www.redjournal.

org

Clinical Investigation

Persistence of Late Substantial Patient-Reported

Symptoms (LAPERS) After Radiochemotherapy
Including Image Guided Adaptive Brachytherapy
for Locally Advanced Cervical Cancer: A Report
From the EMBRACE Study
Anders S. Vittrup, MD,* Kari Tanderup, MSc, PhD,*
Søren M. Bentzen, MSc, PhD,y Nina B.K. Jensen, MD, PhD,*
Sofia Spampinato, MSc,* Lars U. Fokdal, MD, PhD,*
Jacob C. Lindegaard, MD, DMSc,* Alina Sturdza, MD,z
Maximilian Schmid, MD,z Barbara Segedin, MD,x
Ina M. Jürgenliemk-Schulz, MD, PhD,k Kjersti Bruheim, MD, PhD,{
Umesh Mahantshetty, MD,# Christine Haie-Meder, MD,**
Bhavana Rai, MD,yy Rachel Cooper, MD,zz
Elzbieta van der Steen-Banasik, MD,xx Marit Sundset, MD,kk
Fleur Huang, MD,{{ Remi A. Nout, MD, PhD,## Elena Villafranca, MD,***
Erik Van Limbergen, MD, PhD,yyy Bradley R. Pieters, MD, PhD,zzz
Li Tee Tan, MD,xxx Ludy C.H.W. Lutgens, MD,kkk Peter Hoskin, MD,{{{
Richard Pötter, MD,z and Kathrin Kirchheiner, MSc, PhD,z
on behalf of the EMBRACE Collaborative Group
*Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; yDepartment of
Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland;
z
Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna/
General Hospital of Vienna, Vienna, Austria; xDepartment of Radiotherapy, Institute of Oncology,

Corresponding author: Anders Schwartz Vittrup, MD; E-mail: anders. Foundation outside the submitted work. J.L., R.N and R.P. report grants
[email protected] from Varian Medical Systems outside the submitted work. R.N., R.P., and
The EMBRACE study was supported by Elekta AB and Varian Med- M.Sc. report grants from Elekta AB outside the submitted work. R.N.
ical System through unrestricted research grants and study sponsoring reports grants from Accuray outside the submitted work. M.Sc. reports
through the Medical University of Vienna. The work of this manuscript personal fees and nonfinancial support from Elekta AB outside the sub-
was supported via a research grant from the Danish Cancer Society (grant mitted work. A.S. reports grants from Stiftung Philanthropie Österreich,
number R146-A9459-16-S2). grants from Rosch, and personal fees from Elekta outside the submitted
Disclosures: A.V. and K.T. report grants from the Danish Cancer So- work.
ciety during the conduct of the study. K.T, M.Sc., and A.S. report grants Data sharing statement: Research data are the property of the
from Elekta AB and Varian Medical Systems during the conduct of the EMBRACE Consortium and are not available for sharing.
study. S.S. and N.J. report grants from the Danish Cancer Society outside Supplementary material for this article can be found at https://doi.org/
the submitted work. N.J. reports grants from the Danish Cancer Research 10.1016/j.ijrobp.2020.08.044.

Int J Radiation Oncol Biol Phys, Vol. -, No. -, pp. 1e13, 2020
0360-3016/$ - see front matter Ó 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ijrobp.2020.08.044
2 Vittrup et al. International Journal of Radiation Oncology  Biology  Physics

Ljubljana, Slovenia; kDepartment of Radiation Oncology, University Medical Centre, Utrecht, The
Netherlands; {Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital,
Oslo, Norway; #Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India;
**Department of Radiotherapy, Gustave-Roussy, Villejuif, France; yyDepartment of Radiotherapy
and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; zzLeeds
Cancer Centre, St James’s University Hospital, Leeds, United Kingdom; xxRadiotherapiegroep,
Arnhem, The Netherlands; kkClinic of Oncology and Women’s Clinic, St. Olavs Hospital, Trondheim,
Norway; {{Department of Oncology, Cross Cancer Institute and University of Alberta, Edmonton,
Alberta, Canada; ##Department of Radiation Oncology, Leiden University Medical Center, Leiden, The
Netherlands; ***Department of Radiation Oncology, Hospital of Navarra, Pamplona, Spain;
yyy
Department of Radiation Oncology, Universitair Ziekenhuis Leuven, Leuven, Belgium;
zzz
Department of Radiation Oncology, Amsterdam University Medical Centers, University of
Amsterdam, Amsterdam, The Netherlands; xxxOncology Centre, Cambridge University Hospitals NHS
Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom; kkkMaastricht Radiation
Oncology (MAASTRO) Clinic, Maastricht, The Netherlands; and {{{ Cancer Centre, Mount Vernon
Hospital, London, United Kingdom

Received Jul 9, 2020. Accepted for publication Aug 19, 2020.

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in
the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced
cervical cancer (LACC).
Methods and Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer
[EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE],
version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up
(baseline and 3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC
symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition
(treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial
symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms
with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was
evaluated.
Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median
follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS
events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neurop-
athy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/
burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (inter-
quartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding
EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event.
Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS
events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events
occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of
distinguishing between transient and persisting symptoms in the aftercare of LACC survivors. Ó 2020 Elsevier Inc. All rights
reserved.

