MIMS Oncology 2018

Colorectal Cancer 43

potentially resectable disease. For pa- indicates that they may also not respond TREATMENT APPROACHES
tients with unresectable metastatic dis- to the anti-EGFR agents.
ease, chemotherapy improves survival
over best supportive care. For patients who develop progressive
disease after first- and second-line regi-
In the last two decades, a greater un- mens, regorafenib, a tyrosine kinase in-
derstanding of the biology of colorectal hibitor, or trifluridine/tiparicil, a cytotoxic
cancer has led to the development of agent, have been shown to have a small
a number of new agents effective in the survival benefit over best supportive care.
treatment of metastatic disease, allowing
for the use of different combinations of The site of the primary tumour can also
drugs, depending on the tumour charac- influence the treatment regimen. A review
teristics as well as the site of the primary of trials incorporating targeted agents
tumour. The general condition of the pa- has indicated that patients who have
tient and the aim of the treatment must metastatic disease from primary tumours
be taken into consideration. For a patient arising in the left colon have improved
with liver metastases that require down- survival with chemotherapy combined
staging prior to resection or for a patient with the anti-EGFR agents, providing they
with significant tumour burden, a combi- are KRAS wild type, whereas for primary
nation of agents is prescribed, whereas if tumours arising in the right colon, combi-
the patient is elderly or has a limited tu- nation chemotherapy with bevacizumab
mour burden, a single agent may be pre- may improve survival.13 Immunotherapy
scribed. Patients with a poor performance is an exciting new development in the
status, i.e., those who spend more than treatment of many cancers. For patients
50% of the day resting, will generally not with metastatic colorectal cancer with a
benefit from chemotherapy. mismatch repair gene defect who have
progressed on chemotherapy, pembroli-
The backbone of most regimens is 5FU zumab is a new treatment option.
which can be administered intravenously
with leucovorin or orally. There are several In summary, the multitude of effective
oral forms, including capecitabine, S-1 agents has created a variety of different
and tegafur. Oxaliplatin and irinotecan regimens allowing for personalised treat-
are intravenous chemotherapy agents ment and improvement in overall survival
that are prescribed with 5 FU. of patients with metastatic disease.

The targeted or biological agents have FOLLOW-UP
been developed to target certain path-
ways or molecules that are active in colo- For patients with stage II and III disease,
rectal cancer and thereby inhibit tumour most guidelines recommend follow-up
growth. These agents include the anti- to detect recurrence, although the evi-
angiogenic agents bevacizumab, afliber- dence for improved survival after treat-
cept and ramucirumab and the anti- ment of the recurrence is limited. Since
epidermal growth factor receptor (EGFR) approximately 75% of recurrences occur
agents cetuximab and panitumumab. within the first three years of treatment,
Together, these agents allow for a number patients are examined at three- to six-
of different regimens for first- and second- monthly intervals during this period, CEA
line treatments. It is important to establish levels are monitored and imaging with
the molecular profile of the tumour before CT-scans is performed. Colonoscopy can
deciding on the regimen. RAS is one of the be repeated three years after diagnosis,
many oncogenes involved in colorectal then five-yearly if no polyps are found. Fol-
cancer and patients with mutations in RAS low-up is also required for management
will not respond to the anti-EGFR agents. of possible long-term treatment-related
Patients with mutations in the BRAF gene side effects. Patients should be advised to
who develop metastatic disease have maintain a healthy weight, not smoke and
a poor prognosis and current evidence exercise regularly. Recent evidence has
shown that aspirin may decrease the risk

HANDBOOK OF ONCOLOGY

44 SOLID TUMOURS

of recurrence, but results of randomised colon cancer. N Engl J Med. 2004;350:
trials are awaited. 2050-59.
6. Bipat S, et al. Rectal cancer: local staging
SUMMARY and assessment of lymph node involve-
ment with endoluminal US, CT, and MR
Colorectal cancer is a common disease Imaging – a meta-analysis. Radiology.
and screening is effective in reducing 2004;232:773-83.
mortality. Treatment of localised disease 7. MacFarlane JK, et al. Mesorectal excision
in the colon is surgery followed by ad- for rectal cancer. Lancet. 1993;341:457-460.
juvant chemotherapy for patients with 8. Andre T, et al. Improved overall survival
stage III disease. Neoadjuvant chemora- with oxaliplatin, fluorouracil, and leucov-
diation is indicated for locally advanced orin as adjuvant treatment in stage II or III
rectal cancer. The combination of surgi- colon cancer in the MOSAIC trial. J Clin On-
cal techniques and systemic treatment al- col. 2009; 27:3109-16.
lows for resection of metastases, offering 9. Prospective pooled analysis of six phase
potentially curative treatment. A number III trials investigating duration of adjuvant
of effective treatment regimens are now oxaliplatin based therapy for patients with
available for patients with unresectable stage III colon cancer: the IDEA (Interna-
metastases, resulting in improved survival. tional Duration Evaluation of Adjuvant)
chemotherapy collaboration. J Clin Oncol
REFERENCES 35 no. 15. Doi: 10.1200/JCO.2017.35.15.
10. Rolf S, et al. Preoperative versus postop-
1. National Health Laboratory Service (NHLS). erative chemoradiotherapy for locally ad-
National Cancer Registry South Africa 2013. vanced rectal cancer: results of the Ger-
Available at http://www.nioh.ac.za/assets/ man CAO/ARO/AIO-94 randomized phase
files/NCR2013.pdf. Accessed 11 January 2018. III Trial after a median follow-up of 11 years.
J Clin Oncol. 2012;30:1926-33.
2. Zauber AG, et al. Colonoscopic pol- 11. Habr-Gama A, et al. Operative versus non-
ypectomy and long-term prevention of operative treatment for stage 0 distal rectal
colorectal-cancer deaths. N Engl J Med. cancer following chemoradiation therapy:
2012;366(12):687-96. long-term results. Ann Surg. 2004;240:711-7.
12. Kopetz S, et al. Improved survival in meta-
3. Brenner H, et al. Effect of screening sigmoi- static colorectal cancer is associated
doscopy and screening colonoscopy on with adoption of hepatic resection and
colorectal cancer incidence and mortal- improved chemotherapy. J Clin Oncol.
ity: systematic review and meta-analysis of 2009;27:3677-83.
randomised controlled trials and observa- 13. Holch JW, et al. The relevance of primary
tional studies. BMJ. 2014;348:g2467. tumour location in patients with metastatic
colorectal cancer: a meta-analysis of first-
4. Inadomi JM. Screening for colorectal neo- line clinical trials. Eur J Cancer. 2017;70:
plasia. N Engl J Med. 2017;376:149-56. 87-98.

5. Nelson H, et al. A comparison of laparosco-
pically assisted and open colectomy for

HANDBOOK OF ONCOLOGY

Breast Cancer 45

Breast Cancer TREATMENT APPROACHES

Dr K Tabane cancer, which is important in determining
the treatment approach.
MBChB,FCP(SA); Certificate of Medical
STAGING
Oncology (Physicians)
 Specialist Physician, Medical Breast cancer is staged according to the
Oncologist, Director: Sandton Oncology TNM criteria, which takes into account
tumour size, locoregional nodal involve-
According to the CANSA statistics, breast ment, and the presence or absence of
cancer is the most common cancer af- distant metastasis (see Table 1).
fecting South African women.
By definition, early breast cancer is can-
Unfortunately, the national registry has cer that is limited to the breast and/or ax-
been fraught with challenges, and this has illa. However, a tumour in excess of 5 cm,
hindered accurate assessment of the bur- involvement of multiple locoregional
den of disease. This is currently in the pro- lymph nodes, skin changes and/or inva-
cess of being updated with NHLS and the sion of the chest wall imply the diagnosis
Department of Health. of locally advanced breast cancer.

South Africa is among the most unequal TUMOUR BIOLOGY
societies in the world. This is apparent in
the disparate care of patients in the pri- In broad terms, breast cancer biology is
vate sector compared to those in the pub- divided into favourable vs unfavourable
lic sector. Breast cancer is unfortunately biology. The surrogate for this is the IHC 4
no different, with the majority of women test, which includes assessment of oestro-
in the private sector presenting with early gen receptors (ER), progesterone recep-
stage breast cancer, where the treatment tors (PR), HER2 neu expression, and Ki67.
intent is usually curative, compared to the
public sector, where women present with HER2 neu overexpression is found in 20-
advanced stage disease, with subsequent 30% of all breast cancers, and portends a
poorer outcomes, against the backdrop poorer prognosis with a propensity for dis-
of limited resources. tant spread.

The most common presentation of The diagnosis is made on immunohis-
breast cancer is the finding of a breast tochemistry, and an equivocal result is
lump, or axillary lymphadenopathy. Oth- confirmed by SISH and reported accord-
er symptoms may include thickened skin ing the College of American Pathologists
with an orange-peel appearance (peau (CAP).
d’orange), an enlarged node at the base
of the neck, a bloody nipple discharge, or Immunohistochemistry is a surrogate for
ulceration of the breast and surrounding profiling of tumour biology which is best
tissues. characterised by tumour micro-arrays,
which are not readily available.
The risk of breast cancer increases with
age. However, increasingly younger pa- Tumour biology is divided into luminal
tients are being diagnosed. Only 10-15% A-like, luminal B-like, HER2-enriched, and
of breast cancers are as a result of a ge- basal-like.
netic aberration, meaning that the major-
ity of breast cancers are sporadic.1 Luminal A cancers tend to be ER/PR-
positive, HER2-negative, with a low Ki 67 of
The diagnosis is made on a mammo- less than or equal to 14%.
gram combined with a breast ultrasound.
A core biopsy of the breast mass, rather Luminal B-like cancers are ER-positive,
than a fine-needle aspiration (FNA) is pre- PR-negative, HER2-negative, with a high Ki
ferred. Core biopsy allows for more ac- 67 of >14%.
curate assessment of the biology of the
HER2-enriched are HER2-overexpressing,
and the basal-like cancers include, but
are not limited to, triple-negative breast

HANDBOOK OF ONCOLOGY

46 SOLID TUMOURS

Table 1. Breast carcinomas TNM staging

Primary tumour

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

Tis Carcinoma in situ

Tis (DCIS) Ductal carcinoma in situ

Tis (LCIS) Lobular carcinoma in situ

Tis (Paget’s) Paget’s disease of the nipple NOT associated with invasive carcinoma
and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast
parenchyma. Carcinomas in the breast parenchyma associated with
Paget’s disease are categorised based on the size and characteristics
of the parenchymal disease, although the presence of Paget’s disease
should still be noted.

T1 Tumour ≤20 mm in greatest dimension

T1mi Tumour ≤1 mm in greatest dimension

T1a Tumour >1 mm but ≤5 mm in greatest dimension

T1b Tumour >5 mm but ≤10 mm in greatest dimension

T1c Tumour >10 mm but ≤20 mm in greatest dimension

T2 Tumour >20 mm but ≤50 mm in greatest dimension

T3 Tumour >50 mm in greatest dimension

T4 Tumour of any size with direct extension to the chest wall and/or to the
skin (ulceration or skin nodules)

T4a Extension to the chest wall, not including only pectoralis muscle
adherence/invasion

T4b Ulceration and/or ipsilateral satellite nodules and/or oedema (including
peau d’orange) of the skin, which do not meet the criteria for
inflammatory carcinoma

T4c Both T4a and T4b

T4d Inflammatory carcinoma

Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed (e.g., previously removed)

N0 No regional lymph-node metastases

N1 Metastases to moveable ipsilateral level I, II axillary lymph node(s)

N2 Metastases in ipsilateral level I, II axillary lymph nodes that are clinically
fixed or matted; or in clinically detected ipsilateral internal mammary
nodes in the absence of clinically evident axillary lymph-node
metastases

N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one
another (matted) or to other structures

N2b Metastases only in clinically detected ipsilateral internal mammary
nodes and in the absence of clinically evident level I, II axillary lymph-
node metastases

HANDBOOK OF ONCOLOGY

Breast Cancer 47

Regional lymph nodes (N) (cont.) TREATMENT APPROACHES

N3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s)
with or without level I, II axillary lymph-node involvement; or in clinically
detected ipsilateral internal mammary lymph node(s) with clinically
evident level I, II axillary lymph-node metastases; or metastases in
ipsilateral supraclavicular lymph node(s) with or without axillary or
internal mammary lymph-node involvement

N3a Metastases in ipsilateral infraclavicular lymph node(s)

N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary
lymph node(s)

N3c Metastases in ipsilateral supraclavicular lymph node(s)

pNX Regional lymph nodes cannot be assessed (e.g., previously removed, or
not removed for pathologic study)

pN0 No regional lymph-node metastasis identified histologically

pN0(i-) No regional lymph-node metastases histologically, negative
immunohistochemistry (IHC)

pN0(i+) Malignant cells in regional lymph node(s) no greater than 0.2mm
(detected by H&E or IHC including isolated tumour-cell clusters (ITC))

pN0mol-) No regional lymph-node metastases histologically, negative molecular
findings (RT-PCR)

pN0(mol+) Positive molecular findings (RT-PCR), but no regional lymph-node
metastases detected by histology or IHC

pN1 Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or in
internal mammary nodes with metastases detected by sentinel lymph-
node biopsy, but not clinically detected

Micrometastases (greater that 0.2 mm and/or more than 200 cells, but
pN1mi none greater than 2.0 mm)

pN1a Metastases in 1-3 axillary lymph nodes, at least one metastasis greater
than 2 mm

pN1b Metastases in internal mammary nodes with micrometastases or
macrometastases detected by sentinel lymph-node biopsy, but not
clinically detected

pN1c Metastases in 1-3 axillary lymph nodes and in internal mammary lymph
nodes with micrometastases or macrometastases detected by sentinel
lymph-node biopsy, but not clinically detected

pN2 Metastases in 4-9 axillary lymph nodes; or in clinically detected
internal mammary lymph nodes in the absence of axillary lymph-node
metastases

pN2a Metastases in 4-9 axillary lymph nodes (at least one tumour deposit
greater than 2.0 mm)

pN2b Metastases in clinically detected internal mammary lymph nodes in the
absence of axillary lymph-node metastases

HANDBOOK OF ONCOLOGY

48 SOLID TUMOURS

Regional lymph nodes (N) (cont.)

pN3 Metastases in 10 or more axillary lymph nodes; or in infraclavicular
(level III axillary) lymph nodes; or in clinically detected ipsilateral internal
mammary lymph nodes in the presence of one or more positive level
I, II axillary lymph nodes; or in more than three axillary lymph nodes
and in internal mammary lymph nodes with micrometastases or
macrometastases detected by sentinel lymph-node biopsy, but not
clinically detected, or in ipsilateral supraclavicular lymph nodes

pN3a Metastases in 10 or more axillary lymph nodes (at least one tumour
deposit greater than 2.0 mm); or metastases to the infraclavicular (level
III axillary lymph) nodes

pN3b Metastases in clinically detected ipsilateral internal mammary lymph
nodes in the presence of one or more positive axillary lymph nodes; or
in more than three axillary lymph nodes and in internal mammary lymph
nodes with micrometastases or macrometastases detected by sentinel
lymph-node biopsy, but not clinically detected

pN3c Metastases in ipsilateral supraclavicular lymph nodes

Distant metastasis (M)

MO No clinical or radiologic evidence of distant metastases

cM0(i+) No clinical or radiographic evidence of distant metastases, but deposits
of molecularly- or microscopically-detected tumour cells in circulating
blood, bone marrow, or other nonregional nodal tissue that are no
larger than 0.2 mm in a patient without symptoms or signs of metastases

M1 Distant detectable metastases as determined by classic clinical and
radiographic means and/or histologically proven larger than 0.2 mm

Anatomic stage/Prognostic groups

0 Tis N0 M0

IA T1 N0 M0

IB T0 N1mi M0

T1 N1mi M0

IIA T0 N1 M0

T1 N1 M0

T2 N0 M0

IIB T2 N1 M0

T3 N0 M0

IIIA T0 N2 M0

T1 N2 M0

T2 N2 M0

T3 N1 M0

T3 N2 M0

IIIB T4 N0 M0

T4 N1 M0

HANDBOOK OF ONCOLOGY

Breast Cancer 49

cancer, a particularly aggressive type of Treatment for breast cancer is personal- TREATMENT APPROACHES
breast cancer. ised, based on patient factors including
comorbidities, tumour factors (biology),
INITIAL WORK-UP AFTER staging, and so on. A “one-size-fits-all” ap-
A BREAST-CANCER DIAGNOSIS proach is not appropriate, and each case
needs to be evaluated looking at the fac-
Staging tests that should be performed tors mentioned above.
after a breast-cancer diagnosis are a
chest x-ray, abdominal ultrasound, blood SURGERY
tests (which must include a liver function The choice of surgery is influenced by the
test and a calcium level). Tumour markers size of the tumour, the location within the
are not standard tests, but may aid in the breast, the presence or absence of delete-
overall assessment and monitoring of a rious mutations, and patient preferences.
patient following diagnosis.
The timing of surgery is determined by
INDICATIONS FOR AN MRI BREAST the initial stage of the cancer, tumour
size, and the use of neoadjuvant chemo-
An MRI of the breast is not a standard imag- therapy.
ing technique in all breast-cancer patients.
Doing an MRI pre-operatively increased The trend towards bilateral mastec-
mastectomy rates and was not shown to tomies has been increasing across the
reduce re-excision rates.2 Furthermore, globe, fuelled by media awareness and
there was no difference in eight-year local celebrities who have undergone this pro-
recurrence rates (97% vs 95%) or disease- cedure. Contralateral prophylactic mas-
free survival rates (89 vs 93%)3 in patients in tectomy does not confer a survival ben-
whom preoperative MRI had been utilised, efit, except in patients with a hereditary
compared to those who did not undergo breast cancer.4
preoperative MRI, based on a meta-analy-
sis of in excess of 3 000 patients with newly CHEMOTHERAPY
diagnosed breast cancer. Not all patients with breast cancer require
chemotherapy. This is based largely on
Indications for an MRI of the breast in- disease biology and chemotherapy sensi-
clude lobular cancer, BRCA-positive pa- tivity of a particular type of breast cancer,
tients, or patients harbouring other high- the intensity of oestrogen receptor and
risk mutations and multifocal/multicentric progesterone receptor expression, and
breast cancer. Ongoing clinical trials are HER2 neu status.
evaluating the use of breast MRI to assess
response to neoadjuvant chemotherapy. Indications for neoadjuvant

TREATMENT MODALITIES FOR chemotherapy
NON-METASTATIC BREAST CANCER Locally advanced breast cancer – Stage
IIB-IIIC tumours (see Table 1) must be con-
Treatment of non-metastatic breast can- sidered for neoadjuvant chemotherapy,
cer is best managed in a multidisciplinary as they are often too large for upfront re-
team comprising radiologists, breast sur- section. In addition, smaller tumours with
geons, plastic surgeons, medical and ra- an unfavourable tumour-to-breast ratio
diation oncologists, as well as allied servic- are considered for neoadjuvant thera-
es that include lymphoedema therapists, py, as this may improve the likelihood of
psychologists and dieticians. breast conservation.

