti-VEGF concurrently
with radiotherapy. Such MDT can provide sometimes increased toxicity (Crane
et al. 2003) or decreased radiosensitivity (Machiels et al. 2007; Willett et al. 2009).
2.2 Does Neoadjuvant Treatment Reduce the Rate

of Permanent Stoma? Surprisingly NO
One of the most common medical beliefs is that preoperative treatment especially
nCRT with long interval will ‘‘downsize’’ the tumor (T2-T3-T4) and increase the
chance of a conservative treatment, namely sphincter saving surgery (SSS) using
either low anterior resection (LAR) or inter sphincteric resection (ISR) (Rullier
et al. 2013). In fact, conservative treatment of rectal cancer is a very complex
situation with the interaction of many multifactorial parameters related to the
tumor, the patient, the surgeon, and the general culture of a specific country or
area. Here, more than everywhere else, only randomized trials can give strong
evidence regarding the benefit of any preoperative treatment in terms of conser-
vative treatment. Two literature reviews have analyzed this question (Bujko et al.
2006; Gerard et al. 2012). Both authors came to the same conclusion: for T2-3 (4)
rectal cancers the rate of permanent stoma (for distal and middle rectum) have
dramatically decreased during the past decades from 70 to 25 % (and sometimes
10 %), but this increase in sphincter preservation was due to technical surgical
innovation and new concepts regarding the distal margin to be respected (from 5 to
2 even 1 cm) (Pahlman et al. 2013). In none of the randomized trials the group
using the experimental treatment showed a significant increase in the rate of SSS
despite often an increase in sterilization (ypCR) of the operative specimen (Fig. 1).
A recent randomized trial performed in South Korea (Park et al. 2011) compared
(as in the German CAO/ARO trial) postoperative CRT with nCRT. Despite a
highly significant difference in the rate of ypCR (0 vs. 20 %) there was a non-
significant increase in the rate of sphinter saving surgery (62 vs. 70 %). In a Nordic
trial (Braendengen et al. 2008; Braendengen et al. 2011) nCRT when compared to
short course RT with immediate surgery for T4 tumor was able to increase R0
surgery, local control, and sphincter preservation.
2.3 The Clinical Complete Response Hypothesis
The Lyon R96-2 trial using sphincter preservation as the main endpoint was the
only trial showing a benefit of the neoadjuvant treatment to improve the rate of
conservative treatment (Table 2). The addition of a boost using contact Brachy-
therapy X Ray 50 kV (CBX) 90 Gy in 3 fractions to EBRT increased the SSS rate
from 44 to 76 % without increase in toxicity and preservation of a good bowel
function (Gerard et al. 2004). Two points were of interest in this trial: first the rate
of clinical complete response (CCR) was increased in the CBX boost group from 2
to 29 % and this finding may explain why the surgeons were more in favor of a
Fig. 1 Forest plot summarizing the results of recent randomized trials about sphincter
preservation and showing the lack of benefit of neo adjuvant treatment (with the exception of
the Lyon R 96-2 trial)
conservative approach in the boost group. When the surgeon see only a partial
response he does not modify his surgical initial decision, but when he cannot see or
palpate anymore a lesion he may reappraise his decision and perform a more
conservative technique (Ortholan et al. 2006). Second, not only Anterior Resection
was more frequent in the boost group, but also most of all ‘‘organ preservation’’ as
10 patients out of 45 in the CBX group were able to preserve the whole rectum
after CCR using either a local excision or only a careful surveillance (Watch and
wait). These data has been updated after 10 years of follow-up and the gain in
stoma-free rate was maintained on the long-term without detrimental effect on
local control or survival (Ortholan et al. 2012).
2.4 How to Increase Safely the Rate of CCR to Perform More

Conservative Treatment
There are mainly three ways to increase the CCR rate:

(1) Increase the interval between the end of the neoadjuvant treatment and the
surgery: the Lyon R 90-1 trial compared an interval of 2 versus 6 weeks. An
increase in ypCR was observed (2 vs. 13 % p: 0.005), but it did not translate in
Table 2 Lyon R96-02 randomized trial 1996–2001 (Géard 2004; Ortholan et al. 2012)
Inclusion criteria T2-T3 \ circumference B6 cm from anal verge (distal
rectum) Operable patient-any age [18
Randomization A- Preoperative EBRT alone (39 Gy/13 F/3 W)
B- Preoperative same EBRT + boost CBX (90 Gy/3F)
Boost usually given before EBRT. Surgery TME: 5 weeks
after end EBRT. No chemoradiotherapy
Endpoint Sphincter preservation
Hypothesis: A: 40 % B: 70 %
1996–2001 88 patients included
EBRT (43 pts) CBX + EBRT (45 points)
Med age 67 69
T2 12 10
T3 29 33
CCR 1 (2 %) 11 (29 %)
APE 24 11
Sph. Savint Tt 19 (44 %) 34 (76 %) p = 0.004

Watch and Wait Organ 0 7
0 10
Loc Excision preserved 0 3
Distant meta 3 y 11 9
10 year ov. Surv 56 % 55 %
10 year loc rec 5 (15 %) 4 (10 %)
10 year stoma free 27 % 61 % p \ 0.001
At 10 years, 9 patients with organ preserved with no local recurrence, good anorectal function for
all. Rectal bleeding G2 during the first 3 years. CCR Clinical Complete Response, APE Abdo-
mino-Perineal Excision
a better SSS rate (Francois et al. 1999; Glehen et al. 2003). In Sao Paulo, Habr
Gama has been for many years a strong advocate of a conservative treatment
in case of CCR after nCRT. By increasing the interval before evaluation of the
response from 5 to 12 weeks habr gama was able to increase the rate of CCR
from 30 to 55 % (Habr-Gama et al. 2009; Habr-Gama et al. 2014). In the
stockholm trial after short course an interval of 5 weeks (compared to
immediate surgery) increased the ypCR without difference in toxicity, but
without increase in SSS (Pettersson et al. 2010, 2012). It is probably after 2 to
3 months after the end of the nCRT that the optimal tumor response can be
seen (Sloothaak et al. 2013; Wang et al. 2005).
(2) Concurrent use of one or two chemotherapy with radiotherapy: The FFCD
9203 and EORTC 22921 trials have shown that the addition of 5FU to pre-
operative irradiation is increasing ypCR and most of all local control in T3-4
rectal cancer, but without gain in SSS (Bosset et al. 2006; Gerard et al. 2006).
The addition of oxaliplatin to 5FU or Capecitabine is not adding any benefit to
the patient and may increase the risk of diarrhea (Gerard et al. 2010; Aschele
et al. 2011; Schmoll et al. 2013).
(3) Radiation dose escalation is probably the most efficient way so far. In Toronto
the dose escalation from 40 to 45 until 50 Gy was associated with a pro-
gressive increase of ypCR from 10 to 19 % (Wiltshire et al. 2006). In the
ACCORD 12 trial a biological dose escalation of 15 % (from 45 to 50 Gy with
the same protraction time of 5 weeks) increased the ypCR from 13 to 19 %
(Gerard et al. 2010). The main limitation of such dose escalation, even with
modern RT technique as IMRT or Proton therapy is the tolerance of the
normal pelvic tissues and OAR (Gerard et al. 2004, 2003). The most efficient
way to escalate the RT dose with regards to the ‘‘Toxicity/Benefit’’ ratio is
using endocavitary irradiation, which can concentrate the dose to the primary
tumor without arming too severely the surrounding OAR. With HDR Iridium
combined with EBRT it is possible to achieve in T3 tumors a CCR rate of
70 % (Vuong et al. 2007). The randomized trial performed in Danemark
(Jakobsen et al. 2006, 2012) despite an increase in ypCR in the group treated
with Ir HDR did not show an increase in SSS and lead to more toxicity. Same
findings in a phase III trial in Pakistan (Tunio et al. 2010). On the other hand
as previously reported a safe dose escalation using CBX 50 kV was able to
significantly increase CCR, sphincter saving, and most of all organ preser-
vation. Unfortunately, this trial performed in a single institution in a limited
number of patient has not influenced clinical practices (Gerard et al. 2004;
Ortholan et al. 2012).
3 Aim of the Ongoing and Upcoming Randomized Trials
The most relevant and standard endpoint of CRT is overall survival, but in practice
this endpoint is seldom used because it requires to include more than 1,000
patients and a very long follow-up. Disease Free Survival at 3 years is often the
main endpoint of trial aiming at increasing survival. Other endpoints as ypCR,
TRS (tumor regression score) (Taylor et al. 2011; Patel et al. 2011; Nougaret et al.
2013), R0 surgery may be used, but none can be considered as a robust surrogate
endpoint of overall survival (Methy et al. 2010). Toxicity, rate of organ preser-
vation, quality of life, and bowel or sexual functions are always major endpoints
(Table 3). From a pragmatic point of view neo or adjuvant treatments are aiming at
improved four clinical objectives:
(1) Local Control In T2 T3 tumors it will be difficult to demonstrate a further
improvement over 95 % local control. In T4 following the trial of Braendegen
(Braendengen et al. 2008, 2011), the GRECCAR 4 trial (EUDRACT N
1234556…) is comparing a standard radiation dose of 50 Gy combined with
capecitabine to 60 Gy dose in a reduced boost volume. Different techniques of
Table 3 Ongoing or up coming randomized control trials in operable T2-3-4 Nx M0 rectal

cancer
Study Inclusion Regimen Endpoint N
criteria pt
RAPIDO T3 c-d • Cap50 + TME 3y DFS 600
Sweden ongoing T4 • 5 9 5-chemo (folfox) TME 60–70 %
Nx
PRODIGE23 T3-T4 • Cap 50 + TME 3y DFS 500
France NCT Nx • Folfirinox-cap 50 65–75 %
01804790 +TME
Ongoing
Aristotle T3-T4 • Cap45 TME 3y DFS 600
UK Nx • Capiri 45 TME 60–70 %
Ongoing
GRECCAR4 T3-T4 First-line chemo R0 resection 250
France Folfirinox poor response 85 ? 95 %
Ongoing • Cap50-TME
N1048 • Cap60-TME
GRECCAR4 T3-T4 First-line chemo folfirinox RO resection 250
France ongoing Good response 95 versus
95 %
• CAP50-TME
• TME
PRODIGE X T3-T4 • CAP50-TME Toxicity - Q.L 250
France up coming Age • 5 9 5-TME
[70 years
OPERA T2 T3a-b CAP45 Organ 236
preserved
European • EBRT boost 5.4 Gy
5–25 %
up coming • CBX boost 90 Gy/3F
NCCTG T3 • Folfox + TME • R0 1060
N1048 (US) if response [20 % • Survival
• nCRT
BACCHUS (UK) up T3 ±6 cycles bevacizumab with
coming FOLFOX or FOLFOXIRI preop
COPERNICUS (UK) T3 Firs line chemo + 5 9 5
up coming
(continued)
Table 3 (continued)
Study Inclusion Regimen Endpoint N
criteria pt
Poland T2-T3a Preop 5 9 5 versus CRT 6 weeks Local control 200
NCT00738790 local excision pCR
GRECCAR7 T3-4 CRT and interval 7 weeks versus Pathological 250
NCT01648894 11 weeks: TME response
Rectum 51B UZB T3-4 CRT versus RT with simultaneous pCR
NCT01224392 integrated TBODSV
Rectum TEM spain T2T3 CRT TEM versus TME Local control
NCT01308190
radiotherapy are tested to increase the tumor dose without increasing toxicity.
Proton therapy if financially available is a promising technology (Thariat et al.
2013) to be used for rectal adenocarcinoma, which require dose above 90 Gy
for 80–90 % rate of ypCR (Appelt et al. 2013).
(2) Survival As none of the medical regimens tested in RCT has so far been able
to increase survival (in opposition with colon cancers), various trials are
testing different drugs combination and strategy to try to reduce the rate of
distant metastases without detrimental effect on the local control and the
overall toxicity rates. The Swedish RAPIDO trial is using a first-line che-
motherapy with a short course (5 9 5 gy) versus a standard long course CRT
in T3c-d T4 M0 tumors. The French Prodige 23 is comparing in T3T4 M0 a
standard ‘‘Cap 50’’ regimen versus the same regimen preceded by four cycles
of first-line chemotherapy using a Folfirinox regimen. The British Aristotle
RCT is comparing Cap 45 versus the same treatment with the addition of
concurrent irinotecan. With the growing development of targeted treatment
toward specific molecular pathways some RCT intend to select patients
according to some specific mutations and to use an adapted MTD.
(3) Toxicity and constraint reduction in the French ACCORD 12 trial it was
observed that in patients over 70 years of age the rate of treatment interruption,
surgery not performed and postoperative toxicity was significantly increased
using Capox 50 (or Cap 50) when compared to younger patients (Francois et al.
2014). A new Prodige randomized trial is upcoming who will test the
hypothesis that after 70 years of age a short course radiotherapy (5 9 5 Gy in a
small posterior pelvic volume) with delayed surgery will be better tolerated
than the Standard Cap 50 and will lead to more patients able to undergo with
reduced toxicity a TME surgery. No randomized trial has ever proved that in
‘‘goodT3 tumors’’ a surgery alone was as efficient as CRT (or 5 9 5 Gy) to
achieve an optimal local control. Some institutions with a highly dedicated
colorectal team tend to expect that TME alone can be proposed for these ‘‘good
T3 tumors’’. In Greccar 4 these patients staged with MRI are treated with a first-
line chemotherapy using a Folfirinox regimen. In case of ‘‘good response’’
judged on MRI the patients are randomized between a standard Cap 50 nCRT
or a TME without any a nCRT. So far no RCT is comparing the standard nCRT
strategy versus TME surgery first-line. In MSKCC New York, following a
phase II study using first-line Folfox and Bevacizumab with a 25 % ypCR in T3
tumors (Schrag et al. 2014) an upcoming phase III trial is testing the hypothesis
that combined first-line chemotherapy and MTD may replace n CRT. It is not
sure that replacing the toxicity of radiotherapy by the toxicity (cardio-vascular)
of this new approach will benefit the patient.
Following all recent trials capecitabine (oral) is replacing 5FU (iv), which is for
the patients a benefit in terms of simplicity and toxic risk.
(4) Conservative treatment This is possibly one of the most promising hypothesis.
How to increase not so much Sphincter Saving using AR or ISR (Rullier et al.
2013), but organ preservation after CCR? The upcoming European trial OPERA
(Organ Preservation for Early Rectal Adenocarcinoma) will include T2 T3a-b
and after Cap 45 will compare a boost using EBRT (5.4 Gy) versus a boost using
CBX (90 Gy). The hypothesis is that taking advantage of an increase in CCR in
the CBX group the organ preservation rate will increase from 5 to 25 %. One
still controversial question in case of CCR is to decide between local excision as
proposed by Lezocche (Lezoche et al. 2012) or Garcia-Aguilar et al.(2012)
(Sauer et al. 2004) and the GRECCAR group (Rullier et al. 2013) or close
surveillance (Habr-Gama et al. 2014; Perez et al. 2013; Maas et al. 2011).
4 Conclusion
Important improvements have been made in the past decade in the treatment of
rectal cancers and its overall prognosis is now slightly better than colon cancer.
Chemotherapy and new molecular targeted drugs should be able to improve sur-
vival in the future. Robust prognostic and predictive markers will be necessary to
tailor and optimize these ‘‘targeted’’ treatments for each individual patients. The
growing development of colorectal screening will lead to the discovery of more
early rectal cancers. In these patients and especially when elderly and frail, organ
preservation (as for squamous cell carcinoma of the anal canal) should be an
important step forward to better quality of life. Only well-conducted randomized
control trials will bring strong enough evidence to influence and modify the
clinical and surgical practices.
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Neoadjuvant Radiotherapy (5 3 5 Gy):
Immediate Versus Delayed Surgery
Krzysztof Bujko, Maciej Partycki and Lucyna Pietrzak
Abstract
Goals: To evaluate the role of length of the interval between 5 9 5 Gy and
surgery. Methods: PubMed was searched to perform a systematic review.
Results: There were 10 studies on 5 9 5 Gy with delayed surgery (no of
patients (n) = 1343), and six studies on 5 9 5 Gy with consolidation
chemotherapy delivered over a long interval prior to surgery in a tight
sequence (n = 244). In total, there were four randomized studies, five phase II
studies, and seven retrospective studies. Trials that compared immediate with
delayed surgery after 5 9 5 Gy showed a benefit in terms of lower rate of
severe acute post-radiation toxicity (4.2 % absolute difference) in the imme-
diate-surgery group. However, this benefit was counterbalanced by the increase
in minor postoperative complications (13 % of absolute difference) in the group
with immediate surgery compared with that with the delayed surgery. The
pathological complete response (pCR) rate was about 10 % higher in the
delayed-surgery group. There were no differences in sphincter preservation and
R0 resection rate between the two groups. Small studies suggest no differences
in the oncological outcomes. Regarding elderly patients who were unfit for
chemotherapy, short-course radiotherapy with delayed surgery produced
favourable outcomes for ‘‘unresectable’’ cancer or for small cancer after full-
thickness local excision. A watch-and-wait policy in complete responders after
short-course radiotherapy is feasible. A pCR of over 20 % was recorded after
K. Bujko (&) M. Partycki L. Pietrzak