Introduction life (QoL). Traditionally, morbidity has been assessed solely

by physicians. However, patient-reported outcomes (PROs)
For locally advanced cervical cancer (LACC), the introduc- provide complementary information to physician-assessed
tion of image guided adaptive brachytherapy (IGABT) with morbidity5,6 and are increasingly recognized as reflecting
repeated imaging has improved local control and survival patients’ experience of symptom burden after treatment.
The majority of patients with LACC experience mild-to-
while reducing severe morbidity.1-4 This allowed for a
moderate morbidity after IGABT,7-12 but the impact on
change in the design of studies to also focus on mild-to-
QoL is closely linked to whether treatment-related
moderate morbidity and their impact on patients’ quality of
Volume -  Number -  2020 Persistence of symptoms in the EMBRACE study 3

symptoms occur only transiently or remain persistently in was 50 days as the maximum. Doses to tumor volumes and
their life. LACC is diagnosed in women at a median age of organs at risk were reported according to the Groupe
approximately 50 years; thus, LACC survivors often have a Européen de Curiethérapie and European Society for
long remaining life, which could be burdened by persistent Radiotherapy and Oncology (GEC-ESTRO)
morbidity. However, in general, the persistence of recommendations.15,16
morbidity has not been addressed within radiation therapy
trials; commonly used statistical methods for summarizing Assessment of morbidity
morbidity outcomes assess occurrence (crude incidence
rates and actuarial estimates) or time patterns on a cohort
PROs were assessed with the validated EORTC QoL core
level (prevalence rates, European Organization for
questionnaire (QLQ-C30)17 and cervical cancer-specific
Research and Treatment of Cancer [EORTC] scoring) but
module (QLQ-CX24).18 Patients rated questions into 4
do not reflect the persistence of symptoms in individual
categories: Not at all, a little, quite a bit, and very much.
patients.13 To bridge this gap, a new methodology was
Physician-assessed morbidity was graded according to the
recently introduced that identifies patients with late,
National Cancer Institute Common Terminology Criteria
persistent, substantial, and treatment-related symptoms
for Adverse Events (CTCAE), version 3.0.19 Assessment of
(LAPERS).14
PRO and physician-assessed morbidity was performed at
The EMBRACE study is an observational prospective
baseline and during follow-up: every 3 months in the first
multi-institutional study with a focus on IGABT for LACC.
year, every 6 months in the second and third years, and
The primary aim of this descriptive analysis was to apply
yearly thereafter. In patients with evidence of local, nodal,
the LAPERS methodology to the EMBRACE cohort to
or systemic recurrence, PRO and morbidity assessments
benchmark the proportion of patients with persistence of
were censored at the time of recurrence.
late substantial treatment-related patient-reported symp-
toms. The secondary aims were to compare the proportion
of patients with LAPERS events to existing methodologies Statistical analyses
(crude incidence rates and prevalence rates) and thereby
distinguish transient occurrence from persistence of a LAPERS analysis
symptom and to describe the overlap between LAPERS The LAPERS methodology identifies individual patients
events and severe physician-assessed morbidity. with late, persistent, substantial, and treatment-related
symptoms (LAPERS events).14 LAPERS is based on indi-
Methods and Materials vidual symptoms, in contrast to the EORTC scales, which
display a linearly transformed mean value across symptoms
with a score ranging from 0 to 100 at each timepoint.
The EMBRACE study is an observational, prospective, An overview of the 5 steps in the LAPERS methodology
multi-institutional study (www.embracestudy.dk, is shown in Figure 1. Patients with a baseline assessment
NCT00920920) with 23 institutions contributing to enroll- and at least 3 late follow-up assessments (from 6 months
ment from 2008 to 2015. The study was approved at all after treatment and onward) were included in the analyses
institutions per the local ethics requirements. Data used for (first step). The 4 EORTC answer categories were assigned
this analysis were extracted on July 15, 2019. Patients were a score from 1 (not at all) to 4 (very much). Quite a bit
eligible if they had histologically verified LACC of Inter- (score 3) or very much (score 4) were considered clinically
national Federation of Gynecology and Obstetrics (FIGO) relevant (substantial symptoms; second step). A symptom
stage IB to IVB and were eligible for definitive radio- was regarded as persistent in an individual patient if the
chemotherapy with IGABT. median score during late follow-ups (from 6 months and
ongoing) was 2.5 (third step), thus requiring substantial
Treatment symptoms to be present in at least half of the late follow-up
visits. Because early follow-up scores (3 months after
Treatment consisted of external beam radiation therapy treatment) could be affected by acute morbidity, they were
(EBRT) with concomitant chemotherapy followed by not included in the late follow-ups.
IGABT. EBRT was delivered either by 3-dimensional Symptom scores at baseline may be related to the pres-
conformal radiation therapy or by intensity modulated ra- ence of the tumor and do not always represent the true
diation therapy or volumetric arc therapy. The prescription baseline from before the onset of disease. Improvement
dose ranged from 45 Gy to 50 Gy according to institutional from baseline to early follow-up could be interpreted as a
practice. Concomitant cisplatin was administered weekly return to the true baseline. Therefore, the baseline condition
(40 mg/m2 body surface) during treatment. IGABT was was defined as the minimum score of baseline and early
delivered as either high dose rate or pulsed dose rate, and follow-up assessment (fourth step). Substantial symptoms at
dose prescription was according to institutional practice. both baseline and early follow-up were interpreted to
Magnetic resonance imaging was required for the first represent a pretreatment chronic condition. Progression of a
brachytherapy fraction. The aim for overall treatment time symptom was defined as a worse median score at late
4 Vittrup et al. International Journal of Radiation Oncology  Biology  Physics

