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Published by tasch, 2018-07-05 10:15:27

MIMS Oncology 2018

Keywords: Medical,Medical Journal,Medical magazine,MIMs,MIMs magazine,Online Magazine

Flexibility: Complements any existing food or supplement program to help meet patients’ nutritional needs.
Quick and Easy Administration: A small amount of high protein, high calorie nutritional

supplement is taken with medication.

Simplicity: No extra work required by patients as it fits in with their current medication routine.
Great Taste: Plum-Mango and Peach-Vanilla.

Nutritional Content:

Volume: 125 ml Energy: 255 kcal
(2.0 kcal/ml)

Protein: 11.5g/125 ml Flavours: Plum-Mango
and Peach-Vanilla

Omega-3: 1.7g/125 ml Prebiotic dietary fibre:

(FOS, GOS): 3.1g

50% of fat is MCT oil Osmolarity:

600 mOsm/L

®Registered Trademark of Société des Produits Nestlé S.A.

144 CARING FOR PATIENTS WITH CANCER

Figure 2. Probiotic bacterial strains and possible mechanisms against various cancers31

Liver and gall LEGEND
bladder cancer Probiotic bacteria
Possible mechanism involved
Blood cancer Skin and oceasonpchear geal
ImmL.ukneoLfmi.rakoendforuif,alaLc.toireernytus,ri Epigenetic changes ImmLu. nrhoammondousluastoGryG
L. rhamnosus Bladder and prostate
Head and neck cancer
cancer SupprBpe.rseasccduaornlseocsrceser ntis
Anti-oxidant Potentiates drug activity
L. acidophilus Imunomodulatory L. casei
L. freudenreichii, Cervical cancer
ImmuLn.oamcoiddouplahtiloursy
L. gasseri
Breast cancer

Colon and rectal
cancer

probiotics (e.g., yoghurt, maas) in the diet However, the use of multivitamins has not
is advised. been shown to improve cancer-recur-
rence risk or cancer mortality in breast-
Following from the immune-related ef- cancer patients,32, 33 nor colon-cancer
fects of cancer, novel research has support- survivors.34 A systematic review of the role
ed the role of the gut microbiome in the oc- of nutrient supplements, including vita-
currence and progression of intestinal and mins, minerals and protein, confirmed
extra-intestinal cancers.29, 30, 31 Anti-cancer no solid evidence for the uses of sup-
drugs are known to trigger an immune re- plements in cancer cachexia.35 There is
sponse, and certain gut microbiota strains also evidence of greater risk of death in
have been shown to synergise with many cancer patients using alternative medi-
of these drugs, optimising the immune re- cine for cancer treatment.36 A review of
sponse against cancers. Strains that have clinical, evidence-based guidelines for
been researched include Lactobacillus nutrition for surgical cancer patients is
(L. plantarum, L. brevis, L. casei) and Bifidobac- detailed elsewhere.37
terium (B. breve, B. longum).30,31 A summary of
probiotic strains and potential mechanism The ACS38 and NCCN39 do not recom-
of action of probiotics in cancer is summa- mend the routine use of nutrition supple-
rised in Figure 2. However, it is necessary to mentation, unless indicated to correct a
progress with caution as most of these stud- nutrient deficiency. ACS, however, does
ies are conducted on animal models. As endorse a daily multivitamin during can-
such, these benefits may be exaggerated cer therapy for those unable to meet
and should not be extrapolated to humans, their nutrient needs through food alone.
with further clinical trials needed.29 Despite evidence to the contrary, many

HANDBOOK OF ONCOLOGY

The Role of Nutrition in Cancer Patients and Cancer Survivors 145

Figure 3. Potential consequences of obesity-induced dysfunction of adipose tissue on tumour TREATMENT APPROACHES
initiation, progression and recurrence43

Adipocyte Obesity á Aromatase
Adipose tissue activity

dysfunction Hormones (oestrogen)

á Levels of ECM proteins Adipocyte progenitors
and endotrophin

Fibrosis

Cancer stem cells Lipid metabolites and
lipolytic enzymes

Inflammatory Adipokines (leptin,
cytokines (IL-6, TNF, adiponectin)
CCL2, PAI-1)

Obesity-induced systemic changes
Hyperinsulinaemia (insulin IGF-1 signalling pathways)

Hyperglycaemia (hyperclycaemic memory)

Tumour initiation Tumour progression Drug resistance and cancer recurrence

cancer survivors continue to supplement microbiome are metabolic changes that
with vitamins and minerals.4 The concern is may contribute directly or indirectly to
that despite limited evidence, a patient’s cancer progression.41 See Figure 3.
desire for and reliance on supplements
may divert their attention from following a A multidisciplinary approach to obe-
healthy and well-balanced diet.40 sity management will help to assist with
the development and maintenance of
WEIGHT MANAGEMENT dietary and lifestyle behaviours that are
necessary for weight loss and successful
Excess body weight is a known risk factor weight-loss maintenance. A registered
for many cancers, including bowel, breast dietician, as part of a multidisciplinary
(post-menopause), gallbladder, liver, kid- team, can provide support in this regard.
ney, stomach and oesophageal cancer.6 A weight-loss goal of 5-10% reduction (cur-
Unfortunately, this trend continues post-di- rent body weight) within six months is rec-
agnosis with an increasing number of can- ommended.42 Along with dietary chang-
cer patients who are overweight or obese es, ACS recommends at least 150 minutes
at diagnosis gaining additional weight as of moderate-intensity activity per week for
a side effect of treatment.3, 41 This is con- weight loss in cancer patients.38
cerning as excess adiposity has been
associated with higher rates of cancer- Intentional weight loss may prove to be
related mortality in men and women.3,41,42 an effective concurrent treatment in re-
Hyperinsulinaemia, increased IGF-1, hy- ducing cancer progression.41, 42, 43 Much of
perglycaemia, dyslipidaemia, and altera- the research on weight gain following can-
tions in adipokines, cytokines and the gut cer diagnosis has been done on breast-
cancer patients in particular,44 but there is

HANDBOOK OF ONCOLOGY

146 CARING FOR PATIENTS WITH CANCER

also evidence of weight gain in cancers intake, increased catabolism of muscle
of the liver and colon.43 In breast-cancer protein and lipolysis, and metabolic and
patients, it is reported that women are un- neurohormonal perturbations.46-49 Symp-
likely to return to the lower pre-diagnosis toms include anorexia, muscle-wasting,
weight.44 Proposed mechanisms of weight fatigue, anaemia, oedema and taste
gain included changes in eating patterns changes (dysgeusia), all of which lead to
related to diagnosis- or treatment-related an increase in treatment toxicity and poor
depression, decreased physical activity, patient prognosis.4, 46, 49 The health-care
a potential role of hormones and meno- practitioner can diagnose cancer-related
pause in changing metabolism and the malnutrition in cancer patients, as sum-
development of insulin resistance.43, 44 marised in Table 2. Referral to a registered
dietician for medical nutrition therapy and
That said, obesity might have a paradox- support is advised.
ical protective effect in cancer patients.
An observational study (n=175) reported Cancerous tumours can affect energy
the median survival time for overweight intake due to poor taste, lack of appe-
and obese patients was significantly tite, and difficulties in swallowing.51 For this
higher compared to those with a low or reason, the prevalence of malnutrition in
normal weight, as defined by body mass cancer patients is considerable: 55% of
index (BMI). It is proposed that because patients eat less than before the diagnosis
BMI does not account for body compo- of cancer, yet only 41.4% and 50% of these
sition (i.e., fat mass versus fat-free mass/ patients receive nutrition counselling and
lean body mass), BMI itself cannot predict nutritional support, respectively.52
survival in cancer patients.45 Thus, weight
loss measures alone are not sufficient to Interestingly, cancer cachexia is not
ignore changes in muscle loss and/or fat always reversible by increasing energy
gain.46 Cancer patients are encouraged intake, and is distinct from starvation
to maintain good muscle mass as this has and age-related decreases in lean body
been shown to predict better outcomes in mass.48 Changes in gut function also de-
cancer patients.45 crease hunger hormones by altering
secretion of gastro-intestinal peptides
CANCER-RELATED MALNUTRITION and stomach-empting. Inflammatory cy-
AND CACHEXIA tokines such as tumour-necrosis factor
alpha, interleukin-1 and interleukin-6 are
Cancer patients are at high risk for can- also implicated in decreasing food intake
cer-related malnutrition and cachexia.4 and appetite. Cancer therapies such as
Weight loss and cachexia are well-de- chemotherapy and radiation can also al-
fined morbidity and mortality risk factors ter taste perception and cause nausea,
in cancer patients.45 Cancer cachexia is vomiting, mucositis, cramping, bleeding
defined as more than 5% weight loss with- and dysgeusia.49, 51
in a six-month period.46 The pathogenesis
of cancer cachexia is related to a vari- It is well established that nutrition support
able combination of decreased energy is a key role in managing cancer cachexia
when timeously delivered with adequate

Table 2: Criteria for nutrition diagnosis of malnutrition in adult oncology patients50

The presence of two or more of the following criteria or characteristics supports a
nutrition diagnosis of malnutrition in adult oncology patients:
n Insufficient energy intake
n Unintended weight loss
n L oss of subcutaneous fat
n Loss of muscle mass
n Localised or generalised fluid accumulation (that may mask weight loss)
n R educed grip strength

HANDBOOK OF ONCOLOGY

The Role of Nutrition in Cancer Patients and Cancer Survivors 147

Figure 4. Cancer-cachexia pathophysiology 49 TREATMENT APPROACHES

Gastro-intestinal tract
Dysbiosis, decreased food

intake, endotoxaemia

Pancreas Immune system Brain
Insulin Mcp, lymphocytes Inflammation,
resistance, tumour-
endocrine Amino acids Tumour Fatty acids associated
dysfunction adipokines anorexia,
Skeletal muscle depression
Proteolysis, Fat tissue
catabolism, Thermogenisis,
oxidative stress, browning,
weakness lipolysis,
Bone cytokine,
Bone metastasis á REE
promotes TGF-β
release Amino acids Glucose Lactate Fatty acids
Liver – Acute phase proteins, decreased
IGF-1 and albumin synthesis, steatosis, cori
cycle, á REE

provision of energy as part of a concurrent at diagnosis and at regular points through
treatment plan.47 Referral of cancer pa- the disease course.4, 50, 54-58 These screening
tients for nutrition counselling with a reg- tools are available for use by the health-
istered dietician is highly recommended, care practitioner.59
given the strong support for the beneficial
effects of the prevention and reduction of Patient situations that may benefit from seek-
malnutrition.53 Table 3 summarises the esti- ing individualised dietary advice include:60
mated energy needs of cancer patients. n For survivors experiencing anorexia
Refer to Table 4 for nutritional interven-
tion guidelines to support side effects and or early satiety, and who are at risk of
symptoms in cancer patients. becoming underweight, consuming
smaller, more frequent meals with
At present, there are no guidelines avail- minimal liquids consumed during meals
able for the treatment of cancer cachex- can help to increase food intake.
ia.48 Cancer patients should be screened Liquids can and should be consumed in
using a validated and reliable malnutrition between meals to avoid dehydration.
screening tool to identify malnutrition risk.50 n F or survivors who cannot meet their
Such screenings can be done by a regis- nutritional needs through foods alone,
tered dietician, using validated malnutri- fortified, commercially prepared or
tion-screening tools, such as the Nutritional homemade nutrient-dense beverages
Risk Screening 2002 (NRS, 2002), Malnutri- or foods (e.g., milk-based drinks, fruit
tion Universal Screening Tools (MUST), and smoothies) can improve the intake of
the Mini Nutritional Assessment (MNA), both energy and nutrients.

HANDBOOK OF ONCOLOGY

148 CARING FOR PATIENTS WITH CANCER

Table 3. Estimating the energy needs of cancer patients64

Condition Energy needs (kJ/kg/day)
Cancer, nutritional repletion, weight gain 126-147
Cancer, inactive, non-stressed 105-126
Cancer, hypermetabolic, stressed 147
Haematopoietic cell transplant 126-147
Sepsis 105-126

Table 4. Nutrition-intervention strategies for patients with cancer

Side effect/ Strategies
symptom
Anorexia n E ncourage small, more frequent nutrient-dense meals and snacks.
(poor, or lack of, n Recommend adding kilojoules in the form of protein (e.g., milk, yoghurt,
appetite)
cheese, egg) and healthy fats (e.g., avocado, nuts, nut butters, olive
Nausea and oil) to favourite foods.
vomiting n Recommend the use of protein- and energy-containing supplements,
e.g., whey protein powder, nutritional supplements.
Diarrhoea n Keep nutrient-dense foods nearby and snack frequently, e.g., nuts,
dairy, fruit, etc.
n A dvise capitalising on times when feeling best to eat main meals.
n Recommend eating meals and snacks in a pleasant atmosphere.
n S uggest viewing eating as part of the treatment.
n E ncourage activities of daily living and physical activity to stimulate
appetite, as tolerated.
n Recommend eating small, more frequent meals and snacks rather than
larger meals.
n Cold- and room-temperature foods are better tolerated than hot foods
with an odour. Advise the avoidance of foods with strong odours.
n Suggest sipping on cool or room, temperature, clear liquids in small
amounts, e.g., tea, apple juice, electrolyte replacement.
n A dvise the avoidance of high-fat, greasy, spicy or overly sweet foods.
n A dding lemon and ginger to food, tea and water may help manage
nausea.
n E ncourage the consumption of bland, soft, easy-to-digest foods on
scheduled treatment days.
n Encourage compliance with medications prescribed to control
nausea.
n Consider changing the timing of medication intake, i.e. before a meal,
with a snack, etc.
n E ncourage the intake of hydrating liquids such as water, electrolyte
replacement, clear juice, broth, popsicles, and sports drinks.
n R ecommend a low-fibre diet and the avoidance of high-fibre foods,
such as whole-grain breads and cereals. Include foods rich in soluble
fibre such as fibre, oats and stewed apple.
n A dvise the avoidance of sugar alcohol-containing foods, such as
sugar-free gum and cooldrinks.
n Encourage the intake of soluble fibre, e.g., apples, bananas, white rice,
pasta.
n E ncourage compliance with medications prescribed to control
diarrhoea.
n C onsider changing the timing of medication intake, i.e. before a meal,
with a snack, etc.

HANDBOOK OF ONCOLOGY

The Role of Nutrition in Cancer Patients and Cancer Survivors 149

Side effect/ Strategies TREATMENT APPROACHES
symptom
Constipation n Recommend increasing the intake of high-fibre foods, e.g., whole
grains, fresh and cooked fruit and vegetables, especially those with
Oesophagitis skins and seeds, dried fruit, beans, nuts.
(sore and/
or inflamed n Encourage the intake of fluid, mostly water. A goal of one glass
throat), (250ml) water per kilogram of body weight is estimated.
sore mouth,
mucositis or n R ecommend the use of probiotic-containing foods, e.g., yoghurt
thrush) and maas or probiotic supplements. (Refer to the probiotic strains for
Fatigue various cancers in Figure 2.)
(tiredness)
n Encourage activities of daily living and physical activity, where
Neutropaenia possible. Walking can aid in gut peristalsis and improve constipation.
(low white-
blood-cell n Encourage patients to read food labels and choose products that
count) contain 6 g or more of fibre per 100 g product.
Dysgeusia
(altered taste n Encourage compliance with fibre supplements and/or medication
and altered that affect bowel function and are prescribed to manage
smell) constipation.
Thickened saliva
n R ecommend the intake of softer, moister foods with sauces, dressings
or gravies.

n Advise the avoidance of dry, course, rough foods.
n Avoid alcohol, citrus, caffeine, tomatoes, vinegar and hot peppers.
n Suggest experimenting with food temperature (e.g., warm, cool, icy,

room temperature) to find which temperature is most soothing.
n R ecommend good oral hygiene, e.g., rinse mouth frequently, keep

mouth clean.
n E ncourage compliance with medications prescribed to manage oral

pain, oral infection oesophagitis and/or painful swallowing.
n R ecommend the intake of small, frequent meals and snacks.
n R ecommend the intake of easy-to-prepare, easy-to-eat foods, e.g.,

high-fibre cereal with milk, yoghurt and fruit, whole-wheat toast with
peanut butter.
n Advise keeping nutrient-dense snacks nearby and snack frequently,
e.g., fresh fruit, raw nuts, yoghurt.
n S uggest eating when appetite is best.
n E ncourage activities of daily living and physical activity, where
possible.
n A dvise frequent hand-washing and keep kitchen surfaces and utensils
clean.
n A dvise the avoidance of raw or under-cooked animal products,
including meat, pork, game, poultry, eggs and fish.
n A dvise washing all fruit and vegetables before eating.
n “ When in doubt, throw out” and “No oldy or mouldy”.
n Recommend good oral hygiene practices, e.g., rinse mouth
frequently, keep mouth clean
n S uggest trying marinades and spices to mask strange tastes.
n Recommend using plastic utensils if metallic-utensil tastes are a
problem.
n Recommend eating cooler rather than warmer foods.
n S uggest sipping on fluids throughout the day to keep oral cavity moist.
n S uck on ice cubes.
n R ecommend diluting thickened oral saliva with water or sparkling
water.
n Recommend using a cool mist humidifier when resting and sleeping.

HANDBOOK OF ONCOLOGY

150 CARING FOR PATIENTS WITH CANCER

Side effect/ Strategies
symptom n S uggest sipping on liquids throughout the day to keep the oral cavity
Xerostomia
(dry mouth) most.
n S uggest trying tart foods to stimulate saliva (if open mouth sores are not

present).
n R ecommend alternating bites of food with sips of liquids at meals.
n Recommend eating soft, moist foods with extra sauces, dressings or

gravies.
n Advise avoidance of alcoholic beverages and alcohol-containing

mouthwashes.
n R ecommend good oral hygiene, e.g., rinse more frequently, keep

mouth clean.
n Recommend using a cool mist humidifier when resting and sleeping.