The Maria Sklodowska-Curie Memorial Cancer Centre,
5, W. K. Roentgena, 02-781, Warsaw, Poland
172 K. Bujko et al.
short-course radiotherapy and consolidation chemotherapy compared with

about 10 % after 5 9 5 Gy and delayed surgery. Favourable outcomes after
short-course radiotherapy and consolidation chemotherapy were observed in
patients with potentially resectable stage IV disease. Conclusions: Evidence
showed that 5 9 5 Gy with delayed surgery can be used routinely for the
management of elderly patients who are unfit for chemotherapy in case of
‘‘unresectable’’ cancer or early cancer prior to local excision. Short-course
radiotherapy with consolidation chemotherapy is a promising treatment that can
be used routinely for potentially resectable stage IV disease.
Keywords
Rectal cancer Pre-operative short-course radiotherapy
1 Introduction
In the treatment of rectal cancer, pre-operative radiotherapy is preferable to post-

operative radiotherapy because of its higher efficacy regarding the reduction of the
risk of local relapse and lower toxicity (Sauer et al. 2004; Frykholm et al. 1993).
Short-course radiation (five fractions of 5 Gy over 1 week) with immediate surgery
(i.e., surgery performed within the subsequent week) has been the neoadjuvant
radiotherapy regimen for resectable rectal cancer that was tested most extensively
in randomized trials (Frykholm et al. 1993; Bujko et al. 2006; Ngan et al. 2012;
Folkesson et al. 2005; Martling et al. 2001; Peeters et al. 2007; Sebag-Montefiore
et al. 2009; Stockholm Colorectal Cancer Study Group 1990). This treatment
resulted in a relative reduction of local recurrence of about 60 % compared with
surgery alone, and was associated with acceptable toxicity. In addition, this treat-
ment is cheap (only five fractions are administered) and convenient. Less is known
about the results of short-course radiotherapy and delayed surgery. Therefore, the
current systematic review focused on papers that described this regimen.
2 Materials and Methods
A search of PubMed was performed up until February 2014 using the terms ‘‘rectal
cancer’’ and ‘‘short-course radiotherapy’’ or ‘‘5 9 5 Gy’’ and the related citation
function. In addition, abstracts of the ESTRO, ASTRO or ECCO conferences from
2010 to 2013 were searched. Original articles qualified for this review if the
original data had shown results after short-course radiation (5 9 5 Gy) and sur-
gery delayed for more than 2 weeks. Additional studies were searched manually
from the reference lists of relevant articles. Only English-language studies were
included. The literature search and data extraction using a data-collection form
Neoadjuvant Radiotherapy (5 9 5 Gy): Immediate Versus Delayed Surgery 173
were performed independently by the two authors. Any disagreements were

resolved by consensus.
3 Results
The PubMed search yielded a total of 543 records. After exclusion of reviews,
duplicates, case reports or irrelevant studies, 47 abstracts of potential relevance
were obtained. Moreover, four papers of potential interest were identified in the
reference lists. In total, 51 full-text copies of the original articles were acquired. Of
these, 17 articles describing 16 studies met the entry criteria and constituted the
material used in this review (Tables 1 and 2). The studies were divided into the
following two groups: 10 studies on 5 9 5 Gy with delayed surgery (Table 1)
(Pettersson et al. 2010, 2012, 2013; Pach et al. 2012; Latkauskas et al. 2012; Yeo
et al. 2013; Faria et al. 2014; Bujko et al. 2013a; Pettersson et al. 2012; Radu et al.
2008; Hatfield et al. 2009; Veenhof et al. 2007), and six studies on 5 9 5 Gy with
consolidation chemotherapy delivered over a long interval prior to surgery (Radu
et al. 2008; Bujko et al. 2013b; van Dijk et al. 2013; Myerson et al. 2014; Widder
et al. 2005; Shin et al. 2011) (Table 2).
Pre-operative short-course radiation alone was used in 1343 patients. There
were three randomized studies; two compared short-course radiotherapy and
immediate surgery with short-course radiotherapy and delayed surgery (Pettersson
et al. 2010, 2012, 2013; Pach et al. 2012), whereas the third one compared short-
course radiotherapy and delayed surgery with long-course chemoradiation and
delayed surgery (Latkauskas et al. 2012). There were three phase II studies (Yeo
et al. 2013; Faria et al. 2014; Bujko et al. 2013a). The four remaining studies were
retrospective (Pettersson et al. 2012; Radu et al. 2008; Hatfield et al. 2009;
Veenhof et al. 2007).
Pre-operative short-course radiation with consolidation chemotherapy was used
in 244 patients. There was one randomized study that compared this treatment with
long-course chemoradiation (Bujko et al. 2013b), two phase II studies (van Dijk
et al. 2013; Myerson et al. 2014) and three retrospective studies (Radu et al. 2008;
Widder et al. 2005; Shin et al. 2011).
3.1 Acute Radiation Adverse Effects
Acute toxicity occurring over the 5 days of short-course radiation delivery has
been described well in previous randomized studies that evaluated short-course
radiation and immediate surgery (Bujko et al. 2004; Marijnen et al. 2002). The
studies presented here (Pettersson et al. 2010; Bujko et al. 2013a, b) confirmed
previous observations. Acute toxicity during short-course radiotherapy, most often
of grade I–II severity, occurred in about 10 % of patients. Gastrointestinal
symptoms or sacral pain of short duration were observed most frequently. How-
ever, most of the post-radiation toxicity, such as abdominal pain and cramps,
Table 1 Studies using short-course radiotherapy (5 9 5 Gy) alone and delayed surgery in rectal cancer
174
Author, study Patients’ Treatment Interval % of % of % of % of pCR % of Median % of local % of

type, no of characteristics from day acute sphincter postoperative R1 + R2 follow- recurrence survival
patients 1 of toxicity preservation complications resections up in
radiation months
therapy
to
surgery
in weeks
Pattersson (2010, Stage II–III 5 9 5 Gy 1.4 Severe-0 68 versus Total: 52.5 0.4 versus 7 versus n.d. n.d. n.d.
2012, 2013) resectable immediate surgery versus 7 versus 4.2 62 versus versus 39.4 9.8 versus 7 versus
Stockholm III cancers versus 5 9 5 Gy versus versus 5 79 versus 41, 2 n.d.
randomized, delayed surgery planned p = 0.01
interim analyses versus 25 9 2 Gy 9–13 Severe: 11.1
of 303, 398, and delayed surgery versus 9.8
585 patients versus 4
p = 0.132
Post-operative
deaths: 0.8
versus 1.2
versus 1
Pach et al. Stage I–III 5 9 5 Gy and Planned: n.d. 53 versus n.d. 0 versus 16 versus 86 2 versus 63
(2012), Polish resectable immediate surgery 1.7–2.2 57 p = 0.63 10 8 10# versus
randomized, cancers versus 5 9 5 Gy versus 5- p = 0.003 p = 0.24 73 at
N = 154 and delayed 6 5 years,
surgery p = 0.24
Latkauskas et al. Stage II-III 5 9 5 Gy and 7.1 n.d. 76 versus 41 versus 26 3 versus 13 versus n.d. n.d. n.d.
(2012), resectable delayed surgery versus 85 p = NS p = NS 13 9 p = NS
Lithuanian cancers versus 11.3
randomized, chemoradiation
N = 83, interim 25 9 2 Gy 5-FU
analysis and Lv
(continued)
K. Bujko et al.
Table 1 (continued)
radiation months
therapy
to
surgery
in weeks
Yeo (2013), Stage II–III 5 9 5 Gy 8 Grade 3+: 99 15 1 6 n.d. n.d. n.d.

prospective, resectable concurrent 5-FU, 34
phase II, N = 71 cancers Lv
Faria et al. Stage II–III 5 9 6 Gy delayed 8.4 Total: 42 73 37 10 0 23 2 n.d.
(2014), resectable surgery Grade 3:
phase II, N = 52 cancers 8
Bujko (2013), Stage I–II 5 9 5 Gy + 4 Gy 8 versus Total: 27 Local 19 versus 32 36 versus 8 24 After n.d.
phase II, N = 89 B3 cm boost or 13.3 versus 64 excision: 67 p = 0.18 64 local
28 9 1.8 Gy p = 0.001 versus 80 p = 0.016 excision
+3 9 1.8 Gy Grade 3–2 p = 0.30 11.8
boost, 5-FU, Lv, versus 8 versus 6.2
local excision for at 2 years,
good responders p = 0.53
Pattersson et al. Mostly 5 9 5 Gy delayed 8 Grade 3: 55 38 8 14 38 n.d. n.d.
(2012), because of surgery 5.4
retrospective, unresectable
Neoadjuvant Radiotherapy (5 9 5 Gy): Immediate Versus Delayed Surgery
N = 112 cT4, unfit for

chemotherapy
Radu et al. unresectable 5 9 5 Gy delayed 7.7 Grade 3: 57 n.d. 9 9 26 12.5 at 62.5 at
(2008), cT4 or unfit surgery 4 3 years 3 years
retrospective, for
N = 24 chemotherapy
175
(continued)
Table 1 (continued)
176

radiation months
therapy
to
surgery
in weeks
Hatfield et al. cT2–4, unfit 5 9 5 Gy delayed 9 Grade 3+: 62.5 31 8 15 18 0 75 at

(2009), for surgery 5 2 years
retrospective, chemotherapy
N = 43
Veenhof et al. Stage II–III 5 9 5 Gy 1.3 n.d. 44 versus Major: 30 0 versus 17 versus 34 2 versus 66
(2007), resectable immediate surgery versus 7 49 versus 35 12 12 4# versus
retrospective, cancers or 5 9 5 Gy p = 0.54 p \ 0.01 p = 0.60 73 at
N = 108 delayed surgery Minor: 51 5 years,
versus 53 p = 0.12
p = 0.83
Abbreviations used pCR—pathological complete response, n.d.—no data, Lv—lecovorin, NS—non significant
# crude rates
Lack of p-value in the table confers that it was not provided by the authors
K. Bujko et al.
Table 2 Studies using short-course (5 9 5 Gy) radiotherapy with consolidation chemotherapy and delayed surgery in rectal cancer
Author, study Patients’ Treatment Interval from day % of patients with % of % of patients % of % of Median % of local % of
type, no of characteristics 1 of radiation acute toxicity patients with post- pCR R1 + R2 follow- recurrence survival
patients therapy to with operative resections up in
surgery in weeks sphincter complications months
preservation
Bujko (2013b), Unresectable 5 9 5 Gy after one week 3 12 versus 12.3 Grade C3: 26 61 versus 27 versus 16 21 5 versus n.d. n.d. n.d.
randomized, stage II–III cycles of FOLFOX versus versus 25 60 versus 15
interim cancers chemoradiation (50.4 Gy, 8
analysis, FOLOX) delayed surgery
N = 97
Van Dijk et al. Potentially 5 9 5 Gy within 2 weeks up to 26.5 Grade3 + : 39 70 31 26 9 n.d. 6# 80 at 2 years
(2013), resectable 6 cycles of
phase II (), stage IV CAPOX + bevacizumab
N = 50 disease delayed surgery
Myerson et al. Stage II–III, 5 9 5 Gy after 2 weeks 4 17.3 Grade C3: 27 % 75 n.d. 25 5 26 5 at 87 disease-
(2014), phase 9 % M1 cycles of FOLFOX delayed haematological 30 months free at
II, N = 76 cancers surgery 20 % 30 months
nonhaematological for M0
patients
Radu et al. Potentially FOLFOX, 5 9 5 Gy after one 8 1 toxic death 7 of 9 n.d. 2 of 9 3 of 9 31 50 at 0 at 3 years
(2008), resectable week 2 cycles of FOLFOX 3 years
retrospective, stage IV
N = 13 disease
Widder et al. Stage III 5 9 5 Gy after 1 week 3 cycles 15, 19 Grade 2: 2 of 2 1/2 0 2 of 2 0 n.d. n.d. n.d.
(2005) resectable of CAPOX delayed surgery
retrospective, cancers
N=2
Neoadjuvant Radiotherapy (5 9 5 Gy): Immediate Versus Delayed Surgery
Shin et al. Potentially 4–9 cycles of FOLFOX, 14 Grade 3: 50 100 n.d. 1 of 6 1 of 6 17 0 100
(2011), resectable 5 9 5 Gy after one week 2–5
retrospective, stage IV cycles of FOLFOX
N=6
Abbreviations used pCR—pathological complete response, n.d.—no data, Lv—lecovorin, FOLFOX—5-FU, lecovorin and oxaliplatin combination, CAPOX—capecitabine, lecovorin and oxaliplatin
combination
# crude rates
Lack of p-value in the table confers that it was not provided by the authors
177
178 K. Bujko et al.
urgency, and diarrhoea occurred not during but 3–7 days after the completion of
radiotherapy. This toxicity was reported in 27–41 % of patients (Pettersson et al.
2010, 2012; Faria et al. 2014; Bujko et al. 2013a, b; Radu et al. 2008; Hatfield et al.
2009; van Dijk et al. 2013) (Tables 1 and 2). Usually, toxicity was minor (grade I–
II). Severe side-effects occurred in 2–5 % of patients. The symptoms resolved
within the subsequent week. Because in the immediate surgery schedule, operation
takes place before the occurrence of acute post-radiation toxicity, more side effects
were seen when surgery was delayed. Pattersson et al. (2010), in the interim
analysis of the Stockholm III randomized trial, reported severe acute toxicity in
4.2 % of patients in the 5 9 5 Gy and delayed-surgery group and in none of the
patients in the 5 9 5 Gy and immediate-surgery group. One prospective study that
compared long-course chemoradiation (n = 25) with 5 9 5 Gy and delayed sur-
gery (n = 64) reported that acute toxicity was seen more often in the chemora-
diation group (64 % vs. 27 % of patients, P = 0.001) (Bujko et al. 2013a). Severe
complications were reported in 8 and 2 % of these patients, respectively.
In only one study, reported by Yeo et al. (2013), was short-course radiation
simultaneously combined with 5-Fu and leucovorin. Surgery was delayed for
7 weeks. Grade III–IV acute toxicity occurred in 38 % of patients. Surprisingly,
the pathological complete response (pCR) rate in this study was only 1 %. Lower
toxicity was reported when short-course radiation was combined with sequential
consolidation chemotherapy delivered after a 1–2 week interval from completion
of irradiation (Bujko et al. 2013b; van Dijk et al. 2013; Myerson et al. 2014).
Grade III–IV toxicity was reported in 26–50 % of patients (Table 2). Most of the
acute side-effects occurred during the delivery of chemotherapy. The interim
analysis of the randomized trial that compared the above schedule with long-
course chemoradiation did not reveal differences in acute toxicity (26 % vs. 25 %)
(Bujko et al. 2013b).
3.2 Sphincter or Organ Preservation
Three randomized studies that compared short-course radiotherapy and delayed

surgery with other schedules showed that the rates of anterior resection were not
different between the treatment-assigned groups (Pettersson et al. 2013; Pach et al.
2012; Latkauskas et al. 2012) (Table 1).
Short-course radiation was administered 6 weeks prior to full-thickness local
excision in patients with cT1-3 N0 small tumours (B3 cm) (Table 1) (Bujko et al.
2013a). Good response to radiation (pCR or downstaging to ypT1 cancer with
negative margin) was diagnosed in the local excision specimen in 67 % of
patients. No further treatment was administered in this group. In patients with poor
response, conversion to abdominal surgery was required. The local recurrence rate
in patients with good response to radiation was 11.8 % at 2 years; all of these
patients underwent rescue radical surgery.
A study aimed at evaluating the watch-and-wait policy in clinical complete
responders 10 weeks after short-course radiation among elderly patients who were
unfit for chemotherapy is currently ongoing (ClinicalTrials.gov: NCT01963862).

Tumours smaller than 5 cm and involving less than 60 % of the bowel wall
circumference qualify for this study. Six patients have been treated thus far
(unpublished data). Clinical complete response was observed in three of them.
Among them, one patient developed local recurrence, and the remaining two
patients had sustained complete response at the last follow-up (6 and 12 months
from irradiation).
3.3 Postoperative Complications
The Stockholm III randomized trial showed the presence of more post-operative
complications in the short-course radiotherapy and immediate-surgery group than
in the short-course radiotherapy and delayed-surgery group (52.5 % vs. 39.4 %;
P = 0.01) (Pettersson et al. 2013). However, the rates of severe complications,
namely post-operative deaths and complications requiring re-operation, were not
different between these groups (Table 1). No difference in post-operative com-
plications was observed in a small retrospective study that compared the two
schedules described above (Veenhof et al. 2007) (Table 1).
No differences in post-operative complication rates were detected in the ran-
domized trials that compared short-course radiotherapy and delayed surgery with
long-course chemoradiation or with short-course radiotherapy and consolidation
chemotherapy (Latkauskas et al. 2012; Bujko et al. 2013b) (Tables 1 and 2).
3.4 Radical Resection Rate
In all randomized trials shown in the Tables 1 and 2, there were no significant
differences in the rates of positive surgical margin between the treatment-assigned
groups (Pettersson et al. 2012; Pach et al. 2012; Latkauskas et al. 2012; Bujko
et al. 2013b).
3.5 Pathological Complete Response
pCR after short-course radiotherapy and delayed surgery was most often diagnosed
in about 10 % of patients and varied between 1 and 12 % (Table 1). In patients
with tumours with a size B3 cm, the pCR rate was as high as 34 % (Bujko et al.
2013a). Two randomized studies that compared short-course radiotherapy and
immediate surgery with short-course radiotherapy and delayed surgery (Pettersson
et al. 2013; Pach et al. 2012) reported a higher rate of pCR in the delayed-surgery
group (Table 1). The comparison of short-course radiotherapy and delayed surgery
with long-course chemoradiation in a randomized study (Latkauskas et al. 2012) or
in a phase II study (Bujko et al. 2013a) revealed that the pCR rate was higher in the
chemoradiation groups (Table 1). The rates of pCR after short-course radiotherapy
180 K. Bujko et al.
and consolidation chemotherapy varied between 21 and 26 % (Table 2). An

interim analysis of a randomized study that compared short-course radiotherapy
and consolidation chemotherapy with long-course chemoradiation revealed a
higher pCR rate in the short-course radiotherapy group (21 % vs. 8 %; the P-value
was not given) (Bujko et al. 2013b).
3.6 Long-Term Oncological Outcomes
Data on the long-term outcomes after short-course radiotherapy and long interval
to surgery are scarce and are based on a small number of patients. The oncological
outcomes in this setting seem to be similar to those observed in other studies that
used long-course pre-operative radio(chemo)therapy for similar cancer stages. A
small randomized study that compared short-course radiotherapy and immediate
surgery with short-course radiotherapy and delayed surgery showed more local
recurrences in the delayed-surgery group: 2 % versus 10 % (the P-value was not
given) (Pach et al. 2012). However, this difference did not translate into a survival
benefit (Table 1). No differences in local recurrence and survival were observed in
a retrospective study that compared the two schedules mentioned above (Veenhof
et al. 2007).
4 Discussion
The indications for using a long or short interval between 5 9 5 Gy and surgery in
relation to the characteristics of patients or tumours are discussed below.
4.1 Resectable Cancer
The evidence is too weak to allow the recommendation of short-course pre-

operative radiotherapy and delayed surgery for resectable cancer. Whether
delaying surgery by 4–8 weeks is beneficial is unknown, because the full results of
the large Stockholm III trial have not been published. Local-recurrence evaluation
(primary end-point) will be available in 2015 (Glimelius 2013).
The interim analysis of the Stockholm III trial has revealed the presence of
benefit in terms of lower rate of post-operative complications (13 % of absolute
difference) in the delayed-surgery group compared with the immediate-surgery
group (Pettersson et al. 2013) (Table 1). The lack of pelvic bone-marrow recovery
after immediate surgery, which manifests itself as insufficient production of leu-
kocytes, is probably a main cause of this increased risk of post-operative com-
plications (Pettersson et al. 2013). However, the benefit of fewer post-operative
complications associated with delayed surgery was counterbalanced by the
increase in acute adverse post-radiation effects in this group. About 5 % more
patients had severe post-radiation complications in the case of delayed surgery
compared with immediate surgery (Table 1) (Pettersson et al. 2010). This is