1st step: Availability of baseline & at least 3 late follow-ups ( ≥ 6 months post
treatment) (late symptoms)

2nd step: Definition of substantial symptoms

(clinically relevant cut-off : "quite a bit", "very much")

3rd step: Definition of late persistent symptoms:

Median of late follow-up scores > "a little" (representing substantial symptoms)

4th step: Definition of baseline condition:

Minimum between Baseline (BL) & early assessment after treatment (3M)

BL 3M 6M 9M 12M 18M 24M 30M 36M 48M 60M Median

very a a not a a quite quite very very very quite
much little little at all little little a bit a bit much much much a bit

5th step: Definition of progression:

Any worsening from baseline condition to median of late follow-up scores
(likely treatment-related symptoms)

Fig. 1. Stepwise selection of patients with LAPERS events based on longitudinally assessed patient-reported symptoms
using EORTC quality of life questionnaires (Adapted with permission from Kirchheiner et al.14) Abbreviations: BL Z
baseline; LAPERS Z late, persistent, substantial, treatment-related symptoms; M Z months; EORTC Z European Orga-
nization for Research and Treatment of Cancer.

follow-ups compared with the baseline condition (fifth step). Overlap between LAPERS events and severe CTCAE
For 79 patients without a valid 3-month assessment, the events in the LAPERS cohort
baseline condition was assumed to be equal to the baseline For symptoms in the EORTC questionnaires (C30 and
scoring. For some symptoms, the baseline condition could CX24) with a corresponding physician-assessed symptom
not be meaningfully judged with the methodology in CTCAE version 3.0, the overlap of LAPERS events and
described; thus, the fourth and fifth steps were omitted. This severe CTCAE events (crude incidence rates of grade 3-5)
included symptoms related to stress at diagnosis and during was evaluated for patients in the cohort eligible for the
treatment (insomnia, tiredness, need to rest, and weakness) LAPERS analysis. The following symptoms had a corre-
and tumor-related symptoms frequently occurring at base- sponding symptom in CTCAE: diarrhea, difficulty con-
line and as acute morbidity (vaginal discharge). In addition trolling bowel, blood in stool, urinary frequency, leaking of
to the analysis of individual symptoms, fatigue encom- urine, lymphedema, insomnia, menopausal symptoms, and
passing tiredness, need to rest, and weakness were analyzed fatigue.
on a scale level based on raw scores.20 LAPERS rates are
the proportion of patients who experience a LAPERS event Comparison of patient and disease characteristics
for a given symptom. LAPERS rates are given with 95% between eligible and noneligible patients for the
confidence intervals based on the Clopper-Pearson exact LAPERS analysis
method for binomial data. Differences were analyzed with the c2 test for categorical
variables and the nonparametric Mann-Whitney U test for
LAPERS in comparison to traditional summary measures continuous variables. IBM SPSS statistical software for
To put LAPERS rates into perspective, additional summary Windows (version 26.0; IBM Corp., Armonk, NY) was
measures were evaluated for each symptom in the cohort used for all statistical analyses.
eligible for the LAPERS analysis. Crude incidence rates
were defined as the proportion of patients answering “quite
a bit” or “very much” (substantial symptoms) as their worst Results
answer category during follow-up. Prevalence rates were
defined as the proportion of patients answering “quite a bit” The EMBRACE study included 1416 patients (flowchart in
or “very much” (substantial symptoms) at given timepoints Fig. E1). Twenty-one patients did not meet the inclusion
in follow-up. The ratio between LAPERS rates and crude criteria, 17 were registered without further information, 34
incidences rates was calculated for each symptom to did not receive treatment as planned, and 3 were falsely
represent the proportion of symptomatic patients with excluded without subsequent information registered. One
persistent symptoms. center did not participate in the assessment of PROs (95
Volume -  Number -  2020 Persistence of symptoms in the EMBRACE study 5

Table 1 Patient, disease and treatment characteristics in the cohort eligible for the LAPERS analyses (n Z 741)
Patient and disease characteristics at diagnosis
Age Median y (range) 49 (22-83)
World Health Organization Performance status 0* 77%
1y 22%
2z-3x 1%
Comorbidity 29%
Smoker status Yes 29%
No 68%
Missing 3%
Local FIGO tumor stagek 1B 17%
2A 4%
2B 61%
3A 1%
3B 14%
4A 2%
Histology Squamous cell carcinoma 85%
Adenocarcinoma 12%
Adenosquamous carcinoma 3%
Lymph node status (CT, PET-CT or histologic confirmation) Node positive 50%
Node negative 50%
Surgical lymph node staging 27%
Treatment characteristics