The treatment consists of surgery, which Smaller tumours with an unfavourable
could be a lumpectomy, mastectomy or biology (triple-negative breast cancer,
bilateral mastectomy, chemotherapy with HER2-overexpressors) are often treated
or without HER2-blockade in appropriate with neoadjuvant chemotherapy, as
patients (HER2-positive), radiation treat- these tumours are chemotherapy-sensi-
ment and hormonal blockade in patients tive, and the patients will be candidates
whose tumours are endocrine-responsive.
HANDBOOK OF ONCOLOGY

50 SOLID TUMOURS

for chemotherapy at some stage in their ADJUVANT CHEMOTHERAPY
treatment course.
Adjuvant chemotherapy is chemotherapy
A large meta-analysis by the Early administered following definitive surgery
Breast Trialist Collaborative Group, which for breast cancer, with the aim of reducing
included 4 756 patients from 10 clinical the risk of local and distant breast-cancer
trials, found an increased rate of breast recurrence.
conservation among patients treated
with neoadjuvant chemotherapy (65% vs The indications for adjuvant chemother-
49%). There was no difference in the risk apy have shifted from the use of clinic-
of breast-cancer recurrence between pathological factors to genomic profiling
the neoadjuvant group and the adjuvant of an individual cancer.8
chemotherapy group (15-year rate of
38.2% vs 38%) and breast-cancer mortality The traditional indications for chemo-
(34.4% versus 33.7%)5. therapy were tumour size of more than
2 cm, positive axillary nodes, triple-nega-
The choice of chemotherapy depends tive breast cancer, HER2-positive breast
on patient factors and physician prefer- cancer, the presence of lymphovascular
ences. The chemotherapy regimens used invasion, and young age.
in this setting are the same as those used
in the adjuvant setting. Recently, however, a number of
genomic profiling tests have received FDA
These largely comprise anthracycline- approval, and these quantify the risk of
containing vs non-anthracycline-contain- breast-cancer recurrence with or without
ing regimens. chemotherapy. In South Africa, two tests,
namely the Oncotype DX test and the
The most common neoadjuvant chemo- Mammaprint tests, are in use. The tests are
therapy schedule in HER2-negative breast reported as a risk group (low-risk, interme-
cancer is adriamycin, cyclophosphamide diate-risk or high-risk for Oncotype DX, or
3-weekly x 4, followed by weekly paclitaxel low-risk vs high-risk for Mammaprint.)
x 12 weeks, or 3-weekly docetaxel x 4.
The low-risk group patients do not attain
In patients who cannot tolerate an an- a benefit from chemotherapy, and the
thracycline, TC (docetaxel, cyclophos- high-risk group are managed with chemo-
phamide) administered 3-weekly x 4 is a therapy. An ongoing clinical trial is under-
good alternative. way to assess the benefit of chemother-
apy in the intermediate-risk group where
20-30% of cancers overexpress HER2 neu Oncotype Dx test is used. (TailoRx )
protein. This makes the cancers more ag-
gressive, with a higher propensity for dis- The tests are indicated in endocrine-
tant spread. responsive, HER2-negative breast cancer,
including patients with 1-3 positive axillary
The addition of trastuzumab to neoadju- nodes, and assist the clinician with decision-
vant and subsequently adjuvant thera- making pertaining to the additional benefit
py increases complete pathological re- of chemotherapy in addition to hormone
sponse rates, which in turn have been blockade in patients who have undergone
linked to a survival benefit in breast can- definitive surgery for breast cancer.
cer.6 The duration of trastuzumab is a total
of one year. This has challenged the traditional in-
dications for chemotherapy, sparing pa-
In 2013, the FDA approved pertuzumab, tients from the short- and long-term effects
an anti-HER2 monoclonal antibody that of chemotherapy. Clinical trials have indi-
binds HER2/HER3 heterodimers, which is cated that the use of genomic profiling
believed to be an important mechanism changes clinician opinion in approximate-
that is responsible for trastuzumab resist- ly 25%-30% of cases.
ance. The combination of pertuzumab to
trastuzumab and chemotherapy improves HORMONAL BLOCKADE
complete pathological response rates
compared to trastuzumab and chemo- Patients whose cancers are hormone-
therapy alone.7 responsive are candidates for adjuvant

HANDBOOK OF ONCOLOGY

Breast Cancer 51

hormonal blockade with tamoxifen or Table 2. Factors determining choice TREATMENT APPROACHES
aromatase inhibitors. Tamoxifen is used in of treatment in ABC
premenopausal patients with or without
luteinising hormone-releasing hormone Disease Patient
agonists (LHRH), and aromatase inhibitors characteristics characteristics
are mainly indicated for postmenopausal Prior adjuvant
women. Aromatase inhibitors can also be chemotherapy Patient
used in high-risk premenopausal women preferences
combined with an LHRH agonist.9 Disease burden (e.g., oral vs
IV treatment)
In this instance, high-risk disease includes Prior therapies and
node-positive patients, those who were response Socio-economic
deemed to require adjuvant chemother- Aggressiveness of and psychological
apy, high grade and presence of lympho- disease factors (e.g.,
vascular invasion. ER/PgR, HER2 distance between
receptor status home and
Clinical trials have also supported con- Disease-free hospital; costs)
sideration for 10 years compared to five interval
years of hormonal blockade. This is on the Age, PS,
basis of an increased risk of recurrence up comorbidities
to 15 years following completion of five
years of adjuvant endocrine therapy.10 Menopausal status
Two large trials have demonstrated the
superiority of 10 years vs five years of hor- According to the ABC3 guidelines, visceral
monal blockade with tamoxifen.11 There crisis is defined as “severe organ dysfunc-
have been conflicting data on 10 years of tion as assessed by signs and symptoms,
aromatase inhibition. laboratory studies, and rapid progression
of disease. Visceral crisis is not the mere
RADIATION presence of visceral metastases, but im-
plies important visceral compromise lead-
The indications for postoperative radiation ing to a clinical indication for a more rap-
are a tumour size of 5 cm or more, positive idly efficacious therapy, particularly since
axillary nodes (including patients with 1-3 another treatment option at progression
positive nodes), and patients who have will probably not be possible.”
undergone a lumpectomy.
The first-line treatment for endocrine-
Radiation can be omitted in elderly responsive metastatic breast cancer is
women (over 70) following a lumpectomy therefore hormonal blockade, and chem-
for a small luminal A-like cancer. otherapy should be considered only once
the hormonal-blockade treatment op-
TREATMENT OF METASTATIC tions have been exhausted. It is important
BREAST CANCER to emphasise that the presence of meta-
static disease is not an indication for sys-
The median survival for metastatic breast temic chemotherapy.
cancer is two to three years, with 25% of
patients being alive at five years. The in- A new class of drugs, CDK 4/6 inhibitors,
tention of treatment is to increase survival has received regulatory approval in com-
with a good quality of life. The choice of bination with aromatase inhibitors in first-line
treatment depends on disease biology, metastatic breast cancer, or with fulves-
patient factors, tumour burden (includ- trant, an anti-oestrogen that downregulates
ing the presence or absence of a visceral
crisis), previous treatment, and the rate of
disease progression (see Table 2). Patients
with a visceral crisis should be treated with
combination chemotherapy, provided
that their performance status permits.

HANDBOOK OF ONCOLOGY

52 SOLID TUMOURS

the oestrogen receptor (ER) in previously male breast cancer, and those patients
treated patients. treated with aromatase inhibitors must ei-
ther have undergone an orchidectomy,
CDK pathway is overactive in a num- or be treated with an LHRH agonist.
ber of cancers, including breast cancer.
CDK inhibition leads to activation of the The approach to treatment of metastat-
tumour-suppressor gene, Rb, leading to ic breast cancer in males is similar to the
cell-cycle arrest. treatment in females.

For patients in whom chemotherapy is Overall, the prognosis of males with
deemed appropriate, single-agent chem- breast cancer is comparable to females.
otherapy is preferred over combination
chemotherapy (in the absence of a vis- WHEN TO REFER
ceral crisis), as there is no prospective evi-
dence to demonstrate the survival benefit Any patient who presents with a breast
of combination chemotherapy over sin- lump must be referred for investigation
gle-agent sequential chemotherapy. with a mammogram, and at least a breast
ultrasound, regardless of age.
Chemotherapy options to be consid-
ered for this indication include anthra- A core biopsy, rather than a fine-needle
cyclines, taxanes, capecitabine, vinorel- aspiration (FNA), must be performed on
bine, gemcitabine, eribulin and cisplatin, the breast mass, and any axillary glands
among others. The final choice of drug must be cytologically evaluated.
depends on toxicities, previous therapies,
and patient preferences. The histology must contain the following:
n T he diagnosis
MALE BREAST CANCER n G rade of the tumour
n Subtype (lobular vs ductal)
Male breast cancer is a rare disease, and n T he immnunohistochemistry, that
accounts for 0.5-1% of all breast cancers
diagnosed in the US. includes oestrogen receptor,
progesterone receptor expression, HER2
The treatment recommendations for neu expression and Ki 67
male breast cancer are adapted from the
guidelines for the management of female Once the diagnosis is made, the patient
breast cancers, as there is a paucity of should be referred to a breast surgeon,
clinical trials in this patient population. preferably within a multidisciplinary team
for further management.
Male breast cancers are higher in pa-
tients who harbour a genetic mutation of REFERENCES
BRCA 2 more than BRCA 1. BRCA 2-posi-
tive men have a 6% absolute lifetime risk 1. Couch FJ, Nathanson KL, Offit K. Two dec-
of developing breast cancer, significantly ades after BRCA: setting paradigms in per-
higher than the average man. Other non- sonalized cancer care and prevention.
BRCA mutations, such as PTEN, PALB2, P53, Science. 2014;343(6178):1466.  .
may also be implicated.
2. Houssami N, Turner R, Morrow M. Preop-
In addition, conditions that increase the erative magnetic resonance imaging in
oestrogen ratio, e.g., obesity, gynaeco- breast cancer: meta-analysis of surgical
mastia, alcohol, marijuana use, and Kline- outcomes. Ann Surg. 2013 Feb;257(2):249-
felter syndrome may increase the risk of 55. Doi: 10.1097/SLA.0b013e31827a8d17.
male breast cancer.
3. Houssami N, Turner R, et al. An individual
Patients with non-metastatic breast person data meta-analysis of preoperative
cancer are managed with surgery, ra- magnetic resonance imaging and breast
diation therapy, and adjuvant hormonal cancer recurrence. J Clin Oncol. 2014
blockade with tamoxifen, if indicated. The Feb;32(5):392-401.
majority of male breast cancers are en-
docrine-responsive. There are insufficient 4. Fayanju OM, Stoll CR, et al. Contralateral
data for the use of aromatase inhibitors in prophylactic mastectomy after unilateral
breast cancer: a systematic review and
HANDBOOK OF ONCOLOGY meta-analysis. Ann Surg. 2014;260(6):1000.

5. Early Breast Cancer Trialists’ Collaborative
Group (EBCTCG). Long-term outcomes for

Breast Cancer 53

neoadjuvant versus adjuvant chemother- assay on decision making about adjuvant TREATMENT APPROACHES
apy in early breast cancer: meta-analysis chemotherapy in early-stage estrogen-
of individual patient data from ten ran- receptor-positive breast cancer in an on-
domised trials. Lancet Oncol. 2018;19(1):27. cology practice with a unified treatment
Epub 2017 Dec 11. policy. Annals of Oncology. 2011 Nov;22
6. Cortazar P, Zhang L, et al. Pathologi- (11):2381-2386.
cal complete response and long-term 9. Pagani O, Regan MM, et al. International
clinical benefit in breast cancer: the CT- Breast Cancer Study Group. Adjuvant
NeoBC pooled analysis. Lancet. 2014 exemestane with ovarian suppression
Jul;384(9938):164-72. in premenopausal breast cancer. TEXT
7. Gianni L, Pienkowski T, et al. Efficacy and and SOFT Investigators. N Engl J Med.
safety of neoadjuvant pertuzumab and 2014;371(2):107.
trastuzumab in women with locally ad- 10. Pan H, Gray R, et al. 20-Year risks of breast-
vanced, inflammatory, or early HER2-pos- cancer recurrence after stopping endo-
itive breast cancer (NeoSphere): a ran- crine therapy at 5 years. EBCTCG N Engl J
domised multicentre, open-label, phase 2 Med. 2017;377(19):1836.
trial. Lancet Oncol. 2012;13(1):25. 11. Davies C, Pan H, et al. Adjuvant tamox-
8. Geffen  S, Abu-Ghanem  N, et al. The im- ifen: longer against shorter (ATLAS). Lancet.
pact of the 21-gene recurrence score 2013;381(9869):805. 

