Treatment Approaches • Drug-Class Overview
1st Biosimilar Filgrastim
authorised for use in
S4 FILGRASTIM TEVA 30 Growing Filgrastim Teva
(Solution for injection or infusion). Reg. No.: 46/32.16/0317.
S4 FILGRASTIM TEVA 48 in a new direction Affordable granulocyte-colony
(Solution for injection or infusion). Reg. No.: 46/32.16/0318. stimulating factor (G-CSF) treatment
to reduce healthcare costs and improve
Each pre-filled syringe contains 30 MIU (300 µg) or 48 access to high quality biologics.
MIU (480 µg) of filgrastim in 0,5 ml or 0,8 ml of solution
for injection or infusion respectively. For full prescribing
information please refer to the package insert approved
by the medicines regulatory authority.
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HANDBOOK OF ONCOLOGY
Information for Prescribers vi......................................................................................................................................
Cancer incidence and response to the crisis in Africa 2..................................................
Prof HM Simonds
TREATMENT OPTIONS IN ONCOLOGY
Chemotherapy: target therapy and immunotherapy 8......................................................
Prof BL Rapoport
Radiation-therapy overview 17..............................................................................................................................
Prof V Sharma
Recent advances in targeted radionuclide therapy of cancers:
moving towards personalised care 24.........................................................................................................
Dr IO Lawal
Prof MM Sathekge
Lung cancer 32..............................................................................................................................................................................
Dr S Dalvie
Colorectal cancer 39............................................................................................................................................................
Dr B Robertson
Breast cancer 45..........................................................................................................................................................................
Dr K Tabane
Female genital tract cancers 54...........................................................................................................................
Prof LM Dreosti
Prostate cancer 61....................................................................................................................................................................
Dr PW van Zijl
Kidney and bladder cancers 67...........................................................................................................................
Dr PW van Zijl
Treatment options for inoperable and metastatic
malignant melanoma 73.................................................................................................................................................
Dr A Bonthuys
HANDBOOK OF ONCOLOGY
BLOOD, LYMPH AND RELATED CONDITIONS
The acute leukaemias 78................................................................................................................................................
Prof N Novitzky
Multiple myeloma 85.............................................................................................................................................................
Dr K Antel
Prof VJ Louw
Dr E Verburgh
Myelodysplastic syndromes 93..............................................................................................................................
Prof VJ Louw
Dr E Verburgh
Dr K Antel
Dr E Verburgh
Dr K Antel
Prof VJ Louw
CARING FOR PATIENTS WITH CANCER
Oncological emergencies 108...............................................................................................................................
Dr A Bonthuys
Childhood cancer and its warning signs 118.....................................................................................
Prof M Kruger
Common childhood cancers 123.......................................................................................................................
Prof M Kruger
HIV-related cancers 128................................................................................................................................................
Dr DJ Eedes
Medical ethics in cancer care 135...................................................................................................................
Dr M de Villiers
The role of nutrition in cancer patients and cancer survivors........................141
Mrs MC Piderit
Mrs CE Julsing Strydom
Palliative care: an introduction 155..................................................................................................................
Dr R Krause
Management of cancer pain 160......................................................................................................................
Dr M Raff
DRUG-CLASS OVERVIEW 169..............................................................................................................
HANDBOOK OF ONCOLOGY
Information for Prescribers
MIMS Handbook of Oncology – Volume 2 is made to any “off-label” use of drugs.
comprises two main editorial sections – Readers are referred to current manufac-
Treatment Approaches and Drug-Class turers’ product literature for registered
Overview. indications and dosages.
Section 1: Treatment Approaches
These up-to-date, research-based thera- Important information of which to take
peutic articles are geared to the medical cognisance when prescribing:
practitioner who is participating in a multi- When prescribing any product mention-
disciplinary team and required to assist ed in MIMS Handbook of Oncology –
patients and their families across the Volume 2, doctors should be mindful of
continuum of care with the latest treat- the important points listed below:
ment approaches. The information, provid- n Hypersensitivity to the ingredient(s)/
ed by leading academics and oncolo-
gists in South Africa, will enable the doctor components of any medicine contra-
to guide the patient appropriately when indicates its use.
approached for information, understand n Medicines should not be prescribed
the side effects of treatment modali- to pregnant or lactating women
ties and assist with supportive care through- unless the anticipated benefit clearly
out the cancer journey. The Handbook is outweighs any potential risk to the
also accredited for Continuing Professional foetus.
Development. Please see guidelines for n The possibility of drug accumulation
CPD participation in the accompanying should be considered in the pres-
CPD booklet. ence of significant renal or hepatic
Section 2: Drug-Class Overview impairment.
This section features a comprehensive over- n Tolerance to medicines is likely to be
view of a selection of drug classes relevant less with extremes of age.
to oncology. In each case, this takes the n Drug inter ferences with laboratory
form of an editorial review discussing the tests and physical incompatibilities
important aspects of the entire drug class. common with parenteral solutions
These summaries contain facts on disease have not been included.
and therapeutic entities, as well as general n Monoamine oxidase inhibitors (MAOIs)
drug information, such as indications, have a prolonged action, so patients
common adverse reactions, drug interac- should not take any of the foods or
tions and more. Expert pharmacology medicines known to cause reactions
consultants compiled this section and it is for at least 14 days after stopping
essentially based on the latest available treatment.
international medical information. n Certain medicines (i.e. those that
cause CNS depression) may lead to
Please note that some agents mentioned drowsiness and impaired concentra-
in the Drug-Class Overview may not be tion, which may be aggravated by
available in South Africa. Also, no reference the simultaneous intake of alcohol or
HANDBOOK OF ONCOLOGY
Cancer Incidence and Response
to the Crisis in Africa
Prof HM Simonds Africa provide national statistics on can-
cer deaths, namely Egypt and South Af-
MB ChB MRCP (UK) FRCR (UK) rica,5 which makes mortality data highly
unreliable on the continent. What is very
PGDipHE (UCT) likely is that the GLOBOCAN data under-
Associate Professor, Division of estimate both incidence and mortality
Radiation Oncology, Stellenbosch University rates. High mortality rates are due in part
to a lack of basic health care, poor ac-
The global burden of disease research has cess to treatment centres or lack of avail-
shifted in recent years to focus on the non- able specialist services.
communicable diseases, with an empha-
sis on the incidence of cancer prevalence Average life expectancy is generally
and mortality. The projected number of low due to non-communicable diseases,
cases worldwide will rise from 12 million in including heart disease and rampant in-
2008 to 22.2 million by 2030, essentially a fectious diseases, with many millions af-
doubling of the burden of disease.1 The fected by malaria, diarrhoeal disorders,
availability of good quality data remains HIV infection and tuberculosis. As a result,
a challenge on the continent due to lim- certain areas of the continent are at the
ited government input or lack of infrastruc- lowest population risk for malignancy in
ture for data collection in many countries. the world, i.e., Central and West Africa
Data is limited specifically to pathology for men and Central and North Africa for
registries, and small centres or cities in women.2
Conversely, certain malignancies have
This introduction will review some basic a specifically high incidence in selected
global and South African incidence data, populations in Africa: cervical cancer in
and provide examples of challenges and East African women and oesophageal
successes in service delivery and preven- cancer in South African men. These spe-
tion on the continent. cific diseases and disease patterns are
clearly linked to environmental factors
INCIDENCE IN AFRICA and viral agents.2
The frequently quoted Global Cancer In- In South Africa specifically, data show
cidence, Mortality and Prevalence (GLO- that despite the relative economic stabil-
BOCAN) data provide estimates on the ity in comparison to many other African
global and country-specific incidence of countries, the incidence of cancer deaths
malignancies.2 In Africa in 2012 there were is only 9.5% in comparison to 19.5% from
more than 850 000 new cases of cancer, infectious diseases and 17.8% from heart
with the common causes including breast, disease.5
cervix, prostate, liver and colorectal can-
cer.2,3 In comparison to the GLOBOCAN International Agency for Research in
data of 2008, the new cases were esti- Cancer (IARC) data confirm that South
mated at approximately 720 000. The risk Africa had nearly 80 000 cases of new ma-
of developing cancer by the age of 75 lignancies diagnosed in 2012, with the ma-
years is 12%. jority being prostate (13%), breast (13%),
and cervical and lung (9.4%) carcinoma.2
The reality of cancer on the continent
is the poor outcomes, with 590 000 pa- MEASURES IN PLACE TO RESPOND
tients succumbing to cancer in 2012; TO NEED
this is again relatively unchanged from
2008 with 540 000 deaths.4 What is impor- Estimations point to a significant increase
tant to note is that only two countries in of malignancies and disproportionately
HANDBOOK OF ONCOLOGY
Cancer Incidence and Response to the Crisis in Africa 3
high rates of death by 2030 due the pro- A Lancet commission was established TREATMENT APPROACHES
jected increase in the African population.1 to address challenges in delivering ad-
Clearly, basic oncological services will equate and safe surgical care on a global
have to be increased to meet this future scale.9 A large prospective cohort study
need. This includes diagnostic and radiol- – The African Surgical Outcomes Study –
ogy services, as well as interventions with was undertaken in 25 African countries in
surgery, chemotherapy and radiotherapy.6 2016 to assess peri-operative mortality re-
sults in order to inform the commission.10
Pathology services are available in many The study found many alarming outcomes.
countries, but delay, lost samples and poor Staffing is wholly inadequate, with a ratio
infrastructure remain a challenge. The Af- of 0.7:100 000 surgeons per population,
rican Organization for Research and Train- and almost all surgical procedures were
ing (AORTIC) and the African Strategies for undertaken as emergencies or urgent
Advancing Pathology (ASAP) are increas- cases. This clearly spells concern for oncol-
ing educational activities and providing ogy patients and access to what in most
connections on the continent to support cases would be essential curative proce-
development of services. Telepathol- dures in solid tumours. In addition, a signifi-
ogy is a vital key to improving services in cant lack of oncology-specialist surgeons
countries with very limited resources and further limits appropriate care. In South
many such collaborations have been es- Africa, there is good access to subspecial-
tablished, one such example being the ists and to multidisciplinary teams working
Malawian-UK pathology collaboration to in established oncology departments or in
assist in the diagnosis of paediatric and private units across the country. Despite
haematological malignancies.6 Pathology this, there remain challenges of extended
services are readily available across South waiting lists and bed shortages, which are
Africa,7 although limitations do exist in the common to almost all countries globally.
state system because of limited qualified Many health care systems prioritise cancer
staff in some regions. cases, but the large number of emergen-
cy cases will still lead to delays.
Access to radiology services is highly
differential across the continent, with the Radiotherapy resources are costly, tech-
well-resourced countries of Egypt and nically challenging and skill-dependent.
South Africa offering easy access and oth- All these factors are a known barrier to the
ers suffering owing to lack of equipment installation and functioning of radiothera-
or frequent equipment breakdowns. A py centres in Africa. More than 90% of all
review of public-sector radiology services radiotherapy equipment is found in South
in Tanzania showed a limited number of and Northern Africa.11 More than 50%
general x-ray units at 5.7 units per million of the continent has no access to radia-
population, in comparison to South Africa tion services. Interruption of radiotherapy
at 19.6 units per million (fewer than the treatments are a frequent occurrence not
WHO recommendation of 20 units per only because of machine breakdowns,
million).8 There was also a distinct lack of but because many patients cannot afford
access to CT-scanning which in many the daily costs of travelling for therapy.12
cases is essential for adequate staging in- Free or state-funded access is limited
formation in oncology. Many clinicians will and user fees provide yet another barrier
stage using a simple chest x-ray and USS to accessing treatment and remaining
due to lack of access or funding for more compliant with ongoing daily schedules.
advanced radiological imaging modali- Expanding radiation facilities is a major
ties. Qualified staff and adequate training step towards improving outcomes through
programmes in the resource-limited coun- partnerships with the International Atomic
tries remain a challenge, but many larger Energy Agency (IAEA) and other public-
centres are training specialists on a super- private collaborations. Many countries
numerary basis in order to strengthen staff are establishing new centres or upgrading
numbers in parent countries.
HANDBOOK OF ONCOLOGY
existing ones with modern radiotherapy in all regions. Formal education is very lim-
equipment. Staff training in oncology and ited, with only four countries offering any
medical physics is being undertaken by a palliative-care training.15 The World Health
number of host countries, including Zimbab- Assembly resolution WHA67.19, has spe-
we, Tanzania, South Africa and Egypt. Ac- cifically called for improved access to
cess to radiotherapy in South Africa is widely palliative care as a core service, with an
available in the private sector, but is chal- emphasis on primary health care and
lenging in some areas of the public sector, community/home-based care.16 The res-
with many lacking functional equipment or olution has pushed palliative care to the
qualified staff. top of the agenda for many government
agencies and this will hopefully translate
In addition to the challenges in deliv- to an increase in access to services.
ering adequate radiotherapy services,
similar difficulties are seen in delivering PRACTICAL IMPLEMENTATION
chemotherapy services. Although special- OF PREVENTION
ist training is not necessarily a prerequisite
for chemotherapy prescription, access Many public health initiatives are driving
and affordability are persistent barriers. the access to primary- and secondary-
Complex issues are at play in the registra- prevention measures in cancer. The chal-
tion of drugs in many countries, including lenge in Africa is multifaceted and com-
high taxes, untested generics and stock plex. Most measures rely on functionally
shortages.13 The WHO Essential Medicines accessible primary health-care services
List drugs are not available in many coun- to provide support for vaccination pro-
tries due to these barriers.14 Many of the grammes and diagnostic screening. It is
so-called second-generation drugs which beyond the scope of this article to cover
can treat a number of malignancies as all activities in preventative medicine, but
well as tamoxifen for breast-cancer pa- some examples are given below.
