2014 ESMO Handbook of Rehabilitation During Cancer Treatment and Follow Up

REHABILITATION ISSUES DURING
CANCER TREATMENT AND FOLLOW-UP

fatigue
Edited by Henk van Halteren www.esmo.org
The ESMO Handbook of Rehabilitation Issues During Cancer Treatment

and Follow-Up is intended primarily to be read by physicians working
in the field of medical oncology. The aim of this publication is to
provide key information in the form of a comprehensive and well-
arranged handbook that will help physicians gain better understanding
of the issues surrounding patient rehabilitation. chronic pain lifestyle changes
This kind of book is currently lacking in the field of medical oncology

and is envisioned to be an important and useful new resource for
medical oncologists. This volume deals with clinical topics such as
pain, fatigue and gastrointestinal sequelae and also discusses other
aspects such as social and financial issues and lifestyle changes.
physical complaints psychological complaints
mucocutaneous changes gastrointestinal

sequelae
ESMO Handbook Series

European Society for Medical Oncology REHABILITATION ISSUES DURING
Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland
Edited by Henk van Halteren
ESMO Press · ISBN 978-88-906359-5-3
ISBN 978-88-906359-5-3
decreased exercise capacity

urological sequelae
www.esmo.org 9 788890 635953 social issues ESMO Handbook Series
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ESMO HANDBOOK OF
REHABILITATION ISSUES
DURING CANCER TREATMENT
AND FOLLOW-UP
ESMO HANDBOOK OF
REHABILITATION ISSUES
DURING CANCER TREATMENT
AND FOLLOW-UP
Edited by
Henk van Halteren

Department of Medical Oncology,
Admiraal de Ruijter Hospital,
Goes, The Netherlands
ESMO Press
First published in 2014 by ESMO Press
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Contents
Contributors ix
Reviewers xi
Acknowledgements xii
Introduction xiii
Section I. How to deal with physical/psychological complaints during

treatment and follow-up
1 Safeguarding Exercise Capacity Throughout and After
Cancer Treatment 1
Introduction 1
Reduced Cardiorespiratory Fitness 2
Reduced Muscle Mass and Strength 3
Increased Fat Mass 4
Reduced Bone Health 4
Exercise as Medicine in the Management of Cancer 4
Physical Activity and Cancer Outcome 7
Physical Activity Guidelines 8
Further Reading 9
2 Cancer Pain 11
Introduction 11
Personalised Assessment of Pain 15
Procedural-related Pain 17
Treatment-related Pain 18
Pharmacological Approaches in Treating Cancer Pain 21
Adjuvant Drugs 30
Particular Cases 31
v
Refractory Pain 34
Conclusions 35
Further Reading 35
3 Cancer-related Fatigue 37
Introduction: Fatigue in Rehabilitation 37
Prevalence Rates 38
Influencing Factors 39
Diagnosis and Assessment 40
Treatment Strategies 41
Conclusion 45
Further Reading 46
4 Psychological Deterioration 47
Introduction 47
Mental Disorders 49
Treatment Options 51
Psychotherapeutic Interventions 51
Further Reading 52
5 Mucocutaneous Changes 54
Introduction 54
Mucositis 54
Skin Complaints 56
Further Reading 63
6 Gastrointestinal Sequelae 66
Introduction 66
Potential GI Side Effects 67
Effect on Patients 67
Pathophysiology 68
Prevention and Self-management of GI Problems 69
Clinician-led Management of Acute GI Side Effects 70
Clinician-led Management of Chronic GI Side Effects 71
Conclusion 74
Further Reading 75
vi Contents
7 Urological Complications 77
Introduction 77
Radiotherapy 77
Brachytherapy 81
General Chemotherapy 81
Intravesical Chemotherapy 82
Urological Sequelae of Oncological Surgery 84
Further Reading 85
8 Sexuality/Reproductive Issues 87
Sexual Function 87
Fertility Issues in Cancer Patients 90
Conclusion 95
Further Reading 96
Section II. How to deal with social network problems during treatment
and follow-up
9 Cancer: Social Issues 98
Prevalence 98
Social Problems as a Source of Distress 98
Social Relations and Contacts 99
Special Aspects of Social Issues in Cancer 103
Conclusions 104
Further Reading 105
10 Financial Issues 106

Introduction 106
Job Loss 108
Interventions 110
Compensation for Occupational Disease 112
Further Reading 113
Contents vii
Section III. How to improve quality of life during follow-up
11 Lifestyle Changes 115
Introduction 115
Lifestyles and the Four Most Common Cancers 116
Lifestyle and Cancer In General 119
Summary 123
Further Reading 124
Section IV. How to merge the patients’ regular cancer surveillance and
rehabilitation plan
12 Survivorship Care Planning 125
Introduction 125
Survivorship Care Plans 126
Progress in Survivorship Care Delivery 129
Summary/Future Directions 132
Further Reading 133
Index 136
viii Contents
Contributors
Andritsch E. University of Graz, Clinical Department of Oncology,

University Medical Center of Internal Medicine, Graz, Austria
Boers-Doets C.B. IMPAQTT, Wormer, The Netherlands and
Leiden University Medical Center, Leiden, The Netherlands
Bossi P. Head & Neck Medical Oncology Unit, Fondazione IRCCS,
Istituto Nazionale dei Tumori, Milano, Italy
Bruinvels D.J. Instituut voor Klinische Arbeidsgeneeskunde,
Amsterdam, The Netherlands
Buffart L.M. EMGO Institute for Health and Care Research,
VU University Medical Center, Department of Epidemiology and
Biostatistics, Amsterdam, The Netherlands
De Wachter S. University of Antwerp and Department of Urology,
Antwerp University Hospital, Antwerp, Belgium
De Win G. Department of Urology, Antwerp University Hospital,
Antwerp, Belgium
Donnellan C. Department of Gastroenterology, Leeds Teaching Hospitals
NHS Trust, Leeds, UK
Farthmann J. Freiburg University Medical Center, Freiburg, Germany
Hasenburg A. Freiburg University Medical Center, Freiburg, Germany
Howell D. Princess Margaret Cancer Centre, University Health
Network, University of Toronto, Toronto, ON, Canada
Jones J.M. Princess Margaret Cancer Centre, University Health
Network, University of Toronto, Toronto, ON, Canada
ix
Kreitler S. School of Psychological Sciences, Tel-Aviv University;
Psycho-Oncology Research Center, Sheba Medical Center,
Tel Hashomer, Israel
Lalla R.V. Section of Oral Medicine, University of Connecticut
Health Center, Farmington, CT, USA
Maher J. Macmillan Cancer Support, London, UK
May A.M. Julius Center for Health Sciences and Primary Care,
University Medical Center Utrecht, Utrecht, The Netherlands
Pimentel F.L. Lenitudes, SGPS, Portugal; Health Sciences Department,
University of Aveiro, Aveiro, Portugal; Oncology Department,
Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal
Ripamonti C.I. Supportive Care in Cancer Unit, Fondazione IRCCS,
Istituto Nazionale dei Tumori, Milano, Italy
Schuurman J.G. A-CaRe, Amsterdam, The Netherlands
Schwab R. Freiburg University Medical Center, Freiburg, Germany
Smith L. Macmillan Cancer Support, London, UK
Weis J. Department of Psychooncology, Tumor Biology Center,
Freiburg, Germany
Wyndaele J.J. University of Antwerp and Department of Urology,
x Contributors
Reviewers
The editors and authors wish to thank the following reviewers:
Rob Newton, Edith Cowan University Health and Wellness Institute,

Edith Cowan University, Joondalup, Australia
Søren Laurberg, Aarhus Universitetshospital, Aarhus C, Denmark
Frank Van der Aa, Functional and Reconstructive Urology,
Neurourology, Department of Urology, UZ Leuven; Research Unit Cell
and Gene Therapy, Department of Development and Regeneration,
KU Leuven, Belgium
Adriaan Logmans, Obstetrics & Gynaecology Department,
AZ Sint-Lucas, Gent, Belgium
Olga Švestková, Department of Rehabilitation Medicine,
Charles University, Prague; The First Faculty of Medicine and
General University Hospital, Prague, Czech Republic
Ziv Amir, School of Nursing, Midwifery and Social Work,
University of Manchester, Manchester, UK
Jennifer Ligibel, Department of Medicine, Harvard Medical School,
Adult Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Martijn Brinkhuis, Admiraal de Ruijter Hospital, Goes,
The Netherlands
xi
Acknowledgements
I would like to thank the ESMO Publishing Working Group,

in particular Professor Michele Ghielmini, for supporting the
realisation of this book.
I would also like to thank Professor Hans-Helge Bartsch for his help in
compiling the table of contents and identifying chapter authors.
Above all, I would like to thank all the authors and reviewers who
enabled us to make this book a reality.
Henk van Halteren

xii
Introduction
Everybody wishes to enjoy a long and healthy life. To achieve this, one
seeks to maintain a sound spirit and a healthy body. Once the diagnosis
of cancer comes in, the whole picture changes in a horrible way. Cancer
affects man’s well-being in many different ways. Physical activity is
frequently reduced and it can be mentally hard to deal with the new
situation. The partner and family members may be put under pressure.
Disease symptoms or (late) adverse events delay the process of
recovery during and after cancer therapy. The disease and its necessary
treatment often undermine the employment process and raise financial
issues. Inability to actively take part in the social process may lead to
isolation and aggravate grief.
Medical professionals who are working within the field of oncology

should have an open mind towards this continuous and complex process
and help whenever and wherever possible. Being a good medical
professional goes well beyond technical skills or a high scientific trial
accrual. The term “personalised medicine” is currently used to point out
that there could well be a tailored, targeted treatment regimen for every
cancer patient in the near future. This term, however, has a second
meaning: behind every disease there is a unique person who deserves
personal guidance through his/her treatment and rehabilitation process.
After reading this handbook, you will most certainly be able to comply
with this personalised medicine goal.
Henk van Halteren

xiii
Safeguarding Exercise Capacity
Throughout and After Cancer 1
Treatment
L.M. Buffart
EMGO Institute for Health and Care Research, VU University Medical Center,
Department of Epidemiology and Biostatistics, Amsterdam, The Netherlands
A.M. May
Julius Center for Health Sciences and Primary Care,
University Medical Center Utrecht, Utrecht, The Netherlands
Introduction
Advances in early detection and treatment have improved survival rates
of cancer over the past decades, with approximately 60% of patients liv-
ing more than 5 years after diagnosis. Despite this longevity, cancer and
its treatment are often associated with physical and psychosocial side
effects, i.e. both long-term effects present during treatment and persist-
ing afterwards, and late effects, which did not occur during treatment but
appear later. In the process of destroying cancer cells, radiation therapy
and chemotherapy also cause alterations to normal tissue and body func-
tions, resulting in toxicities in many organs and body systems. Also,
hormonal therapies such as androgen and oestrogen suppression, while
highly effective for treating prostate and breast cancer, respectively,
cause considerable side effects. While controlling the cancer, there is
significant impact on the patient, including the cardiovascular, pulmo-
nary, gastrointestinal, (neuro)endocrine, immune, and musculoskel-
etal systems. As a consequence, cancer survivorsa experience reduced
cardiorespiratory fitness, reduced muscle mass and strength, increased
The Centers for Disease Control and Prevention defined a cancer survivor as anyone who has been
a
diagnosed with cancer, from the time of diagnosis through the rest of life.
1
fat mass, reduced bone health, and fatigue. Furthermore, many cancer
survivors are at increased risk for anxiety, depression, sleep disturbances,
reduced self-esteem, and lymphoedema. These adverse long-term and
late effects severely impact the patient’s quality of life (QoL).
Reduced Cardiorespiratory Fitness

Cardiorespiratory fitness is determined by the transport of oxygen from
the environment to skeletal muscles via several components of the pul-
monary and cardiovascular systems including blood and blood vessels
and by the capacity of skeletal muscle to utilise this oxygen. Cancer and
its treatment may affect cardiorespiratory fitness via several mechanisms.
For example, pulmonary mechanics and gas exchange may be disrupted
by a tumour in the lungs, and anaemia may reduce the oxygen-carrying
capacity. Systemic therapy may result in cardiac limitations. For exam-
ple, anthracyclines could lead to atrial and ventricular arrhythmias, peri-
carditis, myocarditis, a reduced ejection fraction, and cardiomyopathy.
Alkylating agents such as cisplatin may result in myocardial ischaemia/
infarction, hypertension, heart failure, and arrhythmias. Chemotherapeutic
agents may also reduce the muscle capacity for oxygen utilisation.
Furthermore, radiotherapy in the chest area might cause cardiac or pul-
monary limitations, such as angina, dyspnoea, heart failure, pericardial
constriction, atherosclerosis, and mediastinal fibrosis, and may cause
localised damage to muscle agents. In addition, androgen-suppression
therapy results in considerable changes to the quantity and quality of
skeletal muscle. Finally, low cardiorespiratory fitness levels may also
result from reduced physical activity after cancer diagnosis, leading
to a reduction in cardiac output, oxidative capacity, and muscle cross-
sectional area.
The best direct measurement of cardiorespiratory fitness is the peak
oxygen uptake (peakVO2). A review by Steins Bisschop and colleagues
showed that most studies of cancer survivors reported reduced peakVO2
levels (between 16 and 25 mL/min/kg). Lower peakVO2 values in cancer
survivors compared to the healthy population indicate decreased
cardiorespiratory fitness levels and, consequently, are an indication for
physical exercise training. Moreover, screening for cardiac, pulmonary,
2 Buffart and May

or musculoskeletal limitations before the start of an exercise programme
is recommended. Low peakVO2 has also been shown to be related to an
increased risk of premature death.
PeakVO2 can be measured during a cardiopulmonary exercise test
(CPET) with continuous gas exchange analysis during incremental exer-
cise, which is generally conducted on a cycle ergometer or treadmill and
is considered feasible and safe. It can be used to monitor individual car-
diorespiratory fitness and allows exercise programmes to be tailored to
individual fitness levels by using either a percentage of peakVO2, a per-
centage of the peak heart rate, or the heart rate at the anaerobic threshold
to guide exercise intensity.
Exercise during or after cytotoxic cancer treatment was found to be asso-
ciated with significant improvements in peakVO2 compared to a non-
exercise control group. Larger improvements were found in patients who
participated in an exercise programme after completion of cancer treat-
ment. This suggests that exercise during adjuvant therapy is of primary
importance to maintain cardiorespiratory fitness.
Reduced Muscle Mass and Strength

Muscle wasting is present in approximately 50% of cancer survivors,
contributing to decreased responsiveness to cancer treatment and severe
dose-limiting toxicities, in turn contributing to poor prognosis and
increased morbidity and mortality. Because muscle strength is related to
muscle mass, muscle wasting also contributes to weakness and reduced
functional ability and independence. In addition, due to its mediating
role, muscle wasting may have serious consequences on glucose metab-
olism and chronic low-level systemic inflammation. Muscle wasting
results from an imbalance between the rate of muscle protein synthesis
and degradation and, in particular, from accelerated muscle protein deg-
radation. Mechanisms underlying muscle protein degradation include
tumour- and treatment-related increases in pro-inflammatory cytokines
and proteolysis-inducing factors, as well as testosterone suppression,
reduced food intake, and low physical activity levels.
Safeguarding Exercise Capacity Throughout and After Cancer Treatment 3

Increased Fat Mass
Cancer and its treatment are commonly associated with changes in body
composition. The specific detrimental changes in total weight, lean body
mass, and fat mass differ by cancer and treatment types. An increase in fat
mass is common during adjuvant treatments, for example for breast, colon,
prostate, and gynaecological cancer, which has a significant impact on the
risk of type 2 diabetes, asthma, chronic back pain, osteoarthritis, metabolic
syndrome, and cardiovascular disease. In addition, obesity has been asso-
ciated with a poorer overall and cancer-specific survival.
Reduced Bone Health

Hypogonadism and the subsequent oestrogen deficiency associated
with cancer treatment (chemotherapy, hormone therapy) can result in an
imbalance between function of the osteoblasts and osteoclasts, result-
ing in greater bone resorption than formation. The result is a net loss
of bone density and an increased fracture risk. Patients with breast or
prostate cancer in particular are at increased risk for reduced bone health.
Premenopausal women who are treated with alkalytic agents are at
increased risk for cessation of ovarian function, which reduces oestrogen
levels. Also, men treated with androgen-suppression therapy experience
a decrease in oestrogen that parallels the reduction in testosterone. Fur-
thermore, a high incidence of osteopenia and osteoporosis is observed in
long-term survivors of Hodgkin’s and non-Hodgkin’s lymphoma treated
with stem cell transplantation.
Exercise as Medicine in the Management of Cancer

Several reviews and meta-analyses demonstrate beneficial effects of
physical activity and exerciseb in cancer survivors during and after treat-
ment on physical and psychosocial outcomes. These include increased
cardiorespiratory fitness, muscle mass and strength, reduced fatigue and
depression, and improved QoL. The Physical Activity across the Can-
cer Continuum (PACC) framework proposes four time periods following
Exercise is a specific type of physical activity that is planned, structured, and repetitive and aims to
b
improve or maintain physical fitness, performance, or health.
4 Buffart and May

diagnosis during which physical activity can have an important role: pre-
treatment, during treatment, survivorship, and end-of-life care.
The aim of exercise pre-treatment is to improve physical fitness (including
cardiorespiratory fitness and muscle strength) prior to surgery or systemic
therapy to enable patients to undergo treatment with fewer side effects or
to enhance post-treatment recovery. In a systematic review of randomised
controlled trials (RCTs) and non-RCTs, Singh and colleagues reported
that the data available from patients with lung cancer, prostate cancer, and
cancer of the abdominal area (e.g. colon, colorectal, liver) suggest that
exercise – aerobic, resistance, or pelvic floor training alone or in com-
bination – may have a positive effect on rate and duration of continence,
functional walking capacity, and cardiorespiratory fitness. Some studies
reported improved QoL and reduced length of hospital stay (which is an
important prognostic variable for a positive surgical outcome), but findings
were inconsistent, likely due to lack of power and differences in training
duration prior to surgery.
In a meta-analysis by Speck and colleagues, results of exercise during
and after cancer treatment were presented separately. During treatment,
small to moderate significant effects of exercise were reported for cardio-
respiratory fitness, upper and lower body muscle strength, body weight,
functional QoL, anxiety, and self-esteem. After treatment, large signifi-
cant effects were found for upper and lower body muscle strength and
breast cancer-specific concerns, and small to moderate significant effects
for physical activity level, cardiorespiratory fitness, overall QoL, fatigue,
insulin-like growth factor-1 (IGF-1), and symptoms and side effects.
Similar effects were reported in other meta-analyses on this topic.
Resistance exercise is a potent stimulus of muscle synthesis, and con-
sequently increasing muscle mass, endurance, and strength, thereby
improving physical function and QoL. Exercise (aerobic, resistance,
or a combination of both) during cancer treatment can improve upper
and lower body muscle strength more than usual care. In a recent meta-
analysis of RCTs evaluating the effects of resistance exercise during and
after cancer treatment, Strasser and colleagues reported a significant
increase in lower and upper body muscle strength and lean body mass.

Improvements in lower body muscle strength were greater in cancer sur-
vivors who completed an exercise intervention after cancer treatment,
compared to those who exercised during cancer treatment. Whether there
is a dose–response relationship remains unclear; however, the results
suggest that exercise volume may be more important than exercise inten-
sity in order to induce muscle protein synthesis.
Exercise and, in particular, resistance training and high-impact loading
exercise can positively influence bone health by its osteogenic effects.
Resistance exercises should be performed at sufficient intensity and
should specifically load a target bone, thus both the hips and the spine.
Weight-bearing activities such as jumping and skipping are more osteo-
genic than activities with lower impact forces; however, aerobic exercises
using upper and lower body muscles and/or trunk rotation at sufficient
intensity, such as aerobic dance, may also benefit patients with osteogen-
esis. Walking interventions generally have limited effect on bone health
because the relatively low ground reaction force does not reach sufficient
intensity to augment bone density.
The relative benefit of exercise versus pharmacological treatment is yet
to be determined. Although exercise can be an effective non-pharmaco-
logical strategy for preserving bone health during and after cancer treat-
ment, adequate calcium and vitamin D supplementation and treatment
with pharmacological agents such as bisphosphonate and RANK-ligand
monoclonal antibody may also be important. These agents are, however,
associated with considerable side effects.
Few studies have examined the effects of physical activity in palliative
cancer patients. The few case reports and uncontrolled trials available
suggest that the role for physical activity is promising, as it may maintain
physical function, independence in activities of daily living, and overall
QoL. It is therefore recommended to encourage palliative cancer patients
to consider a physical activity intervention under the specific direction
and guidance of their attending medical team.
6 Buffart and May

Physical Activity and Cancer Outcome
Sufficient levels of physical activity may also be important to improve
disease-free and overall survival. Observational studies showed that
higher levels of moderate-to-vigorous physical activity were associated
with lower mortality risk in survivors of breast, colon, and prostate can-
cer, with physically active survivors having approximately 50% lower
mortality. However, to establish a causal relationship between physical
activity and survival, additional RCTs are needed.
RCTs evaluating the effects of physical activity on biomarkers related
to cancer prognosis have recently been summarised by Ballard-Barbash
and colleagues. The results suggest that exercise may result in beneficial
changes in circulating levels of insulin, IGF-1, and IGF-1 binding pro-
teins in breast cancer survivors. There is also evidence that exercise leads
to beneficial changes in circulating levels of C-reactive protein and in
natural killer cell cytotoxic activity in cancer survivors, including breast,
prostate, and gastric cancer. In prostate cancer survivors, there is con-
sistent evidence that exercise does not increase prostate-specific antigen
(PSA) or testosterone levels. Evidence for other biomarkers is limited or
non-existent. Also, the mediating role of immune, endocrine, or muscu-
loskeletal systems on the effects of exercise on cancer outcomes requires
further investigation.
Furthermore, the interaction between physical activity and primary can-
cer treatment remains unclear. In the START trial, Courneya and col-
leagues found chemotherapy completion rates to be higher in patients
who completed a resistance exercise programme during adjuvant
chemotherapy treatment for breast cancer (89.8%), compared to a usual
care control group (84.1%) or an aerobic exercise group (87.4%). This
resulted in higher survival rates among the exercise groups compared to
the control group.
In addition to observational data on survival and experimental data on
biomarkers in cancer survivors, a few studies in animals suggested that
exercise may inhibit tumour growth, but others did not. At present, fur-
ther investigation on the effects of physical activity on chemotherapy
completion rates and tumour growth is needed.

Physical Activity Guidelines
Given the increasing number of studies showing the safety and benefits
of physical activity, exercise should be part of the standard care for all
cancer survivors. Several evidence-based physical activity guidelines for
cancer survivors have been published.
In 2010, the American College of Sports Medicine (ACSM) published
physical activity guidelines for cancer survivors, which were based on
extensive systematic review of the literature on adult survivors of breast,
prostate, colon, haematological, and gynaecological cancers. The expert
panel reported consistent evidence regarding the safety of exercise dur-
ing and after cancer treatment (including intensive treatments such as
bone marrow transplant) and beneficial effects on cardiorespiratory fit-
ness, muscle strength, QoL, and fatigue. The ACSM recommends that
cancer survivors should be as physically active as their abilities and con-
ditions allow. Importantly, the recommendation is that cancer survivors
should avoid being physically inactive regardless of cancer stage or treat-
ment. Adult cancer survivors are advised to engage in either at least 150
minutes per week of moderate intensity or 75 minutes per week of vigor-
ous intensity aerobic physical activity, or an equivalent combination of
both. Muscle-strengthening activities involving all major muscle groups
are recommended at least two sessions per week. Several precautions for
exercise should be taken into account, including arm and shoulder prob-
lems, skeletal fractures, infection risk, ostomy, and swelling or inflam-
mation in the abdomen, groin, or lower extremity.
Lymphoedema is not a contraindication to exercise. A recent RCT
showed that women with breast cancer-related lymphoedema can safely
lift heavy weights during upper body resistance exercise, without fear of
lymphoedema exacerbation or increased symptom severity.
Comparable physical activity guidelines have been published by the
American Cancer Society (ACS), Exercise and Sport Science Australia,
Comprehensive Cancer Center the Netherlands, the German Cancer
Association, and the British Association of Sport and Exercise Science.
8 Buffart and May

Current physical activity guidelines for cancer survivors are rather
generic. Additional research is needed in order to develop more specific
guidelines for a given exercise prescription (e.g. mode, frequency, inten-
sity, duration), for a given cancer site at a particular phase of the can-
cer trajectory, and for specific outcomes. Future studies should focus on
identifying clinical, personal, physical, psychosocial, and intervention
moderators explaining “for whom” or “under what circumstances” inter-
ventions work. In addition, more insight into the working mechanisms of
exercise interventions on health outcomes in cancer survivors is needed
to improve the efficacy and efficiency of interventions. Existing pro-
grammes should also embrace the interests and preferences of patients to
facilitate optimal uptake of interventions, and must take the principles of
exercise training into account.
Declaration of Interest:
Dr Buffart has reported no conflicts of interest.
Dr May has reported no conflicts of interest.
Further Reading
Ballard-Barbash R, Friedenreich C, Courneya KS, et al. Physical activity, bio-
markers, and disease outcomes in cancer survivors: a systematic review. J
Natl Cancer Inst 2012; 104:815–840.
Buffart LM, Galvão DA, Brug J, et al. Evidence-based physical activity guide-
lines for cancer survivors: current guidelines, knowledge gaps and future
research directions. Cancer Treat Rev 2014; 40: 327–340.
Courneya KS, Friedenreich CM (Eds). Physical Activity and Cancer. Heidelberg:
Springer-Verlag, 2011.
Fong DYT, Ho JWC, Hui BPH, et al. Physical activity for cancer survivors: a
meta-analysis of randomised controlled trials. BMJ 2012; 344: e70.
Lustberg MB, Reinbolt RE, Shapiro CL. Bone health in adult cancer survivor-
ship. J Clin Oncol 2012; 30:3665–3674.
Singh F, Newton RU, Galvão DA, et al. A systematic review of pre-surgical exer-
cise intervention studies with cancer patients. Surg Oncol 2013; 22:92–104.
Speck RM, Courneya KS, Mâsse LC, et al. An update of controlled physical
activity trials in cancer survivors: a systematic review and meta-analysis. J
Cancer Surviv 2010; 4:87–100.

Steins Bisschop CN, Velthuis MJ, Wittink H, et al. Cardiopulmonary exercise
testing in cancer rehabilitation: a systematic review. Sports Med 2012;
42:367–379.
Strasser B, Steindorf K, Wiskemann J, Ulrich CM. Impact of resistance
training in cancer survivors: a meta-analysis. Med Sci Sports Exerc 2013;
45:2080–2090.
10 Buffart and May

Cancer Pain
C. I. Ripamonti
2
Supportive Care in Cancer Unit,
Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano, Italy
P. Bossi
Head & Neck Medical Oncology Unit,
Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano, Italy
Introduction
Pain is a frequent and impacting symptom not only in advanced cancer
but in any phase of the disease. Pain can be caused by cancer itself or
comorbidities; it may result following surgery, radiotherapy (RT), chem-
otherapy (CT), targeted therapy (TT), supportive care treatments, and/or
diagnostic procedures; or it may be unrelated to cancer. It is influenced
by genetics, personal past history, mood, expectation, and culture. Pain is
“an unpleasant sensory and emotional experience associated with actual
or potential tissue damage or described in terms of such damage”. The
perception of the intensity of pain is not proportional to the type or to
the extent of the tissue damage, but it is dependent on the interactions
between nociceptive and non-nociceptive impulses in ascending path-
ways, as well as the activation of descending pain-inhibitory systems.
Pain is always a subjective sensation; it is what the patient says it is and
may be affected by emotional, social, and existential components; thus it
has been defined as “total pain”.
Pain has been defined as the fifth vital sign by the American Pain Society
and its routine assessment is emphasised by international guidelines.
Cancer pain may be acute, chronic, or episodic (Table 1). Table 2 shows
the most frequent chronic pain syndromes. From a pathophysiological
point of view, pain can be classified as nociceptive (somatic and visceral),
neuropathic (central, peripheral, sympathetic), or idiopathic (Table 3).
11
However, in the clinical setting, pain is more frequently a mixed pain and may
involve multiple mechanisms, explaining the utility of combinations of differ-
ent classes of analgesic drugs. Table 4 shows the semantic descriptors of neu-
ropathic pain according to the International Association for the Study of Pain.
Table 1 Temporal Classification of Pain in Cancer
n A
cute pain: follows injury to the body and generally disappears when the body injury heals. It is usually due to
a definable nociceptive cause. It has a definite onset and its duration is limited and predictable (i.e. pain related
to surgery, biopsy, pleurodesis, pathological fracture, chemotherapy, radiotherapy, diagnostic and interventional
procedures). It is often associated with objective physical signs of autonomic nervous system activity. Acute pain
may also indicate a progression of disease and is often accompanied by anxiety
n C
hronic pain: due to the presence and/or progression of the disease and/or to treatments (i.e. chemotherapy-
induced neuropathy and/or osteoporosis, post-surgery, post-radiotherapy). Chronic pain may be accompanied
by changes in personality, lifestyle, and functional abilities and by symptoms and signs of depression. Chronic
pain with overlapping episodes of acute pain (i.e. breakthrough pain) is probably the most common pattern
observed in patients with ongoing cancer pain. This indicates the necessity for monitoring the intensity of
pain and associated symptoms and the analgesic treatments. Furthermore, the appearance of acute pain, or
progression of a previously stable chronic pain, is suggestive of a change in the underlying organic lesion and
requires clinical re-evaluation
n B reakthrough pain (episodic pain): defined as
a) unpredictable transient flares of severe or excruciating pain in patients already being managed with analgesics
who have a controlled baseline pain. It is difficult to treat adequately due to its rapid onset and offset
b) predictable episodic pain: caused by: (1) insufficient amount of opioids taken at regular intervals; (2) long
intervals between analgesic drug administrations; (3) incident pain, for example due to the patient’s moving
(bone metastases), swallowing (head & neck cancer), or coughing
Table 2 Chronic Pain Syndromes in the Cancer Patient

Pain due to direct involvement
Tumour invasion of bone
n Multifocal or generalised bone pain
n Pain syndromes of the bony pelvis and hip
n Base of skull metastases

• Orbital syndrome
• Parasellar syndrome
• Middle cranial fossa syndrome
• Jugular foramen syndrome
• Clivus syndrome
• Sphenoid sinus syndrome
• Cavernous sinus syndrome
• Occipital condyle syndrome
• Odontoid fracture and atlantoaxial destruction
n Vertebral body metastases
• Atlantoaxial syndrome
• C7-T1 syndrome
• T12-L1 syndrome
• Sacral syndrome
n Back pain and epidural spinal compression
12 Ripamonti and Bossi

Tumour invasion of nerves: peripheral nerve syndrome
n Paraspinal mass
n Chest wall mass
n Retroperitoneal mass
n Painful mononeuropathy
n Cervical, brachial, lumbar, sacral plexopathies
n Painful polyneuropathy
n Epidural spinal cord compression
n Painful radiculopathy
n Leptomeningeal metastases
Tumour invasion of viscera

Tumour invasion of blood vessels
Tumour invasion of mucous membranes
Pain due to cancer therapy
n Postoperative pain syndrome
• Post-thoracotomy
• Steroid pseudorheumatism
• Post-mastectomy
• Post-radical neck resection
• Phantom pain syndromes (limb, breast, anus, bladder pain)
• Post-surgical pelvic floor myalgia
• Stump pain
• Postoperative frozen shoulder
n Postchemotherapy pain syndrome
• Mucositis
• Chronic peripheral neuropathy (toxic, paraneoplastic)
• Aseptic necrosis of femoral or humeral head
• Plexopathy
• Raynaud’s phenomenon
n Postradiation pain syndrome
• Radiation myelopathy
• Mucositis
• Radiation necrosis of bone
• Radiation-induced peripheral nerve tumours
• Radiation fibrosis of brachial or lumbosacral plexus
• Radiation enteritis and proctitis
• Burning perineum syndrome
n Chronic pain associated with hormonal therapy
• Gynaecomastia with hormonal therapy for prostate cancer
Pain directly related or unrelated to cancer
n Paraneoplastic syndrome
n Myofascial pain syndrome
n Postherpetic neuralgia
n Debility, constipation, bed sores, rectal or bladder spasm, gastric distension
n Osteoporosis
Cancer Pain 13
Table 3 Types of Pain
n Nociceptive
pain: results from an acute or persistent injury to visceral or somatic tissues
n S omatic nociceptive pain: site-specific, described by patients as “aching”, “stabbing” or “throbbing”, “tender”,
“squeezing” and involves injury to bones, joints, skin, mucosa, or muscles
n V isceral nociceptive pain: results from injury to organs or viscera, is poorly localised and/or referred and
may be characterised as “cramping” or “gnawing” if it involves a hollow viscus (e.g. bowel obstruction), or as
“aching”, “stabbing” or “sharp” (similar to somatic nociceptive pain) if it involves other visceral structures such
as the myocardium
n N
europathic pain: suggests injury to the peripheral or central nervous system. Neuropathic pain may be
associated with referred pain along nerve distribution (pain is perceived in a location that is not the source
of the pain), and all other descriptors of pain (see Table 4). It is described as “shooting”, “sharp”, “stabbing”,
“tingling”, “ringing”, “numbness”. It is caused by radiculopathy, peripheral neuropathy, phantom limb, or spinal
cord compression
Table 4 Semantic Descriptors of Neuropathic Pain

n A
llodynia: pain caused by a stimulus which normally does not provoke pain
n C
ausalgia: continuous burning pain, allodynia and hyperpathia in succession or a traumatic nervous lesion;
disturbed vasomotor functions are often intercurrent, as well as, later on, disturbances to trophism
n C
entral pain: pain associated with a lesion of the central nervous system
n D
ysaesthesia: unpleasant sensation of tingling, stabbing, or burning whether spontaneous or provoked
n H
yperaesthesia: increase in sensitivity to specific stimuli
n H
yperalgesia: increased response to a stimulus which is normally painful
n H
yperpathia: painful syndrome characterised by increased reaction to a stimulus, especially a repetitive stimulus
n P araesthesia: abnormal sensation, either spontaneous or evoked
Despite the availability of several effective treatments including non-

opioids, opioids, adjuvant drugs, invasive management of refractory
pain and updated guidelines from authoritative learning societies, under-
treatment is still too frequent. Lack of pain control and poor relief is still
documented in several publications across all types of primary cancers,
solid and haematological malignancies, stages of disease, and settings
of care.
The presence of comorbidity, older age, social conditions, and disparities
may further complicate the management of pain, requiring a more holis-
tic approach to assure an adequate and personalised treatment.