HANDBOOK OF ONCOLOGY

54 SOLID TUMOURS

Female Genital Tract Cancers

Prof LM Dreosti well-differentiated, non-clear histologies.
Adjuvant chemotherapy for poorly-differ-
MBBCh, BSc(Hons), FCP(SA) entiated clear-cell histology stage Ia and
 Professor and Head of Department of Ib can be considered. Stage Ic and stage
Medical Oncology, University of Pretoria IIa disease should be treated with adju-
vant chemotherapy following surgery.3,4
OVARIAN CARCINOMA
GENERAL CONSIDERATIONS Advanced disease FIGO

After cervical cancer, ovarian cancer is Stage IIb-IIIc
a leading cause of death from gynae- The standard of care remains maximal
cological malignancies. The current inci- debulking surgery by an experienced on-
dence in South Africa is not known, but in cology gynaecologist first. The degree to
2004, there were 470 cases documented which debulking is undertaken has been
(1.66% of cancers reported in females) by the subject of much research. It has gen-
the National Cancer Registry. The disease erally been accepted that all visible tu-
is diagnosed at an early stage in only a mour be bulk-reduced to a maximum size
small percentage of women. In the major- of two cm. However, in recent years, this
ity, i.e., approximately 85% of patients, the has changed and the current standard is
disease is diagnosed at a late stage with to bulk-reduce all visible tumour deposits
a dismal outcome, <30% of women surviv- to the extent that there is no visible re-
ing beyond five years. Unfortunately, the maining tumour or a maximum of one cm
symptoms are non-specific, resulting in a in diameter.5
delay in diagnosis. The symptoms of early-
and late-stage disease are similar. Following maximum debulking surgery,
adjuvant chemotherapy with a plati-
Ovarian cancer is more commonly seen num and taxane are standard of care.6
in the older age groups, with a peak in the Neoadjuvant chemotherapy or interval
seventh and eighth decade of life. Risk debulking surgery is a consideration for
factors include early menarche and late those patients who are unable to un-
menopause, as well as hormonal replace- dergo initial debulking surgery. Generally,
ment therapy. A family history and, specifi- three cycles of platinum-based chemo-
cally, associated genetic syndromes such therapy followed by debulking surgery
as BRCA mutations are associated with and another three cycles of platinum-
the highest risk for developing the disease. based chemotherapy are given.7 The ad-
vantages are easier surgery, less time in
The importance of histological subtype theatre, less blood loss and a shorter stay
has become clearer over the past few in hospital. The survival rate for patients
years.1,2 This is particularly relevant with re- undergoing primary or interval debulking
gard to prognosis and response to chem- surgery is the same.
otherapeutic agents. Histological sub-
types include serous carcinoma, which is Advanced stage ovarian cancer
the commonest, followed by mucinous,
endometrioid and clear-cell carcinomas. FIGO Stage IV
Transitional-cell-, mixed-cell- and undiffer- Where possible, these patients under-
entiated histology are uncommon. go primary debulking surgery followed
by chemotherapy. If this is not possible,
Staging is best done following a staging chemo­therapy with interval debulking sur-
laparotomy and is described by the FIGO gery can be considered. Unfortunately, in
cancer staging system (see Table 1). some patients even this is not possible; pal-
liative chemotherapy with single-agent
Early stage disease FIGO Stage I-IIa
Surgery alone is still the first and best op-
tion for stage Ia and Ib, especially with

HANDBOOK OF ONCOLOGY

Female Genital Tract Cancers 55

platinum may be the only choice. Very control arm.8 Concerns about catheter TREATMENT APPROACHES
advanced stage disease, poor perfor- placement, infection, catheter mal-
mance status (PS), renal dysfunction and function and abdominal pain have lim-
comorbidities may preclude even this ited this approach to highly specialised
treatment in some patients. units well-versed in the management
of IP catheters and the problem of IP
TREATMENT chemotherapy.
INTRAPERITONEAL CHEMOTHERAPY
CHEMOTHERAPY
Intraperitoneal chemotherapy (IP) has Since the 1970s, platinum-based chemo-
been hotly debated in recent years; in therapy has been used to treat ovar-
fact, it is not a new modality of treat- ian cancer; initially with cisplatinum and
ment, and several earlier studies de- later carboplatinum. The GOG III study
scribe this form of treatment. While the demonstrated that cisplatinum and pa-
results of a recent trial are very prom- clitaxel were superior to cisplatinum and
ising, there were several methodologi- cyclophosphamide.9
cal issues with the study, including the

Table 1. FIGO staging of ovarian cancer

Stage I – Tumour is confined to the ovary/ovaries

Ia Only one ovary is affected by the tumour, the ovary capsule is intact
No tumour is detected on the surface of the ovary
Malignant cells are not detected in ascites or peritoneal washings

Ib Both ovaries are affected by the tumour, the ovary capsule is intact
No tumour is detected on the surface of the ovaries
Malignant cells are not detected in ascites or peritoneal washings

Ic The tumour is limited to one or both ovaries, with any of the following:
The ovary capsule is ruptured
The tumour is detected on the ovary surface
Positive malignant cells are detected in the ascites or peritoneal washings

Stage II – Tumour involves one or both ovaries and has extended into the pelvis.

IIa The tumour has extended and/or implanted into the uterus and/or the fallopian
tubes
Malignant cells are not detected in ascites or peritoneal washings

IIb The tumour has extended to another organ in the pelvis
Malignant cells are not detected in ascites or peritoneal washings

IIc Tumours are as defined in IIa/b, and malignant cells are detected in the ascites
or peritoneal washings

Stage III – The tumour involves one or both ovaries with microscopically confirmed
peritoneal metastasis outside the pelvis and/or regional lymph-node metastasis.
Includes liver capsule metastasis.

IIIa Microscopic peritoneal metastasis beyond the pelvis

IIIb Microscopic peritoneal metastasis beyond the pelvis, 2 cm or less in greatest
dimension

IIIc Microscopic peritoneal metastasis beyond the pelvis, more than 2 cm in greatest
dimension and/or regional lymph nodes metastasis

Stage: IV – Distant metastasis beyond the peritoneal cavity and liver parenchymal
metastasis.

HANDBOOK OF ONCOLOGY

56 SOLID TUMOURS

Subsequently, carboplatinum was substi- Despite these differences, there was a
tuted for cisplatinum and the results did clear benefit in progression-free survival
not differ. As the incidence of renal toxic- in both studies, for the arms containing
ity is lower with carboplatinum, the stand- bevacizumab with chemotherapy and
ard of care became carboplatinum and followed by maintenance bevacizumab.
paclitaxel (colloquially known as carbo/ Unfortunately, there was no clear overall
taxel). Carboplatinum and docetaxel are survival benefit.
equivalent to carboplatinum and pacli-
taxel.10 The difference is in the toxicity pro- In a subset of patients with high-risk
file, with more neurotoxicity seen with pa- disease, a survival benefit was seen. Fol-
clitaxel and more myelosuppression with lowing the results of two trials with beva-
docetaxel. cizumab, research with multiple new
agents, including tyrosine kinase inhibitors
The addition of a third or even a fourth (TKIs), is ongoing.
chemotherapy agent to the carbo-
platinum and taxane backbone has not RELAPSED OVARIAN CANCER
improved outcome, but has merely in-
creased the toxicity. There have been The majority (80%) of patients with ovarian
multiple trials of this nature, but none has cancer will suffer a relapse. The choice of
improved survival rates. The use of single- subsequent lines of chemotherapy is then
agent carboplatinum as opposed to the determined by the platinum-free interval.
doublet is sometimes recommended in This is defined as the time interval from the
poor PS patients with multiple comorbidi- last platinum dose until progressive dis-
ties who are unable to tolerate the toxicity ease. In general, those patients with plat-
of this combination. This follows the results inum-refractory or resistant disease have
of ICON 3 where carboplatin and pacli- a poor prognosis and do not benefit from
taxel as standard of care were compared the re-introduction of a platinum-contain-
to single-agent carboplatin or to a third ing regimen. The response rates of liposo-
arm of cyclophosphamide, adriamycin mal doxorubicin, topotecan, paclitaxel
and cisplatin.11 The outcome of all three and gemcitabine are similar in this setting.
arms was similar.
The re-introduction of a platinum-based
ANTI-ANGIOGENIC AGENT regimen is, however, recommended in
patients with partially-sensitive tumours
There has been no further improvement and especially fully-sensitive tumours. Fol-
in the outcome of patients treated with lowing the results of the CALYPSO study,14
standard-of-care chemotherapy for the pegylated liposomal doxorubicin with car-
past 15 years. Ovarian cancer, by its na- boplatin is often recommended, but other
ture, is known to be a highly vascular tu- regimens such as carboplatin and gemcit-
mour. The addition of bevacizumab as an- abine also show responses.
ti-angiogeneic agent has recently been
tested in two large phase III studies. Finally, the OCEANS study13 showed
clear progression-free survival benefit of
Both the GOG 218 trial and the ICON the addition of bevacizumab chemo-
7 trial demonstrated no overall survival therapy, as did the AURELIA study,15 the
benefit.12,13 Both studies added beva- latter study being in the refractory setting.
cizumab to the carboplatin/paclitaxel In both studies, bevacizumab was added
backbone, although the dose differed: to a chemotherapy backbone and con-
15 mg/kg in the GOG 218 and 7.5 mg/ tinued until disease progression.
kg in ICON 7. Other differences included
the cycle at which the bevacizumab CANCER OF THE CERVIX
was initiated and the number of cycles
(months) the bevacizumab was contin- Squamous carcinoma of the cervix is the
ued (16 cycles in GOG 218 and 12 cycles most common histological subtype. Other
in ICON 7). histological subtypes include adenocar-
cinoma and small-cell carcinoma. The
HANDBOOK OF ONCOLOGY mainstay of cancer of the cervix remains

Female Genital Tract Cancers 57

surgery followed by chemoradiation with subtypes: a meta-analysis. Gynaecol On- TREATMENT APPROACHES
the use of cisplatin as a radiosensitiser. The col. 2011;122:541-547.
treatment of locally recurrent disease is 3. Vergote I, et al. Prognostic importance of
surgery, if possible, or radiation if this has degree of differentiation and cyst rupture
not been given previously. For advanced in stage I invasive epithelial ovarian carci-
or recurrent disease, chemotherapy can noma. Lancet. 2001;357:1761-82.
be considered. Single agents such as plat- 4. Bell J, et al. Randomised phase III trial of
inum alone, paclitaxel or topotecan all three versus six cycles of adjuvant carbo-
have response rates. Combination chem- platin and paclitaxel in early stage epi-
otherapy with platinum and paclitaxel has thelial ovarian carcinoma: a Gynecologic
been demonstrated with a modest sur- Oncology Group study. Gynecol Oncol.
vival benefit of approximately two months 2006;102:432-439.
with significant toxicity.16 5. Polterauer S, et al. Prognostic value of re-
sidual tumor size in patients with epithelial
Adenocarcinoma of the cervix carries a ovarian cancer FIGO stages IIA-IV: analysis
very poor prognosis. Small-cell carcinoma of the OVCAD data. Int J Gynecol Cancer.
should be treated in a similar manner to 2012;22:380-385.
small-cell carcinoma of the lung. 6. Du Bois A, et al. A randomised clinical trial of
cisplatin/paclitaxel versus carboplatin/pacli-
ENDOMETRIAL CANCER taxel as first-line treatment of ovarian cancer.
J Natl Cancer Inst. 2003;95:1320-1329.
The treatment recommendations for early- 7. Vergote I, et al. Neo-adjuvant chemothera-
stage disease, stages I to III are primar- py or primary surgery in stage IIIC or IV ovar-
ily surgery followed by radiation therapy. ian cancer. N Engl J Med. 2012;363:943-953.
The GOG 122 trial17 compared whole ab- 8. Armstrong DK, et al. Intraperitoneal cis-
dominal radiotherapy to adjuvant chem- platin and paclitaxel in ovarian cancer.
otherapy in patients with stages III to IVa N Engl J Med. 2006;354:34-43.
disease. There was both a progression-free 9. Ozols RF, et al. Phase III trial of carboplatin
as well as an overall survival benefit that and paclitaxel compared with cisplatin
favoured the chemotherapy arm of dox- and paclitaxel in patients with optimally re-
orubicin and cisplatin. This form of adju- sected stage III ovarian cancer: a gyneco-
vant chemotherapy has not been widely logic oncology group study. J Clin Oncol.
used because the control arm in the study 2003;21:3194-3200.
was not considered a standard of care. 10. Vasey PA, et al. Phase III randomised trial
Chemotherapy used as a single agent or of docetaxel-carboplatin versus paclitaxel-
in combination has been studied in stage carboplatin as first-line chemotherapy for
IV disease. ovarian carcinoma. J Natl Cancer Inst.
2004;96:1682-1691.
Randomised trials including doxorubicin 11. International Collaborative Ovarian Neo-
alone or in combination have failed to plasm Group. Paclitaxel plus carboplatin
show a survival advantage. The GOG 177 versus standard chemotherapy with either
trial18 compared platinum plus paclitaxel single-agent carboplatin or cyclophos-
to the same combination together with phamide, doxorubicin, and cisplatin in
doxorubicin (TAP). A progression-free and women with ovarian cancer: the ICON3
an overall survival benefit were seen, but randomised trial. Lancet. 202;360:505-515.
at the expense of considerable toxicity, 12. Perren TJ, et al. A Phase III trial of bevaci-
including grade 3 symptomatic heart fail- zumab in ovarian cancer. N Engl J Med.
ure. Granulocyte colony-stimulating fac- 2011;365:2484-2496.
tor (G-CSF) was required. 13. Aghajanian C, et al. OCEANS: A random-
ised, double-blind, placebo-controlled phase
REFERENCES III trial of chemotherapy with or without
bevacizumab in patients with platinum-
1. Hess V, et al. Mucinous epithelial ovarian sensitive recurrent epithelial ovarian, pri-
cancer: a separate entity requiring specific mary peritoneal, or fallopian tube cancer.
treatment. J Clin Oncol. 2004;22:1040-1044. J Clin Oncol. 1201;30:2039-2045.
14. Pujade-Lauraine E, et al. Pegylated lipo-
2. Lee YY, et al. Prognosis of ovarian clear cell somal doxorubicin and carboplatin com-
carcinoma compared to other histological pared with paclitaxel and carboplatin

HANDBOOK OF ONCOLOGY

58 SOLID TUMOURS

for patients with platinum-sensitive ovar- Study. Gynecologic Oncology. 2010;116:
ian cancer in late relapse. J Clin Oncol. 44-49.
2010;28:3323-3329. 17. Randall ME, et al. Randomised phase III
15. Pujade-Lauraine E, et al. AURELIA: a ran- trial of whole-abdominal irradiation versus
domised phase III trial evaluating bevaci- doxorubicin and cisplatin chemotherapy in
zumab (BEV) plus chemotherapy (CT) for advanced endometrial carcinoma: a Gy-
platinum (PT)-resistant recurrent ovarian necologic Oncology Group Study. J Clin
cancer (OC). J Clin Oncol. 2012:30(Suppl) Oncol. 2006;24:36-44.
(AbstLBA5002). 18. Fleming GF, et al. Phase III trial of doxo-
16. Moore DH, Tian C, Monk BJ, et al. Prognos- rubicin plus cisplatin with or without pa-
tic factors for response to cisplatin-based clitaxel plus filgrastim in advanced en-
chemotherapy in advanced cervical car- dometrial carcinoma: a Gynecologic
cinoma: a Gynaecologic Oncology Group Oncology Group Study. J Clin Oncol. 2004;
22:2159-2166.

HANDBOOK OF ONCOLOGY

XTANDITM offers significant improvements in overall survival while maintaining quality of
life, vs. placebo *
XTANDITM delays the time to chemotherapy from months to years 2 **

A generally well tolerated treatment, with dosing that’s simple and convenient 1, 2, 3

* in patients both before and after chemotherapy 2, 3
** in chemo naïve patients

Treat what really matters in mCRPC, treat with XTANDI TM

References: 1. XTANDITM Package insert dated 30 September 2016. 2. Beer TM, Armstrong AJ, Rathkopf DE et al. Enzalutamide in Metastatic Prostate Cancer before
Chemotherapy. N Engl J Med 2014;371(5):424-433. 3. Scher HI, Fizazi K, Saad F et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy.
N Engl J Med 2012;367(13):1187-1197.

For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority.

S4 XTANDITM 40 mg soft capsules. Reg. No. 48/26/0404. Each soft capsule contains 40 mg of enzalutamide. Applicant: Astellas Pharma (Pty) Ltd, Reg. No. 33565
2002/024956/07, EOH Business Park, Gillooly’s View, 5 Osborne Lane, Bedfordview, 2007, Tel: 011 615 9433, Fax: 011 615 9427 x/LakeA4add/6-8-2015

XTANDITM offers significant improvements in overall survival while maintaining quality of
life, vs. placebo *
XTANDITM delays the time to chemotherapy from months to years 2 **

A generally well tolerated treatment, with dosing that’s simple and convenient 1, 2, 3

* in patients both before and after chemotherapy 2, 3
** in chemo naïve patients

Treat what really matters in mCRPC, treat with XTANDI TM

References: 1. XTANDITM Package insert dated 30 September 2016. 2. Beer TM, Armstrong AJ, Rathkopf DE et al. Enzalutamide in Metastatic Prostate Cancer before
Chemotherapy. N Engl J Med 2014;371(5):424-433. 3. Scher HI, Fizazi K, Saad F et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy.
N Engl J Med 2012;367(13):1187-1197.

For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority.