EBRT technique 3-dimensional CRT 64%

IMRT or VMAT 36%
EBRT CTV-E prescribed dose Median dose, Gy (IQR) 45 (45-46)
EBRT CTV-E nodal regions Pelvic 84%
Pelvic þ PAN and/or inguinal 16%
EBRT treated volume 43 Gy Median, cm3 (IQR) 2481 (2139-3030)
Missing 1%
EBRT lymph node boost No lymph node boost 64%
Lymph node boost 36%
EBRT treated volume 57 Gy in lymph node boost patients Median, cm3 (IQR) 128 (22-338)
(n Z 264)
Brachytherapy dose rate Pulsed dose rate 40%
High dose rate 60%
Brachytherapy technique Intracavitary 57%
Intracavitary/interstitial{ 43%
CTVHR D90 in EQD210 Median dose, Gy (IQR) 91 (87-95)
Rectum D2 cm3 in EQD23 Median dose, Gy (IQR) 61 (57-66)
Bowel D2 cm3 in EQD23 Median dose, Gy (IQR) 58 (48-67)
Bladder D2 cm3 in EQD23 Median dose, Gy (IQR) 75 (69-84)
ICRU rectovaginal point dose in EQD23 Median dose, Gy (IQR) 64 (60-70)
Concomitant chemotherapy (including reduced-dose cycles) 0 cycles 6%
1-4 cycles 27%
5 cycles 67%
Abbreviations: CRT Z conformal radiation therapy; CT Z computed tomography; CTV-E Z clinical target volume of elective field; CTVHR D90 Z
dose received by 90% of the high-risk clinical target volume; D2 cm3 Z minimum dose in the maximally exposed 2 cm3; EBRT Z external beam
radiation therapy; EQD23 Z equal dose in 2 Gy fractions with a/b of 3 for normal tissue; EQD210 Z equivalent dose in 2 Gy fractions with a/b of 10 for
tumor; FIGO Z International Federation of Gynecology and Obstetrics; ICRU Z International Commission on Radiation Units; IMRT Z intensity
modulated radiation therapy; IQR Z interquartile range; LAPERS Z late, persistent, substantial, and treatment-related symptoms; PAN Z paraortic
nodes; PET Z positron emission tomography; VMAT Z volumetric modulated arc therapy.
Missing data were <1% unless otherwise stated.
* Asymptomatic, able to carry out all normal activities without restriction.
y
Symptomatic, restricted in strenuous activity but ambulatory and able to carry out light work.
z
Symptomatic, ambulatory, and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours.
x
Symptomatic and in a chair or bed for >50% of the day but not bedridden.
k
A total of 43 patients with FIGO stage 4B were allocated to a local FIGO stage based on the clinical examination at baseline.
{
At least 1 brachytherapy fraction with intracavitary/interstitial treatment.
6 Vittrup et al. International Journal of Radiation Oncology  Biology  Physics

