The words you are searching are inside this book. To get more targeted content, please make full-text search by clicking here.
Discover the best professional documents and content resources in AnyFlip Document Base.
Search
Published by tasch, 2018-07-05 10:15:27

MIMS Oncology 2018

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

Myelodysplastic Syndromes 93

Myelodysplastic Syndromes TREATMENT APPROACHES

Prof VJ Louw PREVALENCE OF DISEASE

MBChB, MMed (Int Med), FCP(SA), The prevalence of MDS in South Africa is
unknown.5 De novo MDS is a disease of the
PhD(HPE) elderly, with a slight male predominance,
 Honorary Professor, Clinical and is unusual in patients under the age
Haematology, UCT Department of of 50 years, although some rare forms
Medicine, Division of Haematology have been found in children. The me-
dian age at diagnosis is about 70 years.6
Dr E Verburgh If found in younger people, a secondary
cause needs to be excluded. In Western
MB ChB MMed FCP PhD countries, the incidence varies between
 Senior Specialist, Division of Clinical 1.2 and 4.1 per 100 000.7,8 This is probably
Haematology, UCT Department of an underestimation, as unexplained cyto-
Medicine paenias in the elderly are not always in-
vestigated with a bone marrow aspiration
Dr K Antel due to other comorbidities.

MBChB, FCP (SA), MMed (Int Med), Cert IMPACT ON SOCIETY

Clin Haem (Phys) MDS has a dramatic impact on the quality
 UCT Department of Medicine, Division of life of patients, who are often retirees,
of Haematology and are in the phase of their life where
they hoped to be enjoying the fruits of
The myelodysplastic syndromes (MDS) are their life’s labour, travelllng or playing
a group of malignant stem-cell disorders an active role in the lives of loved ones.9
that give rise to inefficient haematopoiesis Frequent doctor’s visits, hospitalisations,
which results in variable degrees of bone- symptomatic anaemia with or without the
marrow failure.1 need for red-cell and/or platelet transfu-
sion, infections, bleeding symptoms, as
This typically manifests in one or more well as the constant fear that the disease
cytopaenias and a variety of dysplastic may transform to AML, all contribute to a
changes in blood cells in the bone mar- decrease in quality of life. Previously, very
row and peripheral blood.2 This develop- few treatments were available to these
ing bone-marrow insufficiency gives rise patients. Fortunately, good progress is be-
to clinical features related to the affected ing made, but often at a high financial
cell lines, namely increased risk of infection cost to the individuals, insurers and society.
if neutropaenic, and symptomatic anae-
mia and bleeding if thrombocytopaenia.3 DIAGNOSTIC ISSUES
Anaemia is the most common manifesta-
tion, with the vast majority of patients de- The main challenge diagnostically is a
veloping anaemia and subsequent trans- lack of awareness of the disease. As a
fusion-dependence at some stage. The general rule, all patients with unexplained
greatest risk of MDS is of transformation to cytopaenia(s), where common causes
acute myeloid leukaemia (AML), which is have been excluded, should undergo an
difficult to treat, especially in a typically evaluation of a peripheral blood smear
elderly population, who often have many and a unilateral bone-marrow aspirate
comorbidities. and trephine biopsy.2,10,11 Without this, a
proper diagnosis and prognostication of
If no predisposing disorder can be found, MDS are not possible. Most patients will
it is called de novo MDS. If a patient has a
predisposing disorder, it is called second- HANDBOOK OF ONCOLOGY
ary MDS and in cases where it is thought
to be related to prior chemo- and/or ra-
diotherapy, the term therapy-related MDS
is used.4

94 BLOOD, LYMPH AND RELATED CONDITIONS

present with anaemia only, which is usu- haemoglobinuria (PNH), aplastic anae-
ally macrocytic, but often normocytic, mia, myeloproliferative neoplasms, and
while the presence of neutropaenia and so on). Whether the presence of autoim-
thrombocytopaenia is more variable. mune disorders seen in association with
About 50% of patients will present with a MDS, is causal or not is less clear. Depend-
pancytopaenia (leukopaenia, anaemia ing on the nature of the stem-cell muta-
and thrombocytopaenia). An isolated tion, different cell lines may be variably
thrombocytopaenia or neutropaenia is affected, with a variable risk of progres-
seen in less than 5% of patients. In some sion to AML. Other factors, such as comor-
rarer subsets, patients may present with a bidities, transfusion needs, the degree of
thrombocytosis. Once suspected, it is best anaemia, transfusion-related iron over-
to involve a clinical haematologist or hae- load and its complications, may impact
matopathologist to assist with further inves- negatively on disease progression, bone-
tigations on the bone marrow, as there are marrow function and overall survival.
a number of critical cytogenetic tests (e.g.,
karyotyping, fluorescent in situ hybridisation TREATMENT OF MDS
(FISH)) and sometimes others that need to
be done upfront to avoid having to repeat Treatment of MDS is based on the subtype of
the bone-marrow test. The results of these MDS, patient-related factors (e.g., age, per-
tests form a critical component of the prog- formance status, patient preferences and
nostic scoring systems used to estimate the comorbidities), and predictive factors for
level of risk for transformation to AML, a fac- treatment outcome (e.g., classification of an
tor which will have a major impact on the individual patient as lower or higher risk).
treatment choice for an individual patient.
Investigation for the more common cy- Roughly one-third of patients have a
togenetic abnormalities with karyotyping stable, non-progressive course; one-third
or FISH has become routine for diagnosis will die from cytopenic complications
and prognostication, while screening for (e.g., bleeding or infections) and one-third
the now more than 100 known mutations will die from AML.11 A range of prognostic
with novel molecular methodologies, (e.g., scoring systems has been described over
next-generation sequencing) is not yet the years, with continuous refinement as
widely available. our understanding of the prognostic im-
pact of certain clinical and pathological
PATHOPHYSIOLOGY features has grown. The most widely used
prognostic scoring system used at pre-
The pathophysiology of MDS is incom- sent is the Revised International Prognos-
pletely understood and is made more dif- tic Scoring System (IPSS-R) (see Table 1).12
ficult due to the large range of mutations Very-low- and low-risk patients are usu-
found. MDS is caused by a stepwise ac- ally classified and treated as lower-risk
cumulation of mutations in a haematopoi- patients, while high- and very-high-risk
etic progenitor cell, which leads to the patients are considered higher-risk and
formation of a malignant clone. It is con- treated as such. Patients who fall in the
sidered and classified as a malignancy. intermediate category can be treated as
These may occur de novo with ageing, either lower or higher risk, depending on a
or may be secondary to exposure to cer- range of individual factors. Survival varies
tain environmental factors (e.g., tobacco, from weeks to several years, depending
benzene, chemotherapy, radiation [acci- on the risk group.
dental or therapeutic], and so on). Some
patients have an underlying predisposing The goal of treatment in patients with
condition, such as a congenital genetic lower-risk MDS is to improve symptoms
disorder (e.g., Fanconi anaemia, Down’s related to anaemia and other cytopae-
syndrome, Bloom’s syndrome, and so on) nias, improve quality of life and improve
or another predisposing haematologi- haematology, while the goal of therapy in
cal disorder (e.g., paroxysmal nocturnal higher-risk disease is to either modify the
natural history of the disease by delaying
HANDBOOK OF ONCOLOGY disease progression and improving survival

Myelodysplastic Syndromes 95

or to completely alter the natural history of [G-CSF]), immune-suppressive treatments TREATMENT APPROACHES
disease with a bone-marrow or stem-cell and immunomodulatory agents (e.g., le-
transplantation.5 nalidomide).5 In patients with higher-risk
disease, demethylating agents (e.g., aza-
In lower-risk disease, treatment options cytidine, decitabine), intensive chemo-
include growth factors (e.g., erythropoie- therapy and stem-cell transplantation
tin, granulocyte colony-stimulating factors

Table 1. Revised international prognostic scoring system (IPSS-R) in myelodysplastic syndrome

Prognostic variable Score

0 0.5 1.0 1.5 2.0 3.0 4.0

Cytogenetics* Very   Good   Intermediate Poor Very
good poor

Bone-marrow blast ≤2   >2 to <5   5 to 10 >10  
(percent)

Haemoglobin (g/dL) ≥10   8 to <10 <8     

Platelets (cells/microL) ≥100 50 to <50      
100

Absolute neutrophil ≥0.8 <0.8        
count (cells/microL)

This scoring system was applied to an initial group of 7012 patients with primary MDS by
the French-American-British classification who had at least two months of stable blood
counts, ≤30 percent bone-marrow blasts and ≤19 percent peripheral blood blasts, and
who were observed until progression to AML transformation or death (did not receive
disease-modifying agents for MDS). Patients could be stratified into five groups with the
following estimated overall survival and progression to AML.

Risk group IPSS-R score Median overall Median time to
survival (years) 25 percent AML
evolution (years)

Very low ≤1.5 8.8 >14.5

Low >1.5 to 3.0 5.3 10.8

Intermediate >3 to 4.5 3.0 3.2

High >4.5 to 6 1.6 1.4

Very high >6 0.8 0.7

The prognostic value of the IPSS-R was validated in an external cohort of 200 patients
with MDS

AML: acute myeloid leukaemia; MDS: myelodysplastic syndrome. *Cytogenetic definitions:
Very good: -Y, del(11q).Good: Normal, del(5q), del(12p), del(20q), double including del(5q).
Intermediate: del(7q), +8, +19, i(17q), any other single, double not including del(5q) or -7/del(7q),
or independent clones. Poor: -7, inv(3)/t(3q)/del(3q), double including -7/del(7q), complex: 3
abnormalities. Very poor: Complex: >3 abnormalities.

Source: This research was originally published in Blood. Greenberg PL, Tuechler H, Schanz J, et al. Revised
International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood 2012. Copyright © 2012 the
American Society of Hematology. Graphic 85832 Version 2.0

HANDBOOK OF ONCOLOGY

96 BLOOD, LYMPH AND RELATED CONDITIONS

are options. Clinical trials should be con- 2. Verburgh, et al. A new disease categori-
sidered in all patients where available, as
there are no curative options as yet, apart zation of low-grade myelodysplastic syn-
from stem-cell transplantation. Despite
recent advances in stem-cell transplanta- dromes based on the expression of cytope-
tion, this remains an option for a minority
of patients, due to the frequent presence nia and dysplasia in one versus more than
of multiple comorbidities, the scarcity of
matched donors and limitations in perfor- one lineage improves on the WHO classi-
mance status.5
fication. Leukemia. 2007 Apr;21(4):668-77.
All patients require supportive care,
which may include psychosocial support, Epub 2007 Feb 15.
clinical and haematological monitoring
for disease deterioration or progression, 3. Louw, VJ. Myelodysplastic syndromes.
quality-of-life assessment, transfusion, iron
chelation therapy (in transfusional iron Tropical Hemato-Oncology. 1st ed. Charn:
overload), antibiotics for infections and
cytokines (e.g., erythropoietin, G-CSF, Springer International AG; 2015: 269-277.
etc.). Thrombopoietin-receptor agonists 4. Wong TN, et al. Role of TP53 mutations in
and similar agents are under active inves-
tigation for the management of clinically the origin and evolution of therapy-related
significant thrombocytopaenia. Iron che- acute myeloid leukaemia. Nature. 2015
lators (e.g., deferasirox, deferoxamine) Feb;518(7540):552-5. Epub 2014 Dec 08.
have been shown in non-randomised, but 5. Louw VJ, et al. Guideline for the treatment
prospective trials to improve survival and of myelodysplastic syndromes (MDS) in South
improve cell counts in a significant per- Africa. S Afr Med J. 2011;101(12):900-906.
centage of patients.13,14 6. Ma X, et al. Myelodysplastic syndromes: In-
cidence and survival in the United States.
SPECIALIST REFERRAL Cancer. 2007;109:1536-42.
7. Sant M, et al. Incidence of hematologic
Although very few patients with MDS will malignancies in Europe by morphologic
be cured, many of the above-mentioned subtype: results of the HAEMACARE pro-
treatments may result in improved quality ject. Blood. 2010;116(19):3724.
of life, decreased transfusions, a reduction 8. Smith A, et al. Incidence of haemato-
in complications, decreased progression logical malignancy by sub-type: a report
to AML and increased overall survival. As from the Haematological Malignancy Re-
the diagnostic and therapeutic aspects search Network. Br J Cancer. 2011 Nov;105
have become very complex and increas- (11):1684-92. Epub 2011 Nov 01.
ingly individualised, all patients with unex- 9. Ryblom H, et al. Self-perception of symp-
plained cytopaenias and/or diagnosed toms of anemia and fatigue before and
MDS, should be referred to a clinical after blood transfusions in patients with my-
haematologist. elodysplastic syndromes. Eur J Oncol Nurs.
2015;19(2):99-106.
REFERENCES 10. Swerdlow SH, Campo E, Harris NL, et al.
World Health Organization classification of
1. Vardiman JW, et al. The 2008 revision of the tumours of haematopoietic and lymphoid
World Health Organization (WHO) classi- tissues. Volume 2. Lyon: IARC Press; 2008.
fication of myeloid neoplasms and acute 11. Giagounidis A, et al. Morphology, cytoge-
leukemia: rationale and important chang- netics and classification of MDS. Best Pract
es. Blood. 2009;114:937-951. Res Clin Haematol. 2013;26:337-53.

12. Greenberg PL, et al. Revised international

prognostic scoring system for myelodysplas-

tic syndromes. Blood. 2012;120(12):2454.

Epub 2012 Jun 27.

13. Angelucci E, et al. Deferasirox for transfu-

sion-dependent patients with myelodys-

plastic syndromes: safety, efficacy, and

beyond (GIMEMA MDS0306 Trial). Eur J

Haematol. 2014;92:527-36.

14. Rose C, et al. Prospective evaluation of

the effect of deferasirox on hematologic

response in transfusion-dependent patients

with low-risk MDS and iron overload: The

Rythmex Study. Blood. 2016;128:2008.

HANDBOOK OF ONCOLOGY

Lymphoma 97

Lymphoma TREATMENT APPROACHES

Dr E Verburgh cases in the past decade.6, 7 However,
seeing that South Africa is the epicentre of
MBChB MMed (Int Med) FCP(SA) FCP(I) the HIV pandemic, this increase is modest,
suggesting that with the more pressing con-
PhD(KUL) cerns of HIV and TB, as well as poor access
 Senior Specialist, Clinical to health care, we are failing to diagnose
Haematology, Groote Schuur Hospital, large numbers of patients with lymphoma.8
UCT Department of Medicine, Division of We do know that outcome after lymphoma
Haematology treatment is poor compared to resource-
rich regions where HIV status does not nec-
Dr K Antel essarily influence the outcome.9

MBChB, MMed (Int Med), FCP (SA), Cert PATHOPHYSIOLOGY

Clin Haem (Phys) Lymphoma occurs when a specific cell
 UCT Department of Medicine, Division type at various stages along lymphocyte
of Haematology development undergoes malignant dys-
regulation, resulting in tumour growth.
Prof VJ Louw This is analogous to solid cancer types
deriving from their organ cell of origin.
MBChB, MMed (Int Med), FCP(SA), What makes the lymphoid malignancies
unique, are the sheer magnitude of de-
PhD(HPE) velopmental stages and cell types that
 Honorary Professor Clinical can give rise to different subtypes of lym-
Haematology, UCT Department of phoma (see Table 1 for the current WHO
Medicine, Division of Haematology classification of lymphomas).10 Moreo-
ver, lymphoid cells are derived from stem
Lymphoma is consistently among the top cells in the bone-marrow compartment,
10 most common malignancies world- and, via the bloodstream, continue their
wide. It is also among the top 10 malig- journey, and developmental maturation,
nancies for long-term cure.1 Moreover, through the lymphoid tissues, including
due to treatment advances in devel- thymus, spleen and lymph nodes. Clearly,
oped countries, lymphoma is showing sig- lymphoid cells form an integral part of the
nificantly improved outcomes in the past biosystem, pervading every part of the
decade compared with earlier data, a human body, and they are not confined
trend that is expected to continue.2 A re- to one anatomical region. It follows that
cent age-standardised incidence rate of lymphoma can harbour as a tumour in lit-
all subtypes of lymphoma in Europe was erally every organ of the body, although
24.5 per 100 000.3 the diagnostic hallmark of lymphomatous
transformation is usually invasion of either
As the incidence and subtypes of lym- bone marrow or lymphoid tissue, or both.
phoma vary throughout different regions This diversity of disease expression leads
of the world, so the outcome of lympho- to diagnostic difficulty, as lymphoma can
ma is variable, depending on local fac- mimic or be confused with many other dis-
tors that impact outcome, such as age on ease states.11
presentation, concomitant HIV, access to
treatment and expert referral centres. In DIAGNOSTIC ISSUES
sub-Saharan Africa, haematological ma-
lignancies are a significant cause of death Five typical clinical “presentation syn-
and disability, but data on the presenta- dromes” of lymphoma and some com-
tion and outcome of lymphoma remain mon disease confounders:
scarce.4, 5 Lymphoma has a 10 to hundred-
fold increased incidence in the HIV-infect- HANDBOOK OF ONCOLOGY
ed – in the Johannesburg academic com-
plex an almost 20% increase was seen in
the proportion of HIV-positive lymphoma

98 BLOOD, LYMPH AND RELATED CONDITIONS

n B -symptoms (consisting of a triad abnormal “ward hb” should always
of unexplained temperature >38°C, be followed by a full blood and dif-
drenching night sweats and >10% ferential count (FBC).
weight loss in previous six months) n Tumour masses that can quietly grow
in body cavities, eventually causing
- The obvious clinical confounder is symptoms by disturbance of function.
the constitutional symptoms of solid These can either grow:
organ cancers, connective tissue - contiguous to lymph-node sites, such
diseases, endocrine syndromes, and as lymphoblastic lymphoma, causing
especially, of infectious diseases such a mediastinal mass, or mucosa-as-
as HIV and TB. sociated lymphoid tumours, such as
MALT lymphoma in the stomach, or
n S ignificant lymphadenopathy that diffuse large B-cell lymphoma caus-
is non-painful, often symmetric, with ing obstruction along the gastro-in-
rubber-hard consistency. Although testinal tract; or they can be
lymphoma can be present in small - remote, such as follicular lymphoma
nodes, the “index diagnostic” lymph presenting in the humerus or skin, or
node in lymphoma will be greater primary central nervous system lym-
than 1,5 cm and be present in excess phoma, presenting as a brain paren-
of two weeks. chyma tumour.