S4 XTANDITM 40 mg soft capsules. Reg. No. 48/26/0404. Each soft capsule contains 40 mg of enzalutamide. Applicant: Astellas Pharma (Pty) Ltd, Reg. No. 33565
2002/024956/07, EOH Business Park, Gillooly’s View, 5 Osborne Lane, Bedfordview, 2007, Tel: 011 615 9433, Fax: 011 615 9427 x/LakeA4add/6-8-2015

Prostate Cancer 61

Prostate Cancer TREATMENT APPROACHES

Dr PW van Zijl than 4 ng/ml lead to an approximate 30-
35% increase in the likelihood of detecting
MBChB, MMed, FC Rad Onc prostate cancer at prostate biopsy. Men
 Clinical and Radiation Oncologist with this level should be encouraged to
in private practice, Life Wilgers Hospital, undergo TRUS-guided biopsy.
Pretoria n PSA velocity and free fraction –

Second to lung cancer, prostate cancer velocity is the increase of PSA values
is the most commonly diagnosed cancer over time. A cut-off of 0.75 ng/ml per
in men 50 years and older. This is true for year increases the sensitivity of PSA
developed countries as well as develop- testing alone. It is recommended
ing countries.1 In the USA, the incidence of that three levels of PSA be obtained
prostate cancer is 160 per 100 000.2 over an 18-month period. Free PSA is
significantly lower in men who have
IMPACT ON SOCIETY prostate cancer compared with men
who do not have prostate cancer.
Until 2004, the development of castration- A free PSA level of 25% and below
resistant prostate cancer was a uniformly in patients with a PSA of 4-10 ng/ml
lethal event. These patients mostly devel- detected 95% of prostate cancers;
oped skeletal-related events. Docetaxel, above this level very few prostate
which prolonged survival, and zoledronic cancers are diagnosed.3
acid, a bisphosphonate, which delays the n S creening – PSA, although very useful in
progression of skeletal-related events had diagnosis, is now challenged as it does
a significant impact on the disease. Since not seem to reduce prostate cancer
then, findings demonstrating the benefit of mortality. If it does reduce mortality,
early chemotherapy together with three the reduction is likely to be small.
new drugs have added to our ability to The European Randomised Study of
curb the impact. Prostate Cancer (ERSPC) concluded,
however, that PSA screening could
During the last decades, mortality rates reduce prostate cancer mortality. The
have declined sharply, mainly because of Prostate, Lung, Colorectal and Ovarian
improved treatments and earlier diagnosis. Cancer Screening Trial (PLCO) showed
no or very little reduction in prostate
It is not only mortality, but morbidity, lack cancer mortality.4
of productivity (in younger working-age n Imaging – diagnostic work-up prior to a
men) and the financial burden of costly decision on the treatment modality of
treatment that impact on society. choice should include a detailed pelvic
MRI to the risk factors (see below).
DIAGNOSTIC ISSUES
PATHOPHYSIOLOGY
A number of methods are used in the di-
agnosis of prostate cancers and there are More than 95% of cancers of the prostate
several diagnostic issues to consider. are adenocarcinomas. Most tumours arise
in the peripheral zone of the prostate.
These include:
n PSA – Prostatic-specific antigen (PSA) GLEASON SCORE
Histological grading is one of the most
for adenocarcinomas of the prostate important variables in prognosis determi-
n D RE – Digital rectal examination (DRE) nation. Five distinct patterns, from well- to
n TRUS – Transrectal ultrasound (TRUS) and poorly-differentiated, were described in
the original Gleason grading scale. The
biopsy.
HANDBOOK OF ONCOLOGY
Compared to DRE, the appropriate use of
PSA alone can give a diagnostic advan-
tage of five to 10 years. PSA levels of more

62 SOLID TUMOURS

sum of the grades of the most common are identified. For each, group-specific
and the second most common growth options are recommended. Metastatic
patterns give the final Gleason Score – disease is set out as a separate entity with
e.g., 3 + 4 = 7. The higher Gleason Scores different treatment lines.
(e.g., 8-10) have the worst prognosis.
Table 2 explains the various risks groups.
PROSTATE RISK-BASED APPROACH Very-low-risk patients must have disease
TO TREATMENT that is detectable by PSA only (i.e., not on
RISK FACTORS AND STRATIFICATION imaging or DRE) with Grade Group 1 dis-
ease and PSA <10.
The following factors play a role in selecting
the correct initial treatment: anatomic ex- Table 1. International Society
tent of disease (The American Joint Com- of Urological Pathology (ISUP)
mittee on Cancer [AJCC] TNM stage), his- Grade Group classification system
tological grade (Gleason/Grade group),
PSA, expected outcome of each treat- Grade Gleason score and pattern
ment, potential complications of each group
treatment and patient’s general condition: 1 Grade 6 (3+3)
life expectancy and comorbidities. 2 Grade 7 (3+4)
3 Grade 7 (4+3)
Since 2014, the International Society of 4 Grade 8 (4+4, 3+5, or 5+3)
Urological Pathology (ISUP)5 consensus 5 Grade 9 or 10 (4+5, 5+4, or 5+5)
group has implemented the new Grade
Group system which uses the traditional Source: Adapted from Epstein JI, Egevad L, Amin
Gleason scoring to classify findings in five MB, et al. The 2014 International Society of Urological
groups (see Table 1). Pathology (ISUP), Consensus Conference on Gleason
Grading of Prostatic Carcinoma: Definition of Grading
The National Comprehensive Cancer Patterns and Proposal for a New Grading System. Am
Network (NCCN) guidelines recommend J Surg Pathol. 2016;40:244
that risk-appropriate treatment should be
offered to patients. Very low-, low-, inter-
mediate-, high- and very high-risk groups

Table 2. Pretreatment risk stratification for prostate cancer

Risk group Clinical stage Gleason Score Serum PSA

Standard risk groups

Low-risk T1c-T2a ≤6 <10 ng/mL

Intermediate-risk T2b 7 10 to 20 ng/mL

High-risk T2c 8 to 10

Risk groupings used by Memorial Sloan-Kettering and Seattle groups1, 2

Low-risk ≤T2a ≤6 <10 ng/mL

Intermediate-risk One elevated risk factor: Clinical stage ≥T2a disease, Gleason
score ≥7, PSA ≥10 ng/mL

High-risk Two elevated risk
factors

PSA: prostate specific antigen; T1c: tumour identified by needle biopsy (e.g., because of elevated
PSA); T2a: tumour involves one-half of one lobe or less; T2b: tumour involves more than one-half of
one lobe, but not both lobes; T2c: tumour involving both lobes

Source: 1. Zelefsky M, et al. Int J Radiat Oncol Biol Phys. 2000;47:1261. 2. Blasko J, et al. Int J Radiat Oncol Biol Phys.
2000;48:111

HANDBOOK OF ONCOLOGY

Prostate Cancer 63

TREATMENT OPTIONS The advantages of active surveillance TREATMENT APPROACHES
include prevention, avoidance of danger
Traditional thinking such as local, locally of anaesthesia and complications during
advanced and metastatic is useful, but surgery (i.e., erectile dysfunction [ED], in-
when patients are classified in the risk continence, rectal damage); radiother-
groups set out in Table 2, treatment op- apy damage to surrounding organs (i.e.,
tions can be better selected. bladder and kidneys and ED in some pa-
tients), hormonal issues with ED, osteopo-
When a patient suffers metastatic dis- rosis, depression and gynaecomastia.
ease, the intent must be clear: prolonged
survival, symptom control or supportive Disadvantages of active surveillance
care only. See Figure 1 for an algorithm for are anxiety and depression from frequent
the treatment of prostate cancer. investigations, sepsis and infections from re-
peated biopsies and higher mortality due
ACTIVE SURVEILLANCE to disease progression in some patients.
Patients eligible for active surveillance
have very low-risk disease. Surveillance implies PSA evaluation every
three to six months, annual DRE and multipar-
Advantages of this approach is the ametric MRI, as well as annual biopsy.
delay of interventional treatment – e.g.,
radical prostatectomy, external beam The following criteria define clinically sig-
radiation therapy (EBRT) and hormonal nificant progression:
management – deferring the treatment to n PSA progression: PSA doubling time in
avoid side effects, but still treating cura-
tively when indicated. less than three years based on multiple
PSA readings at three-monthly intervals

Figure 1. Algorithm for the treatment of prostate cancer

Prostate cancer

Non-metastatic Metastatic

Low risk Intermediate risk High risk Pain control

• Watch and wait Surgery EBRT-RA/IMRT Radiotherapy
• Active EBRT-RA/IMRT + Hormonal Hormonal treatment
therapy Bisphosphonates
surveillance Chemo/surgery
• Surgery ­radical New drugs

prostectomy
• R adiotherapy

EBRT-RA/IMRT • Carbazitaxel
Brachytherapy ­pd103 • Enzalutamide – post

Brachytherapy + EBRT Rx progression on
Hormonal therapy • Alpharadin-Ra223 for

bone mets

taxotere

1125

±­• Hormonal therapy for those who have poor performance status

IMRT - intensity-modulated radiotherapy; RA - RapidArc; EBRT - external beam radiation therapy

HANDBOOK OF ONCOLOGY

64 SOLID TUMOURS

n Clinical progression: doubling of size six weeks of daily treatment. Acute symp-
is determined by TRUS or DRE, local toms appear typically during the third
progression or distant metastases week of radiation and resolve within days
or weeks after completion of radiotherapy.
n G leason Score progression on repeat
biopsies. Late toxicities include chronic urethritis in
10% of patients with strictures in 2% of pa-
RADICAL PROSTATECTOMY (PLUS tients. Haemorrhagic cystitis has become
OR MINUS LYMPH-NODE DISSECTION) uncommon with CRT.
Eligible patients include all risk groups if
general medical condition, life expec- Grade 2 or 3 rectal toxicities at 10 years
tancy and possible complications are are 8% for CRT and 1% for IMRT. Impotency
justified. (Prostatectomy in metastatic dis- rates after EBRT vary in reports between
ease is still regarded as experimental and 36% and 68% three years after treatment.
should be done in a clinical trial situation.) The heterogeneity in the population treat-
ed with EBRT probably explains the vari-
The advantage of radical prostatecto- ability of erectile dysfunction.
my, plus or minus lymph-node dissection,
is the potential of complete cure and/or Newer radiotherapy systems use Rapid-
effective long-term control. Arc volumetric-modulated arc therapy
(VMAT) techniques, delivering high doses
Full pathological staging is possible and in shorter treatment times with high accu-
gives detail on the spread and charac- racy levels. This allows for dose escalation.
ter of the tumour. The disadvantages are
anaesthetic and other possible complica- PROSTATE BRACHYTHERAPY
tions during surgery, which include bleed-
ing, embolism, mortality risks, incontinence Eligible patients have local disease, thus
post-surgery, and impaired erectile func- very low risk, low risk, or by exception inter-
tion. The patient should discuss various mediate risk.
procedures, i.e., open (retro-pubic or per-
ineal) or robotic-assisted, with his urologist. Ultrasound transperineal image-guided
placement of seeds has shown improved
EXTERNAL BEAM RADIOTHERAPY long-term outcomes with reduction of
Eligible patients are from all risk groups, but treatment-related complications. High
it is ideal for intermediate-risk groups as all doses of radiation delivered directly (and
lymph-node groups can be covered in only) result in good tumour outcomes with
the treatment fields. cancer-control rates equal to surgery and
EBRT. However, good results can also be
The minimal radiotherapy for radical obtained in patients with low risk (varying
treatment should be conformal radiother- between 85% and 95%) and in intermedi-
apy (CRT). Intensity-modulated radiother- ate-risk cases (between 48% and 63%).3
apy (IMRT) allows for the sparing of other
pelvic organs – e.g., bladder and rectum, For seed implant, the gland size should
reducing possible side effects consider- ideally be below 60 cm3 (MRI scans, TRUS
ably. Image-guided radiotherapy tech- and DRE).
niques take organ movement into consid-
eration. Types of treatment are:
n Low-dose-rate (LDR) permanent seed
The advantages are long-term cancer
control; in fact the procedure can be cu- implants
rative. These are non-invasive treatments n High-dose-rate (HDR) brachytherapy
reducing the risk of urinary incontinence.
Erectile function is often preserved. Pa- where transperineal catheters are
tients can remain productive at work and placed in the prostate after loading
attend radiation before or after work. with high-dose-rate isotope: more than
one fraction is used for this technique.
The disadvantages of these treatments n B rachytherapy plus external beam
are that they are delivered over a period of radiotherapy. In these cases, a lower
dose of external beam radiotherapy is
HANDBOOK OF ONCOLOGY delivered to the para-prostatic tissue
(45 Gy to 50 Gy) compared to 74 Gy

Prostate Cancer 65

and higher where only EBRT is used. with the latter showing a reduction in TREATMENT APPROACHES
It can be argued that this will lead to prostate-cancer mortality compared to
underdosing of para-prostatic spread the intermittent regimen. While ADT has
of the cancer. a major role to play in improving results of
treatment and managing symptomatic
Disadvantages of brachytherapy: This is disease, patients who rely on ADT alone
an invasive technique, causing a risk of will ultimately relapse.4
infections and bleeding, impotence, stric-
tures of the urethra treated with dilatations Disadvantages of ADT include hot flush-
and gastro-intestinal morbidity – e.g., rec- es, libido loss and erectile dysfunction. Lat-
tal bleeding, rectal ulcer or prostatorectal er changes in weight, hair, muscle, bone,
fistulae (rare). fat, testicular size, penile length and gy-
naecomastia have been observed.
HORMONAL MANAGEMENT
Hormone treatment includes androgen Anaemia, hyperlipidaemia and hyper-
deprivation therapy (ADT) which results glycaemia have also been recorded.
in medical castration and anti-androgen Fatigue, depression and emotion varia-
therapy. Anti-androgen drugs are classified tions may also occur. In castration-resist-
as first- and second-line receptor blockers ant prostate cancer, ADT should not be
(such as bicalutamide, enzalutamide cy- stopped as some prostate-cancer cells
proterone acetate) or an androgen syn- remain sensitive.
thesis inhibitor (abiraterone acetate).
Abiraterone acetate (Zytiga) is a selec-
Eligible patients are from intermediate tive inhibitor of CYP 17, a key enzyme along
risk-, high- and very high-risk groups, as the biosynthesis of androgens – both in the
well as those with metastatic disease. adrenal glands and in tumour cells. It has
demonstrated significant anti-tumour ac-
Androgen-deprivation therapy tivity (PSA declines by 50% in 50-60% of
Sustained-release luteinising hormone- both chemo-naive and chemo-refractory
releasing hormone (LHRH) agonists and metastatic castration-resistant prostate
antagonists are available in one-month, cancer). It has demonstrated improved
three-month and six-month formulations. OS (14.8 vs 10.9m, HR 0.65, 95%CI0.54-0.77)
Phase II data indicate equivalence be- in the post-docetaxel setting 6 and in the
tween agonists and antagonists. Antago- pre-chemo setting 7 (although not statisti-
nists (Degarelix) do not result in the flare-up cally significant).
of symptoms and are therefore indicated
in cord compression and cases of severe Abiraterone is generally well tolerated,
outflow obstruction. but does cause some fluid retention, and
hypokalaemia in rare cases. If hyperten-
Androgen-deprivation therapy (ADT) is used: sion develops, it should be treated, but the
n In combination with radiotherapy for a drug must be continued as long as there is
a clinical benefit.
limited time period, depending on the
risk group. This has shown to increase Enzalutamide (Xtandi) is a novel andro-
the radiation effectiveness with better gen receptor signal inhibitor. It has shown
outcomes an overall survival benefit vs placebo in the
n I n relapsed patients after radiotherapy AFFIRM trial in patients’ post progression
and/or surgery on docetaxel.8 Median survival was 18.4 vs
n I n metastatic disease 13.6 months with HR 0.63;95% CI, 0.53-0.75).
n A s the only therapy in frail patients with It was superior in all secondary parameters,
limited life expectancy. namely PSA reduction, time to progression,
radiological progression-free survival and
Intermittent versus continuous ADT has time to first skeletal-related event.
been tested in large randomised studies,
Enzalutamide is well tolerated, with later
onset of fatigue, mild diarrhoea and hot
flushes. It does not require the use of con-
comitant steroids.

HANDBOOK OF ONCOLOGY

66 SOLID TUMOURS

In the pre-chemo setting (Prevail trial)9, symptomatic skeletal event and biochem-
enzalutamide also showed a 29% reduc- ical parameters) was positive as well.
tion in the death rate at the time of data
cut-off and benefit on the secondary end- Side effects included myelosuppression
points. The same side effect profile was and mild diarrhoea, however patients
observed. generally tolerate these very well. Re-
grettably, the treatment is costly and few
Chemotherapy funders will allow access to 223-Ra.
In patients with metastatic disease show-
ing progression after hormonal manage- REFERENCES
ment, chemotherapy is indicated.
1. Kirby RS, Patel MI. Fast Facts: Prostate Can-
Docetaxel has been shown to reduce cer. 6th ed. Oxford: Health Press; 2009;6-7.
pain, lower PSA levels and increase the
survival rate. Docetaxel can be used at 2. Ries L, et al. SEER Cancer Statistics Re-
three-weekly intervals or at a lower dose view. National Cancer Institute (Bethes-
at weekly intervals. The addition of pred- da).1975-2005.
nisone 10 mg daily will improve response.
3. DeVita VT, Hellman S, Rosenberg SA. Prin-
Cabazitaxel, a second-generation tax- ciples and Practice of Oncology. 9th ed.
ane, has been shown to increase survival Philadelphia: Lippincott Williams & Wilkins;
in patients who have failed docetaxel 2011;1222-1269.
therapy. In a phase III trial,10 cabazitaxel
plus  prednisone  significantly increased 4. Marcus PM, Kramer BS. ASCO Educational
survival compared with mitoxantrone plus Book. 2012;96-100.
prednisone in men whose disease had
progressed on docetaxel. An initial report 5. Epstein JI, et al. Contemporary Gleason
of a phase III trial found that a dose of Grade of prostate cancer. Am J Surg
20 mg/m2 was as effective and less toxic Pathol. 2017 Apr;41(4):e1-e7.
than the approved dose of 25 mg/m2. This
mitigates the side effects typical of taxa- 6. De Bono JS, et al. Abiraterone and in-
nes to a level similar to and less than those creased survival in metastatic prostate
of docetaxel. cancer. N Engl J Med. 2011;164(21):1995.