patients). For the remaining 1246 patients, the completion Whereas other statistical summary measures identify the
rate of EORTC questionnaires was 78%. In total, 1047 occurrence of a symptom (incidence methods) or presence
patients had responded to at least 1 EORTC questionnaire at a certain timepoint (prevalence rates), the LAPERS
during follow-up. The criteria for the LAPERS analysis methodology addresses another aspect: persistence over
(first step in Fig. 1) were fulfilled for 735 to 741 patients, time in individual patients. Because of these inherent
depending on symptom. This variation occurred because methodologic differences, the proportion of patients with
some patients completed only selected items on the ques- LAPERS events was lower than the proportion of patients
tionnaire. The median follow-up in the LAPERS subcohort identified by crude incidence rates and in general lower
was 59 months (interquartile range, 42-70 months). than the prevalence rates, thereby highlighting that occur-
Patient, disease, and treatment characteristics of the rence of a symptom does not necessarily amount to
cohort eligible for the LAPERS analysis are shown in persistence of the symptom. In fact, the highest ratio be-
Table 1. A comparison of patient and disease characteristics tween LAPERS rates and crude incidence rates was 39.1%
between patients eligible for the LAPERS analysis and (need to rest), indicating that <40% of patients who
noneligible patients is seen in Table E1. Statistically sig- experienced substantial symptoms during follow-up did so
nificant differences between the cohorts were present for persistently. For pain/burning feeling when urinating, the
World Health Organization performance status, smoking, ratio was only 2.2%. Prevalence rates reflect the occurrence
local FIGO stage, histology, lymph node status, tumor and change of symptoms over time on a cohort level.
width at diagnosis, and length of follow-up. However, they do not reflect persistence of symptoms in
Table 2 shows LAPERS rates, crude incidence rates, and individual patients. This is exemplified by pain/burning
prevalence rates of substantial symptoms (“quite a bit” or feeling when urinating, which displayed a LAPERS rate of
“very much”). The proportion of patients experiencing a 0.4% but prevalence rates that ranged from 2.8% to 4.6%.
LAPERS event ranged from 0.0% (vaginal bleeding) to The findings in this report clearly show that late morbidity
20.4% (tiredness) across all symptoms. In total, 47.6% of after radiation therapy can display a reversible or highly
patients experienced 1 LAPERS events, 20.4% experi- fluctuating pattern over time, which is consistent with the
enced 3 LAPERS events, and 9% experienced 5 LAP- findings in other publications.21-24
ERS events. Correction for baseline condition was applied Because this analysis is the first to evaluate persistence
in 20 of 26 symptoms. The correction amounted to <1% of patient-reported symptoms after IGABT for LACC in
for 14 of 20 symptoms. The proportion of symptomatic individual patients, a direct comparison with the literature
patients with persistent symptoms (LAPERS rate/crude is limited. Furthermore, no normative data exist for
incidence rate) ranged from 0.0% (abnormal vaginal persistence of symptoms in the general population. How-
bleeding) to 39.1% (need to rest). ever, the results from this report can be put into perspective
Longitudinal symptom profiles for diarrhea, blood in with published literature applying other summary measures
stool, peripheral neuropathy, and insomnia are shown in to report on patient-reported symptoms.
Figure 2. Diagrams displaying different summary measures Gastrointestinal morbidity after radiation therapy affects
and risk maps for the same symptoms are shown in activities of daily living, affects QoL, and is associated with
Figure 3. Figure 4 shows the overlap between LAPERS increased levels of distress.8,25-27 Even though the etiology
events and severe CTCAE events (grade 3-5) for 9 symp- behind these symptoms is multifactorial,28 a clear relation
toms with a corresponding EORTC/CTCAE assessment. In to dose-volume parameters has been established.9,29,30
total, 12% of LAPERS events occurred in parallel with a Among the gastrointestinal symptoms in the present
corresponding severe CTCAE event. Depending on the report, diarrhea and difficulty controlling bowels had the
symptom, this percentage ranged from 0% (blood in stool) highest LAPERS rates (6.0% and 4.6%, respectively) and
to 22% (fatigue). The overlap was larger within the general the highest ratios between LAPERS rates and crude inci-
(noneorgan-specific) symptoms (14%) compared with dence rates (18.9% and 19.7%, respectively). The poten-
organ-related symptoms (9%). For CTCAE severe events, tially debilitating effects of these symptoms highlight the
46% occurred in parallel with a corresponding LAPERS need to distinguish patients with persisting symptoms from
event. At the individual symptom level, this percentage patients with transient symptoms (Fig. 3).
ranged from 0% (blood in stool) to 75% (lower-limb lym- On the other hand, a LAPERS event for blood in stool
phedema). The overlap was larger among general symp- occurred in only 0.5% of patients. The explanation is
toms (52%) than among organ-related symptoms (37%). 2-fold: Only 12% of patients reported substantial blood in
stool during follow-up (crude incidence), and among these
patients, only 4.2% had persisting symptoms. The preva-
Discussion lence rates peaked 24 months after treatment (Fig. 3) and
decreased to very low levels at subsequent follow-ups. This
This report provides benchmark outcomes for patient- is in line with earlier findings of posteradiation therapy
reported late, persistent, substantial, and treatment-related sigmoidoscopies.23 The explanation could be the onset of
symptoms (LAPERS events) from the EMBRACE study. fibrosis preventing further bleeding from the telangiectasia
Volume -  Number -  2020 Persistence of symptoms in the EMBRACE study 7