- The endemic occurrence of HIV and APPROACH TO DIAGNOSIS BASED
TB mandates that firm diagnostic al- ON DISEASE MANIFESTATION
gorithms be followed to ensure that
lymphadenopathy related to TB/HIV Lymphadenopathy and tumour masses
is successfully differentiated from lym- suspicious for lymphoma — in these cases,
phoma. Empirical TB treatment in the excision biopsy is the mainstay of diagno-
HIV-infected should likewise be sub- sis. Fine-needle aspiration cytology is not
jected to firm guidelines and close sufficient for lymphoma diagnosis and can
follow-up.12 Lymphadenopathy in the never be used to rule out a diagnosis of
immunocompetent should never be lymphoma; “the issue is to get the tissue”.
subjected to empiric TB treatment. Gaining advice from an expert in lympho-
Histological diagnosis is mandatory. ma diagnosis is mandatory to avoid time
and life lost due to fruitless fine-needle as-
n Cytopaenias, especially anaemia, piration and aimless biopsies. Increasingly,
resulting from bone-marrow invasion expert radiologists can employ core biop-
with failure of normal blood-cell sy techniques to replace surgical biopsy.
production In patients with same-size, moderately
enlarged lymphadenopathy, the cervical
- The differential diagnosis can be an- area is always selected before the axillary
other haematological myeloid malig- area and before the inguinal area for di-
nancy, such as AML or MDS. agnostic biopsies. This increases diagnos-
tic yield and avoids false negative results.
- The differential diagnoses of cyto- Substantial lymphocytosis — in these cas-
paenias are vast and span across im- es, the diagnosis of a lymphoma can eas-
munological and systemic diseases. ily be made on flow cytometry of blood.
Remember that acute lymphoblastic leu-
n Lymphocytosis due to the above- kaemia (ALL) can be diagnosed in blood
mentioned lymphomatous bone- and is the leukaemic counterpart of acute
marrow invasion with subsequent spill of lymphoblastic lymphoma. However, in
tumour cells in the bloodstream clinical practice, a sustained lymphocy-
tosis is most often seen with the indolent
- These blood-borne, or "leukaemic” lymphomas, such as chronic lymphocytic
lymphoma cells can be easily typified
and diagnosed as malignant. The
pitfall for a missed diagnosis is when
the differential count was not re-
quested. Determination of white-cell
count should always include a differ-
ential count. By the same logic, an

HANDBOOK OF ONCOLOGY

Lymphoma 99

leukaemia (CLL). The diagnosis becomes Traditional staging procedures include the TREATMENT APPROACHES
more urgent if the lymphocytosis is ac- triad of:
companied by signs of bone-marrow fail- n Imaging, usually computed
ure such as anaemia and thrombocyto-
paenia. Bone-marrow examination (BME) tomography (CT) of the neck-thorax-
will be carried out at the discretion of the abdomen-pelvis or other affected
haematologist. area, but increasingly nuclear study
with FDG-PET CT is employed for
HELPFUL NON-FBC BLOOD TESTS WHEN enhanced metabolic screening of a
CONSIDERING LYMPHOMA neoplasm.13
n L actate dehydrogenase (LDH): The n Histology of tumour mass or lymph-
node excision biopsy. This includes
more advanced the stage and the genetic and molecular techniques to
more aggressive the lymphoma, the enhance diagnostic differentiation.
higher the LDH will be. LDH is not solely n B one-marrow examination (BME),
connected to red-cell destruction including cytogenetic and molecular
syndromes or acute liver and cardiac tests.
states and is a mandatory and useful
test when searching for malignancy. These procedures are not necessary in all
Note that normal LDH does not exclude cases – for example, in certain low-grade
lymphoma. lymphomas with circulating tumour cells
n ESR is usually raised, but is not specific (“leukaemic phase of lymphoma”), flow
enough to use as screening test. cytometry on blood and clinical evalua-
n R aised canalicular liver enzymes tion may be cost-effective and sufficient
(alkaline phosphatase [ALP] and for diagnosis, whereas a FDG-PET CT has
gamma-glutamyl transferase [GGT]) become preferable as a baseline investi-
are likewise non-specific to lymphoma, gation for Hodgkin’s lymphoma and may
but in this setting must prompt obviate the need for a BME.
consideration of the liver as a site of
lymphomatous infiltration. Staging after therapy
n Coombs positivity, with low Investigations are planned based on the
haptoglobin, and increased following considerations:
reticulocyte count, is useful when an n is the treatment non-curative? – then
associated haemolytic anaemia is
suspected. clinical evaluation may trump invasive
tests or even imaging.
APPROACH TO THE DIAGNOSTIC n is treatment curative? – evaluation of
AND STAGING PROCEDURES OF the areas of initial disease is mandatory
LYMPHOMA to re-stage and confirm remission.
In some lymphoma cases, the diagnosis
is straightforward and the patient can be TREATMENT AND PROGNOSTIC
referred for staging and treatment. On the APPROACH
other hand, many patients are under scru-
tiny with a possible differential diagnosis of Based on “cell of origin”: tumour histology,
lymphoma. In these cases, it is advised to lymphoma is divided into Hodgkin’s (HL)
consult with the clinical haematologist or and non-Hodgkin’s lymphoma (NHL).
oncologist early on to guide the diagnos-
tic biopsy of suspicious tissue. Hodgkin’s lymphoma: Globally, it can be
said that HL has a simple classification
Staging before therapy and a straightforward, excellent prognosis.
Patients with a preliminary/probable diag- Classic Hodgkin’s lymphoma subtypes ex-
nosis of lymphoma are best referred for full hibit an excellent (>80%) cure rate.14
work-up and staging to a clinical haema-
tologist or oncologist. Non-Hodgkin’s lymphoma: There are
close to a hundred NHL subtypes based
on cell of origin, exhibiting extremely

HANDBOOK OF ONCOLOGY

100 BLOOD, LYMPH AND RELATED CONDITIONS

Table 1. The 2016 WHO classification of non-Hodgkin’s and Hodgkin’s lymphoma

Commonly encountered clinical entities are given in bold, Cell of origin in margin

Non-Hodgkin’s lymphoma: B-cell neoplasms

Precursor B-cell Precursor B-lymphoblastic lymphoma/leukaemia
neoplasm

Mature Chronic lymphocytic leukaemia/small lymphocytic lymphoma
B-cell neoplasm (CLL)

Monoclonal B-cell lymphocytosis

B-cell prolymphocytic leukaemia

Splenic marginal zone lymphoma

Hairy cell leukaemia

Lymphoplasmacytic lymphoma ➝ Waldenström
macroglobulinemia

Monoclonal gammopathy of undetermined significance (MGUS),

IgM

µ heavy chain disease
γ heavy chain disease
α heavy chain disease

Monoclonal gammopathy of undetermined significance (MGUS),
IgG/A
Plasma-cell myeloma
Solitary plasmacytoma of bone
Extra-osseous plasmacytoma
Monoclonal immunoglobulin deposition diseases

Extranodal marginal zone lymphoma of mucosa-associated

lymphoid tissue
(MALT lymphoma)

Nodal marginal zone lymphoma

Follicular lymphoma
n Duodenal-type follicular lymphoma
n Paediatric-type follicular lymphoma
n Primary cutaneous follicle-centre lymphoma

Mantle-cell lymphoma
n I n situ mantle-cell neoplasia
Diffuse large B-cell lymphoma (DLBCL), not otherwise specified
(NOS)
n Germinal centre B-cell-type
n Activated B-cell-type
T-cell/histiocyte-rich large B-cell lymphoma

Primary DLBCL of the central nervous system (CNS)

Primary cutaneous DLBCL, leg type

EBV+ DLBCL, NOS

DLBCL associated with chronic inflammation

Lymphomatoid granulomatosis

Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK+ large B-cell lymphoma

HANDBOOK OF ONCOLOGY

Lymphoma 101

Table 1. (cont.) TREATMENT APPROACHES

Non-Hodgkin’s lymphoma: B-cell neoplasms

Precursor B-cell Precursor B-lymphoblastic lymphoma/leukaemia
neoplasm

Plasmablastic lymphoma
Primary effusion lymphoma

Burkitt lymphoma
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6
rearrangements*
High-grade B-cell lymphoma, NOS

*B-cell lymphoma, unclassifiable, with features intermediate
between DLBCL and classical Hodgkin’s lymphoma

Non-Hodgkin’s lymphoma: T- and NK-cell neoplasms

Precursor Precursor T-lymphoblastic lymphoma/leukaemia
T-cell neoplasm

Mature T-cell prolymphocytic leukaemia
T-cell and T-cell large granular lymphocytic leukaemia
NK-cell neoplasm Aggressive NK-cell leukaemia
Systemic EBV+ T-cell lymphoma of childhood
Hydroa vacciniforme-like lymphoproliferative disorder
Adult T-cell leukaemia/lymphoma
Extranodal NK-/T-cell lymphoma, nasal-type
Enteropathy-associated T-cell lymphoma
Monomorphic epitheliotropic intestinal T-cell lymphoma

Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma

Mycosis fungoides
Sézary syndrome
Primary cutaneous CD30+ T-cell lymphoproliferative disorders:
n Lymphomatoid papulosis
n Primary cutaneous anaplastic large cell lymphoma
Primary cutaneous γΔ T-cell lymphoma

Peripheral T-cell lymphoma, NOS
Angio-immunoblastic T-cell lymphoma
Anaplastic large-cell lymphoma, ALK+
Anaplastic large-cell lymphoma, ALK–

T-cell prolymphocytic leukaemia

T-cell large granular lymphocytic leukaemia

Hodgkin’s lymphoma

Germinal centre Nodular lymphocyte-predominant Hodgkin’s lymphoma
B-cell neoplasm
Classical Hodgkin’s lymphoma:
n Nodular sclerosis classical Hodgkin’s lymphoma
n Lymphocyte-rich classical Hodgkin’s lymphoma
n Mixed cellularity classical Hodgkin’s lymphoma
n Lymphocyte-depleted classical Hodgkin’s lymphoma

HANDBOOK OF ONCOLOGY

102 BLOOD, LYMPH AND RELATED CONDITIONS

Table 1. (cont.)

Non-Hodgkin’s lymphoma: T- and NK-cell neoplasms

Precursor Precursor T-lymphoblastic lymphoma/leukaemia
T-cell neoplasm

Post-transplant lymphoproliferative disorders

Majority mature n Plasmacytic hyperplasia PTLD
B-cell neoplasm- n Infectious mononucleosis PTLD
seldom n Florid follicular hyperplasia PTLD
T-/NK-cell n Polymorphic PTLD
n Monomorphic PTLD (B- and T-/NK-cell types
n Classical Hodgkin’s lymphoma PTLD

Histiocytic and dendritic cell neoplasms

Histiocyte and n Histiocytic sarcoma
dendritic- cell-type n Langerhans-cell histiocytosis
neoplasm n Langerhans-cell sarcoma
n Indeterminate dendritic cell tumour
n Interdigitating dendritic cell sarcoma
n Follicular dendritic cell sarcoma
n Fibroblastic reticular cell tumour
n Disseminated juvenile xanthogranulomata
n Erdheim-Chester disease

diverse predilection for site and degree of without radiotherapy, scheduled to recur at
disease expression. two- to four-week intervals. Patients are hos-
Moreover, they display vastly disparate pitalised for high-risk or aggressive disease,
behaviour clinically, which is why it is most but mostly treatment is on an out-patient
useful, from a clinical and treatment point basis. Chemotherapy combinations are
of view, to approach lymphoma based used and, increasingly, biological therapy is
on three clinical presentation patterns added (see Tables 3 and 4). The most well-
(see Table 2).15 known biological drug in lymphoma and
n T he low-grade or indolent lymphoma the first among anti-tumour cell antibody
therapy in any tumour type, is rituximab,
group an anti-CD20 humanised monoclonal anti-
n The high-grade or aggressive body therapy. Nevertheless, the backbone
of most initial chemotherapy schedules for
lymphoma group lymphoma remains corticosteroid therapy.
n The very high-grade or very aggressive Increasingly, the malignant activation path-
ways in lymphoma growth are being tar-
lymphoma group geted by novel biological drugs, of which a
Certain upfront characteristics predict the few examples are given, denoted by an *.
grade of aggressiveness of the lymphoma. These drugs are novel in action and hold the
Making the correct subtype diagnosis is promise of revolutionising lymphoma thera-
becoming increasingly important, as treat- py, but this comes at a prohibitive price.
ment for lymphoma is becoming progres-
sively more tailored to subtype. Once the EARLY DIAGNOSIS OF LYMPHOMA
diagnostic subtype is known, treatment AND REFERRAL: FUTURE
can be approached within the framework DIRECTIONS
of one of these three clinical groups.
Lymphoma is high on the list of differential
Lymphoma is treated with classic chem- diagnoses of many commonly occurring
otherapeutic agents and new targeted clinical syndromes. Its incidence increases
biological therapies.

Depending on the tumour type, treat-
ment is typically delivered in cycles, with or

HANDBOOK OF ONCOLOGY

Lymphoma 103

Table 2. The three clinical lymphoma groups and the approach to diagnosis TREATMENT APPROACHES

Clinical Cell-of-origin Typical Typical Risk to Diagnostic
lymphoma lymphoma patient if urgency
disease causing demo- subtypes undiagnosed
expression encountered and
lymphoma graphics in clinical untreated
practice

Low-grade Mature B- Usually a Chronic Not all Less urgent
or indolent cells and less disease lymphocytic indolent to diagnose
lymphoma often ma- of the leukaemia lymphomas and also
ture T-cells elderly, (CLL) need treat- easier.
peak ment Disease
incidence Splenic often spills
around 60 lymphomas Treatment into blood-
years delay stream
Follicular unlikely to ("leukae-
lymphoma impact mic"), is
mortality diagnosed
on BME
or easily
accessible
mass, or
occurs in
large spleen

High-grade Mature B- Wide Diffuse large Undiagnosed Early
or aggres- cells and less spectrum B-cell lymph- and untreat- diagnosis is
sive lymph- often ma- of occur- oma ed patients crucial, as
oma ture T-cells, rence across have a risk of increased
occurring at age groups, Hodgkin’s dying within stage of
an interme- prognosis lymphoma weeks to disease
diate devel- better in the months decreases
opmental young Peripheral cure rate
stage T-cell lymph- and
omas increases
mortality.
Tumour lysis
syndrome is
possible

Very Immature B- Wide Acute Undiagnosed Refer with-
high-grade cell or T-cell spectrum lympho- and untreat- out delay
or very blastic cells of occur- blastic ed patients (attention
aggressive or rence across lymphoma have risk of to hydration
lymphoma Burkitt cells age groups, dying within and renal
with high prognosis Burkitt days to protection)
turnover better in the lymphoma weeks High LDH
rate young can point to
tumour lysis
syndrome

HANDBOOK OF ONCOLOGY

104 BLOOD, LYMPH AND RELATED CONDITIONS

Table 3. The three clinical lymphoma groups and the approach to treatment

Clinical Initial Common Stem-cell and Expected
lymphoma treatment chemotherapy
disease approach treatment biological* treatment treatment
expression and timing regimens
of therapy - Note that possibilities outcome
Low-grade rituximab forms
or indolent Treat lym- an integral part Ibrutinib* – a bruton Largely non-
lymphoma phoma of most B-cell kinase inhibitor curative
sympto- lymphoma Curative treatment treatment –
High-grade matically, chemotherapy with allogeneic unless allogeneic
or aggres- i.e., based regimens stem-cell transplant stem-cell
sive lym- on effects Bendamustine is reserved for young transplant.
phoma of disease patients with a high Intent is to reduce
burden. CHOP/CHOEP burden of disease disease burden
If asymp- and
tomatic, CVP restore to
watch asymptomatic
and wait FC state

Treat ag- Ist line: Nivolumab* and Intent of
gressively CHOP pembroluzimab* – treatment
and with- Da-EPOCH checkpoint inhibitors is curative.
out delay, ABVD +/- In patients not Predictors of
even if radiotherapy achieving remission, prognosis
only a BEACOPP + autologous stem include age,
small radiotherapy cells can be used to disease extent,
disease intensify treatment site of disease,
burden 2nd line: Allogeneic stem- raised LDH,
DHAP cell transplant can anaemia
ICE cure patients with Typical population
GDP resistant disease survival rates for
IGEV NHL patients are
High-risk disease around 50% and
Very-high- Treat Intense inpatient qualifies for alloge- for HL >80%
grade or aggres- chemotherapy neic stem-cell Intent of
very ag- sively and regimens such transplant. An exciting treatment is
gressive without as: new therapy for curative and can
lymphoma delay, hyperCVAD resistant disease is be achieved in
high likeli- CODOX-M-IVAC Chimeric Antigen 40-80% of cases,
hood of Da-EPOCH Receptor T (CAR-T)* depending on
tumour +/- dose-dense cells utilising adoptive patient age
lysis syn- rituximab immunotherapy and the growth
drome directed at tumour and genetic
cells characteristics of
the tumour

HANDBOOK OF ONCOLOGY

Lymphoma 105

Table 4. Acronyms for and ingredients of common chemotherapy regimens TREATMENT APPROACHES

ABVD Adriamycin, Bleomycin, Vincristine, Dacarbazine

BEACOPP Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine,
Procarbazine, Prednisone

B-R Bendamustine-Rituximab
CHOP +/- R
Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin
CHOEP +/- R (Vincristine), Prednisone +/- Rituximab

Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin
(Vincristine), Etoposide, Prednisone +/- Rituximab

CVP Cyclophosphamide, Oncovin (Vincristine), Prednisone

CODOX-M Cyclophosphamide, Oncovin (Vincristine), DOXorubicin, Methotrexate

IVAC Ifosfamide, VP-16 (Etoposide), Ara-C (Cytarabine)

Da-EPOCH-R Dose-adjusted Etoposide, Prednisone, Oncovin (Vincristine),
Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin) with Rituximab

DHAP Dexamethasone, High-dose Ara C (Cytarabine), Platinol (Cisplatin)

FC(-R) Fludarabine, Cyclophosphamide (-Rituximab)

GDP Gemcitabine, Dexamethasone, Platinol (Cisplatin)
HyperCVAD
fractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin),
Dexamethasone alternating with Methotrexate and Cytarabine

ICE Ifosfamide, Cisplatin, Etoposide

IGEV Ifosfamide, Gemcitabine, Vinorelbine, Prednisone

in an ageing and industrialised popula- are not yet seen. Increasing awareness,
tion, as well as in HIV-infected individu- coupled with access to the correct diag-
als. However, its elusiveness to diagnosis, nostic techniques, will increase early and
and its unpredictable clinical behaviour, accurate diagnoses. Histological diagno-
complicates and obscures the diagnostic sis via biopsy is still essential, but the future
process. The only remedy is for the gen- lies with newer molecular techniques that
eralist to become well acquainted with have the potential for earlier diagnosis on
the colleagues at the local haematology more readily procurable patient material.
laboratory and haemato-oncology clinic Sophisticated approaches to sequencing
to enable timely advice and early refer- DNA (analogous to GeneXpert TB assay)
ral. This relationship should be reciprocal, are being developed with the potential to
in that the haematologist should be able detect lymphoma in the blood of patients.
to direct the generalist to the correct di- Various platforms for next-generation se-
agnostic procedures as carried out by quencing (NGS) are being developed by
radiologists, surgeons, nuclear-medicine which lymphoma subtypes can be detect-
specialists and specialist physicians. The ed accurately, thereby enabling earlier
oncological radiotherapist is integral to and more efficient targeting of therapy.16
the therapy of certain aggressive lympho-
mas such as Hodgkin’s lymphoma. With a large number of novel agents in
development, the future of lymphoma treat-
Aggressive lymphoma is a malignancy ment looks better than ever, but the basics
with high curative potential with early of a good clinical diagnostic approach
treatment. The many obstacles to lympho- through early and efficient diagnosis, fol-
ma diagnosis in sub-Saharan Africa, leads lowed by correct treatment, remain founda-
to late-stage diagnoses, whereby the ex- tional to the management of these patients
cellent cure rates of first-world countries if we want to optimise their outcomes.