because the organ at risk (rectum) is removed before radiation damage is mani-
fested clinically in cases in which surgery is performed immediately.
Recently, several articles have evaluated whether delaying surgery for a few
days has an impact on these patients. The Dutch trial showed that, for elderly
patients treated with short-course radiation and immediate surgery, the rate of non-
cancer-related mortality at 1 year post-treatment was lower when surgery was
performed at 0–3 days compared with 4–7 days (van den Broek et al. 2013).
Similar results were observed in a pooled analysis of the Stockholm I and II trials
(Fokstuen et al. 2009) and in one retrospective study (Hartley et al. 2002).
However, this was not confirmed by the verification set of 600 patients (van den
Broek et al. 2013) and by the interim analysis of the Stockholm III trial (Pettersson
et al. 2012). In this trial, the rate of post-operative complications was 52.5 % in
patients in whom surgery was performed within 5 days after the last fraction of
irradiation compared with 55 % in patients in whom surgery was delayed between
5 and 30 days (hazard ratio, 1.11; 95 % confidence interval, 0.53–2.30). One
possible explanation for this discrepancy may be that, in some studies, surgery was
postponed in patients with poor condition after consultation with the anaesthetist,
which would result in a bias (van den Broek et al. 2013).
4.2 ‘‘Unresectable’’ Cancer
‘‘Unresectable’’ cancer in this article was defined as a large fixed lesion involving
mesorectal fascia or neighbouring organs. Tumour shrinkage is required for radical
surgery of such advanced cancers. Long-course chemoradiation with an interval of
about 6 weeks before surgery is used routinely, because the long chemoradiation
period and the long interval to surgery cause significant tumour shrinkage and
downstaging in the majority of patients (Braendengen et al. 2008).
However, often, chemotherapy cannot be used in elderly patients with comor-
bidity. Because tumour shrinkage and downstaging increase with time (Graf et al.
1997; Francois et al. 1999), short-course radiation and delayed surgery seem to be a
logical management for those patients (Radu et al. 2008). In fact, this treatment
produced favourable long-term outcomes with acceptable acute toxicity (Pettersson
et al. 2012; Radu et al. 2008; Hatfield et al. 2009) (Table 1). Less acute toxicity is
observed in patients after short-course radiation and delayed surgery compared with
what is observed after long-course chemoradiation (Bujko et al. 2013a). There are
sufficient data to conclude that, for patients who are unfit for chemotherapy, short-
course radiation and delayed surgery can be used routinely. However, there are
insufficient data to conclude that this treatment can be used routinely also for fit
patients. Thus, long-course chemoradiation remains the standard procedure.
This standard procedure was compared with short-course radiation combined
with sequential consolidation chemotherapy in a randomized study (Bujko et al.
2013b) (Table 2). The planned accrual of 540 patients was recently completed.
182 K. Bujko et al.
Results are expected at the beginning of 2015. The similarly designed RAPIDO
trial is ongoing (Nilsson et al. 2013).
Interestingly, after 5 9 5 Gy and consolidation chemotherapy (Table 2), the
pCR rate is doubled compared to short-course radiation alone with a long interval
to surgery (Table 1). However, it remains unknown whether this difference is
related to the longer interval between the onset of radiation and surgery when
consolidation chemotherapy was added, or to enhance local effectiveness caused
by the addition of chemotherapy.
4.3 Potentially Resectable Stage IV Disease
The Dutch phase II study reported by van Dijk et al. (2013) showed favourable
results in patients with potentially resectable stage IV disease after the use of
5 9 5 Gy and consolidation chemotherapy delivered in a tight sequence (Table 2).
The main rationale for this approach is that chemotherapy can be delivered in full
doses, whereas, if traditionally combined simultaneously with long-course irra-
diation, the chemotherapy doses must be reduced. The results of this study,
together with the results of the other studies presented in Table 2, strongly suggest
the routine use of 5 9 5 Gy and consolidation chemotherapy either for potentially
resectable (van Dijk et al. 2013; Myerson et al. 2014) or unresectable (Radu et al.
2008; Tyc-Szczepaniak et al. 2013) stage IV disease.
4.4 Organ Preservation
Organ preservation (both the sphincter and rectum) after long-course chemoradi-
ation was assessed either after using a watch-and-wait policy for complete
responders (Habr-Gama et al. 2014) or local excision for good responders (Bujko
et al. 2013a; Pucciarelli et al. 2013). Such procedures are expected to be especially
beneficial for elderly patients with co-morbidity because of low morbidity and lack
of post-operative deaths. The post-operative death rate in elderly patients, when
measured within a period of 3–6 months after total mesorectal excision, is higher
than it is commonly believed. For example, a Dutch population-based study
reported 16 % of post-operative mortality at 6 months in patients older than
75 years compared with 4 % in younger patients (Rutten et al. 2007). Because
elderly patients are often unfit for chemotherapy, the question arises regarding
whether, for organ preservation, short-course radiation assures similar oncological
results and yields less early adverse post-radiation effects than does long-course
chemoradiation. A small prospective study provided a positive answer to this
question by using full-thickness local excision (Bujko et al. 2013a) (Table 1).
However, that study should be interpreted with caution because of the small
number of patients included and the short follow-up. A watch-and-wait policy for
complete clinical responders after 5 9 5 Gy is feasible.
Fig. 1 Response of radiosensitive or radioresistant cancer to short-course radiotherapy in

relation to the duration of the rest period between irradiation and surgery. Irreparable DNA
damage, which ceases unlimited cancer cell division, occurs only at the time of irradiation.
Extending the rest period between radiation and surgery does not produce additional DNA
damage. In radiosensitive cancers, DNA damage eventually leads to a pathological complete
response (pCR). The manifestation of pCR is heavily dependent on the duration of the interval
between the beginning of radiation and surgery (Graf et al. 1997; Francois et al. 1999). Within a
few days following the start of radiation, non-viable cancer cells look morphologically intact
(Suit and Gallager 1964) and no downstaging occurs (Marijnen et al. 2001) (lower scenario). If
the interval to surgery is extended to 6–8 weeks, non-viable cancer cells undergo lyses (Francois
et al. 1999; Suit and Gallager 1964) (upper scenario). This figure explains why a lack of
downstaging after short-course radiotherapy and immediate surgery does not confer poor
prognosis. It is well known that pCR and downstaging are associated with an excellent prognosis
(Maas et al. 2010; Bujko et al. 2007). In the context described above, a long rest period serves as
a prognostic test for indentifying patients with excellent prognosis and for guiding further
treatment, for example, local excision or a watch-and-wait policy without surgery
4.5 Radiobiological Considerations
Numerous articles have presented outcomes in relation to the length of the interval
between long-course radiotherapy or chemoradiotherapy and surgery, which pro-
vide additional insight into the issue in question. Four randomized trials (Bujko
et al. 2006; Ngan et al. 2012; Francois et al. 1999; Saglam et al. 2014), one
population-based study (Sloothaak et al. 2013), one systematic review (Foster
et al. 2013), and one meta-analysis (Petrelli et al. 2013) addressed this issue. The
body of evidence from these studies and evidence presented in the ‘‘Results’’
section of the present article show that, with a longer interval to surgery, the pCR
184 K. Bujko et al.
rate and downstaging increase, whereas long-term outcomes remain much the
same. It is also well known that pCR and downstaging are associated with an
excellent prognosis (Maas et al. 2010; Bujko et al. 2007). Thus, the question arises
regarding why pCR and downstaging rates are not surrogate prognostic end-points
in patients with a long rest interval; pCR or downstaging confers excellent
prognosis only for patients with these features, and not in a total group. This
question is answered in Fig. 1. In conclusion, there are two ways to obtain
enhanced downstaging or pCR: 1) by extending the rest period; then, local control
remains much the same (Fig. 1); or 2) by enhancing the tumoricidal effect of
radiation (by adding concomitant chemotherapy, for example), which demon-
strates the benefits of local control (Bosset et al. 2006).
In two studies that compared short-course radiation and delayed surgery with
long-course chemoradiation and delayed surgery, the pCR rates were lower in the
short-course radiotherapy groups than in the chemoradiation groups (Latkauskas
et al. 2012; Bujko et al. 2013a) (Table 1). However, this does not necessarily mean
that local control will be lower. Although the rest period between the completion
of radiotherapy and surgery was the same in both groups (6–7 weeks), the interval
between the onset of irradiation and surgery was 1 month longer in the long-
course chemoradiation groups. The interval should be measured between the start
of radiation and surgery, and not between the completion of radiation and surgery.
This is because each fraction of radiation sterilizes the same proportion (not
number) of cancer cells (Benzen 2009). Thus, overwhelming cell killing occurs
during the first 1–2 fractions. For this reason, an inherent bias favouring the
chemoradiation group was inadvertently introduced into the design of the trials
mentioned above.
With delayed surgery, there is a risk of tumour regrowth and the development
of a cancer phenotype that produces distant metastases. If one imagines that the
interval from irradiation to surgery lasts a few months instead of weeks, then most
tumours would inevitably regrow. When does a tumour repopulation start? The
evaluation of a labelling index showed the accelerated proliferation of cancer cells
in some tumours 1 month after 5 9 5 Gy (Gasinska et al. 2007). Based on PET/
CT examinations, another study showed decreased metabolic activity at 6 weeks
from chemoradiation compared with the baseline values (Perez et al. 2012).
However, increased metabolic activity in some tumours was observed between 6
and 12 weeks after chemoradiation. Thus, the long interval potentially jeopardizes
oncological outcomes. This effect was not shown in the randomized studies (Bujko
et al. 2006; Ngan et al. 2012; Francois et al. 1999; Saglam et al. 2014) or in the
meta-analysis (Petrelli et al. 2013).
Acknowledgments The study was supported by grant No. N N403 580538 from the Polish
Ministry of Science and Higher Education. The study sponsor had no role in the study design, in
the collection, analysis and interpretation of data; in the writing of the manuscript; and in the
decision to submit the manuscript for publication.
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Early and Late Toxicity
of Radiotherapy for Rectal Cancer
Ines Joye and Karin Haustermans
Abstract
With the implementation of total mesorectal excision surgery and neoadjuvant
(chemo) radiotherapy, the outcome of rectal cancer patients has improved and a
substantial proportion of them have become long-term survivors. These advances
come at the expense of radiation- and chemotherapy-related toxicity which
remains an underestimated problem. Radiation-induced early toxicity in rectal
cancer treatment mainly includes diarrhea, cystitis, and perineal dermatitis, while
bowel dysfunction, fecal incontinence, bleeding, and perforation, genitourinary
dysfunction, and pelvic fractures constitute the majority of late toxicity. It is now
generally accepted that short-course radiotherapy (SCRT) and immediate surgery
is associated with less early toxicity compared to conventionally fractionated
chemoradiotherapy with delayed surgery. There are no significant differences in
late toxicity between both treatment regimens. While there is hardly an increase
in early toxicity after preoperative SCRT with immediate surgery, late toxicity is
substantial compared to surgery alone. Early toxicity is more frequent when a
longer interval between SCRT and surgery is used and is comparable to the
toxicity observed with conventionally fractionated radiotherapy except that it
occurs after the end of the radiotherapy. So far, randomized phase III trials failed
to demonstrate a substantial gain in tumoural response when oxaliplatin or
molecular agents are added to the multimodality treatment. Moreover, the
addition of these drugs increases toxicity and remains therefore experimental.
I. Joye K. Haustermans (&)

Radiation Oncology, Leuven Cancer Institute and Department of Oncology,
University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
190 I. Joye and K. Haustermans
Keywords
Rectal cancer Toxicity Neoadjuvant treatment
Abbreviations
CRT Chemoradiotherapy
SCRT Short-course radiotherapy
TME Total mesorectal excision
1 Introduction
For patients with rectal cancer two preoperative radiation approaches are com-
monly used: preoperative short-course radiotherapy (SCRT) (5 9 5 Gy) followed
by immediate surgery, and preoperative long-course chemoradiotherapy (CRT)
with a radiation dose to 45–50.4 Gy in fractions of 1.8 to 2 Gy combined with
fluoropyrimidine-based chemotherapy followed by total mesorectal excision
(TME) 6–8 weeks after the end of the CRT (Kapiteijn et al. 2001; Sauer et al.
2004; Sebag-Montefiore et al. 2009; Swedish Rectal Cancer Trial 1997). Over the
past years, outcome of rectal cancer patients has improved and a substantial
proportion of them have become long-term survivors. These advances come at the
expense of treatment-related toxicities which remain an underestimated problem.
Radiation-induced bowel injury is more common than Crohn’s disease. Only a
fifth of the patients with these complaints visit a gastroenterologist and most who
do so are managed ineffectively (Andreyev et al. 2013).
Increased awareness and recognition of treatment-related toxicity is of major
importance as the associated morbidity affects quality of life. Nowadays, radiation-
induced toxicity is no longer regarded as a constellation of vague and poorly
defined symptoms, but as a real disease which needs to be investigated and can be
treated appropriately. Treatment-related toxicity is classified as early and late,
depending on the onset of symptoms. Early side-effects are observed during or
shortly after treatment. In contrast, late toxicity develops after latent times of
months to many years. The cut-off time to distinguish early from late effects has
arbitrarily been set to 90 days after the onset of radiotherapy. Diarrhea, cystitis,
and perineal dermatitis constitute the majority of radiation-induced early toxicity
in rectal cancer treatment. Late toxicity mainly includes bowel dysfunction, fecal
incontinence, bleeding and perforation, genitourinary dysfunction, and pelvic
fractures. Progressive cell depletion and inflammation are the leading mechanisms
of early side-effects. The pathogenetic pathways of late toxicity are more complex
and involve processes as vascular sclerosis and fibrosis (Bentzen 2006; Denham
et al. 2000). It is clear that early and late radiation effects are independent with
regard to their pathogenesis and, in general, conclusions from the severity of early
toxicity on the risk of late effects cannot be drawn. However, interactions between
Early and Late Toxicity of Radiotherapy for Rectal Cancer 191
acute and chronic toxicities have been described in early-responding tissues that
have a protective function against mechanical and/or chemical exposures. These
consequential late effects have been demonstrated in intestine, urinary tract, oral
mucosa, skin, and lung tissues (Dörr and Hendry 2001; Dörr et al. 2005).
The fractionation sensitivity of tissues differs and is reflected by the a=b ratio.
A higher a=b ratio means that tissue responses are less dependent on the amount of
radiation administered with each fraction. Conversely, tissues with a lower a=b
ratio are more sensitive to fractionation which means that a larger dose of radiation
per fraction can enhance tumor response, but can also increase side-effects.
Acutely responding tissues typically have an a=b ratio in the range of 7–20 Gy
while for late-responding tissues, a=b ranges from 0.5 to 6 Gy (Joiner and van der
Kogel 2009).
The aim of this paper is to provide an overview of the evidence on early and
late treatment-related toxicity in patients treated with SCRT and CRT. Because of
the plethora of reports and the wide variety in treatment schedules, we mainly
focus on toxicity data available from large phase III randomized trials.
2 Toxicity Profiles
2.1 SCRT + Surgery Versus Surgery Alone
With the implementation of TME surgery and the administration of SCRT local
recurrence rates of locally advanced rectal cancer have decreased from 30 to 50 %
to less than 15 % (Heald and Ryall 1986; Kapiteijn et al. 2001; Swedish Rectal
Cancer Trial 1997; van Gijn et al. 2011). In the Swedish Rectal Cancer Trial it was
shown that preoperative SCRT improved the 5-year overall survival rate from 48
to 58 % (Swedish Rectal Cancer Trial 1997). Long-term follow-up of the Dutch
TME trial could not confirm the benefit in overall survival, but showed preoper-
ative radiotherapy improved 10-year survival in patients with cTNM stage III
cancer and a negative circumferential resection margin (van Gijn et al. 2011). The
gains in outcome have to be balanced against the acute and late adverse effects of
treatment. This is of particular concern in patients with a low risk of local
recurrence.
The Dutch TME trial showed that there was hardly an increase in early toxicity
after preoperative SCRT followed by surgery within 1 week (Marijnen et al.
2002). Twenty-six percent of all irradiated patients experienced adverse effects,
mostly grade I, representing only minor complaints. Grade 2 or 3 complications
occurred in 7 % of the patients.
Of special concern is the acute lumbosacral plexopathy, causing long-lasting
pain, and/or neurologic symptoms at the level of the lower lumbar plexus
(Frykholm et al. 1996). Several patients treated with SCRT in Sweden developed
acute pain in the back, in the gluteal region or in the legs during radiotherapy.
Some of them suffered from chronic severe pain and permanent neurological
symptoms. In the Dutch trial 53 patients experienced pain or discomfort in the legs
or in the gluteal region and treatment was interrupted or medication was needed in
18 patients (Marijnen et al. 2002). However, longstanding pain or neurologic
symptoms did not occur after a median follow-up of 25.4 months. The difference
between both series might be attributed to the location of the upper border of the
radiation field (L5–S1 in the Dutch trial versus. mid L4 in the Swedish series) and
to the shielding of the lordotic area at the dorsum of the sacrum in 90 % of the
patients in the Dutch trial.
In contrast to early toxicity, late toxicity after SCRT immediately followed by
surgery is substantial. Late toxicity data are extensively reported by Swedish
series. The Stockholm I and II trials randomized 1,406 patients with clinically
resectable rectal cancer between surgery with or without preoperative radiotherapy
(Martling et al. 2001; Stockholm Rectal Cancer Study Group 1990). In the
Stockholm I trial, a two-field technique was used and the beam limits extended
from the upper border of the L2 vertebra down to the anal verge. The Stockholm II
trial had a slightly different radiation protocol: a four-field box technique was used
and a smaller volume was irradiated (beam limits were from the upper border of
the L4 vertebra down to and including the anal canal).
Long-term toxicity results of the Stockholm trials, the Swedish rectal cancer
trial and the Dutch TME trial uniformly showed irradiated patients had signifi-
cantly more bowel movements and fecal incontinence compared to nonirradiated
patients (Dahlberg et al. 1998; Peeters et al. 2005; Pollack et al. 2006a, b). Swedish
patients also had an increased risk of hospital admissions during the first 6 months
from the primary treatment, mainly for infections and gastrointestinal disorders
(Birgisson et al. 2005a). Six months after treatment, irradiated patients in the
Swedish series had in increased relative risk of small bowel obstruction and
abdominal pain (Birgisson et al. 2005a, 2008; Holm et al. 1996). The higher
incidence of small bowel obstruction in irradiated patients was not confirmed by
the Dutch TME trial. The fact that Swedish series used extensive radiotherapy
fields (the upper border including L2), limited portals and did not mandate
blocking can explain this difference.
Late follow-up of the Stockholm trials showed an increased urinary inconti-
nence in irradiated patients (Pollack et al. 2006a). Voiding problems were not
significantly different in the Dutch TME trial between irradiated and nonirradiated
patients. However, urinary dysfunction was of concern since approximately 39 %
of the patients reported to be incontinent for urine in both groups and 57 % of
patients wore pads (Peeters et al. 2005).
Interestingly, after a mean follow-up of 15 years, an increased incidence in
cardiovascular disease was found in irradiated patients in the Stockholm trials
(Pollack et al. 2006a). It was hypothesized pelvic irradiation invokes an inflam-
matory response in the pelvic arteries and an increased secretion of growth factors
into the bloodstream has been suggested to accelerate the atherosclerotic process
in remote arteries (Baerlocher et al. 2004; Chuang 1994). However, long-term
follow-up of the Swedish Rectal Cancer Trial and the Dutch TME trial did not
confirm the increased risk of cardiovascular disease after preoperative irradiation
(Birgisson et al. 2005a; Peeters et al. 2005).
Currently, one paper showed an increased risk of secondary cancer in patients