Intravenous radiation: Radium-223 7. Miller K, et al. Phase III COU-AA-302, study
of abiraterone acetate plus prednisone in
(Xofigo) men with chemotherapy-naïve patients
Radium-223 (223-Ra), a new intravenously with metastatic castration resistant pros-
administrated radionuclide (alpha parti- tate cancer. Eur Urol. 2017 September; pii:
cles), demonstrated improvement in sur- S0302-2838(17)30728-5.
vival in patients with castration-resistant
prostate cancer with bone-only metastat- 8. Scher HI, et al. Increased survival with
ic disease. It can also be used to improve enzalutamide in prostate cancer after
pain symptoms. chemotherapy. N Engl J Med. 2012 Sep 27;
367(13):1187-97.
In the phase III Alsympca trial11, a month-
ly infusion was well tolerated, and im- 9. Beer TM, et al. Enzalutamide in metastatic
proved overall survival (14 vs 11.2 months, prostate cancer before chemotherapy.
HR 0.7, 95% CI 0.55-0.88), and assessment N Engl J Med. 2014;371:424-433.
of all secondary endpoints (time to first
10. de Bono J, et al. Prednisone plus cabazitax-
el or mitoxantrone for metastatic castration
resistant prostate cancer progressing after
docetaxel treatment: a randomised open-
label trial. Lancet. 2010;376(9747):1147.

11. Parker C, et al. Alpha emitter radium-223
and survival in metastatic prostate cancer.
N Engl J Med. 2013 Jul;369(3):213-23.

.
Acknowledgement: Prof JP Jordaan, former
Head Department of Oncology, School of Clini-
cal Medicine, University of KwaZulu Natal.

HANDBOOK OF ONCOLOGY

Kidney and Bladder Cancers 67

Kidney and Bladder Cancers TREATMENT APPROACHES

Dr PW van Zijl been described. Specific inherited syn-
dromes associated with renal cell carci-
MBChB, MMed, FC Rad Onc noma include von Hippel-Lindau disease,
 Clinical and Radiation Oncologist tuberous sclerosis complex, hereditary
in private practice, Life Wilgers Hospital, papillary renal carcinoma, hereditary par-
Pretoria aganglioma and pheochromocytoma.
Factors that favour a hereditary contribu-
KIDNEY CANCER tion in patients without a clear genetic
disease include first-degree relatives with
The two most common types of kidney a tumour, onset before the age of 40, and
cancer are renal cell carcinoma (RCC) bilateral or multifocal disease.
and urothelial carcinoma of the renal pel-
vis. RCC constitutes approximately 85% of PATHOLOGY 
primary renal neoplasms. Urothelial (transi- All solid renal masses require resection or
tional cell) carcinomas of the renal pelvis biopsy for accurate diagnosis unless the
account for approximately 8% of kidney presence of a metastatic lesion can be
tumours, and other parenchymal epithe- established by biopsy. RCCs are classified
lial tumours are rare. The rest of this discus- to reflect the morphology, growth pattern,
sion will focus on RCC, while urothelial cell cell of origin, and the histochemical and
carcinomas are covered in the section on molecular basis of the different types of
bladder cancer. adenocarcinomas.

EPIDEMIOLOGY The subtypes of RCC include:
The incidence of RCC varies globally from n Clear-cell (75-85%)
region to region, with the United States n Papillary (chromophilic 10-15%)
having approximately 65 000 new cases n Chromophobe (5-10%)
annually and approximately 13 500 deaths n Oncocytic
each year. In South Africa, there are an n Collecting duct (Bellini’s duct)
estimated 500 to 600 new cases per year.
RCC is approximately 50% more common Clear-cell carcinomas typically have a
in men compared to women, occurring deletion of chromosome 3p and arise
predominantly in the sixth to eighth dec- from the proximal tubule. A poor prognosis
ade, with the median age of diagnosis at is associated with a higher nuclear grade
64 years. or the presence of a sarcomatoid pattern.

RISK FACTORS TREATMENT

Cigarette-smoking possibly contributes to Localised (resectable) RCC
one-third of cases and is also associated Surgery is potentially curative in the ma-
with more advanced disease at presenta- jority of patients with localised RCC and
tion. Hypertension and obesity, occupa- is therefore the preferred treatment for
tional exposure to toxic compounds such patients with stages I, II and III disease.
as cadmium, asbestos and petroleum Treatment can involve either a radical ne-
products, analgesic abuse and nephrop- phrectomy or a variety of renal-sparing ap-
athy all contribute to the development of proaches (partial nephrectomy or ablative
RCC. Acquired cystic disease of the kid- techniques) in carefully selected patients,
ney, chronic hepatitis C infection and sick- depending upon the extent of disease.
le cell disease are also linked to increased
incidence of RCC. Patients who are not candidates for sur-
gical resection, such as elderly patients
Although most RCCs are sporadic, sev-
eral syndromes associated with RCC have HANDBOOK OF ONCOLOGY

68 SOLID TUMOURS

and those with significant comorbidity, TARGETED THERAPIES AND
could be considered for non-surgical pro- CHECKPOINT INHIBITORS
cedures such as cryoablation, radiofre-
quency ablation (RFA), embolisation and A growing understanding of the biology of
palliative radiotherapy. RCC has led to the development and reg-
istration of several targeted therapies and
Attempts to improve control after surgery immune checkpoint inhibitors.
by adding adjuvant therapy is not stand-
ard care despite a positive trail (S-TRAC)1 in Targeted agents either block the mam-
which observation was compared to one- malian target of rapamycin (mTOR), while
year adjuvant sunitinib. (There was a statisti- a number of agents target the vascular
cal progression-free survival, but no overall endothelial growth factor (VEGF) path-
survival benefit, and toxicity was such that way through tyrosine kinase inhibitors (TKIs)
it is not generally recommended.) or monoclonal antibodies (MAB).

Advanced disease (stage IV) Checkpoint inhibitors block the pro-
Almost all patients with metastatic renal grammed cell-death protein or ligand (PD
cell cancer (mRCC) are incurable. The or PD-L) through monoclonal antibodies.
selection of treatment depends on many
factors, including prior treatment and site mTOR target inhibitors
of recurrence, as well as individual patient
considerations, such as performance sta- Two mTOR inhibitors, temsirolimus and everoli-
tus (PS). mus, have shown clinical activity in RCC.

Options include surgery, immunotherapy, Temsirolimus, an intravenously-adminis-
molecular targeted therapy and radiation tered mTOR inhibitor, has resulted in pro-
for the management of metastatic lesions. longed overall survival (OS) compared
with IFN in a phase III randomised con-
Surgery trolled trial that enrolled intermediate-
Nephrectomy can aid in the palliation of and poor-risk patients. The hazard ratio
symptoms caused by the primary tumour, (HR) for death was 0.73 (95% CI, 0.58-0.92,
related ectopic hormone or cytokine pro- p = 0.008).4
duction. Two randomised studies have
demonstrated an overall survival benefit in Everolimus is an orally administered
selected patients with metastatic disease mTOR inhibitor that was evaluated in a
who have undergone initial cytoreductive second-line phase III trial in patients with
nephrectomy prior to the administration of metastatic RCC with a clear-cell compo-
interferon-alpha (IFN).2,3 nent that had progressed during or within
six months of stopping treatment with suni-
Patients with solitary or a limited number tinib or sorafenib.5
of distant metastases can achieve prolong-
ed survival with nephrectomy and surgical Based on these results, everolimus is indi-
resection of the metastases. This is more cated for patients with metastatic clear-
likely in patients with a long disease-free cell RCC who have progressed on previ-
interval between the initial nephrectomy ous vascular endothelial growth factor
and the development of metastases. (VEGF) tyrosine kinase inhibitors (TKIs),
while temsirolimus is indicated for poor-risk
Cytokine therapy disease. Although the benefit associated
Cytokine therapy represents the early with everolimus is significant in comparison
days in immunotherapy. Although there to placebo, its value relative to other TKIs
are data from the mid-1990s to substanti- remains to be determined.
ate the use of interleukin-2 (IL-2), it has not
been compared to the new-generation The most frequent side effects of the
checkpoint inhibitor and is generally not mTOR inhibitors were asthenia, rash,
offered any more. anaemia, lymphopaenia, nausea, and
anorexia. Severe adverse events were un-
HANDBOOK OF ONCOLOGY common; the most frequent grade 3 or 4
adverse events were anaemia, asthenia,
hyperglycaemia and pneumonitis. Hyper-
sensitivity reactions have been reported

Kidney and Bladder Cancers 69

and may be severe or life-threatening TKI therapy based on a phase III trial11 TREATMENT APPROACHES
and therefore premedication is recom- where overall survival and response rate
mended. was better than everolimus. (Median OS
25 versus 19.6m, HR 0.73, 95% CI 0.57-0.93.)
Angiogenesis target inhibition: The toxicity profile was also more favour-
able. The combination of nivolumab and
mAb and VEGF TKIs ipilumimab (CTLA-4 inhibitor) has been ap-
Bevacizumab is a mAb that binds circu- proved in treatment-naïve patients.12
lating VEGF and prevents its interaction
with the VEGF receptor. Two phase III trials Other mAbs (atezoluzimab and pem-
have demonstrated improved progres- brolizumab) are also being trialled in this
sion-free survival (PFS) with bevacizumab setting, but results are not yet published.
plus IFN compared to IFN alone.6 Various combinations of PD-1 inhibitors
with TKIs are being investigated and seem
The most important adverse events in promising.
the bevacizumab arm included hyperten-
sion, thrombo-embolic events, bleeding Patterns of response differ from those
and gastro-intestinal perforation. with molecular targeted agents or cyto-
toxic chemotherapy. Special immune-
Sunitinib is a multikinase inhibitor target- response criteria were developed for pa-
ing VEGFR-1, VEGFR-2, PDGFR and c-Kit. It tients in the setting of melanoma and now
was more effective compared to IFN in a apply here as well. Lesions may undergo
phase III trial of 750 patients, with good- or progression before they respond, take
intermediate-prognosis metastatic clear- long to respond or shrink and become
cell RCC, in the first-line setting.7 long-term responders.

Sorafenib is a small molecule inhibitor of Toxicity of these mAbs is completely differ-
multiple TKs, including VEGF receptor 2, ent to that of chemotherapy and typically
FLT3, PDGF receptor, and fibroblast growth presents with skin, gastro-intestinal and later
factor receptor-1 (FGFR1), as well as C- endocrine abnormalities. The full clinical pic-
RAF and B-RAF. In the phase III TARGET tri- ture is still unfolding as follow-up after treat-
al, patients with advanced RCC who had ment reflects the long-term side effects.
failed prior standard therapy were ran-
domly assigned to sorafenib or placebo. Price will limit access as all of these drugs
The median PFS was significantly longer in are very expensive.
those receiving sorafenib compared with
placebo.8 NON-CLEAR-CELL RCC
The activity of agents such as sunitinib,
Axitinib is an orally available inhibitor of sorafenib and temsirolimus in patients with
the VEGF receptors 1, 2, and 3. Its registra- non-clear-cell RCC still has to be con-
tion was based on the AXIS phase III trial firmed, although preliminary results and
in second-line metastatic clear-cell RCC subset analyses suggest that these agents
patients who were randomly assigned to have some activity. Subsets of non-clear-
treatment with either axitinib or sorafenib.9 cell tumours occasionally also respond
to chemotherapy. Major responses have
Pazopanib is an oral agent multikinase been reported with various combinations
inhibitor that was approved for patients of platinum agents, taxanes, gemcitabine
with previously untreated advanced renal and doxorubicin in patients with collect-
cell carcinoma and for patients who had ing-duct tumour and sarcomatoid RCCs.
progressed on cytokine therapy.10 Immunotherapy is being investigated in
this setting.
Checkpoint inhibitors
Immunotherapy with mAbs directed BLADDER CANCER
against PD-1 or cytotoxic T-lymphocyte
antigen (CTLA-4) has become an impor- Bladder cancer is the most common can-
tant part of the treatment of mRCC. cer of the urinary tract with a peak inci-
dence in the sixth to eighth decade. An
Nivolumab (PD-1 inhibitor) has been ap-
proved as a second-line therapy following HANDBOOK OF ONCOLOGY

70 SOLID TUMOURS

estimated 1 600 new cases are diagnosed (TURBT), which is usually carried out at the
in South Africa each year. time of diagnosis. Many patients can be
successfully managed with a localised
RISK FACTORS resection.
Exposure to tobacco remains the biggest
risk factor. Smoking is associated with over Additional intravesical therapy is gener-
half of bladder cancer cases in men and ally recommended for patients with inter-
one-third of cases among women. Men mediate- to high-risk, non-muscle-invasive
are three times more likely to develop bladder tumours. This option results in high
bladder cancer than women. Occupa- local concentrations of a therapeutic
tional exposure to chemicals may also agent within the bladder, decreasing the
play a role; metalworkers, mechanics and risk of recurrence and the need for cys-
hairdressers seem to have increased risk. tectomy. Bacillus Calmette Guerin (BCG)
is the most commonly used agent for intra-
SIGNS AND SYMPTOMS vesical immunotherapy for high-grade dis-
Bladder cancer characteristically causes ease (Ta, Tis, T1). Mitomycin C is the most
painless macroscopic or microscopic hae- commonly used chemotherapy agent
maturia. Other possible symptoms include and is appropriate for the intravesical use
dysuria or painful micturition, frequency or for intermediate-risk disease.
urgency.
Following initial treatment, careful sur-
DIAGNOSIS veillance for secondary tumours of the
The gold standard for diagnosing blad- urinary tract is required for both low- and
der cancer is biopsy obtained during cys- high-risk patients. Additional primary tu-
toscopy. It is also important for accurate mours can develop in the urothelium
staging, which determines further man- anywhere along the genito-urinary tract.
agement, since the major prognostic fac- Subsequent surveillance should include
tors in carcinoma of the bladder are the a careful programme of cystoscopy and
depth of invasion into the bladder wall urine cytology.
and the degree of differentiation of the
tumour. Indications for cystectomy include pro-
gression to high-grade disease (Tis or T1)
PATHOLOGY or multiple tumours with frequent recur-
The most common pathology in bladder rences within a short period of time, de-
malignancy is urothelial or transitional cell spite treatment or complications such as
carcinoma (85-90%). Other histologies in- bleeding with anaemia and any muscle-
clude squamous carcinoma, adenocarci- invasive (T2) disease.
noma, small-cell cancer, lymphomas and
sarcomas. Muscle-invasive disease

TREATMENT Radical cystectomy with a urinary di-
The management of bladder cancer can version is the mainstay of treatment for
be divided into three broad groups, based muscle-invasive bladder cancer. Radical
on the stage of the disease: cystectomy entails removal of the blad-
n N on-muscle-invasive disease der, adjacent organs, and regional lymph
n Muscle-invasive disease nodes.
n Metastatic disease.
Neoadjuvant chemotherapy has been
Non-muscle-invasive disease shown in randomised clinical trials to re-
The initial treatment of non-muscle-inva- sult in a survival advantage for patients
sive bladder tumours is a complete tran- with muscle-invasive bladder cancer
surethral resection of the bladder tumour who receive such chemotherapy prior to
undergoing cystectomy, and should be
HANDBOOK OF ONCOLOGY considered for all eligible patients. Cispl-
atin-based chemotherapy (see section on
metastatic disease) is the standard in this
setting.11

Kidney and Bladder Cancers 71

Postoperative adjuvant chemotherapy the combination of gemcitabine and carbo- TREATMENT APPROACHES
has been studied in several small phase III platin is a reasonable alternative.15
trials as an alternative to neoadjuvant
treatment. Meta-analyses of these trials Single-agent therapy or taxane-based
suggest a survival benefit when patients regimens could be considered for these
are given chemotherapy following radical patients. The combination of gemcit-
cystectomy. This is a reasonable option for abine with a taxane rather than a plati-
high-risk patients who have not had neo- num has been evaluated,16 with encour-
adjuvant chemotherapy. aging results.