tients, are essentially very cheap, but
supply issues, even in more developed One of the many successes in Africa is
centres such as Tanzania and South Af- the widespread awareness of the need
rica, lead to product shortages. The ma- for immunisation in West and North Af-
jor barriers to delivery of chemotherapy rica against hepatitis B. This endeavour
when stock is available is cost to the pa- reduces the development of hepatocel-
tient through user fees, or inadequate lular carcinoma which in most instances is
access to diagnostic services. Treatment an untreatable, fatal disease. In addition,
algorithms abound and there is no lack The Prevention of Liver Fibrosis and Can-
of advice and support for the oncologist cer in Africa (PROLIFICA) project looks to
or physician prescribing chemotherapy; improve point-of-care diagnostic tests to
protocols adapted to resource-limited set- identify chronic hepatitis B-carriers and
tings make these guidelines user-friendly proactively provide antiviral therapy to re-
and valuable. duce the incidence of the disease.17
Faced with the many challenges of di- The large positive clinical trials in the HPV-
agnosis and access to treatment, many vaccination of girls and young women
patients will be diagnosed in the later now present the opportunity of primar-
stages of cancer. Thus, palliative-care ac- ily preventing cervical cancer, but also
cess is one of the most immediate and es- of potentially preventing vulval carci-
sential services that need to be upgraded noma, anal carcinoma and oropharyn-
on the continent. The majority of formal geal carcinoma, to mention a few.18 Nu-
services are limited to Kenya, Uganda merous successful roll-out programmes
and South Africa. Many countries have no have started in many countries, with the
palliative care beyond that which is de- assistance of funding from the Vaccine Al-
livered by family physicians. It is thus vital liance (GAVI). The challenges of vaccina-
that palliative-care education is a priority tion uptake are many, particularly with re-
gard to parents of young girls. Community
HANDBOOK OF ONCOLOGY
Cancer Incidence and Response to the Crisis in Africa 5
educational drives have greatly assisted vaccination is available, early detection is TREATMENT APPROACHES
with acceptance. The practical difficulties possible and people have access to qual-
of the absence of integrated school vac- ity oncological care.
cination programmes, the obtaining of pa-
rental consent and lack of immediate ben- REFERENCES
efit have hampered roll-out programmes
across the continent in both low- and mid- 1. B ray F, Jemal A, Grey N, et al. Global can-
dle-income countries. cer transitions according to the Human
Development Index (2008-2030): a popu-
The reduction of tobacco consumption lation-based study. The Lancet Oncology.
is without a doubt the most urgent public 2012;13(8):790-801.
health intervention needed on the con-
tinent. A study in Uganda demonstrated 2. Fe rlay J, Steliarova-Foucher E, Lortet-
that the direct and indirect costs of tobac- Tieulent J, et al. Cancer incidence and
co-related health issues translate to 2.3% of mortality patterns in Europe: estimates for
the total national expenditure on health.19 40 countries in 2012. Eur J Cancer. 2013;
These data are translatable to most coun- 49(6):1374-403.
tries on the continent. Taxes and revenues
are usually not diverted to health care to 3. F erlay J, Shin H, Bray, F. Estimates of world-
offset these costs, and will not cover the wide burden of cancer in 2008: GLOBO-
full cost of the adverse effects. What is im- CAN 2008. International Journal of Cancer.
portant to resolve is the conflict of interest 2010;127(12):2893-2917.
between government and the tobacco
industry and the urgency for intervention 4. G BD 2015 Disease and Injury Incidence
from the WHO and global health leaders and Prevalence Collaborators, Vos T, Al-
to reduce consumption and access.20 len C, Arora M, et al. Global, regional, and
national incidence, prevalence, and years
Secondary preventative measures, in- lived with disability for 310 diseases and in-
cluding mammography screening, cervi- juries, 1990-2015: a systematic analysis for
cal smears, HPV-testing and PSA-testing, the Global Burden of Disease Study 2015.
are all well established in terms of detect- Lancet. 2016;388(10053):1545-1602.
ing early disease or precursors of disease,
but lack of infrastructure and financial 5. S TATS SA. Statistical release P0309.3 Mortality
backing in struggling health-care systems and causes of death in South Africa, 2015:
limit their use in Africa. Innovation with Findings from death notification. 2017. http://
cheap on-site HPV testing and encourag- www.statssa.gov.za/publications/P03093/
ing a culture of breast self-examination are P030932015.pdf. Accessed January 2018.
some methods that have been success-
fully adopted in Africa. In better resourced 6. C azap E, Magrath I, T Kingham P, et al. Struc-
countries such as South Africa, a variety tural barriers to diagnosis and treatment of
of screening procedures are provided cancer in low- and middle-income coun-
without co-payment to those who have tries: the urgent need for scaling up. Journal
health insurance. In the public sector, a of Clinical Oncology. 2016; 34:1,14-19.
pap smear at ages 30, 40 and 50 years
is freely available at local district clinics, 7. C arey P, Fudzulani R, Scholfield, et al. Re-
but access to routine PSA-screening and mote and rapid pathological diagnosis in
mammography is limited by logistical dif- a resource challenged unit. J Clin Pathol.
ficulties and infrastructure availability. 2014;Jun;67(6):540-3.
CONCLUSION 8. N goya P, Muhogora W, Pitcher R. Defining
the diagnostic divide: an analysis of regis-
With cancer cases projected to increa- tered radiological equipment resources in
se twofold in the coming decades, it is im- a low-income African country. Pan African
perative that there is a focus on preven- Medical Journal. 2016;25:99.
tion and health education to ensure that
9. M eara J, Hagander L, Leather A, et al. Sur-
gery and global health: a Lancet Commis-
sion. The Lancet. 2014;383(9911):12-13.
10. B iccard B, Madiba T, Kluyt H. Perioperative
patient outcomes in the African Surgical
Outcomes Study: a 7-day prospective ob-
servational cohort study. The Lancet. Pub-
lished online Jan 2018.
11. A bdel-Wahab M, Bourque JM, Pynda Y,
et al. Status of radiotherapy resources in
Africa: an International Atomic Energy
Agency analysis. Lancet Oncol. 2013;14:
HANDBOOK OF ONCOLOGY
12. J eremic B, Vanderpuye V, Abdel-Wahab S, 17. S pearman W, Afihene M, Ally R, et al. Hep-
et al. Patterns of practice in palliative ra- atitis B in sub-Saharan Africa: strategies to
diotherapy in Africa – case revisited. Clin achieve the 2030 elimination targets. The
Oncol (R Coll Radiol). 2014;26:333-43. Lancet Gastroenterology & Hepatology.
13 International Union Against Cancer: WHO
Essential Medicines List http://www.uicc. 18. D ochez C, Burnett R, Mbassi S, et al. Im-
org/who-essential-medicines-list. Accessed proving skills and institutional capacity to
January 2018. strengthen adolescent immunisation pro-
grammes and health systems in African
14. M artei Y, Binagwaho A, Shulman L, et al. Af- countries through HPV vaccine introduc-
fordability of cancer drugs in sub-Saharan tion. Papillomavirus Research. 2017;4: 2017:
Africa: effects of pricing on needless loss of 66-71.
life. JAMA Oncol. 2017;3(10):1301-1302.
19. N yamurungi K, Olakira S, Kadobera D, et al.
15. R hee JY, Garralda E, Torrado C, et al. Pal- The health cost of tobacco use in Uganda.
liative care in Africa: a scoping review from Health Policy and Planning. 2017;32:1153-
2005-16. Lancet Oncol. 2017;18(9):522-e531. 1160.
16. W orld Health Organization. WHA67.19 – 20. T he PLOS Medicine Editors. Tobacco con-
Strengthening of palliative care as a com- trol: developing an innovative and effec-
ponent of comprehensive care through- tive global strategy. PLOS Medicine. 14(5):
out the life course. WHA Resolution; Sixty- e1002308.
seventh World Health Assembly, 2014.
Js21454ar/. Accessed January 2018.
HANDBOOK OF ONCOLOGY
8 TREATMENT OPTIONS IN ONCOLOGY
Chemotherapy: Target Therapy
Prof BL Rapoport Table 1. Curative cancers
Dip. In Med. (UBA), MMed (Med) Wits Adult cancer
Specialist Physician and Medical
Oncologist; The Medical Oncology Hodgkin’s and non-Hodgkin’s
Centre of Rosebank, Johannesburg; lymphoma
Extraordinary Professor, Department of
Immunology, Faculty of Health Sciences, Germ-cell cancer
University of Pretoria
Acute leukaemias (acute myeloid
Chemotherapy is a form of treatment that leukaemia)
uses pharmacological agents to stop the
growth of cancer cells, either by cell-killing Choriocarcinoma
or by stopping them from dividing. Chem-
otherapy may be administered orally, by Childhood cancer
injection, infusion, or subcutaneously, de-
pending on the type or stage of the can- Acute lymphoblastic leukaemia
cer being treated. Chemotherapy may
be given alone or in conjunction with oth- Burkitt’s lymphoma
er treatment modalities, such as surgery,
radiation therapy, or biological therapy.1 Wilms’ tumour
PRINCIPLES OF CANCER Embryonal rhabdomyosarcoma
Table 2. Cancers treated with neoadjuvant
Chemotherapy in the treatment of neo- chemotherapy
plastic diseases is currently used in three
clinical settings: Anal cancer
1. PRIMARY TREATMENT Bladder cancer
FOR METASTATIC DISEASE
Chemotherapy and other systemic treat-
ments have been the primary approach to Oesophageal cancer
treat advanced and metastatic malignant
diseases for which there are no other ac- Laryngeal cancer
tive anticancer treatments. In the majority
of patients, the treatment goals are to pal- Non-small-cell lung cancer (locally
liate cancer-related symptoms, improve advanced disease)
the overall quality of life, prolong time to
disease progression and survival.2,3 Cancer Osteogenic sarcoma
chemotherapy can be curative in a rela-
tively small subset of patients who present to shrink a tumour before the primary thera-
with advanced disease. These curative py, which is usually surgery, is given. This treat-
malignancies are summarised in Table 1. ment modality is used for patients who pre-
sent with localised or loco-regional disease.4
2. NEOADJUVANT CHEMOTHERAPY The cancers treated with neoadjuvant
TREATMENT chemotherapy are summarised in Table 2.
Neoadjuvant chemotherapy is a form of In certain cancers such as anal cancer,
treatment that is administered as a first step gastro-oesophageal cancer, laryngeal
cancer, head and neck malignancy and
HANDBOOK OF ONCOLOGY non-small-cell lung cancer (NSCLC), clini-
cal benefit from chemotherapy is seen
when the treatment is administered with
radiation therapy either concurrently or
Chemotherapy: Target Therapy and Immunotherapy 9
3. ADJUVANT CHEMOTHERAPY Table 3. Cancers treated with adjuvant TREATMENT APPROACHES
TREATMENT chemotherapy and other systemic
Adjuvant chemotherapy refers to addi-
tional treatment given following the pri- Chemotherapy
mary treatment with the aim to lower the
risk of cancer recurrence. Adjuvant anti- Breast cancer
cancer therapy is not restricted to chemo-
therapy and may include other modali- Colorectal cancer
ties, including radiation therapy, hormone
therapy, targeted therapy, or biological Gastric cancer
Non-small-cell lung cancer (NSCLC)
Malignant tumour recurrence, either
locally, regionally or systemically, follow- Wilms’ tumour
ing surgery or radiation is primarily due
to occult micro-metastases spread. The Osteogenic sarcoma
purpose of adjuvant therapy is, therefore,
to decrease the incidence of both local Anaplastic astrocytomas
and systemic recurrence and to improve
the overall survival of cancer patients. Biological agents
It has been shown that chemotherapy
treatments with clinical activity in the ad- Malignant melanoma: alpha-interferon,
vanced disease setting may have cura-
tive potential following resection of the Malignant melanoma: nivolumab (anti-
primary tumour. It has been demonstrated PD1), ipilimumab (anti-CTLA-4)
that adjuvant chemotherapy is effective
in extending both disease-free survival Breast cancer: transtuzumab (anti-
(DFS) and overall survival (OS) in patients HER2)
with malignant diseases such as breast
cancer, colorectal cancer (CRC), Wilms' Antihormones
tumour, NSCLC, anaplastic astrocytomas
and gastric cancer.1,9-13 The benefit of ad- Breast cancer (hormone receptor
juvant treatment is not limited to chemo- positive)
therapy agents. Patients with high-risk
malignant melanoma have improvement Tamoxifen (anti-oestrogen)
in DFS and OS from adjuvant immuno-
therapy treatment with alpha-interferon Anastrozole and letrozole (aromatase
(biologic agent), nivolumab (anti-PD1 im- inhibitors)
munotherapy) or ipilimumab (anti-CTLA4
immunotherapy).14-15 The antihormonal Targeted therapy
agents tamoxifen (anti-oestrogen), anas-
trozole and letrozole (both aromatase in- GIST: Gastro-intestinal stromal tumour
hibitors) are active agents in the adjuvant
therapy of postmenopausal women with Imatinib therapy (a targeted therapy
hormone receptor-positive breast tumours against C-Kit/CD117)
cancer. Anti-hormone treatment is usually
administered for five to 10 years.16,17 Re- one year.18 Cancers with proven benefit
cent clinical trials have shown that adju- to adjuvant treatment are summarised in
vant imatinib therapy (a targeted therapy Table 3.
against C-Kit/CD117) given to patients
with surgically resected gastro-intestinal COMBINATION CHEMOTHERAPY
stromal tumours (GIST) is more effective
when given for three years as opposed to Historically, combination chemotherapy
started when several active drugs from dif-
ferent classes were used in the treatment
of the acute leukaemias and lymphomas.
Following the initial success with hemato-
logic malignancies, combination chemo-
therapy was extended to the treatment of
When several agents of a class are avail-
able and are equally effective, a drug
should be chosen by a principle of non-
overlapping toxicities. This methodology
HANDBOOK OF ONCOLOGY
10 TREATMENT OPTIONS IN ONCOLOGY
results in maximisation of the combination Table 4. Common side effects
chemotherapy dose intensity. of chemotherapy
DURATION OF CHEMOTHERAPY Fatigue
Numerous randomised trials for the adju- Hair loss
vant treatment of breast and colorectal
cancer have confirmed that six months Thrombocytopaenia
is as effective as 12 months of chemo- (easy bruising and bleeding)
therapy treatment. Ongoing studies are
going to determine whether three months Neutropaenia and infection
of adjuvant chemotherapy will yield the
same level of clinical benefit as six months Anaemia (low red-blood-cell counts)
of treatment of early-stage colon cancer.19
The potential risk of cumulative adverse
effects, such as anthracycline-related car- Chemotherapy-induced nausea and
diotoxicity and taxane and/or platinum vomiting (CINV)
neurotoxicity must always be factored into
the decision-making process. Addition- Appetite changes
ally, there is no evidence that chemother-
apy treatment is of clinical benefit in con- Constipation
tinuing therapy until disease progression. A
randomised clinical study in patients with Diarrhoea
metastatic CRC comparing continuous
and intermittent palliative chemotherapy Mucositis
determined that a policy of drug holiday
and re-challenging with the same agents Neuropathy
provides a reasonable treatment choice
for these patients. Similar observations have Skin and nail changes
been reported in the treatment of metastat-
ic disease of other tumour types, including Urine and bladder changes and kidney
NSCLC, breast cancer, germ-cell cancer, problems
ovarian cancer, and small-cell lung cancer.