treated with SCRT (Birgisson et al. 2005b). After a follow-up of 14 years 9.5 % of
the radiotherapy patients developed a secondary cancer, compared to 4.3 % of the
nonirradiated patients. The secondary cancers mainly involved organs within or
adjacent to the irradiated volume (colon, prostate, bladder, ureter).
The Dutch TME trial analyzed the grade of sexual dysfunction between irra-
diated and nonirradiated patients (Marijnen et al. 2005). SCRT had a negative
impact on sexual function in males and females. Irradiated males experienced
more ejaculation disorders, further deteriorating over time, which can be explained
by the fact that seminal vesicles have been irradiated and might stopped func-
tioning. For up to 2 years, irradiated men had a decrease in erectile function,
suggesting late radiation damage to the small vessels.
While data from the Stockholm trials showed an increase in the number of
femoral head or pelvic fractures in patients receiving preoperative radiotherapy,
there was no difference in bony fractures in the Dutch TME trial (Holm et al. 1996;
Peeters et al. 2005). This could be explained by the fact that the Dutch TME trial
used a three- or four-field technique compared to the two-field technique used in
the Stockholm I trial.
There is no consensus on whether late toxicity impairs social life: Pollack and
colleagues reported no significant difference in quality of life scores between
irradiated and nonirradiated patients (Pollack et al. 2006b). However, Dahlberg
et al. showed an impaired social life in 30 % of the irradiated patients compared to
10 % of the surgery alone group (Dahlberg et al. 1998). In the Dutch TME trial, it
was shown that despite the significant increase in fecal incontinence and sexual
dysfunction in irradiated patients, there were few differences in quality of life
between patients with and without SCRT (Marijnen et al. 2005). Interestingly,
there was no significant difference in the overall perceived health between patients
who underwent an abdominoperineal resection (APR) compared to those who
underwent a low anterior resection. APR patients had fewer physical and psy-
chological problems. This finding suggests that sphincter saving surgery may not
always improve the quality of life.
2.2 Preoperative SCRT Versus Preoperative CRT
Three randomized trials directly compared preoperative SCRT with preoperative

CRT (Bujko et al. 2006; Ngan et al. 2012; Siegel et al. 2009). The Polish and
Australian trials showed that local recurrence and overall survival were similar
between SCRT and CRT. However, the Australian trial indicated CRT may be
more effective than SCRT in reducing the risk of local recurrence, especially for
distal tumors. As shown by both trials, overall and grade III–IV early toxicity is
more frequent in patients treated with CRT compared to those treated with SCRT
(Table 1) (Bujko et al. 2004; Ngan et al. 2007). After a median follow-up of
4 years, the Polish study group found no significant differences in severe late
toxicity, anorectal, and sexual dysfunction, treatment compliance or quality of life
Table 1 Early and late toxicity in phase III trials randomizing between SCRT and CRT
Trial Toxicity Preop Preop p-value
parameter SCRT (%) CRT (%)
Acute Polish trial Grade 3–4 3.2 (5/155) 18.2 (29/157) p \ 0.001
toxicity (Bujko et al. 2004) adverse effects
All complications 24 (37/155) 85 (132/157) p \ 0.001
Compliance 97.9 69.2
TROG trial Grade 3–4 1.9 28
(Ngan et al. 2007) adverse effects
Late Polish trial Overall toxicity 28.3 (39/138) 27.0 (38/141) p = 0.810
toxicity (Bujko et al. 2006)
Severe toxicitya 10.1 (14/138) 7.1 (10/141) p = 0.360
TROG trial Grade 3–4 small 3.2 (5/155) 5.1 (8/158) p = 0.53
(Ngan et al. 2012) or large intestine
toxicity
Grade 3–4 5.8 (9/155) 8.2 (13/158) p = 0.53
adverse effects
a
Toxicity was scored as severe when it met any of the following criteria: toxic death, grade III-IV
or requiring major surgical intervention or hospitalization
SCRT = short-course radiotherapy; CRT = chemoradiotherapy
(Bujko et al. 2006; Pietrzak et al. 2007). The similar late toxicity profile of the two
treatment regimens was confirmed by the Australian study. After a median follow-
up of 5.9 years grade III and IV late toxicity occurred in 5.8 % after SCRT versus
8.2 % after LCRT (p = 0.53). Outcome and toxicity data from the Berlin study
will be analyzed after a median follow-up of 5 years (Siegel et al. 2009).
2.3 Preoperative CRT Versus Postoperative CRT
The German CAO/ARO/AIO-94 trial randomized 823 patients with stage II and III
rectal cancer between preoperative and postoperative CRT (Sauer et al. 2004).
Long-term results after a median follow-up of 11 years showed preoperative CRT
improved local control, but had no effect on overall survival, disease-free survival
or distant metastases (Sauer et al. 2012). The overall rates of acute and long-term
adverse effects were lower with the preoperative approach than with the postop-
erative approach, especially with respect to acute and chronic diarrhea and the
development of strictures at the anastomotic site (Sauer et al. 2004). This resulted
in an improved compliance with the chemoradiotherapy regimen if it was given
before major surgery. Women showed higher hematologic and acute organ toxicity
in the entire cohort as well as in the subgroup analyses according to pre- and
postoperative CRT (Wolff et al. 2013). Interestingly, it was suggested acute
toxicity was associated with an improved long-term outcome (Wolff et al. 2013).
2.4 CRT Versus Long-Course Radiotherapy
Three trials randomized patients with rectal cancer between long-course radio-
therapy with or without fluoropyrimidine-based chemotherapy (Bosset et al. 2006;
Brændengen et al. 2008; Gérard et al. 2006). While the EORTC 22921 and the
FFCD 9203 trials included patients with resectable T3/T4 Nx M0 rectal cancer,
Braendengen et al. investigated the role of chemotherapy in patients with unre-
sectable T4 primary rectal carcinoma or with local recurrence from rectal carci-
noma (Brændengen et al. 2008). The three trials led to similar outcome and
toxicity results. Patients treated with chemotherapy had less local recurrences and
a higher chance of pathological complete remission (pCR) of the tumor. The
EORTC and French studies did not reveal any survival gains, whereas Braend-
engen et al. showed significant benefits related to time to treatment failure and
cancer-specific survival for patients treated with CRT. The gains in outcome of the
CRT group come at the expense of an increased acute toxicity, mainly due to
gastrointestinal morbidity (i.e., diarrhea). There is a tendency towards more late
toxicity in the CRT group, which frequently occurs as fecal and urinary inconti-
nence and erectile dysfunction (Brændengen et al. 2011). The addition of che-
motherapy to preoperative radiation therapy can impair social functioning
(Brændengen et al. 2012; Tiv et al. 2010). However, Braendengen et al. showed
there was no statistically significant difference in health-related quality of life
between patients who received chemotherapy and those who did not (Brændengen
et al. 2012).
2.5 SCRT Versus SCRT with Delayed Surgery
In an attempt to increase the efficiency of radiotherapy for elderly patients with

co-morbidities and unresectable rectal cancer, SCRT has been associated with a
prolonged interval to surgery. The idea is to obtain similar downstaging and
downsizing of the tumor as when CRT is applied. This treatment is more toxic than
SCRT with immediate surgery, primarily because the main organ at risk for early
toxicity (the rectum) is not removed before the occurrence of adverse effects.
Retrospective series showed SCRT with a prolonged interval to surgery was
associated with early toxicity rates less than 10 % (Hatfield et al. 2009; Pettersson
et al. 2012; Radu et al. 2008). However, such series tend to underestimate toxicity
as they are affected by reporting bias (e.g., Hatfield et al. restricted the assessment
of severe early toxicity as to whether hospital-admission was necessary) (Hatfield
et al. 2009). In prospective studies toxicity grades I and II are more accurately
scored and therefore higher—and more reliable––toxicity rates are reported.
Whether SCRT with delayed surgery is a valuable option for all rectal cancer
patients is not yet known. The multicentric randomized Stockholm III trial will
probably give more evidence. In this 3-arm trial, patients with primary resectable
rectal cancer are randomized to preoperative SCRT followed by surgery within
1 week or after 4–8 weeks, or long-course preoperative RT (25 9 2 Gy) with

surgery after 4–8 weeks. In an interim analysis no significant difference in early
toxicity could be detected between the different treatment schedules (Pettersson
et al. 2010).
2.6 Influence of Cytotoxic Agents
Randomized trials have shown that the addition of 5-fluorouracil (5-FU) or its
prodrug capecitabine to preoperative radiotherapy increases pCR and local control
rates over radiotherapy alone. However, with the exception of the Swedish trial,
phase III clinical trials failed to show that addition of (C) RT to TME surgery
results in an improved survival (Bosset et al. 2006; Gérard et al. 2012; Peeters
et al. 2007). Current strategies therefore aim at improving the outcome by the
addition of other drugs to the multimodality treatment.
Oxaliplatin in combination with 5-FU has shown to enhance tumor response in
metastatic colorectal cancer and to improve survival in the adjuvant setting
(André et al. 2004; Goldberg et al. 2004). It was expected that oxaliplatin to standard
preoperative CRT in rectal cancer might both increase pCR and reduce microme-
tastases at distant sites. Unfortunately, most phase III trials so far failed to show an
improvement in tumoural response (Aschele et al. 2011; Gérard et al. 2010; Gérard
et al. 2012; Rödel et al. 2012; Roh et al. 2009; Schmoll et al. 2013). While an
increase in pCR rate was only shown in the German CAO/ARO/AIO-04 trial, 3 other
trials reported an increase in grade 3 and 4 toxicity when oxaliplatin was added to the
preoperative regimen. Patients mainly suffered from diarrhea, nausea, dermatitis,
fatigue, and peripheral neuropathy. Hematological problems were less frequent.
Although the addition of oxaliplatin to the preoperative regimen significantly
increased acute grade 3 or 4 toxicity, it did not result in more surgical complication
or postoperative deaths within 60 days. The 3-year follow-up results of the
ACCORD trial showed, grade 3 or 4 toxicity was equal (5.4 vs. 6.5 % with and
without oxaliplatin respectively) and mainly involved gastrointestinal or sexual
problems (Gérard et al. 2012). There was no significant difference in bowel
incontinence, erectile dysfunction, and social life disturbance between both groups.
A meta-analysis concluded the combination of oxaliplatin and fluorouracil in the
preoperative setting still seems promising, either with a modified schedule or as
induction therapy prior to CRT or after CRT, prior to surgery (An et al. 2013). It is
clear longer follow-up is needed to assess further impact on efficacy end points.
In an attempt to further enhance tumoural response, phase I/II studies evaluated
the addition of targeted agents as radiosensitizers in rectal cancer (Dewdney et al.
2012; Marquardt et al. 2009). Up to now, studies with epidermal growth factor
receptor inhibitors (i.e., cetuximab) and with VEGF inhibitors (i.e., bevacizumab)
have failed to show a significant benefit in pCR compared to standard CRT.
Moreover, caution is needed regarding the toxicity pattern (diarrhea, skin toxicity,
perforations) and surgical complications (wound healing, bleeding, fistulisation)
(Marquardt et al. 2009). No randomized phase III studies are currently available.
Therefore, the use of these agents in the preoperative treatment for rectal cancer
remains experimental.
3 Toxicity Management
With the strict application of dose-volume constraints and with the use of
advanced radiation delivery techniques, radiation-induced side-effects are reduced,
but not abolished. The first step for the correct management of radiation toxicity is
to identify the pathophysiological mechanisms of the symptoms. The effects of
dietary manipulation and cytoprotective and anti-inflammatory drugs have been
investigated (Fuccio et al. 2012; Wedlake et al. 2013). To date, there is insufficient
evidence to recommend nutritional intervention or administration of cytoprotective
drugs during pelvic radiotherapy. In severe toxicity total replacement of diet with
elemental formula may be appropriate. Probiotics seem promising in reducing the
incidence and severity of radiation-induced diarrhea but can only be introduced
into clinical practice with rigorous safety analysis, especially in immunocom-
promised patients (Chitapanarux et al. 2010; Delia et al. 2007).
Optimal toxicity management requires close collaboration between general
practitioners, gastro-enterologists, radiation oncologists, oncologists, dieticians,
nurses, and surgeons. Andreyev et al. reported that patients who were given tar-
geted intervention in a detailed clinical algorithm had better improvements in
radiotherapy-induced gastrointestinal symptoms than did patients who were given
usual care (Andreyev et al. 2013). The authors also found that this algorithm-based
care could be managed by a trained nurse.
4 Future Prospects
Efforts are made to decrease the incidence of radiation-induced toxicity. In

radiotherapy, conformal techniques have been developed to precisely deliver high
doses of radiation to the tumor mass while the surrounding normal tissue is spared.
In that way, intensity-modulated radiotherapy (IMRT), volumetric-modulated arc
therapy (VMAT) and proton therapy allow for a precise dose delivery to the target
volume, thereby reducing the doses to the organs a risk (i.e., small bowel)
(Samuelian et al. 2012; Wolff et al. 2012). It remains to be seen whether the
dosimetrical benefits of these highly conformal radiation techniques will translate
into less acute and late toxicity.
Currently, studies are undertaken investigating parameters that predict treatment-
related toxicity. Identification of these parameters would be a promising step
towards an individualized risk-adapted treatment for rectal cancer patients. It
remains to be seen whether new treatment schedules (e.g., SCRT followed by
neoadjuvant chemotherapy and surgery), RAPIDO trial will shed new light on
toxicity profiles in rectal cancer treatment (Nilsson et al. 2013).
5 Conclusions
Treatment-related toxicity in rectal cancer patients is substantial and depends on

the type of neoadjuvant treatment and the timing of surgery. With the advent of
new treatment techniques, some patients with rectal cancer can be considered
long-term survivors. Awareness and recognition of treatment-related toxicity has
gained in importance. In their decision-making of which treatment to prescribe,
physicians consider toxicity, need for downsizing, treatment costs, convenience,
and patients’ preference. Results from ongoing randomized trials are expected to
shed new light on toxicity profiles in rectal cancer.
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Immediate Surgery or Clinical
Follow-Up After a Complete Clinical
Response?
Angelita Habr-Gama and Rodrigo Oliva Perez
Abstract
Neoadjuvant chemoradiation (CRT) is considered as one of the preferred
treatment strategies for patients with locally advanced rectal cancer. This
treatment strategy may lead to significant tumor regression, ultimately leading
to complete pathological response in up to 42% of patients. Assessment of
tumor response following CRT and before radical surgery may identify patients
with complete clinical response that could be managed non operatively with
strict follow-up (Watch & Wait Strategy).
Radical surgery has always been the mainstay of the treatment of rectal cancer.
However, local recurrence rates were still considerably high in a subset of patients
even after appropriate surgery including total mesorectal excision (Simunovic
et al. 2003). The concern for local recurrences prompted the surgical and radiation
oncology community to consider additional therapy in selected patients considered
to be at a higher risk for local disease relapse. Indeed, additional postoperative
radiation (adjuvant) did improve local disease control even though at a consid-
erably high cost in terms of toxicity and long-term complications (Ooi et al. 1999).
The solution for this problem was the use of preoperative therapy in patients with
locally invasive rectal cancer that was shown to improve local disease control and
A. Habr-Gama (&)
University of São Paulo School of Medicine, Rua Manoel da Nóbrega 1564,
São Paulo, SP 04001-005, Brazil
R. O. Perez
Angelita and Joaquim Gama Institute, University of São Paulo School of Medicine
Colorectal Surgery Division, Ludwig Institute for Cancer Research, São Paulo, Brazil
204 A. Habr-Gama and R. O. Perez
significantly decrease immediate and long-term toxicities. The addition of