Most patients with bladder cancer Since up to 50% of patients with ad-
would, if possible, prefer to keep their vanced RCC are not candidates for
native bladder. Use of multimodal ap- chemotherapy due to age or comor-
proaches, including complete TURBT, ra- bidities (e.g., renal function, heart failure,
diation therapy, and chemotherapy, used neuropathy and so on), immunotherapies
together or in sequence, offers an alter- were investigated and reported great
native to radical cystectomy, preserving phase II data.
the bladder and its function while provid-
ing long-term disease control for carefully PD-1 inhibitors (pembrolizumab and
selected patients. The pooled analysis of nivolumab) and PD-L1 inhibitors (atezolu-
the RTOG (2014)13 included 468 patients zimab, avelumab and durvalumab) have
who had chemo-radiation; the response all shown survival advantage in trials in the
rate was 69% and disease-specific control second-line setting and acceptable toxic-
rates were 71% at five years. ity. Phase III trials are currently being run
to test these drugs in the first-line setting,
Patients with extensive comorbid dis- adjuvant and neoadjuvant setting.
ease, or those who are otherwise not can-
didates for radical cystectomy, could be SECOND-LINE THERAPY
considered for radiotherapy, with or with-
out chemotherapy, or alternatively chem- Although a significant number of patients
otherapy alone. responds objectively to first-line therapy,
most eventually progress (median surviv-
Metastatic disease: chemotherapy al with chemotherapy is 15 months) and
may be candidates for second-line chem-
and immunotherapy otherapy. A number of chemotherapy
agents has clinical activity after patients
A cisplatin-based combination chemo- have progressed on MVAC or GC.
therapy regimen is the preferred initial ther-
apy for patients with metastatic urothelial These agents include paclitaxel, doc-
cancer who are cisplatin candidates. Cis- etaxel, vinflunine, ifosfamide and oxaliplatin.
platin-based combination chemotherapy None of these agents can, however, be
results in superior survival when compared considered as standard second-line thera-
with single-agent cisplatin. Not all patients py. Patients with advanced bladder cancer
with urothelial cancer are appropriate who have failed an initial chemotherapy
candidates for cisplatin therapy. regimen should be encouraged to partici-
pate in clinical trials whenever possible.
Other regimens include MVAC (metho-
trexate, vinblastine, doxorubicin and cis- Immunotherapy has proven survival
platin) or GC (gemcitabine and cisplatin). data in this setting. All five of the mAbs list-
Given the similar efficacy and lesser toxic- ed above are approved by the FDA. The
ity, GC rather than MVAC is often consid- Keynote-045 trial17 compared pembroli-
ered as the standard first-line regimen for zumab versus platinum-containing chemo
patients with advanced urothelial carci- and showed a 10.3 versus 7.4 m OS, HR
noma of the bladder.14 0.7, 95% CI 0.57-0.86. The difference was
even bigger at 12 and 18 months, again
For those patients who are candidates for demonstrating that if the immune system
chemotherapy, but not able to receive cispl- can be correctly activated longer-term
atin, usually because of poor renal function, response is possible.

HANDBOOK OF ONCOLOGY

72 SOLID TUMOURS

REFERENCES carcinoma: results of a randomised phase
III trial. J Clin Oncol. 2010;28(6):1061.
1. Ravaud A, Motzer RJ, Pandha HS, et al. 11. Motzer RJ, et al. Nivolumab versus everoli-
Adjuvant sunitinib in high-risk renal-cell car- mus in advanced renal-cell carcinoma. N
cinoma after nephrectomy. N Engl J Med. Engl J Med. 2015;373(19):1803. Epub 2015
2016; 375:2246-2254. Sep 25.
12. European Association of Urology. Updated
2. Mickisch GH, et al. Radical nephrectomy guidelines recommendations for the treat-
plus interferon-alfa-based immunotherapy ment of first-line metastatic clear cell renal
compared with interferon alfa alone in cancer. Eur Urol. 2017;73(3):311-315
metastatic renal-cell carcinoma: a ran- 13. Mak RH, et al. Long-term outcomes in pa-
domised trial. Lancet. 2001;358(9286):966. tients with muscle-invasive bladder cancer
after selective bladder-preserving com-
3. Flanigan RC, et al. Nephrectomy followed bined-modality therapy: a pooled analysis
by interferon alfa-2b compared with inter- of radiation-therapy group protocols 8802,
feron alfa-2b alone for metastatic renal-cell 8903, 9506, 9706, 9906 and 0233. J Clin On-
cancer. N Engl J Med. 2001;345(23):1655. col. 2014;32(34):3801.
14. Von der Maase H, et al. Gemcitabine and
4. Hudes G, et al. Temsirolimus, interferon alfa, cisplatin versus methotrexate, vinblastine,
or both for advanced renal-cell carcino- doxorubicin, and cisplatin in advanced
ma. N Engl J Med. 2007;356(22):2271. or metastatic bladder cancer: results of
a large, randomised, multinational, multi-
5. Motzer RJ, et al. Phase 3 trial of everolimus center, phase III study. J Clin Oncol. 2000;
for metastatic renal cell carcinoma: final 18(17):3068.
results and analysis of prognostic factors. 15. De Santis M, et al. Randomised phase II/
Cancer. 2010;116(18):4256. III trial assessing gemcitabine/carboplatin
and methotrexate/carboplatin/vinblastine
6. Rini BI, et al. Bevacizumab plus interferon in patients with advanced urothelial can-
alfa compared with interferon alfa mono- cer who are unfit for cisplatin-based chem-
therapy in patients with metastatic renal otherapy: EORTC study 30986. J Clin Oncol.
cell carcinoma: CALGB 90206. J Clin On- 2012;30(2):191.
col. 2008;26(33):5422. 16. Calabrò F, et al. Gemcitabine and pacli-
taxel every 2 weeks in patients with previ-
7. Motzer RJ, et al. Overall survival and up- ously untreated urothelial carcinoma. Can-
dated results for sunitinib compared with cer. 2009;115(12):2652.
interferon alfa in patients with meta- 17. Bellmunt J, de Wit R, Vaughn DJ, et al.
static renal cell carcinoma. J Clin Oncol. Pembrolizumab as second-line therapy for
2009;27(22):3584. advanced urothelial carcinoma. N Engl J
Med. 2017; 376:1015-1026.
8. Escudier B, et al. Sorafenib for treatment
of renal cell carcinoma: final efficacy and Acknowledgement: Dr SJ Fourie, clinical and
safety results of the phase III treatment ap- radiation oncologist in private practice, Pre-
proaches in renal cancer global evalua- toria
tion trial. J Clin Oncol. 2009;27(20):3312.

9. Rini BI, et al. Comparative effectiveness of
axitinib versus sorafenib in advanced renal
cell carcinoma (AXIS): a randomised phase
3 trial. Lancet. 2011 Dec;378(9807):1931-9.
(Epub 2011 Nov 4).

10. Sternberg CN, et al. Pazopanib in lo-
cally advanced or metastatic renal cell

HANDBOOK OF ONCOLOGY

Treatment Options for Inoperable and Metastatic Malignant Melanoma 73

Treatment Options for Inoperable TREATMENT APPROACHES
and Metastatic Malignant Melanoma

Dr A Bonthuys have seen the emergence of several nov-
el treatment options. In melanoma, these
MBChB; MSc; F.C. Rad Onc (SA); largely comprise immunotherapies and
targeted therapies. Immunotherapy aims
MMed (Rad Onc) to destroy malignant cells by inducing or
 ICON Clinical Executive enhancing immune-system activation.

Malignant melanoma accounts for less Immunotherapies fall into three general
than 5% of all cutaneous malignancies, categories:
yet it is responsible for the majority of skin- n Checkpoint inhibitors
cancer deaths. The incidence of mela- n C ytokines and
noma has been steadily increasing over n Anti-cancer vaccines.
the past few decades and is currently the
fifth most common cancer in men and Targeted therapies act on specific cellular
the sixth most common cancer in women pathways, targets or ligands and mostly
worldwide, accounting for 6% and 4% of result in inhibition of cellular proliferation
new cancer cases respectively.1 The aver- and tumour growth. The choice, sequenc-
age age at diagnosis is 57 years, with the ing and combination of these approach-
highest incidence occurring between 55 es remains essentially undefined and pa-
and 74 years of age.2 In addition, melano- tients should be encouraged to enrol in
ma is the second most common cancer in clinical trials whenever possible. At pre-
young adults (age 15 to 29 years).3 sent, treatment is largely directed by pa-
tient-specific factors, drug availability and
The vast majority of melanomas (84%) affordability. This is a rapidly expanding
present at an early stage and may be cu- field of oncology and this ever-changing
ratively managed with surgical resection. landscape is a daunting one. An overview
This provides excellent five-year overall of currently available systemic options will
survival rates which approach 98%. Loco- be briefly discussed.
regional nodal metastases are found in 9%
of patients at diagnosis, and here the five- TREATMENT OPTIONS FOR LOCALLY
year overall survival rates are around 63%. ADVANCED/UNRESECTABLE AND
Four percent of patients will have inopera- METASTATIC MELANOMA
ble or metastatic disease at diagnosis. For IMMUNOTHERAPIES
these patients, and for those who develop
recurrent or metastatic disease following As early as the 1950s, spontaneous tu-
initial definitive therapy, treatment options mour regressions have been shown with
are limited, and five-year survival rates are immune-modulating agents, suggesting a
less than 20%.2 role for these agents in tumour therapeu-
tics. Interleukin-2 was the original therapy
Treatment for metastatic disease com- utilised and has shown modest response
prises systemic therapy with or without ra- rates of around six to 16%.9 Use of this agent
diotherapy. Highly selective patients may has been limited by treatment-related
be suitable for metastatectomy. Tradition- toxicities, including acute constitutional
al approaches utilising cytotoxic chemo- symptoms, chronic fatigue, myelosuppres-
therapy have shown disappointing results. sion, depression, thyroid dysfunction and
Chemotherapy has not been shown to im- multi-organ failure. Its use is thus limited
prove overall survival and response rates by strict patient selection and preferential
are typically less than 20%. Those that do use in experienced, high-volume centres.
respond, have a median duration of re-
sponse of less than six months.3 In an at- HANDBOOK OF ONCOLOGY
tempt to improve outcomes, recent years

74 SOLID TUMOURS

Continued research in this area has fo- progression-free survival and overall surviv-
cused on a more-specific immunotherapy al. Importantly, extended follow-up sug-
approach and has led to the develop- gests ipilimumab results in durable remis-
ment of the more targeted checkpoint sions with long-term survival approaching
inhibitors. 20% (10-year overall survival rate of 21%).4-6

Immune system activation is brought A second inhibitory pathway results via
about by the presentation of intracellu- programmed cell-death receptor 1 (PD-1).
lar peptide fragments on the surface of This receptor is present on activated T-cells
antigen-presenting cells (APCs). These and binds to its ligand, (PD-L1). Similarly to
peptide fragments are presented in as- CTLA-4 above, this interaction serves as a
sociation with the mixed histocompat- physiological brake and the immune re-
ibility complex (MHC) molecules. These sponse is down-modulated (see Figure 1
MHC-peptide complexes are recognised C). Certain tumour cells express PD-L1 and
by T-cells and result in T-cell activation. this allows for evasion of the immune sys-
This activation also leads to upregulation tem by the tumour cell. Pembrolizumab
of the cytotoxic T-lymphocyte antigen 4 and nivolumab are monoclonal antibod-
(CTLA-4) which functions as a physiologi- ies directed against the PD-1 receptor
cal brake via an inhibitory feedback loop and allow for immune-system activation
(see Figure 1A). Ipilimumab is a monoclo- (see Figure 1D). Both agents have shown
nal antibody directed against CTLA-4 (see improved response rates, progression-free
Figure 1B). Phase III trials, including both survival and overall survival when com-
previously treated and untreated disease, pared with chemotherapy. In addition,
have shown that ipilimumab provides im- they are associated with a lower risk of ad-
proved response rates, response duration, verse events.7,8 Importantly, data suggest

Figure 1. New modalities of cancer treatment for NSCLC: focus on immunotherapy

Tumour antigen Deactivated Activated
presentation CD8+ T-cell CD8+ T-cell

MHC TCR

B7 CTLA-4 CD28 CD28
CTLA-4: B7 binding B7 CTLA-4

Anti-CTLA-4
antibody

Tumour antigen Deactivated Cytolytic molecules Activated
presentation CD8+ T-cell CD8+ T-cell

MHC TCR

Tumour cell PD-1 PD-L
PD-L1 PD-L1 Anti-PD-1 antibody
Tumour cell
PD1: PD-L1 Tumour cell death
binding

Tumour cell growth
and proliferation

Source: Davies M. New modalities of cancer treatment for NSCLC: focus on immunotherapy. Dovepress. Accessed
January 2018. https://www.dovepress.com/new-modalities-of-cancer-treatment-for-nsclc-focus-on-immunothera-
py-peer-reviewed-fulltext-article-CMAR.

HANDBOOK OF ONCOLOGY

Treatment Options for Inoperable and Metastatic Malignant Melanoma 75

nivolumab may provide long-term survival significantly decreased. Thus, for patients TREATMENT APPROACHES
in up to 50% of patients. who are candidates for targeted therapy,
a combination of a BRAF and a MEK in-
Despite these important clinical ben- hibitor rather than a single agent is recom-
efits, immune-checkpoint inhibitors are mended.
associated with a unique spectrum of
side effects termed immune-related ad- A small proportion of acral and mu-
verse events (irAEs). These may occur at cosal melanomas will harbour somatic
any time during the course of treatment mutations or amplifications of KIT. Imatinib
and may involve any organ system. The (small molecule inhibitor of KIT) has dem-
most commonly occurring irAEs include onstrated improved responses in patients
dermatitis, enterocolitis, thyroid dysfunc- with melanoma harbouring KIT mutations.
tion and fatigue. These may also include However, these responses were of limited
pneumonitis, hypophysitis and associated duration and did not translate to an im-
endocrinopathies, uveitis, hepatitis, neu- provement in survival.
rological, cardiac, rheumatological and
renal toxicities. In certain cases, these re- CHEMOTHERAPY
actions have been fatal. Experience with At present, the role of chemotherapy is
these agents has allowed for effective limited to patients who have progressed
management of irAEs, with improved pa- on immunotherapy or where these treat-
tient education, clinical monitoring, early ment options are not clinically appropri-
recognition and prompt, algorithm-based ate, affordable or available. Chemother-
initiation of appropriate treatment. apy agents which have shown activity in
melanoma include dacarbazine, temo-
TARGETED THERAPY zolomide, nitrosoureas (carmustine and
lomustine), platinum compounds (cispl-
Approximately half of patients with meta- atin and carboplatin) and albumin-bound
static melanoma will show BRAF mutations. paclitaxel (nab-paclitaxel). These agents
BRAF inhibitors vemurafenib and dab- may be used as single agents, or as com-
rafenib have shown improved response bination regimens.
rates, progression-free survival and overall
survival when compared with standard CURRENT RECOMMENDATIONS
chemotherapy.
The mainstay of treatment for inoperable
Patients treated with BRAF inhibitors show or metastatic melanoma remains sys-
median response durations of around five temic therapy, with surgical metastatec-
to seven months.10,11 Treatment is generally tomy reserved for a highly select group
well tolerated. of patients. Primary systemic therapy ap-
proaches include i) immunotherapy (anti-
The most frequently occurring toxicities PD-1 antibody alone or in combination
include arthralgia, fatigue and cutane- with anti-CTLA-4) and ii) targeted therapy
ous events (rash, photosensitivity and the (combination of a BRAF and a MEK inhibi-
development of squamous cell carcino- tor preferred).
mas). Small molecule inhibitors of MEK act
downstream of BRAF in the MAP kinase The appropriate choice and sequenc-
pathway, and a combination of these ing of treatments lacks supporting pro-
agents with a BRAF inhibitor has resulted spective data, and at present, is largely
in further improvement in progression-free empiric and based on tumour- and pa-
and overall survival when compared with tient-specific factors. Patients should be
BRAF inhibition alone. Here, a median pro- enrolled in a clinical trial wherever pos-
gression-free survival of between 11 to 14 sible. Cytotoxic chemotherapy is limited
months and a median overall survival ap- to patients who have progressed on the
proaching two years has been achieved.12 above options, or where these treatment
Importantly, the combined approach is options are not clinically appropriate, af-
well tolerated, and the incidence of cu- fordable or available.
taneous squamous cell carcinoma was
HANDBOOK OF ONCOLOGY