Source: Adapted from Hamilton, 2017

For survivors who are unable to meet their nu- CONCLUSION
tritional needs through these measures and
who are at risk of becoming malnourished, The guidelines for nutrition for cancer pre-
other means of nutritional support may be vention should not be overlooked for pa-
needed, such as pharmacotherapy using tients with diagnosed cancer, underscor-
appetite stimulants, enteral nutrition via tube- ing the importance of consuming a heathy
feeding, or intravenous parenteral nutrition. diet for both cancer prevention and to im-
prove health outcomes in cancer patients
RISK OF CHRONIC DISEASE and cancer survivors.21 With improved
knowledge of the importance of a healthy
There is emerging evidence of shared dis- diet to prevent cancer, survivors are mo-
ease pathways for cardiovascular disease tivated and encouraged to improve their
and cancer, the two leading causes of nutrition after diagnosis. Nutritional as-
death around the world. Chronic inflamma- sessment should be an integral part of a
tion is a major theme among many diseases, cancer-treatment plan, beginning at di-
including cardiovascular disease and can- agnosis and extending throughout the
cer.61 Obesity, hyperglycaemia, hypertension post-diagnosis period of treatment.3
and hypertriglyceridemia induce inflamma-
tion, all of which are linked to both diseases. Cancer survivors report that better pa-
Hormones (e.g., leptin), cytokines, growth tient-provider communication and greater
factors and other metabolic changes have knowledge about how to reduce cancer
also been linked to both diseases.62, 63 risk are factors associated with a greater
likelihood of attending medical appoint-
Likewise, obesity and type 2 diabetes are ments.7 The health-care provider thus plays
associated with an increased incidence a key role in promoting healthy-eating
and mortality from many cancers.41 The behaviours among cancer survivors.60
factors potentially contributing to the pro- Strategies such as incorporating nutrition
gression of cancer in obesity and type 2 di- as part of the health-care treatment plan
abetes include hyperinsulinemia, increases of cancer survivors, with the support and
in IGF-1, hyperglycaemia, dyslipidaemia, in- guidance of a registered dietician, are ad-
creased levels of adipokines and cytokines, vised.53, 58, 63
and alterations in the gut microbiome.
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HANDBOOK OF ONCOLOGY

The Role of Nutrition in Cancer Patients and Cancer Survivors 151

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37. Arends J, et al. ESPEN guidelines on nutrition oncology patients: a systematic review. Sup-
in cancer patients. Clin Nutr. 2017;36(1): portive Care in Cancer. 2016;24(1)469-480.
11-48.
54. Caccialanza, et al. Nutritional support in
38. A CS Guidelines for Nutrition and Physical cancer patients: a position paper from
Activity. https://www.cancer.org/healthy/ the Italian Society of Medical Oncology
eat-healthy-get-active/acs-guidelines-nu- (AIOM) and the Italian Society of Artificial
trition-physical-activity-cancer-prevention/ Nutrition and Metabolism (SINPE). J Can-
summary.html. Accessed 7 January 2018. cer. 2016;7(2):131-135.

39. N CCN Clinical Practice Guidelines in On- 55. V an Bokhorst-de van der Schueren MAE,
cology: Survivorship Version I; 2015. Avail- et al. Nutrition-screening tools: does one
able online: http://www.nccn.org/profes- size fit all? A systematic review of screen-
sionals/physician_gls/pdf/survivorship.pdf . ing tools for the hospital setting. Clin Nutr.
Accessed 7 January 2018. 2014;33:39-58.

40. H arvie M. Nutritional supplements and can- 56. Shaw C, et al, Comparison of a novel, simple
cer: potential benefits and proven harm. nutrition screening tool for adult oncology
Am Soc Clin Oncol Educ Book. 2014;e478- inpatients and the Malnutrition Screening
86. Tool (MST) against the Patient-Generated
Subjective Global Assessment (PG-SGA).
41. G allagner EJ, LeRoith D. Obesity and dia- Support Care Cancer. 2015;23:47-54.
betes: the increased risk of cancer and
cancer-related mortality. Physiol Rev. 57. J ager-Wittenaar H, Ottery FD. Assessing
2015;95:727-748. nutritional status in cancer: role of the
Patient-Generated Subjective Global As-
42. Ligibel JA, et al. American Society of Clini- sessment. Curr Opin Clin Nutr Metab Care.
cal Oncology Position Statement on Obesi- 2017;20(5):322-329.
ty and Cancer. J Clin Oncol. 2014;32:3568-
3574. 58. Talwar B, et al. Nutritional management in
head and neck cancer: United Kingdom
43. Park J, et al. Obesity and cancer – mech- National Multidisciplinary Guidelines. Jour-
anisms underlying tumour progression nal of Laryngology & Otology. 2016;130
and recurrence. Nat Rev Endocrinol. (S2):S32-S40.
2014;10(8):455-465.

HANDBOOK OF ONCOLOGY

The Role of Nutrition in Cancer Patients and Cancer Survivors 153

59. Rock CL, et al. Nutrition and Physical Activ- 9. El-Shami K, et al. American Cancer Society TREATMENT APPROACHES
ity Guidelines for Cancer Survivors. Ca Can- Colorectal cancer survivorship care guide-
cer J Clin. 2012;62:242-274. lines. Cancer J Clin. 2015;65(6):428-455.

60. Coa, et al. Capitalizing on the “teach- 10. Gallo M, et al. Adverse glycaemic effects
able” moment to promote healthy dietary of cancer therapy: indications for a ration-
changes among cancer survivors: the per- al approach to cancer patients with dia-
spectives of healthcare providers. Support betes. Metabolism Clinical and Experimen-
Care Cancer. 2015;23(3):679-686. tal. 2018;78:141-154.

61. Koene RJ, et al. Shared risk factors in cardi- 11. George SM, et al. Better post diagnosis diet
ovascular disease and cancer. Circulation. quality is associated with reduced risk of
2016;133:1104-1114. death among postmenopausal women
with invasive breast cancer in the Wom-
62. Masoudkabir F, et al. Cardiovascular dis- en’s Health Initiative. Cancer Epidemiol
ease and cancer: evidence for shared dis- Biomarkers Prev. 2014;23(4);1-9.
ease pathways and pharmacologic pre-
vention. Atherosclerosis. 2017;263:343-351. 12. Hackshaw-McGeagh LE, et al. A systematic
review of dietary, nutritional, and physical
63. Resnick MJ, et al. Prostate Cancer Survi- activity interventions for the prevention of
vorship Care Guideline: American Soci- prostate cancer progression and mortality.
ety of Clinical Oncology Clinical Practice Cancer Causes Control. 2015;26:1521-1550.
Guideline Endorsement. J Clinical Oncol.
2015;33(9):1078-1085. 13. Mayer DK, et al. Summing it up: an inte-
grative review of studies of cancer survi-
64. Chao P, et al. The Malnutrition Univer- vorship care plans (2006-2013). Cancer.
sal Screening Tool (MUST) and a nutrition 2015;1:121(7):978-996.
education program for high risk cancer
patients: strategies to improve dietary in- 14. Miller KD, et al. Cancer Treatment and
take in cancer patients. Bio Medicine. Survivorship Statistics, 2016. Cancer J Clin.
2015;5(3):30-35. 2016;66:271-289.

FURTHER READING 15. Pelser C, et al. Prediagnostic lifestyle factors
and survival after colon and rectal cancer
1. A ICR’s Guidelines for Cancer Survivors. diagnosis in the National Institutes of Health
Available online: http://www.aicr.org/pa- (NIH)-AARP Diet and Health Study. Cancer.
tientssurvivors/aicrs-guidelines-for-cancer. 2014;120:1540-1547.
html. Accessed 7 January 2018.
16. Reeves MM, et al. Weight loss interven-
2. Arends J, et al. ESPEN expert group rec- tion trials in women with breast cancer:
ommendations for action against cancer- a systematic review. Obesity Reviews.
related malnutrition. Clin Nutr. 2017;36(5): 2014;5(9):749-768.
1187-1196.
17. Chao P, et al. The Malnutrition Univer-
3. B ower JE, Lamkin DM. Inflammation and sal Screening Tool (MUST) and a nutrition
cancer-related fatigue: mechanisms, con- education program for high risk cancer
tributing factors, and treatment implica- patients: strategies to improve dietary in-
tions. Brain, Behaviours and Immunity. take in cancer patients. Bio Medicine.
2013;30:S48-S57. 2015;5(3):30-35.

4. Chan, et al. What should we tell prostate 18. S tanton AL, Rowland JH, Ganz Pa. Life
cancer patients about (secondary) pre- after diagnosis and treatment of can-
vention? Curr Opin Urol. 2014;24(3):318-323. cer in adulthood. American Psychologist.
2015;70(2):159-174.
5. Cho J, et al. A review of breast cancer sur-
vivorship issues from survivors’ perspectives. 19. V an Blarigan EL, Meyerhardt JA. Role
J Breast Cancer. 2014;17(3):189-199. of physical activity and diet after colo-
rectal cancer diagnosis. J Clin Oncol.
6. D e Waele E, et al. Nutrition therapy in ca- 2015;33(16):1825-1834.
chectic cancer patients. The Tight Ca-
loric Control (TiCaCo) pilot trial. Appetite. 20. Wright SJ, et al. What are colorectal cancer
2015;91:298-301. survivors preferences for dietary advice?
A best-worst discrete choice experiment.
7. Demark-Wahnefried W, et al. Weight man- J Cancer Surviv. 2017;11:782-790.
agement and physical activity throughout
the cancer care continuum. Cancer J Clin. 21. Zhang B, et al. Association of whole grain
2017;22. Doi: 10.3322/caac.21441. intake with all-cause, cardiovascular, and
cancer mortality: a systematic review and
8. Donovan MG, et al. Mediterranean diet: dose-response meta-analysis from pro-
prevention of colorectal cancer. Clin Nutr. spective cohort studies. Eur J Clin Nutr.
2017;4:59. Doi: 10.3389/fnut.2017.00059 . 2018;72:57-65.

HANDBOOK OF ONCOLOGY

Palliative care

Palliative Care: an Introduction 155

Palliative Care: an Introduction TREATMENT APPROACHES

Dr R Krause WHAT IS PALLIATIVE CARE?

MBChB MFam Med MPhil (Palliative Hospices have been around for centuries,
but the modern hospice movement was
Medicine) Post Graduate Diploma in established by Dame Cecily Saunders and
her colleagues. In 1967 they opened the
Health Professional Education world’s first modern hospice in London.
 Senior Lecturer of School of Public Dame Saunders introduced the concept
Health and Family Medicine (Palliative of “Total Pain” which details that pain in
Medicine), UCT Health Sciences Faculty patients with life-threatening illnesses is
caused not only by physical suffering, but
Palliative care (PC) has been practised also by psycho-social and spiritual suffer-
for many years on the fringes of the South ing.5 Dr Balfour Mount, who was inspired
African health-care system. It was margin- by Dame Saunders, coined the term “pal-
alised to non-governmental services and liative care”, derived from the Latin word
sporadic hospital services. “pallium” which means “to cloak”.6 Pallia-
tive care aims to “cloak” or protect the
However, due to local needs analy- patient from the suffering caused by a life-
ses, the cost-effectiveness of palliative threatening illness.
care and international palliative care
progress,1-3 palliative care is globally rec- In 2002 the WHO defined palliative care as:
ognised as a fundamental part of health- “An approach that improves the quality of
care services. These positive palliative care life of patients and their families facing the
outcomes have been achieved by using problems associated with life-threatening
effective compassionate communication illness, through the prevention and relief of
skills, shared decision-making, holistic pain suffering by means of early identification
and symptom control, family involvement and impeccable assessment and treat-
and by using a team approach. ment of pain and other problems, physi-
cal, psychosocial and spiritual.7
The integration of palliative care into
global health services was further rein- Palliative care:
forced in 2014 when the World Health n P rovides relief from pain and other
Assembly (WHA) unanimously agreed on
resolution 67.19, recognising “that pallia- distressing symptoms
tive care, when indicated, is fundamen- n Affirms life and regards dying as a
tal to improving quality of life, wellbeing,
comfort and human dignity for individuals, normal process
being an effective person-centred health n Intends neither to hasten nor postpone
service that values patients’ need to re-
ceive adequate, personally and culturally death
sensitive information on their health status, n Integrates the psychological and
and their central role in making decisions
about the treatment received”.4 spiritual aspects of patient care
n Offers a support system to help patients
The aim of the WHA resolution was to
ensure that palliative care was strength- live as actively as possible until death
ened as part of integrated care within n Offers a support system to help the
the continuum of care. The integration of
palliative care into daily care of patients family cope during the patient’s illness
requires societal understanding of the pal- and in their own bereavement
liative care approach, the development n Uses a team approach to address the
of health-care workers’ competencies needs of patients and their families,
to deliver the care, dedicated palliative including bereavement counselling, if
care services and an attitude that there is indicated
“no end to caring”. n W ill enhance quality of life, and may
also positively influence the course of
illness

HANDBOOK OF ONCOLOGY

156 PALLIATIVE CARE

n I s applicable early in the course and poor response to treatment) and spe-
of illness, in conjunction with other cific indicators (e.g., metastatic cancer
therapies that are intended to or stage 4 or 5 kidney disease) to deter-
prolong life, such as chemotherapy mine who requires palliative care.9 The
or radiation therapy, and includes Supportive and Palliative Care Indicator
those investigations needed to better Tool (SPICT) (https://www.spict.org.uk/)
understand and manage distressing was designed in Scotland, using a practi-
clinical complications.” cal, evidence-informed guide to identify
patients at risk of dying and who require
Core concepts of these principles are that: palliative care alongside curative treat-
n It is a patient- and family-centred ments.10 These tools were designed in
developed countries and do not include
approach communicable diseases such as HIV and
n It aims to relieve a bio-psycho-social TB. Locally, in Groote Schuur hospital, an
adapted tool has been used to include
and spiritual suffering these conditions. In cancer care both the
n I t involves a team GSF framework and the SPICT tool agree
n It starts at diagnosis of a life-threatening that poor performance status and/or pro-
gressive metastatic cancer are indicators
illness and continues into bereavement for palliative care.
n I t is must be integrated in measures that
PALLIATIVE CARE WITHIN
aim to prolong life THE DISEASE TRAJECTORY
n E uthanasia is not a palliative care
Figure 1, as adapted by the WHO dia-
practice. gram of 1998, illustrates how palliative care
should be practised within the continuum
It is also generally considered that the of care and highlights a few important
term “best supportive care” is essential- factors:
ly equivalent to “palliative care” and is n I t should be initiated with the diagnoses
sometimes used because of the miscon-
ception around palliative care.6 Many of a life-threatening illness and should
believe that by introducing palliative care continue into bereavement care.
into the care trajectory you are “giving n I t can be introduced slowly with the
up” on the patient and that palliative care diagnosis of a life-threatening illness,
is only for the final stages of life. These mis- and slowly becomes central to care as
conceptions have been proven wrong, the illness progresses.
with research proving that palliative care n Palliative care is not an excuse for poor
improves quality of life and may lead to service delivery and should never be a
longer survival.3 substitute for poor resources.
n H ospice referrals are traditionally done
INITIATING PALLIATIVE CARE too late in care and thus palliative care
cannot be limited to only hospices.
Internationally, there are many disparities This service should be available in all
and inequalities around when palliative settings where patients present with life-
care should be initiated8 and in response, threatening illnesses.
many indicator tools have been devel- n An imperative part of palliative care
oped to ensure patients are identified for is bereavement care and care of
palliative care. The Gold Standard Frame- vulnerable children. Neglect of these
work (GSF) indicator tool is a tool devel- two vital aspects of care can lead to
oped in the United Kingdom and used to prolonged distress and impairment. It is
identify patients who are nearing the end especially in the South African setting,
of their life and is based on patients’ need that we are all responsible for orphans
for palliative care. It uses the well-known and vulnerable children.11
“surprise question” (“Would I be surprised
if a patient dies within 12 months?”) and
general indicators (e.g, physical decline

HANDBOOK OF ONCOLOGY

Palliative Care: an Introduction 157

Figure 1. Practising palliative care within the continuum of care TREATMENT APPROACHES

Active disease-directed care Minimal disease-directed care

Curative care Care of
vulnerable

children

End-of-life
care

Palliative care

Bereavement
care

Diagnosis Referral to hospice

KEY COMPONENTS n I t provides care and education to the
OF PALLIATIVE CARE SERVICES family in relation to the patient’s goals.