The two main problems associated with sys- Weight changes
temic cancer chemotherapy are the toxic-
ity to the healthy body tissues and the de- Chemo brain (can affect
velopment of cellular drug resistance. concentration and focus)
ADVERSE EFFECTS OF Mood changes
Changes in libido and sexual function
The most common side effects of chemo-
therapy are summarised in Table 4. Fertility problems
IMMUNOSUPPRESSION toxicities can occur acutely after adminis-
AND MYELOSUPPRESSION tration, within hours or days, or chronically,
Chemotherapy agents have a broad from weeks to years.
spectrum of side effects that depend on
the type of drug, route of administration, Virtually all chemotherapeutic regi-
and combination used. In general chemo- mens can cause depression of the im-
therapy drugs affect rapidly-dividing cells, mune system, myelosuppression leading
such as blood cells and the cells of the mu- to leukopaenia, neutropaenia, anaemia,
cous membranes. Chemotherapy-related and thrombocytopaenia. Anaemia and
thrombocytopaenia, when they occur,
HANDBOOK OF ONCOLOGY are treated with blood transfusion. Neu-
tropaenia (a decrease in the neutrophil
granulocyte count below 0.5 x 109/litre)
can be improved with G-CSF (granulo-
cyte-colony-stimulating factor, e.g., fil-
grastim, pegfilgrastim). Immunosuppres-
sion and myelosuppression may result in
dose reductions and dose delays. These
dose reductions and delays may compro-
mise cancer-treatment outcome.20-22
Chemotherapy: Target Therapy and Immunotherapy 11
ANAEMIA AND THROMBOCYTOPAENIA of chemotherapeutic treatments that kill TREATMENT APPROACHES
A combination of factors may contribute
to anaemia in cancer patients. These fac- FATIGUE
tors include myelosuppressive chemother- Fatigue may be related to cancer or anti-
apy, and possible cancer-related causes cancer treatment. Fatigue may last for
such as haemolysis, bleeding, renal dys- months following treatment. Anaemia is a
function, iron deficiency or anaemia of cause of fatigue which is usually multifac-
chronic disease. Treatments to mitigate torial and can be caused by chemother-
anaemia include iron supplements, blood apy, surgery, radiotherapy, primary, meta-
transfusions, erythropoietin.23 static disease or nutritional depletion. 23-32
Chemotherapy can cause thrombocy- ALOPECIA
topaenia, which can lead to easy bruis- Alopecia can be caused by chemothera-
ing and bleeding. Extremely low platelet py agents that kill hair follicles and can be
counts may require platelet transfusions.24 complete or partial. These are most often
Chemotherapy treatments may be de- temporary side effects: Hair usually starts
layed to allow platelet counts to recover. to regrow during or a few weeks after
treatment completion. It can be associ-
CHEMOTHERAPY-INDUCED NAUSEA ated with change of colour, texture, thick-
AND VOMITING ness, and style. Severe alopecia occurs
most frequently with drugs such as doxo-
Chemotherapy-induced nausea and vom- rubicin, daunorubicin, paclitaxel, doc-
iting (CINV) are the most feared anti-cancer etaxel, cyclophosphamide, ifosfamide or
treatment-related side effects. CINV is com- etoposide. Permanent alopecia can oc-
mon with many treatments, including plat- cur, but is not common. Chemotherapy
inum-based regimens (both cisplatin and induces alopecia in women more often
carboplatin). An additional group at risk is than men.33
young women with breast cancer receiving
combination chemotherapy with doxoru- SECONDARY NEOPLASM
bicin- and cyclophosphamide (AC)-based Development of secondary neoplasia
treatment. Several novel classes of anti- following completion of chemotherapy
emetics have been developed, helping to or radiotherapy treatment can occur.
manage these symptoms successfully in a Secondary acute myeloid leukaemia is
significant portion of patients. Traditional the most common secondary neoplasm,
regimens to prevent CINV involved a com- which appears mainly after treatment with
bination of a corticosteroid plus a 5-hydrox- alkylating agents (cyclophosphamide
ytryptamine receptor antagonist (5HT3-RA) and others) or topoisomerase inhibitors
and a neurokinin-1 receptor antagonist (etoposide).34 It has been noted that long-
(NK1-RA). These agents include ondan- term survivors of childhood malignancies
setron and granisetron (5HT3-RA) and have a 13 times higher risk of developing
aprepitant and fosaprepitant (NK1-RA). secondary neoplasms during the 30 years
Successful treatment of these unpleasant after treatment compared to the general
and sometimes crippling symptoms results population.35
in a significant increase in quality of life and
more efficient treatment cycles. Dehydra- INFERTILITY
tion may occur when patients do not eat Some chemotherapy agents are toxic to
or drink enough, due to poor CINV control the gonads and may cause infertility.36
and gastro-intestinal damage. Poor CINV Drugs with high risk include procarbazine
control may compromise overall antican- and other alkylating agents, including cy-
cer treatment outcome.25-30 clophosphamide, ifosfamide, busulfan,
melphalan and chlorambucil.37 Agents
GASTRO-INTESTINAL SIDE EFFECTS
HANDBOOK OF ONCOLOGY
Mucositis, diarrhoea, abdominal cramps,
and constipation are common side effects
12 TREATMENT OPTIONS IN ONCOLOGY
with medium risk include doxorubicin and associated with high levels of serum uric
platinum compounds, including cisplatin acid, potassium and phosphate. High
and carboplatin.37 Drugs with low risk of levels of phosphate cause secondary
gonadal toxicity include vincristine, vin- hypoparathyroidism, resulting in hypo-
blastine, bleomycin, dactinomycin, and calcaemia. Complications of tumour lysis
antimetabolites such as methotrexate, syndrome include kidney damage, hyper-
mercaptopurine, and 5-fluorouracil.37, 38 kalaemia, and cardiac arrhythmias. Tu-
Female infertility as a result of chemother- mour lysis syndrome prophylaxis with high
apy appears to be secondary to prema- fluid intake, alkalisation of the urine, and
ture ovarian failure.36 prophylactic allopurinol is indicated in pa-
tients with a significant tumour-cell load,
TERATOGENICITY particularly with haematological malig-
Chemotherapy treatment is teratogenic nancies. Tumour lysis syndrome is a severe
during pregnancy, especially during the fatal complication if left untreated.46,47
first trimester. During the second and third
trimesters, chemotherapy exposure is not CARDIOTOXICITY
associated with an increase in teratogen- Cardiotoxicity is typically prominent with
ic risk.39 the use of anthracycline drugs (doxo-
rubicin, epirubicin, and idarubicin). This
PERIPHERAL NEUROPATHY toxicity is cumulative. The cause of car-
Peripheral neuropathy occurs in approxi- diotoxicity is due to the production of free
mately 30 to 40 percent of patients treated radicals in the cell and subsequent DNA
with chemotherapy agents. Chemothera- damage.48-51
py-induced peripheral neuropathy (CIPN),
is a progressive, and often irreversible or HEPATOTOXICITY
partially reversible condition. Symptoms Hepatotoxicity can be caused by com-
include pain, tingling, numbness, and cold monly used chemotherapy drugs. Risk fac-
sensitivity in the hands and feet.40 Agents tors associated with liver damage include
associated with CIPN include vinca alka- the primary malignant condition and met-
loids (vincristine), taxanes (paclitaxel and astatic liver disease, viral hepatitis, immu-
docetaxel), proteasome inhibitors (bort- nosuppression and nutritional deficiency.
ezomib), and the platinum-based drugs Chemotherapy drugs associated with
(cisplatin and oxaliplatin). Thalidomide liver toxicity include irinotecan and oxali-
is another anticancer agent used in the platin. Hepatotoxicity includes damage to
treatment of multiple myeloma causing hepatocyte, hepatic sinusoidal syndrome,
peripheral neuropathy.40, 41 The severity cholestasis and liver fibrosis.52
of CIPN is determined by the particular
chemotherapy drug used, the duration of NEPHROTOXICITY
therapy and the total dose. Cisplatin and Nephrotoxicity can be caused by tu-
oxaliplatin neuropathy may deteriorate mour lysis syndrome, pre-renal dehydra-
several months after the treatment com- tion, direct effects of chemotherapy
pletion.40, 43, 44 Neuropathic pain can be drug in the kidneys, tubular damage and
managed pharmacologically. However, obstructive uropathy. Cisplatin is particu-
treatment of numbness is ineffective.45 larly nephrotoxic and may induce acute
TUMOR LYSIS SYNDROME
Tumor lysis syndrome is a condition as- OTOTOXICITY
sociated with the breakdown of cancer Ototoxicity to the inner ear is a common
cells that causes the release of chemi- side effect of platinum-based agents.
cals from the intracellular compartment. Ototoxicity symptoms include dizziness
It is particularly common with leukaemias and vertigo.55,56
and lymphomas. Tumour lysis syndrome is
HANDBOOK OF ONCOLOGY
Chemotherapy: Target Therapy and Immunotherapy 13
OTHER SIDE EFFECTS be utilised in various forms. As discussed, TREATMENT APPROACHES
monoclonal antibodies can be employed
Less common side effects include skin as a targeted therapy to block an abnor-
erythema, dry skin, fingernail changes, mal protein in a malignant cell. Mono-
xerostomia, water retention, and sexual clonal antibodies can also be utilised as
dysfunction and impotence. Specific immunotherapy. Some monoclonal an-
chemotherapeutic agents cause distinct tibodies, when attached to specific pro-
toxicities, including cardiac toxicity (dox- teins on cancer cells, flag the malignant
orubicin)48 and interstitial lung disease cells and the immune system can detect
(bleomycin).57 and kill those cells.
TARGETED THERAPIES Other types of monoclonal antibodies
AND IMMUNOTHERAPY work by releasing the brakes on the im-
mune system so it can destroy cancer cells.
Targeted therapy should be distinguished The PD-1/PD-L1 and CTLA-4 pathways are
from chemotherapy. Targeted therapies crucial to the immune system’s capacity
are a relatively new class of anticancer to control cancer growth. These pathways
agents that can overcome many of the are often referred to as “immune check-
effects seen with cytotoxic treatments. Tar- points.” Many cancers overexpress these
geted therapies can be classified into two pathways to evade the immune system
groups: small molecule and antibodies. and immune surveillance. Monoclonal
The toxicity associated with the usage of antibodies can block immune checkpoint
cytotoxics is primarily due to the lack of cell pathways overexpressed in tumours. The
specificity. Cytotoxic drugs kill any rapidly following monoclonal antibodies are im-
dividing cells, including tumour or normal mune checkpoint inhibitors: ipilimumab
cells. Targeted therapies are designed to (anti-CTLA-4), nivolumab and pembroli-
affect specific cellular proteins, pathways, zumab (anti-PD1).62, 63 Checkpoint inhibi-
or processes that are utilised primarily by tor toxicities, referred to as immune-relat-
malignant cells. Although the toxic effects ed adverse events, include skin adverse
are often less severe than those seen with events, gastro-intestinal toxicities (colitis),
cytotoxic chemotherapeutics, severe side oral complications, pulmonary toxicities,
effects may occur. Initially, the targeted and endocrinological complications (thy-
therapies were supposed to be selective roiditis and hypophysitis).64, 65
for one specific protein. However, there
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HANDBOOK OF ONCOLOGY
Radiation-Therapy Overview 17TREATMENT APPROACHES
Prof V Sharma cancer among females (22%), followed
by cervical cancer in 15.58% of patients.
MD (Rad), MD (Rad Onc), PhD Breast cancer comprised 32.5% of female
r Professor and Head, Department of cancers in individuals over 65 years of
Radiation Oncology, Charlotte Maxeke age. 3
Johannesburg Academic Hospital,
University of Witwatersrand Currently, the top five cancers in South
Africa in males are prostate, colorectal,
Global cancer burden is growing and in lung, Kaposi sarcoma and bladder. The
2030 alone, about 21.6 million new can- top five female cancers are breast, cervix,
cer cases and 13 million cancer deaths colorectal, uterus and lung. The life-time
are expected to occur, simply due to the risk for cancer for South African men is 1:6
growth and ageing of the population. The and for women it is 1:9.
future burden may be further increased
by the adoption of unhealthy behaviours CANCER DIAGNOSIS
and lifestyle associated with rapid income
growth (e.g., smoking, poor diet and phys- The seven warning signals for cancer
ical inactivity) and changes in reproduc- include:
tive patterns (e.g., fewer children, later 1. A change in bowel or bladder habits
age of first child birth) in low- and middle- 2. A sore that does not heal
income countries (LMICs). Tobacco use 3. Unusual bleeding or discharge
is responsible for almost six million deaths 4. Thickening or a lump in the breast or
annually, 80% of which are in LMICs; by
2030, this number will reach eight million. elsewhere
By 2030, tobacco-attributable deaths 5. Indigestion or difficulty in swallowing
will double in LMIC from 3.4 million to 6.8 6. Obvious change in a wart or mole
million.1 7. Nagging cough or hoarseness
Overall, 645 071 new cancer cases and To make a diagnosis, it is important to have
455 695 cancer deaths were estimated a good history, general physical examina-
to have occurred in Africa in 2012. Breast tion, blood tests, and radiological investi-
cancer was the second most commonly gations – x-ray of the specific area, chest
diagnosed cancer and the fifth leading x-ray, CT scan, MRI, PET scan and biopsy.
cause of cancer deaths among women
in Africa in 2012 (100 000 cases, 49 000 To reduce the risk of cancer, the following
deaths). The incidence of breast cancer behavioural patterns should be followed:
among southern African women is among n Do not use tobacco
the first five breast cancers of all African n E at a healthy diet3
regions. Cervical cancer is the fourth most n Maintain a healthy weight and be physi-
frequently diagnosed cancer (92 000
cases) and the leading cause of cancer cally active
deaths (57 000) in African women.2 n Protect yourself from the sun
n Get immunised
According to the South African Cancer n Avoid risky behaviours
Registry data for the year 2013, prostate n R egular medical care
cancer accounted for 18.86 % of all male
cancers, with the age-standardised rate RADIATION-THERAPY TREATMENT
(ASR) of 44.30/100 000 of the population.
Prostate cancers formed 60.4% of the can- When used for the treatment of cancer,
cers affecting male patients over 65 years ionising radiations such as x-rays or gam-
of age. Breast cancer was the leading ma rays work by damaging the DNA of
exposed tissue, leading to cellular death.