Table 2 Overview of LAPERS rates, level of baseline correction, crude incidence rates of patients with substantial symptoms (quite a
bit or very much) as maximum answer category during follow-up, ratio of LAPERS events/crude incidence to represent the proportion
of symptomatic patients with persistence, and prevalence rates of substantial symptoms
LAPERS Prevalence rates
LAPERS BL Crude rates/crude
rates, % correction, incidence incidence BL, % 3 mo, % 12 mo, % 24 mo, % 60 mo, %
Symptoms (95% CI) % rates, % rates, % (n Z 741) (n Z 662) (n Z 674) (n Z 594) (n Z 365)
Gastrointestinal Nausea 1.1 (0.5-2.1) 0.5 17.7 6.2 5.8 4.2 3.3 2.5 2.5
Vomiting 0.3 (0.0-1.0) 0.0 7.8 3.8 2.6 1.4 1.3 1.9 0.5
Abdominal cramps 3.7 (2.4-5.3) 1.9 28.9 12.8 11.8 9.6 7.4 8.4 4.7
Diarrhea 6.0 (4.4-7.9) 0.7 31.7 18.9 5.2 8.5 9.0 9.1 9.3
Difficulty controlling 4.6 (3.2-6.4) 0.4 23.4 19.7 1.2 6.1 5.6 6.5 9.0
bowel
Blood in stool 0.5 (0.1-1.4) 0.0 12.0 4.2 1.5 0.6 2.9 4.2 1.4
Constipation 1.4 (0.7-2.5) 0.9 17.6 8.0 11.1 4.4 4.9 5.6 6.1
Urinary Urinary frequency 11.7 (9.4-14.2) 3.9 46.3 25.3 21.7 21.3 16.6 16.3 14.6
Pain/burning feeling 0.4 (0.1-1.2) 0.1 17.8 2.2 4.5 4.6 3.2 3.2 2.8
when urinating
Leaking of urine 5.4 (3.9-7.3) 0.7 21.5 25.1 4.3 5.5 5.6 7.1 6.9
Difficulty emptying 2.0 (1.1-3.3) 0.3 16.5 12.1 3.3 3.0 4.2 4.4 5.5
bladder
Vaginal Irritation/soreness in 2.0 (1.1-3.3) 0.4 19.7 10.2 5.6 7.0 3.8 4.6 2.5
vagina/vulva
Vaginal discharge 1.6 (0.8-2.8) NA 19.7 8.1 29.6 9.9 3.5 3.0 1.6
Abnormal vaginal 0 (0.0-0.5) 0.0 8.0 0.0 22.9 0.6 1.1 2.2 1.1
bleeding
Other organs Dyspnea 4.2 (2.9-5.9) 0.8 21.8 19.3 5.6 5.6 6.6 6.1 8.0
Peripheral neuropathy 11.5 (9.3-14.0) 1.4 39.2 29.3 6.2 12.6 13.2 14.2 15.1
Lower limb lymphedema 9.6 (7.6-12.0) 0.7 30.5 31.5 4.1 8.7 11.1 10.6 9.8
Pain lower back 10.3 (8.2-12.7) 3.9 43.4 23.7 24.3 16.5 16.4 15.7 14.8
General Pain, unspecific 8.4 (6.5-10.7) 3.1 44.0 19.1 23.5 13.4 14.0 15.1 12.7
Appetite loss 3.4 (2.2-4.9) 0.5 21.4 15.9 13.8 6.7 5.5 4.2 3.9
Menopausal symptoms 17.4 (14.7-20.3) 2.6 48.4 36.0 10.5 26.9 20.5 18.4 16.0
Insomnia 16.2 (13.6-19.0) NA 50.5 32.1 23.3 20.4 17.4 18.2 17.5
Tiredness 20.4 (17.5-23.4) NA 53.5 38.1 22.7 22.4 23.1 20.4 18.1
Need to rest 19.8 (17.0-22.9) NA 50.6 39.1 25.5 22.8 19.3 17.7 18.1
Weakness 11.9 (9.6-14.4) NA 43.2 27.5 18.2 16.9 13.1 13.5 13.2
Scale Fatigue 15.8 (13.2-18.6) NA 45.9 34.4 22.0 19.8 16.5 15.5 15.6

Abbreviations: BL Z baseline; CI Z confidence interval; LAPERS Z late, persistent, substantial, and treatment-related symptoms; NA Z not
applicable.
Baseline correction: Patients not scored as having a LAPERS event in follow-up due to no progression compared with the baseline condition. Crude
incidence: Patients with substantial symptoms as the worst scoring during follow-up. Symptomatic patients with persistence: LAPERS/crude incidence
ratio. Prevalence rates: Patients with substantial symptoms at specific timepoints in follow-up with numbers at risk shown below the timepoints.

or active management with laser coagulation or formalin a higher degree, with more frequent use of incontinence
application.23 Compared with other gastrointestinal end- material and more limitations in daily activities due to
points, rectal bleeding rarely affects QoL.31 urinary symptoms, among patients with endometrial cancer
Urinary morbidity is well known after pelvic radiation in the PORTEC-1 postoperative radiation therapy group
therapy with IGABT for LACC.1,2,7,21,32 Among the uri- compared with the surgery group.26 Urinary incontinence
nary symptoms in the present report, urinary frequency and has been linked with a negative effect on QoL,34 which
leaking of urine had the highest LAPERS rates of 5.4% and emphasizes the importance of identifying the 1 of 4
11.7%, respectively. Urinary frequency displayed fluctu- symptomatic patients with persisting urinary frequency or
ating prevalence rates over time, and leaking of urine dis- urinary incontinence (Table 2).
played increasing prevalence rates.7,14 In this report, Peripheral neuropathy is more common in cervical
urinary frequency had the highest correction for baseline cancer (CC) survivors compared with healthy controls.35-37
condition (3.9%) of all symptoms. The rationale behind the The risk of cisplatin-induced peripheral neuropathy is
correction was to exclude patients with a pretreatment closely related to the cumulative dose.38 Peripheral neu-
chronic condition. The high level of correction for urinary ropathy induced by other chemotherapeutic agents has
frequency is in agreement with a population-based survey previously been reported to affect QoL.39 Radiation-
estimating that urinary frequency affects 7.4% of women in induced lumbosacral neuropathy has also been
the general population.33 Urinary incontinence was seen to described.40 To our knowledge, the consequences of
8 Vittrup et al. International Journal of Radiation Oncology  Biology  Physics