Basic palliative care principles can be n I t insures the continuum of care for
applied by all health-care workers and both the patient and the family which
all health-care workers should be trained includes bereavement care.
in palliative care. However, the aware-
ness of basic palliative care is not equiv- n I t collaborates with other health-care
alent to a palliative care service. A pal- workers, such as oncologists, to ensure
liative care service includes the following the patient receives optimal care.
components:
n It is delivered by a team: In most n I t practises and advocates using
an evidence-based palliative care
cases, the team will consist of palliative approach.
care-trained nurses, social workers,
spiritual care workers and doctors. In Integrating palliative care into current
many oncology settings, allied health- services requires education for all health-
care workers, such as occupational care workers, development and imple-
therapists and speech therapists, are mentation of policies for palliative care
integral parts of the team. and collaborative leadership. At Groote
n I t provides pain and symptom control Schuur hospital, palliative care services
to the patient. Although pain is not just have been slowly incorporated into on-
physical pain, the service will ensure cology services and emergency medicine
that the patient will have access to services since 2011, and Groote Schuur
the necessary drugs to manage his/her hospital currently has a nurse-driven pal-
pain and symptoms. liative care service across the hospital,
n I t provides psycho-social and spiritual initiating palliative care to approximately
care to the patient. In this context, 80 patients per month. This could not have
“spiritual” means the relationship we been achieved without training nurses, so-
have with ourselves and the world, and cial- and allied health-care workers and
“spiritual care” means the exploration doctors in palliative care.
of the individual meaning of life and
providing comfort, strength and CORE COMPETENCIES OF A
balance. PALLIATIVE-CARE HEALTH WORKER

Universal access to palliative care will re-
quire that all health-care workers undertake

HANDBOOK OF ONCOLOGY

158 PALLIATIVE CARE

basic training in palliative care. The basic undergraduate and postgraduate train-
competencies required to work with pal- ing. The Policy speaks to the inclusion of
liative care patients are: palliative care training for all health-care
n To apply the principles of palliative care professionals at a basic level; at an in-
termediate level for health-care workers
in the health-care worker’s current work whose work includes palliative care indi-
setting rectly, e.g., oncologists and physicians,
n To ensure that the patient receives and at an advanced level working to pal-
pain- and symptom control liative care as a speciality in South Africa.
n To ensure that the patient receives All of this speaks to the enabling and the
psycho-social and spiritual care strengthening of palliative care across the
n T o respond to the family’s need in whole health-care system and to have the
relationship to the patient’s goals necessary funding to achieve this.12
n To function well in an interdisciplinary
team The South African National Policy is an
n To ensure that the patient is cared for in opportunity to develop palliative care in
an ethical manner South Africa, however there are still many
n T o effectively communicate with barriers until full integration. Palliative care
patients, families and colleagues is an evidence-based approach, but most
n T o develop self-awareness and positive of the evidence is being developed in Eu-
resilience. rope and America, countries which have
a different spectrum of illnesses and dif-
INTEGRATING PALLIATIVE CARE ferent resources. There is a huge need to
SERVICES INTO HEALTH-CARE ensure good palliative care-focussed Afri-
SERVICES can research in all settings that deal with
patients with life-threatening illnesses. We
As stated previously, palliative care has need to ensure a change of mindset in all
been practised on the fringe of the South disciplines which should ensure that there
African health-care services for many are policies, guidelines and services avail-
years. However, Resolution 67.19 under- able for patients in order for patients and
pinned the development of the decision their families to receive the best compre-
of the South African Minister of Health, hensive care until the very end. Although
Aaron Motsoaledi, to create a national most health-care workers are involved in
task team to ensure aspects that are cov- the care of patients with life-threatening
ered in the Resolution are implemented in illnesses, very few have received formal
South Africa. The framework of the Nation- training in palliative care.
al Palliative Care Policy was accepted in
April 2017 and in the foreword of the poli- Palliative care can be described as an
cy Minister Motsoaledi states: “We cannot essential human right to improve quality
overlook the importance of integrating of life and dignity in death.13 The African
palliative care as an essential compo- palliative care revolution is moving for-
nent in the continuum of health-service ward; health-care facilities should be able
delivery” and continues by stating: “I am to deliver this service, which cannot be
confident that this Policy will translate into achieved without their having basic pal-
services which are responsive, appropri- liative care competencies.
ate and ensure universal access on an
equitable basis.”12 REFERENCES

This National Policy will enable pallia- 1. Stuart-Clark H, Vorajee N, Zuma S, et al.
tive care to be incorporated into National Twelve-month outcomes of patients ad-
documents such as the Essential Medicine mitted to the acute general medical ser-
Lists and guidelines to ensure drug availa- vice at Groote Schuur Hospital. SAMJ.
bility for pain and symptom control across 2012;102(6):549-53.
the spectrum of care. It will also drive the
inclusion of palliative care training in both 2. Desrosiers T, Cupido C, Pitout E, et al. A
hospital-based palliative care service for
HANDBOOK OF ONCOLOGY patients with advanced organ failure in
sub-Saharan Africa reduces admissions

Palliative Care: an Introduction 159

and increases home death rates. Jour- global perspective. Journal of Pain and TREATMENT APPROACHES
nal of Pain and Symptom Management. Symptom Management. 2002;24(2):91-6.
2014;47(4):786-92. 8. Gardiner C, Ingleton C, Gott M, et al. Ex-
3. Temel JS, Greer JA, Muzikansky A, et al. Early ploring the transition from curative care to
palliative care for patients with metastatic palliative care: a systematic review of the
non–small-cell lung cancer. New England literature. BMJ Supportive & Palliative Care.
Journal of Medicine. 2010;363(8):733-42. 2011;1(1):56-63.
4. Organization WH. Strengthening of pal- 9. Thomas K. The GSF prognostic indicator
liative care as a component of integrated guidance. End of Life Care. 2010;4(1):62-4.
treatment throughout the life course. Jour- 10. Highet G, Crawford D, Murray S, et al.
nal of Pain & Palliative Care Pharmacother- Development and evaluation of the sup-
apy. 2014;28(2):130-4. portive and palliative care indicators tool
5. Clark D. From margins to centre: a review (SPICT): a mixed-methods study. BMJ Sup-
of the history of palliative care in cancer. portive & Palliative Care. 2013;1-6.
The Lancet Oncology. 2007;8(5):430-8. 11. Drenth N, Herbst A, Strydom H. Compli-
6. Hui D, De La Cruz M, Mori M, et al. Con- cated grief in the South African context: a
cepts and definitions for “supportive care,” social work perspective. British Journal of
“best supportive care,” “palliative care,” Social Work. 2013;1-18.
and “hospice care” in the published lit- 12. Health SADo. National Policy Framework
erature, dictionaries, and textbooks. Sup- and Strategy on Palliative Care 2017 –
portive Care in Cancer: Official Journal of 2022. In: Health Do, editor: in press; 2017.
the Multinational Association of Supportive 13. Brennan F. Palliative care as an internation-
Care in Cancer. 2013;21(3):659-85. al human right. Journal of Pain & Symptom
7. Sepúlveda C, Marlin A, Yoshida T, et al. Palli- Management. 2007;33(5):494-9.
ative care: the World Health Organization’s

HANDBOOK OF ONCOLOGY

160 PALLIATIVE CARE

Management of Cancer Pain

Dr M Raff or haematological malignancies. Cancer-
related pain may be presented as a major
BSc, MBChB, FCA(SA) issue of health-care systems worldwide if
 Director, Pain Clinic, Christiaan we consider that the incidence of cancer
Barnard Memorial Hospital, Cape Town was 12 667 470 new cases in 2008 and,
based on projections, it will be greater
Cancer pain prevalence ranges from 33% than 15 million in 2020.4
in patients after curative treatment to 59%
in patients on anticancer treatment and The patient may suffer from pain, but it
to greater than 70% in patients with meta- must be appreciated that pain has other
static, advanced or terminal phase.1 No implications, such as the burden that the
difference in pain prevalence was found patient has to bear resulting from the pain.
between patients undergoing anticancer Cancer pain has a significant negative ef-
treatment and those in an advanced or fect on patient quality of life5,6 Higher levels
terminal phase of the disease.1 of pain are associated with poorer quality
of life, including decreased social activi-
It must be noted that pain results not ties, decreased physical functioning and
only from the disease itself (25%) but from impaired cognitive functioning. Increased
some of the therapeutic modalities (up psychological distress is associated with
to 75%).2 The resulting pain may become higher levels of pain and more than one-
chronic in nature. Treatment may cause third of cancer patients with pain rate their
peripheral neuropathy due to chemo- pain as moderate or severe. Increasing
therapy, radiation-induced brachial plex- cancer pain may be associated with ad-
opathy, chronic pelvic pain secondary to vanced disease with a limited prognosis.6-9
radiation and post-surgical pain.3
Although it is beyond the scope of this
Examples of treatment-related cancer article, the need for psychological assess-
pain syndromes are: 2 ment and help should be emphasised, as
n R esulting from chemotherapy: psychological issues are a component of
the cancer pain experienced and when
- Painful peripheral neuropathy this is the case, psychotherapy should be
- Raynaud’s syndrome considered.10
- Bony complications of long-term
TYPES OF PAIN
steroids
n R esulting from radiotherapy: When dealing with cancer pain, we must
realise that there may be nociceptive
- Radiation-induced brachial pain, neuropathic pain, or a combina-
plexopathy tion of both types of pain, the so-called
mixed pain. Distinguishing between these
- Chronic radiation myelopathy pain types is paramount to treating the
- Chronic radiation enteritis and proctitis pain, as most acute and postsurgical pain
- Burning perineum syndrome is somatic. This type of pain will respond
- Osteoradionecrosis to morphine, paracetamol, nonsteroidal
n R esulting from surgery: anti-inflammatory agents (NSAIDs), and
- Post-mastectomy pain syndrome COX-2 selective inhibitors (coxibs) (see Ta-
- Post-radical neck dissection pain ble 1).
- Post-thoracotomy pain syndrome or
In the case of neuropathic pain, these
frozen shoulder agents will have no effect on the pain
- Post-surgery pelvic floor pain and we would need to employ the sodi-
- Stump pain um channel-blocking anticonvulsants, the
- Phantom limb pain alpha-2 delta selective calcium-channel

Unrelieved pain continues to be a world-
wide problem in patients with either solid

HANDBOOK OF ONCOLOGY

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162 PALLIATIVE CARE

Table 1. Examples of nociceptive pain syndromes are listed in the table below: 2

Origin of Pain Pain Syndromes
Visceral
n Hepatic distension syndrome
Somatic n Midline retroperitoneal syndrome
n Chronic intestinal obstruction
n Peritoneal carcinomatosis
n M alignant perineal pain
n A drenal pain syndrome
n U reteric obstruction

n Tumor-related bone pain
n Tumor-related soft tissue pain
n P araneoplastic pain syndromes (e.g., muscle cramps)

blockers (a2Δ), the serotonin noradrenalin 2. Conduction of the pain impulse from C
re-uptake inhibitors (SNRIs), and the sero- the site of injury to the spinal cord. If the M
tonin-specific re-uptake inhibitors (SSRIs). “message” does not reach the spinal Y
It follows that in a mixed-pain scenario, a cord then pain will not be felt. This can CM
combination of agents would be desirable. be achieved by using sodium-channel MY
blockers. We can clinically achieve this CY
Clinical examples of neuropathic pain are: by using some form of local anaesthet- CMY
n M alignanant painful neuropathies ic or, in the case of neuropathic pain, K
n P lexopathies an anticonvulsant.
n M etastatic spine compression
n P ainful peripheral neuropathies 3. I mpulse transfer at the dorsal horn of
n Paraneoplastic sensory neuropathies the spinal cord. When calcium ions
enter the neuron, there is a release of
PHYSIOLOGY neurotransmitters that will facilitate the
OF PAIN MANAGEMENT passage of the pain impulse to the next
neuron. The entry of the calcium can
Effective pain therapy means using a be prevented by the a2Δ blockers. The
combination of analgesics and adjuvants neurotransmitters released can also be
that act on appropriate physiological tar- prevented from binding to the N-me-
gets. This form of therapy is known as mul- thyl-D-aspartate (NMDA) receptor by
timodal analgesia. means of an NMDA blocker (ketamine).

Clinicians have “six bullets” available to 4. T ransfer of the impulse from the spi-
them for pain management and each nal cord to the brain. This transfer can
“bullet” arises because of the six known be blocked by paracetamol that is
physiological targets: thought to bind at COX-3 receptors, as
1. T he peripheral site of injury. One of well as by NSAIDs and coxibs that work
in the glial cells, blocking COX-2 action.
the foremost responses to tissue injury
is the formation and release of prosta- 5. The brain. Opioids will alter the pain re-
glandins at the site of injury. In order to sponse by binding at specific opioid re-
stop this process, an antiprostaglandin ceptors in the brain (µ,δ,κ).
agent must be used. These agents are
collectively known as the NSAIDs and 6. D escending inhibition from the brain
coxibs. It is obvious that the choice of to the spinal cord. The brain can “talk
agent depends on the medical status back” to the spinal cord and in so do-
of the patient and the various indica- ing prevent further painful input. This is
tions and contra-indications for use of achieved by increasing the levels of
these agents apply. serotonin and noradrenalin at the spi-
nal cord. Re-uptake of noradrenaline
and serotonin can be facilitated by the
SNRIs, the SSRIs, and tramadol.

HANDBOOK OF ONCOLOGY

FOR THE TREATMENT OF

MODERATE TO MODERATELY

SEVERE PAIN

RAPIDLY ACTING1
LONGER DURATION1
MULTIMODAL ANALGESIC1
WELL TOLERATED1

TRAMADOL HYDROCHLORIDE 37,5 mg / PARACETAMOL 325 mg

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Tel 021 707 7000 Fax 021 701 5898
Email [email protected] CUSTOMER CARE LINE 0860 PHARMA (742 762)/+27 707 7000 www.pharmadynamics.co.za
TAMOLTRA. Each tablet contains tramadol hydrochloride 37,5 mg and paracetamol 325,0 mg. S5 A46/2.9/0976. 1. Dhillon S. Tramadol/paracetamol; fixed-dose combination: a review of its
use in the management of moderate to severe pain. Clin Drug Investig. 2010;30(10):711-38. For full prescribing information, refer to the professional information approved by SAHPRA, 27 July
2017. TMB454/04/2018.

164 PALLIATIVE CARE

It is not always necessary to use all of these non-opioid drugs such as paracetamol or
modalities to manage cancer pain and NSAIDs and with other adjuvant drugs.18,19
the clinician will choose those “bullets”
that are appropriate for the specific pa- Certain principles exist when trying to ef-
tient. Pain SA’s choice is as follows: fectively manage cancer pain.
n Antiprostaglandins: NSAIDs or coxibs n P rescribe analgesia for chronic pain
n Sodium-channel blockers: local
on a regular basis and not on an “as
anaesthetics or carbamazepine required” schedule.
n S elective calcium-channel blockers: n Prescribe a therapy which can be
easily administered and managed
pregabalin and gabapentin by the patient. The oral route is the
n NMDA receptor antagonists: ketamine preferred route of administration.20-24
n Spinal-cord conduction modifiers: n A ssess and treat breakthrough pain
(BTP). This can be defined as “a
NSAIDs, coxibs, paracetamol transitory flare of pain that occurs
n µ,δ,κ receptor agonists: opioids on a background of relatively well-
n Noradrenalin and serotonin re-uptake controlled baseline pain”.24 Rescue
dose of medications (as required or
inhibitors: SSRIs, SNRIs, tramadol when necessary) other than the regular
basal therapy must be prescribed for
PAIN MANAGEMENT BTP episodes.

The goal of pain management is to im- MILD PAIN
prove patient comfort, function and safe- Non-opioid analgesics such as paraceta-
ty. This involves optimising analgesia and mol, a NSAID or cyclo-oxygenase-2 in-
activities of daily living, while minimising hibitors (coxibs, COX-2) are the starting
adverse effects of the analgesic therapy. point for the treatment of mild pain. These
This can result in avoidance of aberrant agents are universally accepted as part
drug-taking and prevention of expected of the treatment of cancer pain. It is man-
analgesic side effects. To accomplish datory to periodically monitor and revise
these goals, a comprehensive pain man- the long-term use of NSAIDs or coxibs26
agement regime is needed and it is essen- because they can induce severe toxicity
tial to maximise patient and family edu- such as gastro-intestinal bleeding, platelet
cation, as well as physical and cognitive dysfunction and renal failure.
integrative interventions. 11
MILD TO MODERATE PAIN
In 1986, the World Health Organization The use of drugs on the second step of
(WHO) proposed a strategy for cancer- the WHO ladder has several controversial
pain treatment based on an analgesic lad- aspects. The controversy stems from the
der. This is a three-step ladder progressing absence of definitive proof of efficacy
from non-opioids to weak opioids to strong of the weak opioids. The efficacy when
opioids, according to the pain index (PI) comparing non-opioid analgesics alone,
of the patient.12 It is imperative to “score” and the combination of these with weak
the pain of each patient and thereby opioids, was not conclusive, but did high-
determine if an intervention reduces the light that the effectiveness of the second
pain score. Such a reduction indicates ef- step of the WHO ladder has a time limit of
ficacy and should determine further pain 30-40 days for most patients and that the
management for that particular patient. shift to the third step is mainly due to insuf-
The WHO cancer pain-relief programme ficient analgesia achieved, rather than to
still, after 20 years, remains the reference adverse effects. The problem is that high
point for pain management.13 According doses of the second-step drugs were lim-
to the WHO guidelines, opioid analgesics ited by a “ceiling effect”. This means that
are the mainstay of analgesic therapy
and are classified according to their abil-
ity to control pain from mild to mild-mod-
erate to moderate-severe intensity.2,15-17
Opioid analgesics may be combined with