The main aim is to deliver the maximum
HANDBOOK OF ONCOLOGY
18 TREATMENT OPTIONS IN ONCOLOGY
dose to the tumour, while preventing the traditional portal imaging. An extra benefit
surrounding critical structures from receiv- of the system is the ability to capture imag-
ing doses above specified dose toleranc- es digitally for review and guidance.
es. Besides the tumour itself, the radiation
fields may also include the draining of Various steps in treatment planning are
lymph nodes if they are clinically or radio- shown in Figure 1.
logically involved with the tumour or if there
is a risk of subclinical malignant spread. It TYPES OF RADIATION THERAPY
is necessary to include a margin of normal n E xternal beam radiation therapy (EBRT
tissue around the tumour to allow for uncer-
tainties in daily set-up (such as movement or XRT) or teletherapy
of external skin marks relative to the tumour n Brachytherapy or sealed-source radia-
position) and internal tumour motion (for
example, respiration and bladder-filling). tion therapy
Various techniques have been employed n Systemic radio-isotope therapy or un-
to help ensure the accurate placement of
a treatment field. These include ink marks sealed source radiation therapy
on the skin, tattoo, portal imaging for veri-
fication, and electronic portal imaging – The uncertainties relate to the position of
the process of creating a digital image the radiation source: outside the body,
with improved quality and contrast over sealed radio-active sources placed pre-
cisely in the area under treatment, or ad-
ministered by infusion or oral ingestion (see
Figure 2). It is common to combine radiation
Figure 1. Radiation-treatment planning of a patient
↓ Diagnostic work-up, pathology of the tumour, staging of disease
↓ Curative or palliative treatment and the choice of treatment modality
↓ Immobilisation devices such as mask, 2D simulation, CT scan/3D planning, target
definition, beams computation, analysis of alternative plans and plan selection, dose
↓ Localisation, verification, daily treatment and weekly evaluation
↓ Tolerance to treatment, response assessment
Figure 2. Radiation therapy
External radiation Brachytherapy ** Systemic therapy
Photons, particle Infusion, oral ingestion
therapy*, IORT Permanent
Temporary MIBG, I131,Y90, S89
HDR, LDR Seeds
Ir192, Cs137, Co60 I123
* Protons or carbon ions
** Interstitial, intra-cavitary, intra-luminal, surface mould
HANDBOOK OF ONCOLOGY
Radiation-Therapy Overview 19
therapy with surgery, chemotherapy, hor- Radiosensitivity determines the response TREATMENT APPROACHES
mone therapy and immunotherapy or a of a cancer to radiation. Highly radio-
combination of more than one. sensitive cancer cells are rapidly killed by
modest doses of radiation and include
The purpose of radiation therapy is both leukaemias, most lymphomas and germ-
curative and palliative. The precise treat- cell tumours (20-40Gy). The majority of epi-
ment intent (curative, adjuvant, neoad- thelial cancers are only moderately radio-
juvant, or palliative) will depend on the sensitive, and require a significantly higher
tumour type, location, size and stage, as dose of radiation (60-70Gy) to achieve a
well as the general condition of the pa- radical cure (see Table 1). Some types of
tient. Concomitant chemo-radiation im- cancer are notably radio-resistant, and
proves the effect of radiation by up to need much higher doses to produce a
20% and is used as a radiosensitiser. Ra- radical cure than may be safe in clinical
diation therapy can also be used in non- practice for cancers such as renal-cell
malignant conditions such as trigeminal cancer and melanoma. Metastatic can-
neuralgia, acoustic neuromas, severe thy- cers are generally incurable with radiation
roid eye disease, pterygium, prevention of therapy because it is not possible to treat
keloid scar growth, vascular restenosis and the whole body.
SIDE EFFECTS OF RADIATION THERAPY
Brachytherapy, in which the radiation
source is placed inside or next to the area The radiation therapy is local treatment
requiring treatment, minimises exposure to and the treatment-related side effects can
healthy tissue during treatment of cancers be acute, defined as happening within 90
of the cervix, breast, prostate, skin and days from start of treatment and late af-
other organs. ter 90 days. These can be general as well
as specific to the area of treatment. Side
Systemic radio-isotope therapy is the effects occur because radiation therapy
form of targeted therapy in which the can also damage healthy cells and tissues
chemical properties of the isotope – for near the treatment area. Major advances
example, radio-iodine – are specifically in radiation technology now have made
absorbed by the thyroid gland and/or at- it more precise, leading to fewer side ef-
tached to another molecule or antibody fects. They also depend on the site of
to guide it to the target tissue. The radio- treatment, radiation-therapy dose, dose
isotopes are delivered through infusion per fraction, treatment volume, whether
(e.g., metaiodobenzylguanidine [MIBG] radiation is given alone or in combination
to treat neuroblastoma) or ingestion (e.g., with chemotherapy.
oral iodine-131 to treat thyroid cancer or
thyrotoxicosis, and yttrium-90 to treat neu-
Table 1. Cancers curable by radiation
Cancers curable at early stages with Cancers curable with regimens including
radiotherapy alone radiation therapy
n Prostate carcinoma n Breast carcinomas
n Head and neck carcinoma n Locally advanced lung carcinomas
n Non-small-cell lung carcinomas n Seminoma
n Squamous- and basal-cell skin n Endometrial carcinomas
n CNS tumours, e.g., ependymoma, glioma
cancers n Soft-tissue sarcomas
n Hodgkin’s lymphomas n Rectal and anal carcinomas
n Uterine cervix carcinomas n Lymphomas
n Advanced head and neck carcinomas
n Paediatric malignancies, e.g., Wilms’
HANDBOOK OF ONCOLOGY
20 TREATMENT OPTIONS IN ONCOLOGY
Reactions often start during the second or of radiation oncology treatment. The clini-
third week of treatment. They may last for cal evaluation has been enhanced by
several weeks after the final treatment. improvements in diagnosis with the incor-
Preventing and treating side effects is an poration of computed tomography (CT),
important part of cancer treatment. The magnetic resonance imaging (MRI) and
common general side effects include skin positron emission tomography (PET)/CT
problems, such as dryness, itching, blistering, scans for accurate definition of local, lo-
or peeling. But these side effects often de- coregional and metastatic disease.
pend on which part of the body received
radiation therapy. Patients can also expe- Information on molecular biomarkers
rience fatigue, feeling tired or exhausted is helping to predict tumour response to
almost all the time, and the level of fatigue a particular treatment. Potential targets
depends on whether they are having other for therapy are being identified by using
treatments, such as chemotherapy. Table 2 information on genes, proteins and vari-
outlines site-specific side effects. ous metabolites.4 The tumours are being
classified based on DNA and RNA with
Coping with side effects: Everyone’s ex- the use of micro-arrays. Personalised treat-
perience with cancer treatment is different. ment is possible – for example, epidermal
There are many options for managing side growth factor receptors (EGFR) are over-
effects. The patient and general physician expressed in 80% of patients with broncho-
should consult with the treating specialist for alveolar histology and are predominant in
advice regarding prevention before treat- women and non-smokers. These tumours
ment and how to reduce side effects during are sensitive to erlotinib. Similarly, radia-
treatment and the follow-up period. tion-induced signalling of EGFR has a pro-
survival effect and this can be applied
DEVELOPMENTS IN RADIATION for management. The non-squamous
ONCOLOGY histology has over-expression of vascular
endothelial growth factor (VEGF) and de-
Considerable developments have oc- notes poor prognosis. These tumours are
curred over the last decade in all the areas sensitive to bevacizumab.
Table 2. Radiation-therapy side effects
Treatment site Early Late (>90 days from start
Head and neck (up to 90 days from start of treatment) of treatment)
Chest Dry mouth, mouth and gum sores,
painful swallowing and difficulty in Tooth decay,
Abdomen swallowing, stiffness of jaw, nausea lymphoedema, soft tissue
Pelvis Difficulty in swallowing, shortness of fibrosis in neck
breath, cough, fever
Others Oesophageal stricture,
Nausea, vomiting, abdominal cramps, ulceration and tracheal
diarrhoea oesophageal fistula,
Diarrhoea, bladder irritation, increased radiation lung fibrosis
urinary frequency, rectal bleeding
Skin reaction – dry desquamation, moist capacity of stomach
desquamation. Sexual problems in
males – erectile dysfunction, low sperm Rectal proctitis, rectal
count and females – vaginal itching, strictures, decreased
burning, dryness and infertility urinary bladder capacity,
Skin fibrosis, vaginal
HANDBOOK OF ONCOLOGY
Radiation-Therapy Overview 21
With the development of therapeutic high doses, thus limiting the dose delivered TREATMENT APPROACHES
agents that interfere with major onco- to the surrounding normal tissues. The ma-
genes such as KRAS and MYC, treatment jor benefit has been improved definition
will be improved. It is hoped that, with the of the longitudinal extent of the tumour,
development of multi-agent protocols, re- particularly in the region of gastro-oesoph-
sistance to treatments can be overcome ageal junction in cancer of the oesopha-
and cancers can be controlled. gus. In the head and neck, target volume
was modified in 20% of cases and tumour
Although DNA damage is generally volumes from PET were 25% greater than
regarded as the primary event for ra- CT images.
diation-induced cell lethality, different
mechanisms are being studied, such as PET/CT reduces the gross tumour volume
host-derived blood vessels as a target for (GTV) by down-staging the mediastinal
radiotherapy in terms of tumour control lymph nodes to smaller GTV. This also helps
and complications in normal tissues.5 The in discriminating tumour tissue from ate-
five major biological concepts (intrinsic lectasis or necrosis (22-62%); lowering dose
cellular radiosensitivity; acute/chronic to oesophagus and lung. The treatment
hypoxia and re-oxygenation; differential strategy was modified in 37% of patients
DNA damage-repair processing; cell-cy- with FDG PET, preventing surgery in 20%.7
cle redistribution; and tumour-cell repopu-
lation) are being interpolated for maxim- Virtual simulation, the most basic form
ising the therapeutic index for particular of planning, allows more accurate place-
tumours in particular patients.4 ment of radiation beams than is possible
using conventional x-rays, where soft-tis-
Different fractionation schemes such sue structures are often difficult to assess
as hyper-fractionation, accelerated frac- and normal tissues are difficult to protect.
tionation and hypo-fractionation are be- An enhancement of virtual simulation is
ing employed in addition to conventional three-dimensional conformal radiation
fractionation using external-beam radia- therapy (3DCRT), in which the profile of
tion. In hyper-fractionation, the low dose each radiation beam is shaped to fit the
per fraction has a sparing effect on late- profile of the target from a beam’s eye
responding tissues, whereas accelerated view (BEV), using a multileaf collimator
fractionation reduces the effect due to (MLC) and a variable number of beams.
accelerated repopulation in the later When the treatment volume conforms to
stages of radiation therapy. With the un- the shape of the tumour, the relative toxic-
derstanding of radiobiological mecha- ity of radiation to the surrounding normal
nisms induced by hypo-fractionation, such tissues is reduced, allowing a higher dose
as abscopal/bystander effect, activation of radiation to be delivered to the tumour
of immune system, endothelial-cell death, than in conventional techniques.8
no effect of hypoxia in the tumour and
differential effect on cancer stem cells,9 Intensity-modulated radiation therapy
it can be used more judiciously. Improve- (IMRT) is an advanced type of high-preci-
ment in and determination of therapeutic sion radiation that is the next generation
index is complicated by the spatial and of 3DCRT. IMRT also improves the ability
temporal interactions of radiation therapy to conform the treatment volume to con-
with surgery, conventional chemothera- cave tumour shapes – for example, when
py, and newer biologics/small molecules.4 the tumour is wrapped around a vulner-
able structure, such as the spinal cord or a
The supercomputers and imaging mo- major organ or blood vessel.9 The pattern
dalities, such as CT, MRI, and PET/CT, have of radiation delivery is determined using
become integrated with treatment plan- highly tailored computing applications to
ning and delivery to undergo transition perform optimisation and treatment simu-
from two-dimensional (2D) to 3D to 4D lation. The radiation dose is consistent with
treatments.4 PET-based plans have led to the 3D shape of the tumour by control-
a significant reduction in the volume of ling, or modulating, the radiation beam’s
HANDBOOK OF ONCOLOGY
22 TREATMENT OPTIONS IN ONCOLOGY
intensity. The radiation-dose intensity is oncologists perform stereotactic treat-
elevated near the GTV, while radiation
among the neighbouring normal tissue is ments for tumours in the brain or spine,
decreased or avoided completely. The
customised radiation dose is intended to often with the help of a neurosurgeon for
maximise tumour dose, while simultane-
ously protecting the surrounding normal stereotactic radiosurgery (SRS) for a single
tissue. This may result in better tumour tar-
geting, reduced side effects, and better radiation treatment of the brain. Stereo-
treatment outcomes than even 3DCRT.
Although 3DCRT is still used extensively for tactic body-radiation therapy (SBRT) refers
many body sites, the use of IMRT is increas- to several stereotactic radiation treat-
ing in more complicated body sites, such ments for parts of the body, such as the
as CNS, head and neck, prostate, breast lungs, or for brain.
The advantage of stereotactic treat-
Unfortunately, IMRT is limited by its need ments is that they deliver the right amount
for additional time from experienced med- of radiation to the cancer in a shorter time
ical personnel. Physicians must manually than conventional treatments which can
delineate the tumours one CT image at a often take six to 11 weeks. The treatments
time through the entire disease site, which are given with extreme accuracy, which
can take much longer than 3DCRT prepa- should limit the effect of the radiation on
ration. Then, medical physicists and dosi- healthy tissues. These treatments are suit-
metrists must create a viable treatment able for certain small tumours only.
plan. Proof of improved survival benefit
from either of these two techniques over Tumours located in the pelvis, abdomen
conventional radiation therapy (2DXRT) is and thorax are subject to motion during
growing for many tumour sites. The ability treatment caused by respiration, inherent
to reduce toxicity is generally accepted. bowel mobility and peristalsis, and cardi-
Both techniques enable dose escalation, ac motion. This motion is often accounted
potentially increasing usefulness. for by applying a margin to the target of
interest to encompass the spatial vari-
The change in tumour and normal tissue ability of the target. The use of real-time
biology during treatment requires adaptive tracking techniques allows for a reduction
radiotherapy to truly impact on the thera- in this margin and thus reduces the mor-
peutic index, and its implementation in- bidity associated with unnecessary dose
volves the newer functional imaging (MRI, to the surrounding normal tissues. Continu-
magnetic resonance spectroscopy [MRS], ous localisation systems such as Calypso
PET) to monitor spatial variation in tumour- 4D localisation system for prostate11 and
radiation response and normal tissue func- head and neck cancers, radio-cameras
tion during the course of treatment. for stereotactic radiation for benign and
malignant tumours of the central nervous
Following the advances over the last system, and Align RT (a 3D video-based
decade in intensity-modulated radio- image-guided RT system) for breast can-
therapy (IMRT), namely stereotactic radio- cer have allowed for clinically-relevant
surgery (SRS)/radiotherapy, stereotactic reduction in margins. Use of real-time
body radiotherapy (SBRT), and image- tracking techniques allows for reduced
guided radiation therapy, it has become normal-tissue-dose volumes and dose es-
critical to position patients precisely and calation to the target volume, leading to
reproducibly in the treatment positions.10 improved tumour control.