Personalised Assessment of Pain
Poor pain assessment is the greatest barrier to effective cancer pain manage-
ment. To be adequately treated, cancer pain needs to be identified, assessed,
classified, and managed with a multistep approach that includes, as
reported in the recent review by Hui & Bruera (2014): “systematic screen-
ing, comprehensive pain assessment, characterisation of pain, identification
of personal modulators of pain expression, documentation of personalised
pain goals, and implementation of multidisciplinary treatment plan with
subsequent customised longitudinal monitoring” (Figure 1; Tables 5 and
6). Predictive factors for cancer pain can be assessed with different tools
which help physicians to identify patients with more difficult to control pain
syndromes. Observation of pain-related behaviours and discomfort is indi-
cated in patients with cognitive impairment to assess the presence of pain.
After the comprehensive assessment of pain during the first visit, a close
monitoring of pain and opioid-related adverse effects (nausea, vomiting,
constipation, drowsiness) is paramount. For this purpose a simple symp-
tom assessment tool should be considered as routine clinical practice in
all stages and phases of cancer diagnosis and treatments. The Edmonton
Symptom Assessment System (ESAS) is a 10-item patient-rated symptom
assessment tool. It was developed and validated for cancer populations in
different languages and cultures, and also indicated as a screening tool for
anxiety and depression.
Table 5 Assess and Re-assess the Pain, the Symptoms, and Comorbidities
n C auses, temporal onset, type, site and radiation, duration, intensity, relief and temporal patterns, number of
breakthrough episodes, pain syndrome, pain at rest and/or moving, somatisation
n Acute pain and/or chronic pain; predictable pain; incident pain
n P resence of the trigger factors and the signs and symptoms associated with the pain (sleep, anxiety, depression,
delirium, appetite, existential/spiritual suffering, well-being)
n N eeds for counselling
n C hemical coping, alcoholism, nicotine use, history of addiction, opioid misuse
n P resence of relieving factors
n U se of analgesics and their efficacy and tolerability
n C oncomitant medications
n R equire the description of pain quality
n Treatment-related and/or cancer-related pain or unrelated to cancer or its treatments
n P ost-surgery pain
Cancer Pain 15
Validated assessment tools for the assessment of pain
Visual analogue scale

10cm
no pain worst pain
Verbal scale pain

• No pain 1
• Very mild 2
• Mild 3
• Moderate 4
• Severe 5
• Very severe 6
Numerical scale
no pain 0 1 2 3 4 5 6 7 8 9 10 worst pain
Figure 1 Validated and most frequently used pain assessment tools. From Ripamonti
CI, et al. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol
2012; 23(Suppl 7): vii139–vii154. By permission of Oxford University Press on behalf
of ESMO.
Table 6 Characteristics of An Effective Pain-Relieving Therapy
n P revent the onset of pain: for this purpose drugs are not administered “as required” but rather “by the clock”,
taking into account the half-life, bioavailability, and duration of action of the different drugs
n B e simple to administer: thus easy to manage for the patient himself/herself and his/her family, especially when
the patient is cared for at home. The oral route appears to be the most suitable to meet this requirement, and,
if it is well tolerated, must be considered as the preferential route of administration
n B e individualised: the dosage, the type, and the route of drugs used must be administered according to each
patient’s needs. Individualised pain management should take into account the stage of disease, concurrent
medical conditions, characteristics of pain, and psychological and cultural status of the patient

Procedural-related Pain
Electrodiagnostic testing, imaging, and/or laboratory testing as well as
therapeutic procedures (tracheal suction, wound drain removal, wound
dressing, medication of skin ulcers) can provoke acute pain and discom-
fort. Diagnostic endoscopic examinations with or without visceral dila-
tation and digital examination can cause discomfort or overt pain. Fine
needle aspiration cytology, biopsy of masses and nodules, percutaneous
liver biopsy, transrectal ultrasound-guided prostatic biopsy, venipuncture,
arterial puncture, lumbar puncture, percutaneous or central venous cath-
eter placement, thoracentesis and pleurodesis are examples of procedures
associated with pain. Local anaesthetic and/or systemic analgesics (non-
steroidal anti-inflammatory drugs [NSAIDs] plus opioids) or nerve blocks
are necessary, depending on the type of procedure. However, only a minor-
ity of patients receive any medication before or during a specific proce-
dure. Bone marrow biopsy or aspiration (BMBA) is treated with various
pharmacological interventions: local anaesthetic (with low efficacy when
administered alone), intravenous sedation with benzodiazepine and/or opi-
oids or with inhaled nitrous oxide, and premedication with opioids.
Lumbar puncture is frequently associated with post-dural puncture head-
ache developing from hours to days after the procedure. The use of an
atraumatic needle may reduce pain. Hydration, bed rest, and analgesics
can resolve the symptoms in a few days.
Often, procedural pain is not considered a major problem by the physi-
cian, because of the prevalent importance of obtaining a specific cancer
diagnosis. The importance of recognising and pre-empting pain induced
by medical procedures should be stressed, to avoid the development of
central sensitisation, a phenomenon causing an increase in the area and
the response to noxious stimuli and a reduction in pain threshold.
In many circumstances premedication with local or intravenous anaes-
thetics and/or analgesic drugs is mandatory. No guidelines are available
on the assessment and treatment of pain caused by diagnostic and/or
therapeutic procedures and more research in this setting is necessary.
Cancer Pain 17
Treatment-related Pain
All cancer treatment modalities have the potential to cause pain. Data in
the literature show that about 59% of patients on anticancer treatments,
and 33% of patients after curative treatments, present with pain. Moreover,
5% to 10% of survivors have pain that interferes with functioning. Thirty
per cent of breast cancer survivors report pain 10 years after treatment.
Patients should be informed about pain onset and pain management during
the anticancer treatment to avoid discontinuation of therapies. In addition
patients should be encouraged to take an active role in their pain management.
Pain syndromes related to cancer surgery are well described. The most fre-
quent are breast cancer pain (from wide local excision, lumpectomy, axil-
lary dissection, conserving surgery, radical mastectomy, breast implants/
reconstruction, lymphoedema, frozen shoulder), post-radical neck dis-
section pain, post-thoracotomy pain, post-surgical pelvic floor myalgia,
phantom limb pain, and neuroma pain. Modern, less invasive surgical
techniques such as lumpectomy and axillary dissection and/or reconstruc-
tion do not always result in less post-surgery pain. Acute pain following
surgery requires the administration of an opioid analgesic or the imple-
mentation of more specific strategies such as regional anaesthetic tech-
niques. Patient-controlled analgesia (PCA) can be delivered intravenously
or through an epidural catheter. Post-surgical pain may become a chronic
pain syndrome (Table 2).
Acute pain related to chemotherapy may be due to venous spasm, chemi-
cal phlebitis, vesicant extravasation at the site of infusion followed by
desquamation and ulceration, and anthracycline-associated flare with
local urticaria. Application of warm compresses or reduction of the rate
of infusion can reduce pain due to chemical phlebitis caused by cytotoxic
medications, as well as the infusion of potassium chloride and hyperos-
molar solutions. Acute pain due to severe mucositis is a consequence of
the myeloablative chemotherapy before bone marrow transplantation. It
is frequently observed during radio(chemo)therapy for head and neck
cancer. Continuous intravenous infusion of opioids plus PCA as on-
demand bolus injections are adequate treatment in most cases; the use of
transdermal opioids may be suggested where oral use is contraindicated.

Administration of paclitaxel generates a syndrome of diffuse arthralgias
and myalgias in 10–20% of patients. The causes of the symptoms are
unknown and there is no specific analgesic therapy. Steroids are the usual
treatment. However, independent of the pathology, prolonged treatment
with steroids or their abrupt discontinuation can provoke acute arthral-
gias and myalgias, a syndrome known as “steroid pseudorheumatism”.
Acute painful peripheral neuropathy resulting from cytotoxic chemo-
therapy such as vincristine, cisplatin, and oxaliplatin may persist over
time. The syndrome usually is a sensory-predominant peripheral neu-
ropathy with pain and dysaesthesia that is most severe in the distal legs
and sometimes extending to the hands and distal arms. Concomitant neu-
rological deficit can worsen functioning.
Palmar–plantar erythrodysaesthesia syndrome (hand–foot syndrome)
manifests as a painful erythematous rash in the palms and soles, often
followed by bulla formation and desquamation after the administration
of continuously infused 5-fluorouracil (5-FU), capecitabine (an oral
5-FU precursor), liposomal doxorubicin, and paclitaxel. It is usually self-
limiting; however, symptomatic measures are required while treatment
with pyridoxine induces resolution of the lesions. In patients previously
treated with RT, vinorelbine administration can provoke severe pain at
the tumour site. Pre-treatment with ketorolac and morphine could reduce
the occurrence of this symptom; otherwise, switching to oral vinorelbine
is indicated.
In patients with haematological or lymphoproliferative malignancies and
in those receiving immunosuppressive therapies, acute herpetic neural-
gia is frequent and causes very distressing suffering and severe pain. This
is a typical form of neuropathic pain and should be treated accordingly.
Table 7 shows the most frequent causes of targeted therapy-related pain
and Table 8 shows the most frequent causes of radiotherapy-related
pain. Although the analgesic therapy according to published guidelines
is indicated to treat any type of pain, there is a strong need for well-
conducted trials analysing pathophysiology, epidemiology, prevention,
and treatment of TT-related pain and RT-related pain.
Cancer Pain 19
Table 7 Causes of Targeted Therapy-related Pain
n P apulopustular rash
n E rythema
n H
and–foot skin syndrome
n P aronychia
n F ingertip fissures
n R adiation dermatitis
n E yelashes growth distortion
n O
ral mucositis
n Anal mucositis
n Abdominal discomfort with diarrhoea
From Ripamonti CI, et al. Pain related to cancer treatments and diagnostic procedures: a no man’s land? Ann Oncol 2014;
25:1097–1106. By permission of Oxford University Press on behalf of ESMO.
Table 8 Causes of Acute and Late Radiotherapy-related Pain

Acute phase n cute mucosal inflammation: stomatitis, pharyngitis, oesophagitis, enteritis, proctitis, etc.
A
n Radiation dermatitis
n Pain flare effect
n Procedural pain: brachytherapy, implantation of “fiducial markers” in an organ for
image-guided radiotherapy; passive mobilisation of bone metastatic patients during
radiation treatment
Late phase n R adiation fibrosis syndrome
n Osteoradionecrosis of the jaw
n Chest wall pain
n Oesophageal stricture
n Abdominal pain due to bowel spasm
n Urethral pain – dyspareunia
n Anal stricture
From Ripamonti CI, et al. Pain related to cancer treatments and diagnostic procedures: a no man’s land? Ann Oncol 2014;
25:1097–1106. By permission of Oxford University Press on behalf of ESMO.
Hormonal Therapy-related Pain

Musculoskeletal symptoms, bone demineralisation with consequent
osteopenia and osteoporosis, arthralgia, and myalgia are important side
effects due to aromatase inhibitors (AIs) and are the causes of non-
adherence to or discontinuation of the therapy. Recommendations for
the management of joint symptoms include pharmacological and non-
pharmacological interventions or the switch to a different hormonal

therapy. NSAIDs, low doses of steroids for a short time, paracetamol,
and duloxetine represent the most adequate analgesic approaches. Non-
pharmacological approaches have been employed and need to be evalu-
ated in well-conducted trials.
Supportive Therapy-related Pain

Acute phase reaction symptoms are commonly observed after intrave-
nous administration of new-generation bisphosphonates in patients with
bone metastases, as well as in patients with hormone-induced osteopo-
rosis. The acute phase reactions are less frequent in patients treated with
denosumab. Pain relief is generally achieved with the administration of
NSAIDs and acetaminophen. For patients on regular analgesic opioid
therapy, higher doses of these drugs should be prescribed. The intensity
and incidence of pain caused by bisphosphonates may be reduced by
pretreatment with acetaminophen or ibuprofen.
Granulocyte-colony stimulating factor (G-CSF) and its long-term active
form, pegfilgrastim, may induce bone pain that can result in discontinu-
ation of the growth factor, reducing chemotherapy dose intensity, and
consequently, the patient’s survival. Naproxen was shown to signifi-
cantly reduce pegfilgrastim-induced bone pain by 22% over the whole
5 days of the course, with an absolute difference of 10%. Even with the
preventive use of naproxen, more than 60% of patients still experienced
some pain (19% severe pain).
Pharmacological Approaches in Treating Cancer Pain

In 1986 the World Health Organisation (WHO) published analge-
sic guidelines for the treatment of cancer pain based on a three-step
ladder together with practical recommendations (Table 6). These guide-
lines serve as an algorithm (Figure 2) for a sequential pharmacological
approach to treatment, according to the intensity of pain, reported by the
patient. Non-opioid drugs such as NSAIDs or paracetamol are suggested for
pain of mild intensity, moving on to opioids for more troublesome pain.
Cancer Pain 21
Treatment of cancer pain
STRONG RECOMMENDATION
Periodic reassessment of cancer pain.
STEP 1 Use rescue medications. If pain not
MILD PAIN NSAIDs-PARACETAMOL
NRS 1-3 controlled go on to the next step
WEAK RECOMMENDATION
Periodic reassessment of cancer pain.
MILD-MODERATE STEP 2 WEAK OPIOIDS +/- Use rescue medications. If pain not
PAIN NRS 4-6 NSAIDs-PARACETAMOL controlled do not change opioid but go
on to the next step
STRONG RECOMMENDATION
MODERATE-SEVERE STEP 3 STRONG OPIOIDS +/-
PAIN NRS 7-10 NSAIDs-PARACETAMOL
Go on or, if necessary, opioid or route of opioid

administration switching, using an equianalgesic Increase the dose of opioid every day,
dose of the same or different opioid: Side effects considering the number of opioid
✓ Oral or transdermal long-acting opioid rescue doses used, until pain control
✓ Symptomatic treatment or side effects
✓ Reasses the pain intensity and its causes

✓ Consider the type and/or doses of adjuvants
Always use rescue ✓ Consider opioid or route of opioid administration switching Persisting
doses to treat ✓ Consider invasive interventions pain
breakthrough pain ✓ Team decision
Adjuvant drugs, such as corticosteroids, anticonvulsants, antidepressants, should be considered at any step when necessary
Figure 2 Treatment of cancer pain. From Ripamonti CI, et al. Management of cancer
pain: ESMO Clinical Practice Guidelines. Ann Oncol 2012; 23(Suppl 7):
vii139–vii154. By permission of Oxford University Press on behalf of ESMO.
Opioid analgesics are classified according to their ability to control

mild to moderate pain (i.e. codeine, dihydrocodeine, tramadol, dextro-
propoxyphene, tapentadol) (weak opioids) (Table 9) and those used for
moderate to severe pain (morphine, methadone, hydromorphone, oxy-
codone ± naloxone, fentanyl, diamorphine, buprenorphine, levorphanol,
oxymorphone) (strong opioids) (Table 10). Opioid analgesics may be
associated with non-opioid drugs (paracetamol or NSAIDs) and adjuvant
drugs. The current recommended management of cancer pain consists
of the regular administration of opioids and intermittent rescue doses of
immediate-release opioids or NSAIDs for episodic pain. The treatment
with opioids must be personalised according to the pharmacokinetics
and pharmacodynamics of the drug, as well as the route of administra-
tion and the clinical condition of the patient. All opioids produce toler-
ance with chronic dosing and many patients require dose escalation to

accommodate their decreased sensitivity towards the drugs. This is not
addiction and physicians must assess patients carefully to diagnose pro-
gression of the disease as early as possible.
Table 9 Opioid Analgesics for Mild to Moderate Pain
Drug Class Pharmacology Metabolism Toxicity /
Contraindications
Codeine is an opium alkaloid is a prodrug of is metabolised A relevant accumulation
morphine. The to active drugs of codeine has been
Commercially pharmacodynamic within the body reported in patients
available in effects of codeine by CYP2D6. Poor treated with codeine
association with are largely due to metabolisers and undergoing
paracetamol the production produce no haemodialysis when
of its active CYP2D6 or compared with normal
metabolite, undetectable levels subjects
morphine of it
Not indicated in
Without CYP2D6, presence of renal failure
codeine provides
little or no analgesia
Dihydrocodeine is a semisynthetic has an oral The CCK antagonist can produce severe
analogue of bioavailability of proglumide toxicity when
codeine about 20% and enhances the administered in patients
the same analgesic analgesic effect of with renal impairment
potency as codeine dihydrocodeine
when administered Oxidation of
orally dihydrocodeine is
reduced in patients
with hepatic cirrhosis
resulting in increased
oral bioavailability caused
by a reduced first-pass
metabolism
Tramadol is a synthetic agonist of the µ After repeated oral The elimination time
drug with opioid opioid receptor, administration the of the potent active
and non-opioid also inhibits bioavailability is metabolite is double in
properties and serotonin and about 90–100%, the patients with hepatic or
thus a ceiling dose norepinephrine excretion is mostly renal impairment
reuptake via kidneys (90%)
Not indicated in
presence of renal failure
A severe serotonin
syndrome may occur
when tramadol is
combined with drugs that
increase serotonin activity
Cancer Pain 23
Table 9 (Continued)
Contraindications
Dextro- is a µ agonist and a is a synthetic The analgesic When it is administered
propoxyphene weak N-methyl-D- derivative of effect of DPP regularly, plasma
(DPP) aspartate (NMDA) methadone hydrochloride in concentration gradually
antagonist receptor doses of 65 mg increases with a plateau
or more has been after 2 to 3 days
established in
controlled studies It is metabolised
in the liver to nor-
propoxyphene, which
can accumulate in the
body because of its long
half-life (about 23 hours)
and may produce central
nervous system (CNS)
toxicity
Tapentadol New opioid, it This characteristic It seems to Comparative studies in
binds to the µ reduces the risk of produces fewer large samples of cancer
opioid receptors addiction GI adverse effects patients on chronic
and inhibits in respect to opioid use are necessary
norepinephrine oxycodone
reuptake and thus
has a
ceiling dose

Table 10 Opioid Analgesics for Moderate to Severe Pain
Contraindications
Morphine is a µ opioid Oral morphine Morphine clearance Morphine has three
agonist is the drug of decreases in patients different metabolites:
choice for the over 50 years morphine-3-glucuronide
Morphine is management of old, which helps (M-3-G), morphine-6-
considered the chronic cancer pain to explain elderly glucuronide (M-6-G), and
gold standard step of a moderate to patients’ higher normorphine. M-6-G is
3 opioid (WHO) severe intensity sensitivity to the drug. the active drug and binds
and has been because it provides Younger patients may to the µ receptor. M-3-G
placed by WHO effective pain need larger doses of is not an opioid and may
on its essential relief, is widely morphine to achieve cause toxicity, such as
drug list tolerated, is simple the same analgesic myoclonus and agitation
to administer, and effect
is comparatively Morphine is not safe in
inexpensive patients with impaired
renal function
Individual titration
of dosages and the
prevention of the
adverse effects (e.g.
nausea, vomiting,
constipation) are
recommended
Methadone is a synthetic It has a long and Considered one of It is metabolised by the
opioid and is a unpredictable the new analgesics cytochrome P450 group
µ and δ opioid half-life, large based on impressive of enzymes and does not
receptor agonist interindividual study results and produce active metabolites.
with NMDA variations in clinical successes The main enzyme
receptor pharmacokinetics. mediating N-demethylation
antagonist affinity Although it has It can be an of methadone in the
been used mostly interesting alternative liver is CYP3A4, with
as the maintenance 2° line option lesser involvement of
drug for opioid for patients with CYP1A2 and CYP2D6.
addicts, methadone intolerable opioid Therefore, the most
has also proved side effects or pain important interactions
to be a powerful difficult to manage between methadone and
analgesic and a other drugs are related
suitable drug in Methadone can to drugs that are able to
treating cancer pain prolong the QTc induce or inhibit CYP3A4.
interval. Relative In these circumstances,
contraindication the methadone plasma
to its use is a QTc concentrations will be
interval from 450 reduced or increased,
to 500 ms. Strong respectively
contraindication to its
use is a QTc interval Methadone is safe in patients
>500 ms with impaired renal function
Cancer Pain 25
Table 10 (Continued)
Contraindications
Hydromorphone is a derivative It is highly solubleHydromorphone It produces some
of morphine and about 5–10 administered metabolites, the
with similar times subcutaneously has principal one being
pharmacokinetic more potent than some advantages hydromorphone-3-
and morphine compared to glucuronide and, like
pharmacodynamic morphine because M-3-G, it is likely to
properties The extended- of its high solubility, be responsible for the
release formulation the availability of a neuroexcitatory adverse
“once a day” high concentration effects (myoclonus,
is suitable for preparation (10 seizure, hyperalgesia)
patients with low mg/ml), and a
compliance or bioavailability of High doses of the drug
taking many drugs about 78% and it is should be used with
per day at least as effective caution in patients with
as morphine renal failure
when delivered
by continuous
subcutaneous infusion
Oxycodone ± is a semisynthetic has structural A meta-analysis of The antagonist effects
paracetamol opioid that is relationship to four randomised of opioid receptors of
a derivative of codeine but is controlled trials naloxone administered
Oxycodone + thebaine, with an nearly 10 times attested that orally at low dose should
naloxone agonist action at µ more potent. It oxycodone was as be limited to intestinal
and κ receptors is metabolised safe and effective as opioid receptors only
like codeine, that morphine for cancer-
is demethylated related pain This explains the
and conjugated in improvement of opioid-
the liver to form Its potency is double induced constipation
oxymorphone in a with respect to when the association of
reaction catalysed morphine oxycone + naloxone is
by cytochrome administered
P450 2D6 The max daily dose is
(CYP2D6), and 40 mg twice a day for
is excreted in the oxycodone and 20 mg
urine twice a day for naloxone

Contraindications
Fentanyl is a highly Fentanyl citrate Intravenous fentanyl Intravenous, sublingual,
lipophilic semi- has a very high can be safely used buccal and intranasal,
synthetic opioid potency (about for rapid titration in fentanyl drug delivery has
75 times more cancer patients with a short onset of analgesic
It is not used than morphine) severe pain activity and is suitable in
orally because it and is skin treating breakthrough pain
rapidly undergoes compatible, having The TD route
extensive first- a low molecular of fentanyl Fentanyl can be a valid
pass metabolism weight with good administration is the alternative drug in patients
solubility and most used in clinical with renal impairment
thus suitable for practice
TD administration is not
transdermal (TD) It is indicated in indicated in patients with
administration patients opioid- generalised oedema
Moreover, fentanyl tolerant, with
has a faster onset stable pain, with GI
of analgesic nausea and vomiting
properties when and difficulties in
administered IV swallowing. The
absorption increases
and creates a risk
in patients with
fever or when the
external temperature
increases
Diamorphine is an semisynthetic must be It is about twice as Is more soluble than
analogue biotransformed to potent as morphine morphine when
of morphine and 6-acetylmorphine when administered parenterally;
a pro-drug and morphine administered more rapid onset of
to produce the subcutaneously or analgesia and less vomiting
analgesic effect intramuscularly but more sedation when
administered intravenously
Cancer Pain 27
Table 10 (Continued)
Contraindications
Buprenorphine is a semi-synthetic Sublingual Like the mixed Buprenorphine can be
thebaine administration agonist-antagonists, administered at normal
derivative allows direct drug buprenorphine doses in patients with
absorption into the may precipitate renal dysfunction because
It is a potent systemic circulation, withdrawal in patients it is mainly excreted
partial agonist at thus avoiding the who have received through the liver
the µ receptor. hepatic first-pass repeated doses of a
As a µ partial metabolism morphine-like agonist It is prudent to limit
agonist, there is and developed treatment to patients
a ceiling to the physical dependence. who are opioid naive or
morphine-like Continuous are receiving a low-dose
effects of the drug administration of opioid regimen
naloxone is necessary Buprenorphine can also
to reverse the prolong the QTc interval;
respiratory effects of this effect is less than that
buprenorphine produced by methadone
Transdermal (TD) TD administration is not
buprenorphine indicated in patients with
achieves good generalised oedema
analgesia with
adverse effects similar
to those of other
opioids
Levorphanol is a synthetic is considered a In a randomised It undergoes
potent µ opioid useful alternative trial levorphanol glucuronidation in
agonist and also to morphine, was administered the liver and is then
binds δ and κ hydromorphone, in high-strength or excreted in the kidney.
receptors or fentanyl; low-strength capsules It can be delivered
however, it must for neuropathic pain. orally, intravenously and
be used cautiously Neuropathic pain subcutaneously
to prevent was reduced by the
accumulation. The higher dose but there It has a role in patients
κ receptor binding were more side who are refractory to
may explain its effects other opioids
high prevalence of
psychotomimetic
effects (delirium,
hallucinations)
compared with
other opioids

Contraindications
Oxymorphone is a semisynthetic is a metabolite of is an oral therapeutic Safety and efficacy profiles
µ opioid agonist, oxycodone with option for acute were similar to commonly
considered more high lipidic solubility and chronic/severe used pure opioids
potent than and rapid transfer pain. Available as
morphine across the blood– immediate-release It is metabolised by
brain barrier and extended-release the liver
formulations
Paracetamol and/or an NSAID are effective for treating mild pain and
any intensity of pain at least in the short term and unless contraindicated.
Opioids remain the mainstay of severe pain management in patients with
cancer; however, intraindividual variability in response to different opi-
oids is a common clinical phenomenon.
Although the role of “strong” opioids is universally recognised in the treat-
ment of moderate to severe pain, there is no common agreement regarding
the role and utility of the “weak” opioids for mild to moderate pain (Table
9). The first criticism concerns the absence of definitive proof of efficacy
of weak opioids; moreover their use is limited by the “ceiling effect”, in
which a dose increase does not correspond to an increase in their analgesic
efficacy but only influences the appearance of side effects. As an alterna-
tive to weak opioids, low doses of strong opioids in combination with a
non-opioid analgesic should be considered. Tapentadol is a new opioid
with a ceiling effect that reduces the risk of addiction and has the potential
to be effective in treating neuropathic pain. However, further studies on
this new drug are necessary in cancer pain. Well-performed clinical trials
are necessary to address the relevant issue of the role of weak opioids.
Table 10 shows the most used strong opioids available for treating mod-
erate to severe cancer pain. Most of them are pure µ opioid agonists.
However, there is no evidence from high-quality comparative studies
that other opioids are superior to morphine in terms of efficacy and tol-
erability. Oral short-acting drugs such as morphine or hydromorphone,
or a combination product containing an opioid plus paracetamol such
as oxycodone or hydrocodone, are frequently the first-choice analgesics
used in opioid-naive patients or patients with limited opioid exposure.
Cancer Pain 29
In patients with severe pain, where the relief of pain must be urgent,
intravenous titration of parenteral opioid (usually morphine or fentanyl)
is mandatory. New opioid analgesics are now available such as a oxy-
codone/naloxone combination, which has been shown to provoke less
constipation in respect to other oral opioids. More research is necessary
to better define the maximum daily dose and the cost/benefit of this new
drug in cancer pain.
Hydromorphone or oxycodone, in both immediate-release and modified-
release formulations for oral administration, and oral methadone are
effective alternatives to oral morphine.
Oral opioid administration is the preferred route. However, in some clini-
cal situations, such as vomiting, dysphagia, malabsorption, delirium, or
in cases in which rapid dose escalation is necessary, oral administration
may be impossible and alternative routes must be implemented.
Transdermal fentanyl and transdermal buprenorphine are best reserved
for patients whose opioids requirements are stable. They are usually
the treatment of choice for patients who are unable to swallow, or those
with poor tolerance of morphine or poor compliance. In the presence of
renal impairment, all opioids, but especially those with active metabo-
lites, should be used with caution and at reduced doses and frequency.
Fentanyl and buprenorphine via the transdermal route, or intravenously,
are the safest opioids of choice in patients with chronic kidney disease.
Clinically, the adverse effects of opioids such as nausea, sedation, con-
stipation, tolerance, and physical dependence need to be monitored regu-
larly. It is also important to recognise the endocrine effects of opiates,
because opioids reduce testosterone and produce hypogonadism and
morphine has effects on prolactin and growth hormone.
Adjuvant Drugs
Adjuvant drugs are a class of co-analgesics to administer in combination
with opioids in some pain syndromes. While a large number of adjuvant
drugs have been suggested to have analgesic effects, unfortunately the
evidence is largely anecdotal and few controlled trials of these drugs
have been conducted in cancer patients.