HANDBOOK OF ONCOLOGY

106 BLOOD, LYMPH AND RELATED CONDITIONS

REFERENCES lymphoma treated with R-CHOP in the
cART era. AIDS. 2014 Mar 13;28(5):689-97.
1. Rachet B, Maringe C, Nur U, et al. Pop- Doi: 10.1097/QAD.0000000000000133.
ulation-based cancer survival trends in 10. Swerdlow SH, Campo E, Pileri SA, et al.
England and Wales up to 2007: an as- The 2016 revision of the World Health Or-
sessment of the NHS cancer plan for Eng- ganization classification of lymphoid neo-
land. Lancet Oncol. 2009;10(4):351-369. plasms. Blood. 2016;127(20):2375-2390.
e-pub 2009/03/24; Doi: 10.1016/s1470-2045(09) e-pub 2016/03/17; Doi: 10.1182/blood-2016-
70028-2. 01-643569.
11. Howell DA, Smith AG, Jack A, et al. Time-to-
2. De Angelis R, Sant M, Coleman MP, et al. diagnosis and symptoms of myeloma, lym-
Cancer survival in Europe 1999-2007 by phomas and leukaemias: a report from the
country and age: results of EUROCARE-5 – Haematological Malignancy Research Net-
a population-based study. The Lancet On- work. BMC Hematology. 2013;13(1):9. e-pub
cology. 2014;15(1): 23-34. 2013/11/19; Doi: 10.1186/2052-1839-13-9.
12. Wilson D, Nachega J, Morroni C, et al. Diag-
3. Sant M, Allemani C, Tereanu C, et al. Inci- nosing smear-negative tuberculosis using
dence of hematologic malignancies in Eu- case definitions and treatment response in
rope by morphologic subtype: results of the HIV-infected adults. Int J Tuberc Lung Dis.
HAEMACARE project. Blood. 2010;116(19): 2006;10(1):31-38. e-Pub 2006/02/10.
3724-3734. e-pub 2010/07/29; Doi: 10.1182/ 13. Kostakoglu L, Cheson BD. Current role of
blood-2010-05-282632. FDG PET/CT in lymphoma. Eur J Nucl Med
Mol Imaging. 2014;41(5):1004-1027. Doi: 10.
4. Parkin DM. The evolution of the population- 1007/s00259-013-2686-2.
based cancer registry. Nat Rev Cancer. 14. Borchmann P, Haverkamp H, Diehl V, et al.
2006;6(8):603-612. Doi: 10.1038/nrc1948. Eight cycles of escalated-dose BEACOPP
compared with four cycles of escalated-
5. Parkin DM, Sitas F, Chirenje M, et al. Part I: dose BEACOPP followed by four cycles of
Cancer in Indigenous Africans -- burden, baseline-dose BEACOPP with or without
distribution, and trends. Lancet Oncol. radiotherapy in patients with advanced-
2008;9(7):683-692. e-pub 2008/07/05; Doi: stage Hodgkin’s lymphoma: final analysis
10.1016/s1470-2045(08)70175-x. of the HD12 trial of the German Hodgkin’s
Study Group. J Clin Oncol. 2011;29(32):4234-
6. Patel M, Philip V, Fazel F. Human immuno- 4242. Doi: 10.1200/JCO.2010.33.9549.
deficiency virus infection and Hodgkin’s 15. C onnors JM. Non-Hodgkin’s lymphoma:
lymphoma in South Africa: an emerging the clinician’s perspective – a view from
problem. Adv Hematol. 2011;2011:578163. the receiving end. Mod Pathol. 2013;26
e-pub 2011/02/19; Doi: 10.1155/2011/ (Suppl1):S111-118. Doi: 10.1038/modpathol.
578163. 2012.184.
16. Vogt SLP, Omar, T, Pather S, et al. Molecular
7. Wiggill TM, Mantina H, Willem P, et al. diagnostics for AIDS lymphoma diagnosis
Changing pattern of lymphoma subgroups in South Africa and the potential for other
at a tertiary academic complex in a high- low- and middle-income countries. Journal
prevalence HIV setting: a South African of Global Oncology. 2018:4,1-6.
perspective. J Acquir Immune Defic Syndr.
2011;56(5):460-466. e-pub 2011/01/18; Doi:
10.1097/QAI.0b013e31820bb06a.

8. WHO report 2011. Global Tuberculosis Con-
trol. Geneva: World Health Organization
2011.

9. Coutinho R, Pria AD, Gandhi S, et al. HIV
status does not impair the outcome of pa-
tients diagnosed with diffuse large B-cell

HANDBOOK OF ONCOLOGY

Caring for patients
with cancer

108 CARING FOR PATIENTS WITH CANCER

Oncological Emergencies

Dr A Bonthuys PATHOPHYSIOLOGY

MBChB; MSc; FC Rad Onc (SA); MMed Metastatic spinal cord compression most
commonly results from direct extension
(Rad Onc) of vertebral metastatic tumour depos-
 ICON Clinical Executive its through the periosteum into the spinal
canal. However, in around 25% of cases,
An oncological emergency is an acute injury results from pathological fracture of
medical problem related to a cancer, or the vertebra and direct cord damage,
to its treatment, which may result in seri- retropulsion of a bony fragment or acute
ous morbidity or mortality unless prompt tumour haemorrhage. Occasionally, pa-
treatment is initiated.1 This may occur as ra-spinal tumours or epidural deposits may
a result of structural (obstructive/destruc- infiltrate locally, without associated bony
tive) or metabolic complications. While destruction. In general, spinal cord com-
the majority will complicate a known pression is a poor prognostic sign, with a
cancer diagnosis, occasionally this may median overall survival of six months.4
be the presenting complaint, and a high
index of suspicion is required to allow for PRESENTING SIGNS AND SYMPTOMS
rapid recognition, diagnosis and appro-
priate referral. The single most important determinant
of outcome is the severity of neurologi-
This article will focus on the oncological cal compromise at the time of treatment
emergencies which commonly present initiation.
in general practice, and where rapid
diagnosis and referral has an important Thus, a high index of clinical suspicion is
impact on outcome; in the setting of a required to detect cases early, while neu-
non-haematological malignancy, unless rological function is intact. Eighty percent
stated otherwise. These include spinal of ambulant patients at presentation will
cord compression, febrile neutropaenia, retain the ability to walk, whereas only
hypercalcaemia and superior vena cava 50% with a transverse myelopathy and
syndrome. less than 5% of those with paraplegia will
do so.5 Patients considered high risk for
MALIGNANT SPINAL CORD the development of bone metastases, or
COMPRESSION AND CAUDA those with known bone metastases, should
EQUINA SYNDROME be informed of the associated symptoms,
which may allow for early presentation.
Malignant spinal cord compression is a
neuro-oncological emergency that results Symptoms may be insidious, or occa-
in a potentially irreversible loss of neuro- sionally patients may develop rapid para-
logical function due to the loss of integrity plegia with few preceding symptoms. The
of the spine. It is estimated that between most common early symptom is pain. This
five and 40% of patients with malignant tu- is generally localised to the site of tumour
mours will develop spinal metastases,2 with and results from periosteal expansion.
around 5% of these being complicated by Common late symptoms include par-
spinal cord compression.3 aesthesia, loss of sensation, loss of motor
function, and bladder and bowel incon-
Metastatic tumours from any primary tinence. In adults, the spinal cord ends at
site may result in spinal cord compression, the level of L1, and compression below
however, those with the highest propen- this point results in the cauda equina syn-
sity to metastasise to the spinal column drome (lower back pain, pain radiating
include lung, prostate, breast, kidney, lym- down the leg, peri-anal loss of sensation
phoma and multiple myeloma. and loss of bowel or bladder control).

HANDBOOK OF ONCOLOGY

Oncological Emergencies 109

MANAGEMENT Figure 1. MRI image of multi-level spinal cord TREATMENT APPROACHES
compression
The aim of treatment is to maintain and/
or improve neurological function. De- Source: Image courtesy of https://lookfordiagnosis.
finitive treatment should be commenced com/mesh_info.php?term=Spinal+Cord+
within 24 hours of diagnosis, and all pa- Compression&lang=1
tients should therefore be rapidly referred
for clinical evaluation and spinal imaging. In patients who are not surgical candi-
Patients should be nursed in the supine dates, radiotherapy alone provides the
position during transfer due to the possibil- primary treatment modality. Radiotherapy
ity of spinal instability. For between eight aims to retain/regain neurological func-
and 34% of patients, spinal cord compres- tion, and to control pain. For highly che-
sion is the presenting complaint,2 and a mosensitive tumours, such as lymphomas
full clinical history, general examination or small-cell lung carcinomas, chemother-
and appropriate investigations will assist to apy may occasionally be commenced as
determine the site of primary tumour. Spi- the primary treatment modality, prior to
nal imaging consists of a whole spine MRI, radiotherapy. Prophylaxis against venous
unless contra-indicated. The entire spine thrombo-embolism has not been specifi-
must be imaged as patients frequently cally studied in patients with metastatic
have multi-level disease. SCC, however, anticoagulation should be
considered. Supportive care, such as spe-
Definitive management requires a mul- cialised nursing, rehabilitative physiothera-
tidisciplinary approach, involving the py and pain management, are important
general practitioner, treating physician/ aspects of care. This should involve the pa-
surgeon, radiologist, neurosurgeon, oncol- tient, families and carers and community
ogist, as well as specialist physiotherapy
and nursing care. Surgical stabilisation fol- HANDBOOK OF ONCOLOGY
lowed by radiotherapy has been shown
to be associated with superior functional
outcomes when compared to radiother-
apy alone, with 84% vs 57% of patients
retaining ambulation.6 No difference in
survival between the two approaches has
been shown.

Thus, for select patients with a good prog-
nosis and favourable radiological and
clinical features, an initial surgical ap-
proach is preferred. Indicators for surgical
intervention include:
n patient factors (prognosis, comorbidities,

fitness for surgery, functional status)
n t umour factors (tumour type, control

of primary, number and site of
metastatic deposits, number of spinal
levels involved, inherent radio- or
chemosensitivity, previous radiotherapy)
n the neurological status of the patient
(residual neurological function,
complete paralysis with onset of
symptoms less than 72 hours, paralysis
of rapid onset, vertebral instability,
displaced bony fragments and
unknown primary tumour).2

110 CARING FOR PATIENTS WITH CANCER

support, including primary care and spe- breech in host defences related to the
cialist palliative care, as required. underlying malignancy and obstruction
of lymphatics and hollow organs (biliary
FEBRILE NEUTROPAENIA tract, bronchial, gastro-intestinal or urinary
tracts) by tumours or surgical procedures.
International guidelines define febrile neu- As a result, infectious pathogens may be
tropaenia (FN) as an oral temperature bacterial, fungal and occasionally viral.
of >38.3°C, or of >38.0°C on two or more
consecutive readings at least one hour PREVENTION
apart, and an absolute neutrophil count
(ANC) of <0.5 x 109/L, or <1.0 x 109/L and Preventive strategies include chemopro-
expected to fall below 0.5 x 109/L over phylaxis and/or prophylaxis with G-CSF
the following 48 hours.7,8 There has been (filgrastim or pegfilgrastim). Chemopro-
a steady decrease in mortality rates relat- phylaxis with broad-spectrum antibiotics
ed to febrile neutropaenia, however, this carries the risk of antibiotic-resistant strains,
remains an important cause of cancer- and current guidelines from the European
related mortality and morbidity, as well Organisation for Research and Treatment
as placing financial strain on health-care of Cancer (EORTC) and American So-
resources. In addition, dose-delays and ciety of Clinical Oncology (ASCO) rec-
reductions may translate to compromised ommend that clinicians limit the use of
treatment efficacy. All patients should be antibacterial prophylaxis to patients with
fully informed of the risk of febrile neutro- >20% risk of febrile neutropaenia, or where
paenia, the associated symptoms, and specific indications exist (such as valaci-
how to contact the appropriate services clovir for patients receiving bortezomib-
in the event of concerns. containing regimens, and trimethoprim-
sulfamethoxazole for patients receiving
PATHOPHYSIOLOGY temozolomide).9,11
While febrile neutropaenia may compli-
cate any chemotherapy treatment, the Similarly, primary G-CSF prophylaxis (ini-
risk of febrile neutropaenia increases with tiated with first cycle of chemotherapy)
the dose-intensity of the chemotherapy should be limited to those with >20% risk
regimen utilised. High-risk regimens, de- of febrile neutropaenia, while secondary
fined by ASCO as having a greater than prophylaxis (initiated with the second- or
20% associated risk of febrile neutropae- subsequent cycles of chemotherapy)
nia,9 are commonly used in patients with should be commenced in any patient with
Hodgkin’s lymphoma, non-Hodgkin’s lym- a history of previous febrile neutropaenia,
phoma, testicular malignancies and soft- while on active treatment.
tissue sarcomas (for a detailed list of high-
risk regimens see NCCN Guidelines Version PRESENTING SIGNS AND SYMPTOMS
2.2017; Myeloid Growth Factors, MGF-A
1-4).10 Other factors increasing the risk of The magnitude of the neutrophil-mediat-
febrile neutropaenia include advanced ed inflammatory response may be muted
age (>65 years), history of previous fe- in neutropaenic patients, and thus an
brile neutropaenia, poor performance increase in temperature is often the ear-
status, extensive prior therapy, extensive liest sign of infection. It is thus critical to
bone-marrow infiltration and significant recognise potential neutropaenic fever
comorbidities.7 syndromes and react timeously. Prompt
recognition and early initiation of empiric
Contributory factors to the pathogen- systemic antibacterial therapy are essen-
esis of febrile neutropaenia include the tial in improving outcomes related to fe-
immunosuppressive effects of chemo- brile neutropaenia, and a delay in initiation
therapy, direct effects of chemotherapy of antibiotic treatment has been shown
on the mucosal barriers with seeding of to be associated with a significantly in-
the bloodstream with endogenous flora, creased hospital stay and increased mor-
tality.7 See Figure 2 for a consensus-based
HANDBOOK OF ONCOLOGY

Oncological Emergencies 111

time-dependent algorithm.13 International extended spectrum penicillin and an ami- TREATMENT APPROACHES
guidelines for the prevention and man- noglycoside. Antifungals may be added
agement of neutropaenia have been for patients not responding, or those with
developed, and the approach below is in clinical fungal infections. Oral antibiotics
keeping with these guidelines.7-12 may be substituted safely once the pa-
tient has been afebrile for 48 hours. Treat-
MANAGEMENT ment is discontinued once the ANC is >0.5
x 109/L, the patient is asymptomatic, has
When febrile neutropaenia is suspected, been afebrile for 48 hours and follow-up
body temperature should be determined, blood cultures are negative (see Figures 1
and clinical evaluation for haemodynam- and 2).
ic stability and an obvious source of infec-
tion should follow. A full septic screen, in- HYPERCALCAEMIA
cluding a full blood count and differential
count, blood cultures, urine cultures and Hypercalcaemia is defined as a correct-
sputum cultures, are mandatory. A co- ed serum calcium >2.60 mmol/L. Primary
agulation screen should be performed in hyperparathyroidism and malignancy
any patient where a septic coagulopathy comprise the most common causes,
is suspected. Empiric broad-spectrum an- combined they account for over 90% of
tibiotic therapy should be commenced cases.14 Malignant hypercalcaemia may
immediately following the above cultures, result from direct displacement of calcium
and before any additional investigation. salts due to bony metastases or result as a
Subsequent investigations are directed by paraneoplastic phenomenon.
the clinical findings, but typically include
chest radiology and swabs of any open Malignancies with a high propensity to
wound or skin lesions. metastasise to bone include lung, pros-
tate, breast, kidney, lymphoma and mul-
Patients are grouped according to de- tiple myeloma. Those associated with
fined risk criteria into low- or high-risk group- the secretion of physiological substances
ings. The most commonly used scoring involved in calcium metabolism, such as
system is the Multinational Association of parathyroid hormone (PTH)-related-pep-
Supportive Care in Cancer (MASCC) in- tide, ectopic PTH secretion or calcitriol, in-
dex.8,13 Low-risk patients may be treated clude small-cell lung cancers, lymphoma,
with oral antibacterial therapy, on an out- myeloma and malignancies of the ovary,
patient basis, as randomised controlled trials breast and thyroid.
have shown this group to have <1% mortal-
ity and <6% risk of serious complications.13 Mild to moderate hypercalcaemia is de-
The choice of agent is directed by clinical fined as a level between 2.60-3.00 mmol/L,
evaluation, loco-regional bacterial isolate while severe hypercalcaemia occurs
and resistance patterns. with corrected serum calcium levels
3.01 mmol/L and above; or is complicated
Current local and national guidelines are by clinical symptoms. Hypercalcaemia is
available, and at present single-agent qui- considered a poor prognostic sign.
nolones, or a quinolone in combination with
an extended spectrum penicillin are recom- PRESENTING SIGNS AND SYMPTOMS
mended. Patients typically present with insidious
onset of symptoms consisting of polyuria,
Outpatient parenteral regimens may polydipsia, anorexia, nausea, vomiting,
also be considered. Patients considered constipation, muscle weakness, bony pain,
as high risk, either due to MASCC criteria renal stones and fatigue. In some cases,
or clinical judgement, should be admit- patients may present with confusion, focal
ted and commenced on broad-spectrum neurological signs or coma. Physical find-
parenteral antibiotics, modified once ings usually confirm the above, and symp-
culture and sensitivity results are avail- toms of the underlying malignancy may
able. Current national guidelines promote be detected.
first-line combination therapy with an
HANDBOOK OF ONCOLOGY

112 CARING FOR PATIENTS WITH CANCER

Figure 1. Risk assessment resources

Using the MASCC risk-index score
n Using the visual analogue score, estimate the patient’s burden of illness at the time of the

intitial clinical evaluation. No signs or symptoms or mild signs or symptoms are scored as 5
points; moderate signs or symptoms are scored as 3 points. These are mutually exclusive. No
points are scored for severe signs or symptoms or moribund.
n Based on the patient’s age, past medical history, present clinical features, and site of care
(input/output when febrile episode occured), score the other factors in the model and total
the sum.

Burden of illnes MASCC risk-index score/
How sick is the patient at presentation? model1,2

Characteristic Weight

No signs or Mild signs or Moderate Severe Moribund n Burden of illness
symptoms symptoms signs or signs or - No or mild
symptoms symptoms 5
symptoms - Moderate

Estimate the burden of illness considering symptoms 3
all comorbid conditions
n No hypotension 5

n No COPD 4

n Solid or tumour or
haematologic
malignancy with no
previous fungal

infection 4

n No dehydration 3

n Outpatient status 3

n Age <60 years 2

Source: MASCC Index: Courtesy of the NCCN Guidelines Version 1.2018; Prevention and Treatment of
Cancer-Related Infections, FEV-D.8,13

MANAGEMENT clinical symptoms due to hypercalcaemia,
bisphosphonates should be administered.
Management is symptomatic, as well as The dose and choice of agent will depend
being directed at the underlying cause. on the patient’s renal function and physi-
Hypercalcaemia should be verified by bio- cian preference. Calcitonin, a physiologi-
chemistry, consisting of corrected serum cal PTH antagonist, has been shown to
calcium and serum albumin. Saline diuresis decrease serum calcium in patients with
is the cornerstone of management. For pa- malignant hypercalcaemia, and salmon
tients with adequate renal function, 3-4 L calcitonin (Miacalcic®) is registered for
normal saline fluids per 24 hours are re- use for the treatment of hypercalcaemic
quired and a urine output of 100-150 ml/hr emergencies, along with other appropri-
should be encouraged. Drugs adding to ate agents, when a rapid decrease in se-
calcium conservation, such as thiazide rum calcium concentration is required.
diuretics and calcium supplementation,
should be discontinued. Furosemide may SUPERIOR VENA CAVA SYNDROME
be administered to encourage a calcium Superior vena cava (SVC) syndrome results
diuresis; only once adequate hydration from obstruction of the SVC by invasion or
is obtained. Regular monitoring of renal compression of an adjacent pathologi-
function is required. For patients with cal- cal process which involves the right lung,
cium levels of 3 mmol/L or higher, or with

HANDBOOK OF ONCOLOGY

“Bona
diagnosis

bona
curatio”*

We translate the facts

*Good Diagnosis, Good Cure.