Stereotactic radiation is a specialised
type of external-beam radiation therapy Dunscombe12 has presented a set of rec-
and uses focused radiation beams tar- ommendations likely to enhance safety
geting a well-defined tumour, using ex- and quality in radiotherapy. These include
tremely detailed imaging scans. Radiation the training of staff in specifically safety-
HANDBOOK OF ONCOLOGY related topics, an adequate number of
staff, the proper documentation of stand-
ard operating procedures, the sharing of
information on incidents (incident-learn-
ing), effective and open communication,
the development and maintenance of
Radiation-Therapy Overview 23
check-lists, quality control and preven- in GLOBOCAN 2012. Int J Cancer. 136,E359– TREATMENT APPROACHES
tive maintenance, a dosimetric audit, ac- E386(2015) VC 2014 UICC.
creditation, the minimisation of interrup- 3. S outh African Cancer Registry Report. 2013:
tions, prospective risk assessment, and the 1-2. Http://www.cansa.org.za. Accessed
changing of organisational culture.13 Mar 30, 2018.
4. K insella TJ. Radiation oncology: today and
CONCLUSION tomorrow. Front Oncol. 2011;1:1-2.
5. C onnell PP, Hellman S. Advances in radio-
The major challenge in radiation therapy therapy and implications for the next cen-
is to broaden the current cross-disciplinary tury: a historical perspective. Cancer Re-
team of radiation oncologists, medical search. 2009;69(2):383-392.
physicists and radiation biologists to in- 6. Gupta S, et al. Radiobiological concepts
clude engineers and mathematicians in a of high dose hypo-fractionated radiation
systems-science/biology approach. New therapy. In Pollack A, Ahmed MM, editors.
technologies may reduce costs, as will the Hypo-fractionation: scientific concepts
development of efficiencies (i.e., class solu- and clinical experiences. Ellicott City: Lumi-
tions for planning, better plans that reduce Text Publishing; 2011;2:19-38.
treatment time and improve scheduling). 7. G ambhir SS, Czernin J, Schwimmer J, et al.
Proton therapy with superior dose distri- A tabulated summary of the FDG PET litera-
bution has an advantage over photons, ture. J Nucl Med. 2001;42:1s-93s.
although the cost at 2.4 times that of IMRT is 8. C amphausen KA, Lawrence RC. Principles
prohibitive. Expected improvements in tar- of Radiation Therapy. In Pazdur R, Wagman
get localisation with a higher dose to the LD, Camphausen KA, Hoskins WJ, editors.
target and normal-tissue-dose reduction Cancer Management: a multi-disciplinary
will result in greater tumour control and a approach. 11th ed. London: Cmp United
significant reduction in adverse post-treat- Business Media; 2008.
ment morbidity. Trends point to combined 9. I ntensity Modulated Radiation Therapy. Irsa.
org. http://www.irsa.org/imrt.html. Accessed
(RT+CT) modality treatment, extra-cranial Mar 30, 2018.
10. d’Ambrosio DJ, et al. Continuous localisa-
stereotactic radiation, hypo-fractionation tion technologies for radiotherapy delivery:
protocols and mid-therapy redesign of the Report of the American Society for Radia-
radiation dose (adaptive radiation ther- tion Oncology Emerging Technology Com-
apy). Use of functional imaging for target mittee. Pract Radiat Oncol. 2012;2:145-150.
definition in addition to the consolidated 11. Kupelian P, et al. Multi institutional clinical
quality assurance programme will play an experience with the calypso system in lo-
important role in the future. calisation and continuous, real time moni-
toring of the prostate gland during external
REFERENCES radiotherapy. Int J Radiat Oncol Biol Phys.
1. A merican Cancer Society – cancer facts 12. D unscombe P. Recommendations for safer
and figures 2017. radiotherapy: what’s the message? Front
2. F erlay J, Soerjomataram I, Dikshit R, et al. 13. C lark BG, Brown RJ, Ploquin JL. Patient
Cancer incidence and mortality world- safety improvements in radiation treatment
wide: sources, methods and major patterns through 5 years of incident learning. Pract
Radiat Oncol. 2013 Jul-Sep;3(3):157-63. Doi:
10.1016/j. Prro. 2012.08.001.
HANDBOOK OF ONCOLOGY
24 TREATMENT OPTIONS IN ONCOLOGY
Recent Advances in Targeted
Radionuclide Therapy of Cancers:
Moving towards Personalised Care
Dr IO Lawal Theranostics is a concept closely related
to targeted therapy. Theranostics is a com-
MBBS, FCNP, MMed(Nucl Med) pound word that integrates diagnostics and
Nuclear Medicine Physician, therapeutics in patient management. In
Department of Nuclear Medicine, theranostics, a radiopharmaceutical is used
University of Pretoria and Steve Biko for the diagnostic imaging of a disease and
Academic Hospital a variation of the same molecule is used for
the treatment of the disease.
Prof MM Sathekge
Theranostics involves the following:
MB ChB, MMed (Nucl Med), FAMS, PhD n L ocalisation of site disease and
Professor and Head of Department,
Department of Nuclear Medicine, determining its extent (staging)
University of Pretoria and Steve Biko n Determination of expression of the
biological target in the tumour. Only
Corresponding author: Prof MM Sathekge patients whose tumours overexpress
the biological target will respond to
Targeted cancer therapy relies on the targeted radionuclide therapy
identification of a biological target in the n Examination of off-target distribution
tumour and optimising it for therapeutic in- of the agent. This is the cause of side
tervention. A candidate biological target effects
should be expressed exclusively by the tu- n D etermination of the amount of
mour or must have only low-level expres- therapeutic radiopharmaceuticals
sion in non-malignant tissues. A pharma- required for treatment in a particular
ceutical molecule is designed to target patient
the tumour-expressed biological marker. n M onitoring response to treatment after
targeted radionuclide therapy
For targeted radionuclide therapy of
cancers, a radionuclide, which emits a Theranostics epitomises the concept of
beta, or more recently, an alpha particle, personalised care in cancer treatment.
is complexed to the pharmaceutical to Only patients who will benefit from radio-
form a therapeutic radiopharmaceutical. nuclide therapy are treated. This ensures
Beta and alpha particles are two energetic rational use of scarce resources and pre-
particles that are capable of causing DNA vents adverse effects relating to the use of
damage, leading to death of the tumour ineffective treatment in patients who may
cells. Following in vivo administration, the not benefit from it.
radiopharmaceutical is distributed to the
tumour and the radiation released by the Targeted radionuclide therapy started
radionuclide causes tumour-cell death. more than 70 years ago with the use of
Theoretically, any tumour can be treated radioactive iodine in the treatment of
using targeted radionuclide technique benign and malignant thyroid diseases.1
once a suitable biological target that is Since then, many other radiopharmaceu-
over-expressed by that tumour is identi- ticals have been developed and success-
fied and a radiopharmaceutical target is fully used in the treatment of human can-
designed for its in vivo targeting. Several cers. This focus review will briefly elucidate
radionuclide agents have been designed the recent advances in targeted radionu-
for treatment of different human cancers. clide therapy of cancers.
HANDBOOK OF ONCOLOGY
Recent Advances in Targeted Radionuclide Therapy of Cancers 25 TREATMENT APPROACHES
Figure 1.68 Ga-DOTATATE PET/CT images of patient with multi-resistant neuro-endocrine tumour
showing good response after fourth therapy with 177Lu-DOTATATE. Left panel: before therapy;
right panel: after the fourth therapy with 177Lu-DOTATATE
PEPTIDE RECEPTOR RADIONUCLIDE relief in patients with functional NETs and
THERAPY OF NEURO-ENDOCRINE may halt progression of the disease.
TUMOURS Chemotherapy offers little benefit in well-
differentiated NETs as these tumours are
Neuro-endocrine tumours (NETs) are a slow-growing.
heterogeneous group of tumours that
over-express the somatostatin receptors Peptide receptor radionuclide therapy
(SSTs) on the tumour-cell membrane. They (PRRNT) has evolved in recent years to be a
most commonly arise from the gastro-en- highly effective therapy option in patients
teropancreatic tissues, but can be found with well differentiated NETs. The SSTs over-
in virtually any organ of the body. Liver expressed on well differentiated NETs are
is a common site of distant metastasis.2 the molecular targets. Theranostic radio-
NETs may be functional or non-functional. pharmaceuticals used consist of three
Functional NETs produce biologically ac- parts; a somatostatin analogue, a radio-
tive substances such as serotonin (as in nuclide and a linker molecule connecting
carcinoid), glucagon (as in glucagono- the two. For imaging, Gallium 68 (Ga-68) is
ma) or insulin (as in insulinoma), and so on. the radionuclide used for positron emission
Due to the biological effects of these se- tomography (PET) imaging, while DOTA
creted substances, functional NETs come is a common linker molecule. Ga-68 DO-
to clinical attention early when the tumour TATATE, Ga-68 DOTATOC and Ga-68 DO-
is still very small and presents a diagnostic TANOC are the common radiopharma-
challenge with anatomic imaging. Non- ceuticals for NETs PET imaging. For therapy,
functional NETs are diagnosed at a more Ga-68 is substituted for a radionuclide that
advanced stage, often as a result of pres- emits energetic ionising radiations, such as
sure symptoms from a large tumour bulk or beta particles. Lutetium 177 (Lu-177) and
its metastasis. Yttrium 90 (Y-90) are the two most com-
monly used beta particle-emitting radionu-
Surgical excision with curative intent is clides in PRRNT (see Figure 1).
the preferred treatment option in localised
NETs. Somatostatin analogues with octreo- PRRNT is indicated in patients with meta-
tide or lanreotide are first-line agents in me- stasised, progressive SST-expressing NETs,
tastatic NETs. They provide symptomatic including gastro-enteropancreatic and
HANDBOOK OF ONCOLOGY
26 TREATMENT OPTIONS IN ONCOLOGY
Other tumours overexpressing SSTs, such 60 mg intramuscular injection of octreo-
as paraganglioma/pheochromocytoma, tide LAR alone (control group, n = 110).
neuroblastoma, and medullary thyroid The primary endpoint was progression-
carcinoma may be treated as well. The free survival. Progression-free survival at
ideal patients are those with well differen- 20 months was 65.2% [95% CI, 50.0-76.8] in
tiated tumours, Ki67 ≤20%. the Lu-177 DOTATATE group versus 10.8%
[95% CI, 3.5-23.0] in the control group. The
Contra-indications to PRRNT include the median progression-free survival had not
following: yet been reached in the Lu-177 DOTATATE
n P regnancy group and was 8.4 months in the control
n S evere acute concomitant illnesses group. There was 60% lower risk of death
n S everely compromised renal function, in the Lu-177 DOTATATE group than in the
control. Eighteen patients in the Lu-177
glomerular filtration rate less than 60% DOTATATE group had either complete or
of age-adjusted normal values partial response, compared with three in
n S everely compromised bone-marrow the control arm. Side effects requiring dis-
function; white blood cell (WBC) continuation of treatment occurred in 6%
<3,000/µL, with absolute neutrophil in the Lu-177 DOTATATE group, compared
count <1,000/µL, platelet count with 9% in the control. The commonest
<75,000/µL, red cell count <3,000,000/µL side effects in the Lu-177 DOTATATE group
were nausea and vomiting related to
The following must be ensured before a amino acid infusion. Grade 3 and 4 side
patient is planned for PRRNT: effects were similar in both groups. No
n Histologically proven NET, ideally with renal toxicity was seen.3 Response rate
to Lu-177 DOTATATE demonstrated in this
Ki67 ≤20% (WHO grade 1 or 2) study was higher compared with response
n H igh expression of SSTs type 2, as rates reported in other studies, with similar
patients using other treatment options, in-
demonstrated on a Ga-68 DOTATATE cluding everolimus, alpha-interferon and
PET/CT scan lanreotide.4-6
n K arnofsky performance status above
60% (ECOG <2) In a report of the long-term toxicity of
n Renal scintigraphy documenting good PRRNT in 807 patients with NETs, Bodei, et
renal function and absence of urinary al reported grade 3/4 renal toxicity in 1.5%
tract obstruction of patients, grade 3/4 bone-marrow tox-
n A bsence of any contra-indication icity in 9.5% of patients, myelodysplastic
syndrome in 2.35% and eight patients with
PRRNT must be administered in a well- acute leukaemia, six of whom converted
equipped specialised facility with well- from myelodysplastic syndrome.7
trained staff. Therapy is co-administered
with amino acid solution to prevent the re- PROSTATE-SPECIFIC MEMBRANE
nal side effects of treatment. Anti-emetics ANTIGEN RADIOLIGAND THERAPY
and corticosteroids are given to prevent (PRLT)
the side effects associated with amino
acid infusion. Prostate-specific membrane antigen
(PSMA) is a transmembrane glycoprotein
The results of NETTER-1 trial; a multicen- expressed on the cancer cells in meta-
tre, randomised, controlled trial of the static prostate carcinoma. Its level of
efficacy and safety of Lu-177 DOTATATE expression is even higher in metastatic
in patients with advanced, progressive, castration-resistant prostate carcinoma
SSTR-expressing midgut NETs, was recently (mCRPC). Several small-molecule ligands
reported. Patients were randomised to have been developed, targeting PSMA.
either receive four cycles of Lu-177 DOTA- Ga-68 PSMA is a diagnostic radionuclide
TATE plus a monthly intramuscular injec- available for PET imaging. PSMA can be
tion of 30 mg octreotide (Lu-177 DOTATATE
group, n = 111) or a monthly injection of
HANDBOOK OF ONCOLOGY
Recent Advances in Targeted Radionuclide Therapy of Cancers 27
complexed to Lu-177 or an alpha-emitting mCRPC patients, improvement in quality TREATMENT APPROACHES
radionuclide such as Actinium 225 (Ac-225) of life in 60% and an improvement in per-
or Bismuth 213 (Bi-213) for radioligand ther- formance status in 74% of patients.10
apy of mCRPC.8
Xerostomia is a potential side effect due
PRLT may be considered in patients with to high expression of the PSMA glycopro-
mCRPC who have exhausted or do not tein in the salivary glands. Xerostomia is
tolerate approved therapies. commonly mild and reversible.