Tricyclic antidepressants (amitriptyline, imipramine, desipramine) have
shown analgesic efficacy in various neuropathic syndromes, particularly
when pain has dysaesthetic and paraesthetic characteristics. In some con-
trolled studies, both amitriptyline and desipramine showed efficacy in
the treatment of post-herpetic neuralgia; chlorimipramine and nortriptyl-
ine showed their efficacy in the treatment of central pain; imipramine,
clomipramine, desipramine, and fluoxetine proved efficient in the treat-
ment of neuropathy-induced pain.
Corticosteroids are frequently administered to cancer patients, but their
efficacy in inducing pain relief has been shown only in a limited number
of studies. They are likely to exert their effect by decreasing peritumoural
oedema and signs of inflammation, which, in turn, may reduce periph-
eral nerve stimulation. Dexamethasone has been shown to be effective in
alleviating metastatic spinal cord compression and in treating headache
related to endocranial hypertension.
Anticonvulsants (carbamazepine, phenytoin, valproic acid, clonazepam,
gabapentin, pregabalin) are all drugs utilised in the treatment of neu-
ropathic pain with a component referred to as “stabbing” or “lancinat-
ing”. Clinical experiences have been reported concerning the use of
these drugs in the treatment of neuropathic pain caused by diabetes,
radiotherapy-induced fibrosis or surgical lesions, herpes zoster, and
deafferentation. Gabapentin appears effective in improving analgesia in
patients with neuropathic cancer pain already treated with opioids.
Local anaesthetics: studies regarding the efficacy of intravenous and
subcutaneous administration of local anaesthetics such as lidocaine in
patients with neuropathic cancer pain have shown contradictory results.
Particular Cases
Breakthrough Pain (BTP) or Episodic Pain (Table 1)
Available pharmacological treatment options include oral transmucosal,
buccal, or oral immediate-release morphine sulphate (IRMS) or nasal,
subcutaneous, or intravenous opioids. Although these drugs are fre-
quently used, only a few randomised controlled trials (RCTs) are avail-
able comparing fentanyl versus placebo or versus IRMS. Recently, a fen-
Cancer Pain 31
tanyl nasal spray (FNS) was developed to optimise the absorption of the
drug across the nasal mucosa. In RCTs FNS provided superior pain relief
compared with placebo and with IRMS within 5 minutes but the differ-
ence was significant after 10 minutes. No patient reported significant
nasal effects. Sublingual fentanyl orally disintegrating tablet (sublingual
fentanyl ODT) produced a significant improvement of maximum BTP
intensity within 5 minutes of administration in 68% of BTP episodes
and a maximum effect within 30 minutes in 63% of episodes. BTP can
be partially resolved by the above-mentioned short-acting and potent
drugs. However, further studies are necessary to find the best solution for
BTP episodes because their onset is rapid and the duration is generally
of 5–15 minutes. IRMS is appropriate to treat predictable episodes of
BTP pain.
Bone Pain
Bone pain must be treated with analgesic drugs according to the published
guidelines. Moreover RT, radioisotopes, and TT given in association with
analgesics have an important role in pain management. Bisphosphonates
(BPs) are part of the standard therapy for hypercalcaemia and the preven-
tion of skeletal-related events. Although BPs have an analgesic efficacy
in patients with bone pain due to bone metastases, their use should not
be considered as an alternative to analgesic treatment. In a randomised,
double-blind study, denosumab demonstrated improved pain preven-
tion and comparable pain palliation compared with zoledronic acid. In
addition, fewer denosumab-treated patients shifted to strong opioid
analgesics. Preventive dental measures are necessary before starting BP
and denosumab administration.
Neuropathic Pain (NP)

Neuropathic pain has been associated with a less favourable response to
opioid analgesics than other types of pain. However, opioids may also be
effective in NP, even if high doses are often required. NP, either caused
by tumour infiltration or due to paraneoplastic or treatment-induced
polyneuropathy, may be adequately controlled by opioids with or with-
out adjuvant drugs. There is evidence from systematic reviews that both

tricyclic antidepressants and anticonvulsant drugs are effective in the
management of NP, even if the number needed to treat for these drugs is
3–5. Non-opioids ± strong opioids ± amitriptyline or gabapentin should
be considered the treatments of choice. In patients with NP due to bone
metastases, RT at the dose of 20 Gy in five fractions should be consid-
ered.
Opioid Switching
Opioid switching is a therapeutic approach to consider in clinical situa-
tions where: (1) pain is controlled but there are some intolerable adverse
effects; (2) pain is not adequately controlled and it is impossible to
increase the opioid dose because of adverse effects; or (3) pain is not
adequately controlled, notwithstanding the continuous increase of opioid
dose which does not produce adverse effects.
Different therapeutic strategies may prevent or treat adverse effects: (1)
general measures (reduce the opioid dose, hydrate the patient, correct
abnormal biochemistry if present, reduce the number of pharmacological
associations); (2) administration of symptomatic drugs (adjuvant drugs);
(3) administration by an alternative route; (4) administration of an alterna-
tive opioid; or (5) switching to both an alternative opioid and route. Data
are not available to allow us to compare the advantages and disadvantages
of the different therapeutic strategies such as the use of specific sympto-
matic drugs, the switching of opioid, and/or route of administration.
Patients who have poor analgesic efficacy or tolerability with one opioid
will frequently tolerate another opioid well, although the mechanisms
that underlie this variability in the response to different opioids are poorly
known. The hypothesis is that the benefits of opioid switching are more
likely to be related to subtle differences in pharmacology that emerge
when a new opioid is substituted in a patient who has developed toxicity
to another opioid, rather than to overt differences in pharmacological
profile in patients in stable pain control. However, much more needs to
be understood to answer these questions. For switching from one opioid
to another, it is mandatory to know the dose ratios between the different
opioids and to consider the incomplete cross-tolerance between them.
Cancer Pain 33
Refractory Pain
About 10% of cancer patients have pain which is difficult to manage
with oral or parenteral analgesic drugs. Interventional techniques such
as nerve blocks and intrathecal drug delivery (ITDD) (spinal or epidural)
should be considered in cases of refractory pain. Peripheral nerve blocks
or plexus blocks are indicated when pain occurs in the field of one or
more peripheral nerves or if pain is caused by pathological fracture or
vascular occlusion. The use of neurolytic agents on peripheral nerves
produces a significant incidence of neuritis. Neurolytic blocks should be
limited to those patients with short life expectancy because they are usu-
ally effective for 3–6 months.
Coeliac plexus block is useful in the presence of visceral pain due to
the damage of organs in the upper abdomen. Figure 3 shows the algo-
rithm for ITDD or epidural administration of opioids to be considered
for patients with inadequate pain relief despite systemic opioid escalat-
Intrathecal
ing doses or infusion for refractory cancer pain
opioid switching.
INTRATHECAL (IT) single short trial

Life expectancy < 3 months
Life expectancy > 3 months

somatic or neuropathic pain
EPIDURAL CATHETER
Tunnelled or with implantable system pain intensity pain intensity no IT
somatic or neuropathic pain decreases > 50% decreases < 50% CATHETER
Trial with IT CATHETER

or
pain intensity pain intensity

decreases > 50% decreases < 50%
SPINAL CATHETER
Tunnelled or with implantable system
somatic or neuropathic pain Reassessment and
IT implantable pump treatment of total pain by
interdisciplinary team
Figure 3 Intrathecal infusion for refractory cancer pain. From Ripamonti CI, et al.
Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol 2012;
23(Suppl 7): vii139–vii154. By permission of Oxford University Press on behalf of ESMO.

Conclusions
The WHO 3-step analgesic ladder remains the clinical model for pain
therapy. Its clinical application should be employed only after a complete
and comprehensive assessment and evaluation, based on the needs of
each patient. When applying the WHO guidelines, up to 90% of patients
can find relief from their pain regardless of the settings of care and social
and/or cultural environment.
Such a pharmacological approach is the standard treatment for patients
with cancer pain. Only when such an approach is ineffective are inter-
ventions such as spinal administration of opioid analgesics or neuroinva-
sive procedures recommended.
Survivors need an adequate assessment of pain and its causes before
opioids are prescribed to them, to avoid the possible risk of misuse or
dependence.
Dr Ripamonti has reported no conflicts of interest.
Dr Bossi has reported no conflicts of interest.
Further Reading
Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment
of cancer pain: evidence-based recommendations from the EAPC. Lancet
Oncol 2012; 13:e58–68.
Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of
oral morphine: an evidence-based report. J Clin Oncol 2001; 19:2542–2554.
Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: a clinical practice
guideline from the American Pain Society and College on Problems of Drug
Dependence, in collaboration with the Heart Rhythm Society. J Pain 2014;
15:321–337.
Coleman R, Body JJ, Aapro A, et al. Bone health in cancer patients: ESMO
Clinical Practice Guidelines. Ann Oncol 2014; 25(Suppl 3):iii124-iii137.
Glare PA, Davies PS, Finlay E, et al. Pain in cancer survivors. J Clin Oncol 2014;
32:1739–1747.
Cancer Pain 35
Hui D, Bruera E. A personalized approach to assessing and managing pain in
patients with cancer. J Clin Oncol 2014; 32:1640–1646.
Kress HG, Koch ED, Kosturski H, et al. Tapentadol prolonged release for man-
aging moderate to severe, chronic malignant tumor-related pain. Pain Physi-
cian 2014; 17:329–343.
Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO clinical practice guidelines
for the management of mucositis secondary to cancer therapy. Cancer 2014;
120:1453–1461.
Pachman DR, Watson JC, Lustberg MB, et al. Management options for estab-
lished chemotherapy-induced peripheral neuropathy. Support Care Cancer
2014; 22:2281–2295.
Ripamonti CI, Bareggi C. Pharmacology of opioid analgesia: clinical principles.
In: Bruera E, Portenoy RK (Eds). Cancer Pain. Assessment and Manage-
ment. New York: Cambridge University Press, 2010; 195–229.
Ripamonti CI, Bossi P, Santini D, Fallon M. Pain related to cancer treatments and
diagnostic procedures: a no man’s land? Ann Oncol 2014; 25:1097–1106.
Ripamonti CI, Santini D, Maranzano E, et al. Management of cancer pain: ESMO
Clinical Practice Guidelines. Ann Oncol 2012; 23(Suppl 7):vii139–vii154.

Cancer-related Fatigue
J. Weis
3
Department of Psychooncology,
Tumor Biology Center, Freiburg, Germany
Introduction: Fatigue in Rehabilitation

Due to advances in modern oncology treatment, improved cure rates
have been observed for some tumour sites such as lymphoma, breast or
testicular cancer, and longer survival rates for most tumour types have
been achieved. However, for many patients, this also means that they
may suffer from short- and long-term sequelae subsequent to their illness
and its treatment. Cancer-related fatigue (CrF) is the most common side
effect or late effect of cancer and its treatment. CrF is commonly defined
as: a self-recognised phenomenon that is subjective in nature and expe-
rienced as a feeling of tiredness or lack of energy that varies in degree,
frequency, and duration which is not proportional to physical activities
and not relieved by sleep or rest. Patients often describe CrF as an unu-
sual feeling of exhaustion, weakness, or a loss of activity with sequelae
to emotional and cognitive functions.
CrF has often been described as a multidimensional construct includ-
ing physical, cognitive, and emotional dimensions. The physical domain
describes fatigue as a loss of ability to perform activities due to somatic
symptoms of tiredness and loss of energy. The mental or cognitive
dimension includes loss of concentration, attention, reduced alertness,
or impairment in short-term memory. The emotional dimension covers
symptoms such as loss of motivation, reduced self-esteem, and depres-
sive feelings.
The symptoms and signs of CrF may also be due to other diseases or
functional impairments. CrF is primarily based on the patient’s subjec-
tive feeling of his or her symptoms and impairments. CrF has severe
effects on functional levels and health-related quality of life (HRQoL).
37
The type and extent of CrF vary markedly from one patient to another
and can change over time.
CrF does not affect only the individual patient and their spouse, but also
has many consequences on health economy. Patients complaining about
CrF show higher rates of requesting physician counselling, private prac-
titioner support, or other health services and, also, higher rates of sick
leave and loss of work capacity. Moreover, CrF has been proven to be a
negative predictor for return to work after cancer.
Prevalence Rates
A huge number of studies have been published investigating the preva-
lence and the associating factors of CrF in cancer patients. Prevalence
rates of CrF range from 59–100% in patients with cancer. The highest
prevalence rates were found for CrF as a direct side effect of a combina-
tion of medical therapies such as surgery, chemotherapy, radiotherapy,
and/or hormone therapy. CrF rates were higher in certain tumours (e.g.
pancreatic, breast, lymphoma) and with the use of certain treatments,
such as haematopoietic stem cell transplantation (HSCT) or high-dose
chemotherapy. CrF during treatment is regarded as a risk factor for
developing chronic CrF. Several studies reveal that fatigue commonly
increases during treatment and decreases after the end of treatment.
CrF can persist or recur as long-term sequelae for many years after the
cessation of anticancer and antineoplastic treatment. Long-term CrF may
be present for a long period of time and may persist up to five years after
completion of treatment.Although the label “chronic fatigue” may be accurate
within this context, it should not be confused with the International
Classification of Diseases (ICD) diagnosis of chronic fatigue syndrome
(CFS). The prevalence rates of CrF in long-term survivors vary from
25–35%, depending on the criteria and method used for assessment.
For patients in palliative or end-of-life care, CrF can be associated with
limiting, or even loss, of body functions and overall HRQoL.
38 Weis
Influencing Factors (Figure 1)
Despite a lot of research during the last decade, there is still no comprehen-
sive theory explaining the pathogenesis or the aetiology of CrF. Numerous
factors are discussed as influencing, or even causing, fatigue, including
medical conditions, biochemical and psychological factors and, particu-
larly, mood disturbances. Proposed mechanisms are pro-inflammatory
cytokines, dysregulation of the hypothalamo-pituitary-adrenal axis, de-
synchronisation of circadian rhythm, skeletal muscle wasting, and also
genetic dysregulation. Within the somatic perspective, factors include
states of oxygen insufficiency, metabolic disorders, hormonal imbalance,
as well as blood modifications (anaemia, hypokalaemia, hypocalcaemia).
Extremely high fatigue levels are correlated with specific forms of can-
cer treatment such as interferon-α or interleukin therapy. There are also
various psychosocial factors potentially explaining CrF. Studies on psy-
chological factors focus on the correlation between CrF and psychiatric
comorbidity, particularly depression and anxiety. This is described in the
section on psychological assessment. A strong correlation of fatigue with
sleeping disorders has been shown that may be either a result of distress or
a potential secondary cause of fatigue.
Cancer-related fatigue influencing factors

activity level
medications nutritional disorders
sleep disorders pain

Cancer-related
fatigue
emotional distress anaemia
Anxiety, depression
comorbidities
Infections
Endocrine dysfunction
Cardiac dysfunction
Renal dysfunction
Pulmonary dysfunction
Hepatic dysfunction
Neurological dysfunction
Figure 1 Assessment of factors influencing cancer-related fatigue. Adapted from

Mortimer JE, et al. Studying cancer related fatigue: Report of the NCCN Scientific
Research Committee. J Natl Compr Canc Netw 2010; 8:1331–1339.
Cancer-related Fatigue 39
Diagnosis and Assessment
Due to the complexity of CrF, a systematic assessment is a prerequisite
for planning treatment strategies for the patient. Based on the overview
of contributing factors, the assessment approach should include the fol-
lowing domains and data sources:
n Clinical assessment: pain, anaemia, insomnia, nutritional assess-

ment, activity level, medication side effects, comorbidities;

n Psychological assessment: depression, anxiety, emotional distress,

coping, non-cancer-related psychosocial distress; and

n Self-rating: questionnaires, screening.

Clinical Assessment
Clinical anamnesis of CrF takes a central role in the diagnostic process.
The physician should ask specifically about the type, severity, and tem-
poral course of the patient’s fatigue symptoms, focusing on vegetative
functions (e.g. sleep pattern) and other factors such as types of medi-
cation, nutrition, use of alcohol, tobacco, recreational drugs, medical
history before cancer, physical fitness, and other somatic comorbidi-
ties. Additionally, it is recommended to check the following laboratory
parameters: electrolytes, glucose, transaminase, gamma-glutamyltrans-
ferase (GT), C-reactive protein levels, blood count (particularly red and
white blood cell count, haemoglobin levels) and thyroid-stimulating hor-
mone.
Psychological Assessment
There have been several studies focused on correlation and comorbid-
ity in CrF and psychiatric conditions, especially depression and anxi-
ety. As fatigue is a common symptom of depression, diagnostic efforts
are required that reliably differentiate CrF. Symptoms such as a loss of
drive, sleeping disorders, and cognitive disorders also show overlap with
secondary symptoms of depression. With respect to the course of CrF, it
may be that long-lasting CrF can trigger a depressive episode. For exam-
ple, a continuing level of depression and anxiety may be exacerbated
40 Weis
by the perception of distress in knowing that cancer is a life-threatening
illness, as well as the stress of the anticancer treatment itself, which may
cause both physical and emotional exhaustion. CrF can be an expression
of pre-existing depression and can also be a cause of depression. In clini-
cal practice, a depressive disorder that may underlie CrF can be detected
rapidly and sensitively using just two screening questions. If the patient
answers both questions affirmatively, a depressive disorder is very likely
to be present and, therefore, a further specialised psychiatric diagnostic
evaluation is recommended. In one study, long-term fatigue, in particu-
lar, has been interpreted as a possible psychological ”maladaption” to
remaining late effects of cancer or its treatment.
Self-rating Measurement
Assessment and clinical diagnosis of CrF is an important task for health-
care professionals in cancer care. There is a broad expert consensus that
CrF as a complex and subjective phenomenon can only be measured by
self-report assessment tools. Due to the increasing interest, numerous
instruments to measure CrF have been developed. For screening of CrF,
a global assessment based on linear analogue scale has been proven as a
useful and valid tool. A review of the research literature shows that CrF
may be assessed by either unidimensional or multidimensional instru-
ments. Unidimensional instruments (e.g. FACIT Fa module or the Brief
Fatigue Inventory) are focusing only on physical symptoms of fatigue.
Most of the existing instruments are based on a multidimensional
approach assessing physical, affective, and cognitive aspects of CrF (e.g.
Multidimensional Fatigue Inventory [MFI] or EORTC FA13), which is
in line with an understanding of CrF as a multifaceted syndrome. Most
scales pertain to intensity, with only a few also addressing interferences
with activities of daily living.
Treatment Strategies
Compared with other side effects such as pain or nausea, there is no
clear evidence how to treat CrF. As there are multiple influencing fac-
tors on CrF, treatment is dependent on how easily the causes of CrF can
be determined and treated, e.g. anaemia. If the causes are unknown or
unclear, treatment is focused on how to reduce the symptom itself or help
the patient to improve coping or management strategies. Therefore, most
of the treatment options consist of supportive strategies. Before plan-
ning any treatment, the diagnostic process must be completed, having
excluded potential causes of CrF as discussed above (“Influencing Fac-
tors”). According to the NCCN guidelines for CrF, the treatment algo-
rithm starts with the global screening of CrF followed by differentiated
assessment procedures depending on the level of CrF (see Figure 2).
Fatigue Screening
LASA 0-10
Clinically relevant
none to mild (1-3) moderate (4-6)/severe (7-10)
Assessment of
Influencing Factors
Emotional distress (depression)
Infections, pain, malnutrition
Counselling Endocrine dysfunction
and Information Cardiac dysfunction
Renal dysfunction
Pulmonary dysfunction
Hepatic dysfunction
Neurological dysfunction
no further
(causal therapy)
therapies
Supportive therapies
(psychosocial, exercise,
pharmacological)
Figure 2 Algorithm for the assessment of cancer-related fatigue according to

the NCCN guidelines. From NCCN 2013 Clinical Practice Guidelines in Oncology:
Cancer Related Fatigue. Version 3.2013.
42 Weis
If the assessment process is completed and supportive strategies were
chosen as the recommended treatment option, the subsequent treat-
ment strategies are focused on alleviating the symptoms of CrF. They
should be designed taking into account the clinical status of the patient
(patients currently under treatment, patients after completion of treat-
ment, or patients with progressive disease at the end of life). In addition,
the decision should be made in accordance with the patient’s needs and
individual desires.
The following treatment options for alleviating CrF have been proven to
be effective in treating CrF:
n Physical exercise and training

n Psychosocial interventions

n Pharmacological treatment

Within the last decade, many studies have provided substantial evidence
that individualised physical exercise and training help reduce subjec-
tive fatigue levels. The physical training is focused on improving muscle
strength and endurance, sometimes in combination with relaxation tech-
niques or exercises for body awareness. Physical exercise and training
have been proven as effective strategies against fatigue and the continu-
ing decline of physical functional status. A Cochrane Review (Cramp &
Daniel 2008) shows moderate effects for physical training, especially
for some subgroups of cancer patients, if applied early during ongoing
adjuvant treatment. Various National Cancer Societies generally recom-
mend physical activity to cancer patients. Frequency, as well as intensity,
of exercise and training should be applied in an individualised fashion
depending on the patient’s age, clinical status of cancer, and subjective
level of fitness.
Psychosocial interventions for treating CrF cover a broad range of
interventions such as psychosocial counselling, psychotherapy, or
psychoeducation. Apart from communicating information about CrF, the
main goals of these interventions are: to help the patients to restructure
their cognitive appraisal of CrF; changing their coping strategies as well
as their behaviour; and addressing self-help or self-care strategies to
alleviate the burden of CrF. Some of these interventions include elements
such as relaxation techniques, recommendations for pacing, energy con-
servation, and stress management. Most psychosocial interventions can
be carried out as either individual or group interventions. There is some
evidence that such strategies can improve quality of life and reduce the
subjective feeling of fatigue. A recently published Cochrane review
(Goedentorp et al 2009) shows moderate effects of psychosocial inter-
ventions in decreasing CrF. Other reviews have pointed out that, among
psychosocial treatment strategies, cognitive behavioural interventions
have been proven as most effective against CrF. In addition, it has been
demonstrated that the combination of exercise training and psychosocial
interventions produces better effects than these interventions alone. A
few studies have shown that mind–body interventions such as mindful-
ness-based stress reduction (MBSR) or yoga may be helpful to reduce
CrF, but further research is needed for these types of intervention.
Among the different types of pharmacological treatment of CrF, psycho-
stimulants are particularly discussed. There are some randomised con-
trolled trials showing effects of methylphenidate, especially for patients
with severe levels of long-lasting fatigue and in progressive disease
without psychiatric comorbidity. Vertigo, increased blood pressure, and
dryness of the mouth have been described as possible side effects. A
systematic review has demonstrated heterogeneous results for the use of
methylphenidate. Effects seem to depend on the dosage used, the stage
of cancer, and the treatment setting. A randomised study showed sig-
nificant effects of modafinil for patients with severe fatigue at an early
stage of treatment. Modafinil is approved only for the treatment of nar-
colepsy but has been shown effective for treating CrF in some studies.
However, a review of the literature analysing studies up to 2008 con-
cluded that modafinil cannot be recommended as a medication for CrF
due to shortcomings in most of the studies. Against this background,
psychostimulants cannot be regarded as a standard medication for treat-
ing CrF. In some European countries, methylphenidate and modafinil are
not approved for use in CrF and therefore prescription may be difficult.
44 Weis
Other therapeutic agents less well studied in relation to their use for
reducing CrF include some substances in complementary and alternative
medicine such as l-carnitine, ginseng, and guarana. There are also a few
studies showing that bupropion or selective serotonin reuptake inhibitors
(SSRIs) (e.g. paroxetine) may reduce CrF.
Conclusion
Among cancer-related symptoms, CrF has the highest prevalence rates
over the whole trajectory of cancer. Although CrF is associated with
cancer and its treatment, many somatic and psychosocial factors influ-
ence CrF. Nevertheless, a comprehensive model which includes somatic
as well as psychosocial factors is still missing. For assessment, several
instruments allow standardised uni- or multidimensional assessment of
CrF. Although many assessment tools have been developed, there is no
gold standard for assessing CrF. Among available non-pharmacological
supportive care interventions for patients with CrF, exercise and physi-
cal training in particular, combined with psychoeducation, show the
best results but with little magnitude of effect. These types of treatment
strategies are delivered in inpatient or outpatient rehabilitation services.
Among pharmacological treatments, psychostimulants are effective with
even smaller magnitude of effect, and further research is necessary. In
addition, some complementary drugs have been tested in only a few
studies, but results are still unclear and depend on the individual clinical
situation of the patient. Guidelines for assessment and treatment have
been developed to improve recognition and assessment of CrF and to
improve supportive care of patients suffering from CrF. CrF is still to be
regarded as a major challenge for the future, especially in basic research,
prevention and development of treatment strategies in aftercare, and
rehabilitation programs for cancer patients.
Professor Weis has reported no conflicts of interest.
Further Reading
Brown LF, Kroenke K. Cancer-related fatigue and its associations with depres-
sion and anxiety: a systematic review. Psychosomatics 2009; 50:440–447.
Cramp F, Daniel J. Exercise for the management of cancer-related fatigue in
adults. Cochrane Database Syst Rev 2008; (2):CD006145.
Finnegan-John J, Molassiotis A, Richardson A, Ream E. A systematic review of
complementary and alternative medicine interventions for the management
of cancer-related fatigue. Integr Cancer Ther 2013;12:276–290.
Gamondi C, Neuenschwander H. Pathophysiology of fatigue. In: Bruera E,
Higginson IJ, Ripamonti C, von Gunten CF (Eds). Textbook of Palliative
Medicine. London, UK: Hodder Arnold, 2009; 613−620.
Goedendorp MM, Gielissen MF, Verhagen CA, Bleijenberg G. Psychoso-
cial interventions for reducing fatigue during cancer treatment in adults.
Cochrane Database Syst Rev 2009; (1):CD006953.
Howell D, Keller-Olaman S, Oliver TK, et al. A pan-Canadian practice guide-
line and algorithm: screening, assessment, and supportive care of adults with
cancer-related fatigue. Curr Oncol 2013; 20:e233–246.
Minton O, Stone P. A systematic review of the scales used for the measurement
of cancer-related fatigue (CRF). Ann Oncol 2009; 20:17–25.
Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of
cancer-related fatigue. Cochrane Database Syst Rev 2010; (7):CD006704.
Mortimer JE, Barsevick AM, Bennett CL, et al. Studying cancer related fatigue:
Report of the NCCN Scientific Research Committee. J Natl Compr Canc
Netw 2010; 8:1331–1339.
NCCN (National Comprehensive Cancer Network). Clinical Practice Guidelines
in Oncology: Cancer Related Fatigue. Version 3.2013. Available at: http://
www.nccn.org/professionals/physician_gls/f_guidelines.asp.
46 Weis
Psychological Deterioration
E. Andritsch
4
University of Graz, Clinical Department of Oncology,
University Medical Center of Internal Medicine, Graz, Austria
Introduction
Once the diagnosis of cancer has been made, patients are often con-
fronted with distressing thoughts concerning the meaning of life and
death for the first time in their lives. Cancer patients, and their relatives,
have many concerns that relate to all aspects of their lives and require a
wide range of adaptations. In spite of improvements in treatment strat-
egy and rehabilitation options, cancer patients still experience a variety
of physical, psychological, and social problems. Fear, sadness, and the
sense of losing control can disturb their emotional balance. Poor self-
perception is one of many factors that can weaken a person’s identity or
alter their life-orientation, while social, financial, and occupational con-
sequences may threaten their sense of security. Studies around the world
have shown that chronic illnesses in particular can lead to poverty, and
that, conversely, poverty is a distressing factor in the course of illness and
overall quality of life. Family, friends, community resources, and one’s
individual attitudes and beliefs also influence the adjustment process in
response to a cancer diagnosis.
Inefficient psychological, personal, and social resources increase a
patient’s level of distress, as well as feelings of helplessness and hope-
lessness. Distress is described as an unpleasant experience on an emo-
tional, psychological, social, or spiritual level. These emotional reactions
and psychosocial consequences range from normal feelings of vulner-
ability, sadness, and fear to serious psychological disorders, such as
adjustment disorders, anxiety disorders, post-traumatic stress disorders,
depression, family conflicts, or existential crises (Figure 1).
47
Distress continuum
Normal Severe
Distress Distress
Fears Depression
Worries Anxiety
Sadness Family conflicts
Spiritual crises
Figure 1 Distress continuum. Adapted from Holland J. Distress management in
cancer: standards and clinical practice guidelines, Slide 11. Slide set available at:
http://docs.ipos-society.org/education/core_curriculum/en/Holland_distr/player.html.
Figure 2 shows a more extensive model depicting the pathways between

stressors and the continuum of distress. One should realise that the dif-
ferent stressors could also affect caregivers. The medical team should
aim at preventive measures, particularly if the coping resources available
to the patient do not appear to be sufficient.
Models of pathways to distress

Cancer and Continuum of distress
treatment-related • Worry
stressors • Anxiety
• Fear of death
• Demoralisation
• Feelings of helplessness
Patient
• Feelings of regret, shame, guilt or anger
Psychosocial
• Sadness
stressors
• Depression
Caregiver
• (Anticipatory) grief
• Loss of sense of dignity
• Desire for hastened death
Individual and • Loss of meaning and hope
interpersonal • Mental disorders
factors (e.g. adjustment disorder)
Figure 2 Pathways linking stressors and distress. Republished with permission

of Oxford University Press, from Li M, et al. Adjustment disorders. In: Holland
J, Breitbart W, Jacobsen P, et al (Eds). Psycho-Oncology, Second edition, 2010;
permission conveyed through Copyright Clearance Center, Inc.
48 Andritsch
Mental Disorders
In recent scientific reports, the prevalence of mental disorders among
cancer patients ranged from 9.8% to 38.2%. In one review, the preva-
lence of depression by Diagnostic and Statistical Manual of Mental
Disorders (DSM) or International Classification of Diseases (ICD) cri-
teria was 16.3% in oncological and haematological settings (95% CI
13.4–19.5). The prevalence of dysthymia was 2.7% (95% CI 1.7–4.0),
the prevalence of adjustment disorders was 19.4% (95% CI 14.5–24.8),
and the prevalence of anxiety disorders was 10.3% (95% CI 5.1–17.0).
Including combination diagnoses, the total figure adds up to 38.2% (95%
CI 28.4–48.6) of patients.
The prevalence percentages of depression, adjustment disorders, anxiety
disorders, and combination diagnoses in palliative care settings (24 stud-
ies) were 16.5%, 15.4%, 9.8%, and 29.0%, respectively. The reported
prevalence differs depending on the diagnostic procedure performed
(e.g. clinical interviews, standardised questionnaires) and the stage of
the disease, as shown in Figure 3.
Epidemiology of mental disorders

in cancer patients
Prevalence rates in empiric studies on mental distress
Screening up to approx. 50%, clinical interview up to approx. 30%,

Anxiety disorders
in terminally ill patients up to 80%
Screening up to approx. 50%, clinical interview up to approx. 15%,

Depression
in terminally ill patients up to 77%
Screening or clinical interview up to approx. 50%

Adjustment disorders (frequently mixed anxiety and depressed mood)
Post-traumatic stress
Screening or clinical interview up to approx. 30%
disorder
Cognitive disorders Screening or clinical interview up to approx. 85% in terminally

(delirium) ill patients
Figure 3 Epidemiology of mental disorders in cancer patients. Adapted from Mehnert A, et al.
Psychosocial assessment in cancer patients, Slide 6. Slide set available at:
http://docs.ipos-society.org/education/core_curriculum/en/KochMehnert_assess/player.html.
Psychological Deterioration 49
Adjustment disorders are one of the most frequent psychiatric diagnoses
related to cancer and usually follow a stressful event, such as the diag-
nosis of cancer. They involve emotional and behavioural responses such
depressed mood, anxiety, or a combination of both. Prevalence rates
range from 11–35%.
Anxiety disorders include generalised anxiety disorder, panic disorder,
and post-traumatic stress disorder. In advanced stages of the disease,
patients experience different fears concerning disease recurrence or pro-
gression: imminent death, being dependent on others, losing autonomy,
and suffering associated with pain and toxic treatments.
Depressive disorders are defined by persistent depressed mood or loss
of pleasure. Other symptoms include psychomotor changes and cog-
nitive and somatic troubles. Depression is found more frequently in
patients with advanced disease. Younger age, a family and/or individ-
ual history of depression, poor social support, low level of optimism,
low self-esteem, poor communication skills, and a history of stressful
or traumatic life events, are additional risk factors. Depression and sad-
ness are understandable grief responses, particularly when patients are
confronted with a terminal stage of illness, but clinical depression is a
more severe, unfavourable condition that may further complicate cancer
treatment and patient care.
Existential distress is defined as feelings of helplessness and hopeless-
ness, delirium, loss of dignity, perception of being a burden to others,
and the loss of a will to live or a desire for a hastened death. Whereas
some cancer patients consider life more meaningful following a cancer
diagnosis, others report a loss of meaning or a feeling of absence. The
latter can trigger a search for meaning, but continued search for mean-
ing without success is connected to maladaptive coping and severe anxi-
ety and suffering. Suicidal thoughts are most common in patients with
advanced disease, and can be seen as an attempt to recover a sense of
control in a situation which is perceived as uncontrollable. Based on clin-
ical reports, suicidal thoughts occur in approximately 15% of patients
with advanced cancer.
50 Andritsch
Treatment Options
Psychological care should be provided for all patients with cancer. A
broad spectrum of standardised methods are available for the psycho-
social assessment of cancer patients, and include clinical interviews;
questionnaires, both self-assessment and external-assessment instru-
ments; criteria lists or checklists for the screening of diagnostic criteria;
psychological tests, such as neuropsychological tests; and standardised
behaviour observations.
Other procedures that can be used include psycho-physiological meas-
ures such as observations of behaviour, or psycho-physiological meas-
ures such as biofeedback, imaging procedures such as computed tomog-
raphy or magnetic resonance imaging, psycho-neuro-immunological
measures, and psycho-neuro-endocrinological measures.
In addition to standard treatment measures, the support of family and
friends plays an essential role in both cancer treatment and long-term
adaptation, as these individuals have a dual responsibility of caring for
and caring about the patient. Family members may actively engage in
emotive work with the patient while also attempting to manage their own
inner feelings.
Psychotherapeutic Interventions
Psychotherapeutic interventions will vary depending on the patient, and
also on the stage of the disease. For instance, cancer recurrence requires
many adaptation strategies and techniques, e.g. to learn to live “in the
here and now”. When facing the terminal stage of a disease, not only the
patients but also their significant others will have specific wishes and
needs. The quality of communication between the doctor and patient is a
crucial variable, as good communication skills can reduce fear and anxi-
ety through development of trust and confidence (rapport), as well as a
clearer view of the situation.
Frequently performed psychotherapeutic interventions are detailed below.
Psychoeducation encompasses a broad range of activities that combine
education and other activities such as counselling and supportive inter-
ventions. Psychoeducational interventions may be delivered individually
or in groups, and may be tailored or standardised according to the needs
of the patient. This type of intervention generally includes providing
patients with information about treatments, symptoms, resources, and
services, as well as suggestions for coping with cancer.
Coping skills training includes interventions such as instruction in
relaxation and stress management, assertive communication, cognitive
restructuring and problem solving, counselling, and the planning of
pleasant activities.
Cognitive-behavioural therapy is a type of psychotherapeutic treatment
that helps patients understand the thoughts and feelings that influence
behaviours. It can be employed in the treatment of cancer patients to
eliminate nausea and to control anxiety, pain, and depression.
Dr Andritsch has reported no conflicts of interest.
Further Reading
Breitbart W, Rosenfeld B, Gibson C, et al. Impact of treatment for depression on
desire for hastened death in patients with advanced AIDS. Psychosomatics
2010; 51:98–105.
de Figueiredo JM. Depression and demoralization: phenomenologic differences
and research perspectives. Compr Psychiatry 1993; 34:308–311.
Delgado-Guay M, Parsons HA, Li Z, et al. Symptom distress in advanced cancer
patients with anxiety and depression in the palliative care setting. Support
Care Cancer 2009; 17:573–579.
Kissane DW, Clarke DM, Street AF. Demoralization syndrome – a relevant psy-
chiatric diagnosis for palliative care. J Palliat Care 2001; 17:12–21.
Lederberg M, Holland J. Supportive psychotherapy in cancer care: an essential
ingredient of all therapy. In: Watson M, Kissane DW (Eds). Handbook of
Psychotherapy in Cancer Care. West Sussex: John Wiley and Sons, 2011;
3–14.
52 Andritsch
LeMay K, Wilson KG. Treatment of existential distress in life threatening illness:
a review of manualized interventions. Clin Psychol Rev 2008; 28:472–493.
Levin T, Alici Y. Anxiety disorders. In: Holland J, Breitbart W, Jacobsen P, et
al (Eds). Psycho-Oncology, Second edition. New York: Oxford University
Press, 2010; 324–331.
Li M, Fitzgerald P, Rodin G. Evidence-based treatment of depression in patients
with cancer. J Clin Oncol 2012; 30:1187–1196.
Li M, Hales SRG, Rodin, G. Adjustment disorders. In: Holland J, Breitbart W,
Jacobsen P, et al (Eds). Psycho-Oncology, Second edition. New York: Oxford
University Press, 2010; 303–310.
Mehnert A, Koch U, Schulz H, et al. Prevalence of mental disorders, psycho-
social distress and need for psychosocial support in cancer patients – study
protocol of an epidemiological multi-center study. BMC Psychiatry 2012;
12:70.
Mitchell AJ, Chan M, Bhatti H, et al. Prevalence of depression, anxiety, and
adjustment disorder in oncological, haematological, and palliative-care set-
tings: a meta-analysis of 94 interview-based studies. Lancet Oncol 2011;
12:160–174.
National Comprehensive Cancer Network. Distress management. Clinical prac-
tice guidelines. J Natl Compr Canc Netw 2003; 1:344–374.
Rodin G, Lo C, Mikulincer M, et al. Pathways to distress: the multiple deter-
minants of depression, hopelessness, and the desire for hastened death in
metastatic cancer patients. Soc Sci Med 2009; 68:562–569.
Vehling S, Koch U, Ladehoff N, et al. Prevalence of affective and anxiety dis-
orders in cancer: systematic literature review and meta-analysis. Psychother
Psychosom Med Psychol 2012; 62:249–258.
Watson M, Kissane DW (Eds). Handbook of Psychotherapy in Cancer Care.
West Sussex: John Wiley and Sons, 2011.
Mucocutaneous Changes
R. V. Lalla
5
Section of Oral Medicine, University of Connecticut
Health Center, Farmington, CT, USA
C. B. Boers-Doets
IMPAQTT, Wormer, The Netherlands and Leiden University Medical Center,
Leiden, The Netherlands
Introduction
The mucosal tissues and the skin are commonly affected by cancer treat-
ment including conventional chemotherapy and targeted therapy, as well
as radiation therapy. Antineoplastic therapies have, to a greater or lesser
extent, mucocutaneous adverse events in common. They are defined as
side effects affecting the skin, hair, nail, nail bed, eyes, nostrils, mouth,
throat, alimentary tract, and external genitals. This chapter will discuss
some of the more prominent mucocutaneous toxicities in oncology
patients. We discuss the presentation and management of mucositis asso-
ciated with chemotherapy and radiation therapy, preventive measures to
keep the skin in a healthy condition while on targeted therapy, and paro-
nychia. Management options for other skin complaints can be assessed at
ESMO’s OncologyPRO portal (http://oncologypro.esmo.org/).
Mucositis
Epidemiology
Mucosal damage due to cancer therapy can affect the entire gastrointesti-
nal (GI) tract. Oral mucositis was reported in 10–40% of patients receiving
conventional chemotherapy for solid tumours, 80% of patients receiving
head and neck radiotherapy, and 89% of patients undergoing high-
dose chemotherapy prior to haematopoietic stem cell transplantation.
Of 599 patients receiving chemotherapy for solid tumours or lymphoma,
54
51% developed oral and/or GI mucositis. Oral mucositis developed in
22% of 1236 cycles of chemotherapy, GI mucositis in 7% of cycles, and
both oral and GI mucositis in 8% of cycles.
Clinical signs and symptoms