HANDBOOK OF ONCOLOGY

Management of Cancer Pain 165

doses above a certain threshold cannot in analgesic therapy. Strong opioids may TREATMENT APPROACHES
increase the effectiveness of the drug, be combined with ongoing use of a non-
and the only result is the appearance of opioid analgesic (as per the WHO analge-
side effects. Many authors have proposed sic ladder).
the abolition of the second step of the
WHO analgesic ladder, in favour of the In the presence of renal impairment, all
early use of morphine at low doses. opioids should be used with caution and
at reduced doses and frequency. Fenta-
It is still recommended that for mild to nyl and buprenorphine, via the transder-
moderate cancer pain, weak opioids such mal route or intravenously, are the safest
as codeine and tramadol are given in opioids of choice in patients with chronic
combination with non-opioid analgesics. kidney disease stages 4 or 5 (estimated
glomerular filtration rate <30 ml/min).
MODERATE TO SEVERE PAIN
Opioid-switching is a practice used to
Strong opioids are the mainstay of an- improve pain relief and/or drug tolerabil-
algesic therapy in treating moderate to ity. The most frequent switch is among
severe cancer-related pain. Morphine, morphine, oxycodone, hydromorphone,
oxycodone, hydromorphone, fentanyl, and fentanyl.
tapentadol and buprenorphine are the
most-used strong opioids in Europe.27 It is SCHEDULING AND TITRATION
debatable whether other opioids are su-
perior to morphine in terms of efficacy and All patients should receive regular dos-
tolerability. Oral morphine is used in hos- ing of their medication (so-called by-the-
pices and palliative-care units as the drug clock dosing) with provision of a “rescue
of choice for this type of pain. It provides dose” to manage BTP. The “breakthrough
effective pain relief, is widely tolerated, dose” is usually equivalent to +10% to 15%
simple to administer and inexpensive. of the total daily dose. If more than four
“rescue doses” per day are necessary, the
Oral morphine remains the opioid of total daily prescribed amount is too low
first choice for moderate to severe can- and must be upwardly-adjusted until only
cer pain, but patients presenting with se- one to two episodes of BTP occur daily.
vere pain who need urgent relief should Opioids with a rapid onset and short dura-
be treated and titrated with parenteral tion are preferred as rescue medications.
opioids, usually administered by the sub- Immediate-release opioids should always
cutaneous or intravenous route. A simple be prescribed as a rescue medication in
conversion for parenteral use is that the order to eliminate the pain.
equivalent dose is one-third of the oral
medication. The recommended clinical practice
is thus to administer individual titration of
Hydromorphone, oxycodone and tap- dosages by means of normal-release mor-
entodol, in both immediate-release and phine administered every four hours plus
modified-release formulations for oral ad- rescue doses (hourly) for BTP. The regular
ministration, are effective alternatives to dose of slow-release opioids can then be
oral morphine. adjusted to take into account the total
amount of rescue morphine needed per
Transdermal fentanyl and transder- day. The total daily dose can then be di-
mal buprenorphine are best reserved for vided by the dosage intervals to give a
patients whose opioid requirements are dosage quantum of drug.
stable. They are usually the treatment of
choice for patients who are unable to MANAGEMENT OF SIDE EFFECTS
swallow, those with poor morphine toler-
ance and patients with poor compliance. The most common adverse effects en-
Although not recommended in the NCCN countered when treating cancer pain
Clinical Practice Guidelines in Oncology result from opioid therapy. These adverse
for Adult Cancer Pain11 because it is a effects include constipation, nausea/
partial agonist, buprenorphine has a role vomiting, urinary retention, pruritus and

HANDBOOK OF ONCOLOGY

166 PALLIATIVE CARE

signs of central nervous system (CNS) tox- NEUROPATHIC PAIN
icity (drowsiness, cognitive impairment,
confusion, hallucinations, myoclonic jerks). As previously stated, cancer pain may be
varied in nature, and many cancer pa-
While we can reduce the dosage of tients suffer from neuropathic pain. It has
the agent responsible for the adverse ef- been stated that different types of medi-
fect, we may at the same time reduce cations from those previously mentioned
the analgesic efficacy. The best way to are needed to treat neuropathic pain.
reduce dosages and still achieve analge-
sic efficacy is by using synergism of more An expert panel has published a guide-
than one analgesic agent. The reduced line to the management of neuropathic
dosages of the individual agents should pain in South Africa.31 The most commonly
decrease the individual drug side effects. recommended agents for the manage-
Alternative methods of pain control, such ment of neuropathic pain are gabapen-
as nerve block or radiotherapy, may be tin, pregabalin, duloxetine, carbamaze-
needed when dosage reduction and pine and amitriptyline. These drugs would
synergism prove ineffective in managing be classified as adjuvants in the WHO
the pain. recommendations and their use does not
preclude the use of the other agents de-
Obviously, adverse effects can be man- scribed in the WHO pain ladder. It is impos-
aged symptomatically. Suggested ther- sible to discuss the full recommendations
apy would include the continued use of at this point, but it should be noted that
anti-emetics for nausea, laxatives for con- the recommendation for first-level therapy
stipation, major tranquillisers for confusion includes duloxetine, pregabalin, amitrip-
and psychostimulants for drowsiness. Opi- tyline or a combination of those agents.
oid-switching may aid in resolving symp- Third-line therapy would include tramadol
toms of CNS toxicity. and other strong opioids. It must be em-
phasised that these agents need to be
It is common practice to suggest that prescribed at the correct dosage intervals
laxatives must be routinely prescribed for and at the correct dose.
both the prophylaxis and the manage-
ment of opioid-induced constipation, As a rough guide, prescribe duloxetine
while metoclopramide and antidopa- 60 mg once daily, pregabalin 150 mg twice
minergic drugs should be recommended daily, amitriptyline up to 50 mg once daily,
for treatment of opioid-related nausea gabapentin 400 mg three times a day, and
and vomiting. tramadol at least 100 mg as needed.

BREAKTHROUGH PAIN (BTP) INTERVENTIONAL OR INVASIVE
PAIN MANAGEMENT
The prevalence of BTP is 19% to 95%, de-
pending on the setting in which the pa- When cancer pain becomes difficult to
tient is being managed.28, 30 manage, it may be necessary to try to im-
prove the situation by using interventional
It is imperative that immediate-release techniques. This can be in the form of re-
formulation of opioids be used to treat gional blocks with either neurolytic agents
exacerbations of controlled background such as alcohol, phenol or local anaesthe-
pain. It is also appropriate to anticipate sia. Be warned that a neuritis may ensue
painful episodes such as pain on mov- following neurolysis and the pain from the
ing or on swallowing, and to administer neuritis may be worse than that for which
immediate-release oral morphine at least the block was performed.
20 minutes before such potential pain trig-
gers to prevent the BTP. Neurolytic blocks are best kept for pa-
tients with a short life expectancy. The
Intravenous opioids have a shorter onset most effective of these blocks are the
of analgesic activity in treating BTP epi- coeliac plexus block for pancreatic carci-
sodes compared to oral morphine. noma, and the superior hypogastic block
for visceral pain. It must be remembered
HANDBOOK OF ONCOLOGY

Management of Cancer Pain 167

that opioid therapy may need to be con- n Cancer Care Ontario’s Cancer-related TREATMENT APPROACHES
tinued after such blocks and that the Pain Management Guideline Panel
blocks serve as adjuvant therapy. 2012

Intrathecal drug delivery systems (ITT) n E uropean Society for Medical
may also be used to directly administer Oncology 20126
drugs into the epidural space or into the
cerebrospinal fluid, thereby reducing dos- n European Association of Palliative Care
age requirements and obviously side ef- 2012
fects of otherwise largely parenterally and
orally administered drugs. The drug reduc- n N ational Comprehensive Cancer
tion is approximately 70% if the drugs are Network 2014
epidurally administered and 90% if intrath-
ecally administered. It is imperative that a CONCLUSION
trial of ITT be performed prior to any system
implantation. Cancer pain is a common condition that
severely adversely affects quality of life.
The most commonly used agents for ITT Cancer pain is a significant burden to the
are morphine, ketamine, and local an- patient and his or her family. It must be un-
aesthetics.31,32 Insertion of these devices derstood that a single physician cannot
should only be performed by practitioners manage cancer pain by himself and that
trained in managing these devices. management of cancer pain requires a
multidisciplinary approach. Most cancer
NONPHARMACOLOGICAL THERAPIES pain can be managed safely and effec-
Physiotherapy, psychotherapy and social tively using combination therapies with
support services should be used in con- opioids. There is no need for a cancer pa-
junction with pharmacotherapies to man- tient to suffer unnecessarily.
age the overall pain state. 11
The treating physician must be familiar
THE ROLE OF PALLIATIVE CARE with the available modalities, and when
Palliative care should be integrated ear- pain management becomes difficult, it
ly in the cancer management strategy. is recommended that the patient be re-
Care should be managed by a special- ferred to a specialised unit used to dealing
ised, multidisciplinary team of health-care with cancer pain.
providers with emphasis on the quality of
life of the patient and his or her family. REFERENCES

It is a well known fact that early palliative 1. Van den Beuken-van Everdingen MHJ, De
care leads to better patient and caregiv- Rijke JM, Kessels AG, et al. Prevalence of
er outcomes, improvement in symptoms, pain in patients with cancer: a systematic
quality of life, and patient satisfaction with review of the past 40 years. Ann Oncol.
reduced caregiver burden.34-37 2007;18:1437-1449.

SELECTED PAIN MANAGEMENT 2. Portenoy RK. Sun V. Treatment of cancer
GUIDELINES pain. Lancet. 2011;377(9784):2236-47.3.
Many guidelines for the management of
cancer pain are available in the literature. 3. Borneman T, Piper B, et al. Barriers to pain
Here are a selected few for suggested assessment and management in cancer
reading or referencing: survivorship. J Cancer Surviv. 2008;2:65-71.
n World Health Organization 1996
n French National Federation of Cancer 4. Frankish H. 15 million new cancer cases
per year by 2020, says WHO. Lancet.
Centres 2002 2003;361:1278.
n Scottish Intercollegiate Guidelines
5. Schmidt H, Cleeland CS, Bauer A, et al.
Network (SIGN) 2008 Symptom burden of cancer patients:
n RAND Corporation 2008 validation of the German M. D. Anderson
Symptom Inventory: a cross-sectional mul-
ticenter study. J Pain Symptom Manage-
ment. 2014;49(1):117-25.

6. Oliveira KG, von Zeidler SV, Podestá JR, et
al. Influence of pain severity on the quality
of life in patients with head and neck can-
cer before antineoplastic therapy. BMC
Cancer. 2014;14:39.

7. Zaza C, Baine N. Cancer pain and psy-
chosocial factors: a critical review of the

HANDBOOK OF ONCOLOGY

168 PALLIATIVE CARE

literature. J Pain Symptom Management. recommendations from the EAPC. Lancet
2002;24(5):526-42. Oncol. 2012;13:58-68.
8. Van den Beuken-van Everdingen MHJ, de 24. P ortenoy RK, Hagen NA. Breakthrough
Rijke JM, Kessels AG, et al. Prevalence of pain: definition, prevalence, and charac-
pain in patients with cancer: a systematic teristics. Pain. 1990;41:273-281.
review of the past 40 years. Ann Oncol. 25. Joint Formulary Committee. British National
2007;18(9):1437-1449. Formulary. 55th ed. London: British Medical
9. Zylla D, Kuskowski MA, Gupta K, et al. Asso- Association and Royal Pharmaceutical So-
ciation of opioid requirement and cancer ciety of Great Britain; 2007.
pain with survival in advanced non-small 26. R ipamonti C, Bareggi C. Pharmacology
cell lung cancer. Br J Anaesth. 2014 Jul of opioid analgesia: clinical principles. In:
1;113(Suppl 1):i109-i116. Bruera E, Portenoy RK. Cancer Pain: As-
10. Zaza C, Baine N. Cancer pain and psy- sessment and Management. Cambridge,
chosocial factors: a critical review of Cambridge University Press. 2010;11:195-229.
the literature. J Pain Symptom Manage. 27. Mercadante S, Radbruch I, Caraceni A, et
2002;24(5):526-542. al. Episodic breakthrough pain: consensus
11. National Comprehensive Cancer Network. conference of an export working group
NCCN Guidelines. Adult Cancer Pain; 2017. of the European Association for Palliative
12. World Health Organization. Cancer Pain Care. Cancer. 2002;94:832-839.
Relief. Geneva: World Health Organization; 28. Mercadante S, Villari P, Ferrera P, et al.
1986. Transmucosal fentanyl vs intravenous mor-
13. World Health Organization. Cancer Pain phine in doses proportional to basal opioid
Relief. 2nd ed. Geneva: World Health Or- regimen for episodic breakthrough pain.
ganization; 1996. Br J Cancer. 2007;12:1828-1833.
14. Wallenstein S, Heidrich Gr, Kaiko R. Clinical 29. Zeppetella G, Riberio MDC. Opioids for the
evaluation of mild analgesics: the meas- management of breakthrough episodic
urement of clinical pain. Br J Clin Pharma- pain in cancer patients. Cochrane Data-
col. 1980;10(Suppl 2):319S-327S. base Syst Rev. 2006;1:CDOO4311.
15. Littman G, Walker B, Schneider B. Reas- 30. Chetty S, Baalbergen E, Bhigjee AI, et al.
sessment of verbal and visual analog rat- Clinical practice guidelines for manage-
ings in analgesic studies. Clin Pharmacol ment of neuropathic pain: expert panel
Ther.1985;38(1):16-23. recommendations for South Africa. S Afri
16. Serlin RC, Mendoza TR, Nakamura Y. When Med J. 2012;102(5):312-325.
is cancer pain mild, moderate or severe? 31. Vainio A, Tigerstedt I. Opioid treatment for
Grading pain severity by its interference radiating cancer pain: oral administration
with function. Pain. 1995;61:277-284. vs epidural techniques. Acta Anaesthesiol
17. Lussier D, Portenoy RK. Adjuvant analgesic Scand. 1988;32:179-180.
drugs. In Bruera E, Higginson IJ,Ripamonti C, 32. Myers J, Chan V, Jarvis V, et al. Intraspinal
von Gunten C (eds), Textbook of Palliative techniques for pain management in can-
Medicine. London: Edward Arnold Publish- cer patients: a systematic review. Support
ers. 2006;402-414. Care Cancer. 2010;18:137-149.
18. Paice JA, Ferrell B. The management of can- 33. Ripamonti CI, Santini D, Maranzano E, et al.
cer pain. CA Cancer J Clin. 2011;61:157-182. On behalf of the ESMO Guidelines Work-
19. National Comprehensive Cancer Network. ing Group. Management of cancer pain:
(NCCN) Clinical Practice Guideline in On- ESMO Clinical Practice Guidelines. Ann of
cology. Adult Cancer Pain V.I.; 2009. Oncol. 2012;23(Suppl7):vii139-vii154.
20. Hanks GW, De Conno F, Ripamonti C, et al. 34. Smith TJ, et al. American Society of Clini-
Morphine in cancer pain: modes of admin- cal Oncology provisional clinical opin-
istration. BMJ. 1996;312:823-826. ion: the integration of palliative care into
21. Hanks GW, De Conno F, Cherny N, et al. standard oncology care. J Clin Oncol.
From the Expert Working Group of the Re- 2012;30(8):880-7.
search Network of the European Associa- 35. Temel JS, et al. Early palliative care for pa-
tion for Palliative Care. Morphine and alter- tients with metastatic non-small-cell lung
native opioids in cancer pain. Br J Cancer. cancer. Engl J Med. 2010;363(8):733-42.
2001;84(5):587-593. 36. Girgis A, et al. Physical, psychosocial, rela-
22. Scottish Intercollegiate Guidelines Network. tionship, and economic burden of caring
Control of Pain in Adults with Cancer. A Na- for people with cancer: a review. J Oncol
tional Clinical Guideline. Edinburgh, Scot- Pract. 2013;9(4):197-202.
land: SIGN – Scottish Intercollegiate Guide- 37. Parikh RB, et al. Early specialty palliative
lines Network; November 2008. care – translating data in oncology into
23. Caraceni A, Hanks G, Kaasa S, et al. practice. N Engl J Med. 2013;369(24):2347-
Use of opioid analgesics in the treat- 51
ment of cancer pain: evidence-based
HANDBOOK OF ONCOLOGY

DNA-Alkylating Agents 169

Drug-Class Overview

CONVENTIONAL CHEMOTHERAPY considered non-cell-cycle-specific, al- DRUG-CLASS OVERVIEW
though replicating cells are most suscepti-
Chemotherapeutic agents have a variety ble to cytotoxicity.3,4
of mechanisms whereby they either in-
duce cell death through apoptosis (cyto- As DNA damage can occur at any point
toxic) or prevent cell division without in- in the cell cycle after exposure to an
ducing apoptosis (cytostatic).1 All alkylating agent, prolonged exposure to
cytotoxic chemotherapeutics exert their the alkylating agent is not required.2 Unfor-
effects by disrupting the cell cycle in that tunately, this not the case with cell-cycle-
they directly interfere with the cell DNA or specific agents, as S-phase-specific agents,
target key proteins required for cell divi- for example, require prolonged exposure
sion.2 The cell cycle, a four-stage cycle to target cells circulating into the S-phase.2
(mitosis, Gap 1, synthesis, Gap 2), takes
place as the cell prepares to replicate Alkylating agents form the cornerstone
and divide.2 During mitosis, the chromo- of high-dose chemotherapy regimens as
somes align and separate as the cell di- they have a steep dose-response curve
vides, whereas in the synthesis or S-phase, and anti-tumour activity at standard
DNA synthesis takes place, replicating the dose.5 In high-dose chemotherapy regi-
cell’s genetic material.2 The Gap phases mens, the dose intensity is important to
serve as checkpoint and repair stations, achieve a cure; the dose can be escalat-
preventing cell-cycle progression until all ed as the threshold dose is limited only by
requirements have been met.2 Cancer the toxicity to normal tissues.2
cells have lost the normal cell-cycle con-
trols, becoming insensitive to growth inhib- Cell-cycle-specific agents, on the other
itory signals and acquiring the ability to hand, have a dose-response effect up to
evade apoptosis.2 a threshold. Consequently, increasing the
dose does not increase the number of cell
As cytotoxic agents cause cell death by deaths.2
disrupting the cell cycle, these agents are
also toxic to “normal” cells entering the Electron-deficient alkylating agents react
cell cycle and more so for high-turnover with the electron-rich areas on DNA, RNA
cells such as bone marrow and mucous and proteins, transferring an alkyl group to
membranes.2 these cellular constituents.3,6 By forming
cross-links in and between DNA strands, the
1. DNA-ALKYLATING AGENTS DNA strands are unable to uncoil and sep-
arate, preventing DNA replication and
DNA-alkylating agents are cytotoxic therefore cellular proliferation.7
agents used therapeutically as antineo-
plastic agents. They have a non-specific Alkylating agents are divided into sev-
mechanism of action and are therefore eral classes based on their chemical struc-
ture. These include nitrogen mustards, eth-
yleneimines, alkylsulphonates, nitrosoureas
and triazenes (see Table 1). They can be

Table 1. Classification of DNA-alkylating agents

Nitrogen Ethylenei- Alkylsulpho- Nitrosou- Triazenes Platinum New/
mustards mines nates reas Temo- co-ordina- other
Chlorambucil (aziridine) zolomide tion Trabec-
Cyclophos- Mito- Busulfan Carmus- complexes tedin
mycin- tine Carboplatin
phamide C Cisplatin
Estramustine Oxaliplatin
Ifosfamide
Melphalan
Bendamustine