The following must be ensured before a Due to the densely ionising ability of al-
patient is considered for PRLT. pha particles and their potential to cause
n Ga-68 PSMA PET/CT showing tracer more lethal damage to the cancer cells
(due to double-stranded DNA damage)
uptake within lesions than beta particles, interest is now focused
n S ufficient bone-marrow reserve, WBC on the use of alpha-emitting radionuclides
complexed to PSMA ligand for PRLT of
>3,000/µl, platelets >75,000/µL metastatic prostate carcinoma. The two
n Sufficient renal function reserve defined most commonly used radionuclides are
Bismuth 213 (Bi-213) and Actinium 225 (Ac-
as serum creatinine <2 times the upper 225) (see Figure 2). The longer half-life of
limit of normal Ac-225 of 10 days compared with 46 min-
n R enal scintigraphy documenting good utes of Bi-213 makes it a more effective
renal function and absence of urinary therapeutic radionuclide. Alpha particles
tract obstruction are heavy and only travel a short distance
n Discontinuation of other potentially in the tissue. This accounts for the lower
myelosuppressive therapies for six side effects associated with their use. Ac-
weeks before commencement of PRLT. 225 PSMA is now being used in patients
whose disease is refractory to Lu-177 PSMA
The therapeutic agent in PRLT is adminis- therapy.11 Several prospective trials are
tered intravenously with less stringent need ongoing, evaluating the dosimetry, safety
for amino acid co-administration due to a and efficacy of Lu-177 or Ac-255 labelled
lower risk of renal toxicity compared with PSMA for radioligand therapy of mCRPC.10
PRRNT in NETs. Four to six cycles are admin-
istered at eight- to 12-week intervals. Con- RADIONUCLIDE THERAPY
comitant use of androgen deprivation may OF BONE METASTASES
upregulate the expression of PSMA glyco-
protein, hence this therapy can be contin- Bone is a common site of metastases in
ued in patients being treated with PRLT. several tumours. Presence of skeletal me-
tastases is associated with the occurrence
The efficacy and safety profile of Lu-177 of skeletal-related events (SREs), morbidity,
PSMA for PRLT in metastatic prostate can- drastic reduction in the quality of life and
cer were demonstrated in a multicentre death. Bone metastases are therefore de-
German study of 145 patients who had serving of prompt institution of effective
one to four cycles of Lu-177 PSMA. Grade therapy aimed at alleviating pain and
3/4 anaemia occurred in 15 patients, preventing the occurrence of complica-
grade 3/4 thrombocytopaenia in five pa- tions. For decades, radionuclides such as
tients. No therapy-related death was seen. Phosphorus-32, Strontium-89, and more re-
A low pre-therapy blood-cell count was cently Samarium-153 EDTMP, Rhenium-186
predictive of haematotoxicity. Response HEDP and Rhenium 188 HEDP have been
was assessed, using a fall in PSA level. 45% successfully used in the targeted therapy
of evaluable patients demonstrated a PSA of bone metastases, with effective pain
decline of at least 50% – biochemical re- control and tolerable side effects. The
sponders. A PSA decline of any number use of these beta-emitting radionuclides
was seen in 60% of patients.9 Patient-re- alone, while very effective in pain control,
ported outcome has been evaluated for does not confer survival benefit.
in multiple studies. PRLT with Lu-177 PSMA
led to significant pain relief in 33-70% of HANDBOOK OF ONCOLOGY
28 TREATMENT OPTIONS IN ONCOLOGY
Figure 2. Excellent response to therapy Ra-223 dichloride adsorbs to the hy-
after two cycles of 225Ac-PSMA-617. This droxyapatite crystals of the bone matrix. It
impressive response in a patient with is concentrated more at sites of increased
metastatic castration-resistant prostate bone turnover – a feature characteristic of
cancer was demonstrated by 68Ga-PSMA-11 osteoblastic skeletal metastases. It there-
PET/CT images of before (top panel) and after fore concentrates more at sites of osteo-
(bottom panel) blastic skeletal metastases than normal
bone. The emitted alpha particle causes
Radium-223 dichloride, an alpha-emitting double-stranded DNA damage within a
calcium-mimetic radionuclide, is the first radius of <0.1 mm (versus several mm for
radionuclide for bone metastases therapy beta particles), hence has only minimal
with a survival benefit when used in the haematotoxicity.
treatment of bone metastases.
Radium-223 is indicated in metastatic
prostate-cancer patients with symptomat-
ic bone metastases and no known visceral
The following constitute relative contra-
indications to the use of Ra-223 for bone-
n Karnofsky score <50% or ECOG
performance status >2
n Limited bone-marrow reserve –
absolute neutrophil count <1500/µL,
platelets <100 000/µL and haemoglobin
n F aecal incontinence
The following must be ensured before
a patient is considered for Radium-223
n Therapy indication and no contra-
indications are present
n Exclusion of visceral metastases
n Recent bone scan not older than
three months showing increased tracer
uptake at sites corresponding to region
of bone pain
n R ecent blood count not older than
The treatment is usually performed on an
outpatient basis. Hospitalisation should be
considered in patients with faecal incon-
tinence or those with severe debilitation.
The ALSYMPCA trial was a phase III,
randomised, double-blind, placebo-con-
trolled study that randomly assigned 921
patients in a 2:1 ratio to receive six injec-
tions of Radium-223 or matching placebo.
There was a 14.9 months survival benefit
in the Radium-223 group, compared to
HANDBOOK OF ONCOLOGY
Recent Advances in Targeted Radionuclide Therapy of Cancers 29
the placebo group. Radium-223 compared radio-immunotherapy agent and is indi- TREATMENT APPROACHES
with placebo significantly prolonged time cated in patients with rituximab-relapsed
to first symptomatic SRE.12 or -refractory CD20+ follicular non-Hodg-
kin’s lymphoma. It may be used as a first-
The most frequent side effects of Ra- line agent in other CD20+ B-cell lympho-
dium-223 therapy are diarrhoea, nausea, mas.
vomiting and thrombocytopaenia. Prior
use of chemotherapy or external beam Contra-indications include:
radiotherapy is associated with a higher n P regnancy and continuing
risk of haematotoxicity.13
Bisphosphonates are bone-seeking n K nown hypersensitivity to any
agents that inhibit bone-resorbing action
of osteoclasts. They are commonly used component of the therapy agent
in the treatment of bone metastases. Bi- n Patients <18 years old
sphosphonates have been successfully n Poor bone-marrow reserve, WBC <1500/
labelled to diagnostic and therapeutic
radionuclides for theranostics of bone me- µl, platelets <100 000/µL
tastases. Of all the radio-labelled bispho- n >25% bone-marrow infiltration by
sphonates, zoledronate appears to have
the greatest promise for widespread clini- lymphoma cells on bone-marrow
cal application due to its high uptake in biopsy
bone lesions.14 n Previous bone-marrow or stem-cell
RADIOIMMUNOTHERAPY OF B-CELL
NON-HODGKIN’S LYMPHOMA The following must be ensured
before a patient is considered for
B-cell lymphomas are classified as either radio-immunotherapy:
aggressive or indolent. Diffuse large B-cell n C D20 positivity on
lymphoma typifies aggressive type and
responds favourably to chemotherapy. immunohistochemical staining
Indolent B-cell lymphoma has a poorer re- n Check for correct indication and for
sponse to chemotherapy, often relapses
and may become refractory to re-treat- absence of any contra-indication
ment. Most B-cell lymphomas overexpress n Life expectancy greater than three
CD20 on the tumour-cell membrane.
Rituximab is a monoclonal antibody months, Karnofsky index >70%
(MAbs) against CD20. Treatment of CD20-
expressing B-cell lymphoma with rituximab Pre-therapy imaging with Indium-111 ibri-
leads to a modest response rate. Radio- tumomab to demonstrate bio-distribution
immunotherapy of B-cell lymphoma in- of the agent, which used to be manda-
volves complexing of a therapy radionu- tory, is no longer mandatory prior to insti-
clide to a monoclonal antibody against tution of therapy with Zevalin. Zevalin is
CD20. Binding of a monoclonal antibody administered as an intravenous infusion
to CD20 causes tumour-cell killing via dif- after infusion of cold rituximab to block
ferent immunological mechanisms, in- CD20 expressed of normal circulating B-
cluding apoptosis, antibody-dependent cells and in the spleen. Zevalin is a pure
cell-mediated cytotoxicity and com- beta-emitting radionuclide and its admin-
plement-dependent cytotoxicity. When istration does not expose caregivers to sig-
MAbs are labelled with a therapeutic ra- nificant radiation.
dionuclide, a combination of immunologi-
cal and radiobiological cytotoxicity leads The commonest immediate side effects
to better tumour-killing than either alone. of Zevalin infusion include asthenia, nau-
sea, chills and fever.
Y-90 ibritumomab tiuxetan (Zevalin) is
presently the only commercially available The superiority of Zevalin over cold rituxi-
mab was demonstrated in a phase III trial
that randomised 143 patients with relapsed
or refractory low-grade follicular lympho-
ma or transformed CD20+, transformed
non-Hodgkin’s lymphoma to either receive
HANDBOOK OF ONCOLOGY
30 TREATMENT OPTIONS IN ONCOLOGY
rituximab alone or Zevalin. The overall re- 5. Ducreux M, et al. The antitumoral effect of
sponse rate was 80% for Zevalin, compared the long-acting somatostatin analog lan-
with 56% with rituximab alone.15 reotide in neuroendocrine tumors. Am J
Bone-marrow suppression is a potential
side effect of therapy with Zevalin and 6. Pavel ME, et al. Everolimus plus octreotide
this may persist for up to 12 weeks post- long-acting repeatable for the treatment
treatment. Patients should therefore be of advanced neuroendocrine tumors as-
followed-up with weekly full blood count sociated with carcinoid syndrome (RADI-
until recovery. ANT-2): a randomized, placebo-controlled,
phase 3 study. Lancet. 2014;378:2005-2012.
7. Bodei L, et al. Long-term tolerability of
Nuclear medicine is in a prime position PRRT in 807 patients with neuroendocrine
to utilise personalised care in cancer tumours: the value and limitations of clini-
management. Targeted therapy ensures cal factors. Eur J Nucl Med Mol Imaging.
that a disease is seen, and a determina- 2015;42:5-19.
tion is made as to whether the disease
will respond to therapy; only then is tar- 8. Sathekge M, et al. 213Bi-PSMA-617 targeted
geted radionuclide therapy embarked alpha-radionuclide therapy in metastatic
upon. This ensures that treatment is only castration-resistant prostate cancer. Eur J
offered to patients who will benefit from Nucl Med Mol Imaging. 2017;44:1099-1100.
it, prevents unnecessary adverse effects
and saves cost. The spectrum of cancers 9. Rahbar K, et al. German multicenter study
that can be treated with this technique is investigating 177Lu-PSMA-617 radioligand
widening, with an increasing number of therapy in advanced prostate cancer pa-
biological targets with potential for use tients. J Nucl Med. 2017;58:85-90.
in developing therapeutic radiopharma-
ceuticals for treatment. 10. Fendler WP, et al. 177Lu-PSMA radioligand
therapy for prostate cancer. J Nucl Med.
1. Jadvar H. Targeted radionuclide therapy: 11. Kratochwil C, et al. 225Ac-PSMA-617 for
an evolution toward precision cancer PSMA-targeted alpha-radiation therapy
treatment. AJR. 2017;209:277-288. of metastatic castration-resistant prostate
cancer. J Nucl Med. 2016;57:1941-1944.
2. Lawal I, et al. Gallium-68-dotatate PET/CT is
better than CT in the management of soma- 12. Parker C, et al. Alph emitter radium-223
tostatin expressing tumors: first experience in and survival in metastatic prostate cancer.
Africa. Hell J Nucl Med. 2017;20:128-133. N Engl J Med. 2013;369:213-223.
3. Strosberg J, et al. Phase 3 Trial of 177Lu-Dota- 13. Poeppel TD, et al. EANM guideline for radi-
tate for midgut neuroendocrine tumors. N onuclide therapy with radium-223 of meta-
Engl J Med. 2017;376:125-135. static castration-resistant prostate cancer.
Eur J Nucl Med Mol Imaging. Epub ahead
4. Janson ET, Oberg K. Long-term manage- of print on December 12, 2017. doi:10.1007/
ment of the carcinoid syndrome: treat- s00259-017-3900-4.
ment with octreotide alone and in combi-
nation with alpha-interferon. Acta Oncol. 14. Pfannkuchen N, et al. Novel radiolabeled
1993;32:225-229. bisphosphonates for PET diagnosis and
endoradiotherapy of bone metastases.
Pharmaceuticals. 2017;10:45. Doi: 10.3390/
15. Witzig TE, et al. Randomized controlled trial
of rituximab immunotherapy for patients
with relapsed or refractory low-grade, fol-
licular, or transformed B-cell non-Hodgkin’s
lymphoma. J Clin Oncol. 2002;20:2453-2463.
HANDBOOK OF ONCOLOGY
32 SOLID TUMOURS
Lung Cancer patients between the ages of 55-74 years,
±30 pack-year history and smoking ces-
Dr S Dalvie sation less than 15 years ago. Patients
are screened with low-dose computed
MBCHB, FC(RadOnc) tomography (CT) scans for two years. An-
Specialist, Departments of Radiation nual CT-scans may be considered until the
Medicine and Radiation Oncology, level of risk reduces. There is no benefit to
Groote Schuur Hospital and University of screening with chest x-rays.2
Cape Town, Department of Radiation
Oncology, Groote Schuur Hospital PATHOLOGY AND MOLECULAR
Carcinoma of the lung is responsible for
more deaths than any other cancer. Lung Lung cancer is divided into two broad
cancer is the cause of death of approxi- histological groups, namely non-small-
mately 18% of all cancer patients. The cell and small-cell lung cancer (SCLC).
global incidence rates mirror the smoking The histological diagnosis is non-small-cell
prevalence rates. The estimated overall lung cancer (NSCLC) in 85% of cases, and
incidence rate for southern Africa is 189.6 these are classified further as adenocar-
per 100 000 population.1 The estimated cinoma, squamous-cell carcinoma, and
overall mortality rate for southern Africa is large-cell carcinoma. SCLC occurs in 15%
133.2 per 100 000 population.1 of cases. These types of cancer have dif-
ferent pathophysiologies and responses to
Early stages of the disease are potentially treatment and are discussed separately.3
curable, but most patients are diagnosed
with advanced disease. A contributing There are many genetic mutations in
factor is the non-specificity of presenting patients with lung cancer. The epidermal
symptoms, resulting in a delay in diagnosis. growth factor receptor (EGFR) and the
Additionally, symptoms may only be expe- anaplastic lymphoma kinase (ALK) gene
rienced at an advanced stage of disease. mutations predict response to therapy (dis-
Further factors are the high prevalence cussed later). The EGFR and the ALK are
and incidence rates of tuberculosis (TB) in transmembrane receptors. When a ligand
South Africa. binds, signal transduction cascade results,
which causes cellular proliferation and oth-
The most significant factor in the aetiolo- er hallmarks of malignancy. Tyrosine kinase
gy of lung cancer is smoking. Cancer of the inhibitors (TKIs) inhibit this pathway.3
lung can be related to smoking (present or
past) in 85% of cases. In 5% of cases, cancer Tumour cells also express the pro-
of the lung can be related to passive smok- grammed death ligand (PDL1). PDL1
ing, i.e., exposure to others who smoke. As- binds to the programmed death protein
bestos or radon exposure may also cause (PD1) on the patient’s T-cells. This bond in-
lung cancer. Lung cancers may also de- hibits the immune function of the patient,
velop secondary to radiation therapy to promoting tumour growth. Immune ther-
the chest, for example in lymphoma and apy includes antibodies against either
breast-cancer survivors. Epidemiological PD1 or PDL1.4
studies document an increased incidence
of lung cancer in patients who have been DIAGNOSIS AND PRE-TREATMENT
previously diagnosed with tuberculosis (TB). EVALUATION
Non-smokers most frequently develop ad-
enocarcinoma. Patients with lung cancer usually have a
mass on chest radiograph. A tissue diag-
The most important intervention in re- nosis is mandatory. Fine-needle aspira-
ducing mortality is smoking-cessation tion and biopsy can be accomplished
programmes. Screening for lung can- under CT-guidance or at bronchoscopy,
cer in high-risk patients has been shown
to reduce mortality. High-risk factors are
HANDBOOK OF ONCOLOGY
For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority.