Oral mucositis may present as erythema, erosion, or ulceration of the
oral mucosa. Lesions are typically limited to non-keratinised areas of
the mouth such as the ventral and lateral tongue, buccal mucosa, and
soft palate. The severity of mucositis lesions is directly proportional to
the dose of chemotherapy or radiotherapy. The most common symptom
of oral mucositis is mouth pain. GI mucositis can present as abdominal
pain, bloating, or diarrhoea. In patients receiving conventional chemo-
therapy, mucositis may resolve between 10 to 14 days after cessation of
chemotherapy, while in patients who have received high-dose radiation,
several weeks may be needed for healing.
Morbidity
Mucositis can be very painful and can significantly affect nutritional
intake, mouth care, and quality of life (QoL). Secondary infection of
mucositis lesions can cause systemic sepsis, especially during immuno-
suppression. Severe mucositis has been correlated with systemic infec-
tion and transplant-related mortality. During chemotherapy for solid
tumours or lymphoma, the rate of infection was doubled during cycles
with mucositis and was directly proportional to mucositis severity. A
dose reduction of chemotherapy was twice as likely after cycles with
mucositis. In patients receiving head and neck radiation therapy, mucosi-
tis can lead to severe pain, weight loss, hospitalisation, and unplanned
breaks in radiation therapy. Thus, severe mucositis can be a dose-limit-
ing toxicity of cancer therapy.
Economic impact
Supportive care measures for mucositis include analgesics, liquid diet sup-
plements, feeding through gastrostomy tubes or total parenteral nutrition
(TPN), fluid replacement, and management of infections. In a study of
chemotherapy patients, the cost of hospitalisation was US$3893 per cycle
Mucocutaneous Changes 55
without mucositis, $6277 per cycle with oral mucositis, and $9132 per
cycle with both oral and GI mucositis. In head and neck cancer patients
receiving radiation therapy, oral mucositis was related to an increase in
costs of US$1700 to $6000 per patient, depending on mucositis severity.
Management
The management of mucositis has traditionally been focused on alleviat-
ing mucositis symptoms to ensure patient comfort and allow the contin-
ued delivery of cancer therapy. This includes management of pain, as
well as management of other symptoms such as diarrhoea. While such
symptomatic care continues to be very important, there are also some
targeted interventions that can be used to prevent or reduce the sever-
ity of mucositis. The Multinational Association of Supportive Care in
Cancer/International Society of Oral Oncology (MASCC/ISOO) has
recently updated evidence-based clinical practice guidelines for oral
and GI mucositis. These guidelines include recommendations (based on
higher level evidence), and suggestions (based on lower level evidence).
In cases of inadequate or conflicting evidence, a determination of “no
guideline possible” was made. The MASCC/ISOO Mucositis Guidelines
are presented in Tables 1 and 2. The MASCC/ISOO Mucositis Guide-
lines have also been included in mucositis guidelines published by other
organisations including the European Society for Medical Oncology
(ESMO), the Oncology Nursing Society (ONS), and the US National
Comprehensive Cancer Network (NCCN).
Skin Complaints
At present, evidence for the effectiveness of the management options
for skin complaints is lacking, and the effect of the skin complaints on
health-related QoL and adherence remains poorly understood. Because
of the paucity of adverse event studies from which evidence-based
advice for these complaints can be formulated, we have to base our
recommendations on other sources. There are many reports about suc-
cessful management and expert opinion consensus available that can be
applied until more evidence is available. Since preventive measures are
key in the management of targeted therapy-associated skin complaints,
56 Lalla and Boers-Doets

Table 1 MASCC/ISOO Clinical Practice Guidelines for Oral Mucositis. From Lalla RV,
et al, and The Mucositis Guidelines Leadership Group of the Multinational Association
of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO).
MASCC/ISOO clinical practice guidelines for the management of mucositis secondary
to cancer therapy. Cancer 2014; 120:1453–1461, with permission
(Level of Evidence for each guideline is in brackets following the guideline statement)
RECOMMENDATIONS IN FAVOUR OF AN INTERVENTION (i.e. strong evidence

supports effectiveness in the treatment setting listed)
1. The panel recommends that 30 minutes of oral cryotherapy be used to prevent oral mucositis in patients
receiving bolus 5-fluorouracil chemotherapy (II).
2. The panel recommends that recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) be used
to prevent oral mucositis (at a dose of 60 μg/kg per day for 3 days prior to conditioning treatment and for
3 days post-transplant) in patients receiving high-dose chemotherapy and total body irradiation, followed by
autologous stem cell transplantation, for a haematological malignancy (II).
3. The panel recommends that low-level laser therapy (wavelength at 650 nm, power of 40 mW, and each
square centimetre treated with the required time to a tissue energy dose of 2 J/cm2), be used to prevent
oral mucositis in patients receiving HSCT conditioned with high-dose chemotherapy, with or without
total body irradiation (II).
4. The panel recommends that patient-controlled analgesia with morphine be used to treat pain due to oral
mucositis in patients undergoing HSCT (II).
5. The panel recommends that benzydamine mouthwash be used to prevent oral mucositis in patients with H&N
cancer receiving moderate-dose radiation therapy (up to 50 Gy), without concomitant chemotherapy (I).
SUGGESTIONS IN FAVOUR OF AN INTERVENTION (i.e. weaker evidence supports
effectiveness in the treatment setting listed)
1. The panel suggests that oral care protocols be used to prevent oral mucositis in all age groups and across all
cancer treatment modalities (III).
2. The panel suggests that oral cryotherapy be used to prevent oral mucositis in patients receiving high-dose
melphalan, with or without total body irradiation, as conditioning for HSCT (III).
3. The panel suggests that low-level laser therapy (wavelength around 632.8 nm) be used to prevent oral
mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for H&N cancer (III).
4. The panel suggests that transdermal fentanyl may be effective to treat pain due to oral mucositis in patients
receiving conventional and high-dose chemotherapy, with or without total body irradiation (III).
5. The panel suggests that 0.2% morphine mouthwash may be effective to treat pain due to oral mucositis in
patients receiving radiation therapy for H&N cancer (III).
6. The panel suggests that 0.5% doxepin mouthwash may be effective to treat pain due to oral mucositis (IV).
7. The panel suggests that systemic zinc supplements administered orally may be of benefit to prevent oral
mucositis in oral cancer patients receiving radiation therapy or chemoradiation (III).
Table 1 (Continued)
RECOMMENDATIONS AGAINST AN INTERVENTION (i.e. strong evidence indicates

lack of effectiveness in the treatment setting listed)
1. The panel recommends that PTA (polymyxin, tobramycin, amphotericin B) and BCoG (bacitracin,
clotrimazole, gentamicin) antimicrobial lozenges and PTA paste not be used to prevent oral mucositis in
patients receiving radiation therapy for H&N cancer (II).
2. The panel recommends that iseganan antimicrobial mouthwash not be used to prevent oral mucositis in
patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II), or in
patients receiving radiation therapy or concomitant chemoradiation for H&N cancer (II).
3. The panel recommends that sucralfate mouthwash not be used to prevent oral mucositis in patients receiving
chemotherapy for cancer (I), or in patients receiving radiation therapy (I) or concomitant chemoradiation (II)
for H&N cancer.
4. The panel recommends that sucralfate mouthwash not be used to treat oral mucositis in patients receiving
chemotherapy for cancer (I), or in patients receiving radiation therapy (II) for H&N cancer.
5. The panel recommends that intravenous glutamine not be used to prevent oral mucositis in patients receiving
high-dose chemotherapy, with or without total body irradiation, for HSCT (II).
SUGGESTIONS AGAINST AN INTERVENTION (i.e. weaker evidence indicates lack of
1. The panel suggests that chlorhexidine mouthwash not be used to prevent oral mucositis in patients receiving
radiation therapy for H&N cancer (III).
2. The panel suggests that granulocyte–macrophage colony-stimulating factor (GM-CSF) mouthwash not be
used to prevent oral mucositis in patients receiving high-dose chemotherapy, for autologous or allogeneic
stem cell transplantation (II).
3. The panel suggests that misoprostol mouthwash not be used to prevent oral mucositis in patients receiving
radiation therapy for H&N cancer (III).
4. The panel suggests that systemic pentoxifylline, administered orally, not be used to prevent oral mucositis in
patients undergoing bone marrow transplantation (III).
5. The panel suggests that systemic pilocarpine, administered orally, not be used to prevent oral mucositis in
patients receiving radiation therapy for H&N cancer (III), or in patients receiving high-dose chemotherapy,
with or without total body irradiation, for HSCT (II).
Abbreviations: HSCT = haematopoietic stem cell transplant; H&N = head and neck.

Table 2 MASCC/ISOO Clinical Practice Guidelines for Gastrointestinal Mucositis (not
including the oral cavity). From Lalla RV, et al and The Mucositis Guidelines Leadership
Group of the Multinational Association of Supportive Care in Cancer and International
Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice guidelines for
the management of mucositis secondary to cancer therapy. Cancer 2014; 120:1453–
1461, with permission
(Level of Evidence for each guideline is in brackets following the guideline statement)
RECOMMENDATIONS IN FAVOUR OF AN INTERVENTION (i.e. strong evidence
supports effectiveness in the treatment setting listed)
1. The panel recommends that intravenous amifostine be used, at a dose of ≥340 mg/m2, to prevent radiation
proctitis in patients receiving radiation therapy (II).
2. The panel recommends that octreotide, at a dose of ≥100 μg subcutaneously twice daily, be used to
treat diarrhoea induced by standard- or high-dose chemotherapy associated with HSCT, if loperamide is
ineffective (II).
SUGGESTIONS IN FAVOUR OF AN INTERVENTION (i.e. weaker evidence supports
1. The panel suggests that intravenous amifostine be used to prevent oesophagitis induced by concomitant
chemotherapy and radiation therapy in patients with non-small cell lung carcinoma (III).
2. The panel suggests that sucralfate enemas be used to treat chronic radiation-induced proctitis in patients
with rectal bleeding (III).
3. The panel suggests that systemic sulfasalazine, at a dose of 500 mg administered orally twice a day, be used
to prevent radiation-induced enteropathy in patients receiving radiation therapy to the pelvis (II).
4. The panel suggests that probiotics containing Lactobacillus species be used to prevent diarrhoea in patients
receiving chemotherapy and/or radiation therapy for a pelvic malignancy (III).
5. The panel suggests that hyperbaric oxygen be used to treat radiation-induced proctitis in patients receiving
radiation therapy for a solid tumour (IV).
RECOMMENDATIONS AGAINST AN INTERVENTION (i.e. strong evidence indicates
lack of effectiveness in the treatment setting listed)
1. The panel recommends that systemic sucralfate, administered orally, not be used to treat gastrointestinal
mucositis in patients receiving radiation therapy for a solid tumour (I).
2. The panel recommends that 5-acetyl salicylic acid (ASA), and the related compounds mesalazine and
olsalazine, administered orally, not be used to prevent acute radiation-induced diarrhoea in patients receiving
radiation therapy for a pelvic malignancy (I).
3. The panel recommends that misoprostol suppositories not be used to prevent acute radiation-induced
proctitis in patients receiving radiation therapy for prostate cancer (I).
SUGGESTIONS AGAINST AN INTERVENTION (i.e. weaker evidence indicates lack of
None.
these are discussed, as well as one example of a skin reaction,
paronychia. Recommendations for other skin complaints can be assessed
at the ESMO OncologyPRO portal, including the medical education
programmes Management of Skin Toxicities from EGFR Inhibitor
Therapies and Dermatological Side Effects of Multikinase Inhibitors.
Preventive measures
Prophylactic measures, early detection, and early intervention are of
the utmost importance for skin complaints of targeted therapy. The pri-
mary objectives of adverse event management strategies are: to avoid
interference in the patient’s daily living activities; to maintain or restore
patient comfort and QoL; and to maintain therapy for as long as possible.
Patients should be educated on the most widely accepted best practices
for managing adverse events.
Ideally, all patients should be informed at initiation of their therapy about
the measures they should take to keep their skin in a healthy condition.
Targeted agents dry the skin, therefore use of a fatty cream is recom-
mended to provide oil and maintain hydration of the skin. However, pet-
rolatum (petroleum jelly) is too fatty and can clog the sebaceous glands.
A cream consisting of the correct ratio of water and oil should be used.
The different topical products for the skin, depending on their composi-
tion, are divided into petrolatum, ointment, body butter, balm, cream,
lotion, and gel; petrolatum is the most oily, and gel the most watery, of
these products. In general, products with a higher water content are eas-
ier to spread and better penetrate the skin. Petrolatum should be applied
only to areas with few sebaceous glands, such as fissures on the hands/
fingers and feet/heels.
In addition, patients should also be instructed about moisturising recom-
mendations. A liberal amount of moisturising cream to at least the face,
chest, hands, and feet should be applied regularly throughout the day and
generously at bedtime. Thick emollient creams should be applied gently
and immediately after washing.
Furthermore, infections may develop at a later stage due to skin or
mucosal injury, and special attention is required to avoid or decrease

the risk of infection. In case of an infection, sterile swabs with cotton or
rayon tips are most commonly used for obtaining a culture. If the wound
is moist, a dry swab may be used straight from the packaging. If the
wound is dry, then the swab tip should be moistened with sterile saline to
increase the chance of disinfecting the site.
Patients should be monitored in treatment cycles 1 and 2 actively every
week. From cycle 3 onwards, actively monitor every cycle or every
4 weeks, depending on the treatment schedule. Treating symptoms early
may prevent them from becoming worse. Consider dose modifications
for non-life-threatening adverse events only after management failure
and after consulting with the patient. Avoid two dose modifications for
one non-life-threatening adverse event! In many cases, a single dose
reduction or a dose delay will be sufficient; therefore, it is essential that
the adverse event is treated.
Paronychia
Paronychia, an infectious process in the tissues adjacent to a nail on
a finger or toe, has been reported with EGFR (epidermal growth
factor receptor) and mTOR (mammalian target of rapamycin) inhibitors.
Paronychia affects the area around the fingernail or toenail, and occurs in
the toes more often than in the fingers. It is unknown why some fingers
are affected by targeted therapy and others are not. Paronychia presents
as erythema and oedema of the nail bed and folds, sometimes accom-
panied by a warm feeling of the skin. The infected nail fold may be
swollen, inflamed, and tender. As paronychia can be painful, even sim-
ple manual work may be difficult. Pain can also impede the wearing of
shoes and normal ambulation. In some cases, only sandals can be worn.
The lesions may also bleed easily upon exposure to trauma or ill-fitting
shoes. In addition, paronychia can worsen in colder seasons.
The onset of paronychia is generally after one to two months of treat-
ment with the targeted agent. In addition, patients who have had previous
nail toxicity due to cytotoxic chemotherapy may be at increased risk.
Paronychia may also progress to painful, lateral nail fold pyogenic gran-
uloma-like lesions. Pyogenic granuloma is a vascular lesion that may
occur on both mucosa and skin, and appears as an overgrowth of tissue.
Clinical signs and symptoms
Assessment of nail beds of the hands and feet should be part of the full
body skin exam at baseline, and at every visit. Crusted lesions with
inflammation of the nail fold usually appear as a first sign of paronychia.
Paronychia, including pyogenic granuloma, is associated with both sub-
jective and objective components: burning sensation, skin pain, skin ten-
derness, crust formation, cuticle disruption, nail fold oedema, nail plate
separation or discharge (onycholysis), periungual abscesses, pyogenic
granuloma, erythema, and elevated skin temperature.
Management
If paronychia occurs, treatment is started with the goal of decreasing inflam-
mation, reducing the extent of granulation tissue, and preventing superin-
fection. With mild paronychia, topical treatment of the affected fingers or
toes will be sufficient. In more severe cases, treatment involves a combined
approach, with topical management and systemic antimicrobials.
The patient should continue the use of antiseptic soaks 2–3 times a day
for 15–20 minutes each time (1:1 vinegar in warm water, diluted bleach
[0.005%], povidone-iodine 1:10, potassium permanganate 1:10 000). In
addition, povidone-iodine-based ointments and oral antibiotics (tetracy-
clines if not superinfected, otherwise consider oral quinolones) for 7 to
14 days may be prescribed. In resistant infections, a specimen for culture
of the infected area should be taken to determine antibiotic sensitivity
and resistance. The antibiotic may be adjusted according to the result
of the culture (antibiogram). In case of an infection caused by yeast or
fungus (Candida), antifungals may be prescribed. Ultrapotent topical
corticosteroids may be applied to reduce inflammation.
Painful paronychia may be treated with topical anaesthetics such as lido-
caine HCl gel 4%. If topical anaesthetics are insufficient, oral analgesics
such as acetaminophen/paracetamol or a non-steroidal anti-inflamma-
tory drug (NSAID) may be prescribed.
Pyogenic granuloma can be treated by electro- or chemical cautery with
liquid nitrogen, silver nitrate, or trichloroacetic acid. Silver nitrate appli-
cators should be used once or twice a week. Surgical nail removal is

generally contraindicated, since the skin overgrowth can be managed
with cauterisation. Although the level of evidence is weak for partial
or full nail avulsion, it may be recommended in extreme cases, if other
treatments fail.
Dr Lalla has received research funding from BioAlliance Pharma and
has served as a Consultant for Sucampo AG, iNova Pharmaceuticals,
Fera Pharmaceuticals, and Phillips Gilmore Oncology Communications.
Ms Boers-Doets has received honoraria from or been a consultant or
speaker with Amgen, AstraZeneca, Bayer Pharmaceuticals, Boehringer
Ingelheim, Eusa Pharma, GlaxoSmithKline, Merck Serono, Merck
Sharp & Dohme, Nordic Pharma, Takeda, Novartis, Pfizer, and Roche.
Further Reading
Mucositis
Al-Dasooqi N, Sonis ST, Bowen JM, et al; Mucositis Study Group of the Mul-
tinational Association of Supportive Care in Cancer/International Society of
Oral Oncology (MASCC/ISOO). Emerging evidence on the pathobiology of
mucositis. Support Care Cancer 2013; 21:3233–3241.
Gibson RJ, Keefe DMK, Lalla RV, et al; Mucositis Study Group of the Multina-
tional Association of Supportive Care in Cancer/International Society of Oral
Oncology (MASCC/ISOO). Systematic review of agents for the management
of gastrointestinal mucositis in cancer patients. Support Care Cancer 2013;
21:313–326.
Jensen SB, Jarvis V, Zadik Y, et al; Mucositis Study Group of the Multinational
Association of Supportive Care in Cancer/International Society of Oral
Oncology (MASCC/ISOO). Systematic review of miscellaneous agents for
the management of oral mucositis in cancer patients. Support Care Cancer
2013; 21:3223–3232.
Lalla RV, Bowen J, Barasch A, et al; Mucositis Guidelines Leadership Group of
the Multinational Association of Supportive Care in Cancer and International
Society of Oral Oncology (MASCC/ISOO). MASCC/ISOO clinical practice
guidelines for the management of mucositis secondary to cancer therapy.
Cancer 2014; 120:1453–1461.
McGuire DB, Fulton JS, Park J, et al; Mucositis Study Group of the Multina-
tional Association of Supportive Care in Cancer/International Society of
Oral Oncology (MASCC/ISOO). Systematic review of basic oral care for
the management of oral mucositis in cancer patients. Support Care Cancer
2013; 21:3165–3177.
Migliorati C, Hewson I, Lalla RV, et al; Mucositis Study Group of the Multi-
national Association of Supportive Care in Cancer/International Society of
Oral Oncology (MASCC/ISOO). Systematic review of laser and other light
therapy for the management of oral mucositis in cancer patients. Support
Care Cancer 2013; 21:333–341.
Nicolatou-Galitis O, Sarri T, Bowen J, et al; Mucositis Study Group of the Mul-
tinational Association of Supportive Care in Cancer/International Society of
Oral Oncology (MASCC/ISOO). Systematic review of anti-inflammatory
agents for the management of oral mucositis in cancer patients. Support Care
Cancer 2013; 21:3179–3189.
Peterson DE, Bensadoun RJ, Roila F; ESMO Guidelines Working Group. Man-
agement of oral and gastrointestinal mucositis: ESMO Clinical Practice
Guidelines. Ann Oncol 2011; 22(Suppl 6):vi78–vi84.
Peterson DE, Ohrn K, Bowen J, et al; Mucositis Study Group of the Multinational
Association of Supportive Care in Cancer/International Society of Oral Oncology
(MASCC/ISOO). Systematic review of oral cryotherapy for the management of
oral mucositis caused by cancer therapy. Support Care Cancer 2013; 21:327–332.
Raber-Durlacher JE, von Bültingslowen I, Logan RM, et al; Mucositis Study
Group of the Multinational Association of Supportive Care in Cancer/Inter-
national Society of Oral Oncology (MASCC/ISOO). Systematic review of
cytokines and growth factors for the management of oral mucositis in cancer
patients. Support Care Cancer 2013; 21:343–355.
Saunders DP, Epstein JB, Elad S, et al; Mucositis Study Group of the Multi-
national Association of Supportive Care in Cancer/International Society
of Oral Oncology (MASCC/ISOO). Systematic review of antimicrobials,
mucosal coating agents, anesthetics, and analgesics for the management of
oral mucositis in cancer patients. Support Care Cancer 2013; 21:3191–3207.
Yarom N, Ariyawardana A, Hovan A, et al. Systematic review of natural agents
for the management of oral mucositis in cancer patients. Support Care Can-
cer 2013; 21:3209–3221.
Skin complaints
Boers-Doets CB. The Target System – Approach to assessment, grading, and
management of dermatological & mucosal side effects of targeted anticancer
therapies (Edn 1). Wormer: IMPAQTT, 2014.
Dermatological Side Effects of Multikinase Inhibitors – Medical Education Pro-
gramme. European Society for Medical Oncology, 2014. Available at: http://

oncologypro.esmo.org/Guidelines-Practice.
Eaby B, Culkin A, Lacouture ME. An interdisciplinary consensus on manag-
ing skin reactions associated with human epidermal growth factor receptor
inhibitors. Clin J Oncol Nurs 2008; 12:283–290.
Eames T, Grabein B, Kroth J, Wollenberg A. Microbiological analysis of epi-
dermal growth factor receptor inhibitor therapy-associated paronychia. J Eur
Acad Dermatol Venereol 2010; 24:958–960.
Edmonds K, Hull D, Spencer-Shaw A, et al. Strategies for assessing and manag-
ing the adverse events of sorafenib and other targeted therapies in the treat-
ment of renal cell and hepatocellular carcinoma: recommendations from a
European nursing task group. Eur J Oncol Nurs 2012; 16:172–184.
Lacouture ME, Basti S, Patel J, et al. The SERIES clinic: an interdisciplinary
approach to the management of toxicities of EGFR inhibitors. J Support
Oncol 2006; 4:236–238.
Lacouture ME, Maitland ML, Segaert S, et al. A proposed EGFR inhibitor der-
matologic adverse event-specific grading scale from the MASCC skin toxic-
ity study group. Support Care Cancer 2010; 18:509–522.
Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management
of hand-foot skin reaction associated with the multitargeted kinase inhibitors
sorafenib and sunitinib. Oncologist 2008; 13:1001–1011.
Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev
Cancer 2006; 6:803–812.
Management of Skin Toxicities from EGFR Inhibitor Therapies – Medical Educa-
tion Programme. European Society for Medical Oncology, 2009. Available at:
http://oncologypro.esmo.org/Guidelines-Practice/EGFRI-Related-Skin-Toxicity.
Segaert S, Van CE. Clinical management of EGFRI dermatologic toxicities: the
European perspective. Oncology (Williston Park) 2007; 21(11 Suppl 5):22–26.
Shu KY, Kindler HL, Medenica M, Lacouture M. Doxycycline for the treatment
of paronychia induced by the epidermal growth factor receptor inhibitor
cetuximab. Br J Dermatol 2006; 154:191–192.
Gastrointestinal Sequelae
C. Donnellan
6
Department of Gastroenterology,
Leeds Teaching Hospitals NHS Trust, Leeds, UK
L. Smith
Macmillan Cancer Support, London, UK
J. Maher
Macmillan Cancer Support, London, UK
Introduction
Gastrointestinal (GI) problems such as nausea, vomiting, diarrhoea, and
constipation are very common during and immediately after systemic
cancer treatments. The (often prophylactic) management of these is usu-
ally the responsibility of the medical oncology team. Sometimes, patients
present as emergencies and may be initially managed by hospital Emer-
gency Departments or an acute/emergency oncology service. Guidelines
and protocols for acute GI problems have been produced by organisa-
tions such as ESMO and the National Comprehensive Cancer Network.
Oncologists are therefore familiar with managing these acute issues, and
so we have not covered them in depth in this chapter. However, can-
cer care and primary care professionals tend to be much less familiar
with long-term or late-onset GI effects of treatments, especially where
systemic therapies have been used in conjunction with surgery and/or
radiotherapy for cancers of the upper and lower GI tract and the pelvic
area. Despite the potential for very serious adverse effects on patients’
quality of life, this continues to be an under-recognised area of cancer
rehabilitation and follow-up. This chapter therefore focuses on the key
management strategies for chronic problems.
66
Potential GI Side Effects
Table 1 shows the range of potential GI side effects that may arise
acutely, subacutely, or chronically after cancer treatment.
Table 1 Presentation of Gastrointestinal Side Effects: Acute, Subacute Or Chronic.
Republished with permission of BMJ Publishing Group Ltd, from Andreyev HJN, et
al. Practice guidance on the management of acute and chronic gastrointestinal
problems arising as a result of treatment for cancer. Gut 2012; 61:179–192;
permission conveyed through Copyright Clearance Center, Inc.
Aetiology Acute Subacute Chronic
Infection Bacterial Small intestinal bacterial SIBO
Viral overgrowth (SIBO)
Fungal
Opportunistic
Inflammation (acute) Neutropenic enterocolitis Graft versus host Graft versus host disease
Perforation disease
Haemorrhage
Graft versus host disease
Pancreatic insufficiency
Ischaemic/fibrotic Gastric outflow Graft versus host Biliary strictures
obstruction disease Bowel obstruction
Pancreatic insufficiency Enteropathy and loss of
physiological functions
Graft versus host disease
Pancreatic insufficiency
Metabolic Malabsorption Malabsorption Malabsorption
Hepatic insufficiency
Vascular (ischaemia) Mesenteric vascular Enteropathy and loss of
insufficiency physiological function
Mesenteric thrombosis
Veno-occlusive disease
Vascular (proliferative) Telangiectasia causing bleeding
Effect on Patients
The many side effects listed in Table 1 produce unpleasant and disabling
symptoms that can be highly disruptive to a person’s daily life. Deal-
ing with the physical effects of GI dysfunction causes many difficulties,
such as problems with eating/nutrition, requiring use of faecal incon-
tinence products, coping with severe pain, washing of soiled clothing
and bedding, or needing frequent or lengthy visits to the toilet. The psy-
chological and social impact of having to cope with very unpredictable
Gastrointestinal Sequelae 67
and embarrassing symptoms can be severe, to the extent that people
become “prisoners in their own homes” and feel unable to work, go on
holiday, or enjoy a normal social life. The effect on partners, family, and
friends should not be under-estimated, as they too may have to share in
the restrictions to daily life and any financial hardship, while trying to
support the patient when professional help is unavailable.
Testimonies from people affected by chronic GI problems reveal the
extent of issues that may occur; however, research indicates that many
people are unwilling to tell their oncology team about issues that they
find embarrassing to talk about, think nothing can be done about them, or
think that the doctor is interested only in their cancer cure. The onus is,
therefore, on cancer care professionals to ensure that patients and carers
are aware and informed about the potential GI side effects of treatments,
and that they know who to contact should these problems arise. More
importantly, patients should be questioned regularly about GI problems,
so that early interventions can be initiated. Simple questions such as:
“Do you have any gastrointestinal symptoms that prevent you from
living a full life?” can help to overcome patients’ embarrassment and
reluctance to mention distressing symptoms.
Pathophysiology
Systemic therapies such as cytotoxic chemotherapy, hormonal therapy,
and biological agents directly affect the GI tract. Inflammation, oedema,
atrophy, and ulceration are common acute side effects of treatment
which can cause considerable pain and discomfort for patients. Immu-
nosuppression plus increased bowel permeability increases the risk of
septicaemia. Alterations to the bacterial flora in the gut may result in
small intestinal bacterial overgrowth (SIBO). Some agents may cause
the reactivation of hepatitis B infection. Bile acid malabsorption, pancre-
atic insufficiency, steatosis, and severe sinusoidal obstruction syndrome
are also potential acute side effects of treatment.
Increasingly, cancer treatment involves the combination of one or more sys-
temic therapies with surgery and/or radiotherapy. Both surgery and radio-
therapy are also well-known causes of immediate and long-term effects
68 Donnellan et al.
on GI function, and treatment combinations are constantly evolving. The
stem cell transplant treatment regimen may result in graft versus host dis-
ease (GVHD), which can also adversely affect the GI tract. Pre-existing
non-malignant GI diseases may also be exacerbated by cancer treatment,
or revealed during the cancer diagnostic testing process. In these circum-
stances, it is difficult to ascribe a patient’s GI problems to one form of treat-
ment or another. Therefore, every member of the cancer multidisciplinary
team should have responsibility for recognising and managing treatment-
induced GI problems that are probably multifactorial. A key element is
having access to expert advice from a gastroenterology team.
Prevention and Self-management of GI Problems