HANDBOOK OF ONCOLOGY

170 DRUG-CLASS OVERVIEW Detailed indications for each of the nitro-
gen mustards follow.
classified as monofunctional, bifunctional
or trifunctional, depending on whether Indications13-15
the agent has one, two or three reactive Chlorambucil
groups capable of interacting with the n Hodgkin’s disease
cellular constituents.3,5,6 n Certain forms of non-Hodgkin’s

Therapeutically, the bifunctional agents lymphoma
are the most effective alkylating agents.6 n Chronic lymphocytic leukaemia
n Waldenstrom’s macroglobulinaemia
DNA-alkylating agents target rapidly di-
viding cells. Cyclophosphamide
n Alone or in combination with other
Patients may experience dose-related
side effects that lead to myelosuppression cytostatic agents for various cancers
which involves bone marrow, lymphoid tis- of the neoplastic disease of the
sue, intestinal mucosa, hair cells and the reticulo-endothelial system, such as
reproductive system.3,6 lymphomas, lymphosarcomas,
reticulo-sarcomas, Hodgkin’s disease,
Alkylating agents lack cross-resistance chronic lymphatic leukaemias,
and thus combinations can be employed.5 multiple myelomas
Combinations may reduce the likelihood n Adjunctive chemotherapy agent in
of resistance and increase the therapeu- surgery and/or radiotherapy
tic benefit.5 n As palliative therapy in inoperable
NITROGEN MUSTARDS malignancies
Sulphur mustard was first synthesised as a n Progressive auto-immune disease
vesicant chemical warfare agent in the n Ovarian cancer96
late 19th century for use by the German
army during World War I (WWI).8-10 Estramustine
n Advanced prostate cancer
During WWI, physicians observed that
soldiers exposed to sulphur mustard or Ifosfamide
mustard gas had severe bone-marrow n Oat-cell bronchogenic carcinoma
suppression.1 n Ovarian cancer
n Mammary cancer
This observation led to the recognition of n Pancreatic cancer
the potential cytotoxicity of alkylating n Testicular tumours
agents and the development of nitrogen n Hypernephroma
mustards.1 n Malignant lymphoma
n Chondro-osteosarcoma
Individuals exposed to nitrogen mus- n Leiomyosarcoma
tards developed severe irritating symp- n Rhabdomyosarcoma
toms affecting the respiratory tract, mu-
cous membranes, skin, eyes, and Melphalan
endocrine- and immune systems.10,11 n Multiple myeloma
n Ovarian cancer
As lymphocytes are particularly suscep- n Neuroblastoma in childhood
tible to the cytotoxic effects of nitrogen n Adjunctive in breast cancer
mustards, these agents are used in the
palliation of chronic lymphatic leukaemias Bendamustine
and malignant lymphomas.12 n First-line CLL treatment (Binet stage B

Cyclophosphamide is the most frequently or C) in patients for whom fludarabine
used alkylating agent in chemotherapy.5 combination chemotherapy is not
appropriate
Cyclophosphamide and ifosfamide are n Indolent CD20-positive non-Hodgkin’s
prodrugs that require activation via the cy- lymphoma in combination with
tochrome P450 family of drug-metabolising rituximab
enzymes.5,6

Acrolein, a metabolite of cyclophospha-
mide and ifosfamide, can induce bladder
toxicity which can lead to haemorrhagic
cystitis. To prevent this side effect, 2-mercap-
toethanesulphonate (MESNA) is co-adminis-
tered in cyclophosphamide and ifosfa-
mide therapy.5

HANDBOOK OF ONCOLOGY

DNA-Alkylating Agents 171

Table 2. General side effects of nitrogen mustards4,12,14,16

Haemato- Gastro-intestinal Central nervous Dermatological Miscellaneous
logical system
Bone- n N ausea and n A llergic skin n P ulmonary
marrow vomiting n T remor reactions fibrosis
suppression n Muscle-
n D iarrhoea twitching n S kin hyper- n D rug fever
n A norexia n M yoclonia sensitivity n P eripheral
n M etallic taste n C onfusion reactions
n H epato- n H alluci- neuropathy
n I nterstitial
toxicity and nations
jaundice n A gitation pneumonia
n A bnormal n A taxia n S terile cystitis
liver function n F laccid n I nfertility
tests n T issue damage
paresis
at injection site
n V asculitis DRUG-CLASS OVERVIEW
n I ncreased risk of

secondary
malignancies

n Indolent non-Hodgkin’s lymphoma as The first compound synthesised in this
monotherapy in patients who have class was triethylenemelamine, the syn-
progressed during or within six months thetic precursor of N,N’,N’’-triethylene-
following treatment of multiple phosphoramide (TEPA).5
myeloma with rituximab or a
rituximab-containing regimen TEPA showed a profound cytotoxic ef-
fect, but was chemically too unstable to
n Front-line treatment of multiple be used in clinical practice.5
myeloma (Durie-Salmon stage II with
progress or stage III) in combination ThioTEPA (N,N’,N’’-triethylenethiophos-
with prednisone for patients older that phamide), the major representative of the
65 years not eligible for autologous ethyleneimines, is a more stable sulphur
stem-cell transplant and who have analogue of TEPA with strong alkylating
clinical neuropathy at time of diagnosis activity.5
precluding use of a thalidomide and
bortezomib-containing regimen Following are detailed indications for
ethyleneimines.
Side effects
As with all alkylating agents, the side ef- Indications5,17-20
fects of nitrogen mustards (see Table 2) Mitomycin
are generally dose-related and occur in Mytomycin is an anti-neoplastic antibiotic
rapidly growing tissues, which results in produced by Streptomyces caespitosus
myelosuppression.4 which selectively inhibits the synthesis of
DNA and, at higher drug concentrations,
Contra-indications, special precautions RNA and protein synthesis as well.18
and drug interactions: See MIMS Monthly, n A broad spectrum cytostatic
MDR or manufacturer’s product literature. n Single therapy: breast cancer and

ETHYLENEIMINES gastro-intestinal cancer
Aziridine or ethyleneimines are a group of n Combination therapy: gastric,
alkylating agents which contain an aziri-
dine functional group and are chemically pancreatic, bladder, non-small-cell
and pharmacologically related to the ni- lung, head and neck squamous cell
trogen mustards.17 Ethyleneimines cross- and colorectal cancer
link DNA through the release of the aziri-
dine functional group, disrupting the DNA Side effects
bonds and thereby inhibiting DNA synthe- As with all alkylating agents, ethyle-
sis and function.17,18 neimines cause myelosuppression.4

Table 3 provides general side effects of
ethyleneimines.

HANDBOOK OF ONCOLOGY

172 DRUG-CLASS OVERVIEW

Table 3. General side effects of ethyleneimines17

Haemato- Gastro-intes- Central Dermato- Respiratory Miscellaneous
logical tinal nervous logical
system n L aryngeal n F atigue
Haemoto- n N ausea n A llergic oedema n W eakness
poietic and n D izziness skin n M utage-
depression vomiting n H eadache reactions n A sthma
n C onfusion n W heezing nicity
n D iarrhoea n S kin n A pnoea n A men-
n A bdo- hyper-
sensitivity orrhoea
minal pain reactions n I nterference
n A norexia
n D ysuria n S kin with
n U rinary depig- sperma-
menta- togenesis
retention tion n P ain at
n H aemor- injection site
n C onjunc-
rhagic tivitis
cystitis n I ncreased
risk of
secondary
malignan-
cies

ALKYLSULPHONATES NITROSOUREAS

Busulfan (also known as busulphan) is a Carmustine is the most frequently used
highly cytotoxic bifunctional alkylsulpho- member of the nitrosourea class of alkylat-
nate with a narrow therapeutic index.6,21 ing agents.5 Nitrosoureas’ cytotoxicity is
mediated through the formation of DNA
Busulfan is not structurally related to the interstrand cross-linking with guanine and
nitrogen mustards.22 cytosine.5 Nitrosoureas are highly lipid-sol-
uble and easily absorbed through tissues
Busulfan is indicated for the palliative and cell membranes, therefore able to
treatment of chronic myelogenous leukae- cross the blood-brain barrier for the treat-
mia as well as for conditioning treatment ment of brain tumours.5,6
prior to haematopoietic progenitor cell
transplantation in adults.5,13,21,22

Side effects Indications13
Carmustine
Busulfan can cause dose-related myelo- n Surgical adjunctive to prolong survival
suppression, as well as interstitial pulmo-
nary fibrosis. in recurrent glioblastoma multiforme
n Cardiac tamponade where surgical resection is indicated
n Cataracts n Adjunct to surgery and radiation in
n Hyperpigmentation newly diagnosed high-grade
n Symptoms resembling adrenal malignant glioma patients

insufficiency Side effects13
n Oesophageal varices
n Jaundice n Cerebral haemorrhage or infarction
n Skin complications n Peripheral or brain oedema
n Gynaecomastia n Neck, back and chest pain
n Myasthenia gravis n Allergic reactions
n Asthenia
Contra-indications, special precautions n Sepsis
and drug interactions: See MIMS Monthly, n GI disturbances
MDR or manufacturer’s product literature.

HANDBOOK OF ONCOLOGY

n Electrolyte disturbances DNA-Alkylating Agents 173 DRUG-CLASS OVERVIEW
n Hyperglycaemia
n CNS effects Cisplatin was accidentally discovered in
n Hyper- or hypotension 1965 and used in trials for chemo-resistant
n Urinary incontinence testicular teratomas and relapsed ovarian
n Blood dyscrasia cancer.24 These trials reported a high inci-
n Infections dence of toxicities, in particular nausea
n Abnormal healing and vomiting and nephrotoxicity.24,25
n Visual disturbances Therefore the cisplatin-related analogues
n Pulmonary embolisms were developed to reduce the side ef-
fects experienced by this chemothera-
Contra-indications, special precautions peutic agent.25
and drug interactions: See MIMS Monthly,
MDR or manufacturer’s product literature. Cisplatin
Cisplatin has antitumour activity similar to
TRIAZENES the typical alkylating agents and is highly
Temozolomide is an oral alkylating agent bound to plasma albumin after intrave-
for the treatment of newly diagnosed glio- nous (IV) administration.5,24 The most com-
blastoma multiforme, recurrent malignant mon side effect is nausea and vomiting
glioma, refractory anaplastic astrocytoma which can be overcome by administering
and advanced metastatic malignant 5a-nhtyadgroonxyisttrsypatanmd inceo-3rtic(o5s-tHeTr3o)idsrecdeupritnogr
melanoma.13,23 therapy.24 The dose-limiting side effects of
cisplatin are nephrotoxicity, neurotoxicity
Side effects23 and mild myelosuppression.24 The risk of
nephrotoxicity can be reduced by main-
The main dose-limiting side effect of temo- taining good diuresis in the patient.1
zolomide is myelosuppression5
n Nausea and vomiting Cisplatin is indicated for:13,23
n Fatigue n Advanced non-seminomatous
n Constipation
n Anorexia testicular cancer in combination with
n Headache bleomycin and vinblastine
n Ovarian cancer in combination with
Contra-indications, special precautions doxorubicin or cyclophosphamide
and drug interactions: See MIMS Monthly, n Cancer of the bladder, head, neck,
MDR or manufacturer’s product literature. endometrium, small-cell-lung cancer
n Lymphomas
PLATINUM CO-ORDINATION n Some childhood neoplasms
COMPLEXES n Metastatic breast cancer94
Platinum co-ordination complexes are n Melanoma108
one of the most widely used chemothera-
peutic agents. These agents are used as Carboplatin
standard therapy in ovarian, lung, head Carboplatin, a cisplatin-analogue, is less
and neck, oesophageal and cervical emetogenic, nephrotoxic, neurotoxic and
cancers and are responsible for the high ototoxic than cisplatin, but induces more
cure rate in germ-cell tumours.24 myelosuppression.5,24 Carboplatin is a
more stable compound with a mecha-
Platinum co-ordination complexes have nism of action similar to that of cisplatin,
two active platinum bonds which, once although it requires around a 10-fold high-
aquated in the tissues, bind to macromol- er dose and incubation period.24
ecules in tissue such as RNA and cellular
proteins, and irreversibly to DNA.1,24 Most of Carboplatin is indicated for:13,23,98
the binding results in the forming of intra- n Advanced ovarian cancer of
strand DNA adducts followed by inter-
strand cross-links.1,5,24 With the cell unable epithelial origin in first-line therapy or
to divide, it undergoes apoptosis.5 second-line therapy after failure of
other treatments
n Small-cell lung cancer
n Squamous cell cancer of head and
neck

HANDBOOK OF ONCOLOGY

174 DRUG-CLASS OVERVIEW combination of oxaliplatin and S1 over
S1 alone or the benefit of docetaxel,
n Cervical cancer oxaliplatin and S-1 (tegafur/gimeracil/
n Melanoma110 oteracil combination) as perioperative
regimen over surgery alone90
Oxaliplatin Contra-indications, special precautions
Oxaliplatin is a newer analogue to cispl- and drug interactions: See MIMS Monthly,
atin.24 Its mechanism of action is similar to MDR or manufacturer’s product literature.
the two other platinum co-ordination
complexes, but it forms DNA-adducts NEW/OTHER
50-times faster than cisplatin.24 Oxaliplatin
is active in cisplatin-resistant cell lines and Trabectedin is a marine-derived anti-
used in combination with 5-fluorouracil (5- tumoural agent with a unique mechanism
FU) in colorectal cancer.24 Its main dose- of action.129,130 Trabectedin binds to the mi-
limiting side effect is neuropathy. It does nor groove of DNA, interfering with cell di-
not, however, induce nephrotoxicity.24 vision and genetic transcription processes
and DNA-repair machinery. Trabectedin is
Oxaliplatin is indicated for:13 indicated for the treatment of unresecta-
n In combination with 5-fluorouracil and ble or metastatic liposarcoma or leio-
myosarcoma in patients who have been
folinic acid, for metastatic colorectal treated with an anthracycline-containing
cancer regimen.
n Adjuvant treatment of colon cancer
n Under investigation, the use of the

HANDBOOK OF ONCOLOGY

2. S-PHASE-SPECIFIC DRUGS S-Phase-Specific Drugs 175 DRUG-CLASS OVERVIEW

S-phase-specific drugs are cell-cycle-spe- DHFR, TS and GARFT inhibitors
cific agents that exert their actions when Antimetabolites as a group are some of
the cell has reached the S-phase of the the oldest antitumour agents.25 These
cell cycle.26 These agents are grouped as agents’ targets are incorporated as false
antimetabolites, nucleoside analogues or substrates into the DNA or target enzymes
ribonucleotide reductase inhibitors. such as DNA polymerase, thymidylate syn-
thase (TS), dihydrofolate reductase (DHFR)
During the S-phase, the DNA of the cell is and glycinamide ribonucleotide formyl-
replicated so each chromosome is passed transferase (GARFT), exploiting the num-
intact to its two daughter cells during ber of quantitative differences in the me-
mitosis.27,28 tabolism between cancer cells and
normal cells.4,25 It is these differences that
The DNA molecule contains a linear se- make cancer cells more sensitive to
quence of four components, namely nucle- antimetabolites.4
otides that code for a specific protein.27 A
process called transcription copies the DNA Antifolates
nucleotides into a nucleic acid messenger, lFivoelicr taocdidihy(vditraofmoilnatBe9)wihs icchonisvefurtrtehderinctohne-
namely RNA. RNA is further translated into verted to its active metabolite, tetrahy-
the specific amino acid sequence.27 drofolate.26 Tetrahydrofolate is an essential
cofactor in numerous bodily functions for
Each nucleotide or deoxyribonucleo- nucleotide biosynthesis, DNA synthesis
tide consists of a five-carbon sugar, deox- and repair.26 Methotrexate (MTX) compet-
yribose, with a different nitrogenous base itively and irreversibly inhibits the enzyme
for each of the four nucleotides.28 These dihydrofolate reductase which has a
four nitrogenous bases are thymine (T), cy- much higher affinity for MTX than dihydro-
tosine (C), adenine (A) and guanine (G) folate.26
and for simplicity each nucleotide in a
DNA molecule is referred to by its base.28 It inhibits the conversion of DHFR to tet-
rahydrofolate, as well as the synthesis of nu-
RNA is similar to DNA, differing only in cleotides, DNA, RNA, thymidylates and
that its ribonucleotides are slightly differ- proteins.26
ent to the deoxyribonucleotides.28
Pemetrexed has a similar mechanism of
Each ribonucleotide in RNA consists of a action to that of MTX, but also inhibits the en-
five-carbon sugar, a nitrogenous base, a zymes TS and GARFT, thus inhibiting the syn-
phosphase group and a hydroxyl group.28 thesis of DNA, RNA and the formation of pre-
cursor purine and pyrimidine nucleotides.26
As with DNA, RNA’s four nucleotides dif-
fer from each other in the composition of PURINE ANALOGUES
the nitrogenous base, with three of the A and G are purines as they have a two-
bases being similar to that of DNA – A, C ringed nitrogenous base, a six-membered
and G.28 The fourth nitrogenous base in ring fused with a five-membered ring.28
RNA is uracil (U), which is very similar to the
T-base of DNA.28 Cladribine and fludarabine are purine
nucleotide analogues, which are inactive
ANTIMETABOLITES in their parent form and metabolised to
L-Asparaginase cladribine triphosphate or fludarabine
L-asparaginase is an enzyme that hydro- triphosphate.4 These active triphosphate
lyses circulating L-asparagines into aspar- metabolites inhibit DNA polymerase, an
tic acid and ammonia, thereby rapidly in- enzyme needed for DNA synthesis from
hibiting protein synthesis.4,26 L-asparaginase nucleotides.4 Furthermore, these metabo-
is primarily used for treatment of acute lites can also be mistakenly incorporated
lymphoblastic leukaemia (ALL) and for into DNA, inhibiting DNA synthesis and in-
some mast-cell tumours, as these cells are ducing cell death.4
unable to synthesise the non-essential
amino acid asparagines, where normal 6-Mercaptopurine and 6-thioguanine in-
cells can synthesise their own.26 hibit purine nucleotide synthesis and metab-
olism, which alters the function and synthesis
The main side effects are related to hy- of DNA and RNA, leading to cell death.26
persensitivity reactions from the agent
and manifest as fever, chills, nausea and HANDBOOK OF ONCOLOGY
vomiting, skin rash and urticaria.4