chemotherapy to radiation therapy in these patients seems to be beneficial in terms
of local disease control (Sauer et al. 2004).
The benefits of neoadjuvant chemoradiation were not restricted to long-term
local disease control as confirmed by an update of the German Trial after 11 years
of follow-up (Sauer et al. 2012). One of its main consequences is that it may lead
to variable degrees of tumor regression, reflected by primary tumor reduction in
size (downsizing), in-depth penetration, and possible perirectal node sterilization
(downstaging). In up to 42 % of the cases, complete pathological tumor regression
has been reported (Sanghera et al. 2008). Such findings challenged the role of
standardized radical resection in all patients with rectal cancer particularly after
complete tumor response to neoadjuvant therapy. One could ask about the onco-
logical benefit in a patient following radical rectal resection where not a single
cancer cell is removed (Habr-Gama et al. 1998; Habr-Gama et al. 2004).
But the solution for this riddle is not straightforward, as it seems. Assuring
complete tumor regression is not an easy task, even when radical resection is
performed (Chen et al. 2011). However, exposing patients to considerable morbid
procedure leading to variable rates of urinary, sexual and fecal dysfunctions, the
requirement for temporary or permanent stomas and the expected procedure-
related mortality may not be considered the best alternative (Mass et al. 2012;
Habr-Gama et al. 2004).
In addition, the degree of tumor regression may be influenced by several dif-
ferent factors that should be taken into account. Obviously, radiation doses and
chemotherapy regimens may both influence the rates of complete tumor regression.
Indeed, experimental studies suggest that cancer cells significantly lose their
metastatic potential after being treated with 45 Gy of radiation (Withers and
Haustermans 2004). However, studies have not definitively explained the reasons
why after similar doses some tumors respond completely while others seem to be
absolutely resistant to such therapy. Recent studies in molecular biology have
provided initial hints of possible specific combinations of genetic mutations ren-
dering cancer cells either sensitive or resistant to chemoradiation (Kim et al. 2007).
Another factor that seems to influence tumor regression to neoadjuvant therapy
is the time elapsed between completion of treatment and response assessment. This
was first suggested by data of patients with anal cancer that exhibited and sig-
nificant increase in tumor response simply by waiting 8 weeks after completion of
therapy instead of 4 weeks (Deniaud-Alexandre et al. 2003). In rectal cancer,
retrospective studies also indicated that longer interval periods were associated
with increased rates of complete tumor regression (Moore et al. 2004). This fact
was more recently demonstrated in studies supporting the idea that degree of tumor
downstaging is probably time-dependent suggesting that the more you wait, the
more you get in terms of tumor regression (Tulchinsky et al. 2008; Kalady et al.
2009).
Interestingly, chemoradiation seems to exert significant effects in perirectal
nodes in addition to the primary tumor. First, tumors treated by neoadjuvant CRT
have consistently resulted in decreased rates of stage III or node-positive disease
Immediate Surgery or Clinical Follow-Up 205
(Sauer et al. 2004). The rates of micrometastases among perirectal nodes seem to
be decreased by neoadjuvant CRT (Perez et al. 2005). The observation of residual
mucinous deposits among lymph nodes in the absence of cancer cells also suggests
the possibility of lymph node sterilization as a result of CRT (Perez et al. 2005).
Finally, the overall number of recovered nodes is significantly decreased in
patients after neoadjuvant therapy (Habr-Gama et al. 2008b; Sermier et al. 2006);
again, this effect has also been shown to be time-dependent since longer interval
periods between CRT completion and surgery was associated with fewer recov-
ered nodes (Sermier et al. 2006).
In this setting, patients with apparent complete clinical tumor regression would
be ideal candidates for alternative treatment strategies including no immediate
surgery and rigorous close observation.
The main obstacle to this approach is the risk of leaving microscopic residual
disease within the rectum or in perirectal nodes. Indeed, distinguishing transmural
fibrosis from microscopic residual disease may be quite difficult. Clinical assess-
ment alone has been shown quite disappointing sensitivity and specificity rates in
previous retrospective studies. However, some of these studies included tumor
response assessment performed at 6 weeks from CRT completion, possibly too
early and reflecting the detection of residual disease in the setting of ongoing
necrosis (Hiotis et al. 2002). Also, studies have detected residual microscopic nodal
disease in patients with complete pathological primary tumor regression (ypT0).
Again, these studies included patients managed by radical surgery after 6 weeks
from CRT completion and may also reflect potential interruption of ongoing
radiation-related tumor necrosis (Zmora et al. 2004). This is suggested by the
observation of absence of residual nodal disease in patients with ypT0 after periods
of longer intervals than 6 weeks after CRT completion (Habr-Gama et al. 2008b).
It has been our strategy to assess tumor response at least after 8 weeks from CRT
completion including clinical assessment with digital rectal examination, rigid
proctoscopy and CEA levels in combination with radiological assessment, mainly
performed to rule out residual extra-luminal disease (Habr-Gama et al. 2010).
Only patients fulfilling these stringent criteria have been considered for this
nonoperative approach (Watch & Wait) (Perez et al. 2009). Patients with any small
residual nodule or excisable scar are managed by a full-thickness transanal excision
primarily as a diagnostic (or eventually as therapeutic) approach (Perez et al. 2013).
Only patients with no detectable residual disease or without microscopic disease
after FTLE (ypT0) are considered for observation alone (Habr-Gama 2006).
In a retrospective analysis of patients managed by this approach, patients with
complete clinical response did no worse than patients managed by radical surgery
and pathological complete response in terms of survival (Habr-Gama et al. 2004).
Late local relapses occurred in approximately 10 % of these patients not imme-
diately operated on and in a considerably longer interval when compared to sys-
temic relapses. In addition, patients with exclusive local relapse were all amenable
to salvage resection (Habr-Gama et al. 2006). Recently, other institutions have
observed similar results further supporting this treatment strategy in highly
selected patients (Maas et al. 2012).
Still, assessment of tumor response remains a challenging issue. Clinical
assessment is associated with a learning curve and probably has improved over time
during our 15-year experience period. Even so, a subset of patients who were initially
considered as complete responders presented with residual disease or early tumor
regrowth/recurrence within 12 months of follow-up. It is worth mentioning that we
have arbitrarily considered this period of 12 months as the minimum to consider a
sustained complete clinical response in these patients (Habr-Gamaet al. 2006).
One of the main concerns with this ‘‘Watch & Wait Strategy’’ would be the risk
of harming these particular patients misdiagnosed as complete clinical responses
after delayed surgery. However, in a retrospective review, there was no survival
compromise in patients with initial suspicion for complete clinical response who
had undergone delayed surgery for early tumor regrowth (Habr-Gama et al.
2008a).
The task of identifying patients with complete tumor regression is one of the
most difficult challenges faced by colorectal surgeons. Up till now, this aims at
nearly 30–40 % of patients with distal rectal cancers but this share may actually
increase with modern and newer CRT drugs and regimens. In fact, the addition of
chemotherapy cycles during the RT and the ‘‘resting’’ period between RT and
surgery with a modest increase in RT dose (50.4–54 Gy) has led to a significant
increase in complete clinical response rates to over 50 % of patients (Habr-Gama
et al. 2009; Habr-Gama et al. 2013).
In addition, assessment of tumor response may further improve its accuracy by
the combination of different radiological modalities such as PET/CT and MRI
imaging brought together in a single radiological study as well as using individ-
ualized intervals between CRT completion and assessment of tumor response for
different groups of patients.
1 Conclusions
Complete clinical response may be observed in up to 50 % of patients with rectal

cancer following neoadjuvant chemoradiation. The actual percentage of patients
that will develop complete response may vary according to baseline staging, type
of chemoradiation regimen, and timing of assessment of response. Specific clin-
ical, endoscopic, and radiological features may identify patients likely to have a
complete pathological response. Management of these highly selected patients
without immediate radical surgery and strict surveillance (‘‘Watch & Wait’’) may
provide an interesting alternative avoiding significant morbidity and mortality
associated with radical surgery without compromising oncological outcomes. As
understanding of molecular biology aspects associated with these tumors grows,
additional tools may further improve selection of appropriate candidates for this
organ-sparing procedure in patients with distal rectal cancer.
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Part V
Rectal Cancer with Synchronous
Liver Metastases
Limits of Colorectal Liver Metastases
Resectability: How and Why
to Overcome Them?
For Progress in Cancer Research
Serge Evrard
Abstract
Offering surgery is to date the best case scenario for patients with colorectal
liver metastases (CRLM). Few oncological topics have progressed as much as
the treatment of CRLM. New surgical techniques, conversion therapies, and
imaging allow us to pursue the ultimate limit for surgery of CLM before
compromising patient benefits. Pushing the limits of surgery involves pushing
the limits of conversion therapies too, increasingly taking risks in the surgical
process. Finally, toxicities add up and the patient benefit could disappear. The
apparent paradox of efficiency and toxicity might be addressed by separating
the two treatment targets: (1) The metastatic burden for which a clear escalation
in medical and surgical aggressiveness is still required. (2) The healthy
parenchyma which should be preserved as much as possible and for which a
clear de-escalation is anticipated. A new strategy exists that integrates both
fundamental endpoints in the battle against CLM.
Keywords

Colorectal liver metastases Liver resection Ablation Chemotherapy

Cancer target therapy Cancer survival Quality of life
S. Evrard (&)
Institut Bergonié, Université de Bordeaux, Bordeaux, France
214 S. Evrard
1 Introduction
Articles on colorectal liver metastases (CRLM) frequently start by arguing, first of

all that resection is the only chance for cure with 5-year survivals ranging from 33
(Adam et al. 2009) to 56 % (Karanicolas et al. 2013), and second, that unfortu-
nately only a few patients, probably less than 20 % of the total, will be suitable for
surgery. Some of them present with easily resectable CRLM, and the only
uncertainty lies in whether they should go to perioperative chemotherapy based on
the EORTC EPOC trial results (Nordlinger et al. 2008) or not considering the
negative data on overall survival (OS) recently published (Nordlinger et al. 2013).
Consequently, the reader should understand that increasing resectability in mainly
borderline resectable or initially unresectable lesions is the major preoccupation of
the liver surgeon. That being said, two new facts that should be understood when
exposing the situation. The first deals with the strategy: a median 40-month OS has
been reported for CRLM treated by palliative chemotherapy (Ruers et al. 2012).
As a consequence, a cut-off should exist beyond which R0 resection is no longer of
profit for the patient compared to a chemotherapy-only palliative approach. The
second concerns the technique: initially unresectable CRLM should not be man-
aged with a radical approach such as extensive hepatectomies, (Cauchy et al.
2012) but through a de-escalation process using iterative treatments on a lesion-
per-lesion basis (Gold et al. 2008), and especially intraoperative ablation combined
with resection (Karanicolas et al. 2013; Evrard et al. 2013a). In an effort to reflect
the new technical reality, operability should be used in favor of resectability,
which is becoming increasingly confusing.
That being said, deciding for resectability or, better said, operability is a
challenge for the surgeon who has to deal subjectively with multiple objective
parameters. The Celim study has clearly demonstrated that several expert liver
surgeons can decide differently on the same case (Folprecht et al. 2010). Such
decision-making involves identifying where the limits are, how to overcome them,
and ultimately how the patient could profit from such a demanding procedure.
2 Nature of the Limits?
Resectability limits are mainly based on the necessity to respect the hepatic capital
and its functions. Technical challenges may additionally represent a concern, and
finally, the surgical decision has to be consistent with the oncologic multidisci-
plinary approach designed to manage the tumor.
Limits of Colorectal Liver Metastases Resectability: How and Why to Overcome Them? 215
3 Patient Limits and Tolerance
Immediate iatrogenicity, i.e., mortality and morbidity—is the main concern for the
surgeon dealing with CLM surgery. The primary aim of the liver surgeon is not to
lose his patient in the postoperative period. Hemorrhage, liver failure, and septic
complications are major drawbacks that can be the direct consequences of pushing
the limits of surgery too far. A 1 or 2 % mortality figure is usually reported for
hepatectomies or series combining resection and ablation but higher rates ranging
from 6.4 (Brouquet et al. 2011b) to 10.3 % (Cauchy et al. 2012) have been recorded
when using aggressive procedures, respectively, 2-stage and extensive hepatecto-
mies, which clearly exceed the accepted standard. The second limit is less obvious
and directly linked to postoperative morbidity. Several studies have demonstrated
that postoperative complications diminish the 5-year OS (Matsuda et al. 2013), as
far as dividing them by two (Evrard et al. 2012). In surgical oncology, a maturing
strategy always evolved toward a de-escalation profile, aiming to achieve the same
therapeutical results but diminishing the morbi-mortality. The oldest paradigm is
breast surgery and more recently laparoscopic surgery. Consequently Primum non
nocere should be the first ‘‘commandment’’ for the liver surgeon wanting to push
the limits of CRLM surgery without causing any harm to patients.
4 Anatomical ‘‘Capital’’
Patients’ original liver anatomy may limit the surgical options. An unfavorable
right/left repartition of the parenchyma can sometimes be a real challenge. Fig-
ure 1 exhibits a female patient with a dominant right liver having a 12 mm CRLM
stuck on the right hepatic vein. This right/left repartition precludes a right hepa-
tectomy; indeed the risk of right portal vein embolization cannot be envisaged
since it could lead to a fatal liver failure. The only possible solution remains a local
treatment of the metastasis.
Other anatomical restrictions may arise from previous hepatectomies. A second,
a third, and sometimes a fourth hepatectomy may be possible but with progressive
reduction in the liver capital:
• In fact, liver homeostasis possibilities decrease after each line of surgery. The
limits of parenchymal regeneration are due to the depletion of cellular
homeostasis but also to the diminution of the vascular input (portal and arterial
vessels) and output structures (hepatic veins).
• Previous surgery induces more or less adhesions between the liver and the dia-
phragm. Scarred remaining liver may be a limit by itself (Dupre et al. 2013).
Dividing adhesion can sometimes lead to important hemorrhage, and some liver
fracture, limiting the resection possibilities. As far as that goes, dividing peri-
hepatic adhesions alters the Glisson’s capsulae which impairs the ultra sounds
transmission into the parenchyma. The consequence is a blind area for surgery and
a reduction in therapeutic possibilities. Respecting Glisson’s capsulae as much as
possible is therefore a conservative approach optimizing the surgical care.
216 S. Evrard
Fig. 1 Female patient with

right dominant liver. To be
noticed, a 12 mm diameter
colorectal liver metastasis
stuck on the right hepatic vein
5 Liver Functions
The concept of hepatic capital must also be understood functionally. The quantity,
but also the quality of liver parenchyma, and the vascular flow irrigating it are
parameters of liver functions to be considered.
5.1 Parenchyma Volume and Functions
Before chemotherapy was used for neoadjuvant or induction strategies, the rule of
parenchymal-sparing by hepatectomies was strictly based on volume estimates. It
was widely accepted that up to 75 % of the liver could be retrieved with a healthy
parenchyma. When the patient receives more than 6 or sometimes more than 12
preoperative chemotherapy cycles based on Folfox or Folfiri regimens, the
remaining liver volume must be at least 40 % of the total volume. Some authors
have proposed a prediction of postoperative morbidity and mortality based on an
functional remnant liver volume (RLV)/body weight (BW) ratio. In the series
reported by Truant et al., no deaths occurred in patients with an RLV/BW [ 0.5 %
(Truant et al. 2007).
Hepatic steatosis may occur after treatment with 5-fluorouracil and is associated
with increased postoperative morbidity. Steatohepatitis including inflammation and
hepatocyte damage can occur after treatment with irinotecan. Irinotecan-associated
steatohepatitis can affect hepatic reserve and increase morbidity and mortality after
hepatectomy (Zorzi et al. 2007). Hepatic sinusoidal obstruction syndrome can occur
in patients treated with oxaliplatin. Some authors claim that it does not appear to be
associated with an increased risk of perioperative death (Zorzi et al. 2007). Some
others report compromise perioperative outcome, early recurrence, and decreased
survival in the long term (Tamandl et al. 2011).
5.2 Input and Output Vascular Flow
It is generally accepted that at least one portal pedicle, as the input flow, two
contiguous segments and one hepatic vein, as the output flow are the minimum
required anatomic structures to be spared. Most of the time, this extreme strategy
has to use portal induced atropho-hypertrophy in order to enhance the volume of
the two residual segments. It should be emphasized that any vascular structure,
especially the portal output vessels, is precious and must be preserved whenever
possible. The direct hepatic veins originating from segment 1 must never be cut
only to mobilize the liver. Indeed, the necessity to cut a main hepatic vein (right,
median, or left) can be avoided by direct hepatic veins allowing saving a segment.
6 Vascular Technical Limits
LM in close contact with a major portal pedicle are most of the time resected R1 if
the pedicle cannot be sacrificed. An invasion of both right and left portal pedicles
is a definitive surgical contraindication. Invasion of one major (right or left) portal
pedicle plus an invasion of the median and contralateral hepatic veins can be
considered as a relative unresectablity scenario. Invasion of hepatic veins does not
represent a definitive contra-indication as some surgical techniques sometimes
allow clearing or reconstructing the vessels.
7 Oncologic Limits
By respecting oncologic limits the relevance of the surgical procedure is guar-

anteed. In other words, a surgeon is not allowed to define what is feasible under
exclusive technical considerations. The first oncologic rule to be observed is the
R0 rule: all visible disease has to be removed. It will be later discussed that R1
resection might be acceptable under certain circumstances.
218 S. Evrard
7.1 Systemic Control of the Disease
5FU was first introduced at the beginning of the 1980s. Due to the moderate
efficiency of 5 FU and FUFOL regimens, the maximum number of lesions
accepted was three. ‘‘No more than 3’’ was an active rule for 15 years. In 1986,
Starzl’s team (Iwatsuki et al. 1986) reported that no patient operated on from more
than 4 CRLM was alive 3 years later. In a review published in 1991, Muller et al.
(Muller et al. 1991) evidenced that only solitary or very small and unilateral
metastases may profit from surgery. The introduction of oxaliplatin and irinotecan
in the Folfox and Folfiri regimens extended the efficacy perimeter. Progressively,
the number of metastases and the bilaterality were no longer a limitation
(Minagawa et al. 2000); attention was focused not on what have to be retrieved
from the liver but rather on what had to stay. The introduction of cetuximab and
bevacizumab supported this trend. In the joined analysis of their strategies over
time, the Mayo Clinic and the MD Anderson observed a clear increase in the OS of
patients due to a concomitant use of polychemotherapies and biological therapies
and the increased number of hepatectomies (Kopetz et al. 2009), especially after
2004. The more chemotherapies and biological are used, the more hepatectomies
are performed and the better the survival. If we accept this correlation between
systemic medical treatment and surgery, it means that each period of time has its
own oncological limits. As suggested by some authors (Boige et al. 2007; Cardona
et al. 2013; Gallagher et al. 2007), the intraarterial use of chemotherapy would
provide a greater number of technical possibilities. In the future, major progresses
in systemic treatment could lead to the end of the R0 rule. A new concept of R2
debulking surgery could become useful and pertinent for the patient, providing that
medical treatment controlled the rest of the disease.
In this respect, we should critically analyze the respective role of chemotherapy
and surgery. Indeed, for 3–6 CLM, surgery is evidently the main curative treat-
ment, whereas systemic treatments are adjuvant to surgery. For 12 bilateral CRLM
however, are the roles inverted? Is not chemotherapy the main treatment and
surgery adjuvant to medical treatments? That implies that there must be a turning
point between curative and palliative strategy in CRLM care which is so far
unknown. The Clocc trial reported an unexpected long survival of 40 months in
the control arm treated by chemotherapy only. An increased PFS of 10.6 % at
3 years was reported compared with 27.6 % in the control arm, but there was no
statistical difference of OS at 5 years. The use of PFS as a surrogate marker of OS
in colorectal cancer (Buyse et al. 2007) is not as pertinent as thought. The EORTC
EPOC trial made the same disappointing observation (Nordlinger et al. 2013).
7.2 Extrahepatic Disease
Lung and peritoneum are the two main extrahepatic locations for metastases. Some
authors claim that they are not contraindications to treat CRLM (Brouquet et al.
2011a; Allard et al. 2013) but the series published are, most of the time, highly
selective. Paucy extrahepatic locations may not preclude CRLM surgery, but they
clearly diminish the OS (Adam et al. 2009). In a series combining resection and
intraoperative ablation of CRLM, 3-year OS decreased by two (30 months vs. 60)
in patients with extrahepatic disease (Evrard et al. 2013a). Other extrahepatic
metastases like adrenal gland, bone, and muscle are usually contraindications.
7.3 Margin Clearance
The clear surgical resection margin accepted to achieve cure has evolved from 10
(Cady et al. 1992) to 2 mm (Kokudo et al. 2002), and more recently to 0 mm
(de Haas et al. 2008). So, there does not seem to be a margin limitation, but the
size of the margin may be dictated by the location of the CLM in the liver
structures. In other words, a lesion resected with a 1 mm margin may have a worse
recurrence outcome due to worst anatomical topography. Some authors remain
committed to the R1 and R0 resection distinction (Andreou et al. 2013). Neve-
theless, a large series of 2,715 patients analyzed by a propensity score case-match
approach concluded that a 1 mm cancer-free resection margin achieved in patients
with CLM should be considered the standard of care (Hamady et al. 2014).
8 How to Overcome Limits?
The surgeon has to consider the limits of resectability and push them, guided by a
pertinent multidisplinary strategy that makes sense from an oncological point of
view, only if the patient is not harmed. The question remains though––how can
this challenging and paradoxical job be carried out? Going further from an
oncological point of view but offering a better outcome for the patient, this strategy
has to take into account a major characteristic of CLM disease, the high rate of
recurrence.
8.1 Increasing the Remaining Liver Function
8.1.1 Decrease Chemotherapy Toxicities