GI problems during and after cancer treatment may be minimised by
ensuring that patients and their carers fully understand the effect on the
GI function, how to manage minor symptoms themselves, and when and
where to seek help. A personalised approach to information provision
is recommended, so that patients and carers are offered and are able to
repeatedly access high-quality advice and support in a format that they
find useful and relevant. This should be offered at several time points
before, during, and after treatment.
The importance of taking appropriate precautions against GI infections
when immunosuppressed and of seeking urgent medical help for red flag
symptoms should be stressed clearly for patients. At the end of treatment
and during follow-up, the risk of long-term effects must be highlighted,
to allow appropriate referral for patients who develop late-onset symp-
toms even after discharge from oncology services. For some, patient
support groups are highly beneficial, especially for those with chronic
problems, where tips for coping with problems can be shared.
With the right advice and support, patients can often self-manage certain
long-term problems with techniques such as:
n Dietary changes, such as low-fat diet, low-fibre diet, lactose-free diet

n Pelvic floor exercises

n Biofeedback methods

However, a chronic symptom (such as diarrhoea) may be the result
of several different diagnoses, and it is important that all causes are
investigated (see the section on Chronic GI Side Effects).
Clinician-led Management of Acute GI Side Effects

Acute GI side effects can rapidly lead to life-threatening situations. The
urgent management of neutropenic sepsis, enterocolitis, haemorrhage,
perforation, ischaemia, infarction, thrombosis, sinusoidal obstruction
syndrome, vomiting, and bowel obstruction are covered in a number of
publications (see Further Reading).
Where gastroenterologists (i.e. non-cancer specialists) are involved in
the management of urgent cases, it is important that they are aware of
the cancer treatment regimen, as the bioavailability of targeted cancer
therapies may be altered by GI treatments.
Key facts for gastroenterological management of acute GI syndromes
during and after cancer treatments are:
n Urgent cross-sectional imaging may help assessment and management

n Perform early upper GI endoscopy and duodenal biopsies and duodenal

aspirate and lower GI endoscopy with biopsies for diarrhoea

n Flexible sigmoidoscopy rather than colonoscopy is usually adequate

initially
n Always consider taking biopsies and asking for histological evidence

of viral infection, especially if multiple ulcers are seen, even if there

has been bleeding
n Ensure platelet support is available before endoscopic intervention

when the platelet count is below 80 × 109

n Avoid biopsies from an area of obvious radiation-induced change

unless absolutely necessary

n Colonoscopy is contraindicated in neutropenic enterocolitis

n Infections in the neutropenic patient can kill quickly; early empirical

treatment may be required

n Seek specialist help early

70 Donnellan et al.
Clinician-led Management of Chronic GI Side Effects
Cytotoxic chemotherapy, biological agents, and hormonal therapy used
alone may affect the GI tract long term, but this has not been well stud-
ied. Some of these patients may have problems which continue long after
systemic treatment, or are late-onset or are as a result of hormonal ther-
apy – constipation, diarrhoea, pain, flatulence, and bloating have been
reported. It is likely that SIBO is the primary cause, which can be treated
with antibiotics (see below).
If radiotherapy (to the pelvic area or upper GI area) and/or surgery (to the
upper/lower GI tract) is used in conjunction with chemotherapy, then the
complex interactions of these interventions on the GI tract can often be very
disruptive to normal physiology. While most patients will not experience
long-term problems, a significant number have their quality of life affected
by chronic symptoms (Table 2), and close monitoring will be needed.
There has been a commonly held but erroneous view that nothing can be
done for patients with chronic GI problems, and, as a result, oncologists
rarely make referrals to gastroenterology. Evidence is now available that
patient outcomes can be improved by having a referral route from oncol-
ogy to a gastroenterologist who uses a systematic approach to diagnos-
ing and treating post-cancer bowel dysfunction.
Each symptom has a number of potential diagnoses. For example, chronic
diarrhoea may have several different causes (see Table 3). Chronic dys-
phagia, retching, and nausea can also have multiple causes, including
stricture, inflammation, infection, or abnormalities in the motility of the
upper GI tract.
A systematic approach to identifying each symptom and then conducting
the appropriate battery of tests in order to make accurate GI diagnoses
has proved to be clinically effective in the ORBIT trial. This approach
has several advantages – firstly, it highlights that significant GI problems
can be adequately treated; secondly, it is a reminder that several different
conditions may need to be treated before symptoms resolve themselves;
and thirdly, it supports the premise that most patients can be managed by
a suitably trained and supported nurse.
Table 2 Chronic Gastrointestinal (GI) Problems After Cancer Treatment for
Different Tumour Sites. Republished with permission of BMJ Publishing Group Ltd,
from Andreyev HJN, et al. Practice guidance on the management of acute and
chronic gastrointestinal problems arising as a result of treatment for cancer. Gut
2012; 61:179–192; permission conveyed through Copyright Clearance Center, Inc.
Tumour site Treatment Types of chronic GI Percentage affected
modalities symptoms by chronic symptoms
affecting quality of life
Oesophago-gastric Chemotherapy Anorexia, diarrhoea, nausea, 50% (?)
Radiotherapy reflux, weight loss
Surgery
Pancreas Chemotherapy Malabsorption, weight loss, wind n/a
Radiotherapy
Surgery
Colorectal Chemotherapy Bleeding, diarrhoea, frequency, Chemoradiation ± surgery: 50%
Radiotherapy incontinence, tenesmus, urgency Short course radiotherapy: 66%
Surgery Colonic surgery: 15%
Rectal surgery: 33%
Anal Chemoradiation Bleeding, frequency, incontinence, n/a
(Surgery) urgency
Gynaecological Radiotherapy Bleeding, diarrhoea, flatulence, 40% after treatment which
Surgery frequency, incontinence, includes radiotherapy
± malabsorption, pain, urgency
Chemotherapy
Head and neck Chemoradiation Dysgeusia, dysphagia, Up to 50%
(Surgery) dependency on tube feeding,
pain, trismus, weight loss,
xerostomia
Urological Chemotherapy Bleeding, constipation, 30% after radiotherapy
Radiotherapy diarrhoea, flatulence, frequency,
Surgery incontinence, malabsorption,
pain, urgency
The first step is to take an accurate history of cancer treatments and to

understand the full range of symptoms (not just GI) that the patient is
experiencing through the use of standardised, holistic needs assessment.
The patient’s diet and bowel habits should also be fully elucidated by
using bowel and food diaries for at least a week. This may help to iden-
tify any food triggers for certain symptoms, or whether there is excessive
intake of nutritional supplements, fibre, fat, or alcohol.
72 Donnellan et al.
Table 3 Common Causes and Investigations for Chronic Diarrhoea after Cancer
Treatment.
Condition Investigation
New/recurrent neoplasia CT scan ± colonoscopy
New inflammatory bowel disease Colonoscopy ± small bowel imaging
Stricture formation CT scan
Bile acid malabsorption SeHCAT scan
Small intestinal bacterial overgrowth Breath test or aspirate and culture from small bowel
New coeliac disease Tissue transglutaminase (tTG) and duodenal biopsy
Irritable bowel syndrome History ± investigations to exclude organic pathology if symptoms severe
Pancreatic insufficiency Faecal elastase
Constipation with overflow History
Dietary/alcohol problems History
Drug side effects History
Endocrine abnormalities Thyroid function tests
Carbohydrate malabsorption Dietary history and trial of low carbohydrate diet
Short bowel syndrome History, imaging to determine length of small bowel, urinary sodium to
determine if dehydrated/Na deficient (if <20 mmol/l)
For each symptom, a range of investigations will be required. Space

does not permit the full description of the National Cancer Survivorship
Initiative (NCSI) algorithm, which is currently under review. The current
version is available at www.ncsi.org.uk (see Further Reading).
Basic investigations such as haematological and biochemical profiles and
inflammatory and tumour markers should be carried out. Vitamin B12 lev-
els, thyroid function test, coeliac screen, selenium homocholic acid taurine
(SeHCAT) scan, and upper/lower endoscopy (as appropriate) are useful.
Treatments will vary according to the abnormalities found, which may
be multiple. These may include:
n Loperamide for rapid transit

n Cholestyramine or colesevelam for bile salt malabsorption

n Antibiotics for SIBO (such as metronidazole, tetracyclines, quinolo-

nes, and rifaximin), although most data supporting these are from
small, open-label trials
Specialist dietetic support is an important component of managing
patients who may have poor or imbalanced nutritional intake, as well as
providing support for weight loss or weight gain, both of which are com-
mon after cancer treatment. They will also advise on time-limited trials
of specific diets, such as those low in carbohydrates (for carbohydrate
malabsorption), low in lactose (if lactose intolerance), or low FODMAP
(fermentable oligonucleotides, disaccharides, monosaccharides, and pol-
yols, for irritable bowel syndrome).
A helpful series of cases studies are described by Muls et al (2013).
Psychological counselling may be needed; for example, where severe
GI problems have been the cause of breakdown of relationships, loss of
confidence, anxiety, or depression.
Specialist care of people with GI problems due to GVHD should follow
appropriate guidance, such as the British Committee for Standards in
Haematology guidelines.
Conclusion
There is a growing body of evidence that a significant number of people
experience poor quality of life for years after cancer treatment, due to
unresolved GI problems such as diarrhoea, faecal incontinence, bleed-
ing, and pain. Oncology teams and primary care physicians have a
responsibility to ensure that potential side effects are regularly discussed
with patients, and that diagnosis and treatment of symptoms are a routine
part of the post-treatment follow-up of all cancer patients. Patients can be
encouraged to self-manage certain symptoms with dietary changes and
exercises. However, a clear referral route to gastroenterology is essential
to ensure that chronic problems are accurately diagnosed with a sys-
tematic, algorithmic method. Patients who are successfully treated often
report that they have “got their life back”.
Acknowledgements
With grateful thanks for Dr Jervoise Andreyev, Royal Marsden Hospital
NHS Foundation Trust, London, UK, for advice on the manuscript.
74 Donnellan et al.
Dr Donnellan has received educational grants from Sanofi and Merck
Sharp & Dohme.
Dr Smith has reported no conflicts of interest.
Professor Maher has reported no conflicts of interest.
Further Reading
Andreyev HJ. A physiological approach to modernize the management of cancer
chemotherapy-induced gastrointestinal toxicity. Curr Opin Support Palliat
Care 2010; 4:19–25.
Andreyev HJN, Benton BE, Lalji A, et al. Algorithm-based management of
patients with gastrointestinal symptoms in patients after pelvic radiation treat-
ment (ORBIT): a randomised controlled trial. Lancet 2013; 382:2084–2092.
Andreyev HJN, Davidson SE, Gillespie C, et al. Practice guidance on the man-
agement of acute and chronic gastrointestinal problems arising as a result of
treatment for cancer. Gut 2012; 61:179–192.
Bohm M, Siwiec RM, Wo JM. Diagnosis and management of small intestinal
bacterial overgrowth. Nutr Clin Pract 2013; 28:289–299.
Dignan F, Clark A, Amrolia P, et al; on behalf of the Haemato-oncology Task
Force of the British Committee for Standards in Haematology and the Brit-
ish Society for Blood and Marrow Transplantation. Guideline: Diagnosis
and Management of Chronic Graft-versus-Host Disease; 2012. Available at:
http://www.bcshguidelines.com/documents/bjh_9129_Rev_EV.pdf.
Henson CC, Davidson SE, Ang Y, et al. Structured gastroenterological inter-
vention and improved outcome for patients with chronic gastrointestinal
symptoms following pelvic radiotherapy. Support Care Cancer 2013;
21:2255–2265.
Kosmidis PA, Schrijvers D, Andre F, et al. ESMO Handbook of Oncological
Emergencies. Abingdon: Taylor and Francis, 2005.
Muls AC, Watson L, Shaw C, et al. Managing gastrointestinal symptoms after
cancer treatment: a practical approach for gastroenterologists. Frontline Gas-
troenterol 2013; 4:57–68.
National Comprehensive Cancer Network. Guideline on Antiemesis. Version 1;
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antiemesis.pdf.
Pelvic Radiation Disease Association website: http://www.prda.org.uk/
patient-stories.
Royal Marsden Guide (Algorithm) To Managing Pelvic Radiation Disease
(PRD). July 2013 (under peer review). Previous draft (version 7) available at:
www.ncsi.org.uk/wp-content/uploads/RMH-Bowel-Algorithm-v7-2011.pdf.
Vicary P, Johnson M, Maher J, on behalf of patient representatives of the Mac-
millan Late Effects Project Group. To my oncologist – an open letter from a
patient at the end of follow-up. Clin Oncol 2007; 19:746-747.
76 Donnellan et al.
Urological Complications
J. J. Wyndaele
7
University of Antwerp and Department of Urology,
S. De Wachter
University of Antwerp and Department of Urology,
G. De Win
Department of Urology, Antwerp University Hospital, Antwerp, Belgium
Introduction
To put the risk, incidence, diagnosis, and treatment of urological seque-
lae of oncological and urological oncological treatment in one frame is
not easy. There are differences in tumour grade and type, differences in
patient age and general condition, and differences in treatment modali-
ties and application techniques to be considered. Finally, the clinical his-
tory of the individual patient will determine which complications exist
and how they should preferably be managed.
Radiotherapy
Radiation Cystitis
A number of patients treated with radiotherapy in the pelvic region
develop lower urinary tract (LUT) symptoms. Radiotherapy is more
likely to cause radiation cystitis in patients being treated for prostate
cancer than for bladder cancer. After external beam therapy (70–78 Gy),
up to 9% develop radiation-induced cystitis with recurrent haematuria.
Zelefsky et al (1999) described acute grade 2 problems in 28% and grade
3 in 1/772. In terms of late complications, 9% grade 2 and 0.5% grade
77
3 problems were found using the Radiation Therapy Oncology Group
(RTOG) criteria (Table 1).
Table 1 Acute and Chronic Toxicity Grading of Radiation Therapy on the Lower
Urinary Tract of the Radiation Therapy Oncology Group (RTOG) and the European
Organisation for Research and Treatment of Cancer (EORTC)
Grade 1 2 3 4
Acute Frequency of Frequency of urination Frequency with urgency Haematuria requiring
urination or or nocturia that is less and nocturia hourly or transfusion / acute
nocturia twice pre- frequent than every more frequently / dysuria, bladder obstruction
treatment habit / hour. Dysuria, urgency, pelvis pain or bladder spasm not secondary
dysuria, urgency bladder spasm requiring requiring regular, frequent to clot passage,
not requiring local anaesthetic (e.g. narcotic / gross haematuria ulceration or
medication Pyridium) with/without clot passage necrosis
Chronic Slight epithelial Moderate frequency; Severe frequency and dysuria; Necrosis / contracted
atrophy; minor generalised severe telangiectasia (often bladder (capacity
telangiectasia telangiectasia; with petechiae); frequent <100 cc); severe
(microscopic intermittent haematuria; reduction in haemorrhagic cystitis
haematuria) macroscopic haematuria bladder capacity (<150 cc)
The acute reaction is an inflammatory response, with tissue oedema and

hyperaemia occurring within 4–6 weeks. In the second phase, necrosis
of the vascular endothelium and perivascular fibrosis may appear. The
obliterating endarteritis increases bleeding tendency and makes the blad-
der wall more sensitive to infection, which could result in fistula forma-
tion.
With recurrent and progressive ischaemia, the bladder wall develops
fibrosis and shrinks. This process may develop 10 or more years after
the radiation therapy.
Signs and symptoms

Radiation cystitis can cause symptoms of dysuria, urgency, urinary fre-
quency, nocturia, haematuria/haemorrhage, recurrent infections, and
pain. In the case of fistula formation, urinary leakage and pneumaturia
can appear. Urethral stricture has been described and can worsen the
symptoms.
Diagnosis is based on history, cystoscopy, and imaging. Quality of life
78 Wyndaele et al.
can be measured with the Expanded Prostate Cancer Index Composite
(EPIC) questionnaire.
Treatment
Haematuria can be treated with increased diuresis and/or bladder irriga-
tion. The first step in treatment should be clot evacuation, which can be
carried out by placing a two- or three-way wide-lumen bladder catheter
and irrigating with water or sodium chloride solution.
Cystoscopy with eventual coagulation of the bladder wall is indicated in
persistent haematuria, with bladder tamponade, or to confirm the cause
of bleeding.
Oral antifibrinolytic therapy should be continued for several weeks,
especially with persistent bleeding after endoscopic haemostasis.
Intravesical therapy:
n Aminocaproic acid 0.02% solution as a continuous bladder irrigation
over a number of days

n Instillation with guanylhydrazone (GAG) products such as chondroi-

tin sulphate or hyaluronic acid to restore the GAG protection layer on

the bladder wall gives results comparable with those of hyperbaric
oxygen
n Potassium aluminium sulphate (ALUM) 1% solution irrigation at

100–600 ml/h. Be prepared for toxic reactions

n Formalin 1% solution under anaesthesia for 10 min. Note: there are

many side effects and vesicoureteral reflux must be ruled out before
application
n Silver nitrate 0.25–1% solution as an alternative to formalin
Hyperbaric oxygen therapy. There is no generally accepted treatment
regimen (examples from the literature: 10–74 treatments, 1.4–3 atm of
oxygen, 75–130 min duration). There are few side effects, but long-term
response rates differ in the literature: 30–74%, 80%, and 96%.
Urological Complications 79
Salvage cystectomy. This is to be performed in very resistant cases only.
The complication rate is high.
Sexual Problems
Erection
Erectile problems and other sexual dysfunctions can be a complication
of radiation therapy. The onset is usually slow. In recent studies sexual
dysfunction was reported by 35.9% and 43% at presentation. Radiother-
apy adversely affected all aspects of sexual function. This is caused by
interference with the blood supply and the nerves of the penis.
Treatment starts with phosphodiesterase-5 (PDE5) inhibitors, first as
monotherapy, followed, if needed, by combination therapy with intra-
corporeal injection of vasoactive drugs. Eventually, vacuum devices and
surgery can be used. Comorbidities, such as cardiovascular disease and
diabetes, should be taken into consideration. Positive results have been
described in 66–77% of cases.
Fertility problems
These are discussed separately in the chemotherapy section.
Urinary Incontinence
At 15 years follow-up, urinary leakage rates appear comparable for radio-
therapy and radical prostatectomy. Urinary frequency with episodes of leak-
age is most often seen. Decreased capacity of the bladder and bladder over-
activity (OAB) can be present. Stress incontinence can be the consequence
of radiotherapy after surgery in up to 12% of cases. Transurethral resection
of the prostate (TURP) after radiotherapy is also a risk factor for inconti-
nence. Urodynamic investigation can help refine the causal diagnosis.
Initial therapy encompasses pelvic floor exercises, biofeedback, and elec-
trical stimulation. Behavioural modification with adaptation of drinking
habits, voiding frequency, optimal weight, and medication changes related
to incontinence are important. Bladder-relaxing drugs can be prescribed
to treat OAB and urinary urgency/leakage. Surgery (artificial sphincter,
80 Wyndaele et al.
bladder augmentation, bulbourethral sling) or injection of bulking agents
can be used, but carry a higher risk for complications after radiotherapy.
Condom catheter drainage or diaper use can limit the negative social
effects of incontinence.
Brachytherapy
Brachytherapy is used as a stand-alone treatment or in combination with
external beam radiotherapy. Urological complications occur in approxi-
mately 2% of patients.
Acute complications include urinary retention, necessitating in-dwell-

ing catheterisation and sometimes transurethral resection. The latter
increases the risk of developing urinary incontinence. Acute irritative
urinary symptoms disappear during follow-up in most patients. In high-
dose rate (HDR) brachytherapy as monotherapy, acute grade 3 morbidity
has been low. Late toxicity has been described: dysuria in 10.3%, haema-
turia in 1.3%, and urinary retention in 9%, but no urinary incontinence.
Potency problems have been described in 14–66% of patients. Erectile
dysfunction was found in 31% of cases.
Long-term health-related quality of life (HRQoL) was not different after
brachytherapy, when compared with radical prostatectomy or external
beam radiation. The addition of external beam radiotherapy to HDR
brachytherapy does not seem to increase the risk for early and late grade
3 and 4 urological complications. Eight years after such treatment, erec-
tile dysfunction was seen in 42% of cases.
General Chemotherapy
Haemorrhagic Cystitis
This is caused by acrolein, a metabolite of the oxazaphosphorine-
alkylating agents cyclophosphamide and ifosfamide, which is excreted
by the kidneys and concentrated in the bladder. After a single applica-
tion, oedema and hyperaemia of the bladder urothelium can occur within
hours of administration, progressing to ulceration and rupture of blood
vessels. Haemorrhage can be very severe. With repeated treatments, the
bladder wall changes become irreversible and the bladder wall becomes
less elastic, less compliant, and with a small bladder capacity. Induction
of transitional cell carcinoma has been reported.
To prevent haemorrhagic cystitis, aggressive hydration and mesna,
which neutralises the toxicity of the cyclophosphamide metabolite acr-
olein, may reduce the risk. However, mesna is ineffective once haemor-
rhagic cystitis has developed.
Intravesical Chemotherapy
Intravesical thiotepa has resulted in leukopenia in 8% to 54%, throm-
bocytopenia in 3% to 31%, and irritative voiding symptoms in 12% to
69% of cases. Close monitoring of blood counts prior to weekly instil-
lations remains vital in preventing myelosuppressive complications. The
complications associated with mitomycin C are mainly chemical cystitis
and contact dermatitis. Additionally, allergic reactions have been docu-
mented. Most of these complications respond to cessation of therapy
with application of topical steroids as needed. Toxicities associated with
the use of doxorubicin, epirubicin, and ethoglucid are almost exclusively
local and usually described as mild to moderate dysuria, urinary fre-
quency, or urgency. Case reports of systemic reactions to doxorubicin
are notable in that patients responded well to diphenhydramine and, in
one severe case, epinephrine. Newer agents such as mitoxantrone are
undergoing evaluation studies. The ideal agent, which would be highly
effective and minimally toxic, is still to be developed.
Intravesical administration of Bacillus Calmette-Guerin (BCG), which
is used as adjunctive therapy for superficial bladder cancer, can result in
local and/or systemic infections, which require systemic therapy.
Chemotherapy-induced Renal Dysfunction

Nephrotoxicity is a known complication of several chemotherapeutic
agents. Well-known side effects are cisplatinum-induced renal insuffi-
ciency, haemolytic–uraemic syndrome, antidiuretic hormone secretion
problems, and more. Several treatments and trials for prevention have
been described.
82 Wyndaele et al.
Fertility
Alkylating drugs and radiotherapy can have cytotoxic effects on the tes-
ticular germ tissue, and can cause erectile dysfunction or disruption of
the hypothalamic–pituitary–gonadal axis. A recently updated guideline
published by the American Society of Clinical Oncology (ASCO) stated
that, as part of the process of education and informed consent that takes
place before cancer therapy, healthcare providers should address the
possibility of infertility with patients treated during their reproductive
years (or with parents or guardians of children), and be prepared to dis-
cuss fertility preservation options and/or to refer all potential patients to
appropriate reproductive specialists. Sperm banking and cryopreserva-
tion are helpful tools to assist fertility later on. In most cases, two semen
samples, produced through masturbation, are adequate. When infertility
becomes an issue, intracytoplasmic sperm injection (ICSI) can be com-
bined with in-vitro fertilisation (IVF) so that an individual sperm cell can
be directly injected into an oocyte.
Sperm banking should be performed before or in the early phase of treat-
ment to obtain the best results. A recent study has shown that, although
the initial chemotherapy was considered to be low risk for infertility,
prior to bone marrow transplantation, 39% of adolescent patients were
azoospermic and another 15% were oligospermic. With an increasing
percentage of paediatric oncology patients surviving their disease, the
impact of cancer and cancer therapies on future reproductive health has
become a major issue. For adolescents the issue of future reproduction is
complicated by the fact that parents are required to give consent to treat-
ments associated with fertility. For personal or cultural reasons, some
parents prefer not to discuss masturbation with their son or are more
concerned with the survival of their child than about their child’s future
fertility. These situations create ethical dilemmas.
In prepubescent boys before spermache, some new, promising therapies
are being developed. Testicular biopsies can be taken before the start
of therapy, and spermatogonial stem cells, the cells responsible for life-
long production of sperm cells, can be used for cryopreservation. It is
expected that for restoration of later fertility, these cells can be injected
or grafted back into the patient, although more studies are necessary to
validate this concept. However, all of these techniques are quite costly.
In addition, a recent survey showed that only 7% of cryopreserved sperm
is actually used for assisted reproduction. Associated with this superflu-
ous sperm is the ethical dilemma of sperm disposal. Fertility is an issue
that is increasingly being recognised as a concern in boys and sexually
active adults treated for cancer. However, there are solutions that warrant
discussion between doctor, patient, and parent.
Urological Sequelae of Oncological Surgery

The risk of developing genitourinary dysfunction is highest after pelvic
surgery. The autonomic plexus runs along the lateral sides of the rectum,
branching off in the endopelvic fascia, and innervating the detrusor mus-
cle and the bladder neck, alongside colon, rectum, prostate, vagina, and
uterus. The pudendal nerves, except for some intrapelvic branches, run
beneath the levator ani fascia. The location of these nerves in the opera-
tive area makes them susceptible to surgical damage and/or peripheral
neuropathies, which may lead to urinary retention, incontinence, erectile
and sexual dysfunction, and pelvic pain. Possible improvement during
the postoperative period will depend on the type of lesion: neuropraxia
from traction during surgery, or partial or complete denervation. Pelvic
nerve damage may result in decreased detrusor activity with incomplete
bladder emptying, need for Valsalva voiding, and even urinary retention.
Injury of the hypogastric sympathetic fibres may cause decreased blad-
der compliance, bladder hyperactivity (beta-adrenergic denervation),
or bladder neck incompetence (alpha-adrenergic denervation). In male
patients, ejaculatory and erectile dysfunction may occur. The incidence
of LUT dysfunction varies in the literature: from 8–70% after abdomi-
noperineal rectum resection, 16–80% post-hysterectomy, and 20–25%
after low anterior resection. Sexual dysfunction after rectal cancer sur-
gery occurs in 76% of males and 59% of females. Following radical
hysterectomy, decreased sexual satisfaction is reported due to decreased
sexual interest, decreased lubrication, and dyspareunia, whereas other
sexual and vaginal problems disappear over time.
A detailed preoperative urological history is mandatory, as pre-existing
voiding difficulties, incontinence, or pain may predispose the patient
84 Wyndaele et al.
to increased urinary problems postoperatively. Postsurgical monitoring
should address both current and pre-existing voiding complaints such
as poor stream, hesitancy, interrupted voiding, sensation of incomplete
bladder emptying, and signs of recurrent urinary tract infections, as well
as storage symptoms such as urinary frequency, urgency incontinence,
and pain. Cystometric evaluation allows for objective identification of
underlying functional pathology. Uroflowmetry is often not accurate
enough. More specialised tests such as pelvic floor needle electromyo-
graphy (EMG) and sacral latency testing can assist with evaluation of
the urethral sphincter and sacral reflex integrity, whereas electrical per-
ception threshold determination in the bladder and urethra can help to
identify peripheral neuropathy in the LUT. Although no clear guidelines
exist on the specific time points of evaluation, urodynamic evaluation of
symptomatic patients seems feasible after 4–6 weeks.
In case of incomplete bladder emptying or urinary retention, clean inter-
mittent catheterisation is the preferred treatment method, indefinitely or
until bladder contractility has improved. For storage symptoms due to
decreased bladder compliance or insufficiency of bladder neck and/or
urethral sphincter, medication (antimuscarinics, beta 3-adrenergic ago-
nists, alpha-blocking agents) should be considered first. Since the extent
of nerve damage during surgery is unknown and variable for different
patients, the timecourse and extent of recovery is often unpredictable.
This can make repeated evaluations useful over time. Treatment should
be conservative, waiting at least 6 months before any surgical procedure
is considered.
Dr Wyndaele has reported no conflicts of interest.
Dr De Wachter has reported no conflicts of interest.
Dr De Win has reported no conflicts of interest.
Further Reading
Lamm DL. Complications of bacillus Calmette-Guérin immunotherapy. Urol
Clin North Am 1992; 19:565–572.
Le Fur E, Malhaire JP, Nowak E, et al. Impact of experience and technical changes
on acute urinary and rectal morbidity in low-dose prostate brachytherapy
using loose seeds real-time implantation. Brachytherapy 2013; 12:589–595.
Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with
cancer: American Society of Clinical Oncology clinical practice guideline
update. J Clin Oncol 2013; 31:2500–2510.
Mundy AR. An anatomical explanation for bladder dysfunction following rectal
and uterine surgery. Br J Urol 1982; 54:501–504.
Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after
treatment for localized prostate cancer. N Engl J Med 2013; 368:436–445.
Rigaud J, Hetet JF, Bouchot O. Management of radiation cystitis. Prog Urol
2004; 14:568–572.
Thurman SA, Ramakrishna NR, DeWeese TL. Radiation therapy for the treat-
ment of locally advanced and metastatic prostate cancer. Hematol Oncol Clin
North Am 2001; 15:423–443.
Wall RL, Clausen KP. Carcinoma of the urinary bladder in patients receiving
cyclophosphamide. N Engl J Med 1975; 293:271–273.
Wyndaele JJ. Is abnormal electrosensitivity in the lower urinary tract a sign of
neuropathy? Br J Urol 1993; 72:575–579.
Wyndaele JJ, Kovindha A, Madersbacher H, et al. Neurologic urinary inconti-
nence. Neurourol Urodyn 2010; 29:159–164.
Zelefsky MJ, McKee AB, Lee H, Leibel SA. Efficacy of oral sildenafil in patients
with erectile dysfunction after radiotherapy for carcinoma of the prostate.
Urology 1999; 53:775–778.
86 Wyndaele et al.
Sexuality/Reproductive Issues
J. Farthmann
81
R. Schwab
A. Hasenburg
Freiburg University Medical Center, Freiburg, Germany
Sexual Function
The potential changes in sexual function are increasingly seen as a relevant
issue in oncology and as an object of clinical trials. Sexuality is a delicate
topic and, in cancer patients, discussion of sexual function may seem inap-
propriate, when questions of survival are more important. However, sexual
function is not a “lifestyle” problem, but a serious topic that requires atten-
tion. Sexual difficulties have a profound effect on one’s wellbeing and quality
of life; they affect relationships and are associated with high levels of patient
distress. Several factors must be taken into account when evaluating possible
problems for sexual well-being: marital status, gender, age, ethnicity,
and education. Older age and treatment with radiation have been consist-
ently associated with impaired sexual function.
Sexuality issues potentially play a role in patients of all ages. Impairment
of sexual function is found in adult oncological patients, but also in those
who experienced cancer in childhood. This stresses the fact that patients
need counselling at all ages.
Regarding sexuality and cancer, two differentiations must be made: (a)
between male and female patients, and (b) between sexual organ-related
and non-sexual organ-related cancers. In the past, research has been
focused on sexual organ-related cancers, meaning prostate or testicular
cancer in men and breast or gynaecological cancer in women. Among
non-sexual organ-related cancers, most research has been performed on
colorectal cancer. Sexual changes have also been observed in patients
with lymphatic, head and neck, or lung cancer.
87
The quality of a relationship is important as a couple’s quality of life and
marital satisfaction are linked. Glantz et al (2009) described the risk of
being abandoned by a partner after surviving a severe disease to be signifi-
cantly higher for women (20.8%) than for men (2.9%). When counselling
a patient with cancer, the partner should not be neglected. This may lead
to misunderstandings and a vicious cycle. Most women would also have
appreciated their partner being informed about the possible treatment side
effects on sexuality and relationships. Raising the topic of psychological,
relational, and sexual functioning by healthcare providers, could help
pave the way for an easier discussion on this topic, giving patients the
opportunity to improve their coping strategies and reduce anxiety.
What can the physician do?