S4 CIPLA DOCETAXEL 20 (Solution for infusion). Each single-dose vial contains docetaxel trihydrate equivalent to 20 mg docetaxel (anhydrous)
in 0,5 ml polysorbate 80. Inactive ingredients include anhydrous citric acid and polysorbate 80. Reg. No.: 41/26/0162.
Pharmacological classification: A 26 Cytostatic agents.
S4 CIPLA DOCETAXEL 80 (Solution for infusion). Each single-dose vial contains docetaxel trihydrate equivalent to 80 mg docetaxel (anhydrous)
in 2,0 ml polysorbate 80. Inactive ingredients include anhydrous citric acid and polysorbate 80. Reg. No.: 41/26/0163.
Pharmacological classification: A.26 Cytostatic agents.
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Reg. No.: A40/26/0609, 10, 11. Pharmacological classification: A 26 Cytostatic agents.
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Reg. No.: 43/26/1171. Pharmacological classification: A 26 Cytostatic agents.
S4 CIPLA-VINORELBINE 10 / 50 (Intravenous injection). Each single dose vial contains 13,85 mg / 69,25 mg of vinorelbine tartrate which is
equivalent to 10 mg / 50 mg of vinorelbine base per millilitre / 5 millilitres of solution. Reg. No.: 42/26/0083, 84.
Pharmacological classification: A 26 Cytostatic agents.
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Pharmacological classification: A 26 Cytostatic agents.
S4 VINBLASTINE TEVA 10. Each vial contains vinblastine sulphate 1 mg/ml. Reg. No.: 45/26/0373.
Pharmacological classification: A 26 Cytostatic agents.
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34 SOLID TUMOURS
dependent on the anatomical location of STAGING
the tumour. The tissue obtained would be
tested for genetic mutations. The stage of the disease determines the
A CT-scan of the chest and upper abdo- prognosis and the intent of treatment.
men is indicated to evaluate the extent Staging was revised in 2016.
of disease. A bone scan is indicated for
patients with bone pain and an elevated Stages 1,2 and selected stage 3 are usu-
alkaline phosphatase. ally treated with curative intent. Crude
five-year survival rates range from 90% for
Positron emission tomography (PET) is stage 1 to 0% for stage 4 patients.6
an important investigation in selected pa-
tients. It is used to detect occult metasta- STAGE I
ses in patients who have potentially cur-
able disease. However, it can be falsely Stage 1 includes patients with operable
positive from inflammatory conditions or primary tumours of less than or equal to
diseases (e.g., TB and autoimmune diseas- 4 cm in size and no nodal involvement.
es). The findings need to be confirmed his-
tologically. It can also be falsely negative The cornerstone of treatment is sur-
in diseases with a low metabolic activity, gery, most often a lobectomy as this has
e.g., minimally invasive adenocarcinoma. a lower morbidity and mortality than a
pneumonectomy (4% versus 9%). Patients
The gold standard for sampling en- with minimally-invasive adenocarcinoma
larged or FDG-avid lymph nodes is a me- may be treated by focal excision. These
diastinoscopy. This confirms that the nodes tumours spread along the airways rather
are large because of metastatic lung than through the lymphatics.
cancer. Endobronchial and endoscopic
ultrasound-guided biopsies are alterna- Patients who are medically inoperable
tive procedures. These procedures are less may be treated by high-dose external-
invasive, and can be done in-office. Hilar beam radiation. This would comprise the
lymph nodes can also be sampled. daily course of external-beam irradiation
to more than 60 Gray. Whole-body stereo-
The forced expiratory volume in one taxis with high-ablatant doses of irradia-
second (FEV1) is used to assess the pa- tion given in a few sessions is the preferred
tient’s ability to tolerate surgery. The post- therapy. Control rates at two years of
operative predicted FEV1 needs to be more than 90% are being reported.7
more than 800 ml. The carbon monoxide-
diffusing capacity is the best test to evalu- Patients with the resected stage I dis-
ate the patient’s ability to tolerate chest ease are at risk of developing a second
irradiation.5 lung cancer. This risk increases if the pa-
tient continues smoking. 8
The performance status (PS) of patients
is the most important prognostic factor in STAGE II
lung cancer and informs treatment.
Stage II includes patients with potentially
Patients are assessed in terms of the World operable tumours that are more than
Health Organization (WHO) scale: 4 cm with or without involvement of the
n PS 0 – active and asymptomatic hilar nodes.
patient Surgery, as described above, remains
n PS 1 – symptomatic, still active the cornerstone of treatment for patients
n P S 2 – in bed less than half of the day in this stage. Patients who have chest-wall
n P S 3 – in bed more than half of the day involvement should be considered for
n PS 4 – bedridden chest-wall resection.
Patients who have a performance status Adjuvant chemotherapy increases the
of 3 or more are generally not candidates survival rate in this group of patients by
for curative treatment. 5% at five years.9 Patients with stage II and
stage IIIA disease derive maximal benefit.10
HANDBOOK OF ONCOLOGY The agents most consistently used in trials
for adjuvant chemotherapy are one of the
platinums and vinorelbine. Carboplatin is
Lung Cancer 35
frequently used in the palliative setting in Chemotherapy has a documented sur- TREATMENT APPROACHES
patients with lung cancer because of its vival benefit in patients with PS of 0-1.13
tolerability. Data are available for the use Standard chemotherapy is the platinum-
of cisplatin in the adjuvant setting. based doublet in which the agent used
with one of the platinums are vinorelbine,
STAGE IIIA AND IIIB gemcitabine, paclitaxel, docetaxel or
Stage III consists of patients with locally ad- pemetrexed.
vanced disease. Tumours are of all dimen-
sions with spread to mediastinal nodes. Histology is a predictive factor. Pem-
Tumours are greater than 5 cm with any etrexed is more effective in patients with
nodal involvement or more than 7 cm with adenocarcinoma, due to higher thymi-
or without nodal involvement. dylate synthase levels in squamous cell
The cornerstone of treatment for these cancers.14 There is no survival advantage;
patients is combined radiotherapy and only increased toxicity from administering
chemotherapy. Randomised studies show more than four to six cycles of chemother-
an improvement in survival with concur- apy. This contrasts with biological and im-
rent chemotherapy plus radiation thera- mune therapy, which are given for as long
py versus radiation therapy alone or ra- as the patient is responding to treatment.
diotherapy followed by chemotherapy. Therapy may be discontinued in the event
There is, however, an increase in severe of unacceptable toxicity.
oesophagitis in patients receiving concur-
rent treatment. Patients with good PS (0-2) FIRST-LINE THERAPY
are best so treated.11 WITH BIOLOGICAL AGENTS
Surgery has not been found to be ben- Tyrosine kinase inhibitors (TKIs)
eficial in patients with non-bulky disease. Examples are erlotinib and gefitinib. Lung
Patients have been randomised to re- cancers that are EGFR receptor mutation-
ceive either concurrent chemoradiation positive will respond to these agents.15
followed by either surgical resection or The TKIs are taken by mouth daily. Their
continuation of radiation therapy, but no most frequent toxicities are rash and diar-
significant difference in overall survival rhoea.16 A study was undertaken in East
was found. However, there were greater Asia where non-smokers or former light
treatment-related mortalities in the sur- smokers with advanced adenocarcino-
gery arm compared to the chemoradia- ma were randomised to either gefitinib or
tion-alone arm (8% versus 2%), particularly doublet chemotherapy as first-line thera-
for patients undergoing a pneumonec- py. Among those patients whose tumours
tomy.12 harboured EGFR mutations, progression-
free survival was significantly longer with
STAGE IV gefitinib. Gefitinib was also associated
The tumour has spread to the contralat- with a better QoL. In the mutation-nega-
eral lung, or the patient has a malignant tive group, gefitinib resulted in significantly
pleural or pericardial effusion. This stage shorter progression-free survival.17
includes tumours which have spread out-
side of the thorax. When the tumour receptor status is un-
known, chemotherapy remains first-line
Vascular endothelial growth factor
Chemotherapy results in an increase in
survival and quality of life (QoL) in select- receptor (VEGFR)
ed patients with metastatic NSCLC. The Bevacizumab is an antibody to the ligand
one-year-survival rate increases from 10% of the VEGFR. It is not used in patients with
to 30-35%. The median survival increases squamous carcinoma because of con-
from eight to 10 months. cerns about increased haemorrhage.
A randomised study evaluated the ad-
dition of bevacizumab to carboplatin
HANDBOOK OF ONCOLOGY
36 SOLID TUMOURS
and paclitaxel. Bevacizumab was admin- importance of EGFR gene mutation has
istered every three weeks with chemo- subsequently been recognised.22
therapy and subsequently without for one
year until progression of disease. There SMALL-CELL LUNG CARCINOMA
was a significant increase in median sur-
vival from 10.3 months to 12.3 months. A Small-cell lung carcinoma comprises
marginal increase in progression-free sur- about 15% of all lung cancers. It is strongly
vival has been reported when bevaci- related to smoking. It has neuro-endocrine
zumab is administered with cisplatin and differentiation and is more commonly as-
gemcitabine.18 sociated with paraneoplastic syndromes.
It is a rapidly growing tumour and metas-
FIRST-LINE THERAPY tasises early. All patients are considered
WITH BIOLOGICAL AGENTS to have micro metastases. Untreated, the
median survival of patients will be approxi-
PD1 and PDL1 inhibitors mately three months. However, it is sensi-
Pembrolizimab and nivolumab are exam- tive to chemotherapy, which prolongs sur-
ples of these drugs. They can be consid- vival and improves patients’ performance
ered for tumours that do not have any of status (PS). Patients are rarely cured.
the mutations mentioned previously. These
drugs are active in the first-line setting in tu- STAGING AND EVALUATION
mours which express PDL1. Preliminary data The 2016 TNM staging system is used. Pa-
show an increase in progression-free surviv- tients with SCLC can also be staged using
al and overall survival, when compared to a binary staging system, i.e. as having lo-
standard chemotherapy.19 Immune-relat- calised or extensive disease (LD and ED).
ed side effects are the common toxicities. LD can be treated within one radiation
These can occur after cessation of therapy. port. This includes the hemi-thorax and re-
High-dose steroids may be required to con- gional nodes, as well as mediastinal and
trol these side effects. Immunosuppressive ipsilateral supraclavicular nodes.
therapy is an option in severe cases. Exam-
ples are cutaneous vitiligo, lichen planus, Pre-treatment evaluation includes a
colitis, hepatitis and nephritis.20 complete blood-cell count; liver-function
tests, CT of the chest and abdomen and a
SECOND-LINE THERAPY bone scan. PET-CT scans may have a role
n Docetaxel, has shown significantly in evaluating patients with limited disease.
improved survival and QoL, when CHEMOTHERAPY
compared to best supportive care All patients with SCLC may be consid-
in patients who have failed first-line ered for chemotherapy, irrespective of
therapy. PS, unlike patients with NSCLC where
n P emetrexed has an antitumour activity chemotherapy is restricted to patients
similar to docetaxel as a second- with good PS.
line therapy. The response rates for
both agents are just under 10% and A platinum combined with etoposide
the median survival around eight is most frequently used nowadays. Cispl-
months. Pemetrexed has less toxicity atin is the platinum of choice in patients
with lower rates of neutropaenia and with LD who are candidates for concur-
neutropaenic sepsis.21 rent chemotherapy and irradiation to the
n Erlotinib has been evaluated as a chest. Patients who cannot tolerate a
second-line therapy in patients who platinum agent may be treated with the
had not undergone EGFR gene- CAV regimen (cyclophosphamide, doxo-
mutation analysis. There was a rubicin, vincristine). This regimen was previ-
statistical increase in response rates ously used as standard therapy.
(9% versus 1%) and survival (6.7 months
versus 4.7 months) in these patients. The Patients receive between four to six cy-
cles of treatment. There is no gain in increas-
HANDBOOK OF ONCOLOGY ing the dose intensity of chemotherapy
Lung Cancer 37
or adding additional cycles of chemo- 5. Abratt RP, Morgan GM, Silvestri G, et al. Pul- TREATMENT APPROACHES
therapy. monary complications of radiation therapy.
Clinics In Chest Med. 2004;25:165-175.
The overall response rate in patients with
LD and ED is approximately 75% and 50%, 6. Rami-Porta Asamura, H, Travis WD. Cancer
the complete response rate is 50% and Staging Manual. 8th ed. New York: Springer
20% and the median survival is 16 and nine International Publishing; 2016.
7. Nyman J, et al. SPACE – a randomized
Patients will almost always relapse. Such study of SBRT vs conventional fractionat-
patients may be retreated with the origi- ed radiotherapy in medically inoperable
nal regimen if they have been off treat- stage INSCLC. Radiotherapy and Oncol-
ment for three months. Alternatively, they ogy. 2016;121(1):1-8.
may be treated with a regimen to which
the patient has not been exposed, e.g., 8. Taiol E, et al. Second primary lung cancers
CAV. Single-agent topotecan may also demonstrate better survival with surgery
be used with a response rate of approxi- than radiation seminars. Thoracic Surgery.
mately 30%. 2016;28:195-200.