76 SOLID TUMOURS

REFERENCES melanoma (KEYNOTE-002): a randomised,
controlled, phase 2 trial. Lancet Oncol.
1. A merican Cancer Society. Cancer facts 2015;16(8):908-18.
and figures 2018. American Cancer Soci- 8. W eber JS, D’Angelo SP, Minor D, et al.
ety. Available at https://www.cancer.org/ Nivolumab versus chemotherapy in pa-
content/dam/cancer-org/research/can- tients with advanced melanoma who
cer-facts-and-statistics/annual-cancer- progressed after anti-CTLA-4 treatment
facts-and-figures/2018/cancer-facts-and- (CheckMate 037): a randomised, con-
figures-2018.pdf. Accessed: January 2018. trolled, open-label, phase 3 trial. Lancet
Oncol. 2015;16(4):375-84.
2. N ational Cancer Institute: Surveillance, 9. A tkins MB, Kunkel L, Sznol M, et al. High-dose
Epidemiology, and End Results Programme recombinant interleukin-2 therapy in pa-
(SEER). https://seer.cancer.gov/statfacts/ tients with metastatic melanoma: long-term
html/melan.html. Accessed: January 2018. survival update. Cancer Journal of Science
of America. 2000;6(Suppl 1):S11-S4.
3. S osman JA. Cytotoxic chemotherapy for 10. C hapman PB, Hauschild A, Robert C, et al.
metastaticmelanoma.UpToDate. https:// Improved survival with vemurafenib in mel-
w w w . u p t o d a t e . c o m / c o n t e n t s / cyto- anoma with BRAF V600E mutation. N Engl J
toxic-chemotherapy-for-metastatic- Med. 2011;364:2507-2516.
melanoma?source=see_link. Accessed: 11. Hauschild A, Grob J-J, Demidov LV, et al. Dab-
January 2018. rafenib in BRAF-mutated metastatic mela-
noma: a multicentre, open-label, phase 3
4. H odi FS, O’Day SJ, McDermott DF, et al. Im- randomised controlled trial. Lancet. 2012;
proved survival with ipilimumab in patients 380:358-365.
with metastatic melanoma. N Engl J Med. 12. R obert C, Karaszewska B, Schacter J, et
2010;363(8):711. al. Three-year estimate of overall survival
in COMBI-v, a randomized phase 3 study
5. M aio M, Grob JJ, Aamdal S, et al. Five-year evaluating first-line dabrafenib + trametinib
survival rates for treatment-naïve patients in patients with unresectable or metastatic
with advanced melanoma who received BRAF V600E/K-mutant cutaneous mela-
ipilimumab plus dacarbazine in a phase III nom. Presented at the 2016 European So-
trial. Journal of Clinical Oncology. 2015;33 ciety for Medical Oncology meeting.
(10):1191.

6. R obert C, Thomas L, Bondarenko I, et al.
Ipilimumab plus dacarbazine for previously
untreated metastatic melanoma. N Engl J
Med. 2011;364(26): 2517-26.

7. R ibas A, Puzanov I, Dummer R, et al. Pembro-
lizumab versus investigator-choice
chemotherapy for ipilimumab-refractory

HANDBOOK OF ONCOLOGY

Blood, lymph and
related conditions

78 BLOOD, LYMPH AND RELATED CONDITIONS

The Acute Leukaemias

Prof N Novitzky described as 9.6 per 100 000 population,2
but there are no community-based sta-
PhD, FCP(SA), Cert Clin Haem tistics for South Africa. Lymphoblastic leu-
 Emeritus Professor of Haematology, kaemia is more frequent in children and
Departments of Medicine and Pathology, young adults, while myelogenous leukae-
University of Cape Town mia may also be seen in younger patients,
but is more common among older adults.
Acute leukaemias are haematological
malignancies characterised by uncon- ACUTE MYELOGENOUS LEUKAEMIA
trolled proliferation in the bone marrow
of myeloid or lymphoid cells associated Acute myelogenous leukaemia (AML) is a
with a block in their normal differentiation malignancy of an early myeloid/monocyt-
to mature functional elements.1 The con- ic progenitor cell (see Figure 1) that is able
sequence is infiltration of the marrow and to repopulate its own pool. Immature cells
other organs by functionally incompetent (blasts) accumulate in the bone marrow
cells that lead to loss of myeloid and im- and spill over into the blood, as well as mi-
mune function, multiorgan failure and grate to soft tissues and other organs, re-
death. Patients often present with clini- sulting in marrow failure, abnormal coagu-
cal symptoms of pancytopaenia (tired- lation as well as metabolic derangements.
ness, infection and bleeding). In Europe, While marrow failure leads to sympto-
the overall annual incidence has been matic anaemia and thrombocytopaenia,

Figure 1. Myeloid and lymphoid differentiation. Acute leukaemias seem to result from aberrant
differentiation/maturation of myeloid and lymphoid progenitors

Blood stem cell

Myeloid stem cell Lymphoid stem cell

Myeloblast Lymphoblast

Eosinophil Granulocytes
Basophil

Red Neutrophil B-lymphocyte Natural
blood Platelets T-lymphocyte killer cell
cells

White blood cells

HANDBOOK OF ONCOLOGY

The Acute Leukaemias 79

uncontrolled proliferation of the malignant addition, patients often have a bleeding TREATMENT APPROACHES
blasts may result in extreme leucocytosis tendency due to thrombocytopaenia and
and leukostasis with blood hyperviscos- thrombosis from disseminated intravascu-
ity, leading to respiratory failure, uraemia lar coagulation (DIC) precipitated by the
and neurological deficit. Therefore the release of prothrombotic substances from
diagnosis and management of AML is a degrading blasts. This is particularly severe
medical emergency that will require rapid in the group named acute promyelocytic
detection and correction of these abnor- leukaemia (APL). Occasionally, paraspinal
malities.2 Depending on risk factors of the or other tumour masses (chloromas) may
blood disorder, the patient performance lead to spinal cord compression and par-
status and presence of comorbidities, AML aplegia. Central nervous system (CNS) in-
can be cured with standard combination filtration by myelogenous leukaemia is not
chemotherapy or may require other ap- common on presentation, but patients
proaches such as allogeneic stem-cell may develop focal signs due to intracra-
transplantation. nial bleeding or thrombosis.2

The World Health Organization (WHO) DIAGNOSIS
classification of malignancies divides hae-
matological malignancies according to The diagnosis requires a detailed history
morphology, immunophenotyping and and thorough physical examination to
cytogenetic/molecula derangements determine pre-existence of genetic pre-
into distinct groupings.3,4 While the de- disposition, previous exposure to noxious
tailed pathogenesis of AML is not known, agents and presence of infection, bleed-
genomic instability due to genetic factors ing or masses that may compromise the
(Fanconi anaemia, ataxia telangiectasia), function of vital organs. The current clas-
environmental toxins (radiation, benzene) sification of AML was developed under
or cytotoxic drugs (alkylators, topoisomer- the auspices of the World Health Organi-
ase II inhibitors) has been implicated. zation (WHO) which incorporates clinical
These factors lead to loss of genetic ma- features in combination with laboratory
terial, point mutations or chromosomal findings, including genetics in trying to
translocations that cause cellular gain of outline biologically homogeneous enti-
proliferative function and clonal expan- ties that have therapeutic and prognostic
sion of the malignancy. Identification of relevance.3
these aberrant mutations, as well as epi-
genetic changes in malignant cells, have Examination of the peripheral blood
resulted in better understanding of the dis- smear and of the bone marrow (biopsy)
ease process and hold promise for the de- will usually show features of anaemia and
velopment of specific therapies that may thrombocytopaenia with variable morpho-
correct these abnormalities. logical abnormalities of the leukocytes and
the presence of circulating malignant cells.
CLINICAL PRESENTATION
By definition, blasts in the bone marrow
Patients may present with symptoms of exceed 20% of nucleated cells. In promye-
marrow failure (anaemia, thrombocy- locytic leukaemia (see Figure 2), patients
topaenia), respiratory compromise from often have active laboratory features of
malignant pleural effusions or multilobar DIC with clinical bleeding or thrombosis.4
pneumonia and sepsis due to immuno- Cytogenetic analysis provides some of
suppression. Metabolic derangements the strongest prognostic information avail-
are common, particularly in patients with able, predicting outcome of both remis-
advanced disease. Hyperuricaemia may sion induction and post-remission therapy.
result in renal failure due to interstitial ne- Based on the karyotype outcome, three
phritis, while hyperphosphataemia, lac- prognostic groups are described with five-
tic acidosis and hyperkalaemia must all year survival of 55-60% in the favourable
be actively identified and corrected. In group, 10-15% in the unfavourable group,
and 35-40% in the intermediate group.

HANDBOOK OF ONCOLOGY

80 BLOOD, LYMPH AND RELATED CONDITIONS

Figure 2. Cytological preparation (May- or idarubicin (12 mg/m2) for three days (7+3
Grünwald-Giemsa) of promyelocytic regimen) leads to CR in 50-80% (depend-
leukaemia cells. Typical coarse granules ing on risk factors), particularly in patients
and multiple Auer rods in the cytoplasm are with favourable and intermediate-risk cy-
shown togenetics.7 AML in remission is defined as
a normal peripheral blood-cell count (ab-
More recently, a number of molecular solute neutrophil count >1,000/mm3 and
markers have also been associated with platelet count >100,000/mm3) and nor-
prognostication.2,5,6 mocellular bone marrow with less than
5% blasts and no signs or symptoms of the
TREATMENT disease. Achieving remission may be ad-
Treatment of AML is usually divided into versely affected by clinical factors such as
induction of remission chemotherapy advanced age, poor performance status,
and post-remission treatment. Induction leukocyte >30x109/L, antecedent haema-
chemotherapy has the goal of reducing tological disorder (myelodysplasia or my-
the tumour bulk to undetectable levels eloproliferative syndrome) and therapy of
(<5% blasts), which is associated with re- another malignancy.8 Alternatively, epige-
covery of the blood parameters, a condi- netic modifications of malignant cells with
tion named as complete remission (CR). In 5-azacytidine (Vidaza) or decytabine (Da-
the first instance, patients will require resus- cogen) have also been associated with
citation and reversal of all metabolic ab- marrow recovery, particularly if there is an
normalities before undertaking intensive antecedent marrow disorder, and are cur-
combination chemotherapy. During in- rently being actively studied in this group.2,8
duction therapy, patients will require trans-
fusion with blood products to maintain a Patients with promyelocytic leukaemia
haemoglobin level >8 gr/dL and platelet require a different approach both in sup-
counts >10 x109/L. portive therapy as well as for the treatment
of the malignancy. Due to severe coagu-
The treatment of AML remains unsat- lopathy, such patients need aggressive
isfactory and the majority of patients, replacement of coagulation factors with
particularly the older group, are likely to blood products to prevent bleeding. Since
die of the disease. Myelosuppression is a all trans retinoic acid (ATRA; Vesenoid) can
consequence of the treatment so facilities reverse the block in differentiation typical
must have capacity for adequate blood- of the disease caused by the chimeric
product support (platelets and red cells) PML-RARa protein product, combination
and have expertise in the treatment of op- of daily ATRA (40 mg/m2) with anthracy-
portunistic infections. cline chemotherapy has been associated
with a nearly 90% remission rate. Prescrip-
Clinical trials over the last 30 years have tion of ATRA can lead to hyperleukocyto-
shown that in younger patients (<65 years) sis and respiratory distress, now known as
one or two cycles of a combination con- the differentiation syndrome, which can
taining cytarabine at 100-200 mg/m2 for be prevented by early administration of
seven days and an anthracycline antibi- corticosteroids. Molecular remission (un-
otic such as daunorubicin (75-90 mg/m2) detectable PML-RARa on PCR) following
intensification therapy is associated with
HANDBOOK OF ONCOLOGY favourable long-term outcome.9 The in-
clusion of arsenic trioxide (ATO) as part of
the induction (ATRA + ATO) or following in-
duction with ATRA and anthracyclines has
been associated with improved survival.

Depending on risk factors, following re-
mission induction, treatment is typically
with high doses of cytarabine (2 gr/m2,

The Acute Leukaemias 81

twice daily for four days). Patients with Epstein Barr virus has also been associated TREATMENT APPROACHES
intermediate and unfavourable cytoge- with a B-cell leukaemia in immunocompe-
netics will benefit from intensification with tent patients and subjects with immunode-
allogeneic stem-cell transplantation from ficiency virus infection.
an HLA identical donor. Patients in sec-
ond remission should also be considered CLINICAL PRESENTATION
for this procedure. The chance of having ALL typically presents in children and
an HLA-compatible donor ranges from young adults, being the most common
20-40% among siblings (same parents) paediatric cancer, although older pa-
to 1/10000- 1/100000, depending on the tients may also develop this malignancy.11
genetic diversity of the community. High- Younger patients may present with sys-
dose therapy or immunosuppressive con- temic manifestations of disease, including
ditioning and stem-cell transplantation fever of unknown origin and joint pains,
are associated with procedure-related associated with leukopaenia or pancyto-
mortality of 10-20% and depending on the paenia. More often they have palpable
mentioned risk factors, disease recurrence lymphadenopathy, hepatosplenomegaly
of 15-30%.7 Thus, selection criteria from and features of marrow failure such as
various co-operative groups, such as Eu- pallor, ecchymoses and petechiae. Less
ropean Bone Marrow Transplantation So- frequently (5-7% of cases), patients may
ciety (EBMT criteria) have been proposed present with cranial nerve abnormalities
to assist in the selection of patients who will from meningeal leukaemia. Due to the
benefit most from this procedure.10 Hap- heterogeneity of this disease, precursor
loidentical stem-cell transplantation with B- and T-cell leukaemias are considered
post-transplant high-dose cyclophospha- as separate entities. Mediastinal masses
mide is emerging as a viable alternative are common in T-cell leukaemia and may
for those who lack HLA-compatible do- lead to medical emergency from airway
nors, although long-term survival data are obstruction by lymphoid masses. T-ALL fre-
still unavailable. quently presents with elevated leukocyte
count, but is highly responsive to therapy.
ADULT ACUTE LYMPHOBLASTIC Occasional, testicular masses may be the
LEUKAEMIA initial complaint, or develop later during
therapy as both the CNS and testis are
Adult acute lymphoblastic leukaemia (ALL) sanctuaries with poor tissue penetration of
is a discrete clonal malignant disorder that cytotoxic agents.11
affects an early lymphoid progenitor (see
Figure 1) and represents a heterogeneous DIAGNOSIS
group of diseases that have distinct phe- The differentiation of AML from acute lym-
notypes and variable outcomes. Although phocytic leukaemia has important thera-
there are no local data regarding the in- peutic implications.3 Investigations should
cidence of ALL, in the US there were 5 960 include complete blood count with the
new cases in 2017.11 Depending on the line- differential count, a chemistry panel and
age, they are classified as precursor T-cell coagulation studies as well as careful
and precursor B-cell leukaemias, implying a screening for evidence of active infection.
thymic or bone-marrow origin of malignant According to WHO, the diagnosis and
lymphocytes.3 The pathogenesis of malig- characterisation of lymphoblastic leukae-
nant transformation remains unclear, but mia is based on the blood and marrow
genomic instability leading to chromosom- morphological features, as well as immu-
al translocations and mutations of genes nophenotyping, cytogenetic analysis and
associated with control of cell proliferation molecular characteristics of the malignant
and apoptosis are likely. Human T-cell leu- clone.3 Lymph-node and mediastinal bi-
kaemia virus 1 has also been described in opsy samples are also useful in some clini-
T-cell malignancies in some patients from cal situations, whereas testing of the CSF
Asian countries and the Caribbean basin.
HANDBOOK OF ONCOLOGY