Cancer and cancer treatment can exacerbate former sexual function
problems or may create new ones. As sexual dysfunction may be pre-
sent in healthy individuals, these issues can often be overlooked initially.
Awareness of these potential problems will help the patient to adapt
to post-treatment difficulties. A pretreatment discussion of sexuality
and intimacy provides a baseline for comparison with the subsequent
re-evaluation during and after treatment.
People have different opinions on what is normal, so the doctor has to
find out whether the patient has been content with his/her sexual life in
the past. Questions like “Has anything changed in your sexuality after
the diagnosis?” are very helpful to ascertain if there is any need to go
deeper into this topic. Asking “How were your sexual desires recently?
How was it on your partner’s side?” help to start the conversation. For
some patients, the cancer diagnosis can be used as an excuse to refrain
from being sexually active.
According to the Pfizer Global Study, 80% of cancer patients would like
to have more information about the impact of their illness and subsequent
therapy on their sexuality. Ninety-one percent of cancer patients were
afraid to ask their treating physician about sexual problems, and 97% of
doctors did not inform their patients about possible sexual dysfunction.
This emphasises the need for intensive training in communication skills.
88 Farthmann et al.
Physicians need to be aware that the way they approach, counsel and
address sexual problems may be influenced by their own sexual experi-
ences. When talking about sexuality issues, the doctor should try to use
similar language to that of the patient and avoid, as best as they can,
technical medical terminology. Somatic and psychological problems of
sexual dysfunction are difficult to differentiate and are interdependent.
Physical limitations
Treatment of cancer is often multimodal, which makes it necessary to
differentiate between the side effects of the various therapeutic interven-
tions. Stigma may be obvious, such as alopecia, scars, a colostomy, or
a urostomy. These can greatly alter the patient’s body image and self-
esteem. Cancer of sexual organs, in particular, can lead to mutilating
changes, including negative body image, decreased body function, or
weight gain or loss. Women tend to agree to coitus, even when having
pain, in order not to disappoint their partners. Some side effects of cancer
treatment may be transient, but changes in sexual functioning, sense of
self, and relationship interferences may be ongoing. Furthermore, the
patient’s situation before the disease – for example, whether the integrity
of the body has been an important aspect for the patient – has an impact
on the coping process.
Psychological issues
It might be difficult to differentiate between problems related to the
sequelae of the disease, fatigue, or depressive symptoms. Patients suffer-
ing from depression should be offered antidepressant therapy. Some of
these agents can induce a lack of desire, but a severe depression can also
impair sexual function. Specific pharmacotherapy may be necessary,
often for only a few weeks, to improve the mental situation as well as
the patient’s sexual desire. If overall well-being increases, sexual life and
the patient’s relationship with their partner may benefit. In a randomised
trial, breast cancer patients who received group intervention had a higher
rate of symptom resolution regarding sexual problems.
Sexuality/Reproductive Issues 89
Fertility Issues in Cancer Patients
One in 46 women and one in 69 men will develop cancer before reaching
40 years of age. Survival rates are higher in the population aged 15–44
years at diagnosis. The 5-year survival rate of 81% in this population group
is linked with increased detection at an early stage and optimised treatment.
Highly toxic, multidrug chemotherapy and radiotherapy improve the
outcome of young patients but lead to more severe side effects and
long-term physical and psychological sequelae. Chemotherapy and
radiotherapy are known to be gonadotoxic by damaging ovarian follicles
in females and spermatogonia in males.
The risk of impaired fertility or permanent infertility after oncological
treatment depends on a range of factors such as radiotherapy, chemother-
apeutic agents (Table 1), and cumulative dosage of the medication. Age
is another important factor: due to socioeconomic and lifestyle changes,
especially in the Western world, parenthood is increasingly postponed to
a later moment in reproductive life. Consequently, many cancer patients
have not fulfilled their family planning at the time of diagnosis. Fertility
concerns are, therefore, common in young patients.
Partridge et al (2004) showed that, in breast cancer patients, about 60% of
women specify concerns of becoming infertile after treatment. Up to 29%
reported that infertility concerns influence their decision-making process. As
reported by Ruddy et al (2014), approximately 10% of breast cancer patients
will discontinue endocrine therapy before the specified time and up to 1% will
refuse to receive chemotherapy. There are still gender differences in providing
fertility-related information. New data by Armuand et al (2012) show that about
80% of males received information about the impact of treatment on fertility
and nearly 70% on fertility preservation methods. Twenty-five percent to 50%
decided to store frozen sperm. In contrast, only 48% of females were counselled
about the impact of treatment on fertility, 14% received information about fer-
tility preservation, and only 2% to 10% underwent fertility preservation.
Directly after diagnosis, all young patients should be referred to a
specialist because fertility preservation should be started before onset of
oncological therapy to obtain optimal results.
90 Farthmann et al.
Table 1 Gonadotoxic Potential of Chemotherapy and Radiotherapy in Females
and Males. Adapted from Sonmezer M, et al. Fertility preservation in female
patients. Hum Reprod Update 2004; 10:251–266 and Rodriguez-Wallberg KA, et al.
Fertility preservation during cancer treatment: clinical guidelines. Cancer Manag Res
2014; 6:105–117.
Gonadotoxicity Chemotherapy in Radiotherapy in females Radiotherapy in
males and females males
Low risk • Treatment protocols for
Hodgkin´s lymphoma
without alkylating agents
• Bleomycin
• Actinomycin D
• Vincristine
• Methotrexate
• 5-Fluorouracil
Intermediate risk • Cisplatin with low • Pelvic or whole abdominal • Testicular radiation dose
cumulative dose radiation dose 5–10 Gy in 1–6 Gy from scattered
• Carboplatin with low postpubertal girls pelvic or abdominal
cumulative dose • Pelvic or whole abdominal radiation
• Doxorubicin radiation dose 10–15 Gy in • Craniospinal radiotherapy
prepubertal girls dose ≥25 Gy
• Craniospinal radiotherapy
dose ≥25 Gy
High risk • Cyclophosphamide • Total body irradiation for • Total body irradiation for
• Ifosfamide bone marrow transplant/ bone marrow transplant/
• Melphalan stem cell transplant stem cell transplant
• Busulfan • Pelvic or whole abdominal • Testicular radiation dose
• Nitrogen mustard radiation dose ≥6 Gy in adult >2.5 Gy in adult men
• Procarbazine women • Testicular radiation dose
• Chlorambucil • Pelvic or whole abdominal ≥6 Gy in prepubertal
radiation dose ≥10 Gy in boys
postpubertal girls
• Pelvic or whole abdominal
radiation dose ≥15 Gy in
prepubertal girls
Unknown risk • Taxanes
• Oxaliplatin
• Irinotecan
• Monoclonal antibodies
• Tyrosine kinase
inhibitors
Fertility preservation in women
In women, the oocyte pool is generated during foetal life, continuously
declining as a result of intrinsic factors such as the initial pool and geneti-
cally determined oocyte apoptosis. This process is non-reversible. Extrin-
sic factors like chemotherapy and radiotherapy can accelerate the decline
of the oocyte pool, leading to premature ovarian failure (POF) or infertility.
Fertility preservation methods help oncological patients to maintain the
possibility of giving birth and the gonadal function. Several fertility pres-
ervation methods are well established, while others are still experimental.
Ovarian stimulation with gonadotrophins is a standard method and leads
to multiple follicular growths. The obtained oocytes can be cryopre-
served, either fertilised or unfertilised. The live birth rate per transfer
using thawed frozen fertilised oocytes is ~30–40% in women under 35
years of age. The ovarian stimulation can be started at any time in the
menstrual cycle, due to random-start antagonist protocols. More than
one stimulation cycle can be performed if the delay of oncological ther-
apy is reasonable. For women with hormone-positive tumours, letrozole
administration during ovarian stimulation impedes high serum oestrogen
levels, which are undesirable in this situation.
Due to new technologies like vitrification of unfertilised oocytes, the
live birth rates per embryo transfer achieved with this method are almost
34%. This is an optional method for single women or young patients.
A second method of fertility preservation in young female cancer patients
is suppression of ovulation function by administration of a gonadotrophin
releasing hormone agonist (GnRHa). The published data are still contro-
versial. A recently published meta-analysis shows promising results. The
data prove a highly significant reduction in the risk of POF. In patients
treated with GnRHa, only 22% developed POF, versus 37% in controls.
Karimi-Zarchi et al (2014) reported a significant improvement in ovar-
ian function after leuprorelin administration in hormone-negative breast
cancer survivors, whereas the German ZORO study found no differences
(Gerber et al 2011). Unfortunately, data are scarce regarding long-term
fertility outcomes, such as pregnancy and successful birth rates.
92 Farthmann et al.
Another option for fertility preservation is the freezing of ovarian tissue
and retransplantation after cancer treatment. Retransplantation can be
performed in an orthotopic or heterotopic site. After retransplantation, a
temporary restoration of ovarian function has been observed in almost all
cases. Thereafter, pregnancies can be achieved either by natural concep-
tion or by assisted reproduction methods. The expected pregnancy rate
per transplantation is approximately 20%. To date, 24 live births have
been reported in the literature. This is the only method of fertility pres-
ervation that can be offered to prepubertal girls. However, patients who
have been diagnosed with systemic haematological malignancies are not
eligible for this method, because of the risk of cancer retransmission.
In both sexes, germ cells are very sensitive to irradiation (Table 1).
The extent of the damage is dependent on the number of treatments,
the cumulative dose, and the radiation field. The gonadotoxic effect of
radiotherapy is well known; a dose of 2 Gy applied to the gonadal area
will reduce the oocyte pool by up to 50%, a dose of 6 Gy in adult women
or 10 Gy in postpubertal girls leads to a high percentage of permanent
gonadal damage.
In women receiving radiation therapy, transposition of ovaries or gonadal
shielding are appropriate methods to reduce ovarian damage. The suc-
cess rate of this method is approximately 50%.
In malignancies of the lower genital tract of low risk, conservative
gynaecological surgery should be taken into consideration. Approxi-
mately 50% of women diagnosed with cervical cancer under the age of
40 years can be adequately treated by this method. Patients with border-
line tumours of the ovaries or low-risk ovarian cancer can be offered a
unilateral oophorectomy. Young (obese) females with well-differentiated
endometrioid uterine cancer may be treated with progestins over possi-
bly several years instead of hysterectomy. They need regular histological
biopsies of the uterine cavity during this treatment. When the biopsy is
proven benign, starting a pregnancy may be safe. In the future, uterine
transplantation may become possible in young patients who have under-
gone hysterectomy.
Fertility preservation in men
In boys, spermatogonial stem cells located on the basement membrane
of seminiferous tubules start to develop with the beginning of puberty.
By age 13 to 14 years, effective spermatogenesis is usually established.
Chemotherapy and radiotherapy impair spermatogenesis (Table 1). The
degree of damage is dependent on the agent applied, the dosage, and the
fractionation schedule of radiation. If a population of germ stem cells
survives therapy, regeneration of spermatozoa may continue for years. Sperm
banking is an inexpensive and well-established method for fertility preserva-
tion prior to chemo- or radiotherapy, without delay of the subsequent treat-
ment. Sperm can be obtained after ejaculation or, in cases of azoospermia,
by biopsy of the testicle. In case of radiation, shielding of the testicles should
be offered, as even a small dosage will lead to irreversible azoospermia.
Fertility-sparing surgery in testicular cancer may be offered to patients
with low-risk cancer in the form of partial or unilateral orchidectomy, in
cases where the contralateral testicle is not involved. Prepubertal boys may
benefit from freezing testicular tissue. If diagnosed with azoospermia later
in life, retransplantation of germ stem cells may lead to resumption of
spermatogonia generation. Preclinical trials in this field are very promis-
ing; nonetheless, this method is still highly experimental.
Evaluation of fertility after cancer treatment

After successful treatment of the malignancy, many young survivors are
interested in their reproductive potential. In women, regular menstrual
cycles do not rule out reproductive dysfunction. The fertile lifespan is
shortened, even if menstruation is restored after therapy. Ovarian func-
tion can be assessed by measurement of the antral follicle count, anti-
Müllerian hormone, and follicular stimulating hormone (FSH) concen-
tration during the early follicular phase. In men, reproductive function
can be evaluated by semen analysis, FSH level, and testosterone level.
Parenthood after cancer

Approximately 80% of long-term cancer survivors of reproductive age
see themselves as potential parents. Unfortunately, both men and women
94 Farthmann et al.
have an increased risk of infertility as shown in the Childhood Cancer
Survivor Study.
Patients infertile due to oncological therapy can be advised to adopt a
child or to use third-party reproduction such as heterologic insemination
or embryo donation, depending on the particular national guidelines and
individual ethical aspects. Nevertheless, most long-term survivors pre-
fer to have biological children. A high percentage of those who remain
childless will suffer from psychological alterations such as distress (up
to 30%) and depression (up to 40%).
However, patients who maintained their reproductive function may have
concerns regarding the health of the future offspring. Women who con-
ceived after cancer therapy showed a live birth rate of 63–73%. A higher
miscarriage rate was noted after pelvic irradiation. An exposure of the
genital organs of >10 Gy in women or more than 2.5 Gy in prepubertal
girls led to increased risk for stillbirth and neonatal death. The risk of
preterm birth and low birth weight are increased as well. No association
was found in men after irradiation of the testicles.
Fortunately, there is no increased risk of congenital malformations,
single-gene defects, or cytogenetic abnormalities among children of
childhood cancer survivors, irrespective of the applied therapy.
Conclusion
It is of major importance to sensitise physicians working with cancer
patients on the issues of quality of life, fertility, and sexuality. The poten-
tial long-term consequences of oncological therapy must be considered
and discussed with the patient and his/her partner, and the doctor should
address these issues frankly. By understanding that sexuality is an impor-
tant and normal aspect of life and not a “luxury issue” even in a palliative
situation, physicians can support their patients and help them to maintain
a good, or at least acceptable, quality of life. Special training in sexual
medicine may be helpful but is not mandatory.
Fertility preservation counselling should be an integral part of treatment
in young cancer patients. A close collaboration between oncologists and
4
fertility preservation specialists is essential. There is also an important
psychological aspect of fertility preservation counselling: perhaps for
the first time since diagnosis, patients may envision life after cancer. As
new techniques in the field of onco-fertility have made great advances,
these patients have a good chance to maintain their reproductive poten-
tial in the face of a potentially life-threatening circumstance, and in spite
of highly toxic therapy. Thus, with these successes, they have a good
chance of leading a normal, fulfilled family life.
Dr Farthmann has reported no conflicts of interest.
Dr Schwab has reported no conflicts of interest.
Professor Hasenburg has reported no conflicts of interest.
Further Reading
Armuand GM, Rodriguez-Wallberg KA, Wettergren L, et al. Sex differences in
fertility-related information received by young adult cancer survivors. J Clin
Oncol 2012; 30:2147–2153.
Barton SE, Najita JS, Ginsburg ES, et al. Infertility, infertility treatment, and
achievement of pregnancy in female survivors of childhood cancer: a report
from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2013;
14:873–881.
Del Mastro L, Ceppi M, Poggio F, et al. Gonadotropin-releasing hormone ana-
logues for the prevention of chemotherapy-induced premature ovarian failure
in cancer women: systematic review and meta-analysis of randomized trials.
Cancer Treat Rev 2014; 40:675–683.
Gerber B, von Minckwitz G, Stehle H, et al; German Breast Group Investigators.
Effect of luteinizing hormone-releasing hormone agonist on ovarian func-
tion after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO
study. J Clin Oncol 2011; 29:2334–2341.
Glantz MJ, Chamberlain MC, Liu Q, et al. Gender disparity in the rate of part-
ner abandonment in patients with serious medical illness. Cancer 2009;
115:5237–5242.
Grzankowski KS, Carney M. Quality of life in ovarian cancer. Cancer Control
2011; 18:52–58.
96 Farthmann et al.
Hasenburg A, Amant F, Aerts L, et al. Psycho-oncology: structure and profiles of
European centers treating patients with gynecological cancer. Int J Gynecol
Cancer 2011; 21:1520–1524.
Karimi-Zarchi M, Forat-Yazdi M, Vafaeenasab MR, et al. Evaluation of the
effect of GnRH agonist on menstrual reverse in breast cancer cases treated
with cyclophosphamide. Eur J Gynaecol Oncol 2014; 35:59–61.
Nielsen SN, Andersen AN, Schmidt KT, et al. A 10-year follow up of reproduc-
tive function in women treated for childhood cancer. Reprod Biomed Online
2013; 27:192–200.
Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues
in young women with breast cancer. J Clin Oncol 2004, 22:4174–4183.
Rodriguez-Wallberg KA, Oktay K. Fertility preservation during cancer treat-
ment: clinical guidelines. Cancer Manag Res 2014; 6:105–117.
Ruddy KJ, Gelber SI, Tamimi RM, et al. Prospective study of fertility concerns
and preservation strategies in young women with breast cancer. J Clin Oncol
2014; 32:1151–1156.
Signorello LB, Mulvihill JJ, Green DM, et al. Congenital anomalies in the chil-
dren of cancer survivors: a report from the childhood cancer survivor study.
J Clin Oncol 2012; 30:239–245.
Cancer: Social Issues
S. Kreitler
9
School of Psychological Sciences, Tel-Aviv University;
Psycho-Oncology Research Center, Sheba Medical Center,
Tel Hashomer, Israel
Prevalence
In recent years there has been growing awareness that cancer is not only
a medical problem but a social one too. Social support, social function-
ing, relationships, and impact on family have been identified as major
issues across all age groups, genders, and diagnoses of cancer. Social
issues account for at least a third of the problems mentioned by patients.
The main ones are social life, relationship with spouse or partner, coping
with children, communication, and getting on with family.
Social problems were reported by patients also before the recent surge
in cancer survival. An early study showed that more than 50% of patients
rated interactions with family and friends, communication with spouse,
care provided by spouse, dating, and sexuality as problems. Social
issues figure prominently as problems revealed in social media such as
Facebook and Twitter.
Social Problems as a Source of Distress

Social problems constitute a serious source of distress for cancer patients.
The level of psychological distress in cancer patients is higher than in
other patients despite a similar level of physical distress, and it reflects
mainly worry over future prospects or social issues. Patients better able
to solve social problems have less anxiety and depression, and suffer less
from cancer-related problems. In brain cancer patients, the main reasons
for hospitalisation included social issues. Social issues strongly affect
the patients’ quality of life. Thus, dealing with the social issues is likely
98
to have a greater impact on the well-being of cancer survivors than other
factors.
Despite their prevalence, social issues are discussed in clinical consulta-
tions to a lesser extent than other psychological problems. A study of
general practitioners found that the doctors waited until close to death
before discussing end-of-life issues and then dealt more with physi-
cal symptoms than with the involved social problems. A study of the
contents of communications in clinical consultations showed that 44%
of the patients and 39% of clinicians reported that they would discuss
social activities. Social issues were actually discussed in 46% of the
consultations, but patients felt they were discussed less often than the
physicians reported.
Social Relations and Contacts

The patient and the family
Social issues in the relations with and communication within the family
are mentioned by most patients. Cancer has long been identified as a
family disease as much as an individual’s disease. Cancer of a family
member may cause an anxiety-laden crisis situation for the family, which
undergoes changes in its sense of stability, its regular allotment of roles,
and its routine behaviours and interactions. In addition, family members
may be overburdened, and the patient may react to this situation with
increased stress and suffering.
Relations with the spouse

A major social problem in the family involves gaining support from the
spouse. For this to occur, the patient must be ready and able to share his
or her experiences and suffering with the spouse, whereas the spouse
needs to be able to provide understanding, empathy, emotional support,
and acceptance. Adequate communication seems to be a basic require-
ment. Communication is, however, often less than perfect. Common
reasons are that the patient may be unable or reluctant to share all of his
or her suffering, while the spouse may be unable or unwilling emotion-
ally to shoulder the burden, may be distressed, may be too busy with
Cancer: Social Issues 99

helping in daily tasks, or may lack the skills in order to provide adequate
support. The result would be increased tension in the patient–spouse
dyad. Studies show that spouses may behave toward the patient in a
way that seems unsupportive or insensitive because they do not always
accept the patient’s views about what is happening and do not behave
in accordance with the patient’s expectations. A patient who feels that
he or she does not have sufficient support from the spouse is frustrated
and disillusioned, and suffers from heightened levels of distress, anxiety,
and depression.
Tension is particularly high when the patient and spouse hold different
views about the treatment that should be given or have different styles of
communicating about cancer – whether open discussion or denial.
The level of social and other problems in the family is of such great
importance for the well-being of the patient that a recent meta-analytic
review concluded that, in terms of distress, the major factor is the state
of the couple considered as an emotional system rather than the state of
each individual separately.
Relations with other close family members

Children may also contribute to the patient’s social problems. Minors
may feel anxious and confused and may require attention and support
from the patient. Tension may be evoked by the difficulty or reluctance
of the patient (and sometimes the spouse too) to disclose the medical
situation to the children. Children may harbour different misconceptions
about cancer that may intensify their fear and suffering. Their result-
ing emotional reactions may enhance the social burden on the patient.
Vulnerable children may manifest symptoms (e.g. anorexia, phobias)
that require care and attention, which may be withdrawn from the
support focused on the patient.
Grown-up children are often expected to provide emotional and instru-
mental support to the sick parent. However, this may not always be
forthcoming for several reasons: faulty communication on the part of the
parents, who expect help without asking for it, or who may not explain
to the children the seriousness of the situation, as well as the inability or
100 Kreitler
reluctance of the children to stop their other obligations and occupations
and free themselves for helping the sick parent. This may drive a wedge
in the relations between the parent-patient and the grown-up children.
Sometimes the patient still has elderly parents. One’s parents may pro-
vide the patient with support in many ways, emotional and otherwise.
However, relations with one’s parents may also contribute to the load
of the patient’s social problems. One problem relates to the issue of
communication. Patients may hesitate to disclose their diagnosis to the
parents for reasons such as the desire to protect them if their health is
frail or shame because of having violated the expected order of things,
according to which children die after their parents. In addition, patients
may feel guilty for being unable to help their parents while they are sick.
Sometimes elderly parents (mainly the mother) may become overly
involved in supporting the patient, who may be a grown-up married son
or daughter. The situation may become complicated when the parent
tries to replace the patient’s spouse. In such circumstances, the patient
may be torn in the conflict between the spouse and the parent.
Thus, it is evident that families may potentially create social difficulties
for patients. Not surprisingly, among women with a high social burden,
those with a higher number of first-degree relatives had higher all-cause
and breast cancer mortality.
Relations with other close individuals

Family relatives, lovers, friends, and acquaintances may constitute a
source of support in different respects. A precondition for their help is
that they receive adequate information about the cancer diagnosis and
treatment. Patients may be reluctant to provide information to individu-
als who are not close family members because they would like to pre-
serve their image as “healthy” and avoid pity from others. Further, these
“close individuals” have needs of their own that are not always easy to
meet. Some may need detailed communication about the medical issues,
while others may want to know as little as possible. In return for the
support they provide, some may desire appreciation on the part of the
patient, or even help from others, including the patient, with problems

they themselves may have. Often the close individuals do not know how
to help the patient. They may also overlook the fact that the patient is
weak and sick, so that it may be difficult for him or her to spend a lot of
time with the many different supporters. These difficulties may explain
findings, such as that patients with sexual partners had more problems
in social and domestic environments and lower scores on psychological
well-being. A study with prostate cancer patients found that 3 out of 10
patients living in a relationship could not confide in their spouse.
A serious source of social problems concerns maintaining former rela-
tionships. A person who becomes a cancer patient naturally expects one’s
friends to provide the needed support. Often they do, but sometimes they
do not, or they reduce their support or even disappear from the person’s
life over time. The reasons may be discomfort with the cancer diagno-
sis, the wish to dissociate from suffering, fear that they may be called
upon to provide more help than they are ready to give, or because they
no longer enjoy the relationship with the patient. Disappointment from
friends is a difficult social issue for cancer patients, who may anyway
regard their life during the disease as a series of losses.
Studies show that individuals tend to distance themselves from cancer
patients because they regard cancer as a stigma. Also, cancer patients
tend to distance themselves from others because they do not want to
overburden them with their suffering or are ashamed of their external
appearance. These factors render it difficult to maintain former relation-
ships or form new ones.
Relationships with therapeutic carers and internet groups

Patients tend to look for support from others, notably those involved in
cancer. This includes the doctors and clinicians who are expected by
many patients to manifest understanding for their plight, as well as
other patients, mainly survivors and the internet-based organised or
non-organised groups that provide information, support, understanding,
advice, and the sense of belonging to a community.
102 Kreitler
Special Aspects of Social Issues in Cancer
Loneliness and isolation
Due to difficulties in maintaining former relationships and forming new
ones, many cancer patients find themselves isolated from social contacts.
However, even when this is not the case, many patients feel loneliness. The
complaint of loneliness is very common and has been documented exten-
sively. It is shared by patients of all ages, diagnoses, or disease stages. It
reflects the helplessness and hopelessness patients experience in view of
their existential plight in losing contact with life and approaching death, a
plight they feel no one can understand or alleviate. Loneliness may persist
even when it is discussed with others. It leads to despair, depression, and
demoralisation and may intensify suffering from the disease and the treat-
ments. Loneliness affects not only a patient’s emotional state and quality of
life but also his or her health and pain by intensifying stress reactivity, weak-
ening physiological repair processes, and increasing immune dysregulation.
Communication
Communication is the pivotal point which can make the difference between
more or fewer social problems for the patient. The major barriers to com-
munication on the patient’s side are: reluctance to share and thus reveal
one’s weaknesses, low trust in others, desire to experience one’s strength
through coping by oneself, a wish to maintain one’s independence and
avoid indebtedness to others, feeling different from healthy people, desire
to guard one’s secrets and privacy, fear of being rejected and ridiculed,
and shame and guilt about the disease. The major barriers on the part of
the targeted listeners are: desire to dissociate from suffering, fear of get-
ting over-involved, fear of cancer, and not knowing how to respond. On
both sides, there may be beliefs in certain taboo topics that may not be
discussed, prohibitions against emotional expression, and lack of commu-
nication skills. To improve communication, it is important to consider that
contents, styles, and degree of communication vary with culture.
Social support
Social support is probably the most widely researched theme in psycho-
oncology. The majority of studies show positive effects of social support

in improving quality of life, lowering depression and anxiety, enhancing
benefit finding, increasing compliance with treatment, and even improv-
ing medical outcomes. The positive effects may be attributed to emo-
tional factors, such as the patients’ increased confidence in themselves,
enhanced feeling of being guarded and loved, and the sense that one’s
well-being is important to others. However, social support also enables
cognitive elaboration of the difficulties and hence better adjustment.
Notably, too much social support may overburden an exhausted patient.
Furthermore, not every kind of social support is equally beneficial. The
best type is “positive social interaction”, without conflict. Additionally,
not every patient is able to use social support. There is a set of beliefs
referring to themes such as emotional expression, readiness to limit one’s
independence and privacy, trusting others, and feeling similar to others
that renders an individual receptive to social support. When this motiva-
tional disposition is weak, the individual may be reluctant to seek social
support or unable to benefit from it.
Conclusions
Many studies and observations prove the importance of social issues for
the patient’s quality of life, emotional state, and health. Social factors
may contribute to the patient’s well-being as well as disrupt the patient’s
peace of mind and undermine efforts for recovery. They are operative
in the different stages of the disease, in both genders, and in all age
groups and cultures. They become evident in the relations with one’s
spouse, children, parents, family members, friends, acquaintances, other
patients, and members of common internet groups.
All people need contact with others. Cancer patients are even more in
need of contact with others, especially with those with whom they can
share their anxieties and pain. Many cancer patients complain of loneli-
ness, which reflects their unfilled need for contact with others who can
listen and provide support. Some patients complain also of solitude. Many
patients report social problems which probably reflect the feeling that they
do not gain enough support and understanding from others. When support
is available, it instils hope and strength in the patient, but, when missing, it
104 Kreitler
fuels despair and demoralisation. Inadequate communication is one major
cause for lack of support. Barriers to optimal communication characterise
both the patient and those expected to provide support.
It is recommended that assessment of social issues should become part
of routine clinical practice. When problems are detected, it is advisable
to initiate interventions for improving the situation, including the teach-
ing of communication skills and of social problem-solving methods.
Dr Kreitler has reported no conflicts of interest.
Further Reading
Cull A, Stewart M, Altman DG. Assessment of and intervention for psychosocial
problems in routine oncology practice. Br J Cancer 1995; 72:229–235.
Hagedoorn M, Sanderman R, Bolks HN, et al. Distress in couples coping
with cancer: a meta-analysis and critical review of role and gender effects.
Psychol Bull 2008; 134:1–30.
Helgason AR, Dickman PW, Adolfsson J, Steineck G. Emotional isolation: prev-
alence and the effect on well-being among 50-80-year-old prostate cancer
patients. Scand J Urol Nephrol 2001; 35:97–101.
Kent EE, Smith AW, Keegan TH, et al. Talking about cancer and meeting
peer survivors: social information needs of adolescents and young adults
diagnosed with cancer. J Adolesc Young Adult Oncol 2013; 2:44–52.
Kroenke CH, Kwan ML, Neugut AI, et al. Social networks, social support
mechanisms, and quality of life after breast cancer diagnosis. Breast Cancer
Res Treat 2013; 139:515–527.
Lewis FM. The family’s “stuck points” in adjusting to cancer. In: Holland JC,
Breitbart WS, Jacobsen PB, et al (Eds). Psycho-Oncology, Second edition.
New York: Oxford University Press, 2010; 511–515.
Resendes LA, McCorkle R. Spousal responses to prostate cancer: an integrative
review. Cancer Invest 2006; 24:192–198.
Rokach A. Terminal illness and coping with loneliness. J Psychol 2000;
134:283–296.
Taylor S, Harley C, Campbell LJ, et al. Discussion of emotional and social
impact of cancer during outpatient oncology consultations. Psychooncology
2011; 20:242–251.

Financial Issues
D. J. Bruinvels
10
Instituut voor Klinische Arbeidsgeneeskunde,
Amsterdam, The Netherlands
J. G. Schuurman
A-CaRe, Amsterdam, The Netherlands
Introduction
The financial burden of cancer and its treatment can be substantial. In
addition, work disability and job loss after treatment may also lead to
financial problems. Extra cost during treatment may be related to lost
income, increased insurance premiums, deductibles, co-payments, trans-
portation costs, and child care expenses.
Cost concerns are common among patients with cancer who have health
insurance. A relatively high prevalence of present and future cost concerns is
present among patients treated at both academic and community hospitals.
Patients may have a wide range of cost concerns and additional expenses.
Healthcare providers may be accustomed to identifying vulnerable popula-
tions for whom cost-related concerns may be a significant barrier to care,
such as the poor or underinsured. However, cost concerns may extend
beyond the groups that are traditionally considered vulnerable. For example,
a quarter of patients who were treated at an academic centre reported travel
costs as an additional expense. Many patients receiving care at a tertiary care
centre travel farther from home than those cared for in a community site.
Given both the economic uncertainty many patients face and the increas-
ing costs of cancer treatment, it may be helpful for healthcare providers to
discuss concerns with all patients, rather than relying on demographic char-
acteristics to determine with whom costs should be discussed.
What is the impact of financial problems? Nearly one-third of adult
cancer survivors reported cancer-related financial problems. Survivors
106
reporting financial problems were more likely to report forgoing or
delaying recent medical care, prescription medications, dental care, eye-
glasses, or mental health care within the past year, specifically because
of concerns about cost. The development of interventions to aid cancer
survivors and their families as they confront financial stress is challenging,
in part because it entails expansion of existing models of survivorship
care as well as multilevel intervention efforts.
A recently proposed model of cancer rehabilitation recognises the need
for comprehensive care. It is suggested to give attention to social and
vocational needs, as well as expanding survivorship care to include
services that promote self-management, and encourage survivors to
remain in, or return to, the workforce. This has the potential to reduce
overall and individual cancer costs and should be considered as a way to
reduce financial burden.
Despite the potential benefits of outpatient cancer rehabilitation services,
accessing this care entails navigating multiple barriers. The diversity of
health insurance coverage with its broad mix of payers and numerous plan
types has complicated authorisation and reimbursement. Most rehabilitation
services are fully or partially covered through the majority of insurance plans.
However, the limited coverage schedule, funding caps, and strict guidelines
for continuation of therapy may mean that some survivors of cancer can-
not receive their recommended therapy. Private health insurers are mandated
to cover physical and occupational therapy services in some countries and
regions, but coverage for these services can vary widely and have substantial
co-payments that discourage the financially stressed survivor of cancer.
Finally, accessing rehabilitation services is dependent on referral, and
the ability of providers and administrative staff to understand health
insurance plans, so that the appropriate services can be obtained.
Providers must be able to ensure timely pre-authorisations and
prescriptions for continuation of services, locate high-quality in-network
providers, understand referral processes, and assist patients in making
sense of complex benefits schedules. At present, the existing patch-
work of national or regional mandates, complex benefits schedules, and
variable patient cost sharing among health insurance plans may be
contributing to the underuse of cancer rehabilitation services.
Financial issues 107
Job Loss
The most widely used method to make money and decrease financial
burdens is by having paid work. However, cancer survivors are hit
harder with job losses. A recent meta-analysis showed that cancer sur-
vivors were 1.37 times more likely to be unemployed than healthy peo-
ple (33.8% compared with 15.2%). Increased risks for unemployment
were identified for survivors of breast cancer, gastrointestinal cancers,
and cancer of the female reproductive organs. Survivors of blood cancer,
prostate cancers, and testicular cancer did not have a higher unemploy-
ment risk. Cancer survivors who live in countries or time periods — such
as the current economic climate we have today — with high unemploy-
ment rates may especially be at risk. These data were collected before
the deterioration of the world economy; experts now wonder if this gap
could be widening.
A recent meta-analysis with a focus on predictors of return to work and
employment in cancer survivors showed that job demands, such as heavy
work, create a barrier for cancer survivors to return to work. Heavy work
and chemotherapy were negatively associated with return to work. Less
invasive surgery was positively associated with return to work. Breast
cancer survivors had the greatest chance of return to work. Old age, low
education, and low income were negatively associated with employ-
ment. Moderate evidence was found for extensive disease being nega-
tively associated with both return to work and employment. For female
gender a negative association with return to work was found. Based on
these findings a limited number of prognostic factors of return to work
and employment can be identified at the time of cancer diagnosis. Clini-
cians should be aware of these prognostic factors (Table 1) and should
consider early rehabilitation or even prehabilitation of cancer patients.
Consequently, development of interventions involving clinicians and
other professionals to enhance work participation of cancer survivors
is needed. The need to improve efforts of oncology specialists, primary
care providers, and occupational health professionals in the return to
work process is essential to success.
108 Bruinvels and Schuurman

Table 1 Prognostic Factors for Return to Work and Employment
Return to work Employment
Factor Effect Level of evidence Effect Level of evidence
Socio-demographics
Age (old) weak strong
➝
Gender (female) moderate inconsistent
➝
Education (low) weak strong
➝
➝
Income (low) ➝ insufficient strong
➝
Marital status (single) inconclusive inconsistent
➝
➝
Ethnicity (minority) inconsistent
➝
Urbanicity (high) weak
➝
Job characteristics
Physical exertion (high) strong
➝
Working hours (high) insufficient weak

➝
Self-employment weak ➝ weak

➝
➝
Occupational class (low) weak weak
➝
Job tenure (long) weak weak

➝
Paid sick leave inconclusive

➝
Employee accommodation inconclusive

➝
Employer discrimination inconclusive

➝
Occupational healthcare weak

➝ ➝
Social support insufficient

Disease
Surgery only weak
➝ ➝
Less invasive surgery strong

Chemotherapy strong inconclusive
➝
Radiotherapy only = inconclusive = insufficient

Extensive disease moderate moderate
➝
Cancer site ↕ strong ↕ weak

Interventions
Interventions aimed at work participation and securing income can be
divided into three groups: ‘stay at work’ interventions (prehabilitation),
‘return to work’ interventions (rehabilitation), and interventions aimed at
patients in a palliative phase.
Stay at Work
The principle behind ‘stay at work’ or prehabilitation is prevention. In
the case of cancer and work, it is tertiary prevention. Where primary and
secondary prevention aim at preventing the disease – cancer – tertiary
prevention aims at minimising the impact of cancer. Tertiary prevention
is often conceptualised as care-related prevention. It has three goals: pre-
venting complications, curing or stabilising the disease, and reducing the
effects of loss of, for example, mobility or sensory functions.
In 2009, a large-scale cancer rehabilitation research programme – the
A-CaRe programme – was launched in The Netherlands. The aim of the
programme was to strengthen the evidence for the contribution of direct
and early physical rehabilitation on physical fitness and mental health.
The intervention did not require extra skills and knowledge beyond the
normal daily practice of doctors, physiotherapists, and other healthcare
providers. However, the timing of the interventions was innovative. It is
uncommon for rehabilitation to start in anticipation of future complica-
tions. Consequently in The Netherlands and most of the other European
countries, prehabilitation is not covered by basic healthcare insurance.
In The Netherlands, basic healthcare insurance is prescribed by the
Healthcare Insurance Law. Although this legislation states that the treat-
ment for a high risk of a disease cannot and should not be distinguished
from the treatment of the disease, this is not implemented in Dutch health-
care. Dutch healthcare providers are therefore challenged to search for
alternative ways to finance prehabilitation. The possibility for patients to
stay at work during their treatment makes it interesting for employers or
employment insurance companies to finance prehabilitation.