Both oxaliplatin and irinotecan induce liver toxicities that potentially impair
resectability (see above). Preoperative chemotherapy is sometimes mandatory as a
conversion strategy to surgery, but also because it allows testing the chemosen-
sibility of the tumors, which is a major prognostic factor. Decreasing preoperative
chemotherapy and the toxicity of targeted therapies increase surgical possibilities.
Ideally, the patient should undergo surgery as soon as the surgeon approves, which
means that the role of the MDT decision to discuss the file every four cures of
chemo is key.
220 S. Evrard
8.1.2 Parenchyma Atropho-Hypertrophy

Liver is the only organ capable of homeostasis, which offers fantastic therapeutic
opportunities. The idea is to get atrophy of the invaded segments and hypertrophy
of the healthy parenchyma. Two techniques are available.
Portal Vein Occlusion

Introduced by Kinoshita et al. (Kinoshita et al. 1986) in 1986, it is the oldest and
the best-known technique. The principle is to obliterate a portal vein to induce
hypertrophy in the contralateral segments. Portal Vein Occlusion (PVO) can be
performed in the preoperative setting by a radiologist to prepare an extensive
hepatectomy, or intraoperatively by the surgeon to prepare a 2-stage procedure.
Obliteration can be performed proximally by ligation or using a plug or distally
with coils, glue, lipiodol. Several studies suggest that these different approaches
would yield comparable results (Aussilhou et al. 2008). A logical drawback of
PVO may be a growth stimulation not only for the healthy parenchyma but also for
the metastases (Elias et al. 1999). Some authors reported the concomitant use of
neoadjuvant chemotherapy after PVO without diminishing neither hypertrophy of
the future remnant liver nor additional toxicity (Covey et al. 2008). PVO results
are appreciated after 4 weeks by a CT-scan and can lead to either 1-stage or
2-stage surgeries.
ALPPS
First described in Regensburg, Associating Liver Partition and Portal vein Ligation
for Staged hepatectomy (ALPPS), is a new 2-step technique for obtaining short-
term parenchymal hypertrophy in patients requiring extended right hepatic
resection with limited functional reserve. A first step includes a right portal vein
ligation (PVL) and an in situ splitting (ISS) of the liver parenchyma letting the
targeted liver volume vascularized by the artery only. The ischemic part of the
liver is retrieved approximately 9 days later. Schnitzbauer et al. reported an
increase of the median volume of the future remnant liver of 74 % but with a high
mortality rate of 12 % (Schnitzbauer et al. 2012). The experience is preliminary
and a registry for a prospective study is open to collect data.
8.1.3 2 Stage with or Without PVO

The two-stage procedure is also based on liver function homeostasis: to retrieve all
the CLM in one procedure when it is not feasible, one hemi-liver can be treated
after the other, avoiding liver failure (Adam et al. 2000). In between, a PVO can be
added to enhance the growing capacities of the future remnant liver. This artful
strategy has no equivalent in surgical oncology, and allows treating more patients.
In a selected population, a 2-stage procedure offers good survival results as seen in
the MD Anderson series (Brouquet et al. 2011a) with a 64 % 5-year OS. Never-
theless, mortality was 2 % after the first stage and 6 % after the second, and only
75 % of the patients were apt to proceed to the second stage. For this group, the
survival was worse compared to a group treated by chemotherapy only (13 vs.
42 %). A 2-stage procedure is very useful but complex and costly (Dupre et al.
2013; Abbott et al. 2013) and needs a good selection of patients, especially to
avoid failure at the second step.
8.1.4 Nonanatomical Resection

Liver transplant surgery during the 1980s and the 1990s contributed a great deal to
the development of resectional liver surgery. Liver transplant surgery is based on
vascular principles that imply a respect of the anatomical structures. As evidence,
if the segment unit is respected, its vascular and biliary structures are automatically
intact. At this time, the number of CLM which was authorized was among 3. Thus,
having anatomical resections was not a challenge. Nevertheless, the number of
CLM to resect progressively increased and some authors claimed that anatomical
resections would be better than nonanatomical (DeMatteo et al. 2000), probably
with the idea that surgical margins would be the largest.
After more than 10 years of controversies, nonanatomical resections were
finally accepted as a de-escalation strategy (Gold et al. 2008; Sui et al. 2012)
resulting in superior oncological outcomes, a better iterativity and a lower con-
sumption of healthy parenchyma.
8.1.5 Intraoperative Ablation and the CARe Concept

After the imposition of nonanatomical resection the question arose on the place of
intraoperative ablation to continue the concept of tumoral focused treatment with a
high propensity to spare healthy parenchyma. Enthusiastically introduced by Elias
et al. (2000) and Curley et al. (1999) from both sides of the Atlantic Ocean,
radiofrequency ablation was rapidly ostracized (Abdalla et al. 2004). The reason
was a competition with radiologists who wanted to conquer the CLM market by
using RF percutaneously. By comparing the results on resection to treat easily
resectable lesions to those on ablation to treat lesions without any possibility of
clear margin, they attempted to discredit RF (Abdalla et al. 2004). The first attempt
was to separate results from intraoperative RF and pecutanous route. Clearly, the
local recurrence rates were less than 10 % in the surgical arm and more than 25 %
in the percutaneous arm (Evrard and Mathoulin-Pélissier 2006). Intraoperative
ablation progressively evolving toward a new concept of complementarity to
resection rather than toward being a competitor (Leblanc et al. 2008). In 2012, two
prospective studies (Ruers et al. 2012; Evrard et al. 2012) were published con-
firming the place of intraoperative RF to complement resection for nonresectable
CLM. Local recurrence rates of ablated lesions were inferior to 9 % (Ruers et al.
2012) and 5-year OS reached 43 % (Evrard et al. 2012). A confirmation study,
based on a large international population was realized by joining four prospective
databases. Preliminary results have already been reported (Evrard et al. 2013a) and
a branded concept of CARe (Combined Ablation plus Resection) will be soon
published. Currently, several surgeons (including the author) believe that ablation
should be indicated not only for unresectable CLM but to face complex situations
including bilateral diseases (Karanicolas et al. 2013; Leblanc et al. 2008). In some
222 S. Evrard
cases it could substitute 2-stage procedures and result in better survival and lowest
cost (Abbott et al. 2013). Anatomical resections, nonanatomical resections, 2-stage
resections, and finally CARe are the four successive main steps in the history of
CLM surgery. A de-escalation story …
8.1.6 Increasing the Radicality of Surgery

Approaches to enhance surgical radicality include intensifying the preoperative
medical strategy, the second include more specific technical options.
Increase Chemotherapy and Targeted Therapies Efficacy

Unresectable or borderline resectable CLM are treated by downsizing chemo-
therapy regimens including targeted therapies. Some studies have reported con-
version rates ranging from 19 (Adam et al. 2009) to 28 % (Folprecht et al. 2010).
These regimens were based on Folfox and Folfiri, more or less associated with
cetuximab or bevacuzimab. More aggressive strategies are tested like triplet
chemotherapy (Folfirinox), triplet plus antigiogenics, new antigiogenics, etc. It is
too early to hypothesize the level of conversion that will be reached in the future.
What is clear, however, is that aggressive conversion strategies are a major trend
and that the surgeon who operates following chemotherapy has to take it into
account. It has been shown that after more than 12 cycles of preoperative che-
motherapy, extensive radical hepatectomies should be avoided due to poor surgical
outcomes and poor survivals (Cauchy et al. 2012).
Another way to increase downsizing treatments is to change the route of
administration like with the arterial pump and hepatic artery infusion (HAI)
(Cardona et al. 2013; Goere et al. 2010; Ammori et al. 2013). For initially unre-
sectable CLM, a 24 % rate of resection was obtained with HAI by oxaliplatin and
intravenous 5 FU and a 5-year OS of 56 % (Goere et al. 2010). HAI of oxaliplatin
plus irinotecan plus intravenous FUDR—dexamethasone led to a conversion rate
of 47 %. When HAI was performed in first line, a 5-year 51 % rate was observed
(Kemeny et al. 2009). Even if aggressive, this conversion approach is gaining
increasing acceptance.
This being said, this chapter does not contradict a previous one where it was
claimed that the MDT should decide to go to surgery, as soon as the surgeon
approves.
Treating Invaded Vessels

Invaded vessels are a major reason for unresectability. For portal pedicles, there is
no technical joker. A lesion in close contact with a portal pedicle can be resected
R1 if the pedicle cannot be sacrificed. Vascular resections followed by a recon-
struction are not used for CLM and hyperthermic ablation cannot be used due to
biliary duct sensitivity.
For hepatic vein, more aggressive techniques are available. Techniques of
resection plus grafting reconstruction have been reported but with mediocre results
(Hemming et al. 2002; Aoki et al. 2004). Mortality after vascular reconstruction
could be as high as 33 % (4/12) (Cauchy et al. 2012). On the contrary, ablation
Fig. 2 The same patient

after an intraoperative RF
with vascular exclusion.
Complete destruction of the
lesion without harming the
right liver veinous drainage
with vascular exclusion is a good indication to treat LM close to them (Evrard

et al. 2013b). Indeed, portal vascular endothelium is highly resistant to heat (Sato
et al. 2005). Vascular exclusion is required to prevent blood cooling and local
recurrences. Nevertheless, new technologies like powerful RF generators (up to
200 watts compared with 50 watts for the first generation of generators) or
microwaves generators allow to treat such lesions without vascular clamping.
Figure 2 illustrates such an intraoperative ablation.
Hanging Maneuvers for Big Lesions

Big lesions have their own concerns as shown in Fig. 3. Some of them preclude the
division of the right triangle ligament which usually is realized first. It is thus
necessary to cut first the liver without any mobilization which is dangerous. The
liver hanging maneuver, which is a technique of passing a tape along the retro-
hepatic avascular space and suspending the liver during parenchymal transection,
facilitates anterior approach of major hepatectomy. The liver hanging maneuver
has 94 % feasibility. Absolute contraindication is tumor infiltration to the retro-
hepatic avascular space (Ogata et al. 2007).
Radical Extensive Hepatectomy

Extensive hepatectomy is sometimes necessary to remove the metastases burden.
A PVO is often necessary. The question if extensive radical hepatectomy should
be done as a standard based on the concept of retrieving a maximum of unknown
micrometastases, has a clear negative answer. In the Beaujon Hospital series,
patients with initially unresectable CLM without extrahepatic diseases responding
to chemotherapy had a 5-year PFS of 13 % and a 5-year OS of 40 % after major
hepatic resection. Mortality, however, was high at 10 %, and margins were
involved in 39 % of the cases. Patients requiring more than 12 cycles of chemo-
therapy to achieve resectability had more postoperative complications, a 3-year
DFS of 0 % and a 5-year OS of less than 30 %. Authors clearly concluded
224 S. Evrard
Fig. 3 Massive solitary

CLM of the right liver with
major adhesions with the
diaphragm. Impossibility to
mobilize the right liver first
and thus a hanging maneuver
was necessary for anterior
hepatotomy
(Cauchy et al. 2012) that patients responding only after 12 chemotherapy cycles
should undergo conservative strategies including repeated resection, ablation, or
intraarterial chemotherapy instead of extensive radical surgery.
Ex Vivo Surgery
These exceptional procedures may be indicated in very particular cases of vena
cava involvement (Malde et al. 2011; Magge et al. 2013)
Isolated Liver Perfusion

Isolated hepatic perfusion (Ammori et al. 2013) was proposed 20 years ago as an
aggressive treatment limited to the liver (Bartlett et al. 2001). This approach stayed
confidential both because of the spread of active systemic treatments and because
of the complexity and the cost of the procedure. Some attempts of percutaneous
isolation have been reported (Miao et al. 2008; van Etten et al. 2004).
Liver Transplant
CLM is a classical contraindication for liver transplant, and it probably should stay
so. A limited number of experiences have been reported (Hagness et al. 2013) that
show an interesting pattern of recurrence observed after transplantation. If pul-
monary recurrence were of indolent character, re-metastases to the liver transplant
were prognostically adverse and confirm that delayed metastases in CR cancer
may originate from previous metastases (Klein 2009).
9 Increasing Surgeon’s Skill
There is a clear deficit in practicing intraoperative ultrasounds (IOUS) in liver

surgery, even in some of the most renowned HPB teams. Indeed, in these teams, the
surgical decision is made preoperatively, usually based on an MRI, and the surgery
has just to execute the plan. The main explanation for why intraoperative ablation
was hard to break is the weak diffusion of IOUS. Moreover, some teams that decided
to make intraoperative ablation felt the necessity to call a radiologist in the OP room
to perform the IOUS. Yet, IOUS are the surgeons’ eyes. They allow perfect guid-
ance to determine the cutting plan, to push down a needle, and to discover among
20 % of additional lesions (Torzilli and Makuuchi 2003). Contrast-enhanced IOUS
is now available (Fioole et al. 2007; Shah et al. 2010). Some advanced HPB courses
offer specific IOUS subjects (ESSO course, University of Milan).
10 For the Benefit of Which Patient ?
As already mentioned, the main concern when extending the frontier of resect-
ability is to not harm the patient. The last one, but not the least, should be to
determine how the patient really benefits from the efforts and finally the question
of quality of live (QoL) should be asked.
Overall survival is the primary endpoint for the patient and surgery will remain
indicated as long as it provides longer OSs compared to a systemic treatment. For
extended CLM diseases, surgery acts as a closing treatment in the efficiency
perimeter delineated by the systemic treatment. This perimeter increases with time
and progresses in surgery and in systemic treatments provide a synergistic result
(Kopetz et al. 2009). In the surgical world that abides by the R0 rule, the perimeter
of surgery will never overcome that of systemic treatments, like nothing travels
faster than the speed of light. Violating this rule would mean creating a new
paradigmatic world where the patient would never be cured and instead would
benefit from becoming chronic. This new R2 oncological rule inaugurates a new
concept that will need one or two decades before breaking it. Not only invasive
surgery but also interventional radiology, percutaneous ablation, HIFU, and ste-
reotaxic radiotherapies will invest this scope of action.
But back in the old R0 world, extending the limits of resectability cannot be
infinite; a cut-off exists beyond which the gain in OS will not be significant. But
where? At the present time the answer to this question is unknown. What is sure is
that an R0 surgery brings additional PFS as demonstrated by the CLOCC trial
(Ruers et al. 2012). The ARF2003 study demonstrated that QoL improved during
the period of clinical remission. Consequently, the PFS is a good surrogate marker
of QoL rather than of OS. Extending the limits of resectability or operability could
thus provide, at least, an improvement in the quality of life of patients.
11 Conclusion
Resectability must give way to operability as the CARe concept is now evidence
of the modern surgical approach that allows treating more and more patients. To be
more proactive but less toxic is the main watchword to intensify the surgical fight,
facing the escalation in medical conversion therapies. Therapeutical endpoints
must be well-defined and understood through the real patient benefit they provide.
226 S. Evrard
Acknowledgments I acknowledge Ms Jone Iriondo-Alberdi for medical writing assistance in