To initiate specialised tests or to discuss
specific needs with an expert pathologist,

please visit www.ampath.co.za

YOUR CONSULTING PATHOLOGISTS

114 CARING FOR PATIENTS WITH CANCER

Figure 2. Time-dependent algorithm for the initial assessment and management of cancer
patients with neutropaenic fever and suspected sepsis syndrome

Triage 0'
All patients receiving systemic anti-cancer therapy within the previous 6 weeks*

Assumption: Neutropaenic fever/sepsis syndrome

Temperature, Initial assessment saturation
pulse, respiratory rate, blood pressure, arterial O2
Initial intervention
1. IV access (CVAD, if in situ, or peripheral line, 18G) plus normal saline.
2. Blood work: complete blood count and leukocyte differential, blood cultures (CVAD +
peripheral site, or two separate peripheral sites), electrolytes (Na, K, lCacl, tTaCteO.2), blood urea
nitrogen and serum creatinine, blood glucose, serum

Medical assessment 15'
(within 15 minutes of triage)

Severe sepsis syndrome
(¶ SIRS and altered mental status or hypoperfusion ∆ or hypoxia)

Yes No 30'
Goal-directed therapy ◊ Identify potential sources of infection (LIRT, URT,
n R esuscitation
periodontium, skin, GI tract, GU tract)
facilities
n O ptimise Sepsis syndrome
(neutropaenic fever syndrome due to probable or
haemodynamics
and O2 delivery documented infection together with systemic
n I nitiate empiric manifestations of infection) §
antibacterial therapy
n C ritical-care services Yes No
n S upplemental O2
HANDBOOK OF ONCOLOGY n E mpirical antibacterial therapy
n I V 0.9 percent saline 1L over 1 to 2 hours

Risk for medical complications

High ¥ Low ¥ 60'

n A dmission n C onsider IV ➝ PO or PO
n I V antibacterial terapy therapy
n D ischarge when
n C onsider inpatient ➝
physiologically stable, outpatient
comorbidities are
controlled n D ischarge when
n D uration 4 to 5 afebrile physiologically stable
days (total 7-14 days) and comorbidities are
controlled

n D uration 3-5 afebrile
days (total 7-10 days)

See Legend alongside.

Oncological Emergencies 115 TREATMENT APPROACHES

Figure 2. Legend

CVAD: central venous access device; Na: sodium; K: potassium; Cl: chloride; TCO2: total carbon dioxide; SIRS:
systemic inflammatory response syndrome; LRT: lower respiratory tract; URT: upper respiratory tract; GI: gastro-
intestinal tract; GU: genito-urinary tract; O2: oxygen; IV: intravenous; MASCC: Multinational Association for
Supportive Care in Cancer; PO: per os (by mouth).

* The Northern Ireland Cancer Network states that neutropaenic sepsis is a “time-dependent” condition, the
successful management of which is dependent upon the early recognition of the likelihood that the cancer
patient’s problem represents a neutropaenic fever/sepsis syndrome1. Since more than 70 percent of cancer
treatment-related syndromes, including neutropaenic fever, manifest within four to six weeks of systemic
treatment2, the Northern Ireland Cancer Network has recommended a history of chemotherapy within the past
six weeks as a sensitive discriminator to detect patients with neutropaenic fever/sepsis syndromes by triage
services in health-care facilities1.

¶ SIRS is a clinical syndrome that is a form of dysregulated inflammation. The term SIRS has routinely been
associated with both infectious processes (sepsis) and noninfectious insults, such as an autoimmune disorder,
pancreatitis, vasculitis, thrombo-embolism, burns, or surgery. SIRS was previously defined as two or more
abnormalities in temperature, heart rate, respiration, or white blood cell count.3 However, in practice, its clinical
definition and pathophysiology are nonequivocal such that SIRS and early sepsis cannot be readily distinguished.
Thus, when SIRS is suspected it should prompt an evaluation for a septic focus.

Δ Hypoperfusion is defined by hypotension persisting after initial fluid challenge or blood lactate concentration
≥4 mmol/L.4 Refer to the UpToDate topic review on the definition of sepsis and SIRS for additional details.

◊ Goal-directed therapy for initial resuscitation includes the following: (a) central venous pressure 8 to 12
mmHg; (b) mean arterial pressure ≥65 mmHg; (c) urine output ≥0.5 mL/kg per hour; and (d) central venous
(superior vena cava) oxygen saturation ≥70 percent or mixed venous oxygen saturation ≥65 percent.4 Refer to
the UpToDate topic review on evaluation and management of sepsis for additional details.

§ Sepsis is defined as the presence (probable or documented) of infection together with systemic
manifestations of infection (eg, temperature >38.3 or <36°C, heart rate >90 beats/min, respiratory rate >20
breaths/min, altered mental status, leukocytosis, arterial hypotension, arterial hypoxaemia).4 Refer to the
UpToDate topic review on the definition of sepsis and SIRS for the full diagnostic criteria for sepsis.

¥ Patients at low risk for serious complications are defined as those who are expected to be neutropaenic
(absolute neutrophil count [ANC] <500 cells/microL) for ≤7 days and those with no comorbidities or evidence
of significant hepatic or renal dysfunction. High-risk patients are defined as those who are expected to be
neutropaenic (ANC <500 cells/microL) for >7 days; patients with neutropaenic fever who have ongoing
comorbidities or evidence of significant hepatic or renal dysfunction are also considered to be high risk,
regardless of the duration of neutropaenia. The Multinational Association for Supportive Care in Cancer
(MASCC) risk index can also be used for determining risk. A MASCC score of ≥21 predicts a low risk for medical
complications of neutropaenic fever syndromes that would require hospitalisation and/or prolonged length of
hospitalisation. A score of <21 predicts patients at high risk for such complications.5 Refer to the text for more
details regarding the definitions of low- and high-risk patients based upon clinical criteria and the MASCC risk
score.

REFERENCES
1. B ell MS, Scullen P, McParlan D, et al. Neutropenic Sepsis Guideline. In Edition Northern Ireland

Cancer Network 2010;1-11.
2. M cKenzie H, Hayes L, White K, et al. Chemotherapy outpatients’ unplanned presentations to

hospital: a retrospective study. Support Care Cancer. 2011;19:963-969.
3. L evy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Defini-

tions Conference. Intensive Care Med. 2003;29:530.
4. D ellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for

management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580.
5. K lastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care

in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic
cancer patients. J Clin Oncol. 2000;18:3038-3051.

Source: UpToDate © 2018 (https://www.uptodate.com/contents/image?imageKey=ID%2F57616&topicKey=ID%2F1
6888&source=outline_link)

HANDBOOK OF ONCOLOGY

116 CARING FOR PATIENTS WITH CANCER

lymph nodes or mediastinal structures, or or cerebral compromise, and treat the
from thrombosis within the SVC, as may underlying malignancy. Patients who pre-
result from central venous catheters. An sent with stridor due to severe laryngeal
intrathoracic malignancy is responsible for oedema and occlusion, or with coma,
between 60 and 85% of cases, with the re- represent a true medical emergency and
mainder resulting from thrombosis, fungal immediate treatment with stent place-
infections, fibrosing mediastinitis and post- ment and/or radiotherapy is indicated.
radiation fibrosis. The most common malig- For others, emergency radiotherapy may
nancies associated with SVC syndrome are be deferred until a full diagnostic work-up
small-cell and non-small-cell lung cancers has been concluded. This has not shown
and lymphoma. Together, these account to negatively impact on treatment out-
for approximately 95% of cases. Other ma- comes.16 Evidence-based guidelines for
lignancies which may be associated in- the management of SVC are not avail-
clude any tumour which has metastasised able, and international recommenda-
to the mediastinal lymph nodes, mesothe- tions support radiotherapy and/or stent
lioma, thymoma and germ-cell tumours in- placement.17-19 General measures include
volving the mediastinum. Importantly, this is nursing the patient in a semi-upright posi-
the presenting symptom in roughly 60% of tion, and face-mask oxygen may provide
patients with SVC syndrome.15 symptomatic relief. Intravenous steroids
are helpful in steroid-responsive malig-
PRESENTING SIGNS AND SYMPTOMS nancies such as lymphoma and thymo-
The rate of onset of symptoms is related to ma, and in association with radiotherapy
the rate of obstruction of the SVC. Obstruc- which may result in initial worsening of la-
tion of blood flow within the SVC results in ryngeal oedema. Diuretics may be used;
the dilation of venous collaterals. Despite however, no prospective evidence exists
this, pressure within the venous system re- to support their use.
mains elevated and interstitial oedema of
the head, neck and upper limbs develops. Specific measures include radiotherapy
This oedema may compromise the upper alone, or in combination with placing of
aerodigestive tract, and accounts for the an IVC stent. Chemosensitive tumours,
characteristic symptoms associated with such as small-cell lung cancer, lymphoma
the syndrome. Typical presenting signs and germ-cell tumours are generally treat-
and symptoms include swelling of the neck ed with initial chemotherapy. In these ma-
and upper limbs. Oedema of the upper lignancies, radiotherapy may be added
airways results in stridor, cough, hoarse- and has shown to decrease local recur-
ness, dyspnoea and dysphagia. Cerebral rence rates and improve OS.
oedema typically results in headaches,
and may result in cerebral ischaemia, her- REFERENCES
niation and infrequently death. The diag-
nosis is made clinically, on the basis of the 1. Hanna L, Crosby T and Macbeth F. Practi-
above characteristic signs and symptoms cal Clinical Oncology. 2nd ed. Cambridge:
and is confirmed by chest radiology. The Cambridge University Press; 2015.
majority of patients with SVC will have
an abnormal chest radiograph, however 2. Akram H, Allibone J. Spinal surgery for pal-
the most useful investigation is a contrast- liation in malignant spinal cord compres-
enhanced CT scan of the chest. This will sion. Clinical Oncology. 2010;22:792-800.
detail the level and extent of obstruction,
and the presence of associated thrombus. 3. Prewett S, Venkitaraman R. Metastatic
spinal cord compression: review of the
MANAGEMENT evidence for a radiotherapy dose frac-
The goals of management are to allevi- tionation schedule. Clinical Oncology.
ate symptoms, prevent airway obstruction 2010;22:222-230.

HANDBOOK OF ONCOLOGY 4. Prasad D. Schiff D. Malignant spinal cord
compression. Lancet Oncol. 2005;6:15-24.

5. Barrett A, Dobbs J, Morris S, et al. Practical
Radiotherapy Planning. 4th ed. London:
Hodder Arnold; 2009.

6. Patchell RA, Tibbs PA, Regine WF, et al. Di-
rect decompressive surgical resection in

Oncological Emergencies 117

the treatment of spinal cord compression low-risk febrile neutropenic cancer pa- TREATMENT APPROACHES
caused by metastatic cancer: a randomised tients. J Clin Oncol. 2000;18:3038-3051.
trial. Lancet. 2005;336(9486);643-648. 14. L afferty FW. Differential diagnosis of hyper-
7. K lastersky J, de Naurois J, Rolston K, et al. calcaemia. Journal of Bone Mineral Re-
Management of febrile neutropaenia: search. 1991;6(Suppl 2):S51.
ESMO Clinical Practice Guidelines. Annals 15. U pToDate © Consensus-based Guide-
of Oncology. 2016;27(Suppl5):v111-v118. lines. Malignancy-related superior vena
8. N ational Comprehensive Cancer Network cava syndrome. https://www.upto-
(NCCN): Clinical Practice Guidelines in On- date.com/contents/malignancy-relat-
cology. Prevention and Treatment of Can- ed-superior-vena-cava-syndrome?search
cer-Related Infections. J Natl Compr Canc =superior%20vena%20cava%20syndro
Netw. 2016 Jul;14(7):882-913. me&source=search_result&selectedTitl
9. F lowers CR, Seidenfeld J, Bow EJ, et al. e=1~150&usage_type=default&display_
American Society of Clinical Oncology rank=1. Accessed January 2018.
(ASCO): Antimicrobial prophylaxis and out- 16. S chraufnagel DE, Hill R, Leech JA, et al.
patient management of fever and neutro- Superior vane cava obstruction. Is it a
paenia in adults treated for malignancy. J medical emergency? American Journal of
Clin Oncol. 2013 Feb 20;31(6):794-810. Medicine. 1981;70(6):1169.
10. N ational Comprehensive Cancer Network 17. N ational Comprehensive Cancer Network
(NCCN): Clinical Practice Guidelines in On- (NCCN). NCCN Clinical practice guidelines
cology. Myeloid Growth Factors. Version in oncology. Cancer-associated venous
2.2017;MGF-A 1-4. thromboembolic disease. Version 1. 2017.
11. A apro MS, Bohlius J, Cameron DA, et al. http://www.nccn.org/professionals/physi-
2010 update of EORTC guidelines for the cian_gls/f_guidelines.asp. Accessed Janu-
use of granulocyte-colony-stimulating fac- ary 2018).
tor to reduce the incidence of chemother- 18. Kvale PA, Selecky PA, Prakash UB, et al. Ameri-
apy-induced febrile neutropaenia in adult can College of Chest Physicians (ACCP). Pal-
patients with lymphoproliferative disorders liative care in lung cancer: ACCP evidence-
and solid tumours. European Journal of based clinical practice guidelines (2nd ed).
Cancer. 2011;47:8-32. Chest. 2007 Sep;132(Suppl3):368S-403S.
12. N ational Institute for Health and Care Ex- 19. U pToDate © Consensus-based Guidelines.
cellence (NICE). Neutropaenic sepsis: Malignancy-related superior vena cava
prevention and management in people syndrome. https://www.uptodate.com/
with cancer. Clinical Guideline (CG151). contents/malignancy-related-superior-ve-
Published 19 September 2012. Nice.org.uk/ na-cava-syndrome?search=superior%20
guidance/cg151. Accessed January 2018. vena%20cava%20syndrome&source=
13. K lastersky J, Paesmans M, Rubenstein EB, search_result&selectedTitle=1~150&usag
et al. The Multinational Association for Sup- e_type=default&display_rank=1#H18. Ac-
portive Care in Cancer Risk Index: a mul- cessed January 2018.
tinational scoring system for identifying

HANDBOOK OF ONCOLOGY

118 CARING FOR PATIENTS WITH CANCER

Childhood Cancer and Its Warning Signs

Prof M Kruger survival rates have improved from poor
survival in the first half of the 20th Century
MB ChB, M Med Paed, M Phil to more than 80% survival in high-income
countries (HICs).5,6 It is especially the sur-
(Applied Ethics), PhD vival of acute lymphoblastic leukaemia,
 Professor, Department of Paediatrics the most common childhood cancer, that
and Child Health, Stellenbosch University improved from less than 10% five-year sur-
vival in the 1960s to more than 80% by 2013
Childhood cancer is rare, but highly cur- for children under 15 years of age. Ado-
able, for which early diagnosis is crucial as lescents between 15 and 19 years of age,
cancer is an important cause of death in however, still do not have the same im-
children past infancy in the USA.1 In low- proved survival rate as younger children,
and middle-income countries (LMICs), the which is probably due to the presence of
diagnosis of paediatric cancer is often de- more high-risk features at diagnosis, which
layed, resulting in the child presenting with impacts negatively on prognosis.
advanced disease, which reduces the
chances of cure.2 For this reason, it is im- It is heartening to note that there has also
portant to ensure that the primary health- been a decrease in the childhood-cancer
care staff in particular are educated in mortality rate of more than 50% from the
recognising the warning signs of child- 1970s to the year 2014, again emphasising
hood cancer. the curative potential of childhood can-
cer.7,8 Certain cancers, however, still have
EPIDEMIOLOGY a poor survival rate, such as brain tumours,
particularly pontine gliomas, and meta-
An estimated 200 000 children are diag- static sarcomas.7,9 More research is need-
nosed with cancer worldwide annually. ed to understand tumour biology and
The world standard population incidence develop innovative cancer medicines for
rate (WSR) for all cancers in children aged these tumours.
0-14 years is 140.6 cases per million person-
years, although the WSR is less than 100 for CHILDHOOD CANCERS VERSUS
sub-Saharan Africa.3 This lower WSR in sub- ADULT CANCERS
Saharan Africa is probably due to either
missed diagnosis or children dying of infec- Cancer in childhood is distinctly differ-
tious diseases prior to developing a child- ent from cancer in adults and therefore
hood cancer. Ribeiro, et al have reported needs a different approach to diagnosis
a marked discrepancy between actual and treatment. The majority of childhood
identified childhood-cancer patients and cancers has a mesenchymal or neuro-
the expected number of paediatric can- ectodermal origin versus adult cancers,
cers, extrapolated from population-based which are usually of epithelial origin.10 Fur-
data in LMICs.4 The most common cancers thermore, specific childhood cancers are
in children under 15 years of age are leu- associated with specific age ranges and,
kaemias, brain tumours, lymphomas neu- in general, the highest incidence is after
roblastoma, nephroblastoma and soft-tis- birth, which declines with the lowest point
sue sarcomas. The age-specific incidence at about 10 years of age. Childhood solid
rate (ASR) for adolescents 15 to 19 years tumours include particularly embryonal
of age is 185.3 per million person-years, of tumours such as neuroblastoma, nephro-
which the most common is lymphoma with blastoma and rhabdomyosarcoma, which
an ASR of 41.8 per million person-years.3 resemble specific organs’ primordial cells.
There is a linear increase in incidence of
SURVIVAL non-embryonal tumours in adolescents,

Childhood cancer is one of the success sto-
ries of the 20th Century as childhood-cancer