Return to Work
Return to work interventions are often considered as the default – vanilla
– flavour of rehabilitation in relation to work resumption. There is some
evidence that rehabilitation or vocational therapy speeds up partial return
to work. Evidence regarding full and, more importantly, stable return to
work is lacking.
Different approaches to rehabilitation are currently investigated in the
Dutch A-CaRe programme. In the clinical part of the programme, the
effectiveness of state-of-the-art exercise interventions with respect to
physical fitness and fatigue are evaluated. In addition, interventions
aimed at restoring psychosocial functioning and quality of life in spe-
cific cancer patient and survivor groups are evaluated. Determining the
cost-effectiveness of these interventions is also part of this programme.
The second part of the programme focuses on web-based interven-
tions to increase patient empowerment, return to work interventions to
strengthen the societal position of the patient, cancer rehabilitation at
home, and implementation of the clinical care programmes focusing on
physical exercise.
Similar studies and programmes exist in other European countries.
Hopefully, new data regarding return to work interventions will be made
available in the coming years.
Palliative Support
Evidence on the effectiveness of stay at work and return to work inter-
ventions for patients in a palliative phase is lacking. However, from the
patients’ perspective there is certainly a great need for evidence-based
interventions. Patients in a stable palliative phase may live for many
years and may have increased healthcare expenses. Not working is, from
a financial perspective, not an option. A large number of these patients
may lose their jobs because they cannot work as productively as co-
workers without cancer.
In addition, patients in a terminal palliative phase may want to end their
working career in dignity. They often want to finish their last project or
want to instruct a colleague how to take over their work. In these cases,

cancer rehabilitation may help to set and achieve individual goals during
those few months that a patient may have to live.
Compensation for Occupational Disease

Sometimes cancers are work related. However, clinicians are often una-
ware of the relation between disease and work. In 1981, in their report to
the US Congress, Doll and Peto estimated that 4% of cancer deaths in the
USA were attributable to occupation. For over 25 years since the report,
this occupational proportion had been used as the basis to estimate the
burden of occupational cancer in many European countries. In 2005 a
similar research study was undertaken to estimate the burden of occupa-
tional cancer in Great Britain. This found that 5.3% (8.2% for men and
2.3% for women) of all cancer deaths recorded in 2005 in Great Brit-
ain could be attributed to past occupational exposure. In addition 4.0%
(5.7% for men and 2.1% for women) of all newly diagnosed cancers in
2004 in Great Britain were also attributed to past occupational exposure.
Asbestos
Silica
Diesel Engine Exhaust
Mineral oils
Shift work
Working as painters
Other agents
0 500 1000 1500 2000 2500 3000 3500 4000 4500
Deaths per year in Great Britain
Figure 1 Occupational cancer deaths by cause in Great Britain, 2005.
From Chen Y. Occupational Cancer in Great Britain 2013. Health and Safety
Executive, January 2014. Contains public sector information published by the
Health and Safety Executive and licensed under the Open Government Licence.
http://www.nationalarchives.gov.uk/doc/open-government-licence/version/2/.

In many European countries, financial compensation schemes are avail-
able for occupational disease. Clinicians should always consider occu-
pational disease when diagnosing cancer. This is not only applicable to
working patients, but also to formerly employed patients and pension-
ers, as occupational cancer often takes many years to become detectable
after exposure to occupational carcinogens. In many European countries,
institutions are available where clinicians can send patients to have their
claim of an occupational disease assessed. Compensation schemes may
help to alleviate the financial burdens of patients and may be used to pay
for additional expenses that are not covered by health insurance.
Dr Bruinvels has reported no conflicts of interest.
Dr Schuurman has reported no conflicts of interest.
Further Reading
Alfano CM, Ganz PA, Rowland JH, Hahn EE. Cancer survivorship and cancer
rehabilitation: revitalizing the link. J Clin Oncol 2012; 30:904–906.
Amir Z, Brocky J. Cancer survivorship and employment: epidemiology. Occup
Med (Lond) 2009; 59:373–377.
Chen Y. Occupational Cancer in Great Britain 2013. Health and Safety Execu-
tive; January 2014. Available at: http://www.hse.gov.uk/statistics/causdis/
cancer/cancer.pdf.
Chinapaw MJ, Buffart LM, van Mechelen W, et al. Alpe d’HuZes cancer reha-
bilitation (A-CaRe) research: four randomized controlled exercise trials and
economic evaluations in cancer patients and survivors. Int J Behav Med
2012; 19:143–156.
de Boer AG, Taskila T, Ojajärvi A, et al. Cancer survivors and unemployment:
a meta-analysis and meta-regression. JAMA 2009; 301:753–762.
de Boer AG, Taskila T, Tamminga SJ, et al. Interventions to enhance return-to-work
for cancer patients. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD007569.
Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks
of cancer in the United States today. J Natl Cancer Inst 1981; 66:1191–1308.
Kent EE, Forsythe LP, Yabroff KR, et al. Are survivors who report cancer-related
financial problems more likely to forgo or delay medical care? Cancer 2013;
119:3710–3717.

Kroes ME, Mastenbroek CG, Couwenbergh BTLE, et al. Van preventie verzekerd.
College voor zorgverzekeringen. Diemen; 2007.
Lötters FJ, Foets M, Burdorf A. Work and health, a blind spot in curative health-
care? A pilot study. J Occup Rehabil 2011; 21:304–312.
Santa Mina D, Clarke H, Ritvo P, et al. Effect of total-body prehabilitation on
postoperative outcomes: a systematic review and meta-analysis. Physiotherapy
2014; 100:196–207.
Silver JK, Baima J, Newman R, et al. Cancer rehabilitation may improve function
in survivors and decrease the economic burden of cancer to individuals and
society. Work 2013; 46:455–472.
Stump TK, Eghan N, Egleston BL, et al. Cost concerns of patients with cancer.
J Oncol Pract 2013; 9:251–257.
Timmons A, Gooberman-Hill R, Sharp L. “It’s at a time in your life when you are
most vulnerable”: a qualitative exploration of the financial impact of a cancer
diagnosis and implications for financial protection in health. PLoS One 2013;
8(11):e77549.
van Muijen P, Weevers NL, Snels IA, et al. Predictors of return to work and
employment in cancer survivors: a systematic review. Eur J Cancer Care (Engl)
2013; 22:144–160.

Lifestyle Changes
F. L. Pimentel
11
Lenitudes, SGPS, Portugal; Health Sciences Department,
University of Aveiro, Aveiro, Portugal; Oncology Department,
Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal
Introduction
Unhealthy lifestyles are thought to be the cause of approximately 50–75%
of cancer cases worldwide. These lifestyle behaviours include smoking,
physical inactivity, alcohol consumption, poor dietary choices, and unsafe
sexual conduct. It is estimated that if such unhealthy behaviours could be
avoided or minimised, up to 2.8 million cancer cases would be prevented
each year.
Once cancers are diagnosed, lifestyle plays a significant role in achieving
the best outcome possible. Thus, with the increasing number of cancer
survivors (associated with improvements in prevention, early detection
and treatment, as well as increased population longevity), lifestyle-
related interventions should continue to be included in rehabilitation
programmes. These programmes include an array of diversified activi-
ties: information and counselling on possible changes of lifestyle and
behaviour, psychological support, social support, strategies for coping
with side effects of anticarcinogenic treatment, and additional treatment
of numerous clinical conditions.
Additionally, cancer survivors are at risk for recurrence, second malignant
neoplasm (SMN), and other psychological or physical conditions, including
cardiovascular disease and diabetes. These problems may result from can-
cer treatments, genetics, or lifestyle behaviours. Adopting healthier life-
styles reduces the risk of recurrence, and at the same time improves the
patients’ health-related quality of life (HRQoL) (e.g. patients experience
less fatigue).
115
In this chapter, we describe the benefits of lifestyle change for cancer
survivors. To achieve this general objective, lifestyle changes will be
framed in the global perspective of rehabilitation programmes.
Lifestyles and the Four Most Common Cancers

In the following sections, we review some of the evidence on the role of
lifestyle interventions for breast, lung, colorectal, and prostate cancer – the
four most common cancers worldwide. However, this does not imply a less
important role for lifestyle in the development and progression of other
types of cancer, as well as the development of chronic diseases.
Breast Cancer
For breast cancer survivors, maintaining regular physical activity, adopting
a healthy diet, and quitting smoking are important steps to enhance health
and well-being over the long-term, as well as attaining relapse-free
survival. However, post-intervention assessment of the maintenance of
physical activity and dietary outcomes in breast cancer survivors is rare.
Excess body weight is correlated with an increased risk of postmenopausal
breast cancer, and obesity is associated with poor prognosis in early-stage
breast cancer. Weight gain after breast cancer diagnosis also represents an
increased risk for poor outcome.
Breast cancer survivors have increased fruit and vegetable consumption,
higher physical activity, and decreased fat and meat intake. However,
evidence also shows that breast cancer survivors do not present with
changes in alcohol consumption, body mass index, or smoking when
compared with cancer-free women.
Physical activity has a key role in survival after breast cancer treatment: it
is safe, feasible, and promotes physical and psychological health benefits.
Post-treatment physical activity interventions result in small to moderate
effects on aerobic fitness, overall HRQoL, fatigue, and insulin-like growth
factor-1, and a reduction of treatment side effects. Compared with inactive
women, those who showed increased physical activity after diagnosis had a
45% lower risk of death, whereas women who decreased physical activity
after diagnosis had a four-fold increase in risk of death. In breast cancer
116 Pimentel
survivors, physical activity and dietary interventions have been demon-
strated as effective in producing short-term behavioural change. There are,
however, fewer data for maintenance of these behavioural changes.
There is also a link between breast cancer survival and history of smoking.
However, smoking appears to be more likely to increase all-cause mortality
as opposed to cancer-specific mortality.
Data on the contribution of socio-demographic factors to successful
changes in lifestyle behaviour are still inconsistent. Nevertheless, younger
women are more likely to implement changes, and associations between
low levels of education with lower levels of physical activity have also
been made.
Breast cancer diagnosis has been suggested as a “teachable moment”
when a woman is more receptive to make healthier lifestyle choices. Thus,
lifestyle recommendations must be provided, particularly: to achieve and
maintain a healthy weight; exercise at a moderate intensity for at least
150 min/week; consume a balanced diet, high in vegetables, fruits, and
whole grains; and limit alcohol consumption. Additionally, this is also an
opportunity to provide smoking cessation services.
Lung Cancer
Smoking has a key role in lung cancer. The prevalence of current smoking
among lung cancer survivors is relatively low (20.9%), but remains higher
among survivors of other smoking-related cancers (38.8%). In early-stage
small-cell lung cancer there is an association between continued smok-
ing and recurrence, as well as an increase in the incidence of a second
primary tumour. Additionally, it is estimated that patients with early-stage
lung cancer who quit smoking have a 70% chance of survival, compared
to a 33% chance if they continue to smoke.
Lung cancer survivors generally report lower HRQoL than other cancer
survivors. However, for those patients who increase exercise after
diagnosis, improvements are seen both in HRQoL and symptoms. In fact,
physical activity in lung cancer patients improves pulmonary function and
perfusion and decreases the risk of pneumonia and thrombotic events, and
thereby improves overall survival and HRQoL.
117 Lifestyle Changes 117

Many survivors of lung cancer have smoked cigarettes in the past, so they
also have a high risk of heart disease, stroke, emphysema, and chronic
bronchitis. Quitting can help improve lung function and has other health
benefits as well. Thus, people recovering from lung cancer must be encour-
aged to follow established guidelines for successful recovery.
Colorectal Cancer
For colorectal cancer survivors, healthy lifestyles (diet, physical activity,
low alcohol intake, smoking cessation, and obesity management) have
positive outcomes in terms of HRQoL and physical functioning, as well as
reduced morbidity and mortality.
Nevertheless, a high proportion of colorectal cancer survivors have
suboptimal health behaviours, and this is associated with a poorer HRQoL.
While the proportion of smokers and those who had consumed alcohol
is lower compared with the general population, excess weight is more
prevalent among colorectal survivors. Overweight colorectal cancer sur-
vivors are more likely to suffer from comorbid cardiovascular disease. In
addition, having received chemotherapy is significantly associated with
being overweight. Thus, reducing excess weight should be one of the
most important targets for intervention, particularly for males, those who
received chemotherapy, and those who are of lower socioeconomic status.
Despite these findings and recommendations, when comparing behaviours
from before and after diagnosis, few lifestyle changes are observed. Some
small changes are, however, observed in terms of fruit and vegetable intake
and physical activity. Lifestyle interventions in colorectal cancer patients,
implemented 6 to 24 months after primary treatment for colon cancer, were
found to produce significant impacts on dietary behaviour, fatigue, aerobic
exercise tolerance, functional capacity, and waist-to-hip ratio.
Initially, colorectal cancer patients can be sceptical about the role of diet
and physical activity as causes of cancer, in part because they believe their
lifestyles have been healthy. Thus, they cannot see how reinstating healthy
behaviours would reduce future disease risk. But ultimately, patients who
make and maintain dietary changes highlight the importance of these
changes in contributing to well-being and a sense of control in their life.
118 Pimentel
Therefore, personalised, evidence-informed guidance on lifestyle choices
must be part of care planning and should be built into survivorship
programmes for colorectal cancer patients. Interventions focusing
on weight management are particularly crucial, since they may reduce
functional decline and improve survival.
Prostate Cancer
In men with early-stage prostate cancer for whom “watchful waiting” was
the medical decision, undertaking major lifestyle changes for one year
was shown to improve prognosis (including reduced prostate-specific
antigen [PSA] levels). However, the intervention intensity required to
achieve these results might not be easily translatable into practice.
Engaging in more than three metabolic equivalent (MET) hours of weekly
physical activity post-diagnosis may reduce the risk of death by 35% in
prostate cancer patients. According to current evidence, smoking has not
been established as a critical factor in prostate cancer survival.
Lifestyle and Cancer In General

Surviving and recovering from a cancer diagnosis represents an
exceptional opportunity to change or improve lifestyle. Nonetheless,
many patients still maintain unhealthy habits in the post-cancer period.
United States (US) estimates (from 2009) show that these habits are still
highly prevalent among cancer survivors: 15.1% were current cigarette
smokers, 27.5% were obese, and 31.5% had not exercised during the
previous 30 days.
In fact, a cancer diagnosis has been shown to have somewhat contra-
dictory effects on lifestyle changes. Most studies found modest or no
differences between adult cancer survivors and individuals with no history
of cancer. However, others also identified positive influences on smoking
and diet and a negative influence on exercise. Even surviving childhood
cancer does not seem to influence lifestyle choices in adult age. The same
pattern is seen in young adult cancer survivors. Yet, data from 9105 cancer
survivors revealed a positive association between the number of lifestyle
recommendations being met and HRQoL.
Lifestyle Changes 119

Nutrition, Obesity, and Exercise
Obesity and energy imbalance (i.e. excessive energy intake and subopti-
mal levels of physical activity) are important factors after cancer diagnosis.
They influence the course of disease, as well as overall health, well-being,
and survival.
Healthy eating plans usually comprise the following goals: (1) meet
nutritional needs through diet alone, not diet supplements; (2) reduce
saturated fats; (3) increase fish intake; (3) reduce red meat intake and avoid
processed meat; (4) consume a varied diet to ensure adequate intake of
vitamins and essential minerals; (5) limit salt; and (6) increase consump-
tion of green and cruciferous vegetables, as well as brightly coloured fruits
and vegetables that contain carotenoids. For cancer patients, there are
even guidelines for “Informed Choices on Nutrition and Physical Activity
During and After Cancer Treatment”. However, a survey investigat-
ing clinicians´ knowledge of the risks and benefits of weight manage-
ment to cancer survivors indicated a lack of awareness of these guide-
lines. In addition, it was found clinicians tend to be overly cautious
when promoting lifestyle changes to cancer survivors. This perception is
corroborated by estimates of the diet in survivors of six major cancers,
which indicated that less than 20% of cancer survivors were meeting
adequate fruit and vegetable intake.
Therefore, despite these recommendations, obesity and sedentary lifestyles
remain highly prevalent among cancer survivors. This is particularly
serious when evidence shows an association between low levels of
physical activity as well as obesity and cancer recurrence and death in
several malignancies (including breast, colon, endometrium, and prostate
cancers). Several biological mechanisms have been proposed to explain
this relationship: changes in insulin-like growth factor levels, immune
regulation, sex and metabolic hormone levels, and prostaglandin ratio.
Of course, the adoption and maintenance of adequate levels of physi-
cal activity is a significant challenge for most healthy adults, and is
likely to be even more challenging after a cancer diagnosis. Frequently,
cancer diagnosis and treatment results in decreased physical activity. Even
survivors who were not exercising before diagnosis may experience declines.
120 Pimentel
Nevertheless, physical activity is usually well tolerated during and after
cancer treatment. Even in older patients, physical activity was found to be
beneficial; additionally, older patients also presented favourable responses
to dietary interventions, and were found to maintain these lifestyle changes,
ultimately leading to sustained weight loss.
Cancer survivors are recommended to do at least 30 minutes of moderate-
intensity physical activity on five or more days per week. There is a dose-
related response (more physical activity produces greater benefits), and
even a modest amount of exercise is beneficial versus doing nothing at all.
Physical activity programmes should, of course, be tailored to the clinical
situation and accompanied by a healthcare professional. Involving family
or friends in the exercise programme may also be beneficial, since it gives
the patient an extra motivation to keep going. However, despite these
benefits of physical activity, less than 50% of all cancer survivors report
meeting physical activity recommendations. Studies also show that cancer
survivors are actually more likely to be physically active than those
without cancer, but in any case most survivors remain insufficiently active.
Good nutritional and exercise habits in cancer patients are linked with
reduced risks of treatment side effects and increased HRQoL during
therapy. Benefits are seen with respect to fatigue, constipation, thrombo-
embolism, body composition, and psychological well-being. Adoption
of healthy lifestyles is linked to a reduction in the risk of recurrence and
improvement in survival.
Elderly long-term survivors of breast, prostate, and colorectal cancer
present a particularly high prevalence of suboptimal health behaviours.
Here, diet and exercise intervention reduces the rate of self-reported
functional decline. This intervention has been successfully undertaken
using telephone counselling and mailed print materials.
Lifestyle advice in the cancer context has been demonstrated as an accepta-
ble means of intervention. A population survey in the United Kingdom veri-
fied that most individuals with a history of cancer (or involved in social net-
works of people with cancer) think that lifestyle advice would be beneficial.
Therefore, it is important that healthcare professionals provide patients with
lifestyle recommendations, and, if necessary, make referrals in this regard.

On a general basis, cancer patients (and then survivors) should be advised
to embrace a healthy diet and exercise programme. This will allow them
to maintain a stable healthy weight, which can ultimately offer health
benefits in terms of general health condition, and may influence cancer
recurrence and death.
Smoking
Smoking is estimated to cause about 30% of all deaths from cancer. Thus,
avoiding all tobacco use is the most important single step individuals can
take to reduce the cancer burden.
Continued smoking after cancer diagnosis can: (1) reduce the effectiveness
of cancer therapies as well as increase their toxicity, (2) delay healing after
surgery, (3) impede patient recovery, (4) and decrease the patient’s chances
for survival.
Despite the evidence, many cancer survivors continue to smoke. Estimates
show a similar prevalence of smoking for US middle-aged or older adults
with or without a cancer history. However, for young adult cancer survi-
vors (18–44 years), smoking prevalence is 70% higher than for the remain-
ing population (40.4% vs 24.6%). In a survey of 9105 cancer survivors
from six major cancer areas, more than 80% of lung cancer survivors were
meeting the smoking recommendations. Nonetheless, tobacco use among
other tobacco-related cancer survivors remains higher than among other
cancer survivors and people without a history of cancer.
Quitting smoking is extremely difficult. Therefore, smoking cessation
services must be proposed to all cancer survivors, with programmes that
promote effective tobacco cessation. Cancer diagnosis and treatment have
been identified as a “teachable moment” for smoking cessation interven-
tions. Here, interventions should be as close to treatment as possible to
attain higher success rates. Higher quit rates are seen among patients with
smoking-related cancers, but one should be attentive to relapses, which
can occur after long periods of abstinence.
122 Pimentel
Summary
Surviving cancer is now an established reality for millions of people
worldwide, who need an adequate rehabilitation programme.
Cancer survivors are a vulnerable population, who are likely to benefit
from the choice of healthy lifestyle behaviours. However, most cancer
survivors are not currently adopting healthy behaviours, which ultimately
results in greater disease risk and healthcare costs.
While cancer survivors should have the same diet, weight, and physical
activity recommendations as the general population, there is also a need
for individual assessment and risk stratification. Particular attention should
be paid to high-risk patient groups: patients who have comorbidities, are
overweight, or are sedentary, as well as those who smoke.
Healthcare providers must understand and recognise the needs of cancer
survivors which are unique and different from other patients. These needs
are related to both the cancer disease and the cancer treatment, and require
surveillance and follow-up care frequently unknown to the healthcare
community. Healthcare systems must take this into consideration.
The increasing importance of nutrition and physical activity for cancer
survivors has been recognised in diverse guidelines. There are recommen-
dations for cancer survivors to have a treatment summary and survivorship
care plan to serve as a roadmap and a communication tool to optimise
co-ordination of care. Several models have been presented; however, the
“shared-care model” is proposed as the optimal approach to co-ordinate
activities between specialised cancer care and primary health care. These
models should, of course, be adapted to local health resources and person-
alised in accordance with the patient’s needs.
Due to the large and increasing number of cancer survivors, more research
is needed to evaluate the impact of lifestyle changes on health-related
outcomes in this population. Concurrent research also needs to address
the relative benefit in various subpopulations as defined by phenotype,
genotype, exposure to treatment, and other lifestyle and environmental
factors.

In conclusion, cancer survivors must be enrolled in rehabilitation pro-
grammes that include strategies to promote healthy lifestyles. Patients,
family, healthcare professionals, and even health systems must be engaged
in these efforts.
Dr Pimentel has reported no conflicts of interest.
Further Reading
Demark-Wahnefried W, Jones LW. Promoting a healthy lifestyle among cancer
survivors. Hematol Oncol Clin North Am 2008; 22:319–342.
Jang S, Prizment A, Haddad T, et al. Smoking and quality of life among female
survivors of breast, colorectal and endometrial cancers in a prospective
cohort study. J Cancer Surviv 2011; 5:115–522.
Johansen C. Rehabilitation of cancer patients – research perspectives. Acta
Oncol 2007; 46:441–445.
Ligibel J. Lifestyle factors in cancer survivorship. J Clin Oncol 2012;
30:3697–3704.
Pekmezi DW, Demark-Wahnefried W. Updated evidence in support of diet and
exercise interventions in cancer survivors. Acta Oncol 2011; 50:167–178.
World Cancer Research Fund, American Institute for Cancer Research. Food,
Nutrition, Physical Activity, and the Prevention of Cancer: a Global
Perspective, 2007. Available online at: http://www.dietandcancerreport.org/.
124 Pimentel
Survivorship Care Planning
J. M. Jones
12
D. Howell
Princess Margaret Cancer Centre, University Health Network,
University of Toronto, Toronto, ON, Canada
Introduction
Over 12 million new cases of cancer are diagnosed worldwide every year.
Encouragingly, due to improvements in early detection combined with
more effective treatments, mortality rates have dropped significantly over
the past three decades for some of the most prevalent cancers. As a result,
there are now over 28 million individuals worldwide living with a personal
history of cancer (“cancer survivors”). With continued projected increases
in the incidence of cancer and improvements in overall survival rates, this
number is expected to double by 2050.
While the increasing number of cancer survivors is a positive trend,
patients transitioning from primary cancer treatment to follow-up care,
termed the “re-entry phase”, face multiple adaptive physical, func-
tional, psychosocial, and spiritual tasks. The evidence suggests that the
majority of cancer survivors adjust well over the long term; however, a
number of unmet needs have been identified and very few cancer survi-
vors receive any comprehensive post-treatment survivorship care. It is
therefore not surprising that patients commonly report that they do not
know what to expect once treatment is over; some feel that they are not
being cared for and others describe feeling “abandoned”. Over the last
two decades, patient advocacy groups, expert consensus panels, and a
number of governmental reports have recommended improvement in
the quality of post-treatment survivorship care. These improvements
will ensure continuity of care and help to address the unmet needs of
125
cancer survivors, particularly their need for support as they transition
from acute cancer treatment to the follow-up phase of the trajectory.
In 2006, the Institute of Medicine (IOM) released a pivotal report “From
Cancer Patient to Cancer Survivor: Lost in Transition”, which identified
cancer survivorship as a distinct yet relatively neglected phase of the cancer
trajectory. The recommendations included in this report defined compo-
nents for clinical care, research, training, and education and catapulted the
“cancer survivorship” movement and related initiatives in the United States,
Canada, Australia, and countries across Europe. Since that time, there has
been agreement on the essential elements of survivorship care delivery,
which include: surveillance for recurrence of the primary cancer and screen-
ing for new cancers; assessment of medical and psychosocial late effects;
development of interventions for addressing the consequences of cancer
and its treatment; health promotion; and better co-ordination of care
between oncology specialists and primary care practitioners.
The definition of rehabilitation in cancer care closely aligns with the
philosophy of survivorship care with its focus on rebuilding the lives of
people with cancer and maximising functioning as well as quality of life.
In fact, some suggest rehabilitation could be considered “a surrogate” for
survivorship care due to their overlapping objectives. Rehabilitation for
late effects is identified as an essential high-need element of survivorship
care delivery and further integration of a rehabilitation approach and/or
specific cancer-focused rehabilitation services in survivorship care plan-
ning and service delivery requires further development.
Survivorship Care Plans

One of the key recommendations of the IOM report is the need for
follow-up “survivorship care plans” (SCPs) to prepare survivors for tran-
sition from the active treatment to the post-treatment survivorship phase
of the cancer trajectory (Figure 1). These plans of care are essential tools
to empower and inform both survivors and primary care practitioners of
the follow-up care, screening and surveillance monitoring required. It is
recommended that all patients completing primary cancer treatment should
receive a written SCP delivered in a designated clinic visit to facilitate the
126 Jones and Howell

transition to the lifelong surveillance and follow-up phase of cancer care.
SCPs are a communication tool for patients and defined as a dynamic,
comprehensive care summary and follow-up plan written by the principal
provider(s) of oncology treatment.
Post-treatment Survivorship care plan Survivorship programmes
care plan components
• P ost-treatment 1. Information about timing Multidisciplinary care: focused on the
summary and content of follow-up specialist rather than the primary care provider;
the key provider in these survivorship models
• Advice on 2. Identification and has been the cancer specialty team
screening for new management of late and
cancers long-term effects Integrated care: emphasis on establishing
• S urveillance for 3. Recommendations for primary care-based support for the survivor
recurrence healthy living, diet, exercise, with the expectation that communication
between the oncology team and primary care
and smoking cessation provider will continue
•C
are co-ordination
strategy with 4. Information about financial
primary care benefits and return to work Rehabilitation: enhances recovery after
practitioners acute illnesses through vocational rehabilitation
5. Referral to specialists that promotes return to functional capacity
•O
ngoing symptom including psychological and and well-being
management social support
Self-management: promote skills for
• Health promotion 6. Family and caregiver chronic illness management including problem
support solving, decision-making, making the best use of
professionals, and taking action
Figure 1 Critical elements of survivorship care planning. Republished with permission

of John Wiley & Sons, Inc., from McCabe M, et al. Survivorship programs and care
planning. Cancer 2013; 119(11 Suppl):2179–2186; permission conveyed through
Copyright Clearance Center, Inc.
The basic components recommended for inclusion in a SCP are as follows:

n Cancer type, treatments received, and their potential consequences

n Specific information about the timing and content of recommended

follow-up
n Recommendations regarding preventive practices and how to maintain

health and well-being

n Information on legal protections regarding employment and access to

health insurance, and

n Information about available psychosocial services in the community
Survivorship Care Planning 127

More recently, the American Society of Clinical Oncology (ASCO) has
also recommended a number of additional care components to consider
in the development of SCPs and survivorship care delivery, including:
(1) account for the increased risk for other chronic diseases and outline
methods to address this risk; (2) assess and address psychosocial needs;
(3) information about fertility planning for patients at reproductive age;
(4) known side effects (persistent and late effects) of cancer and treatment;
(5) screening guidelines and symptoms of recurrence including secondary
primaries; (6) discuss and incorporate survivors’ values and preferences
regarding their care; (7) use discussions about cancer-related concerns as
teachable moments to educate survivors about behaviour change: tobacco
cessation, obesity control, reduction in alcohol use, and other health pro-
motion issues, i.e. exercise. These elements are synonymous with prefer-
ences for SCP components identified by cancer patients and a need for
education about late and long-term effects of treatment and access to
resources/referrals for clinical management.
As a clinical tool, the SCP can be used to prepare patients for the transi-
tion to post-treatment care. In addition, the SCP has the potential to foster
patient use of self-care strategies that manage the ongoing effects of treat-
ment, while facilitating the uptake of health behaviours that have the poten-
tial to reduce the risk of future complications The inclusion of standardised
information in the SCP may also help to reduce variation in clinical practice
and help to foster improvement in the quality of transition care processes.
Globally, over the past decade there has been growing momentum in the
implementation of SCPs, and various types of care plans and SCP tem-
plates have now emerged in response to the IOM recommendations.
Regardless of differing adaptations of the SCP, there is consensus that the
essential IOM elements should be addressed and that SCPs are a core ele-
ment of survivorship care delivery and a standard of quality care for cancer
programmes.
Ultimately, SCPs must be tailored to the individual and consideration
given to differences in risk for late and long-term effects based on factors
such as patients’ age, their type and stage of cancer, treatments received,
degree and intensity of follow-up care required, and the needs for clini-
cal and rehabilitation interventions. Active engagement of patients in
the development of care plans that emphasise their role in their recov-
ery is important. An explanation should be given, detailing the various
health sector professionals who are available to offer guidance and sup-
port in the surveillance and clinical management of late and long-term
effects of treatment. SCPs are considered an essential tool to facilitate
communication among healthcare sectors and could help the transition of
patients to primary care and leverage changes in healthcare integration.
Progress in Survivorship Care Delivery