CHEMOTHERAPY AND IRRADIATION 9. Arriagada R, et al. Cisplatin-based adju-
There is a small but significant improve- vant chemotherapy in patients with com-
ment in survival in patients who receive pletely resected non-small-cell lung can-
concurrent chest irradiation, although cer. N Engl J Med. 2004;350:351-360.
this results in an increase in oesophagitis.
It should therefore be administered to LD 10. Strauss GM, et al. Adjuvant paclitaxel plus
patients with good PS. carboplatin compared with observation in
stage IB non-small-cell lung cancer: CALGB
SCLC is associated with a high incidence 9633 with the Cancer and Leukemia Group
of brain metastases. Prophylactic cranial B, Radiation Therapy Oncology Group, and
irradiation decreases this relapse rate and North Central Cancer Treatment Group Study
increases the three-year survival rate by Groups. J Clin Oncol. 2008;26:5043-5051.
5%. It is indicated for good PS in patients
who achieve a complete response to 11. Furuse K, et al. Phase III study of concurrent
chemotherapy.23 versus sequential thoracic radiotherapy
in combination with mitomycin, vindes-
REFERRAL ine, and cisplatin in unresectable stage III
non-small cell lung cancer. J Clin Oncol.
Patients who present with oncological 1999;17;2692-2699.
emergencies such as superior mediastinal
syndrome, febrile neutropaenia and spi- 12. Albain KS, et al. Radiotherapy plus chemo-
nal cord compression require urgent refer- therapy with or without surgical resection
ral. The severe toxicities of therapy should for stage III non-small-cell lung cancer: a
be managed by an oncologist. phase III randomised controlled trial. Lan-
13. Schiller JH, et al. Comparison of four
1. Jemal A, et al. Global cancer statistics. CA chemotherapy regimens for advanced
Cancer J Clin. 2011;61:69-90. non-small cell lung cancer. N Engl J Med.
2. National Lung Screening Trial Research
Team. Reduced lung-cancer mortality with 14 Scagliotti GV, et al. Phase III study compar-
low-dose computed tomographic screen- ing cisplatin plus gemcitabine with cisplatin
ing. New England Journal of Medicine. plus pemetrexed in chemotherapy-naive
2011;365:395-409. patients with advanced-stage non-small-
cell lung cancer. J Clin Oncol. 2008;
3 Ryan C, Burke L. Pathology of lung tumours. 26:3543-3551.
Surgery (Oxford). 2017 May:35:234-242.
15. Tsao MS, et al. Erlotinib in lung cancer –
4 Chen, Y-M. Immune checkpoint inhibitors molecular and clinical predictors of out-
for non-small cell lung cancer treatment. come. N Engl J Med. 2005; 353:133-144.
Journal of the Chinese Medical Associa-
tion. 2017;80:7-14. 16. Ding PN, et al. Risk of treatment-related tox-
icities from EGFR tyrosine kinase inhibitors:
a meta-analysis of clinical trials of gefitinib,
erlotinib, and afatinib in advanced EGFR-
mutated non-small cell lung cancer. Journal
of Thoracic Oncology. 2017;12(4):633-43.
17. Mok TS, et al. Gefitinib or carboplatin-
paclitaxel in pulmonary adenocarcinoma.
N Engl J Med. 2009; 361:947-957.
HANDBOOK OF ONCOLOGY
38 SOLID TUMOURS
18. Sandler A, et al. Paclitaxel-carboplatin of pemetrexed versus docetaxel in patients
alone or with bevacizumab for non-small- with non-small-cell lung cancer previously
cell lung cancer. N Engl J Med. 2006; treated with chemotherapy. J Clin Oncol.
355:2542-2550. 2004; 22:1589-1597.
22. Shepherd FA, et al. Erlotinib in previously
19. Peters S, Kerr KM, Stahel R. PD-1 blockade treated non-small-cell lung cancer. N Engl
in advanced NSCLC: a focus on pembroli- J Med. 2005;353:123-132.
zumab. Cancer Treatment Reviews. 2018 23. Waqar SN, Morgensztern D. Treatment ad-
January;62:39-49. vances in small cell lung cancer (SCLC)
Pharmacology & Therapeutics. St Louis:
20. Hofmann L, et al. Cutaneous, gastrointes- Washington University School of Medicine;
tinal, hepatic, endocrine, and renal side- 2017.
effects of anti-PD-1 therapy. European
Journal of Cancer. 2016;60:190-209.
21. Hanna N, et al. Randomised phase III trial
HANDBOOK OF ONCOLOGY
Colorectal Cancer 39
Colorectal Cancer TREATMENT APPROACHES
Dr B Robertson for colonoscopy with the expected mor-
tality from colorectal cancer according
MBChB FC Rad Onc to the surveillance epidemiology and
Specialist, Department of Radiation end-results programme (SEER) showed
Oncology, Groote Schuur Hospital a significant decrease in mortality in the
patients who had adenomas removed at
Colorectal cancer is a common disease, colonoscopy.2 Sigmoidoscopy alone has
with approximately 1 360 000 new cas- also been shown to decrease mortality
es worldwide in 2012. According to the from colorectal cancer.3 Further effective
South African National Cancer Registry screening methods include faecal occult
of 2013, it is the second most common blood-testing followed by colonoscopy
cancer in men and the third most com- if the test is positive. The faecal immuno-
mon in women, excluding skin cancers.1 chemical test (FIT), either alone or com-
The incidence increases with age, with bined with stool DNA, has a high sensitiv-
the highest number of cases reported in ity for detecting colorectal cancer, but
South Africa between 65 and 69 years of there are no studies to show the effect
age. Approximately 35-40% of patients on mortality. The advantage of FIT is that
presenting with colorectal cancer will die it does not require the dietary restrictions
from the disease. necessary for accurate interpretation of
faecal occult blood tests. Computed to-
The majority of cases of colorectal can- mographic (CT) colonography can also
cer are sporadic, with only 20% of cases detect polyps, which would then require
being attributable to familial disease. The colonoscopy for removal, but has the risks
two most common inherited conditions associated with exposure to radiation. A
are familial adenomatous polyposis (FAP) recent review recommends screening for
and hereditary non-polyposis colorectal the average-risk population should start at
cancer (HNPCC) or Lynch syndrome. Pa- the age of 50 years and stop at 85 years.4
tients with FAP develop thousands of co- The screening method should be that with
lonic polyps which will eventually become which the patient is most likely to comply.
carcinomas. Lynch syndrome occurs with For patients at higher risk, i.e., those with a
mismatch repair gene defects and these family history, previous colorectal cancer,
patients are at a high risk not only for colo- inflammatory bowel disease or one of the
rectal cancer, but also for cancers of the inherited syndromes, screening should be-
uterus, ovary, renal tract, stomach, small gin at a younger age and take place at
bowel and hepatobiliary system. Factors more frequent intervals.
that predispose patients to developing
sporadic colorectal cancer are numer- DIAGNOSIS AND STAGING
ous and include inflammatory bowel dis-
ease and lifestyle diseases such as obesity, Presenting symptoms of colorectal cancer
smoking and alcohol consumption. include changes in bowel habit, haema-
tochaezia, symptoms of anaemia and
SCREENING abdominal pain. Patients presenting with
these symptoms should be referred for co-
Most cancers in the large bowel start as lonoscopy. More advanced disease may
adenomas, which then become dysplas- present with bowel obstruction or perfora-
tic and progress to carcinomas. This pro- tion or signs of metastatic disease such as
cess is thought to take place over five to hepatomegaly.
10 years, which implies that screening for
polyps may prevent colorectal cancer The definitive diagnosis of colorectal
and therefore deaths from the disease. A cancer is made after biopsy and histology
study comparing mortality from colorec- confirmation of either the primary site or a
tal cancer in patients who were referred
HANDBOOK OF ONCOLOGY
40 SOLID TUMOURS
metastasis. Once the diagnosis is made, features such as lymphovascular invasion
staging is essential in order to provide opti- or poor differentiation. Lesions confined to
mal treatment. Ideally, the patient should the colon in patients who have no contra-
have a full colonoscopy to exclude syn- indications to surgery should be resected
chronous lesions, however this procedure with a primary anastomosis according to
may not be possible if the lesion is ob- the blood supply and lymphatic drain-
structing the lumen. In this situation, a full age. Surgery for uncomplicated primary
colonoscopy should be performed within tumours in the colon can be performed
the first year of diagnosis. Further staging laparoscopically, allowing for shorter post-
includes a CT-scan of the chest, abdo- operative recovery time.5
men and pelvis to detect metastatic dis-
ease. For patients with a primary tumour For patients with a primary tumour in-
in the rectum, magnetic resonance im- volving the rectum, it is important to es-
aging (MRI) of the pelvis or endoscopic tablish the clinical stage prior to surgery,
ultrasound (EUS) determines local staging. using both clinical and radiological evalu-
Serum carcino-embryonic antigen levels ation. Digital rectal examination for tu-
(CEA) are useful for prognosis; in general, mours of the distal rectum can determine
elevated levels predict worse prognosis. sphincter involvement as well as possible
Positron emission tomography (PET) scans involvement of surrounding structures. MRI
are not routinely used for baseline stag- of the pelvis and transrectal ultrasound
ing. For patients with liver lesions detected (TRUS) have been shown to be accurate
on CT, MRI of the liver with gadoxetate in assessing the T stage.6 In general, MRI is
disodium (Primovist®), a liver-specific con- recommended since the entire pelvis can
trast, is useful for defining lesions as well then be visualised, as well as the relation
as detecting further lesions that may not of the tumour to the mesorectal fascia,
be visible on CT. The recommended stag- which will ideally be the circumferential re-
ing system is the tumour, node, metastasis section margin. Lymph-node involvement
(TNM) system as defined by the American is difficult to assess since even small nodes
Joint Committee on Cancer/Union for In- have been shown to contain metastases
ternational Cancer Control (AJCC/UICC), on pathology review and MRI, TRUS and
with T describing the depth of invasion, N CT seem to have equivalent accuracy for
the number of involved nodes and M the potential nodal involvement. If the primary
presence of metastases. TNM staging can tumour or a node involves, or is less than
be determined only after resection of the 1 mm from, the mesorectal fascia, neoad-
primary lesion, although it is possible to es- juvant treatment is recommended.
timate the clinical stage on imaging.
The choice of surgical procedure de-
TREATMENT OF LOCALISED DISEASE pends on sphincter involvement. In gen-
eral, if the sphincters are involved, an
Multidisciplinary team management is im- abdominoperineal resection (APR) will be
portant for patients with colorectal can- performed in which the rectum, anus and
cer, particularly those with advanced entire sphincter complex are resected
disease when the most appropriate com- and a permanent end colostomy is fash-
bination of surgery, chemotherapy or ra- ioned. If the sphincters are spared, then
diation needs to be established. an anterior resection is performed gener-
ally with a temporary covering ileostomy
SURGERY to protect the anastomosis. Standard
Surgery alone is potentially curative for of care for surgery is a total mesorectal
patients with localised early disease. Small excision, ideally performed in a high-vol-
polyps containing adenocarcinoma can ume centre, in which there is sharp dis-
be removed endoscopically and the section around the mesorectal fascia to
patient followed up as long as the mar- remove the mesorectal fat and all lymph
gin is clear and there are no concerning nodes within the mesorectum. This tech-
nique has significantly reduced the local
HANDBOOK OF ONCOLOGY
42 SOLID TUMOURS
recurrence rate from approximately 45% is currently being investigated as a treat-
to less than 10% .7 ment option. Retrospective studies have
shown that for patients who have a com-
CHEMOTHERAPY plete response to neoadjuvant chemora-
The decision for adjuvant chemotherapy diation, surgery may be avoided and this
in adenocarcinoma of the colon is based treatment option is especially attractive
on the pathological stage of the tumour. for patients requiring APR.11 At present, it
In general, stage I and II lesions that are is recommended that chemoradiation fol-
completely resected do not require adju- lowed by watchful waiting be undertaken
vant chemotherapy since the risk of recur- only in the context of a clinical trial.
rence is low. However, stage II lesions that
have high-risk features, such as T4-stage, TREATMENT OF METASTATIC
lymphovascular invasion, poor differen- DISEASE
tiation or tumours that perforate or cause
bowel obstruction, may benefit from Metastatic disease is present in about 25%
adjuvant chemotherapy, although the of patients at initial presentation and a fur-
evidence for this is limited. There is a sig- ther 25% will develop metastatic disease
nificant decrease in risk of recurrence for after treatment of the primary tumour,
patients with stage III disease who receive the most common sites being liver, perito-
adjuvant chemotherapy, the standard neum, distant nodes, lung and bone. The
regimen being a combination of intrave- prognosis of patients with metastatic dis-
nous 5-fluorouracil (5FU), leucovorin and ease has improved substantially since the
oxaliplatin or oral 5FU (capecitabine) and 1980s due to the development of surgical
oxaliplatin.8 Chemotherapy is generally techniques and new systemic agents. In
given for a period of six months and should a review of patients treated at two large
start within four to six weeks of surgery, centres in the US, the median overall sur-
although a recent pooled analysis has vival for patients with metastatic disease
shown that three months in low-risk stage increased from 14.2 months in the early
III patients may be sufficient for patients 1990s to 29.3 months for the time period
receiving the combination of 5FU and ox- between 2004 and 2006.12
aliplatin, whereas for patients receiving
5FU alone, the full six months of treatment SURGERY
should be given.9 The only potentially curative treatment
for metastatic disease involves surgery.
RADIATION Therefore it is essential that all patients
Neoadjuvant radiation has been shown with metastases who are fit for surgery be
in a number of trials to reduce local re- evaluated for possible metastatectomy,
currence in adenocarcinoma of the rec- ideally in a multidisciplinary team setting. In
tum.10 In patients with resectable tumours general, as long as 25-30% of the original
where there is a concern about local con- liver volume can be spared, in a liver with
trol, short-course radiation, i.e., 25 Grey normal function, resection of liver metasta-
(Gy) in five daily fractions with surgery the ses is possible. Limited lung metastases are
following week can be prescribed. For also potentially resectable. Local ablative
locally advanced tumours in which the techniques such as microwave and radi-
mesorectal fascia is threatened by tumour ofrequency ablation as well as stereotac-
and downstaging is required, chemora- tic body radiation can be used in patients
diation is recommended – a dose of 45 who are not surgical candidates. Metasta-
to 50.4 Gy in 25 to 28 fractions, given over ses to bone, peritoneum or distant nodes
a period of five to six weeks, with concur- are usually not considered for resection.
rent 5FU as a radiosensitisor. Surgery is then
performed six to 10 weeks later. Organ CHEMOTHERAPY
preservation with chemoradiation alone Chemotherapy can be used together
with surgery to downstage patients with
HANDBOOK OF ONCOLOGY