176 DRUG-CLASS OVERVIEW

PYRIMIDINE ANALOGUES Once taken up by the cells, azacitidine
T and C are pyrimidines as they have a sin- is metabolised to 5-azacitidine diphos-
gle six-membered ring in their nitrogenous phate or 5-azacitidine triphosphate.29
base.28 5-azacitidine diphosphate is initially re-
duced to 5-azadeoxycytidine diphos-
As T is needed for the synthesis of DNA phate and then to 5-azadeoxycytidine
and RNA, inhibition in the synthesis would
impair DNA and RNA synthesis and even- triphosphate.295-azadeoxycytidinetriphos-
tually lead to cell death.26 5-FU and its
prodrugs capecitabine and tegafur in- phate is incorporated into DNA which
hibit the methylation of deoxyuridylic
acid to thymidylic acid by serving as a leads to the inhibition of DNA synthesis.29
substrate for the enzyme.26 The effects of
RNA and DNA deprivation are most pro- 5-azacitidine triphosphate is incorpo-
nounced in rapidly dividing cells as these
cells take up more 5-FU.26 rated into RNA, which leads to the disrup-

The cellular metabolism of 5-FU leads to tion of RNA metabolism and inhibition of
the production of two active metabolites
capable of inflicting cell injury.26 The first protein synthesis.29
metabolite inhibits DNA synthesis by bind-
ing to TS, an enzyme that produces thymi- Gemcitabine is a fluorine-substituted
dylate, which is needed for DNA synthe-
sis, whereas the second metabolite is deoxycytidine analogue that is phospho-
mistakenly incorporated as an RNA build-
ing block, interfering with RNA processing rylated to a diphosphate and a triphos-
and protein synthesis.26
phate nucleotide form respectively.4
Capecitabine is absorbed from the
gastro-intestinal (GI) tract and hydrolysed The diphosphate form irreversibly inhib-
into 5-FU, but the final conversion of
capecitabine to 5-FU by thymidine phos- its the ribonucleotide reductase (RNR) as
phorylase can only take place in cells or
tissue that express this enzyme.26 Certain a false substrate.26
types of cancers highly express thymidine
phosphorylase, therefore capecitabine is RNR is responsible for the synthesis of
able to target these populations.26
deoxynucleotide triphosphates required
Cytarabine inhibits DNA polymerase,
thereby preventing the progression of cells for DNA replication and repair. Unable to
froAmzathceitiGdi1n-pehoarse5-iantzoacthiteidSi-npehaissea.2c6,2h8 emi-
cal analogue of the cytosine nucleotide replicate or repair its DNA, the cell under-
used in DNA and RNA synthesis.29
goes apoptosis.26
The triphosphate form is a defective

DNA nucleotide. Once incorporated into

the DNA molecule, it prevents the at-

tachment of more nucleotides and the
cell is forced to undergo apoptosis.26

Table 4 provides a detailed indication
and side-effect profile for purine and py-
rimidine analogues and antimetabolites.

Contra-indications, special precautions
and drug interactions: See MIMS Monthly,
MDR or manufacturer’s product literature.

Table 4. General indications and side effects of purine and pyrimidine analogues and
antimetabolites4,13,29,30

Agent Indication Side effects

Purine Cladribine n A cute hairy cell leukaemia n M yelosuppression
analogues n N ausea and vomiting
n I mmunosuppression

Fludarabine n I nitial treatment of B-cell n M yelosuppression
CLL n I mmunosuppression
n F ever
n C LL patients with sufficient n M yalgias
bone-marrow reserve n A rthralgias
whose disease has not
responded to at least one
alkylating-agent-contain-
ing regimen

n N on-Hodgkin’s lymphoma

HANDBOOK OF ONCOLOGY

S-Phase-Specific Drugs 177

Table 4. (cont.)

Purine Agent Indication Side effects DRUG-CLASS OVERVIEW
analogues 6-Mercapto- n M yelosuppression
(continued) purine n A cute leukaemia n I mmunosuppression
Pyrimidine n V alue in ALL n H epatotoxicity
analogues 6-Thioguanine n A cute myelogenous leukaemia
n M yelosuppression
Dacarbazine (AML) n I mmunosuppression
(imidazole) n C hronic granulocytic n H epatotoxicity

117,118 leukaemia n N ausea and
vomiting
Azacitidine n A ML
n C hronic myelocytic leukaemia n D iarrhoea
n M yelosuppression
(CML) in combination with
other therapy with anaemia and
thrombocytopaenia
n M etastatic melanoma n C onstipation
n H odgkin’s lymphoma as part of n E rythema
n E cchymosis
the ABVD regimen (doxoru- n P etechiae
bicin, bleomycin, vinblastine, n R igors
dacarbazine) n W eakness
n H ypokalaemia
n M yelodysplastic syndrome
(MDS) including refractory
anaemia

n R efractory anaemia with
ringed sideroblasts if accom-
panied by:

– Neutropaenia
– Thrombocytopaenia
– Requiring transfusions
n R efractory anaemia with

excess blasts
n R efractory anaemia with

excess blasts in transformation
n C hronic myelomonocytic

leukaemia

Capecitabine n L ocally advanced or meta- n D iarrhoea
static breast cancer n H and-foot syndrome
n M yelosuppression
– In combination therapy with n N ausea and
docetaxel after failure of
cytotoxic therapy, including vomiting
anthracycline

– As monotherapy after failure
of taxanes and an anthracy-
cline-containing regimen

n C olorectal cancer:
– Adjuvant after surgery in

Dukes C colon cancer
– First-line monotherapy when

pyrimidine therapy alone
preferred
n G astric cancer88

HANDBOOK OF ONCOLOGY

178 DRUG-CLASS OVERVIEW

Table 4. (cont.)

Pyrimidine Agent Indication Side effects
analogues Cytarabine n I nduction and maintenance of n N ausea and
continued
remission in acute myelocytic vomiting
5-Fluorouracil leukaemia n M yelosuppression
(5-FU) n A cute lymphocytic leukaemia
Gemcitabine with neutropaenia
n P alliative treatment of breast and
Tegafur and GI-tract cancer thrombo-cytopae-
nia
n B eneficial in hepatoma and n C erebellar ataxia
cancer of the ovary, cervix, n N ausea
bladder, prostate, pancreas, n M ucositis
oropharyngeal areas n D iarrhoea
n B one-marrow
n F irst-line treatment in locally depression
advanced (non-resected n N eurotoxicity
stage II or III) or metastatic n N ausea and
(stage IV) pancreatic adeno- vomiting
carcinoma previously treated n D iarrhoea
with 5-fluorouracil n M yelosuppression
with anaemia and
n T ransitional cell bladder thrombocytopaenia
cancer n C onstipation
n E rythema
n U nresected/locally recurrent or n E cchymosis
metastatic breast cancer in n P etechiae
combination with paclitaxel in n R igors
patients who have relapsed n W eakness
following adjunctive/neoad- n H ypokalaemia
junctive chemotherapy
(including an anthracycline- n D iarrhoea
based regimen) unless gemcit- n N ausea and
abine is contra-indicated
vomiting
n L ocally advanced or meta- n F atigue
static non-small-cell lung n M yelosuppression
cancer n A naemia
n S kin and nail
n A lone or in combination for
recurrent epithelial ovarian changes
cancer patients who have
relapsed following platinum-
based chemotherapy

n N on-Hodgkin's lymphoma
n S oft tissue sarcoma
n C ervical cancer in combina-

tion with cisplatin101
n F irst-line colorectal cancer with

calcium folinate

HANDBOOK OF ONCOLOGY

S-Phase-Specific Agents 179

Table 4. (cont.)

Antifolates Agent Indication Side effects
Methotrexate n G eneral oncology
(MTX) n A cute lymphoma in children n M ucositis
n D iarrhoea
Antifolates Pemetrexed n M alignant pleural mesothe- n M yelosuppression
(continued) lioma in combination with
cisplatin with neutropaenia
and
n I nitial treatment of locally thrombocytopaenia
advanced metastatic non-
small-cell lung cancer other n M yelosuppression
than predominant squamous n S kin rash
cell histology with cisplatin n M ucositis
n D iarrhoea
n M onotherapy in locally ad- n F atigue
vanced or metastatic adeno-
carcinoma of the lung after DRUG-CLASS OVERVIEW
prior chemotherapy

n M onotherapy for maintenance
treatment of locally advanced
or metastatic lung adenocarci-
noma when disease has not
immediately progressed after
standard chemotherapy

S-1 RIBONUCLEOTIDE REDUCTASE
S-1 is a combination of three pharmaco- INHIBITORS
logical compounds, namely tegafur,
gimeracil, and oteracil used for the treat- The precise mechanism of action of hydroxy-
ment of unresectable advanced gastric urea (also known as hydroxycarbamide) is
cancer in combination with cisplatin.112 unknown, but it is believed to inhibit retinoic
Tegafur is a prodrug of 5-fluorouracil (5- acid receptors (RARs), thereby depleting
FU), an oral fluoropyrimidine, and it has deoxynucleoside triphosphate and inhibit-
been developed as a replacement for in- ing DNA synthesis without affecting the syn-
fusional 5-FU therapy. Gimeracil Is a po- thesis of ribonucleic acids or proteins.4,31
tent inhibitor of 5-FU degradation and
oteracil protects against 5-FU-induced GI Hydroxyurea is indicated for malignant
toxicity to tegafur.113 neoplastic disease, recurrent disease,
metastatic disease, CML and tumours of
Trifluridine/tipiracil the head and neck.31
Trifluridine/tipiracil is a combination drug
for the treatment of metastatic colorectal Side effects include bone-marrow sup-
cancer.122 Trifluridine is a thymidine-based pression, GI upsets such as nausea and
nucleoside analogue and tipiracil, a thy- vomiting, dermatological effects, drowsi-
midine phosphorylase inhibitor, prevents ness and elevated serum uric acid, urea
trifluridine degradation by thymidine. and creatinine levels.31

Contra-indications, special precautions
and drug interactions: See MIMS Monthly,
MDR or manufacturer’s product literature.

HANDBOOK OF ONCOLOGY

180 DRUG-CLASS OVERVIEW

3. G2-PHASE-SPECIFIC AGENTS n In combination with cisplatin for
histological confirmed stage IV-B
gDruorwinganthdepGre2p-pahreasfeo,r cells continue to recurring or persistent cervical cancer
mitosis, increasing not amenable to curative treatment
the rate of protein synthesis.27 For DNA rep- with surgical and radiation therapy
lication to take place, the double-strand-
ed DNA coils must be unwound and sepa- n Palliative treatment of small-cell lung
rated into single strands.28 The process of cancer as a second-line
unwinding the DNA for replication can re- chemotherapeutic agent in patients
sult in some sections ahead of the replica- who relapse after an initial response to
tion fork to supercoil and interfere with the first-line agents
topology of DNA, preventing DNA replica-
tion from taking place.28 n Cervical cancer102
Enzymes called topoisomerases relieve
the tension caused by unwinding as they Side effects4
cleave either one strand of the double n Nausea and vomiting
DNA helix (type I) or both strands (type II) n Myelosuppression
ahead of the replication fork, leaving the
DNA molecule to unwind at the cleaved Contra-indications, special precautions
site and relieve the tension.28 Once the and drug interactions: See MIMS Monthly,
tension has been relieved, these enzymes MDR or manufacturer’s product literature.
anneal the stands.28
Although these enzymes are similar in TOPO-II INHIBITORS
some aspects, they differ in their interac- Type II topoisomerase, together with
tion with DNA.32 type I, regulates the topology of DNA.32
Topo-II inhibitors block the enzyme, type II
TOPO-I INHIBITORS topoisomerase, which acts by a different
The camptothecin analogues are plant- mechanism, preventing annealing of the
derived compounds extracted from the DNA after it has been cleaved.32
bark of the Chinese Camptotheca trees.25
These agents inhibit the type I topoisomer- Epipodophyllotoxin
ase enzymes by binding to the topoi- Etoposide is a semi-synthetic epipodo-
somerase I-DNA complex.33 This binding phyllotoxin analogue.32 Etoposide inhibits
prevents annealing of the cleaved strand, the type II topoisomerase enzyme by
resulting in the formation of irreversible binding to the topoisomerase-DNA com-
DNA breaks that lead to cell death.25,33 plex, and thereby prevents annealing of
These agents are commonly used in the the cleaved DNA.32
treatment of gastro-intestinal and pulmo-
nary malignancies.33 During replication, the initial DNA break
is converted into a permanent double-
Detailed indications and side effects of stranded break which can lead to cell
camptothecin analogues follow. death.32

Indications13,89 Etoposide is indicated for the treatment
Irinotecan of non-small-cell and small-cell lung can-
n Advanced colorectal cancer with cer, non-Hodgkin’s lymphoma, gastric
cancer, ovarian cancer and cervical
WHO performance status of two or cancer.4,97,100 Its main side effect is haema-
lower tological toxicity.26
- In combination with 5-FU and folinic
Anthracyclines
acid without prior chemotherapy Anthracyclines, such as doxorubicin and
- For advanced disease or as single daunorubicin, are antimicrobial isolates
from Streptomyces peucetius or Strepto-
agent when established 5-FU- myces galilaeus, whereas epirubicin and
containing regimen has failed idarubicin are semi-synthetic anthracy-
n Gastric cancer cline analogues.25

Topotecan These compounds inhibit DNA and RNA
n Metastatic ovarian cancer after synthesis by preventing the action of the
type II topoisomerase enzyme by intercalat-
failure of first-line or subsequent ing with the DNA.25,34 They cause further
therapy

HANDBOOK OF ONCOLOGY

G2-Phase-Specific Agents 181

Table 5. General side effects of vinca alkaloids4,35

Vincristine Vinblastine Vinorelbine Vinflunine

n N eurotoxicity with n N ausea and n N ausea and n M yelosuppression
peripheral vomiting vomiting n M ucositis
neuropathy n C onstipation
n M yelosuppression n M yelo- n D iarrhoea
n P aralytic ileus n M ucositis suppression n L oss of fertility
n M yelosuppression n S IADH
n S yndrome of n V ascular events n C onstipation
n S IADH
inappropriate
antidiuretic
hormone secretion
(SIADH)

damage by the formation of free radicals chemotherapeutic agents for lung DRUG-CLASS OVERVIEW
which bind and break double-stranded and ovarian cancer
DNA.25,34
Idarubicin
These highly effective antitumour n Acute non-lymphocytic leukaemia
agents’ use is limited by side effects such
as cardiotoxicity.34 including acute myeloblastic
leukaemia in adults as front-line
A detailed indication and side-effect therapy or remission induction in
profile of anthracyclines follows: relapsed or refractory patients.

Indications1,25,89 Mitoxantrone
n Breast cancer, including locally
Daunorubicin
n Acute lymphocytic and myelocytic advanced or metastatic disease
n Adult acute non-lymphocytic
leukaemia
leukaemia at relapse and chronic
Doxorubicin myelogenic leukaemia in blast crisis
n Solid tumours, i.e. breast cancer91 n In combination with low-dose oral
n Haematological malignancies, corticosteroids as initial chemotherapy
for symptomatic treatment of
sarcomas, embryonal tumours of intractable pain related to advanced
childhood hormone-refractory prostate cancer
n Ovarian cancer in combination with n Non-Hodgkin’s lymphoma
cisplatin or cyclophosphamide
Side effects1,25
Epirubicin n Nausea and vomiting
n Monotherapy for breast cancer n Dose-limiting myelosuppression and

(in men and women) mucositis
n Monotherapy for gastric cancer n Cardiotoxicity
n Malignant lymphoma
n Soft-tissue sarcoma Contra-indications, special precautions
n Advanced colorectal cancer and drug interactions: See MIMS Monthly,
n Malignant melanoma
n Combination therapy with other MDR or manufacturer’s product literature.