The development of cancer survivorship initiatives in North America,
including the development and implementation of SCPs, has been influ-
enced by organisations such as the IOM, National Cancer Institute (NCI),
ASCO, the American Cancer Society (ACS), the National Comprehensive
Cancer Network (NCCN), and the Canadian Partnership Against Cancer
(CPAC). In both the USA and Canada, a growing number of institutions
have developed SCPs for their patients. In addition, a handful of internet-
based SCPs are also available including the LIVESTRONG Care Plan
(www.livestrongcareplan.org), which provides a tailored SCP that may be
printed or stored electronically in portable document format. Data from
the first three years since the launch of the LIVESTRONG Care Plan
demonstrated increasing use by survivors from nearly every continent,
with international users accounting for 16% of total users. Other exam-
ples of web-based SCPs include the Journey Forward, which integrates
current follow-up care guidelines and tailored links to educational materi-
als (www.journeyforward.org), and SCP templates developed by ASCO
based on current follow-up guidelines (http://www.cancer.net/survivorship/
asco-cancer-treatment-summaries). Despite these initiatives, the reality is
that most cancer survivors in North America still do not receive SCPs and,
when they do, most SCPs fail to include all of the IOM-recommended
elements.
In Europe, recognition of the need for the development of survivorship
programmes and SCPs is variable across countries. The majority of coun-
tries have yet to include survivorship in national cancer plans. In spite of
this variation, European initiatives in cancer survivorship do exist in a
number of countries, with dedication of some resources to post-treatment

care and rehabilitation. The National Cancer Survivorship Initiative
(NCSI) in the UK has emerged as a leader of survivorship care in Europe.
It has put into practice an approach to care that includes the main features
of SCPs (www.ncsi.org.uk). In this programme, a clinical nurse specialist
is assigned to each patient and is the main contact for the entire course of
treatment and follow-up care. The nurse conducts regular holistic assess-
ments to provide targeted and personalised care and support to each per-
son. At the end of treatment a SCP is provided to the primary care
physician and the patient’s follow-up care is based on a risk-stratified
pathway. Pan-European organisations such as the European Cancer League
(ECL) and the European Oncology Nursing Society (EONS) are also
advocating collaboration regarding cancer survivorship among medical
organisations such as the European Society for Medical Oncology (ESMO)
with education on survivorship at annual meetings. With the exception of
NCSI, SCP initiatives have yet to emerge, though there have been
published descriptions of rehabilitation discharge papers provided by
oncologists to family physicians that outline plans for follow-up care.
Despite consensus on the need for SCPs as an essential element of
survivorship care delivery, to date there has been limited formal evaluation
of these plans and their implementation among cancer survivors. Conse-
quently, the impact of SCPs on reducing cancer-related morbidity and
mortality is one of the major issues still to be addressed. A handful of stud-
ies have provided preliminary evaluation data on SCPs. These studies have
included both qualitative and quantitative approaches. In general SCPs are
highly rated by patients and health professionals and are perceived as use-
ful tools to facilitate co-ordination of care post-treatment. In a study by
Shalom and colleagues (2011), healthcare providers reported that SCPs
increased their feelings of confidence and care for patients post-treatment.
Benefits for patients have included increased knowledge and understand-
ing of post-treatment care and enhanced feelings of well-being. Evalua-
tions of the online LIVESTRONG and Journey Forward plans have dem-
onstrated high satisfaction among users. Evaluation of the UK NCSI
programme reported improvements in patient satisfaction and confidence,
and reductions in healthcare utilisation and costs. The largest randomised
controlled study of SCPs to date was conducted by Grunfeld and

colleagues (2011) and included 408 breast cancer survivors, at a median 35
months post-treatment, whose care was being transferred back to primary
care. Participants randomised to the intervention group received a SCP
with a 30-minute educational session with a nurse. The study results did
not find that the intervention improved distress (primary outcome) or qual-
ity of life, patient satisfaction, or continuity of care (secondary outcomes).
Since its publication, a number of authors have provided alternative expla-
nations of the results, highlighting the urgent need to identify relevant
outcomes and populations that would derive the most benefit from SCPs.
Further high-quality research on SCPs is needed.
While further efficacy studies are clearly warranted, the provision of SCPs
is now viewed as an essential element of cancer care and their delivery is
now being required as part of accreditation in order to standardise current
practice in the USA. For example, by 2015 the American College of
Surgeons (ACS) Commission on Cancer will require that ACS-accredited
facilities, which treat approximately 70% of newly diagnosed cancer
patients in the United States, provide SCPs to all patients. Thus, there is
also a need to evaluate the viability of SCPs and the care processes
necessary for their effective delivery in the context of overloaded clinical
oncology care delivery. Numerous challenges to implementation have
been identified including workforce and reimbursement issues, absence of
guidelines to inform care plans, and lack of training for both those who
deliver SCPs and primary care providers. Given the volume of patients in
ambulatory cancer treatment centres, a feasible SCP will need to be effi-
cient. In a recent US survey of healthcare providers, the majority of oncol-
ogists reported that SCPs should take no more than 20 minutes. In reality,
Stricker and colleagues (2011), who recently reviewed SCPs delivered
within the LIVESTRONG Network of Cancer Survivorship Centers in the
USA, found that one-third of sites providing SCPs spend more than
60 minutes just to create the SCP, with the majority reporting an additional
15–60 minutes delivering the SCP to the patient. Studies are underway to
determine the feasibility of implementing SCPs as part of standard prac-
tice that will generate knowledge for application by others. In addition, an
electronic solution for care plan development is recommended as a key
priority in future research. Engaging key stakeholders throughout the

implementation process and using effective knowledge translation strategies
inclusive of training programmes for SCP providers that include person-
centred communication are fundamental to uptake as part of routine care.
It must be recognised that a SCP is only one of the essential elements
of survivorship care delivery for which there is now consensus. Other
elements must also be considered to ensure the development of quality sur-
vivorship care delivery models and processes of care and to meet the multi-
dimensional needs of cancer survivors. These elements also include health
promotion education, care co-ordination strategies, late effects education
and programmes to reduce risk (i.e. weight management), comprehensive
medical and psychosocial assessment, rehabilitation programmes, and
patient navigation. In addition, strive elements such as self-advocacy train-
ing, medical education, counselling, clear pathways for access to specialist
care, and population-based quality improvement are equally important.
Summary/Future Directions
The burgeoning population of cancer survivors can no longer be
ignored and healthcare sectors must work collaboratively to address the
multidimensional needs of this population. A number of landmark reports
provide clear direction on the essential elements of survivorship care
delivery to address these needs. Significant variation in the application of
these essential elements is reported, but their application may improve
further with elements such as SCPs, endorsed as part of accreditation
standards. Consensus on the integration of SCPs in routine care delivery to
facilitate the transition of patients from active treatment to follow-up care
suggests this is a high priority that is actionable and supported by a clear
evidence base. However, further research on the best approaches for facili-
tating uptake in real-world settings and their effectiveness for improving
outcomes is warranted. The integration of a rehabilitation approach and
specific cancer-focused rehabilitation services is an essential high-need
element of survivorship care delivery. It requires further development and
integration within survivorship care programmes and may be essential to
realise health outcomes. Efforts are under way to prioritise the most essen-
tial elements of survivorship care delivery that may provide the lessons
learned for uptake by other healthcare organisations and the investments

needed. As noted by Earle (2012), just starting the adoption of essential
elements is a beginning, as trying to achieve perfection may be the enemy
of the good. The IOM suggests some elements of care simply make sense
to improve survivors’ experience of living with cancer.
Dr Jones has reported no conflicts of interest.
Dr Howell has reported no conflicts of interest.
Further Reading
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quality-programs/cancer/coc.
Centre for Disease Control. A National Action Plan for Cancer Survivorship:
Advancing Public Health Strategies. Atlanta, GA: CDC; 2004. Available at:
http://www.cdc.gov/cancer/survivorship/pdf/plan.pdf.
Commission of the European Communities. Communication from the Commis-
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Grunfeld E, Julian JA, Pond G, et al. Evaluating survivorship care plans: results
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Index
References to tables are indicated by ‘t’, as in ‘Busulfan, 91t’.

References to figures are indicated by ‘f’, as in ‘Verbal pain scale, 16f’.
A breakthrough pain and, 12t, 22t,

26, 31–32
A-CaRe programme, 110, 111 characteristics of effective, 16t, 21,
Acetaminophen. See Paracetamol 22f, 35
5-Acetyl salicylic acid (ASA), 59t in hormonal therapy-related pain, 20
Acrolein, 81, 82 in neuropathic pain, 29, 31, 32–33,
Actinomycin D, 91t 34t
Acute herpetic neuralgia, 19 opioid switching, 33, 34
Acute pain, 12t, 15, 17, 18 in paronychia, 62
Acute phase reactions, 21 pharmacological approaches,
Adjustment disorders, 47, 48 49, 49t, 21–30
50 in procedural-related pain, 17
Adjuvant therapy in refractory pain, 34
body composition changes, 4 in supportive therapy-related pain,
exercise during, 3 21
Adoption, 95 under-treatment, 14t
Allodynia, 14t WHO recommendations, 21, 25t,
American Cancer Society (ACS), 8, 35
129 Androgen-suppression therapy, bone
American College of Sports Medicine density and, 2, 4
(ACSM), 8 Anthracyclines, 2
American College of Surgeons Antibacterial drugs
Commission on Cancer, 131 in paronychia, 62
American Society of Clinical in SIBO, 73
Oncology (ASCO), 83, 128, 129 Anticonvulsants, 22t, 31
Amifostine, 58t, 59t Antifibrinolytic therapy, 79
Amitriptyline, 31, 33 Anti-Müllerian hormone, 94
Anal tumours, 72t Anxiety, 11t, 15, 39, 40–41, 47–51, 88
Analgesia. See also specific agents Aromatase inhibitors, 20–21
adjuvant drugs, 14, 22, 30–31 Arrhythmias, 2
algorithm for sequential approach, Arthralgia, 19, 20
22f
in bone pain, 32
136
B prevalence, 38
treatment, 41–45
Bacillus Calmette-Guerin (BCG), 82 Capecitabine, 19
Bacitracin, clotrimazole, gentamicin Carbamazepine, 31
(BCoG), 58t Carboplatin, 91t
Benzydamine, 57t Cardiopulmonary exercise testing
Biofeedback, 51, 69, 80 (CPET), 3
Bisphosphonates, 21, 32 Cardiorespiratory fitness, 2–3
Bleomycin, 91t Cardiovascular disease, 4, 80, 115,
Bone density, 4, 6 118
Bone marrow biopsy/aspiration, drug-induced, 2
analgesia during, 17 Carers, 102
Bone pain, 12t, 21, 32 l-Carnitine, 45
Brachytherapy, 81, 20 Central pain, 14t, 31
Brain cancer, 98 Central sensitisation, 17
Breakthrough pain, 12t, 22t, 26, 31–32 Cervical cancer, 93
Breast cancer Childhood Cancer Survivor Study,
fertility and, 83, 90, 92, 93 94–95
lifestyle interventions, 116–117 Child–parent relationships, 100–101
pain, 18 Chlorambucil, 91t
physical activity and, 7, 116 Chlorhexidine, 58t
Brief Fatigue Inventory, 41 Chlorimipramine, 31
British Association of Sport and Cholestyramine, 73
Exercise Science, 8 Chondroitin sulphate (intravesicular),
Buprenorphine, 22, 28t, 30 79
Bupropion, 45 Chronic gastrointestinal sequelae
Busulfan, 91t clinical approach, 71–73
diagnostic tests, 73
C dietetic support, 74
management, 73–74
Canadian Partnership Against Cancer
tumour sites, 72t
(CPAC), 129
Chronic kidney disease, opioids in, 30
Cancer survivors
Chronic pain
challenges for, 125–126
defined, 12t
survival rates, 125
syndromes, 12–13t, 18
survivorship care plans, 126–133
Cisplatin, 2, 19, 82, 91t
Cancer-related fatigue (CrF)
Clinical nurse specialists, 130
defined, 37–38
Clonazepam, 31
diagnostic approach, 40–41
Codeine, 22, 23t, 26t
influencing factors, 39
Coeliac plexus block, 34
NCCN treatment algorithm, 42f
Index 137
Cognitive behavioural interventions, Diarrhoea, 55, 59, 66, 70, 72t
44, 52 Dietetic support, 69, 74
Cognitive disorders, 40, 49 Dihydrocodeine, 23t
Colorectal cancer Diphenhydramine, 82
chronic gastrointestinal sequelae, Distress, 39, 47–48, 50, 98–100, 131
72t Doxepin, 57t
lifestyle interventions, 118–119 Doxorubicin, 19, 82, 91t
Communication skills, 88, 103 Dysaesthesia, 19, 14t
Compensation, 112–113 Dysphagia, 71, 72t
Complementary medicine, 44
Comprehensive Cancer Center the
Netherlands, 8
E
Constipation, 13t, 15, 25t, 26t 30, 66, Edmonton Symptom Assessment
71, 72t, 73t, 121 System (ESAS), 15
Coping skills training, 52 EGFR inhibitors, 61
Corticosteroids Emollients, 60
as co-analgesics, 31 Employment
‘steroid pseudorheumatism,’ 19 cancer-related fatigue and, 38
Cryotherapy, 57t factors affecting return to work,
Cyclophosphamide, 81, 91t 109t
CYP2D6, 23t, 26t job loss, 108
CYP3A4, 25t occupational cancer, 112
Cystitis, 77, 78, 81, 82 palliative support, 111–112
Cystoscopy, 78, 79 ‘return to work’ interventions, 111
‘stay at work’ interventions, 110
Endometrioid uterine, 93
D EORTC FA13, 41
Delirium, 28t, 30, 49t, 50 Epidural analgesia, 18, 34
Denosumab, 21, 32 Epinephrine, 82
Depression Epirubicin, 82
cancer-related fatigue and, 40–41 Episodic pain, 12t, 22, 31–32
epidemiology, 49, 50 Erectile dysfunction, 80–84
screening tool, 15 Erosion, 55
sexual function and, 89 Erythema, 20t, 55, 61, 62
Desipramine, 31 Ethoglucid, 82
Dexamethasone, 31 European Cancer League (ECL), 130
Dextropropoxyphene, 22, 24t European Oncology Nursing Society
Diagnostic and Statistical Manual of (EONS), 130
Mental Disorders (DSM), 49 European Society for Medical
Diamorphine, 22, 27t Oncology (ESMO), 54, 56, 130
138 Index
Exercise and Sport Science Australia, Fluoxetine, 31
8 Follicular stimulating hormone (FSH),
Exercise capacity. See also Physical 94
activity Formalin (intravesicular), 79
bone density, 4 From cancer patient to cancer
cardiorespiratory fitness, 2–3, 5, 8 survivor: lost in transition
defined, 1–2 (Institute of Medicine), 126
fat mass, 4
muscle wasting, 3
peakVO2 and, 1–2
G
reduced bone health, 4 Gabapentin, 31, 33
Existential distress, 50 Gastrointestinal sequelae
acute, 70
chronic, 71–74
F overview, 66
FACIT Fa module, 41 pathophysiology, 68–69
Faecal incontinence, 67 German Cancer Association, 8
Families, impact of diagnosis, 99–102 Ginseng, 45
Fat mass, 4 Glucose metabolism, and muscle
Fatigue. See Cancer-related fatigue wasting, 3
Fentanyl, 27t, 30–32, 57t Glutamine, 58t
Fertility Gonadotoxicity, 91t
evaluation after cancer treatment, Gonadotrophin releasing hormone
94 agonists (GnRHa), 92
female, 92–93 Granulocyte-colony stimulating factor
gonadotoxic potential of cancer (G-CSF), 21
treatments, 91t, 93 Granulocyte–macrophage colony-
issues in cancer patients, 83–84, stimulating factor (GM-CSF), 58t
90, 95–96 Guarana, 45
male, 94 Gynaecological tumours, 8, 72t, 87, 93
Financial issues
factors affecting return to work,
109t
H
health insurance, 106, 107 Haemorrhagic cystitis, 78t, 81–82
interventions, 110–112 Hand–foot syndrome, 19
job loss, 108 Health insurance, 106, 107, 110
occupational cancer, 112–113 Healthy eating plans, 120
rehabilitation and, 107 Hormone therapy
Flatulence, 71, 72t bone health and, 4
Fluorouracil, 19, 57, 91t pain related to, 20–21
Index 139
Hyaluronic acid (intravesicular), 79 K
Hydromorphone, 22, 26t, 28t, 30
Hyperaesthesia, 14t Keratinocyte growth factor-1 (KGF-1),
Hyperalgesia, 26t, 14t 57t
Hyperbaric oxygen therapy, 59t, 79
Hypercalcaemia, 32 L
Hyperpathia, 14t
Laser therapy, 57t
Hypogonadism, 4, 30
Letrozole, 92
Leukopenia, 82
I Leuprorelin, 92
Ifosfamide, 81, 91t Levorphanol, 22, 28t
Imipramine, 31 Lidocaine, 31, 62
Immediate-release morphine sulphate, Lifestyle interventions
31–32 in all cancers, 119–124
Impotence, 80 in breast cancer, 116–117
Infertility. See Fertility in colorectal cancer, 118–119
Institute of Medicine (IOM), 126, 128, in lung cancer, 117–118
129, 133 nutrition, obesity, and exercise,
Insulin-like growth factor-1, 5, 116, 120–122
120 overview, 115–116
Interferon-α therapy, 39 in prostate cancer, 119
Interleukin therapy, 39 smoking cessation, 122
International Classification of Liposomal doxorubicin, 19
Diseases (ICD), 38, 49 LIVESTRONG Care Plan, 129–131
Internet groups, 102 Local anaesthetics (see also
Intracytoplasmic sperm injection Lidocaine), 31
(ICSI), 83 Loneliness, 103,
Intrathecal analgesia, 34 Loperamide, 59t, 73
Intravesical chemotherapy, 82 Lumbar puncture, 17
In-vitro fertilisation (IVF), 83 Lung cancer, 5, 87, 117–118
Irinotecan, 91t Lymphoedema, 2, 8, 18
Iseganan, 58t
Isolation, 103 M
Malabsorption, 30, 67, 68, 72t, 73, 74
J Melphalan, 57, 91t
Job loss, 108 Mesalazine, 59t
Journey Forward, 129, 130 Mesna, 82
140 Index
Metastases N
base of skull, 12t
bone, 21, 32, 33 Nail infections. See Paronychia
causing back pain/spinal Naloxone, 22, 26t, 28t, 30
compression, 13t Naproxen, 21
vertebral body, 12t National Cancer Institute (NCI), 129
Methadone, 22, 24t, 25t, 28t, 30 National Cancer Survivorship
Methotrexate, 91t Initiative (NCSI), 73, 130
Methylphenidate, 44 National Comprehensive Cancer
Metronidazole, 73 Network, 56, 66, 129
Mindfulness-based stress reduction Nausea,15, 25t, 27t, 30, 41, 52, 71, 72t
(MBSR), 44 Necrosis, 13t, 78t, 81
Misoprostol, 58t, 59t Nephrotoxicity, 82
Mitomycin C, 82 Nerve blocks, 17, 34
Mitoxantrone, 82 Neuritis, 34
Modafinil, 44 Neurogenic bladder dysfunction,
Morphine, 19, 22, 23t, 25t, 26t, 29–32, 84–85
57t Neuroma, 18
MTOR inhibitors, 61 Neuropathic pain, 12, 14t, 19
Mucositis treatment, 27, 28t, 29, 31, 32–33,
clinical features, 55 34t
economic impact, 55–56 Neutropenia, 70
epidemiology, 54–55 Nitrogen mustard, 91t
management, 18, 56, 57–59t Nociceptive pain, 14t
MASCC/ISOO Guidelines, 56, Non-steroidal anti-inhibitory drug
57–59t (NSAID), 17, 21, 22, 22t, 29, 62
pain, due to, 13t, 18, 20 Nortriptyline, 31
Multidimensional Fatigue Inventory
(MFI), 41 O
Multinational Association of
Obesity
Supportive Care in Cancer/
after cancer treatment, 4
International Society of Oral
breast cancer and, 116
Oncology (MASCC/ISOO)
colorectal cancer and, 118
Mucositis Guidelines, 56, 57–59t
lifestyle interventions, 120–122
Muscle mass/strength
Occupational cancer, 112–113
reduced, 3
Octreotide, 58t
resistance exercise and, 5–6
Oestrogen deficiency, bone health
Myalgia, 13t, 18, 19, 20
and, 4
Olsalazine, 59t
Index 141
Opioids Pancreatic insufficiency, 67t, 68, 73t
intrathecal administration, 34 Paracetamol, 21–23, 23t, 26t, 29, 62
in mild to moderate pain, 22t, Paraesthesia, 14t
23–24t, 29 Parent–child relationships, 100–101
in moderate to severe pain, 22t, Paronychia, 20, 54
25–29t, 29–30 clinical features, 61–62
in neuropathic pain, 32–33 management, 62–63
overview, 22–23 Paroxetine, 45
in procedural-related pain, 17 Patient-controlled analgesia (PCA),
route of administration, 30, 31–32 18, 57t
in severe mucositis, 18 PeakVO2 (peak oxygen uptake), 2–3
switching, 33 Pegfilgrastim, 21
ORBIT trial, 71 Pelvic floor exercises, 69, 80
Ovarian cancer, 93 Pelvic surgery, complications, 84–85
Oxaliplatin, 19, 91t Pentoxifylline, 58t
Oxycodone, 22, 24t, 26t, 30 Peripheral neuropathy, 13t, 19, 85
Oxymorphone, 22, 26t, 29t Personalised pain assessment, 15–16
Phenytoin, 31
Phosphodiesterase-5 inhibitors, 80
P Physical activity
Paclitaxel, treatment-related pain, 19 benefits for cancer patients, 4–6
Pain. See also Analgesia breast cancer and, 116–117
central sensitisation, 17 cancer outcomes and, 7
chronic pain syndromes, 12–13t in cancer-related fatigue, 43
defined, 11 cardiorespiratory fitness and, 2
neuropathic, 14t, 19, 28t, 29, factors affecting exercise capacity,
31–33, 34t 1–4
pathophysiology, 11, 14t guidelines, 8–9
personalised assessment of, 15–16 lifestyle interventions, 120–122
procedural-related, 17 lung cancer and, 117
refractory, 34 peakVO2 and, 2–3
temporal classification, 12t prostate cancer and, 119
treatment-related, 13t, 15t, 18–21 Physical Activity across the Cancer
Pain assessment tools, 15–16t Continuum (PACC) framework,
Palifermin, 57t 4–5
Palliative patients Pilocarpine, 58t
physical activity, 6 Polymyxin, tobramycin, amphotericin
workplace support, 111–112 B (PTA), 58t
Palmar–plantar erythrodysaesthesia Postchemotherapy pain syndrome, 13t
syndrome, 19 Post-dural puncture headache, 17
142 Index
Postoperative pain syndrome, 13t gastrointestinal sequelae and, 66,
Postradiation pain syndrome, 13t 67–68, 72t, 74
Post-traumatic stress disorder, 47, 48, lifestyle and, 115
49t mucositis and, 55
Potassium aluminium sulphate physical fitness and, 1–2, 4
(intravesicular), 79 poverty and, 47
Povidone-iodine, 62 sexual function and, 87, 88,
Pregabalin, 31 social issues and, 98, 103, 104
Pregnancy, after cancer, 92–93, 95 survivorship care and, 126, 131
Prehabilitation (‘stay at work’ urological complications and,
interventions), 108, 110 78–79, 81
Premature ovarian failure, 92 Quinolones, 62, 73
Probiotics, 59t
Procarbazine, 91t
Procedural-related pain, 17
R
Proglumide, 23t Radiation cystitis
Prostate cancer, 4, 7, 13t, 59t, 77, 81, clinical features, 78
102, 108, 119 RTOG grading, 78t
Psychoeducation, 43–44, 52 treatment, 79–80
Psychological assessment, 40–41 Radiation Therapy Oncology Group
Psychological deterioration (RTOG), 78t, 78
distress, 47–48 Radiotherapy
loneliness and isolation, 103 cardiorespiratory side effects, 2
mental disorders, 49–50 fibrosis related to, 2, 13t, 20t, 31
reactions to cancer diagnosis, 47 gonadotoxicity, 83, 91t, 93
sexual function and, 89 pain related to, 12t, 13t, 19, 20t
social problems, 98–99 radiation cystitis, 77–80
treatment options, 51–52 RTOG grading for urological
Psychostimulants, 44 complications, 78t
Psychotherapeutic interventions, sexual dysfunction, 80
43–45, 51–52 Refractory pain, 34
Pyogenic granuloma, 61, 62 Rehabilitation, 37–38, 107, 110, 115,
126, 127f, 132
Relationships, 99–102
Q Renal dysfunction, chemotherapy-
Quality of life (QoL) induced, 82
cancer-related fatigue and, 37 Resistance exercise, 5–6, 8
Dutch A-CaRe, 111 Retching, 71
fatigue and, 44 ‘Return to work’, 111
Rifaximin, 73
Index 143
S Spouses, impact of diagnosis, 99–100
START trial, 7
Salvage cystectomy, 79 ‘Stay at work’, 110
Selective serotonin reuptake inhibitors ‘Steroid pseudorheumatism,’ 13t, 19
(SSRIs), 45 Stress incontinence, 80
Self-care strategies, 43, 128 Stressors, distress and, 48f
Self-rating measurement, in cancer- Sucralfate, 58t, 59t
related fatigue, 41 Suicidal thoughts, 50
Sensory neuropathy, 19 Sulfasalazine, 59t
Serotonin syndrome, 23t Supportive therapy-related pain, 21
Sexual function Survivorship care
after pelvic surgery, 84 challenges for cancer survivors,
brachytherapy and, 81 125–126
cancer and, 87, 88 financial issues, 107
communication skills, 88–89 future directions, 132–133
physical limitations, 89 IOM recommendations, 126
psychological issues, 89 patient engagement, 128–129
quality of life and, 87, 88, 95 progress in, 129–132
radiotherapy and, 80 research, 130–131
Silver nitrate (intravesicular), 79 survival rates, 125
Skin complaints survivorship care plans (SCPs),
overview, 56, 60 126–133
preventive measures, 60–61
Skull-base metastases, 12t
Sleeping disorders, 39, 40 T
Small intestinal bacterial overgrowth Tapentadol, 22, 24t, 29
(SIBO), 67t, 68, 71, 73t, 73 Targeted therapy-related pain, 19, 20t
Smoking, 117–118, 119, 122, 127t Taxanes, 91
Social issues Testicular cancer, 87, 94
communication, 103 Testosterone, 3, 4, 7, 30, 94
distress and, 98–99 Tetracyclines, 62, 73
loneliness and isolation, 103 Thiotepa, 82
relationships, 99–102 Total parenteral nutrition (TPN), 55
social support, 103–104 Thrombocytopenia, 82
Social media, 98 Tramadol, 22, 23t
Somatic nociceptive pain, 14t Transdermal opioids, 18, 27t, 28t, 30,
Sperm banking, 83, 94 57
Spermatogenesis, 94 Transitional cell carcinoma, 82
Spinal analgesia (see also Intrathecal Transurethral prostatic resection, 80
or Epidural analgesia), 34
144 Index
Treatment-related pain V
hormonal therapy-related, 20–21
prevalence, 18 Valproic acid, 31
radiotherapy-related, 13t, 19, 20t Verbal pain scale, 16f
supportive therapy-related, 21 Vertebral body metastases, 12t
targeted therapy-related, 19, 20t Vincristine, 19, 91t
Tricyclic antidepressants, 30–31, 33 Vinorelbine, 19
Tyrosine kinase inhibitors, 91t Visceral neurocieptive pain, 14t
Visual analogue scale, 16f
U W
Ulceration, 18, 55, 68, 78, 81
Unemployment. See Employment Weakness, 3, 37
Urinary incontinence, 80–81 World Health Organisation (WHO),
Urinary retention, 81, 84, 85 recommendations for analgesia
Urological complications in cancer pain, 21, 25t, 35
after brachytherapy, 81
after intravesical chemotherapy, 82 Z
after pelvic surgery, 84–85
Zinc supplements, 57t
haemorrhagic cystitis, 78t, 81–82
Zoledronic acid, 32
infertility, 83–84, 90, 92
radiation cystitis, 77–80
sexual dysfunction, 80, 84, 88
urinary incontinence, 80–81
Urological tumours, chronic
gastrointestinal sequelae, 72t
Uterine transplantation, 93
Index 145

fatigue
Edited by Henk van Halteren www.esmo.org
The ESMO Handbook of Rehabilitation Issues During Cancer Treatment

and Follow-Up is intended primarily to be read by physicians working
in the field of medical oncology. The aim of this publication is to
provide key information in the form of a comprehensive and well-
arranged handbook that will help physicians gain better understanding
of the issues surrounding patient rehabilitation. chronic pain lifestyle changes
This kind of book is currently lacking in the field of medical oncology

and is envisioned to be an important and useful new resource for
medical oncologists. This volume deals with clinical topics such as
pain, fatigue and gastrointestinal sequelae and also discusses other
aspects such as social and financial issues and lifestyle changes.
physical complaints psychological complaints
mucocutaneous changes gastrointestinal

sequelae

European Society for Medical Oncology REHABILITATION ISSUES DURING
Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland
Edited by Henk van Halteren
ESMO Press · ISBN 978-88-906359-5-3
ISBN 978-88-906359-5-3
decreased exercise capacity

urological sequelae
www.esmo.org 9 788890 635953 social issues ESMO Handbook Series
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REHABILITATION ISSUES DURING

CANCER TREATMENT AND FOLLOW-UP

The ESMO Handbook of Rehabilitation Issues During Cancer Treatment

This kind of book is currently lacking in the field of medical oncology

mucocutaneous changes gastrointestinal

ESMO Handbook Series

decreased exercise capacity

www.esmo.org 9 788890 635953 social issues ESMO Handbook Series

handbook_rehab-issues2014ok.indd 1 18/09/14 13:17

Henk van Halteren

© 2014 European Society for Medical Oncology

Printed through s|s|media limited, Rickmansworth, Hertfordshire, UK

Section I. How to deal with physical/psychological complaints during

10 Financial Issues 106

Andritsch E. University of Graz, Clinical Department of Oncology,

The editors and authors wish to thank the following reviewers:

Rob Newton, Edith Cowan University Health and Wellness Institute,

I would like to thank the ESMO Publishing Working Group,

Henk van Halteren

Medical professionals who are working within the field of oncology

Henk van Halteren

Reduced Cardiorespiratory Fitness

2 Buffart and May

Reduced Muscle Mass and Strength

Safeguarding Exercise Capacity Throughout and After Cancer Treatment 3

Reduced Bone Health

Exercise as Medicine in the Management of Cancer

improve or maintain physical fitness, performance, or health.

4 Buffart and May

Safeguarding Exercise Capacity Throughout and After Cancer Treatment 5

6 Buffart and May

Safeguarding Exercise Capacity Throughout and After Cancer Treatment 7

8 Buffart and May

Safeguarding Exercise Capacity Throughout and After Cancer Treatment 9

10 Buffart and May

Table 2 Chronic Pain Syndromes in the Cancer Patient

n Pain syndromes of the bony pelvis and hip

n Base of skull metastases

12 Ripamonti and Bossi

n Chest wall mass

n Cervical, brachial, lumbar, sacral plexopathies

n Epidural spinal cord compression

Tumour invasion of viscera

n Myofascial pain syndrome

n Debility, constipation, bed sores, rectal or bladder spasm, gastric distension

Table 4 Semantic Descriptors of Neuropathic Pain

Despite the availability of several effective treatments including non-

14 Ripamonti and Bossi

Visual analogue scale

Verbal scale pain

16 Ripamonti and Bossi

18 Ripamonti and Bossi

Table 8 Causes of Acute and Late Radiotherapy-related Pain

Hormonal Therapy-related Pain

20 Ripamonti and Bossi

Supportive Therapy-related Pain

Pharmacological Approaches in Treating Cancer Pain

Go on or, if necessary, opioid or route of opioid

✓ Reasses the pain intensity and its causes

n Pain syndromes of the bony pelvis and hip

n Base of skull metastases

n Chest wall mass

n Cervical, brachial, lumbar, sacral plexopathies

n Epidural spinal cord compression