Diarrhea Blood in stools Peripheral neuropathy Insomnia

2
1
1

3 2

Fig. 2. Longitudinal profiles of symptomatic patients (patients without substantial symptoms during follow-up are not
depicted). Each horizontal line represents 1 patient, each colored box a timepoint (baseline, every 3 months within the 1st
year, every 6 months in the second and third years, and yearly thereafter). Colors reflect the EORTC answers of not at all
(green), a little (yellow), quite a bit (orange), very much (red), and missing data are depicted as white.1 Patients with at least 1
substantial symptom during follow-up (crude incidence without LAPERS).2 Patients with a LAPERS event.3 Patients with
persistent substantial symptoms corrected due to baseline condition (chronic condition). Abbreviations: EORTC Z European
Organization for Research and Treatment of Cancer; LAPERS Z late, persistent, substantial, treatment-related symptoms.
(A color version of this figure is available at https://doi.org/10.1016/j.ijrobp.2020.08.044.)
peripheral neuropathy for LACC after IGABT with EBRT gynecologic cancer survivors.25,41 The present report docu-
and concomitant cisplatin have not been investigated. ments that 9.6% of patients in the EMBRACE study are
However, the present report documents that 11.5% of pa- living with late, persistent, substantial, and treatment-related
tients are living with persistent, substantial, and treatment- lymphedema. The pathophysiologic changes causing
related peripheral neuropathy, which warrants further radiation-induced lymphedema consist of atrophy of the
evaluation of the impact on QoL. lymph nodes, sclerosis of lymph vessels, and fibrosis of the
Lower-limb lymphedema is more common in CC survi- surrounding connective tissue.42 The tendency for irrevers-
vors treated with radiation therapy compared with healthy ibility of these changes is likely the reason why lymphedema
controls.35-37 In addition, surgical lymph node staging has had the highest proportion of symptomatic patients with
been established as an important risk factor.10 Lower-limb persisting symptoms (31.5%) among all organ-related
lymphedema increases distress and affects QoL in symptoms (Table 2).
Volume -  Number -  2020 Persistence of symptoms in the EMBRACE study 9

50% Prevalence
rates
40%

(”Quite a bit” or ”Very much”

Crude
31.7% incidence

Substantial symptoms
30% rate
LAPERS
Diarrhea 20% rate

Correction
10%
6.0% for baseline
condition
0%
BM 3M 6M 9M 12M 18M 24M 30M 36M 48M 60M
741 660 658 563 673 622 594 499 545 488 363
Follow-up (months)
n

50% Prevalence
rates
(”Quite a bit” or ”Very much”

40% Crude
Substantial symptoms

incidence
30% rate
LAPERS
Blood in stools 20% rate
12.0% Correction
10% for baseline
0.5% condition
0.0%
0%
BM 3M 6M 9M 12M 18M 24M 30M 36M 48M 60M
735 653 656 557 660 616 589 492 535 485 364
Follow-up (months)
n

50% Prevalence
rates
(”Quite a bit” or ”Very much”)

40% 39.2%
Crude
Substantial symptoms

incidence
30% rate
Peripheral 20%
LAPERS
rate
neuropathy 11.5%
Correction
10%
for baseline
1.4% condition
0%
BM 3M 6M 9M 12M 18M 24M 30M 36M 48M 60M
738 658 659 561 665 617 592 497 540 488 364
Follow-up (months)
n

50.5%
50%
Prevalence
(”Quite a bit” or ”Very much”)

40% rates
Substantial symptoms

30% Crude
incidence
Insomnia 20% 16.2%
rate
LAPERS
10% rate

0%
BM 3M 6M 9M 12M 18M 24M 30M 36M 48M 60M 72M
741 662 659 565 674 622 594 500 545 488 365 142
Follow-up (months)
n

Persisting substantial symptoms

Transient substantial symptoms
No substantial symptoms

Fig. 3. The graphs (left) show LAPERS rates, correction for baseline condition, crude incidence rates of “quite a bit” or
“very much” as the worst answer category during follow-up, and prevalence rates at each specified timepoint (numbers at risk
are shown in the bottom row). In the risk maps (right), red figures represent patients with persisting substantial symptoms
(LAPERS), yellow figures represent patients with transient substantial symptoms, and green figures represent patients who
did not experience substantial symptoms. The total of the red and yellow figures represent crude incidence. Abbreviations:
BL Z baseline; LAPERS Z late, persistent, substantial, treatment-related symptoms; M Z months. (A color version of this
figure is available at https://doi.org/10.1016/j.ijrobp.2020.08.044.)
10 Vittrup et al. International Journal of Radiation Oncology  Biology  Physics

100%
80%
LAPERS event w/o
CTCAE severe event
60% 36 34 102 91 121 314 568
4 32 80 68 254 LAPERS event with
40% CTCAE severe event
20%
8 6 18 26 51
2 6 3 25 7 76
0%
100%
1
80% 7 17 22 48 CTCAE severe event
2 9 91
9 9 43
60% w/o LAPERS event
15 CTCAE severe event
40% 3 with LAPERS event
8 2 18 26 51
20% 6 6 25 7 76

0%
ls l e a l l
ea oo we in
nc
y a ed ni igue ms ra Al
rrh st bo ur dem elat
e o m t t o e ne
Dia in ing re g
i qu
f
he n-r In
s a
F mp ll g
d ll
oo tro ary
f
k in ymp rga ls
y A
l a
B n n Le
L lo sa
co Uri Al pa
u
tl y no
u e
f fic M
Di

Fig. 4. Overlap between LAPERS events and physician-assessed severe (grade 3-5) CTCAE for symptoms assessed by
both patients and physicians. The top panel shows LAPERS events and the proportion overlapping with corresponding
CTCAE severe events. The lower panel shows CTCAE severe events and the proportion overlapping with corresponding
LAPERS events. Abbreviations: CTCAE Z Common Terminology Criteria for Adverse Events; LAPERS Z late, persistent,
substantial, and treatment-related symptoms; w/o Z without.