HANDBOOK OF ONCOLOGY

182 DRUG-CLASS OVERVIEW

4. M-PHASE-SPECIFIC AGENTS Vinblastine
n Palliative treatment of malignant
bThyethceombepgleintionningofothf ethGe2M-p-hpahsaeseis marked
or mito- non-Hodgkin’s lymphoma
sis.27 Mitosis is further subdivided into pro- n Hodgkin’s disease
phase, metaphase, anaphase and telo- n Cancer of the testes
phase.27 During the prophase-phase, the n Chorio- and breast cancer
chromosomes are condensed and at- n Melanoma109
tached to the microtubules, to be segre- Vinorelbine
gated by the mitotic spindle at the com- n Palliative treatment of advanced,
pletion of mitosis.27 Prophase is followed by
the alignment of the chromosomes in met- inoperable non-small-cell lung cancer
aphase.27 Once aligned, a group of chro- as monotherapy or as combination
mosomes moves towards a pole of the therapy (more effective)
cell in anaphase and the events of the n Metastatic breast cancer in patients in
prophase are reversed in telophase as whom anthracycline first-line
two nuclei form and the cell divides into monotherapy has failed or who have
two identical daughter cells.27 relapsed within six months of
The M-phase-specific agents are mainly anthracycline-based adjuvant
antitubulin agents as they interfere with therapy
the normal microtubule dynamics, such as n Prostate cancer as palliative
spindle formation and disassembly, block- treatment.106
ing the division of the nucleus into two C ontra-indications, special precau-
daughter cells.25 tions and drug interactions: See MIMS
Monthly, MDR or manufacturer’s prod-
VINCA ALKALOIDS uct literature.
n Cervical cancer99
Vincristine and vinblastine are vinca alka-
loids, derived from the periwinkle plant TAXANES
Vinca rosea, whereas vinorelbine and the Paclitaxel and its related semi-synthetic
newer agent vinflunine are semi-synthetic compounds docetaxel and cabazitaxel
analogues.1,4 These agents bind tubulin. are alkaloid esters derived from the Pacific
Tubulin dimers assemble to form and European yew trees respectively.4,36
microtubules.1,27 sPpaecclitifaicxealgaenndtsd, oacsetthaexyelbainredGto2-Mtubpuhlainsein-
By binding tubulin, these agents prevent the microtubules, causing cell arrest at mi-
polymerisation of mitotic spindles, thereby tosis, which may lead to apoptosis.2,36
blocking cells in mitosis.1 Vinca alkaloids
are highly vesicant and M-G1 phase- Although paclitaxel was isolated in 1966,
specific.1,2 it did not appear in clinical practice until
The use of vinca alkaloids is limited by the 1990s.25 Today, it is indicated for a vari-
their dose-related side effects (see Ta- ety of cancers, including metastatic breast
ble 5), such as neuropathy and bone-mar- cancer after combination therapy failure
row suppression for vincristine and vinblas- or relapse after six months of adjuvant
tine respectively.1 chemotherapy (including anthracyclines),
In comparison, vinflunine has a more fa- first-line therapy of advanced or metastat-
vourable side-effect profile as it binds rela- ic breast cancer in combination with tras-
tively weakly to tubulin, and therefore has tuzumab in patients who overexpress HER2
less ability to cause neurotoxicity.35 at a 2+ or 3+ level as determined by immu-
A detailed indication and side-effect nohistochemistry, palliative treatment of
profile of vinca alkaloids follows and Table advanced non-small-cell lung cancer
5 addresses the side effects. when curative surgery and/or radiothera-
py is not applicable, palliative treatment of
Indications4,13,35 stage 3 or 4 locally advanced ovarian can-
cer after surgical resection in combination
Vincristine with cisplatin, and palliative management
of metastatic ovarian cancer after failure
n Acute leukaemia of first-line or subsequent chemotherapy,
n Hodgkin’s disease and related

lymphomas

HANDBOOK OF ONCOLOGY

as well as gastro-oesophageal cancer, M-Phase-Specific Agents 183 DRUG-CLASS OVERVIEW
prostate cancer, bladder cancer, cervical
cancer and head and neck cancer.4,13,99 n Neurotoxicity
Docetaxal has similar therapeutic and toxic n Fluid retention
properties as etoposide and is indicated as
adjuvant treatment of patients with oper EPOTHILONES
node-positive breast cancer in combination Ixabepilone is an epothilone B analogue
with doxorubicin and cyclophosphamide, from a relatively new class of antitumour
locally advanced metastatic breast cancer agents and a novel microtubule inhibi-
in combination with doxorubicin in patients tor.4,38 The epothilones were developed to
who have not received cytotoxic therapy overcome tumour-resistant mechanisms.
for this condition, locally advanced or met- Ixabepilone has activity in drug-resistant
astatic breast cancer after failure of cyto- tumours that overexpress tubulin muta-
toxic therapy, locally advanced or meta- tions.4,38 Ixabepilone binds to the tubulin
static breast cancer in combination with during mitosis and thereby stabilises the
capecitabine after failure of cytotoxic microtubules, halting the cell cycle.4
chemotherapy where previous therapy did
not include an anthracycline, in combina- Ixabepilone is indicated for the treat-
tion with cisplatin for unresected locally ad- ment of locally advanced or metastatic
vanced or metastatic non-small-cell lung breast cancer after cytotoxic chemother-
cancer where chemotherapy has not previ- apy has failed; as combination therapy
ously been administered for this condition, with capecitabine in patients who have
locally advanced or metastatic non-small- failed prior therapy with a taxane and an
cell lung cancer even after failure of plati- anthracycline or where further anthracy-
num-based chemotherapy, metastatic cline therapy is not indicated; as mono-
ovarian cancer after failure of first-line or therapy for patients in whom prior therapy
subsequent therapy, androgen-independ- with a taxane or anthracycline has failed.13
ent metastatic prostate cancer in combina-
tion with prednisone/prednisolone, in com- Ixabepilone’s main side effects include: 4
bination with cisplatin and 5-fluorouracil for n Myelosuppression
induction treatment of patients with inoper- n Hypersensitivity reactions
ative locally advanced squamous cell can- n Neurotoxicity in the form of peripheral
cer of the head and neck.4,13 New research
has shown that docetaxel in combination sensory neuropathy
with gemcitabine may be considered in the Contra-indications, special precautions
treatment of soft tissue sarcomas.111 The and drug interactions: See MIMS Monthly,
combination with gemcitabine should be MDR or manufacturer’s product literature.
used with caution.
OTHERS
Cabazitaxel is indicated for the treat- Eribulin inhibits the growth phase of micro-
ment of patients with hormone-refractory tubules without affecting the shortening
metastatic prostate cancer previously phase and sequesters tubulin into non-
treated with a docetaxal-containing productive aggregates.124 Eribulin exerts its
treatment regimen.37 effects via a tubulin-based antimitotic
mechanism, leading to G2/M cell-cycle
The main side effects of taxanes include:4 block, disruption of mitotic spindles, and
n Nausea and vomiting ultimately, apoptotic cell death after pro-
n Hypotension longed mitotic blockage.
n Arrhythmias
n Hypersensitivity Eribulin is indicated as monotherapy in
n Myelosuppression with neutropaenia patients with locally advanced or meta-
n Peripheral sensory neuropathy static breast cancer who have progressed
after at least two chemotherapy regimens
for advanced disease.13 Prior therapy had
to include an anthracycline and a taxane
unless the patient is not suitable.

HANDBOOK OF ONCOLOGY

184 DRUG-CLASS OVERVIEW

5. MISCELLANEOUS Contra-indications, special precautions
and drug interactions: See MIMS Monthly,
BLEOMYCIN MDR or manufacturer’s product literature.

The exact mechanism of action of bleo- CYP17A1 INHIBITORS

mycin is unknown. It is believed to be a Ketoconazole and abiraterone are cy-
tochrome P450 enzyme inhibitors, more
DNA-cleaving agent that causes single- specifically they inhibit the enzyme CY-
and doubled-stranded DNA breaks in the P17A1 that mediates androgen precursor
region where it binds to the DNA following synthesis.114 In castration-resistant prostate
cancer, androgen receptors are reacti-
free radical formation.4,25,26 Bleomycin is a vated, mediating the synthesis of testos-
terone and dihydrotestosterone from pre-
mixture of cytotoxic glycopeptides isolated cursor steroids.
Ketoconazole
from bacteria which specifically target the
The antifungal agent ketoconale, is indi-
aGc2-cpuhmauselaotef sthinescqeulal cmyocules.4c,2e6 lAls,s bleomycin cated for patients with advanced pros-
it is suitable tate cancer which progresses after andro-
gen deprivation.115
for treating head and neck cancers, Abiraterone acetate

Hodgkin’s disease, non-Hodgkin’s lympho- Abiraterone acetate is a prodrug of abira-
terone, an orally available inhibitor of the
ma and testicular carcinomas.25 Its main cytochrome P450 c17 enzyme complex
dose-limiting side effect is pulmonary toxic- critical to androgen production. Abirater-
ity which may, in rare cases, be fatal.4 one acetate Is used in prostate cancer in
combination with prednisone.105
Other side effects of bleomycin

include:4

n Allergic reactions

n Fever

n Hypotension

n Skin toxicity

n Pulmonary fibrosis

n Mucositis

n Alopecia

HANDBOOK OF ONCOLOGY

6. BIOLOGICALS Biologicals 185DRUG-CLASS OVERVIEW

Signal transduction or biochemical com- Regorafenib is a small molecule inhibitor
munication in the cell plays an essential of multiple membrane-bound and intra-
role in the normal cell cycle and cell divi- cellular kinases involved in normal cellular
sion.26 Binding of a ligand such as a growth functions and in pathologic processes
factor to its cell-surface receptor (usually a such as oncogenesis, tumour angiogene-
tyrosine kinase) leads to activation of the sis, metastasis and tumour immunity.125 Re-
receptor.26 Activation of a receptor in- gorafenib is indicated for metastatic colo-
volves the transfer of a large phosphate rectal cancer previously treated with or
group from adenosine triphosphate (ATP) contra-indicated for fluoropyrimidine-
via a kinase to a protein such as tyrosine based chemotherapy, oxaliplatin- and iri-
which activates a cascade of events.26 notecan-based chemotherapy, an anti-
These events may entitle the switching on VEGF therapy, and, if RAS wild-type, an
or off of a particular process.26 anti-EGFR therapy.13 Regorafenib is fur-
thermore indicated for the treatment of
Growth factors stimulate proliferation, GIST previously treated with two tyrosine
differentiation, interaction with other cells, kinase inhibitors and hepatocellular carci-
and growth and survival in cells.39 In can- noma (HCC) which has been previously
cer cells, growth factors are involved in treated with sorafenib.
invasion, metastasis and angiogenesis as
they activate an altered, mutated signal- Vemurafenib inhibits some mutated
ling process.26, 39 forms of BRAF serine threonine kinase, in-
cluding BRAF V600E, and has been shown
Certain biological chemotherapeutics to inhibit CRAF, ARAF, wild-type BRAF,
such as monoclonal antibodies (MAbs) SRMS, ACK1, MAP4K5, and FGR in vitro.131
and small-molecular-weight agents are Some mutations in the BRAF gene including
targeted at cell-surface- and intracellular V600E result in constitutively activated BRAF
receptors of the tyrosine kinase family.1,26 proteins, which can cause cell proliferation
in the absence of growth factors that
Specific growth-factor targets include epi- would normally be required for prolifera-
dermal growth factor (EGF) and its receptors tion. Vemurafenib is indicated for the treat-
(EGFRs), and vascular endothelial growth ment of unresectable or metastatic mela-
factor (VEGF) and its receptors (VEGFRs).39 noma with BRAF V600E mutation, Erdheim
Chester Disease with BRAF V600 mutation.
Aflibercept acts as a soluble receptor INTERFERONS
that binds to human VEGF-A, to human Interferons (IFNs) are cytokines produced
VEGF-B and to human PlGF. By binding to naturally by host cells in the presence of a
these endogenous ligands, aflibercept pathogen such as a tumour cell, bacteria,
can inhibit the binding and activation of virus or parasite. IFNs bind to specific cell-
their receptors. This inhibition can result in membrane receptors and initiate a com-
decreased neovascularisation and de- plex sequence of events, facilitating com-
creased vascular permeability. Aflibercept munication between immune cells,
is used in combination with 5-fluorouracil, enabling them to destroy a pathogen.4,26
leucovorin and irinotecan-(FOLFIRI), and is The immunomodulating activities of IFNs
indicated for patients with metastatic include the direct antiproliferative effects
colorectal cancer (mCRC) that is resistant on tumour cells, enhancement of the
to or has progressed following an oxalipl- phagocytic activity of macrophages, up-
atin-containing regimen.119 regulating tumour antigen presentation to
cytotoxic T-lymphocytes and activation of
EGF belongs to the human epidermal re- natural killer cells.4,26,39
ceptor (HER) tyrosine kinase family that is Interferon-alpha and beta
responsible for cell proliferation, growth Interferon-alpha (INF-α) and interferon-be-
and survival, whereas VEGF induces en- ta (INF-β) are cytokines which form part of
dothelial cell proliferation and new blood- a large subclass of interferons better known
vessel formation in the growing tumour.26,39 as type I IFNs.41,42 The host cells, in response
to a pathogen, produce cytokines such as
Not all biological chemotherapeutics
target tyrosine kinases as some known as HANDBOOK OF ONCOLOGY
immunomodulating agents are often used
to boost the ability of the immune system
to fight cancer.26 Immunomodulating
agents include certain MAbs, interferons
and interleukins.4,26

186 DRUG-CLASS OVERVIEW and activates certain tyrosine kinase com-
plexes which leads to a series of events to
type I INFs.42 Type I IFNs bind to type I inter- activate the cellular immune system to kill
feron receptors, which in turn activate cer- tumour cells.46,47
tain tyrosine kinase receptors.42-45. Activa-
tion of the tyrosine kinase receptors leads Aldesleukin is indicated for the treatment
to enhanced activation of CD8-positive T- of metastatic renal cell carcinoma and
cells that are the precursors for cytotoxic T- melanoma.47,107
lymphocytes, activation of macrophages
and natural killer cells and upregulating of The side effects of aldesleukin include:47
MHC expression.42-45 n Flu-like symptoms
n Asthenia
The best clinical responses of type I IFNs n Pain
are observed mainly, but not exclusively, in n Hypotension and tachycardia
haematological malignancies and cancers n Confusion
linked to viral infections.42 Until the discovery n Bilirubinaemia and an increase in
of tyrosine kinase inhibitors (TKIs), INF-α was
the treatment of choice in CML and is indi- creatinine levels
cated in the treatment of hairy cell leukae- n Peripheral oedema
mia, low-grade lymphoma, myeloma, cuta- n Nausea and vomiting
neous T-cell lymphoma, as well as some n Diarrhoea
solid tumours such as melanoma, renal cell n Respiratory effects
carcinoma and Kaposi sarcoma.41,42 Inter- n Rash
feron alfacon-1, IFN-α2a and IFN-α2b are re- n Thrombocytopaenia and anaemia
combinantly produced IFNs, whereas IFN-β n Oliguria
is a human interferon produced in mamma-
lian cells.43-45 INF-β has a greater antiprolifera- Contra-indications, special precautions
tive effect on melanoma cells when com- and drug interactions: See MIMS Monthly,
pared to INF-α; it is mainly used in the MDR or manufacturer’s product literature.
treatment of multiple sclerosis.40,42
OTHERS
Side effects of type I INFs include:39,40 Pazopanib
n Flu-like symptoms Pazopanib is a kinase inhibitor indicated
n Lethargy for the treatment of patients with ad-
n Auto-immune disease vanced renal cell carcinoma and ad-
n Myelosupression with neutropaenia vanced soft tissue sarcoma who have re-
n Weight loss ceived prior chemotherapy.116 The
n Myalgias or arthralgias efficacy of pazopanib for the treatment of
n Depression patients with adipocytic soft tissue sarco-
n Pulmonary complications ma or gastro-intestinal stromal tumours has
n Pulmonary arterial hypertension not been demonstrated.

Contra-indications, special precautions MONOCLONAL ANTIBODIES
and drug interactions: See MIMS Monthly, Monoclonal antibodies (MAbs) are bio-
MDR or manufacturer’s product literature. logical agents that usually target specific
antigens which are highly expressed on
INTERLEUKIN-2 cancer cells, but not on normal cells.48
Native human interleukin-2 (IL-2) is a cy-
tokine-signalling molecule of the immune MAbs are subdivided into naked or con-
system secreted by T-cells.46 IL-2 is capable jugated MAbs.39
of enhancing lymphocyte mitogenesis and
cytotoxicity, activation of natural killer cells Naked MAbs are not attached to any
and production of interferon-gamma.46,47 drug or radio-active material, whereas
conjugated MAbs are joined to a toxin or
Aldesleukin radio-active isotope.39
Aldesleukin (also known as proleukin) is a
recombinantly produced human IL-2 with Naked MAbs
the same biological activities of native IL- Alemtuzumab
2. 44,45 Aldesleukin binds to the IL-2 receptor Alemtuzumab is a humanised MAb direct-
ed against the glycoprotein CD52, a
HANDBOOK OF ONCOLOGY

Biologicals 187

cell-surface protein expressed on normal B-lymphocytes, some leukaemias and non-
and cancerous B- and T-lymphocytes.48 By Hodgkin’s lymphomas.1,4,26 Binding of the
binding to CD52, alemtuzumab causes ly- MAb to CD20 leads to apoptosis of the
sis to the lymphocytes via complemented CD20-positive cells.26 Side effects of rituxi-
fixation and antibody-dependent, cell- mab are rare, with most patients only de-
mediated cytotoxicity.48 Alemtuzumab is veloping a rash after the initial treatment.4
used in the treatment of chronic lympho-
cytic leukaemia and in fludarabine-refrac- Trastuzumab
tory patients.48,49 Side effects include tran-
sient neutropaenia, the risk of opportunistic Trastuzumab is a recombinant MAb that
infection, fever, rigors, chills, bronchos- binds to the extracellular segment of the
pasm, hypotension, angio-oedema and HER2.26 Binding of the antibody to the re-
acute lung injury.48 ceptor inhibits DNA repair and cell prolif-
eration, arresting the ctoellthceycilnedautctthioenGo1-f
Bevacizumab phase, which leads
Bevacizumab binds to VEGF and blocks its apoptosis in the cell.39 Furthermore, trastu-
biological activities by preventing it from zumab suppresses angiogenesis as it has
binding with its receptor, VEGFR, on the anti-angiogenic properties preventing DRUG-CLASS OVERVIEW
vascular endothelium.26,39 Bevacizumab new vessel formation required for tumour
inhibits vascular permeability, but increas- growth.26,39 Trastuzumab is indicated for
es tumour blood flow and therefore drug the treatment of metastatic breast cancer
delivery.4 Bevacizumab is indicated in the with HER2 overexpression (in men and
treatment of colorectal cancer, breast women).39,92 Side effects of trastuzumab
cancer, non-small-cell lung cancer and therapy may include a degree of cardio-
renal cancer.4 Side effects of MAbs in- toxicity, dermatitis and acute oesophagitis
clude hypertension, infusion reactions, ar- toxicity.39
terial thrombo-embolic events, GI perfora- Contra-indications, special precautions
tions, wound-healing complications and and drug interactions: See MIMS Monthly,
proteinuria.4 MDR or manufacturer’s product literature.