HANDBOOK OF ONCOLOGY

Childhood Cancer and Its Warning Signs 119

which extends into adulthood. Males un- is diagnosed with a sarcoma before the TREATMENT APPROACHES
der 15 years of age are more affected age of 45 years of age. This syndrome is
than females by the common childhood extremely rare in children.13 Affected pa-
cancers, such as acute lymphoblastic leu- tients will have germline TP53 mutations
kaemia and lymphomas.6 and may develop any of the following
tumours: sarcoma, premenopausal breast
CAUSES cancer, brain tumours, leukaemia, lym-
phoma, adrenocortical carcinoma and
Causes of childhood cancer are unknown. colorectal cancers. Most children with
There is minimal evidence for environmen- anaplastic sarcomas will have a TP53 mu-
tal factors and other exogenous factors to tation.
be involved in the aetiology of childhood
cancer. Children born with a congenital WARNING SIGNS OF
malformation are at higher risk to develop CHILDHOOD CANCER
a childhood cancer.6,11 Nephroblastoma or
Wilms tumour, for example, is associated Early diagnosis is crucial for cure. Limited
with aniridia and Beckwith-Wiedemann disease also needs less intense treatment
syndrome. This is true for both major and and has a shorter duration with reduced
minor malformations, as reported by costs.14 Unfortunately, there is often a time
Merks, et al.12 delay in the diagnosis of childhood can-
cer, which leads to late diagnosis and
Risk factors for acute lymphoblastic leu- advanced stage of disease, necessitating
kaemia (ALL), the most common child- more intense therapy and with reduced
hood cancer, include Down’s syndrome, possibility of cure.15 It is therefore impor-
neurofibromatosis type 1, Bloom syndrome tant for all health-care workers to be able
and ataxia teleangiectasia.6,13 Prenatal to identify the warning signs of childhood
exposure to x-rays also increases the risk of cancer early. These clinical signs are es-
ALL. SEER data from the USA indicate that pecially persistent, and should alert the
more white children will develop ALL than health-care worker to identify potentially
black children.6 Down’s syndrome is also affected children for referral for special-
associated with an increased risk of de- ised investigations.14
veloping acute myeloid leukaemia (AML).
Neurofibromatosis type 1 and tuberous The warning signs are the following: any
sclerosis predispose children to brain tu- abnormal mass or growth, a white spot
mours. Both Hodgkin’s lymphoma (HL) and in the eye, persistent fever, weight loss,
non-Hodgkin’s lymphoma (NHL) are asso- pallor, fatigue or lethargy, any abnor-
ciated with Epstein-Barr virus infections, mal bleeding, persistent or recurrent pain
while both acquired and congenital im- and neurological deterioration.14 Many
munodeficiency are associated with NHL.6 of these signs can also be indicative of
other chronic infections, and a high index
About 5% of childhood cancers are of suspicion is needed when the following
caused by an inherited genetic mutation, systems are affected, i.e., bone marrow,
of which bilateral retinoblastoma is the first lymph nodes, bone, abdominal and soft
described hereditary autosomal domi- tissue masses.
nant cancer.13 This disease usually presents
at a younger age than sporadic unilateral The abnormal mass can be either in the
retinoblastoma. Affected individuals carry abdomen, in a limb or can be enlarged
a germline mutation in the RB1 gene on lymph nodes. Tumours presenting in the
chromosome 13q14. All siblings of children abdomen include nephroblastoma, neu-
with bilateral retinoblastoma should have roblastoma and embryonal rhabdomyo-
regular ophthalmological surveillance in sarcoma. It is important to examine the
the first two years of life and preferably child for hypertension associated with an
also genetics for RB1 gene mutations.13 abdominal mass as both neuroblastoma
and nephroblastoma can cause hyper-
Li-Fraumeni syndrome is a rare familial tension in a child. If not diagnosed and
cancer syndrome, where the proband
HANDBOOK OF ONCOLOGY

120 CARING FOR PATIENTS WITH CANCER

treated, this hypertension may result in hy- Another danger sign is persistent or recur-
pertensive encephalopathy. A white spot rent headache, which can present with
in the eye before the age of one year or without early morning vomiting. The
should alert the health-care worker to headache with associated vomiting is
the potential diagnosis of retinoblastoma. usually due to the raised intracranial pres-
Often the parents notice the white spot sure. Other abnormal neurological signs
when photos with a flash are taken and that may be present are ataxia or poor
the red reflex is absent. balance, onset of weakness of limbs or
trunk, a history of regression of milestones
A child, presenting with general symp- or sudden onset of convulsions. Parents
toms such as prolonged fever, weight loss may also complain about a change in the
and fatigue, may suffer from a childhood child’s temperament.
cancer. The child, presenting with an un-
explained prolonged fever for more than The abovementioned warning signs
two weeks without a clear infection site are not specific to childhood cancer and
and not responding to antibiotics, should health-care systems should have an effec-
be investigated for a childhood cancer. tive referral system to ensure that children
Unexplained weight loss especially is a presenting with these signs are identified,
presenting sign in solid tumours. The child referred and appropriately investigated.
may also complain of nausea, loss of ap- Poiyaidis, et al have described the Saint
petite and night sweats (often present in Siluan warning signs of childhood cancer,
Hodgkin’s lymphoma). which summarise the above-mentioned
warning signs, and after undertaking a
A child with leukaemia may present with campaign to educate primary health-
pallor and fatigue due to the associated care workers in 2001, reported a statisti-
anaemia. Leukaemias cause easy bruis- cally significant increase (p=0.001) in the
ing or bleeding, especially epistaxis, gum referral of new childhood-cancer patients
bleeding, rectal bleeding or bleeding at to the Chris Hani Baragwanath hospi-
any other abnormal site. The bleeding is tal thereafter.16 Such educational pro-
usually the result of low platelets as plate- grammes, when aimed particularly at pri-
lets are not produced because of abnor- mary health-care doctors and nurses, will
mal proliferation of the leukaemic blasts in assist in the early diagnosis of childhood
the bone marrow. Metastatic disease can cancer, resulting in improved survival.
also cause abnormal bleeding as there is
invasion of metastasis in the bone marrow. OPTIMAL TREATMENT
OF CHILDHOOD CANCER
Persistent pain, especially bone pain,
should be deemed pathological, particu- Children should be treated in paediat-
larly if there is a history of the child being ric oncology units, which are usually at-
woken by the pain at night. There should tached to the major university teaching
be a high suspicion in adolescents, who hospitals in South Africa as the treatment
are often active in sport and who present is complex, necessitating the staff to be
with persistent bone pain not responding experienced in the management of both
to standard anti-inflammatory medicines, the treatment, as well as the ability to pro-
as this may be indicative of an osteosar- vide optimal supportive care. The pae-
coma (bone tumour). There is often a diatric oncology team usually includes
history of trauma and although these paediatric oncologists, oncology-trained
adolescents are treated for an injury, the professional nurses, radiation oncologists,
pain does not resolve. Ewing’s sarcoma paediatric surgeons, social workers, dieti-
is another bone tumour that can present cians, physiotherapists and occupational
with bone pain. ALL may present with ar- therapists. Psychological services may
thritis and can be wrongly diagnosed as also be needed. Treatment is usually per
juvenile rheumatoid arthritis. A child with a the standard international treatment pro-
bone tumour or bone metastasis may also tocol, specific for the type of cancer, and
present with pathological fractures.

HANDBOOK OF ONCOLOGY

Childhood Cancer and Its Warning Signs 121

involves onco-chemotherapy, paediatric the health-care community to the possibil- TREATMENT APPROACHES
surgery and/or radiotherapy, as well as ity of a child having developed a cancer.
the management of chemotherapy- or The warning signs are important to share in
radiation-related complications. Com- childhood-cancer awareness campaigns,
mon complications are neutropaenic as this may assist in early identification and
sepsis, bleeding disorders and anaemia. diagnosis. Country policy-makers should en-
Children with amputations will also need sure that there is an effective referral system
extensive rehabilitation to be able to live for these children with adequate treatment
as normal a life as possible and to adjust facilities, as childhood cancer is curable in
to the use of artificial limbs. the majority of patients.

LONG-TERM FOLLOW-UP REFERENCES

Survivors of childhood cancer need life- 1. Siegel RL, Miller KD, Jemal A. Cancer Sta-
long follow-up care, initially in the first five tistics, 2017. CA: A Cancer Journal for Clini-
years to ensure that there is no recurrence cians 2017; ]67(1):7-30.
of the cancer and thereafter for the po-
tential complications of the different treat- 2. Kruger M, Hendricks M, Davidson A, et al.
ment modalities. Up to 75% of children may Childhood cancer in Africa. Pediatr Blood
suffer at least one long-term late effect, de- Cancer. 2014;61:587-592.
pending on the type of the cancer, the po-
sition of the cancer and the treatment re- 3. Steliarova-Foucher E, Colombet M, Ries
ceived.17,18 Radiotherapy, in particular, can LAG, et al. International incidence of
cause long-term effects such as the need childhood cancer, 2001-10: a population
for joint replacement, congestive heart based registry study. Lancet Oncology.
failure (if the chest was irradiated) and 2017;18:719-731.
secondary cancers. Onco-chemotherapy
can also damage the important target or- 4. Ribeiro R, Steliarova-Foucher E, Magrath I,
gans such as the heart, kidneys and liver, as et al. Baseline status of paediatric oncol-
well as cause hearing loss. ogy care in ten low-income or mid-income
countries receiving My Child Matters sup-
As the current treatment aims are to mini- port: a descriptive study. Lancet Oncol.
mise long-term side effects, survivors in re- 2008;9:721-729.
cent decades suffer fewer long-term ad-
verse effects. It is important that a survivor 5. O’Leary M, Krailo M, Anderson JR, Rea-
of childhood cancer should be provided man GH, Children’s Oncology Group.
with a cancer-treatment record that in- Progress in childhood cancer: 50 years of
cludes the following information:19 research collaboration, a report from the
n type and stage of cancer Children’s Oncology Group. Semin Oncol.
n date of diagnosis and dates of relapses 2008;35(5):484-93.
n i maging done with dates
n c ontact details of treating doctors 6. Scheurer ME, Lupo PJ, Bondy ML. Epide-
n l ist of onco-chemotherapy medicines miology of childhood cancer. In: Pizzo PA,
Poplack DG, editors. Principles and Prac-
received, as well as total doses tice of Pediatric Oncology, 7th ed. Phila-
n t ypes of surgery done, radiotherapy delphia (PA): Wolters Kluwer; 2016:2-9.

doses and dates with exact description 7. Curtin SC, Minino AM, Anderson RN. De-
of sites clines in cancer death rates among chil-
n any serious complications during dren and adolescents in the United States,
treatment and the date of therapy 1999-2014. National Center for Health Sta-
completed. tistics Data Brief. 2016;257:1-8.

CONCLUSION 8. Jemal A, Ward EM, Johnson CJ, et al. An-
nual Report to the Nation on the status of
As the majority of children in LMICs are di- cancer, 1975-2014, featuring survival. Jour-
agnosed late, it is important to sensitise nal of the National Cancer Institute. 2017;
109(9).

9. Warren KE. Diffuse intrinsic pontine glioma:
poised for progress. Frontiers in Oncology.
2012;2:205.

10. Triche TJ, Hicks MJ, Sorensen PH. Diagnos-
tic pathology of pediatric malignancies.
In: Pizzo PA, Poplack DG, editors. Princi-
ples and Practice of Pediatric Oncology,

HANDBOOK OF ONCOLOGY

122 CARING FOR PATIENTS WITH CANCER

7th  ed. Philadelphia (PA): Wolters Kluwer; 15. Stefan DC, Siemonsma F. Delay and caus-
2016:131-132. es of delay in the diagnosis of childhood
11. Agha MM, Williams JI, Marrett LL, et al. Con- cancer in Africa. Ped Blood Cancer. 2011;
genital abnormalities and childhood can- 56(1):80-85.
cer. Cancer. 2005;103(9):1939-1948.
12. Merks JH, Ozgen HM, Koster J, et al. Preva- 16. Poyiadjis S, Wainwright L, Naidu G, et al.
lence and patterns of morphological ab- Ped Blood Cancer. 2011;56(2):314-316.
normalities in patients with childhood can-
17. Armstrong GT, Kawashima T, Leisenring W,
cer. JAMA. 2008;299(1):61-69. et al. Aging and risk of severe, disabling,

13. Plon SE, Malkin D. Childhood cancer and life-threatening, and fatal events in the
heredity. In: Pizzo PA, Poplack DG, editors.
childhood cancer survivor study. J Clin On-
Principles and Practice of Pediatric Oncol- col. 2014;32:1-22.

ogy, 7th ed. Philadelphia (PA): Wolters Klu- 18. G eenen MM, Cardous-Ubbink MS, Kre-

wer; 2016:13-31. mer LCM, et al. Medical assessment of

14. Poyiadjis S. Early warning signs of cancer in adverse health outcomes in long-term
children/models for early diagnosis. In: Ste-
fan DC, Rodriguez-Galindo C, editors. Pae- survivors of childhood cancer. JAMA.
2007;297(24):2705-15.
diatric Hematology-Oncology in Countries 19. Poplack DG, Fordis M, Landier W, et al.

with Limited Resources: a practical manu- Childhood cancer survivor care: develop-
al. New York: Springer; 2014:65-72.
ment of the passport for care. Nature Re-
views Clin Oncology. 2014;11:740-50.

HANDBOOK OF ONCOLOGY

Common Childhood Cancers 123

Common Childhood Cancers TREATMENT APPROACHES

Prof M Kruger to an aberrant immune response and pre-
disposing the individual to develop ALL.7
MB ChB, M Med Paed, M Phil (Applied Epstein-Barr virus infection is associated
with both ALL, as well as endemic Burkitt’s
Ethics) cum laude, PhD lymphoma.3 Exposure to ionising radia-
 Professor, Department of Paediatrics tion is a known cause of childhood ALL, as
and Child Health, Stellenbosch University documented after the atomic bomb ex-
plosions in Japan during World War II.3
Common cancers of childhood include
acute lymphoblastic leukaemia (ALL), CLINICAL PRESENTATION
brain tumours, lymphomas, neuroblas- The history of illness is usually short and pre-
toma and nephroblastoma.1,2 Retinoblas- senting signs include pallor, fatigue, fever,
toma needs mentioning as the cancer generalised lymphadenopathy, hepato-
may be more common in sub-Saharan splenomegaly and abnormal bleeding
Africa. Steliarova-Foucher, et al2 report in (petechiae, epistaxis, gum-bleeding, bruis-
their study for the period 2001 till 2010 that ing).3 Children may also have headaches
the world standard population incidence if the central nervous system is affected,
rate (WSR) for leukaemias is 46.4 per million as well as bone pain with lytic lesions in the
person-years, followed by brain tumours bone. The thymus may be enlarged, com-
(WSR 28.2) and lymphomas (WSR 15.2) in pressing the superior vena cava, which is
children 0-14 years of age. known as superior vena cava syndrome
(SVCS), a medical emergency.4 The clini-
ACUTE LYMPHOBLASTIC cal signs of SVCS include cough, dysp-
LEUKAEMIA EPIDEMIOLOGY noea, orthopnoea and cyanosis of the
upper body. This syndrome is usually asso-
Acute lymphoblastic leukaemia (ALL) is ciated with T-cell ALL, but can also occur
the most common leukaemia in white in Non-Hodgkin’s lymphoma (NHL) and
children, while the incidence rate is lower Hodgkin’s lymphoma. Emergency treat-
for black children. The peak incidence is ment includes steroids and chemotherapy
between two and five years of age with a as standard of care. Differential diagnosis
male predominance.3 include juvenile rheumatoid arthritis, idi-
opathic thrombocytopaenic purpura and
PATHOGENESIS other malignancies such as neuroblasto-
As the peak age is between two and five ma or non-Hodgkin’s lymphoma (NHL).
years, there are two hypotheses to explain
the observation, namely the “delayed-in- PROGNOSIS
fection” hypothesis of Greaves and “pop- Age, the initial white cell count, gender,
ulation-mixing hypothesis”.4 According to immunophenotype, ethinicity, ploidy and
Greaves, children who are insulated from both molecular- and cytogenetics deter-
exposure to infections at an early age mine prognosis.3 Younger than one year,
have naïve immune systems and there- older than 10 years, a high initial white cell
fore predispose them to a pathological count of more than 50 000 cells per mm3
response to an infection.5 In support of and males have a worse prognosis.
this hypothesis is the evidence that early
day-care attendance will protect children ALL CLASSIFICATION
against the development of ALL.6 Kinlen ALL is classified into either B-cell or T-cell
describes in his population-mixing hypoth- ALL or undifferentiated leukaemia and dis-
esis,7 that mixing individuals from develop- tinguished from acute myeloid leukaemia
ing and industrialised societies may lead
to infection exposure in populations previ- HANDBOOK OF ONCOLOGY
ously isolated from such infections, leading

124 CARING FOR PATIENTS WITH CANCER

(AML) on the basis of morphology and im- both embryonal tumours.9 A small number
munophenotype.3 The majority of children of tumours will be associated with cancer
will have a precursor B-cell ALL, known as predisposition syndromes such as Li-Frau-
common ALL. It is essential to determine meni’s syndrome, neurofibromatosis types,
the ploidy rate, as hyperdiploidy is associ- tuberous sclerosis 1 and 2 and Gorlin’s syn-
ated with a good prognosis. This classifica- drome.8 The clinical symptoms and signs
tion has implications for both treatment include headaches with or without early
protocol and prognosis. For this reason, morning vomiting (due to raised intracra-
the child with suspected ALL should be nial pressure), cerebellar ataxia, cranial
referred to a specialised paediatric on- nerve palsies, pyramidal tract signs and/or
cology unit for the necessary diagnostic change in temperament.8,9 Correct diag-
investigations. Molecular- and cyoge- nosis is extremely important to ensure the
netics are done to assist in risk stratifica- most appropriate treatment and is made
tion, which again determines intensity of after magnetic resonance imaging and
onco-chemotherapy. The most common biopsy or surgical excision (if possible).8
translocation is t(12;21), associated with a Management is according to histologi-
favourable prognosis, followed by t(1;19). cal type, site and degree of malignancy.
Treatment usually involves a multimodal
TREATMENT AND OUTCOME approach, combining surgery, radiother-
Current event-free survival rates for ALL in apy with or without onco-chemotherapy.
children is more than 80% in high-income There is an improved survival rate if the tu-
countries.3 This is because of multi-agent mour is completely excised. These children
combination onco-chemotherapy, im- often suffer long-term effects, ranging
proved supportive care and optimal in- from neurocognitive disability to seizure
dividual medicine-dosing. The treatment disorders and stroke.
protocol is decided according to risk
stratification and appropriate for cell type LYMPHOMAS
(either T- or B-cell ALL) with risk stratifica-
tion and consists of an induction phase, a Children can develop either Hodgkin’s
post-induction phase and maintenance lymphoma (HL) or non-Hodgkin’s lympho-
therapy for two years, as well as central ma (NHL).
nervous system (CNS) preventive therapy.
A stem cell transplant may be indicated, HODGKIN’S LYMPHOMA
especially for relapses.
Hodgkin’s lymphoma usually presents in
BRAIN TUMOURS adolescence and is rare under five years
of age.10 There is a male predominance
Brain tumours are the second most com- and the tumour is associated with in-
mon childhood cancer and tumours are creased family size and poor socio-eco-
heterogenous in pathology.8,9 More males nomic circumstances. Epstein-Barr virus
than females are affected. The WHO clas- infection is a potential causative factor.
sification system classifies brain tumours by The most common histology according
histology type, site and degree of malig- to the WHO histological classification sys-
nancy. During childhood, the majority will tem is nodular sclerosis subtype, followed
be located infratentorially in either the by mixed cellularity subtype with nodular
cerebellum or brainstem, while the first two lymphocyte-predominant-, lymphocyte-
years of life (astrocytoma) and late ado- rich- and lymphocyte-depleted subtypes
lescence are associated with supraten- being rare. Clinically, patients present with
torial tumours. Common brain tumours enlarged lymph nodes in the neck, axilla,
include pilocytic astrocytoma, medullo- groin or with lymph nodes in the mediasti-
blastoma, ependymoma, and supraten- num. They may also have lost weight in the
torial primitive neuro-ectodermal tumours preceding six months, unexplained fever
(PNET). Medulloblastoma and PNET are of more than 38°C, fatigue and drenching
night sweats, classified as “B” symptoms.
HANDBOOK OF ONCOLOGY