English.
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Rectal Cancer with Synchronous Liver
Metastases: Leave It All in? When (not)
to Resect the Primary?
Florian Lordick
Abstract
Rectal cancer with synchronous distant metastases is challenging the choice of
optimal treatment. Today, it is unknown if and when the primary tumor should
or should not be resected. The current literature was reviewed. Data on the
safety of a primary chemotherapy approach are reported. These publications
indicate that at least in selected situations without severe symptoms or
complications resulting from the primary, the rectum can be left in situ without
major risks for the patient. However, retrospective analyses from randomized
controlled trials indicate a potential prognostic advantage for patients having
the primary tumor resected. The reason for this observation is largely unknown
and requires further investigation. Due to the lack of data from prospective
randomized controlled trials illuminating the situation of rectal cancer with
synchronous distant metastases and due to the rapid changes evolving in the
field of systemic treatment of metastatic colorectal cancer, no clear conclusions
can be drawn at this stage. But a practical algorithm that may reflect current
European treatment patterns is presented in this article.
Potential conflict of interest: Advisory role and/or compensated lectures for Roche, Amgen,
Taiho, Nordic, and Sanofi Aventis. Research support from Roche and Merck Darmstadt.
F. Lordick (&)
University Cancer Center Leipzig, University Clinic Leipzig,
Liebigstr. 20, 04103 Leipzig, Germany
232 F. Lordick
Keywords
Rectal cancer Liver metastasis Synchronous metastases Resection
Chemotherapy
1 Two Cases
The following two cases illustrate two contrary strategies for the treatment of
rectal cancer with synchronous distant metastases.
1.1 Patient 1
A 42-year-old man presented with locally advanced rectal cancer. He underwent

anterior resection followed by external beam radiotherapy combined with che-
motherapy 8 weeks later. He relapsed within 6 months with hepatic metastases
and started treatment with bevacizumab 5 mg/kg every other week plus irinotecan,
infusional 5-fluorouracil, and folinic acid. During the first 4 weeks of treatment
with bevacizumab, he experienced severe perianal pain requiring opioids. Digital
rectal examination revealed a hard luminal mass adherent to the bowel wall. On
endoscopy, wall thickening accompanied by ulcerative lesions around the anas-
tomosis similar to the mucosal changes seen in ulcerative colitis was present
(Fig. 1). MRI showed thickening of the intestinal and vesical wall in the borders of
the previous pelvic irradiation. Multiple biopsies revealed no malignant areas. The
specimens were consistent with mucosal damage, such as seen in ischemic colitis.
Treatment with bevacizumab was stopped, and systemic analgesics and anti-
inflammatory enemas were administered. The patient was still symptomatic after
5 months of follow-up. In addition, a circumscribed necrotic destruction of the
bowel wall developed covered by the surrounding tissue, still without evidence of
tumor. The patient recovered slowly from his symptoms and lived with metastatic
disease for 5 years.
1.2 Patient 2
A 45-year-old man presented with rectal cancer in the upper rectal third (Fig. 2)
with synchronous multiple lung and liver metastases (Fig. 3). He had lost 3 kg of
weight and suffered from moderate diarrhea. Serum CEA was elevated to
1,727 lg/l (normal range \ 5); LDH was elevated to 1,182 U/l (normal
range \ 220). Chemotherapy with irinotecan plus 5-fluorouracil/folinic acid
(FOLFIRI) plus cetuximab was started. Apart from acneiform rash grade 3 and a
severe infusion reaction at the time of the first cetuximab infusion, he tolerated
chemotherapy well until 6 weeks later he presented with an acute abdomen that
was caused by a rectal perforation leading peritonitis and ileus (Fig. 4). The liver
metastases and the primary tumor had responded to treatment. He received an
Rectal Cancer with Synchronous Liver Metastases 233
Fig. 1 Endoscopic aspect of

ulcerous pseudotumor of the
neorectum in patient 1 who
underwent treatment with
bevacizumab after previous
anterior resection of the
rectum and adjuvant
chemoradiotherapy
Fig. 2 Rectal cancer in the

upper third in patient 2.
Magnetic resonance imaging
(MRI)
Fig. 3 Multiple liver

metastases in patient 2.
Computed tomography (CT)
234 F. Lordick
Fig. 4 CT scans of patient 2 six weeks after initiation of chemoimmunotherapy, illustrating an

ileus due to peritonitis caused by a rectosigmoid perforation
anterior rectal resection and a descendostoma as an emergency operation which

led to his fast recovery. Four weeks later, chemoimmunotherapy could be con-
tinued. This man lived for 4 years with his metastatic disease.
These two cases, one of which has been published previously (Lordick et al.
2006) illustrate that both strategies, i.e., primary tumor resection followed by
systemic chemotherapy and primary systemic chemotherapy without resection of
the primary tumor are common practice in the management of rectal cancer with
synchronous distant metastases. The two cases show that both approaches can lead
to complications in due course. The question is: which approach should be pre-
ferred in which situation?
2 How Do We Make a Clinical Decision?
Usually, clinicians and multidisciplinary tumor boards want to be informed about

the following issues when a decision on treatment sequences in colorectal cancer
with synchronous metastases has to be taken:
1. Is the primary tumor symptomatic (obstruction, bleeding, and pain)?
2. How advanced is the metastatic tumor load?
3. Can the disease be treated curatively?
In case of a symptomatic primary, the indication for early resection is more
evident, but other means of controlling symptoms (e.g., colonostomy or stent
insertion for obstruction, radiation for bleeding or pain) can be considered.
Massive metastatic disease, especially when associated with an inflammatory
systemic reaction composed of weight loss, fever, night sweats, increase of serum
acute phase proteins (C-reactive protein), or cytokines (Interleukin-6) indicate an
imminent need for early and maximally active systemic treatment. Treatment of
the primary tumor is then usually postponed or will never be performed, especially
when the situation deteriorates in the further course.
If cure seems achievable, different strategies are to be considered. Most centers
start with systemic chemotherapy for 3 months as used in the EORTC 40983 study
(Nordlinger et al. 2009). Following induction chemotherapy, a rectal-surgery-first
approach must be weighed against a liver-surgery-first approach (Mentha et al.
2006). The risk of progression of resectable liver metastases during neoadjuvant
chemoradiation, especially if this contains oxaliplatin, has probably been overes-
timated in the past (Manceau et al. 2013).
3 Is It Safe to Leave the Primary Tumor in Situ?
3.1 Cohort Studies
Dutch authors collected the outcome data of 850 patients from seven cohort studies
(Scheer et al. 2008). Only patients with asymptomatic primary colorectal cancers
were included. Leaving the primary tumor in situ was shown to be a relatively safe
strategy: the mean complications were intestinal obstruction in 13.9 % [95 %
confidence interval (CI) 9.6–18.8 %] and hemorrhage in only 3.0 % (95 % CI
0.95–6.0 %) of the patients. After resection, the overall postoperative morbidity
ranged from 18.8–47.0 %. The authors conclude: ‘‘For patients with stage IV
colorectal cancer, resection of the asymptomatic primary tumor provides only
minimal palliative benefit, can give rise to major morbidity and mortality and
therefore potentially delays beneficial systemic chemotherapy. When presenting
with asymptomatic disease, initial chemotherapy should be started and resection of
the primary tumor should be reserved for the small portion of patients who develop
major complications from the primary tumor.’’ However, in this publication, the
proportion of patients presenting with rectal cancer is not specified and is not
subject to detailed subgroup analyses.
3.2 MSKCC Series
Another more recent case series from the Memorial Sloan Kettering Cancer
Center, New York, reports that from 233 patients with synchronous metastases and
an unresected primary tumor, 217 (93 %) never required surgical palliation of their
primary (Poultsides et al. 2009). Sixteen patients (7 %) required emergent surgery
for primary tumor obstruction or perforation, 10 patients (4 %) required nonop-
erative intervention (stent or radiotherapy), and 213 (89 %) never required any
direct symptomatic management for their intact primary tumor. Of those 213
patients, 47 patients (20 %) ultimately underwent elective colon resection at the
time of metastasectomy. Of note, location of the primary tumor in the rectum, and
metastatic disease burden were not associated with increased intervention rate.
Also, the use of bevacizumab had no impact on complication or intervention rates.
236 F. Lordick
The authors therefore concluded that ‘‘most patients with synchronous, stage IV
colorectal cancer who receive up-front modern combination chemotherapy never
require palliative surgery for their intact primary tumor. These data support the use
of chemotherapy, without routine prophylactic resection, as the appropriate stan-
dard practice for patients with neither obstructed nor hemorrhaging primary
colorectal tumors in the setting of metastatic disease.’’
4 The Effect of Systemic Chemotherapy

on the Primary Tumor
It has been hypothesized that the effect of systemic chemotherapy on the primary
tumor is not as high as on liver or other hematogenous metastases. Therefore, long-
term control of the primary may not be achievable. This question has not been
investigated in larger series, but a very recent study from the MSKCC gives some
insight (Schrag et al. 2014). Thirty-two patients with clinical stages II–III rectal
cancer participated in this single-center phase II trial. All were candidates for low
anterior resection with total mesorectal excision (TME). Patients were to receive
six cycles of FOLFOX, with bevacizumab included for cycles 1–4. Patients with
stable/progressive disease were to have radiation before TME, whereas responders
were to have immediate TME. Postoperative radiation was planned if R0 resection
was not achieved. Postoperative FOLFOX-6 was recommended, but adjuvant
regimens were left to clinician discretion. The primary outcome was R0 resection
rate. Thirty-two (100 %) of 32 study participants had R0 resections. Two did not
complete preoperative chemotherapy secondary to cardiovascular toxicity. Both
had preoperative chemoradiotherapy and then R0 resections. Of 30 patients
completing preoperative chemotherapy, all had tumor regression and TME without
preoperative chemoradiotherapy. The pathologic complete response rate to che-
motherapy alone was 8 of 32 (25 %; 95 % CI, 11–43 %). The 4-year local
recurrence rate was 0 % (95 % CI, 0–11 %); the 4-year disease-free survival was
84 % (95 % CI, 67–94 %). The authors conclude that ‘‘for selected patients with
clinical stages II–III rectal cancer, neoadjuvant chemotherapy and selective radi-
ation does not seem to compromise outcomes. Preoperative Radiation or Selective
Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROS-
PECT), a randomized phase III trial to validate this experience, is now open in the
US cooperative group network.’’
This study indicates that systemic chemotherapy has a high activity in primary
rectal tumors.
5 Does Resection of the Primary Tumor Confer

with a Better Prognosis?
A crucial question is if resection of the primary tumor confers with a better

prognosis. There is little direct evidence that this is the case in colorectal cancer.
The only disease where this has been studied in randomized controlled trials is
metastatic renal cell cancer (Flanigan et al. 2001; Mickisch et al. 2001). The larger
of the two studies showed that the median survival of 120 eligible patients
assigned to surgery followed by interferon was 11.1 months, while among the 121
eligible patients assigned to interferon alone was 8.1 months (P = 0.05). The
difference in median survival between the two groups was independent of per-
formance status, metastatic site, and the presence or absence of a measurable
metastatic lesion. The smaller of the two studies that was recruited in the EORTC
Genitourinary Group confirmed these results.
In conclusion, resection of the primary followed by systemic therapy resulted in
longer survival among patients with metastatic renal cell cancer than systemic
therapy alone.
5.1 SEER Data
Can the observations from renal cell cancer be transferred to metastatic colorectal
cancer? Data from the Surveillance, Epidemiology and End Results (SEER) data
registry of the National Cancer Institute indicate that the percentage of patients
receiving resection of primary stage IV colorectal tumors is steadily decreasing
from 1988 to 2000 (Cook et al. 2005). The investigators analyzed data from 26,754
patients with stage IV colorectal cancer diagnosed between 1988 and 2000. A total
of 17,658 patients received resection of their primary tumor. A better overall
survival was observed after primary tumor resection compared with a nonresection
strategy. For rectal cancer, the difference was 16 months versus 6 months, and the
1-year-survival was 45 % versus 12 % (p \ 0.001). Such a series, however,
cannot inform us about the reasons why survival for patients having the primary
tumor resected may have been longer. The authors themselves state that ‘‘The
proportion of patients undergoing resection depends on patient’s age and race and
the anatomical location of the primary tumor. The degree to which case selection
explains the treatment and survival differences observed is not known.’’ Clearly,
more detailed information from prospective trials is warranted.
5.2 CAIRO Studies
The Dutch Colorectal Cancer Group retrospectively analyzed the outcome of stage
IV colorectal cancer patients with or without resection of the primary tumor treated
in the phase III CAIRO and CAIRO2 studies (Venderbosch et al. 2011). In these two
238 F. Lordick
studies, 258 and 289 patients had undergone a primary tumor resection and 141 and
159 patients had not. In the CAIRO study, a significantly better median overall
survival and progression-free survival was observed for the resection compared to
the nonresection group, with 16.7 versus 11.4 months [P \ 0.0001, hazard ratio
(HR) 0.61], and 6.7 versus 5.9 months (P = 0.004; HR 0.74), respectively. In the
CAIRO2 study, median overall survival and progression-free survival were also
significantly better for the resection compared to the nonresection group, with 20.7
versus 13.4 months (P \ 0.0001; HR 0.65) and 10.5 versus 7.8 months (P = 0.014;
HR 0.78), respectively. These differences remained significant in multivariate
analyses. The authors concluded: ‘‘Our results as well as data from literature indicate
that resection of the primary tumor is a prognostic factor for survival in stage IV
colorectal cancer patients. The potential bias of these results warrants prospective
studies on the value of resection of the primary tumor in this setting.’’
Do the results from the CAIRO study help us to guide our decisions in rectal
cancer presenting with synchronous distant metastases? Not necessarily. The
publication is dealing with stage IV colorectal cancer without a special focus on
the situation of synchronous metastases. Moreover, no particular focus is put on
the location of the tumor. No subgroup analysis for rectal cancers has been shown.
5.3 FFCD 96-01
This is the strength of a recent French publication from the Fédération Francophone
de Cancérologie Digestive (FFCD) 96-01 study (Ferrand et al. 2013). Among the
294 patients with nonresectable colorectal metastases enrolled in the FFCD 96-01
phase III trial, which compared different first-line, single-agent chemotherapy
regimens, 216 patients (73 %) presented with synchronous metastases at study entry
and constituted the study population. Potential baseline prognostic variables
including prior primary tumor resection were assessed by univariate and multivar-
iate Cox analyses. Among the 216 patients with stage IV colorectal cancer, 156
patients (72 %) had undergone resection of their primary tumor prior to study entry.
The resection and nonresection groups did not differ for baseline characteristics
except for primary tumor location: rectal cancers were more often not resected:
14 % versus 35 % (p = 0.0006). In a multivariate analysis, resection of the primary
was the strongest independent prognostic factor for progression-free survival (PFS)
(hazard ratio (HR), 0.5; 95 % confidence interval [CI], 0.4–0.8; p = 0.0002) and
overall survival (OS) (HR, 0.4; CI, 0.3–0.6; p \ 0.0001). Both median PFS (5.1
[4.6–5.6] versus 2.9 [2.2–4.1] months; p = 0.001) and OS (16.3 [13.7–19.2] versus
9.6 [7.4–12.5]; p \ 0.0001) were significantly higher in the resection group. These
differences in patient survival were maintained after exclusion of patients with rectal
primary (n = 43). The authors conclude that ‘‘resection of the primary tumor may be
associated with longer PFS and OS in patients with stage IV colorectal cancer
starting first-line, single-agent chemotherapy.’’
Limitations of this publication, as stated by the authors themselves are: First,

assessing the impact of primary colorectal cancer resection on survival was not the
primary aim of the FFCD 96-01 trial, which furthermore excluded patients whose
condition worsened after primary tumor resection. As such, the study must be
viewed as an exploratory, hypothesis-generating, post hoc analysis of a prospec-
tive trial. Second, indications for primary resection before patient inclusion in the
FFCD 96-01 trial are unknown, as the study protocol did not require to collecting
such information. Thus, the analysis probably mixed patients who had primary-
related symptoms or complications at diagnosis and patients who had not.
In conclusion, the Dutch and the French retrospective analyses from prospec-
tive randomized trials support the hypothesis that resection of the primary tumor in
case of synchronous distant metastases may improve progression-free and overall
survival. The reason for this potential difference is thus far unknown. This clinical
research question merits prospective investigation.
6 Current Ongoing Studies
Two randomized controlled trials with a comparable design are currently

recruiting patients in Europe: Synchronous is recruiting patients in Germany while
CAIRO-4 is active in the Netherlands (Rahbari et al. 2012). Both studies enroll
patients with colon cancer with synchronous nonresectable metastases. The study
hypotheses are based on the prognostic differences seen in the previous retro-
spective analyses outlined earlier. Of note, both studies exclude patients with
primary rectal tumors, as the study chairs see this situation different from colon
cancers. Therefore, the results of these two important studies will not finally
resolve the question how to manage rectal cancer with synchronous distant
metastases.
7 Practical Consequences
The published data indicate that primary chemotherapy can be administered rel-
atively safely in asymptomatic (colo-)rectal cancer with synchronous metastases.
The severity of symptoms does usually guide the strategy. If severe symptoms
result from the primary tumor, local treatment (colostomy, radiation, stenting, or
resection) is usually administered up-front. The choice of local treatment is tai-
lored to the individual needs.
In patients without symptoms from the primary tumor or with far advanced
metastatic disease or with severe symptoms from metastatic disease, primary
systemic treatment should be given first.
Figure 5 is illustrating the strategy followed in the University Cancer Center of
Leipzig (Fig. 5). This practical algorithm may reflect one of the preferred algo-
rithms that are currently preferred in Cancer Centers in Europe.
240 F. Lordick
3 months of combination CTx (e.g. 6 x FOLFOX or FOLFIRINOX)

RAS mutant: combination with bevacizumab for cycle1-4
RAS wildtype: combination with cetuximab or panitumumab for cycle 1-6
Re-Evaluation of disease status after 3 months of induction CTx
Progressive Progressive Partial

metastases rectal tumor Remission
Salvage RCTx Continuation of CTx

CTx and/or rectal resection in case of irresectable mets
Neoadjuvant RTx or RCTx

Re-Evaluation Re-Evaluation followed by rectal and
after 3 months mets resection if aresectable
Fig. 5 Treatment algorithm of the University Cancer Center Leipzig (UCCL) for patients with
asymptomatic rectal cancer with synchronous distant metastases. Legend CTx = chemotherapy,
mets = metastases, RCTx = radiochemotherapy RTx = radiotherapy
References
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Recurrence Patterns After Resection
of Liver Metastases from Colorectal
Cancer
Halfdan Sorbye
Abstract
Recurrence of metastatic disease after resection of liver metastases from
colorectal cancer remains a major problem as 70–80 % of patients will have a
recurrence, most commonly in the liver or lung. To predict patterns of
recurrence and outcome may guide follow-up and further treatment, as patients
with recurrence might be candidates for repeated surgery or ablation therapy.
A summary of studies shows that after hepatectomy 20–43 % will have a
recurrence only in the remaining liver without extrahepatic disease, whereas
15–37 % will have a recurrence only to the lung. Early recurrence is associated
with poorer outcome compared to late recurrence. Site of first recurrence after
resection of liver metastases is predicted by several baseline variables;
synchronous disease, primary tumor site, hepatic tumor size, CEA level,
number of hepatic lesions, and RAS mutation status. Pattern of recurrence is a
predictor for survival after hepatectomy, with liver-only and lung-only
recurrences having the best survival. In the majority of patients with isolated
hepatic or lung recurrence, repeated metastasectomy is possible resulting in a
40 % 5-year survival rate. Perioperative chemotherapy reduces the risk of liver
recurrence after hepatectomy of colorectal cancer liver metastases.
Keywords