Cetuximab Ramucirumab
Cetuximab is a recombinant, human/ Ramucirumab is a recombinant human
mouse chimeric MAb that binds specifi- IgG1 monoclonal antibody that specifi-
cally to the extracellular domain of the cally binds to VEGFR2 and therefore Inhib-
EGFR, preventing binding of EGF.26,39 Bind- its ligand-induced proliferation, and mi-
ing to the receptor blocks phosphorylation gration of human endothelial cells.120
and activation of receptor-associated ki- Ramucirumab is indicated as a single
nases, which results in inhibition of cell agent or in combination with paclitaxel,
growth, motility, invasiveness, metastasis for treatment of advanced gastric or gas-
and promotes apoptosis.26,39 Cetuximab tro-oesophageal junction adenocarcino-
decreases the production of VEGF and ma, with disease progression on or after
enhances the response to radio- or chem- prior fluoropyrimidine- or platinum-con-
otherapy.4,26 Unfortunately, it targets EGFR taining chemotherapy, in combination
on both normal and cancer cells.26 with docetaxel and for treatment of meta-
static non-small-cell lung cancer with dis-
Cetuximab is indicated for the treat- ease progression on or after platinum-
ment of colorectal cancer, as an adjunct based chemotherapy. Patients with EGFR
to radiotherapy in head and neck cancer or ALK genomic tumour aberrations should
and non-small-cell lung cancer.4 Side ef- have disease progression on FDA-ap-
fects of cetuximab include infusion reac- proved therapy for these aberrations prior
tions, skin rash, hypomagnesaemia, fa- to receiving ramucirumab. Ramucirumab
tigue and interstitial lung disease.4 may be used in combination with the FOL-
FIRI (folinic acid, 5-FU and irinotecan) regi-
Rituximab men, for the treatment of metastatic colo-
The immunomodulating MAb, rituximab, is rectal cancer with disease progression
a cytotoxic MAb that binds to CD20, a with or after prior therapy with bevacizum-
cell-surface marker expressed by mature ab, oxaliplatin, and a fluoropyrimidine.

HANDBOOK OF ONCOLOGY

188 DRUG-CLASS OVERVIEW non-small-cell lung cancer with
tumours having high PD-L1 with no
Panitumumab  EGFR or ALK genomic tumour
Panitumumab is a recombinant, human aberrations
IgG2 kappa monoclonal antibody that – as a single agent for the treatment
binds specifically to the human EGFR.121 of patients with metastatic non-
The EGFR is a transmembrane glycopro- small cell lung cancer whose
tein that is a member of a subfamily of tumours express PD-L1 (TPS ≥1%)
type I receptor tyrosine kinases, including with disease progression on or after
EGFR, HER2, HER3, and HER4. EGFR is con- platinum-containing
stitutively expressed in normal epithelial tis- chemotherapy
sues, including the skin and hair follicle – in combination with pemetrexed
and over-expressed in certain human and carboplatin, as first-line
cancers, including colon and rectal can- treatment of patients with
cers. Binding of ligands to EGFR ultimately metastatic non-squamous non-
results in transcription of genes involved small-cell lung cancer
with cellular growth and survival, motility,
and proliferation. n Head and neck squamous cell cancer
– recurrent or metastatic head and
Panitumumab binds specifically to EGFR
on both normal and tumour cells, and neck squamous cell cancer with
competitively inhibits the binding of li- disease progression on or after
gands for EGFR. platinum-containing
Panitumumab is indicated as a single chemotherapy
agent for the treatment of metastatic
colorectal carcinoma with disease pro- n Hodgkin’s lymphoma
gression on or following fluoropyrimidine, – adult and paediatric patients with
oxaliplatin, and irinotecan chemotherapy
regimens.121 refractory Hodgkin’s lymphoma, or
who have relapsed after three or
PD-1 inhibitors more prior lines of therapy
Pembrolizumab, nivolumab, atezolizum-
ab, avelumab and durvalumab all have a n Urothelial carcinoma
similar mechanism of action. These agents – locally advanced or metastatic
are humanised monoclonal antibodies
that block the interaction between PD-1 urothelial carcinoma in patients
and its ligands, PD-L1 and PD-L2.123 Binding who are not eligible for cisplatin-
of the PD-1 ligands, PD-L1 and PD-L2, to containing chemotherapy
the PD-1 receptor found on T-cells, inhibits – locally advanced or metastatic
T-cell proliferation and cytokine produc- urothelial carcinoma in patients
tion. Upregulation of PD-1 ligands occurs whose disease has progressed
in some tumours, and signalling through during or following platinum-
this pathway can contribute to inhibition containing chemotherapy or within
of active T-cell immune surveillance of tu- 12 months of neoadjuvant or
mours. Inhibition of PD-1 and ligand inter- adjuvant treatment with platinum-
action releases the PD-1 pathway- containing chemotherapy
mediated inhibition of the immune re-
sponse, including the anti-tumour immune n Microsatellite instability-high cancer
response. – adult and paediatric patients with

Pembrolizumab unresectable or metastatic,
Pembrolizumab is indicated for the treat- microsatellite instability-high
ment of123 (MSI-H) or mismatch-repair-
n Unresectable or metastatic deficient
• solid tumours that have
melanoma
n Non-small-cell lung cancer progressed following prior
– as a single agent for the first-line treat- treatment and which have no
satisfactory alternative
ment of patients with metastatic treatment options, or
• colorectal cancer that has
HANDBOOK OF ONCOLOGY progressed following treatment
with a fluoropyrimidine,
oxaliplatin, and irinotecan

n Gastric cancer Biologicals 189DRUG-CLASS OVERVIEW
– recurrent locally advanced or
months of neoadjuvant or adju-
metastatic gastric or gastro- vant treatment with platinum-con-
oesophageal junction taining chemotherapy
adenocarcinoma whose tumours n adult and paediatric (12 years and
express PD-L1 [Combined Positive older) patients with microsatellite
Score (CPS) ≥1], with disease instability-high (MSI-H) or mismatch-
progression on or after two or more repair-deficient (dMMR) metastatic
prior lines of therapy, including colorectal cancer that has progressed
fluoropyrimidine- and platinum- following treatment with a fluoropy-
containing chemotherapy and if rimidine, oxaliplatin, and irinotecan
appropriate, HER2/neu-targeted n hepatocellular carcinoma in patients
therapy who have been previously treated
with sorafenib
Nivolumab
Atezolizumab
Nivolumab is indicated for the treatment Atezolizumab is indicated for the treat-
of:133 ment of:135
n BRAF V600 wild-type unresectable or n Locally advanced or metastatic

metastatic melanoma, as a single urothelial carcinoma in patients who:
agent – are not eligible for cisplatin-
n BRAF V600 mutation-positive unresect-
able or metastatic melanoma, as a containing chemotherapy, or
single agent – have disease progression during or
n unresectable or metastatic melano-
ma, in combination with ipilimumab following any platinum-containing
n melanoma with lymph-node involve- chemotherapy, or within 12 months
ment or metastatic disease who have of neoadjuvant or adjuvant
undergone complete resection, in the chemotherapy
adjuvant setting n Metastatic non-small-cell lung cancer
n metastatic non-small-cell lung cancer in patients who have disease
and progression on or after platinum- progression during or following
based chemotherapy. EGFR or ALK platinum-containing chemotherapy.
genomic tumour aberrations should Patients with EGFR or ALK genomic
have disease progression tumour aberrations should have
n advanced renal cell carcinoma in disease progression
patients who have received prior
antiangiogenic therapy Avelumab
n adult patients with classical Hodgkin’s Avelumab is indicated for the treatment
lymphoma that has relapsed or of:137
progressed after: n metastatic Merkel cell carcinoma in
– autologous haematopoietic
adult and paediatric patients older
stem-cell transplantation (HSCT) than 12 years of age
and brentuximab vedotin, or
– three or more lines of systemic Durvalumab
therapy that includes autologous Durvalumab is indicated for the treatment
HSCT of:138
n recurrent or metastatic squamous cell n Locally advanced or metastatic
carcinoma of the head and neck with
disease progression on or after a urothelial carcinoma patients who:
platinum-based therapy – have disease progression during or
n locally advanced or metastatic
urothelial carcinoma in patients who: following platinum-containing
– have disease progression during or chemotherapy
following platinum-containing – have disease progression within 12
chemotherapy months of neoadjuvant or
– have disease progression within 12 adjuvant treatment with platinum-
containing chemotherapy
n Unresectable, stage III non-small-cell
lung cancer patients whose disease
has not progressed following

HANDBOOK OF ONCOLOGY

190 DRUG-CLASS OVERVIEW post-autologous haematopoietic
stem-cell transplantation (auto-HSCT)
concurrent platinum-based consolidation
chemotherapy and radiation therapy n Hodgkin’s lymphoma after failure of
auto-HSCT or after failure of at least
Ipilimumab two prior multi-agent chemotherapy
CTLA-4 is a negative regulator of T-cell ac- regimens in patients who are not
tivity. Ipilimumab is a monoclonal anti- auto-HSCT candidates
body that binds to CTLA-4 and inhibits the n Systemic anaplastic large-cell
interaction of CTLA-4 with its ligands, lymphoma after failure of at least one
CD80/CD86.128 Inhibition of CTLA-4 has prior multi-agent chemotherapy
been shown to augment T-cell activation regimen
and proliferation, including the activation n Primary cutaneous anaplastic large-
and proliferation of tumour-infiltrating T-ef- cell lymphoma or CD30-expressing
fector cells. Inhibition of CTLA-4 signalling mycosis fungoides (MF) in patients
can also reduce T-regulatory cell function, who have received prior systemic
which may contribute to a general in- therapy
crease in T-cell responsiveness, including
the anti-tumour immune response. Radiolabelled MAbs

Ipilimumab is indicated for previously The radiolabelled antibody, ibritumomab
treated unresectable or metastatic mela- tiuxetan, is a monoclonal mouse antibody
noma.13 conjugated with the chelator tiuxetan to
which a radio-isotope indium-111 is add-
Conjugated MAbs ed.48 The monoclonal antibody section of
Conjugated MAbs have a different mech- ibritumomab tiuxetan is capable of bind-
anism of action to that of the naked MAbs, ing to B-lymphocytes; it therefore delivers
as the interaction between the MAb and a dose of radiation to the cell and the an-
the antigen is either to facilitate the deliv- tibody binds to its neighbouring cells as
ery of the toxin or to specifically target well.48
cancer cells with radiation therapy.39
Ibritumomab tiuxetan is deliberately
Brentuximab vedotin kept as a monoclonal mouse antibody to
Brentuximab vedotin is a CD30-directed ensure rapid elimination from the body.48
antibody-drug conjugate indicated for The main side effect of ibritumomab tiux-
treatment of134: etan is myelosuppression.48
n Previously untreated Stage III or IV
Contra-indications, special precautions
Hodgkin’s lymphoma, in combination and drug interactions: See MIMS Monthly,
with chemotherapy MDR or manufacturer’s product literature.
n Hodgkin’s lymphoma at high risk of
relapse or progression as

HANDBOOK OF ONCOLOGY

7. SMALL-MOLECULE KINASE Small-molecule kinase inhibitors 191 DRUG-CLASS OVERVIEW
INHIBITORS
Dasatinib, imatinib and nilotinib Nilotinib is indicated for the treatment of
adult patients newly diagnosed with Ph+
Imatinib is a two-phenylaminopyrimidine CML in chronic phase, treatment of chron-
derivative tyrosine kinase inhibitor, which ic or accelerated Ph+ CML in adult pa-
inhibits the tyrosine kinase domain of the tients resistant or intolerant to at least one
Bcr-Abl oncoprotein in CML.4,26 Imatinib is prior therapy, including imatinib.4,13
also capable of inhibiting tyrosine kinase
receptors such as PDGF, stem-cell factor Side effects of these agents include
and c-Kit in GI stromal tumours (GIST).4,26 nausea and vomiting, fluid retention with
ankle and peripheral oedema, myalgias
CML is a clonal pluripotent haematopoi- and congestive heart failure.4
etic stem-cell disorder.42 CML contains a
derivate chromosome known as the Phila- Erlotinib
delphia chromosome.42 Here, a balanced Erlotinib inhibits the EGFR and EGFR tyrosine
translocation between the c-Abl gene on kinase, preventing autophosphorylation of
chromosome 9 and the Bcr gene on chro- the kinase and thereby inhibiting the EGF-
mosome 22 is found on a single chromo- signalling pathway.4,26 Erlotinib is used in the
some as a chimeric Bcr-Abl gene which is treatment of locally advanced or meta-
responsible for CML.4,42 static non-small-cell lung cancer after fail-
ure of at least one prior chemotherapy
Similar to imatinib, dasatinib and nilotin- regimen, first-line treatment of locally ad-
ib inhibit the same tyrosine kinase and ki- vanced or metastatic (stage IV) bronchial
nase receptor, but differ from imatinib in adenocarcinoma demonstrating EGF-re-
that they bind to the active and inactive ceptor-activated mutation in patients who
conforms of the Abl kinase domain, over- have never smoked and with ECOG per-
coming imatinib resistance due to muta- formance status of 0-1, and first-line treat-
tions in the Bcr-Abl kinase.4,26 Furthermore, ment of locally advanced unresectable or
research has shown that dasatinib is much metastatic pancreatic cancer in combina-
more potent compared to imatinib tion with gemcitabine.4,13 Its side effects in-
against Bcr-Abl-expressing cells.26 clude hypertension, diarrhoea, skin rash,
anorexia and interstitial lung disease.4
In adults and paediatric patients, imatin-
ib is indicated for CML, CML in blast crisis or Gefitinib
accelerated or chronic phase after inter- Gefitinib has a similar mechanism of ac-
feron-alpha therapy failure.13 In adult pa- tion to erlotinib and is indicated as first-line
tients, imatinib is indicated for patients treatment of patients with metastatic non-
with Philadelphia-chromosome-positive small-cell lung cancer (NSCLC) with tu-
ALL (Ph+ALL) integrated with chemothera- mours having epidermal growth factor re-
py relapse or Ph+ALL as monotherapy, ceptor (EGFR) exon 19 deletions or exon
myelodysplastic or myeloproliferative dis- 21 (L858R) substitution mutations.139
ease (MDS/MPD) associated with PDGF-
receptor gene rearrangement, systemic Lapatinib
mastocytosis (SM) without the D816V c-Kit Lapatinib, a TKI, is indicated as combina-
mutation and eosinophilia, hypereosino- tion therapy for HER2-positive metastatic
philic syndrome (HES) and/or chronic eo- breast cancer.50 Lapatinib combinations
sinophilic leukaemia (CEL) with FIP1-PDGF- include:50
receptor alpha rearrangement, unresected n Use with capecitabine in patients who
and/or metastatic malignant GI stromal
tumours (GIST), adjuvant treatment follow- have received prior therapy, including
ing resection of Kit-positive GIST, unresect- an anthracycline, a taxane and
ed or recurrent and/or metastatic der- trastuzumab
matofibrosarcoma protuberans (DFSP). n Use with letrozole in postmenopausal
women in whom hormonal therapy is
Dasatinib is indicated for Ph+ CML in indicated
chronic phase, chronic-accelerated- or my- Side effects of lapatinib combination
eloid- or lymphoid blast-phase chronic my- therapy include diarrhoea, palmar-plan-
eloid leukaemia in adults resistant or intoler- tar erythrodysesthesia, nausea and vomit-
ant to prior therapy, including imatinib. ing, rash and fatigue.50

HANDBOOK OF ONCOLOGY

192 DRUG-CLASS OVERVIEW 8. PROTEASOME INHIBITORS

Sorafenib and sunitinib A proteasome is an enzyme complex that
Sorafenib and sunitinib are small molecu- plays an important role in the degradation
lar TKIs involved in cellular pathways such of proteins involved in the cell cycle and
as the Raf/MEK/ERK pathway (MAP kinase other cellular processes.26 Bortezomib is a
pathway) as well as cell-surface kinases reversible proteasome inhibitor capable
such as the VEGFRs and platelet-derived of disrupting cellular processes involved in
growth factor (PDGF) receptor-beta.4 the growth and survival of cancerous cells,
These kinases are involved in angiogene- leading to apoptosis.26 Bortezomib is indi-
sis, invasion of the tumour and tumour me- cated for:13,51
tastasis, all of which are inhibited by n Primary treatment of multiple
sorafenib and sunitinib.4 Sorafenib is indi-
cated for the treatment of advanced re- myeloma in combination with
nal cell cancer and advanced inoperable melphalan and prednisone
hepatocellular cancer and locally ad- n Monotherapy for multiple myeloma in
vanced or metastatic differentiated thy- patients who have received at least
roid cancer, whereas sunitinib is indicated one prior treatment and who have
for the treatment of metastatic renal cell progressive disease
cancer after failure of cytokine-based n Treatment of patients with mantle-cell
therapy (interferon-alpha and IL-2) and lymphoma who have received at
GIST after failure of imatinib treatment due least one prior therapy which includes
to resistance or intolerability.4,13 an anthracycline or mitoxantrone
and/or rituximab as part of a
Side effects of the small molecular inhibi- chemotherapy regimen
tor include nausea and vomiting, skin rash, Side effects of bortezomib include nau-
fatigue, asthenia and bleeding complica- sea, diarrhoea, thrombocytopaenia, neu-
tions.4 The use of sorafenib can further tropaenia, peripheral neuropathy, fa-
lead to hypophosphataemia, whereas su- tigue, neuralgia, anaemia, leukopaenia,
nitinib use may lead to cardiotoxicity or constipation, vomiting, lymphopaenia,
congestive heart failure.4 rash, pyrexia, and anorexia.51
Contra-indications, special precautions
Axitinib and drug interactions: See MIMS Monthly,
Axitinib is a TKI including VEGFR-1, VEGFR-2 MDR or manufacturer’s product literature.
and VEGFR-3.132 Axitinib is indicated for the
treatment of advanced renal cell carci-
noma after failure of one prior systemic
therapy.

Ibrutinib
Ibrutinib is a small-molecule inhibitor of BTK
as it forms covalent bonds with a cysteine
residue in the BTK active site, inhibiting en-
zyme activity.140 BTK is a signalling molecule
of the B-cell antigen receptor (BCR) and
cytokine receptor pathways. Ibrutinib in-
hibits malignant B-cell proliferation, survival,
cell migration and substrate adhesion.

HANDBOOK OF ONCOLOGY


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