Fatigue, insomnia, and menopausal symptoms occur in patients has not been addressed.13 By incorporating dura-
the general population43 but are more common in CC sur- tion, LAPERS identifies another group of patients: eg, those
vivors treated with radiotherapy.11,35,44,45 The present who have persistent diarrhea that never reaches the
report found late, persistent, and substantial insomnia in threshold to be classified as a severe event. For the 9
16.2% and menopausal symptoms in 17.4% of patients. For symptoms with a corresponding EORTC/CTCAE assess-
fatigue specifically, an impact on QoL among gynecologic ment, only 12% of LAPERS events were accompanied by
cancer survivors has been reported.46 Vistad et al found that severe physician-assessed morbidity (Fig. 4). On the other
30% of CC survivors treated with radiation therapy had hand, severe CTCAE morbidity was associated with
chronic fatigue, defined as clinically significant fatigue with LAPERS in almost half of the cases (Fig. 4). This high-
a duration of 6 months.44 The present report suggests a lights the need for a complementary approach of both
more favorable level of persistent substantial fatigue of methods.
15.8% within the EMBRACE study. However, these Because some symptoms also occur in the general
numbers are not directly comparable due to different population (eg, diarrhea due to gastroenteritis), it is ques-
assessment scales and definitions. In the EORTC QLQ-C30 tionable whether a transient symptom during follow-up is
questionnaire, the fatigue scale is based on 3 questions: related to the treatment. The median approach of LAPERS
tiredness, weakness, and need to rest.17 LAPERS for sets a criterion for the symptom to be present for at least
tiredness and need to rest was approximately 20%. In half of the follow-up visits. By disregarding transient
comparison, weakness persisted in fewer patients (11.9%), symptoms, a relation to the treatment is more plausible.
partly due to a lower proportion of symptomatic patients Furthermore, symptoms could persist in follow-up due to a
with persistence. This indicates that tiredness and need to pretreatment chronic condition (eg, leaking of urine due to
rest were the predominant symptoms behind persistent age-related incontinence). In this scenario, persistence of
fatigue. symptoms during follow-up may reflect preexisting and not
From a patient perspective, the consequence of a given treatment-related factors. The LAPERS methodology in-
symptom depends largely on 2 aspects: severity and dura- cludes the possibility to correct for the baseline condition
tion. Traditionally, morbidity reporting has focused on the and thus the potential to minimize this bias. However,
occurrence of severe events, often defined by surgical correcting for the baseline condition is not appropriate for
intervention or interference in activities of daily living. all symptoms. Symptoms related to stress at diagnosis and
However, in general, the duration of morbidity in individual during treatment (eg, insomnia and fatigue) and tumor-
Volume -  Number -  2020 Persistence of symptoms in the EMBRACE study 11

related symptoms frequently occurring as acute morbidity treatment modalities.49 LAPERS has the potential to be
(vaginal discharge) could arise at both baseline and 3 used beyond LACC and for other treatment modalities; it
months after treatment, completely unrelated to any pre- could be applied in any large clinical trial featuring lon-
treatment chronic condition. When applying the LAPERS gitudinal morbidity assessment for reporting persisting
methodology it is crucial to consider whether correcting for morbidity in cancer survivors. LAPERS is not restricted to
the baseline condition is appropriate for each symptom the analyses of PRO but can also be applied to physician-
analyzed. If applied, the level of the correction should be assessed mild-to-moderate morbidity.30,50 Furthermore,
reported to enhance comparability between studies. LAPERS has been successfully applied in dose-effect
All symptoms described in this report tend to be analysis.30,50 Further research within the EMBRACE
reversible, which makes it relevant for clinicians and pa- study will investigate the impact of LAPERS on QoL.
tients to distinguish between the risk of experiencing a
symptom transiently and suffering persistently (Fig. 2).
Combining the information gained from LAPERS with Conclusions
incidence methods provides the possibility to make this
distinction (Fig. 3). This increases the informational value Within this large cohort of LACC survivors, a subgroup of
and comprehensiveness of risk communication with pa- patients with LAPERS was identified. The vast majority of
tients, which is important for several reasons. First, it has LAPERS events occurred without corresponding severe
been demonstrated that well-informed patients tend to cope physician-assessed morbidity. Across all symptoms, LAP-
better with side effects.47 Second, knowing which side ef- ERS rates were substantially lower than crude incidence
fects are treatment-related may help ease the unnecessary rates, which emphasizes the importance of distinguishing
fear of recurrence. Third, well-informed patients can between transient and persisting symptoms.
engage more fully in shared decision-making.
The present EMBRACE analysis has several limitations.
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