Common Childhood Cancers 125

A large mediastinal mass may also cause NEUROBLASTOMA TREATMENT APPROACHES
superior vena cava syndrome (see under
ALL). HL is staged according to the Ann Ar- Neuroblastoma is the most common solid
bor staging classification: Stage I is limited tumour in childhood outside the central
to a single lymph-node region, stage II has nervous system and occurs in infants and
two or more involved lymph-node regions children under five years of age, with a
on the same side of the diaphragm, stage median age of about 19 months.13 Slightly
III has involvement of lymph nodes on more boys are affected. Aetiology is un-
both sides of the diaphragm and stage IV known. The tumour arises from immature
has disseminated disease, involving extra- nerve cells in either the adrenal gland or
lymphatic tissue. Risk features at diagnosis any site of the sympathetic chain and is
include the “B” symptoms, bulky disease associated with MYCN amplification.13
and extra-lymphatic involvement. Prog- There is a varying degree of neuronal dif-
nosis is good for low-risk disease, but high- ferentiation and the fully differentiated
risk disease necessitates more intensive ganglioneuroma is benign.
therapy. The differential diagnosis is tuber-
culosis in particular, as the clinical pres- Clinical signs include abdominal mass or
entation is very similar. Treatment involves thoracic mass, pain (in various locations of
onco-chemotherapy with or without ra- the body), inability to walk, changes in the
diotherapy. Stem-cell transplant may be eyes (raccoon eyes: bulging and periorbi-
indicated for high-risk disease, especially tal ecchymosis), diarrhoea and hyperten-
for relapses. sion. Paraspinal tumours can extend into
the neural foramina, causing compression
NON-HODGKIN’S LYMPHOMA of the spinal cord with acute paraplegia.
Investigations should include the determi-
The lymphoma originates either from pre- nation of tumour markers such as HVA and
cursor B-cells or thymic T-cells.11 The most VMA in the urine, neuron-specific enolase
common type in childhood is Burkitt’s lym- (NSE), ferritin and LDG in serum, as well
phoma (BL), a B-cell NHL, which occurs in as bone-marrow aspiration and 123I-MIBG
young children under five years of age11. scintigraphy for evaluation of bone and
There are two distinct clinical presenta- other organ involvement.
tions, namely endemic BL, which presents
with a jaw mass, and sporadic BL, which Biopsy or primary tumour excision should
presents with an abdominal mass. Chil- confirm the diagnosis. Staging is accord-
dren with abdominal masses may present ing to localisation, resectability and meta-
with nausea and vomiting, distension, static involvement. Stage IV needs to be
gastro-intestinal bleeding, intestinal perfo- mentioned as this is a stage found in in-
ration and ileocecal intussusception. The fants under one year of age, character-
disease occurs in the age group four to ised by a localised tumour with dissemina-
seven years of age, with a male predomi- tion to the skin, liver and/or bone marrow
nance. Endemic BL is found in the “ma- but with no bone involvement, which has
larial belt” in Equatorial Africa, associated an excellent survival rate.
with both Epstein-Barr virus infection and
malaria. HIV-infection is also associated Prognosis depends on the stage of dis-
with BL. Diagnosis is made through biopsy ease, the assigned risk, the histology, age
as BL is extremely sensitive to onco-chem- at diagnosis, ploidy and MYCN amplifica-
otherapy, making surgical debulking un- tion. Treatment consists of tumour excision
necessary, except if there is obstruction. (if possible) and onco-chemotherapy.
The current treatment is intensive onco- Acute spinal compression needs emer-
chemotherapy (e.g., LMB protocol) and gency intervention, either through lami-
supportive care.12 Cure can be achieved nectomy or radiotherapy. Autologous
in more than 90% of patients.11,12 stem-cell transplants may be indicated for
advanced disease if complete remission
is achieved. Targeted delivery of radionu-
clides or molecularly-targeted agents are
being investigated for high-risk disease.13

HANDBOOK OF ONCOLOGY

126 CARING FOR PATIENTS WITH CANCER

NEPHROBLASTOMA with an absent red eye reflex. The child
OR WILMS' TUMOUR may also present with strabismus. Diagnosis
is made with either RETCAM or examination
Nephroblastoma is a paediatric kidney under anaesthesia. Local disease has an
tumour in children under five years of excellent prognosis if diagnosed early and
age, usually present in one kidney, but is amenable to local therapy with vision-
may rarely affect both kidneys (bilateral saving procedures, while local extension
disease).14 Clinically, the children present and metastatic disease necessitate onco-
with an asymptomatic abdominal tumour, chemotherapy. Diagnosis may be delayed
but may have fever or pain and loss of in South Africa, as the warning signs may be
appetite. These children may also have missed, resulting in metastatic disease with a
hypertension. The disease may be asso- poor prognosis.16,17
ciated with aniridia, Beckwith Wiedeman
syndrome and other congenital genito- CONCLUSION
urinary anomalies and is associated with
WT1 gene mutations (11p13). In conclusion, early diagnosis is crucial for
improved survival in children with can-
Of note is that nephroblastoma is seem- cer. Other rare cancers are not discussed
ingly more common in sub-Saharan Africa in this brief chapter regarding common
than neuroblastoma, which differs from childhood cancers. These cancers in-
Europe and the USA. This is specifically the clude bone tumours, sarcomas and other
case for black children.2,14 Nephroblasto- embryonal tumours. A high index of sus-
ma is classified into low risk, intermediate picion is needed to ensure early referral
risk and high risk on the basis of the histol- for specialised investigations in a tertiary
ogy type. Staging is done according to centre to diagnose a potential childhood
prechemotherapy imaging for metastasis cancer. Both the South African Children
and local operative findings at tumour Cancer Study Group members (SACCSG)
excision. Prognosis depends on histology and the Childhood Cancer Foundation of
risk, age and response to treatment with South Africa (CHOC) can provide advice
the current survival rate more than 90% for to any health-care worker and/or parent if
favourable histology. Treatment consists concerned about potential warning signs
of pre-operative onco-chemotherapy to of childhood cancer.18,19
shrink the tumour for easier surgical exci-
sion. Postsurgical treatment depends on REFERENCES
stage at excision with limited disease re-
ceiving limited further chemotherapy, 1. Scheurer ME, Lupo PJ, Bondy ML. Epide-
while advanced disease and metastasis miology of childhood cancer. In: Pizzo PA,
necessitates intensive chemotherapy and Poplack DG, editors. Principles and Prac-
radiotherapy to the tumour bed. Lung me- tice of Pediatric Oncology, 7th ed. Phila-
tastasis can be excised if persistent. delphia (PA): Wolters Kluwer; 2016:2-9.

RETINOBLASTOMA 2. Steliarova-Foucher E, Colombet M, Ries
LAG, et al. International incidence of
Retinoblastoma is a rare tumour, but the childhood cancer, 2001-10: a population
most common eye tumour in children and based registry study. Lancet Oncology.
usually affects young infants and children 2017;18:719-731.
under the age of five years.15 There is an im-
pression that the tumour incidence is higher 3. Rabin KR, Gramatges MM, Margolin JF, et
in Central and South America, India and al. Acute lymphoblastic leukemia. In: Pizzo
sub-Saharan Africa. The majority of tumours PA, Poplack DG, editors. Principles and
appear sporadically, but a small group is as- Practice of Pediatric Oncology, 7th ed.
sociated with a germline mutation in the RB1 Philadelphia (PA): Wolters Kluwer; 2016:463.
gene, leading to the hereditary, often bilat-
eral disease in a younger age group. The 4. Freedman JL, Rheingold SR, Fisher MJ. On-
clinical presentation is usually leucocoria cologic emergencies. In: Pizzo PA, Poplack
DG, editors. Principles and Practice of Pedi-
HANDBOOK OF ONCOLOGY atric Oncology, 7th ed. Philadelphia (PA):
Wolters Kluwer; 2016:967.

5. Greaves M. Infection, immune responses
and the aetiology of childhood leukaemia.
Nat Rev Cancer. 2006;6:193-203.

Common Childhood Cancers 127

6. G ilham C, Peto J, Simpson J, et al. Day 12. P atte C, Auperin A, Gerrard M, et al. Results TREATMENT APPROACHES
care in infancy and risk of childhood acute of the randomized BFM/LMB96 trial for inter-
lymphoblastic leukaemia: findings from UK mediate risk B-cell Non-Hodgkin lymphoma
case-control study. BMJ. 2005;330:1294- in children and adolescents: it is possible to
1297. reduce therapy for the early responding
patients. Blood. 2007;109:2773-2780.
7. K inlen LJ. An examination, with a meta-
analysis, of studies of childhood leukaemia 13. B rodeur GM, Hogarty MD, Bagatell R, et
in relation to population mixing. Br J Can- al. In: Pizzo PA, Poplack DG, editors. Prin-
cer. 2012;107:1163-1168. ciples and Practice of Pediatric Oncology,
7th ed. Philadelphia (PA): Wolters Kluwer;
8. P arsons DW, Pollack IF, Hass-Kogan DA, 2016:772.
et al. Gliomas, ependymomas, and other
nonembryonal tumors of the central nerv- 14. F ernandez CV, Geller JI, Ehrlich PF, et al.
ous system. In: Pizzo PA, Poplack DG, edi- Renal tumors. In: Pizzo PA, Poplack DG,
tors. Principles and Practice of Pediatric editors. Principles and Practice of Pediatric
Oncology, 7th ed. Philadelphia (PA): Wolters Oncology, 7th ed. Philadelphia (PA): Wolters
Kluwer; 2016:628. Kluwer; 2016:753.

9. C hintagumpala MM, Paulino A, Pani- 15. H urwitz RL, Shields CL, Shields JA, et al. In:
grahy A, et al. Embryonal and pineal re- Pizzo PA, Poplack DG, editors. Principles
gion tumors. In: Pizzo PA, Poplack DG, and Practice of Pediatric Oncology, 7th ed.
editors. Principles and Practice of Pediatric Philadelphia (PA): Wolters Kluwer; 2016:700.
Oncology, 7th ed. Philadelphia (PA): Wolters
Kluwer; 2016:671. 16. K ruger M, Reynders D, Omar F, et al. Retino-
blastoma outcome at a single institution in
10. M etzger ML, Krasin MJ, Choi JK, et al. Hodg- South Africa. SAMJ. 2014;104(12):859-863.
kin lymphoma. In: Pizzo PA, Poplack DG,
editors. Principles and Practice of Pediatric 17. S tefan DC, Siemonsma F. Delay and
Oncology, 7th ed. Philadelphia (PA): Wolters causes of delay in the diagnosis of child-
Kluwer; 2016:568. hood cancer in Africa. Ped Blood Cancer.
2011;56(1):80-85.
11. A llen CE, Kamdar KY, Bollard CM, et al.
Malignant non-Hodgkin lymphomas in chil- 18. S o uth African Children Cancer Study
dren. In: Pizzo PA, Poplack DG, editors. Prin- Group members (SACCSG): www.saccsg.
ciples and Practice of Pediatric Oncology, co.za.
7th ed. Philadelphia (PA): Wolters Kluwer;
2016:590. 19. C hildhood Cancer Foundation of South Af-
rica (CHOC): www.choc.org.za.

HANDBOOK OF ONCOLOGY

128 CARING FOR PATIENTS WITH CANCER

HIV-Related Cancers

Dr DJ Eedes INCIDENCE

MBCHB FFRAD(T) Twenty-five to 40 percent of all patients
 Clinical Oncology Advisor, with HIV will develop cancer during their
Independent Clinical Oncology Network lifetimes.6
(ICON)
Some studies indicate that people in-
People infected with HIV have a substan- fected with HIV are 500 times more likely
tially higher risk of some types of cancer than uninfected people to be diagnosed
compared to uninfected people of the with Kaposi’s sarcoma, at least 12 times
same age. The very high incidence of more likely to be diagnosed with non-
Kaposi’s sarcoma was noted early in the Hodgkin’s lymphoma, and, among wom-
AIDS epidemic and in this setting has had en, at least three to five times more likely
a highly aggressive course. to be diagnosed with cervical cancer.1

This disease, along with two other can- In addition, people infected with HIV
cers, are known as “acquired immunode- are at higher risk of several other types of
ficiency syndrome (AIDS)-defining can- cancer. These other malignancies include
cers” or ADCs. anal, liver, and lung cancer, and Hodg-
kin’s lymphoma.
These three cancers are:
n Kaposi’s sarcoma (KS) People infected with HIV are at least
n Non-Hodgkin’s lymphoma (NHL) 20 times more likely to be diagnosed with
n I nvasive cervical cancer anal cancer, three times as likely to be di-
agnosed with liver cancer, two to three
A diagnosis of any one of these cancers times as likely to be diagnosed with lung
marks the point at which HIV infection has cancer, and at least eight times more
progressed to AIDS. likely to be diagnosed with Hodgkin’s lym-
phoma.1
The pattern of cancers in HIV-infected
patients has altered with the increased use An increased risk of testicular cancer
of antiretroviral therapy (ART), previously (seminomas in particular) and a two to
known as highly active antiretroviral thera- three times increased risk of head and
py (HAART). neck cancers (40% related to oral HPV
infection) is seen in HIV-infected patients.
In countries where there is a high usage HPV-related head and neck cancers are
of this medication, the incidence of Kapo- known to have a better prognosis than
si’s sarcoma and non-Hodgkin’s lymphoma tobacco-related tumours. Castleman’s
has decreased markedly. However, there disease (giant or angiofollicular lymph-
has been a persistent increase in cancers node hyperplasia, lymphoid hamartoma,
that are now called non-AIDS-defining angiofollicular lymph-node hyperplasia),
cancers (NADCs) when compared to the a lymphoproliferative disorder that can in-
general population. volve single lymph-node stations or can be
systemic, is now seen far more commonly
With the longer life expectancy among in SA related to HIV infection. Although not
HIV-positive patients, directly attributable a true malignancy, it is sometimes treated
to the use of antiretroviral therapy, an in- with chemotherapy.
creased risk of cancer in general has been
described in industrialised countries and People infected with HIV do not seem
this trend is also seen in South Africa. This is to have an increased risk of breast, colo-
exacerbated locally by the uneven avail- rectal, prostate, or many other common
ability, and use, of ART and there is a wor- types of cancer. Thus, screening for these
rying trend in the incidence of both ADCs cancers in HIV-infected people should fol-
and NADCs. low guidelines for the general population.

HANDBOOK OF ONCOLOGY

HIV-Related Cancers 129

For children diagnosed with AIDS, the can increase the risk of liver cancer), has a TREATMENT APPROACHES
risk for developing cancer continues into higher prevalence among people infect-
adulthood even if managed with ART.10 ed with HIV.4 There is also some indication
that the virus may sensitise cells to stimuli
In sub-Saharan Africa, Kaposi’s sarcoma such as tobacco.11
(KS) and non-Hodgkin’s lymphoma (NHL)
incidence and mortality rates have risen Compromised immune systems, causing
dramatically as the HIV/AIDS epidemic both immunosuppression and inflamma-
has evolved. In the developed world, cer- tion, seem to play a role, both directly and
vical cancer is also HIV-related, but sub- indirectly in the development of certain
Saharan Africa had among the world’s cancers.2
highest cervical cancer rates even before
the HIV/AIDS epidemic. Good data re- The development of neoplasia in HIV-
main sparse.15 infected patients mimics that seen in solid
organ-transplant patients on chronic im-
Access to anti-retroviral therapy in South munosuppressive therapy.
Africa is improving, but HIV-related malig-
nancies are an increasingly urgent public People living with HIV seem to develop
health problem. certain cancers at a younger age, pos-
sibly indicating an accelerated disease
Given its high prevalence, HIV plays a progression or higher exposure to risk fac-
major role in the aetiology, treatment, and tors. In a US population data study, lung
outcome of all malignancies in South Africa. and anal cancer, and myeloma were di-
agnosed four years earlier and oral cav-
PATHOGENESIS ity and kidney cancer two years earlier in
HIV-infected patients compared to the
The immunosuppression associated with general population.12
HIV reduces the host’s ability to fight in-
fections that may lead to cancer. Many RISK REDUCTION/SCREENING
people infected with HIV are also infected
with other viruses that are known to cause There are no particular screening guide-
certain cancers. lines for HIV-positive patients, but a high
index of suspicion for unexplained symp-
The following are the most important of toms should guide investigations. Regular
these cancer-related viruses: screening for cervical cancer is especially
n Human herpesvirus 8 (HHV-8), also recommended in HIV-infected women.

known as Kaposi’s sarcoma-associated Taking ART, following current HIV-treat-
herpes virus (KSHV), is the cause of ment guidelines, lowers the risk of Kaposi’s
Kaposi’s sarcoma. sarcoma and non-Hodgkin’s lymphoma
n Epstein Barr virus (EBV) causes some and increases overall survival and is thus a
subtypes of non-Hodgkin’s and vital part of risk reduction.
Hodgkin’s lymphoma.
n Human papillomavirus (HPV) causes The risk of lung cancer can be reduced
cervical cancer and some types of by stopping smoking. Because HIV-infect-
anal, penile, vaginal, vulvar, and head ed people have a higher risk of lung can-
and neck cancer. cer, it is especially important that they do
n Both hepatitis B virus (HBV) and hepatitis not smoke and that primary health-care
C virus (HCV) can cause liver cancer. workers counsel HIV-infected patients
about this.
Infection with most of these viruses is more
common among people infected with The higher incidence of liver cancer
HIV.2-5 among HIV-infected people appears to
be related to more frequent infection with
In addition, studies have shown that hepatitis virus (particularly HCV) and alco-
some traditional risk factors for cancer, es- hol abuse or dependence than among
pecially smoking (a known cause of lung uninfected people. HIV-infected patients
cancer) and heavy alcohol use (which should know their hepatitis status and be
tested for this. If blood tests show that they

HANDBOOK OF ONCOLOGY

130 CARING FOR PATIENTS WITH CANCER

have previously been infected with HBV or of ART. The influence of ART on the risk of
HCV, they should be counselled about re- these and other cancer types is not well
ducing their alcohol consumption. understood.

In addition, if viral hepatitis is active, As ART has reduced the number of
HBV- or HCV-suppressing therapy should deaths from AIDS, the HIV-infected popu-
be considered. Some drugs may be used lation has increased and become older.
for both HBV-suppressing therapy and ART. The fastest growing proportion of HIV-
infected individuals is the over-40 age
Because HIV-infected women have group. These individuals are now develop-
a higher risk of cervical cancer, regular ing cancers common in older age. In 2003,
screening for this disease is recommend- the proportion of these other cancers ex-
ed. Studies have suggested that Pap test ceeded the number of AIDS-defining ma-
abnormalities are more common among lignancies in the Western world. However,
HIV-infected women. Annual screening HIV-infected people do not develop most
for life is generally accepted as a safe ap- cancers at a younger age than is typically
proach in this clinical setting. seen in the general population.

Some researchers recommend anal MANAGEMENT: OVERVIEW
Pap-test screening to detect and treat OF THE MANAGEMENT OF THE
early lesions before they progress to anal THREE AIDS-DEFINING CANCERS
cancer. This type of screening may be KAPOSI’S SARCOMA
most beneficial for men who have had
sexual intercourse with men. Kaposi’s sarcoma (KS) is a vascular tu-
mour associated with human herpes virus
DIAGNOSIS 8 (HHV-8).