Colorectal Cancer Liver Hepatectomy Recurrence Patterns Metastases
Resection
H. Sorbye (&)
Department of Oncology, Haukeland University Hospital, Bergen, Norway
244 H. Sorbye
1 Metastatic Disease from Colorectal Cancer
In patients diagnosed with colorectal cancer (CRC), synchronous or metachronous

metastatic disease occurs in about 30–40 % of cases. In a recent follow-up study,
recurrent disease after primary surgery only developed in 20 % of patients, less
than prior reported (Grossmann et al. 2014). The decrease was explained by
improvements in treatment and a stage shift due to routine preoperative CT
staging. The reported incidence of synchronous metastases has increased over time
from 10–15 % up to 30 % in current series. Localization of recurrent disease after
primary surgery has also undergone changes as compared to historical reports.
Local recurrences have become less common, whereas lung metastases are found
more often (39 % vs. 4–14 %) probably due to increased use of chest CT.
Metastases are now more often located to one organ site. In a recent study,
recurrence was confined to one organ in 58 % of patients, most often liver-only
and lung-only (Grossmann et al. 2014). The eligibility for curative treatment of
first recurrence seems to have increased, with 28 % in this observational cohort
compared to approximately 20 % in older follow-up trials (Grossmann et al.
2014). Curative treatment of recurrent disease was possible in 33 % for liver
metastases and 20 % for lung metastases. Patients having lung resection of pul-
monary metastasis have an expected 5-year survival of 45 % and a median sur-
vival of 50 months (Inoue et al. 2004). Compared to colon cancer, rectal cancers
have a higher risk of developing synchronous and metachronous lung metastases
(Mitry et al. 2010). Advanced age, recent year of diagnosis and a rectal primary
were significantly associated with synchronous pulmonary metastases in a national
cohort of CRC (Nordholm-Carstensen et al. 2014). Molecular mechanisms seem to
predict for recurrence and site of recurrence after primary surgery. KRAS mutation
is associated with lung relapse but not liver relapse (Tie et al. 2011). BRAF mutant
tumors have higher rates of peritoneal metastases, distant lymph node metastases,
and lower rates of lung metastases (Tran et al. 2011).
2 Resection of Liver Metastases from Colorectal Cancer
The liver is the most common site of distant metastatic spread from CRC. Liver
metastases are present in nearly 80 % of stage IV patients and the sole site of disease
in approximately 40 % of these (Grossmann et al. 2014; Siegel et al. 2012; Sorbye
et al. 2007). Hepatic resection is the standard therapy for resectable metastases and
offers the only chance of long-term survival. Radical surgical treatment or ablation
of liver metastases is possible in approximately 20 % of patients with metastatic
disease. When surgical resection of liver metastases is possible, 5-year survival
approaches 35–40 % (Fong et al. 1997). However, relapse is common and occurs in
50–75 % of the patients (Kopetz et al. 2009) (Table 1). Patients undergoing
Recurrence Patterns After Resection of Liver Metastases 245
Table 1 Location of first recurrence after liver resection in mCRC patients in retrospective
studies with [175 patients
Liver Recurrence Location of recurrence, percentage of all Local
resection/ (%) recurrences recurrence
ablation (%)
Liver Lung Extra Liver Lung
only only hepatic all all
(%) (%) only (%) (%) (%)
de Jong et al. 1,669 57 43 36 64
(2009)
Saiura et al. 736 75 38 18 61 30
(2012)a
D’Angelica 637 62 31 27 52 45
et al. (2011)
Hughes and 607 70 40 19 50 25 9
Cuthbertson
(1962)b
Kato et al. 585 68 61 28
(2003)
Pawlik et al. 557 40 34 36 64
(2005)
Fong et al. 456 52 41 21 42 26
(1997)
Malik et al. 430 67 20 68 31
(2007)
Karanjia et al. 283 48 35 54 46
(2009)
Mise et al. 216 73 43 15 66 29
(2010)
Vauthey et al. 193 65 42 37 70 66
(2013)a
Butte et al. 185c 70 27 29 49 45 7
(2012)
a
Additional unpublished data given by personal communication with the author
b
Site of first recurrence available for 376 cases, percentage calculated from this
c
Rectal primary with synchronous metastatic disease
resection of metachronous colorectal liver metastases after adjuvant chemotherapy

with FOLFOX, had increased rate of KRAS mutations in liver metastases compared
with patients treated with 5-FU only (Andreou et al. 2012).
246 H. Sorbye
3 Recurrence After Resection of Liver Metastases from CRC
Metastatic recurrence after curative resection of liver metastases from CRC

remains a major problem, with disease-free survival at 10 years only 18 %. The
liver and lung are the most common sites of recurrence after hepatectomy with
recurrence rates of 40–74 % (D’Angelica et al. 2011) (Table 1). Most liver
recurrences are not local relapses of treated lesions. Local intrahepatic relapse was
only 5.5 % per lesion in the perioperative chemotherapy arm of the 40983 EORTC
study (Tanis et al. 2014). After radiofrequency ablation, local intrahepatic relapse
was 6 % per lesion (Tanis et al. 2014). Tumor and patient-related characteristics
might offer predictive value for outcome, recurrence, and treatment of recurrence.
To predict patterns of recurrence and outcome may guide follow-up and further
treatment, as patients who develop recurrence after liver surgery might be can-
didates for repeated surgery or ablation therapy.
3.1 Factors that Predict Recurrence After Resection

of Liver Metastases
The prognostic determinants of recurrence and survival after hepatectomy are

well-known and include factors such as; elevated carcinoembryonic antigen (CEA)
level, number of liver metastases, size of largest hepatic tumor, bilateral liver
involvement, nodal status of the primary tumor, male gender, synchronous met-
astatic disease, presence of extrahepatic disease, and short disease-free interval
(Rees et al. 2008). A number of clinical scoring systems have been proposed to
synthesize these data and help assessing the patient’s prognosis after resection of
liver metastases and whether surgery is worthwhile (Fong et al. 1999; Nordlinger
et al. 1996). However, the proposed scoring systems demonstrate limited external
validation and their clinical utility remains controversial. Treatment-related
prognostic factors for recurrence are surgical margins and radiological or patho-
logical response to chemotherapy. Larger metastases and node positivity in the
colorectal primary predict early (within 6 m) intrahepatic recurrence, whereas a
positive resection margin was the only predictor for a late recurrence (Malik et al.
2007). Perioperative chemotherapy reduces recurrences with an 8–10 % increase
in PFS and increased overall survival (Nordlinger et al. 2008, 2013). Patients with
elevated CEA and a good performance status seem to benefit the most from
perioperative chemotherapy (Sorbye et al. 2012). Molecular markers may predict
recurrence. KRAS mutation was an independent factor for increased recurrence
risk and worse survival in patients with liver surgery for CRC metastases (Nash
et al. 2010; Stremitzer et al. 2012; Karagkounis et al. 2013). In contrast, metastasis
associated in colon cancer 1 (MACC1) mRNA, but not KRAS mutation was found
to be an independent predictive factor for recurrence after resection of CRC liver
metastases (Isella et al. 2013). In patients with hepatic colorectal liver metastases
treated with resection and modern chemotherapy, increased expression of
thymidylate synthase improves outcome (Maithel et al. 2012). Gene expression

profiles can predict outcome following liver resection in patients with metastatic
CRC (Ito et al. 2013).
3.2 Location of Recurrences After Liver Resection
The site of first recurrence is usually liver or lung. A summary of studies shows that
20–43 % will have a recurrence only in the remaining liver without extrahepatic
disease, whereas 15–37 % will have a recurrence only to the lung (Table 1).
3.3 Factors Predicting Site of First Recurrence After Resection

of Liver Metastases
Several factors are associated with an increased risk of intrahepatic disease or lung
as the first site of recurrence after liver resection. Synchronous presentation of the
primary tumor and hepatic metastasis, receipt of chemotherapy, R1 margin status,
and history of ablation were associated with an increased risk of intrahepatic
recurrence as the initial site of failure (de Jong et al. 2009). In multivariate
analysis, R1 margin status and history of ablation remained associated with
intrahepatic recurrence. When extrahepatic disease as the first site of recurrence
was analyzed in the same study, primary rectal tumor site, primary tumor lymph
node metastasis, hepatic tumor size [5 cm, hepatic tumor number [4 and receipt
of chemotherapy were each associated with an increased risk of extrahepatic
recurrence. In multivariate analysis, rectal primary tumor site and tumor number
[4 each remained associated with the risk of extrahepatic recurrence (de Jong
et al. 2009). Lung recurrence occurred more frequently after hepatectomy when
the primary was located in the lower rectal tumor, whereas liver recurrence was
more frequent when the primary was located in colon (Lee et al. 2014). In a
Japanese publication, patients with [4 liver metastases and size of hepatic tumor
[5 cm more often had recurrence in liver and less in lung after hepatectomy for
CRC metastases (Hirokawa et al. 2014). However, time to recurrence was similar.
In a US study, CEA [ 200 ng/ml, liver tumor size [5 cm and [1 liver metastasis
were independent predictors for other sites of recurrence than a liver-only or lung-
only pattern (Hill et al. 2012). Minor pathologic response to chemotherapy was an
independent predictor of lung and liver recurrences after liver surgery for CRC
metastases (Vauthey et al. 2013).
Few studies have focused on molecular markers and site of recurrence after
hepatectomy in CRC patients. A recent study indicated that KRAS mutation was
predictive for lung recurrence, but not for liver recurrence (Vauthey et al. 2013).
RAS mutation was associated with a shorter 3-year lung recurrence free survival
rate, but not with a shorter liver recurrence free survival rate. At the last follow-up
in this study, lung recurrence was observed in 65 % of patients with RAS mutation
248 H. Sorbye
versus 38 % of patients with wild-type RAS (Vauthey et al. 2013). The cumulative
incidence of liver recurrence did not correlate significantly with RAS mutation
status. These results suggest a propensity for RAS-mutated tumors to metastasize
to lung, and are in line with previous studies showing higher KRAS mutation rates
in lung and brain colorectal metastases compared to colorectal liver metastases
(Tie et al. 2011; Kim et al. 2012). After hepatic resection for colorectal liver
metastases, lack of the CXCR4 tumor expression (a chemokine receptor) was
associated with a lower overall rate of recurrence and associated with a liver-only
or lung-only pattern of recurrence (Yopp et al. 2012).
3.4 Survival According to Recurrence Patterns After Liver

Surgery
Pattern of recurrence seems to be a predictor for survival after hepatectomy. The

median overall survival for patients with posthepatectomy recurrence was
35 months (Hill et al. 2012). Whereas a liver-only or lung-only recurrence had a
median survival of 44 months, other recurrences had a median survival of about
28 months (Hill et al. 2012). Lung-only recurrence was associated with the best
survival measured from the time of recurrence (median 36 months) (D’Angelica
et al. 2011). Survival was shorter for patients with liver-only (24 m) or other single
sites of recurrence (17 m), whereas those with multiple sites had the worst out-
come (13 m). In one study, however, recurrence–free survival was 16–17 months
regardless of site of recurrence after hepatectomy (intrahepatic vs. extrahepatic vs.
intra and extrahepatic) (de Jong et al. 2009). Patients who developed recurrence at
only one metastatic site had significantly greater long-term survival than patients
who developed recurrences at multiple anatomical sites (40 vs. 27 m) (Assumpcao
et al. 2008). Whereas the number of recurrent sites had an important effect on
survival, the location of the recurrent disease did not seem to affect survival.
The time interval from hepatectomy to recurrence is related to the recurrence
pattern and to survival. Initial lung-only recurrence was associated with a late
presentation. Only 28 % of patients with lung-only recurrence experienced
recurrence within the first year, whereas about 50 % of patients with liver-only,
other single sites, or multiple sites of recurrence experienced recurrence within the
first year (D’Angelica et al. 2011). Time to recurrence was an independent factor
for survival (16 m for early vs. 30 m for late recurrence) (D’Angelica et al. 2011).
In another study, 20 % of patients developed early recurrence, i.e., recurrence
within 6 months (Malik et al. 2007). Early recurrence was associated with poorer
survival when compared to late recurrence (22 vs. 41 m). An independent pre-
dictor of early recurrence was the presence of eight or more metastases.
3.5 Resection of Recurrence After Liver Surgery
Patients with limited posthepatectomy recurrence in anatomically favorable

locations might be candidates for further resection. Especially patients with a liver-
only or lung-only recurrence might benefit from repeated surgery. For patients
undergoing a second liver resection, 5-year survival rates between 30–58 % have
been reported (Adair et al. 2012; Kulik et al. 2013; Wicherts et al. 2013). Median
survival was 42–46 months. After initial hepatectomy, more than half of lung
recurrences were resected (D’Angelica et al. 2011). This resulted in a median
survival of 51 months compared to 34 months in patients with resection of a liver
recurrence. In another study, 98 of the 166 patients with recurrence underwent
repeated metastasectomy with curative intent and 85 % of patients with isolated
hepatic or lung recurrence were resected (Mise et al. 2010). The 5-year survival
rate of 37–39 % after repeated resection was similar for hepatic and pulmonary
recurrences (Mise et al. 2010). In one study, 29 % of patients with a recurrence
after hepatectomy underwent another operation with curative intent, resulting in a
3- and 5-year survival rate of 77 and 39 %, respectively (Assumpcao et al. 2008).
Another study found a 5-year survival of 47 % after repeated curative intent
surgery for recurrent colorectal liver metastases (de Jong et al. 2009). The presence
of eight or more initial liver metastases predict for developing a unresectable
recurrence (Malik et al. 2007). Although 50 % of patients with negative CXCR4
tumor expression developed a recurrence, the pattern of recurrence was frequently
amenable to salvage therapy with resection or ablation resulting in long-term
survival free of disease in most cases (Yopp et al. 2012).
4 Perioperative Chemotherapy and Recurrence Patterns

After Resection of Liver Metastases
In the EORTC 40983 study, 364 patients with 1–4 resectable liver metastases were
randomized between surgery alone and surgery + perioperative FOLFOX
(Nordlinger et al. 2013). Place of first recurrence and time to first recurrence
according to baseline factors and perioperative chemotherapy was analyzed and
presented at the 2nd St. Gallen EORTC Gastrointestinal Cancer Conference. The
risk for lung as first place of recurrence increased when CEA was elevated at
baseline, if regional lymph node metastases had been present or when the size of the
largest liver metastasis was [3 cm. Synchronous metastatic disease or presence of
more than one liver metastasis increased the risk for liver recurrence. Primary tumor
location had no effect on recurrence patterns. Perioperative chemotherapy reduced
the number of liver recurrences. Perioperative chemotherapy reduced liver recur-
rence in the subgroups of patients with one of the following characteristics:
CEA [ 30 ng/ml, one liver metastases or initial N1-2 disease. Median survival
after recurrence was 40 months for liver-only (39 % 5-year survival) and
47 months for lung-only (36 % 5-year) and not significantly different.
250 H. Sorbye
5 Conclusion
Several baseline prognostic variables predict site of first recurrence after resection
of liver metastases from CRC; synchronous disease, primary tumor site, hepatic
tumor size, CEA level, number of hepatic lesions, and RAS mutation status.
Pattern of recurrence is a predictor for survival after hepatectomy, with a liver-
only or lung-only recurrence having the best survival. In the majority of patients
with isolated hepatic or lung recurrence, repeated metastasectomy is a possibility,
resulting in a 40 % 5-year survival rate. Perioperative chemotherapy reduces the
risk of liver recurrence after hepatectomy in CRC patients.
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(Recent Results in Cancer Research 203) Florian Otto, Manfred P. Lutz (Eds.) - Early Gastrointestinal Cancer

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Recent Results in Cancer Research

Series Editors: P. M. Schlag · H.-J. Senn

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ISSN 0080-0015 ISSN 2197-6767 (electronic)

Library of Congress Control Number: 2012949069

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Springer is part of Springer Science+Business Media (www.springer.com)

St. Gallen, Switzerland Florian Otto

Part I Staging of Rectal Cancer

Imaging Assessment of Early Rectal Cancer. . . . . . . . . . . . . . . . . . . . 3

Predicting Lymph Node Metastases in pT1 Rectal Cancer . . . . . . . . . 15

Part II Treatment of Early Rectal Cancer

Endoscopic Resection: When Is EMR/ESD Sufficient? . . . . . . . . . . . . 25

Transanal Endoscopic Microsurgery . . . . . . . . . . . . . . . . . . . . . . . . . 31

Part III Surgical Treatment of Rectal Cancer

What Is ‘‘Good Quality’’ in Rectal Cancer Surgery?

Total Mesorectal Excision: Open, Laparoscopic or Robotic. . . . . . . . . 47

Ultra Low Resection Versus Abdomino-Perineal Excision

T4 Rectal Cancer: Do We Always Need an Exenteration? . . . . . . . . . 69

Do T3 Rectal Cancers Always Need Radiochemotherapy?. . . . . . . . . . 95

Quality of Life After Surgery for Rectal Cancer. . . . . . . . . . . . . . . . . 117

Part IV Combined Modality Therapy in Rectal Cancer

Aims of Combined Modality Therapy in Rectal Cancer (M0) . . . . . . . 153

Neoadjuvant Radiotherapy (5 3 5 Gy): Immediate Versus

Early and Late Toxicity of Radiotherapy for Rectal Cancer . . . . . . . . 189

Immediate Surgery or Clinical Follow-Up After

Part V Rectal Cancer with Synchronous Liver Metastases

Limits of Colorectal Liver Metastases Resectability:

Rectal Cancer with Synchronous Liver Metastases:

Recurrence Patterns After Resection of Liver Metastases

J. Waage G. Brown (&)

1 Assessment and Rationale for Treatment Decisions

2 Staging Classification of Early Rectal Cancers

Early rectal cancer can manifest as either a polyp characterised by a rounded or

originally reported by Kikuchi as 0 %. For increasing submucosal invasion, a higher

4 MRI Technique and Quality

institutions. Participation in the MERCURY studies showed that with only a

5 Assessing Nodal Spread Preoperatively

likelihood of malignancy is highly inaccurate and is not recommended as good

7 Assessment of Pelvic Lymph Nodes

Nodal assessment with imaging takes place in two settings:

8 The Anatomy of the Rectum and Mesorectum at High

9 Preoperative Evaluation of Primary Early Rectal Cancer

Assessment of polypoidal and sessile lesions

In selecting patients for local excision, it is currently understood that T1 sm1

Ashraf S, Hompes R, Slater A, Lindsey I, Bach S, Mortensen NJ et al (2012) A critical appraisal

1 Increase in Early Rectal Cancer

Following Council Recommendations of the European Union, many countries

S. L. Bosch I. D. Nagtegaal (&)

carcinomas (CRC). However, as already observed in the early screening trials

2 Risk on Lymph Node Metastasis

3 What Can We Measure?

Fig. 1 Kudo classification

Fig. 2 Haggitt classification

An alternative for tumor size is submucosal width, which is investigated in

4 Monitoring Tumor Behavior

5 Overview of Relevant Factors

Curative endoscopic treatment of early gastrointestinal neoplasia may be possible