The diagnosis and work-up of cancers in It is found in four epidemiological forms:
HIV-positive patients is the same as for the n A IDS-related (epidemic) – prior to ART it
general population.
was 20 000 times more common in HIV-
With the introduction of ART in the mid- infected patients
1990s, the incidence of Kaposi’s sarcoma n Endemic or African – endemic in
and non-Hodgkin’s lymphoma among Equatorial Africa
people infected with HIV was greatly re- n O rgan-transplant-associated – similar to
duced. ART lowers the amount of HIV cir- the classic form
culating in the blood, thus partially restor- n Classic – older men of Mediterranean
ing the immune-system function. or Jewish origin

Although lower than before, the risk The incidence of AIDS-related Kaposi’s sar-
of these two cancers is still much higher coma has declined markedly since ART.
among people infected with HIV than the
general population. This persistently high Cutaneous Kaposi’s sarcoma is the most
risk may be due, at least in part, to the fact common form and affects lower extremi-
that immune-system function remains sub- ties, the face (especially the nose), and
stantially impaired in people treated with genitalia. It is often associated with lym-
ART. In addition, over time HIV can de- pho-oedema.
velop resistance to the drugs used in ART.
Many people infected with HIV have had Visceral Kaposi’s sarcoma may include
difficulty in accessing medical care or tak- all visceral sites, including oral mucosa,
ing their medication as prescribed. lymph nodes, gastro-intestinal tract, lungs,
liver, pancreas, heart, testes, bone mar-
The incidence of cervical cancer, in row, bone and muscle.
contrast, has not shown a reduction in in-
cidence with introduction of ART. Also, the Diagnosis, although easy to the clinically
incidence of several other cancers, par- trained eye, should be via biopsy/histology.
ticularly Hodgkin’s lymphoma and anal
cancer, has been increasing among HIV- Oral mucosa is the presenting site in
infected individuals since the introduction about 15% as the initial site. It is often seen

HANDBOOK OF ONCOLOGY

HIV-Related Cancers 131

on the palate and gingiva and is frequent- patient. However, due to various factors, TREATMENT APPROACHES
ly first detected by a dental practitioner. treatment may need to be tailored to co-
morbidities found in this population.
Prior to ART, 40% of patients had GIT in-
volvement with weight loss, nausea and Outcomes related to presenting CD4
vomiting, abdominal pain, bleeding, ob- counts are unclear, but low CD4 counts
struction and diarrhoea. seem to correlate with more advanced
stage (Ann Arbor III and IV) and poorer
Treatment prognostic features, such as B-symptoms,
ART is central to the management of Ka- bone-marrow and extranodal involve-
posi’s sarcoma. The major goals of treat- ment at presentation. Stage and prognos-
ment are symptom palliation, prevention tic features are known independent indi-
of disease progression, and shrinkage of cators of outcomes.7
tumour to alleviate oedema, organ com-
promise and psychological stress. Treatment

Depending on the clinical picture, treat- The optimal therapy for HIV-infected pa-
ment is either local with intralesional thera- tients is still controversial and most studies
pies, or localised superficial beam radia- are based on patients in developed coun-
tion, or systemic chemotherapy for more tries who have different risk factors to those
widespread disease. locally. The administration of optimal doses
(dose frequency and dose intensity) is a
The chemotherapies used include dox- challenge and the immunosuppression of
orubicin (including liposomal versions), HIV-infected patients may limit this. A high
paclitaxel bleomycin, the vincaloids and rate of dose reduction, treatment delays or
etoposide. Steroids also have a place in treatment interruption is seen in these pa-
the management of Kaposi’s sarcoma. tients. Low CD4 counts limit the use of bone
marrow-suppressive therapies and careful
The prognosis has improved with the in- monitoring of blood counts and the higher
troduction of ART and often treatment is use of prophylactic neutrophil support us-
intermittent and ongoing. The five-year ing granulocyte colony-stimulating factors
survival in patients with limited stage dis- is necessary. Patients with very low CD4
ease is over 80%, but falls if HIV is not con- counts (<50-100 cells/µl) have a higher risk
trolled or in extensive disease. of infection-related mortality if rituximab, a
monoclonal antibody against CD20 pro-
NON-HODGKIN’S LYMPHOMA tein found on the surface of B-cell non-
Ten percent of HIV-infected patients de- Hodgkin’s lymphomas, is used. Rituximab,
velop non-Hodgkin’s lymphoma (NHL). commonly used in combination with stand-
This disease is more common in males than ard chemotherapy for B-cell non-Hodgkin’s
females. lymphomas, reduces CD4 levels which
may lead to catastrophic infections. Rituxi-
The three main non-Hodgkin’s lymphomas mab is known to offer a 10-15% increase in
are long-term survival in the general B-cell non-
i. Systemic NHL (>80%). Hodgkin’s lymphoma population.
n Diffuse large B-cell (75%)
n Burkitt’s lymphoma (15%) For this reason, HIV-infected patients
n Indolent NHL (<10%) with non-Hodgkin’s lymphoma need to
n T-cell lymphoma (1-3%) be on ART from the start of the systemic
n Plasmablastic lymphoma (<1%) therapy and need careful HIV-monitoring
ii. P rimary central nervous system (CNS) during treatment. Discontinuation of ART
is not uncommon in HIV-infected NHL pa-
lymphoma (15%) tients due to treatment complications.
iii. Primary effusion lymphoma – rare (<5%) This further complicates the management
and adds to the causes for death in this
The general management of non-Hodg- cohort of patients.7
kin’s lymphoma is identical in the HIV-in-
fected patient to that of the non-infected HANDBOOK OF ONCOLOGY

132 CARING FOR PATIENTS WITH CANCER

In the era of ART, and despite high-risk various screening methods – PAP, HPV
features and the treatment limitations DNA testing, visual inspection using acetic
highlighted above, the two-year overall acid or Lugol’s iodine are sporadic, if at all
survival of HIV-DLBCL patients reaches 75% available. In countries with limited resourc-
and is similar to HIV-negative patients with es, various models have been proposed.
the same risk factors.7 Most successful seems to be a combina-
tion of “see and treat”. Pre-malignant le-
For these reasons, HIV-related non- sions are treated on the same-day visit to
Hodgkin’s lymphoma should preferably reduce loss to follow-up.
be managed by experienced specialist The age at presentation of changes is on
oncologists or under their guidance at the average 10 years younger in HIV-positive
very least. versus HIV-negative patients.

Note: Hodgkin’s lymphoma is the most Treatment
common NADC and is 15- to 30-fold high-
er than in the non-infected population. Management of immunosuppression: As
Treatment outcomes vary, depending on per guidelines, ART should be instituted
the cohorts looked at. Although the inci- in patients at the appropriate CD4 level
dence of this disease has not decreased count along with other prophylactic meas-
since the introduction of ART, the progno- ures and vaccinations as per guidelines.
sis has significantly improved. Some stud-
ies show outcomes are similar for patients Standard staging in lower- to middle-in-
with similar stages and risk categories as come countries (LMIC) is pelvic examina-
HIV-negative patients. This seems to be tion (by a suitably trained physician), CXR
mainly because HIV-positive patients tol- and ultrasound to exclude hydronephrosis
erate standard chemotherapy regimens which is indicative of the more advanced
well and can be treated in similar ways to stages at presentation. In well-resourced
their HIV-negative counterparts.8 situations, the staging and primary work-
up would be the same regardless of HIV-
INVASIVE CERVICAL CANCER status. The benefit of PET-CT versus stand-
The incidence of both cervical dysplasia ard CT-scans in HIV-positive patients is
and neoplasia is significantly increased in beset with issues of false-positive nodal
HIV-infected women, and the prognosis detection due to HIV/AIDS. CT-scan along
is worse compared with HIV-uninfected with surgical staging seems to be indicat-
women.9 Unlike the positive effect of ART ed as per the clinical indications.
on the incidence of NHL and KS, the im-
pact on cervical cancer has been mar- Surgery and/or chemoradiation are the
ginal to date.13 The burden of HIV-related cornerstones of cervical cancer manage-
cervical cancer is in sub-Saharan Africa, ment and the treatment is as per HIV-neg-
with the most important risk factor being ative patients, guided by disease stage
persistent HPV infection. Cervical cancer and patient factors. Access to trained
is a direct result of this.14 gynaecological surgeons and to radiation
facilities is severely lacking in the areas
Prevention where this is most needed. Neoadjuvant
Studies have shown that HPV vaccines are chemotherapy followed by radical hyster-
well-tolerated in HIV-positive HPV-nega- ectomy is a common approach in areas
tive women, with high levels (75-100%) of without access to radiation.
seroconversion for HPV 6, 11, 16 and 18,
with the higher rates in women with CD4 Palliative care is part of an overall ap-
counts >200 cells/µl. proach to the management of all cancer
patients, and often is all that is available
Screening in low-resource regions. The lack of access
In sub-Saharan Africa, the most important to opioids is problematic. Eighty percent
limiting factor to screening is access. The of the global population lack access to
appropriate opioid analgesics, based on
HANDBOOK OF ONCOLOGY a WHO estimate.16

HIV-Related Cancers 133

Outcomes 2. P owles T, Macdonald D, Nelson M, et al. TREATMENT APPROACHES
Data are lacking from both Western and Hepatocellular cancer in HIV-infected indi-
LMICs owing to HIV-positive patients not viduals: tomorrow’s problem? Expert Review
being included in clinical trials in the West, of Anticancer Therapy. 2006;6(11):1553-
and poor reporting generally. Some stud- 1558.
ies have shown poor treatment comple-
tion rates and resultant poor outcomes in 3. A ngeletti PC, Zhang L, Wood C. The viral eti-
HIV-positive versus HIV-negative patients. ology of AIDS-associated malignancies. Ad-
However, in sub-Saharan Africa regions vances in Pharmacology. 2008;56:509-557.
where there were good resources, out-
comes were comparable stage for stage 4. S ilverberg MJ, Abrams DI. AIDS-defining
and showed no difference in outcome by and non-AIDS-defining malignancies:
HIV-status. Factors that contribute to out- cancer occurrence in the antiretroviral
comes include total radiation dose, the therapy era. Current Opinion in Oncology.
addition of chemotherapy and presenting 2007;19(5):446-451.
haemoglobin levels.13
5. G rogg KL, Miller RF, Dogan A. HIV infection
CONCLUSION and lymphoma. Journal of Clinical Pathol-
ogy. 2007;60(12):1365-1372.
The incidence and prevalence of HIV-
positive patients with cancer can be ex- 6. L evine AM. AIDS-related malignancies. Curr
pected to increase with the extended Opin Oncol. 1994;6:489.
longevity of HIV-positive patients. In well-
resourced settings and in patients where 7. B esson C, Lancar R, Prevot S, et al. Out-
general health is maintained, approaches comes for HIV-associated diffuse large
to HIV-positive patients will mirror that of B-cell lymphoma in the modern com-
the HIV-negative population. The impor- bined antiretroviral therapy era. AIDS. 2017
tance of risk reduction – reducing tobac- Nov 28;31(18):2493-2501. Doi: 10.1097/
co and alcohol exposure, prevention and QAD.0000000001652.
management of intercurrent bacterial, vi-
ral and fungal infections, immune system 8. J acobson CA, Abrahamson JS. Review ar-
support and dealing with other general ticle. HIV-associated Hodgkin’s lymphoma:
health issues related to HIV – along with prognosis and therapy in the era of cART.
appropriate screening, will be central in Advances in Hematology. 2012(4):507257
dealing with this increase. http://dx.doi.org/10.1155/2012/507257.

In South Africa, which has the world’s 9. D ryden-Peterson S, Bvochora-Nsingo M,
highest burden of this disease, the HIV Suneja G, et al. HIV infection and survival
deaths as a percentage of all deaths has among women with cervical cancer. J Clin
fallen from 42% in 2002 to 25% in 2017, Oncol. 2016 Nov 1;34(31):3749-3757.
while the prevalence of this disease has
increased from just under five million to 10. S ingh E, Naidu G, Davies MA, et al. HIV-asso-
seven million over the same period.17 ciated malignancies in children. Curr Opin
HIV AIDS. 2017;12:77.
The impact on the national health-
care budget of managing HIV-related 11. D eeken JF, Tjen-A-Looi A, Rudek MA, et al.
cancers is high and can be expected to The rising challenge of non-AIDS-defining
continue to rise. cancers in HIV-infected patients. Clin Infect
Dis. 2012;55:1228.
REFERENCES
12. S hiels MS, Althoff KN, Pfeiffer RM, et al. HIV
1. H ernández-Ramírez RU, Shiels MS, Dubrow infection, immunosuppression and age at
R, et al. Cancer risk in HIV-infected people diagnosis of non-aids-defining cancers. Clin
in the USA from 1996 to 2012: a population- Infect Dis. 2017;64:468.
based, registry-linkage study. Lancet HIV.
2017 Aug 10;pii:S2352-3018(17)30125-X. 13. G hebre RG, Grover S, Xu MJ, et al. Cervi-
cal cancer control in HIV-infected women:
past, present and future. Gynecol Oncol
Rep. 2017;21:101–108. Published online 2017
Jul 21. Doi: 10.1016/j.gore.2017.07.009.

14. N ational Cancer Institute Factsheet 2011:
HIV and cancer risk. http://www.cancer.
gov/cancertopics/factsheet/Risk/hiv-infec-
tion.

15. S itas F, Pacella-Norman R, Carrara H, et
al. The spectrum of HIV-1 related cancers
in South Africa. Int J Cancer. 2000 Nov
1;88(3):489-92.

HANDBOOK OF ONCOLOGY

134 CARING FOR PATIENTS WITH CANCER

16. C onnor SR, Bermedo MCS, editors. Global 17. S tatistics SA – Statistical Release P0302.
Atlas of Palliative Care at the End of Life. Mid-year population estimates. http://
The Worldwide Palliative Care Alliance, www.statssa.gov.za/publications/P0302/
World Health Organization; 2014. P03022017.pdf

HANDBOOK OF ONCOLOGY

Medical Ethics in Cancer Care 135

Medical Ethics in Cancer Care TREATMENT APPROACHES

Dr M de Villiers are the relative values of life and death –
and to whom?”2
MB ChB DOM FCFP (SA) MBL
 F amily Physician and Consultant, THE MEDICAL PRACTITIONER
AS PROFESSIONAL
ISIMO Health AND PROFESSIONALISM

Many of the most important medical ethi- The term “profession” means “a dedica-
cal issues have arisen in oncology first or tion, promise or commitment publicly
presented themselves most forcefully in made”. Medicine is one of the traditional
the care of cancer patients. Many of the professions and doctors are professionals.
early, important cases related to informed In this context, the medical profession pre-
consent, truth-telling and aspects sur- sents itself to society as a social benefit and
rounding end-of-life care pertain to eu- society accepts the profession, expecting
thanasia and physician-assisted suicide. it to serve the continuum of heath needs
Unethical research involving cancer pa- of the population where they work. Doc-
tients was also conducted.1 In the South tors, as professionals, have a fiduciary duty
African scenario of change and complex- towards those they serve. This means that
ity of health-care policies and the cost professionals have a particularly stringent
of managing cancer during a time of in- duty to ensure that their decisions and ac-
creased biomedical innovation, a tension tions serve the welfare of their patients,
between what is good for society as a even at some cost to themselves.3 The pro-
whole and what is good for the individual fession traditionally issues a code of ethics
patient may become an issue, especially that specifies the obligations arising from
in a resource-constrained environment. this fiduciary duty. Ethical problems often
occur when there appears to be a conflict
Although the incidence and prevalence between these obligations or between fi-
of cancer in the South African population is duciary duties and personal goals.
relatively low compared to other non-com-
municable diseases, the cancer burden in The building blocks of becomng a
the population in terms of the physical, psy- good medical practitioner require a life-
chosocial, emotional and financial impact long commitment to sound professional
on individual patients, their families and the and ethical practices and an overriding
community at large, is significant. It is for dedication to the interests of one’s fellow
that reason that medical ethical issues fea- human beings and society. The ethos of
ture strongly in oncology and specifically in the practice of medicine is founded on
the care of cancer patients. the confidential, trusted doctor-patient
relationship.
Ethical issues in patients with cancer are,
as expressed by Holleb and Braun, “com- The fundamental principles that define
plicated by the fact that because cancer the fiduciary duty centre around the ba-
is a life-threatening illness, many transac- sic ethical principles of patient autonomy,
tions we have with our patients involve beneficence and non-maleficence and
crisis and decision, thus increasing the oc- justice, and translate into professional re-
casions when these values will come into sponsibilities of the doctor that flow from
conflict. Other exacerbating factors are the following principles:4
the number of people involved in the care n Commitment to competence: Being
of the cancer patient; the complexity of
the disease itself; the intricacy of modern committed to lifelong learning and
technology; and the multiplicity of an- being responsible for maintaining the
swers to questions that once seemed ob- medical knowledge and clinical and
vious – What is life? What is death? What
HANDBOOK OF ONCOLOGY

136 CARING FOR PATIENTS WITH CANCER

team skills necessary for the provision of n Commitment to maintaining trust
quality care by managing conflicts of interests:
n C ommitment to honesty with patients: Physicians have an obligation to
Practitioners must ensure that patients recognise, disclose and deal with
are completely and honestly informed conflicts of interest that arise in the
and empowered before they consent course of their professional duties and
to treatment and before treatment activities
occurs.
n C ommitment to confidentiality: Earning n Commitment to professional
the trust and confidence of patients responsibilities: Doctors are expected
means that appropriate confidentiality to work collaboratively to maximise
safeguards be applied to disclosure of patient care, be respectful of one
patient information. another, and to participate in the
n C ommitment to appropriate processes of self-regulation.
relationship with patients: Given the
inherent vulnerability and dependency Revisiting the principles and responsibili-
of patients on medical practitioners, ties of professionalism of the physician in-
practitioners should never exploit volved in the treatment of cancer patients
patients for any reason, including for is necessary to understand the ethical di-
personal financial gain or any other lemmas in cancer care within the context
private purpose. of patient-centric care and the frame-
n C ommitment to improving quality of work of the continuum of care throughout
care: Being dedicated to continuous the cancer journey. To serve the patient’s
improvement in the quality of health best interests, the doctors involved need
care means not only maintaining to create an environment founded on
clinical competence, but also working trust that facilitates the healing process
collaboratively with other professionals of the person. The intense need for trust is
to reduce medical error, increase caused by the patient’s dependence on
patient safety, minimise overuse of the doctor’s skills and judgment when he/
health-care resources and optimise the she has cancer.
outcome of care
n Commitment to improving access to ETHICAL ASPECTS OF CARING
care: A commitment to availability FOR PATIENTS WITH CANCER
of a uniform and adequate standard
of care to all entails the promotion of The social dimensions of ethics include
public health and preventive medicine, justice, rights, respect of human dignity,
as well as public advocacy in support autonomy of the individual and respect of
of equity and access without concern the community.
for self-interest
n Commitment to a just distribution of This provides an opportunity to re-empha-
finite resources: While meeting the sise ethics as a tool for titrating the dynam-
needs of individual patients, doctors ic tension between:
are required to provide health care n The interest of the Individual patient
that is based on the wise and cost- n The interest of the population needs in
effective management of limited
resources so as to ensure that resources general and
are also available for others. n The professional ethics of care
n C ommitment to scientific knowledge:
The profession is responsible for the INFORMED CONSENT
integrity of scientific knowledge which The fundamental principle that justifies the
is based on scientific evidence and need for informed consent is respect for
physician experience. the autonomy of the patient. This is also in
support of a patient-centric approach in
HANDBOOK OF ONCOLOGY so far as respecting a person’s right to de-
termine the course of his or her life. This is

Medical Ethics in Cancer Care 137

a move away from a doctor-centred and of the consequences of screening or no TREATMENT APPROACHES
paternalistic approach to a more patient- screening. This is in support of the ethical
centric approach. principles of beneficence and non-malef-
icence and the fiduciary duty toward the
The role of the doctor is often to provide patient as a professional.
the cancer patient with sufficient infor-
mation to be able to make an informed TRUTH-TELLING/DIFFICULT
decision or informed refusal to undergo CONVERSATIONS
a course of treatment or participate in a
research protocol for a new cancer drug. The treating specialist and sometimes
the family practitioner, because of the
It requires from the doctor a commit- long-standing relationship with a family
ment to the professional values of com- or a patient, as well as a member of the
petence and scientific knowledge to be care team within the continuum of can-
able to assist the patient to take informed cer care, is often consulted by the patient
decisions. and their family after a diagnosis of can-
cer has been confirmed, staging estab-
Emanuel and Joffe5 also maintain that al- lished and treatment plan confirmed. But
though informed consent can be viewed during the cancer journey, there may be
as an event which ends with the patient’s instances where the physician needs to
decision, it is not adequate for the patient engage and have difficult conversations
with cancer where interaction and treat- with regard to the prognostic impact of
ment occurs over a period of time. They cancer progression or when the treating
support the process model which “… is oncologist has decided to discontinue fur-
based on the assumption that medical ther active cancer treatment.
decision-making is a continuous process,
and the exchange of information must In the difficult conversation, the physi-
take place throughout the course of the cian is often confronted with the dilemma
physician-patient relationship.” of whether to tell the truth with regard to
the severity and prognosis of the disease.
The requirement of understanding sug- The ethical principle of beneficence sug-
gests that the patient should comprehend gests that physicians should disclose infor-
the information presented and appreci- mation in a way that benefits and does
ate its relevance for his or her particular not harm the patient.6 There are two ethi-
situation. This is of particular importance in cal guidelines to be observed in regard to
South Africa with its variety of languages, disclosure: appropriate degree of infor-
cultures and levels of education. mation and humane behaviour.

The role of the physician includes the As with informed consent, it is important
early detection of cancer through aware- that information is given in a way that is
ness and screening. In a screening guide- meaningful to patients on their own terms.
line for prostate cancer, the assumption This might mean finding the help of a
that the prognosis for the cancer patient translator, breaking information down into
is better if diagnosed early is disputed parts, or revisiting information at different
based on available evidence. The argu- visits. Supplying informational pamphlets
ment focuses on the impact of routine or suggesting a support group such as
screening and over-diagnosis of cancer People Living with Cancer is a way to help
and the substantial harm associated with the patient. The inclusion of the oncology
subsequent treatment. Although screen- social worker in assisting the patient and
ing for cancer has become accepted in his/her familiy in terms of the psychosocial
medical practice, the practitioner must needs during these difficult conversations,
be aware of the evidence in support of supports a patient-centric approach.
screening programmes when applied in
the patient population cared for by the As discussions with cancer patients may
practice. Patients should therefore be disclose news that is hurtful, it is important
properly counselled prior to any screening
procedure to ensure a full understanding HANDBOOK OF ONCOLOGY

138 CARING FOR PATIENTS WITH CANCER

that doctors communicate with patients needs and the values of patients and their
in a humane and respectful manner. families.

Some doctors believe they are entitled The medical practitioner may have to
to withhold information from patients if deal with a critically ill and fragile patient
they believe the information will have dev- whose only request is to die at home.
astating effects on them. Studies, howev-
er, have shown that a majority of people The complexity of end-of-life decisions
say that they want to be told about their demands that comprehensive attention
diagnosis, even diagnosis of a terminal na- be given to the particular patient and his/
ture. It may also happen that by withhold- her life circumstances. These include the
ing this information the trust relationship patient’s unique biology and the patholo-
between patient and the doctors may be gy of the illness, the patient’s clinical con-
compromised. dition, functional status, physical needs,
desires, life plans, relationships, hopes,
The important principle here is that pa- sufferings, strengths and limitations, per-
tients are ordinarily entitled to full disclosure ceptions and understanding of the illness.7
with regard to their diseases and disorders. Consideration should be given to facilitate
access to other carers to address the of-
Doctors are sometimes requested by ten unmet psychosocial needs of the pa-
family members to withhold information tient and the family.
from the patient for various reasons. This
potential conflict can be simply addressed End-of-life discussions often revolve
by helping family members to understand around matters where there are no clear-
that the doctor’s primary duty is to the pa- cut answers and require the clinician to be
tient. If a patient is able to make decisions comfortable in dealing with uncertainties
about his or her medical care, the doctor and with compassionate truth-telling. The
has a duty to disclose the information rel- ethical principle involved is the respect for
evant to helping that patient make deci- autonomy of the patient and addresses the
sions about exactly what type of care he concept of “self-rule”. In these circumstanc-
or she wants. es, patients should be encouraged to take
an active part in clinical decision-making
CARING FOR THE PATIENT WITH as this facilitates their active involvement in
ADVANCED DISEASE/PALLIATIVE CARE care decisions at the end of life.
Within the continuum of cancer care,
after active cancer treatment has been Beneficence refers to the ethical im-
discontinued, the management and co- perative to ensure that treatment benefits
ordination of the care of the cancer pa- the patient and non-maleficence to the
tient takes place within a multidisciplinary Hippocratic ideal of “first do no harm”.
palliative-care team, including the fam- Within the objective of palliative care to
ily practitioner, oncologist, palliative-care improve quality of life, a key decision is to
specialists, nurses, social workers and re- be able to identify when active treatment
ligious leaders as an essential part of the will improve quality of life and prolong life,
team to ensure that: in contrast to when active care and medi-
n t he patient’s symptoms are adequately cal technology will not positively influence
the course of the illness, but merely pro-
managed long the dying process.
n the psychosocial needs are being
Gwyther8 draws attention to decisions
addressed to withdraw or withhold treatment, when
n care is provided at the most reached in discussion with patient, family
members and the clinical team. This re-
appropriate place spects the essential commitment to the
n the patient and the family’s wishes are patient. She refers to the booklet Guide-
lines for the Withdrawing and Withhold-
understood and addressed. ing of Treatment by the Health Professions
Council of South Africa which states that
This approach is in line with patient-cen-
tric care principles that are respectful of,
and responsive to, the preferences, the

HANDBOOK OF ONCOLOGY

Medical Ethics in Cancer Care 139

“Health-care practitioners should bear This initiative emerged as a consequence TREATMENT APPROACHES
in mind that the decisions of competent of ethical tensions around equity, justice
adult patients to refuse a particular medi- and fairness in the allocation of health-
cal intervention must be respected, even care resources faced by policy-makers
where this would result in serious harm to to address health-care system design in
them or in their own death.” response to ever-increasing resource con-
sumption and financial constraints.
The withholding or withdrawing of treat-
ment must however be distinguished from Although the medical profession has its
participating in assisted suicide or active own codes of ethics, the need for a shared
euthanasia which is illegal. code existed that might bring all stakehold-
ers in health care into a more consistent
The Telegraph of 26 September 2011 moral framework. This view is important for
under the heading “Dying cancer pa- the medical practitioner to contextualise
tients should not be given ‘futile’ drugs”, the dilemma of policy-makers.
refers to current medical practice to
continue with new treatments with no The first ethical principle identified by the
thought to their cost or effectiveness be- Tavistock group was that health care is a
cause they don’t want to disappoint pa- human right and the aim of health-care
tients, leaving them with “false hope” as delivery is to maintain and improve health,
some drugs will only lengthen sufferers’ to alleviate disability and to provide ac-
lives by a few weeks. cess to appropriate health services to all
persons, regardless of their ability to pay.9
This was based on a detailed report,
published in The Lancet Oncology Journal, It is in this context that current medical
which stated that in some cases it may be schemes and the National Health Policy
better for terminally ill patients to “forgo” in South Africa should develop. The prin-
these treatments in favour of better end- ciples of equity, universal coverage and
of-life care. For this purpose, a futile drug social solidarity need to be at the core of
or intervention refers to treatment that will this reform.10
not restore a patient to independence or
at least to an acceptable quality of life, Historically, the allocation of scarce re-
or which is likely only to prolong the dying sources in the health-care environment
phase. or cost-containment has been dealt with
on a policy and business level under the
This ethical debate can then be fur- scope of “distributive justice”.11 Within
ther redirected to the question of waste- the resource-constrained environment of
avoidance in clinical practice. Wasteful South Africa, with its developing economy
treatment and interventions can cause and goal of universal coverage of all citi-
harm. Primum non nocere becomes the zens in terms of health care, policy deci-
strongest argument for eliminating waste sions inform who will have access to care
through non-beneficial practising. and the extent or richness of benefits that
will be provided.
The doctor may also have to deal with
advance directives like a Living Will. These The private sector medical schemes
directives can only be a guide and can- employ strategies to curb the high cost
not cover all eventualities. The directive of cancer treatment within what is pro-
should be discussed with the competent vided for in the prevailing legislation and
patient and family members. regulations, using medical-scheme rules
to determine to which benefits cancer pa-
EQUITY, FAIRNESS tients are entitled. This may be in the form
AND SOCIAL JUSTICE of financial sub-limits for cancer care for
which a patient will be covered – a form
During 1999, a group of experts in ethics of rationing. Provider arrangements and
from over the world, the so-called Tavis- micro-management of health-care en-
tock group, met in the UK to develop counters are also used to reduce the costs
shared ethical principles for those who of cancer care.
shape and deliver health care.9
HANDBOOK OF ONCOLOGY

140 CARING FOR PATIENTS WITH CANCER

Although there may be an ethical objec- REFERENCES
tion to rationing on the basis that doctors
owe an absolute duty of fidelity to each 1. E manuel EJ, Joffe S. Ethics in oncology. In:
individual patient regardless of cost, it Kufe DW, Pollock RE, Weichselbaum RR,
needs to accepted that when resources et al, editors. Holland-Frei Cancer Medi-
(money) are exhausted, real patients are cine. 6th ed; 2003. Chapter 79. Available
deprived of care. The ethical argument at: https://www.ncbi.nlm.nih.gov/books/
therefore shifts to the fairest means of al- NBK12442. Accessed February 2018.
locating scarce resources within a popu-
lation served by the practice. 2. H olleb AI, Braun M. Ethical issues and the
cancer patient. CA – A Cancer Journal for
Thus, the ethical challenge of ration- Clinicians. 1986:36:83-84.
ing care in South Africa with its inequita-
ble distribution of health-care resources, 3. J onsen AR, Braddock CH, Edwards KA. Pro-
also needs to translate to a commitment fessionalism: Ethics in Medicine: University
on the part of doctors to protect patients of Washington School of Medicine; 2011.
from harmful and wasteful medical care Available at http://depts.washington.edu/
and in so doing unleash the means to bioethx/topics/profes.html. Accessed Feb-
serve patients with useful services in an en- ruary 2018.
vironment devoid of waste.11
4. E uropean Federation of Internal Medicine.
These ethical principles must help focus 2004. Medical professionalism in the new
physicians to always be mindful of both in millenium: a physician charter. Ann Intern
the service of their individual patients, as Med. 2002 Feb 5;136(3):243-6. Available at:
well as the good of society as a whole. http://abimfoundation.org/what-we-do/
physician-charter. Accessed February 2018.
CONCLUSION
5. E manuel EJ, Joffe S. Ethical aspects of car-
The dilemma of doctors treating cancer ing for patients with cancer. In: Bast RC Jr,
patients is well summarised by Dr Ezekiel Kufe DW, Pollock RE, et al, editors. Holland-
J Emanuel, a leading scholar in bioethics, Frei Cancer Medicine. 5th ed; 2000. Chap-
during an interview in which he stated the ter 74. Available at: https://www.ncbi.nlm.
following: “Medical ethics is integral to on- nih.gov/books/NBK20970. Accessed Febru-
cology care. When I ran ethics rounds at ary 2018.
the Dana-Farber Cancer Institute, I used
to say that every single oncology patient 6. P unjani NS. Truth telling to terminally ill pa-
faced at least three ethical dilemmas. In- tients: to tell or not to tell. J Clin Res Bioeth.
formed consent is one. Do patients really 2013:4:4.
understand what they are signing? There’s
typically a dilemma about allocating re- 7. C avallo J. A conversation with Ezekiel L.E.:
sources for treatment because these are How medical ethics and public health-
very expensive therapies and many of care policy are converging in oncology.
them put a lot of financial pressure on ASCO Post. 2011 Dec 15.
families. And for many patients, there’s
the dilemma of facing end-of-life care, as 8. G wyther L. Withholding and withdrawing
there will be for all of us...” 5 treatment: practical applications of ethical
principles in end-of-life care. SAJBL. 2008
June;24-26.

9. T avistoc Group. A shared statement of
ethical principles for those who shape and
give healthcare. BMJ. 1999 January 25;318:
249-251.

10. S outh Africa. 2003. National Health Act,
61 of 2003. Policy on national health insur-
ance. Government Gazette. 2011 August
12:34523.

11. B rody H. From an ethics of rationing to an
ethics of waste avoidance. NEJM. 2012
May 24;1949-1953.

HANDBOOK OF ONCOLOGY

The Role of Nutrition in Cancer Patients and Cancer Survivors 141

The Role of Nutrition in Cancer Patients TREATMENT APPROACHES
and Cancer Survivors

Mrs MC Piderit Figure 1. Estimated cumulative cancer
RD (SA) mortality risk in Africa2

Mrs CE Julsing Strydom All cancers excluding
non-melanoma skin cancer
RD (SA), M Dietetics (UP)1 & MSc Dietetics 11.0+
8.5-11.0
(UFS) 7.7-8.5
 Registered Dieticians, Nutritional 7.0-7.7
Solutions <7.0
No Data
Cancer is a major public health problem.
The World Health Organization (WHO) re- Source: GLOBOCAN 2012 (IARC)
ported that globally cancer accounted
for just over one in five deaths from non- NUTRITION AND DIET
communicable diseases. Lung, breast, Cancer survivors are known to want to
colorectal, stomach and liver cancers to- make healthy dietary changes.3, 8, 9, 10
gether are responsible for more than half Breast-cancer patients modify their eating
of cancer deaths.1 The top cancer sites behaviours after diagnosis by between
in South Africa are those of the lung, oe- 30-60%, including increased fruit and veg-
sophagus, breast, prostate, colorectum, etable intake, and decreased consump-
liver and pancreas (see Figure 1).2 tion of red meat, fats and sugary foods.10
Furthermore, colon cancer patients are
Fortunately, with advances in medical disease-free for longer and have greater
care and improvements in cancer detec- overall survival rates when they have a
tion and treatment, cancer-survival rates healthy body weight, are physically ac-
are improving.3,4 It is promising that of the tive, and eat a diet rich in whole grains,
leading causes of death, cancer death vegetables and fruit. Compared to can-
rates are on the decline. The American cer patients who do not engage in these
Cancer Society (ACS) estimates that the behaviours, these cancer patients eat less
cancer-death rate has declined by 26% red and processed meat and consume
from 1991 to 2015, translating into over 2.3 moderate amounts of alcohol.11
million fewer cancer deaths.5
Various types of diets have been pro-
NUTRITIONAL INTERVENTIONS posed for cancer management. These
FOR CANCER PATIENTS include ketogenic diets (80% fat, 8% pro-
tein, 2% carbohydrates),13,14,15,16 vegetarian
It is estimated that one-third of the com- diets17,18 and the Mediterranean diet.19,20
monest cancers can be prevented However, much of this research has been
through lifestyle changes, such as adopt- done on cancer prevention, and not can-
ing a healthy diet and managing weight, cer survivorship. That said, current nutrition
as well as being physically active.6 In- guidelines for cancer survivors are consist-
terventions targeting these modifiable ent with those for cancer prevention.4,12, 21
lifestyle factors could not only prevent The guidelines for nutrition for cancer
cancer, but also encourage healthy be- prevention should not be overlooked by
haviour among cancer survivors, influenc- patients already diagnosed with cancer.
ing the rates of cancer recurrence, and
improving the overall health and wellbe-
ing of cancer patients.4, 7 The role of nutri-
tion in cancer survivors will be discussed in
more detail.

HANDBOOK OF ONCOLOGY

142 CARING FOR PATIENTS WITH CANCER

Table 1. American Cancer Society (ACS) guidelines on nutrition and physical activity for
cancer survivors12

Achieve and maintain a healthy weight
If overweight or obese, limit consumption of energy-dense foods and beverages and
increase physical activity to promote weight loss

Engage in regular physical activity
Avoid inactivity and return to normal daily activities as soon as possible after diagnosis.
Aim to exercise at least 150 minutes per week.
Include strength-training exercises at least two days per week.

Achieve a dietary pattern that is high in vegetables, fruit and whole grains
Follow the American Cancer Society Guidelines on Nutrition and Physical Activity for
Cancer Prevention; i.e., limit consumption of processed meat and red meat; eat at
least 2.5 cups of vegetables and fruit daily; choose whole grains instead of refined
grain products; and, if you drink alcoholic beverages, limit consumption to no more
than one drink daily for women or two drinks daily for men

A healthy diet is important for cancer pre- supplementation, yet 70% were over-
vention and to improve health outcomes weight/obese and 13% were smokers.26
in patients with cancer.21 Published guide-
lines for nutrition and diet for cancer survi- Much of the research in nutrient sup-
vors by the ACS, National Comprehensive plementation has been on the role of
Cancer Network (NCCN) and Ameri- polyphenolic compounds acting as anti-
can Institute for Cancer Research (AICR) oxidants. An antioxidant is a substance in
recommend that cancer survivors strive food that significantly decreases the ad-
to meet their nutritional needs primar- verse effect of reactive oxygen species
ily through food rather than supplements. (ROS)/reactive nitrogen species (RNS) on
Both AICR and NCCN recommend a diet normal physiological functions in humans.
rich in vegetables, fruit and whole grains In theory, polyphenols are able to scav-
(two-thirds of the plate), with less empha- enge the free electrons of ROS/RNS, pro-
sis on animal proteins (one-third part of tecting against cellular damage related
the plate). Whole grain intake is inversely to cancer progression. However, studies
associated with cancer mortality risk, as on antioxidants, whether dietary or sup-
confirmed in a recent systematic review plementary, in cancer progression remain
and meta-analysis of cohort studies.22 inconsistent and inconclusive.27 It is there-
Recommended sources of dietary fat in- fore better to encourage the inclusion of a
clude plant sources (e.g., olive/canola oil, variety of fruit and vegetables to increase
avocados, nuts) and fatty fish, rather than antioxidant intake rather than use antioxi-
red meat3, as saturated fat negatively dant supplements.
influences breast-cancer survival rates.23
The ACS guidelines for nutrition and physi- Immunonutrition is an emerging field, giv-
cal activity in cancer survivors are summa- en the significant role the immune system
rised in Table 1. plays in cancer and cancer treatment.28
It is suggested that immunonutrition for-
NUTRIENT SUPPLEMENTATION mulae, such as anti-inflammatory omega-
3s and probiotics, may aid in improving
The prevalence of dietary and nutri- the immune status of the cancer patient,
ent supplementation in cancer patients modulate the acquired immune response,
is high10; 24,, with reports of at least one in and decrease cancer-treatment toxic-
three (33.3%) cancer survivors using sup- ity, improving disease outcomes.28 Results,
plements.25 When investigating supple- however, remain inconclusive. There-
ment use in breast-cancer patients, 50% fore, including omega-3-containing fish
of participants were taking multivitamin (e.g., salmon, pilchards, sardines, trout,
and mackerel) and foods containing

HANDBOOK OF ONCOLOGY


Click to View FlipBook Version