82 BLOOD, LYMPH AND RELATED CONDITIONS

is mandatory. While peripheral blood may Figure 3. Cytological preparation (May-
not demonstrate malignant blasts, bone- Grünwald-Giemsa) of lymphoblastic
marrow biopsy will always show >20% leukaemia cells
blasts. Immunophenotyping differentiates
precursor B (80%) from precursor T (15%) have also evolved considerably in the past
ALL (see Figure 3). Cytogenetic analysis five to seven years.12,13 However, in older
is useful and will show either a favourable adults, therapy of this malignancy remains
pattern or an unfavourable arrangement a major challenge. Similar to the treatment
that also includes the complex karyotypes of AML, optimal management of patients
(five or more abnormalities). The Philadel- with ALL requires careful attention to sup-
phia chromosome (Ph1; BCR-ABL p190Kd) portive care. Metabolic derangements
is uncommon in paediatric ALL, but oc- are frequently encountered, even before
curs in 25-35% of adult ALL.11 The PH1 chro- chemotherapy is initiated, especially in
mosome may be detected by reverse patients with a high leukaemic cell burden
transcriptase polymerase chain reaction and those with T-cell or mature B-cell ALL.
(RT-PCR) and by fluorescence in situ hy- Patients receiving induction therapy de-
bridisation (FISH). velop severe pancytopaenia and require
similar supportive care to those with AML.
PROGNOSTIC FACTORS Infections need to be treated aggressively
Certain factors at the time of diagnosis or based on empiric and culture-directed
after therapy was commenced have dis- antibiotic combinations.
tinct prognostic relevance. Age (<1 year
or >9 years in children and <35 and >60 The specific treatment of ALL also in-
in adults), leukocyte count (>30 x 109/L for cludes a remission-induction phase and
precursor B-ALL or >100 x 109/L in T-ALL) post-remission maintenance therapy. Most
immunophenotype (pro-B), CNS disease, induction regimens include combination
adverse karyotype and molecular abnor- chemotherapy consisting of vincristine,
malities (BCR-ABL) are all unfavourable prednisone, anthracycline, L-asparginase
factors and are considered in the choice and alkylators such as cyclophospha-
of treatment modality (including referral mide. To avert meningeal leukaemia dur-
for allogeneic haemopoietic stem-cell ing induction, all patients should receive
transplantation). Response to treatment CNS prophylaxis with intrathecal chemo-
with undetectable disease by four weeks therapy (steroids, methotrexate and/or
of induction therapy defines a biologically cytarabine).14 Clinical studies have dem-
more favourable group.11-13 With standard onstrated that post-remission consolida-
chemotherapy, there is an inverse relation- tion with high doses of methotrexate (with
ship between the number of risk factors folinic acid rescue), cytarabine with the
and survival, with five-year survival in ex- addition of vinca alkaloids or L-aspargin-
cess of 50% for none, to 20-40% with 1 or 2 ase over a period of six months increases
and less than 10% in those with cumulative overall survival due to a reduction of dis-
incidence of 3 or 4 risk factors.11,12 Burkitt’s ease recurrence.
leukaemia (L3 or mature B-cell; 5%) is asso-
ciated with a variety of translocations that
involve translocation of the c-myc proto-
oncogene to the immunoglobulin gene
locus t(2;8), t(8;12), and t(8;22).11,13

THERAPY
In children and adolescents, the treatment
of ALL has been a significant therapeutic
success, with over 80% of children surviving
in the long-term. Treatment approaches
for adolescents and young adults with ALL

HANDBOOK OF ONCOLOGY

The Acute Leukaemias 83

Clinical trials have shown that oral mainte- REFERENCES TREATMENT APPROACHES
nance chemotherapy (methotrexate and
mercaptopurine) for two or three years 1. Shai Izraeli. Leukaemia – a developmental
with periodic reinforcements with vincris- perspective. British Journal of Haematology.
tine and prednisone leads to long-term, 2004;126:3-10.
relapse-free survival in the majority of chil-
dren and 35% of adults, depending on pre- 2. PDQ Adult Treatment Editorial Board. Adult
treatment risk factors and response to initial acute lymphoblastic leukemia treatment
therapy.11-15 A group of interest are patients (PDQ®): Health Professional Version. PDQ
who develop the BCR-ABL (p190KD) muta- Cancer Information Summaries [Internet].
tion as they are highly responsive to the ty- Bethesda: National Cancer Institute (US);
rosine kinase inhibition (TKI), typically more 2002-2018. Accessed Feb 2018.
often in the older population. TKIs (imatinib,
dasatinib) have shown to have clinical 3. Leonard JP, Martin P, Roboz GJ. Practical
activity as a single agent and led to high Implications of the 2016 Revision of the
responses with extended survival in elderly World Health Organization classification of
patients. Their inclusion is recommended lymphoid and myeloid neoplasms and
in the routine treatment of children and acute leukemia. J Clin Oncol. 2017 Aug 10;
adults with PH1 ALL.16 35(23):2708-2715.

Allogeneic stem-cell transplantation is 4. Haferlach T, Bacher U, Kern W, et al. Di-
an important post-remission strategy for agnostic pathways in acute leukemias: a
certain patients with adverse biological proposal for a multimodal approach. Ann
factors (hyperleukocytosis, BCR/ABL, MLL) Hematol. 2007;86:311-327.
and can be an effective salvage modal-
ity for those who suffer disease recurrence. 5. Mrózek K, Bloomfield CD. Clinical signifi-
However, this intense modality is reserved cance of the most common chromosome
for those who have HLA-identical donors translocations in adult acute myeloid leu-
and few comorbidities. Despite these as- kemia. Journal of the National Cancer Insti-
pects, procedure-related mortality of 15- tute Monographs. 2008;39:52-57.
25% reduces the overall success of this
strategy.17 These options should also be 6. Bienz M, Ludwig, M, Mueller BU, et al. Risk
considered for patients with detectable assessment in patients with acute my-
minimal residual disease (MRD) in remis- eloid leukemia and a normal karyotype.
sion following induction therapy. Clinical Cancer Research. 2005 February
15;11:1416-1424.
CONCLUSION
7. Robak T, Wierzbowska A. Current and emerg-
Thus, the relevant points in patients with ing therapies for acute myeloid leukemia.
acute leukaemia remain early diagnosis Clin Ther. 2009;31[Theme Issue]:2349-2370.
in patients with unexplained cytopaenia,
pyrexia of unknown origin or persistent 8. Estey E. What is the optimal induction strategy
leucocytosis, correction of electrolyte, for older patients? Best Practice & Research
metabolic and coagulation abnormali- Clinical Haematology. 2011;24:515-522.
ties, adequate supportive care with trans-
fusion of blood products, prevention of 9. Ravandi F, Stone R. Acute promyelocytic
infection and aggressive management of leukemia: a perspective. Clin Lymphoma
sepsis. Following diagnosis and initial sta- Myeloma Leuk. 2017 Sep;17(9):543-544.
bilisation of the patient, this group should
be referred to a clinical haematologist or 10. Barba P, Martino R, Pérez-Simón JA, et al.
medical oncologist with experience in the Combination of the Hematopoietic Cell
treatment of these diseases. Delays in spe- Transplantation Comorbidity Index and
cific therapy lead to complications and the European Group for Blood and Marrow
decreased survival of patients who may Transplantation score allows a better strati-
otherwise have a curable disease. fication of high-risk patients undergoing re-
duced-toxicity allogeneic hematopoie-
tic cell transplantation. Biol Blood Marrow
Transplant. 2014 Jan;20(1):66-72.

11. A uthors PDQ Adult Treatment Editorial
Board. Adult acute lymphoblastic leukemia
treatment (PDQ®): Health Professional Ver-
sion. Source PDQ Cancer Information Sum-
maries [Internet]. Bethesda: National Can-
cer Institute (US); 2002-2018. Accessed Feb
2018.

12. Ribera JM. Advances in acute lymphoblas-
tic leukemia in adults. Current Opinion in
Oncology. 2011;23:692-699.

13. Bassan R, Hoelzer D. Modern therapy of
acute lymphoblastic leukemia. J Clin On-
col. 2011;29:532-543.

HANDBOOK OF ONCOLOGY

84 BLOOD, LYMPH AND RELATED CONDITIONS

14. Pui CH. Recent research advances in child- lymphoblastic leukaemia of childhood and
hood acute lymphoblastic leukemia. J For- adolescence. Br J Haematol. 2016 Mar;172
mos Med Assoc. 2010;109(11):777-787. (6):855-69.
17. El Fakih R, Ahmed S, Alfraih F, et al. Hema-
15. Larson S, Stock W. Progress in the treatment topoietic cell transplantation for acute
of adults with acute lymphoblastic leuke- lymphoblastic leukemia in adult patients.
mia. Current Opinion in Hematology. 2008, Hematol Oncol Stem Cell Ther. 2017 Dec;
15:400-407. 10(4):252-258.

16. Bleckmann K, Schrappe M. Advances in
therapy for Philadelphia-positive acute

HANDBOOK OF ONCOLOGY

Multiple Myeloma 85

Multiple Myeloma TREATMENT APPROACHES

Dr K Antel PREVALENCE OF DISEASE

MBChB, FCP (SA), MMed (Int Med), Cert In South Africa, the incidence rate taken
from the latest published National Cancer
Clin Haem (Phys) Registry is 0.5/100 000,1 however, in the US
 Clinical Haematologist, UCT and Europe the rate is 4-5/100 000 and it
Department of Medicine, Division of accounts for roughly 10% of haematologi-
Haematology cal malignancies.2,3 The disparity with the
global incidence is likely due to under-
Prof VJ Louw diagnosis (with earlier death) and under-
reporting in South Africa.
MBChB, MMed (Int Med), FCP(SA),
MM occurs in all races and all geo-
PhD(HPE) graphic locations, but incidence appears
 Honorary Professor Clinical to vary with sex and ethnicity. MM is twice
Haematology, UCT Department of as common in blacks compared to Cau-
Medicine, Division of Haematology casians4,5 and is slightly more frequent in
men than women. MM is typically a dis-
Dr E Verburgh ease of older adults, with a median age at
diagnosis of 66 years, and only 2% of pa-
MB ChB MMed FCP PhD tients are under the age of 40.5 In Africa,
 Senior Specialist, Division of Clinical a five- to 10-year younger median age is
Haematology, Department of Medicine, described,6 however newer and large
University of Cape Town population-based data are needed from
southern Africa. A higher incidence of MM
Multiple myeloma (MM) is a neoplasm of is seen in HIV-infected persons.7,8
plasma cells characterised by plasma-cell
proliferation in the bone marrow with the pro- PATHOPHYSIOLOGY
duction of a monoclonal immunoglobulin.
Plasma cells are post-germinal centre B-cells The pathophysiology for the development
that produce antibodies. The clinical fea- of MM can be conceptualised as a two-
tures of myeloma result from bone-marrow step process: initial production of a plasma
invasion, cytokine release with stimulation of cell clone producing a monoclonal im-
osteoclastic activity, and the clinical conse- munoglobulin9 and then a “second-hit” re-
quences of excessive immunoglobulin. sulting in the proliferation of the malignant
clone. While some steps in the process have
The production of a monoclonal immu- been elucidated, many remain unknown.
noglobulin (M-protein) is also seen in lym-
phoma, other haematological malignancies In the first step, a combination of ge-
and two plasma-cell dyscrasias: monoclonal netic susceptibility with an aberrant re-
gammopathy of undetermined significance sponse to antigenic stimulation results in
(MGUS) and smouldering multiple myeloma cytogenetic abnormalities (usually in the
(SMM). MGUS and SMM are considered immunoglobulin heavy chain (IgH) lo-
pre-malignant conditions on the pathway cus)10, which results in the presence of a
to myeloma, but vary greatly in their risk of dominant plasma cell clone. In this stage,
progression. The approach to the diagnosis a patient would be clinically diagnosed
and management of these conditions will be with MGUS (or SMM). The variable rate of
briefly included in the discussion. progression is evidenced by the fact that
MGUS is present in over 3% of the popula-
An increase in plasma cells and total im- tion over the age of 50 but only progresses
munoglobulin is seen in various benign con- to MM or a related malignancy at a rate
ditions (HIV and chronic inflammation), the
distinguishing characteristic from MM is that HANDBOOK OF ONCOLOGY
plasma cells in benign conditions are poly-
clonal and produce an array of different im-
munoglobulins.

86 BLOOD, LYMPH AND RELATED CONDITIONS

of 1% per year. Therefore, a “second-hit” is Lesions are more sensitively diagnosed by
required to progress to MM.11 CT, PET CT or MRI than x-ray. Lytic lesions
develop as a result of excessive osteoclas-
The “second-hit” is due to additional ge- tic activity driven by cytokines produced
netic changes (e.g., Ras mutations, p53 by MM cells.
mutations), as well as permissive changes
in the bone-marrow environment and eva- Renal dysfunction occurs in 48% of pa-
sion of immune surveillance.10 The net result tients at diagnosis,5 is often multifactorial
of these changes is an increase in prolifera- in aetiology and is often reversible. Com-
tion and survival of the malignant clone. mon causes for renal dysfunction in my-
eloma are light-chain cast nephropathy
DIAGNOSTIC ISSUES (deposition of light chains in the tubules,
DIAGNOSTIC CRITERIA causing tubular damage); hypercalcemia
(causing polyuria with subsequent volume
The diagnosis of MM has been based on depletion which increases toxicity of the
demonstrating a clonal plasma-cell popu- filtered light chains) and drugs (especially
lation, usually with the production of an NSAIDs, intravenous radiocontrast, antimy-
M-protein, along with end-organ features. eloma agents and bisphosphonates). Less
The 2014 International Myeloma Working commonly, light-chain amyloidosis (AL)
Group (IMWG) updated these criteria (see and light-chain deposition disease (LCD)
Table 1),12 recognising that a subset of pa- result in deposition of light chains at the
tients previously classified as SMM have glomerular basement membrane, which
near inevitable progression to end-organ results in nephrotic syndrome.
damage and for this reason have been in-
cluded as MM (patients with >60% plasma Hypercalcaemia is present at diagnosis
cells in the bone marrow; involved/unin- in 28% of patients and in a smaller propor-
volved FLC ratio of >10). tion can be dangerously elevated, requir-
ing immediate management. Symptoms
CLINICAL FEATURES of hypercalcaemia include anorexia,
Patients with MM commonly present with nausea, vomiting, polyuria, polydipsia,
symptoms related to end-organ features weakness, confusion, or a decreased level
(often recalled by the acronym CRAB): of consciousness.
increased plasma calcium, renal dysfunc-
tion, anaemia and bone pain. An uncom- Patients with myeloma are at an in-
mon presentation, but a medical emer- creased risk for infection due to both im-
gency, is that of spinal cord compression. mune dysfunction and functional factors
Anaemia in MM is typically normocytic and an infection may be the presenting
and normochromic and is present in 73% symptom. Immune dysfunction may result
of cases at diagnosis.5 Anaemia can be from a decrease in normal immunoglob-
related to bone-marrow infiltration, kidney ins (hypogammaglobulinaemia) and im-
damage, cytokines affecting erythropoi- paired function or number of neutrophils
etin release and is dilutional (in the case and lymphocytes.
of a large M-protein). An unexplained nor-
mocytic normochromic anaemia in a pa- Neurological disease can result from
tient (especially with other “red flags” such nerve or spinal cord compression, either
as bone pain, weight loss, fatigue and other from a collapsed vertebra or an extramed-
cytopaenias) warrants further investigation ullary plasmacytoma. Spinal cord com-
with a bone-marrow examination (BME) pression should be suspected in patients
and serum electrophoresis (SPEP). presenting with severe back pain along
with weakness or paraesthesia of the
Bone pain is the presenting feature at di- lower limbs, and bladder or bowel dys-
agnosis in 60% of cases5 and is typically in function. This is a medical emergency and
the back or chest. Imaging may show lytic the patient should be urgently referred for
lesions, pathological fractures, vertebral imaging (MRI preferred over CT), with an
compression fractures, and osteopaenia. urgent assessment by a haematologist or
oncologist and neurosurgeon. Peripheral
HANDBOOK OF ONCOLOGY

Multiple Myeloma 87

Table 1. Revised International Myeloma Working Group diagnostic criteria for multiple TREATMENT APPROACHES
myeloma and smouldering multiple myeloma

Definition of multiple myeloma

Clonal bone-marrow plasma cells ≥10% of biopsy-proven bony or extramedullary
plasmacytoma* and any one or more of the following myeloma-defining events:

Evidence of end-organ damage that can be attributed to the underlying plasma-cell
proliferative disorder, specifically:
Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit
of normal or >2.75 mmol/L (>11 mg/dL)
Renal insufficiency: creatinine clearance <40 ml per min¶ or serum creatinine
>177 µmol/L (>2 mg/dL)
Anaemia: haemoglobin value of >2 g/dL below the lower limit of normal, or a
haemoglobin value <10 g/dL
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTΔ

Any one or more of the following biomarkers of malignancy:
Clonal bone-marrow plasma cell percentage* ≥60%
Involved: uninvolved serum-free light-chain ratio◊ ≥100
>1 focal lesions on MRI studies§

Definition of smouldering multiple myeloma

Both criteria must be met:
Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg
per 24 hours and/or clonal bone-marrow plasma cells 10 to 60%
Absence of myeloma-defining events or amyloidosis

Definition of monoclonal gammopathy of undetermined significance

All three criteria must be met:
Serum monoclonal protein <30 g/L
Bone-marrow plasma cells <10%
Absence of myeloma-defining events or amyloidosis (or Waldenström
macroglobulinemia in the case of IgM MGUS)

PET-CT: 18F-fluorodeoxyglucose positron emission tomography with computed tomography.
* Clonality should be established by showing kappa/lambda-light-chain restriction on flow
cytometry, immunohistochemistry, or immunofluorescence. Bone-marrow plasma cell percentage
should preferably be estimated from a core biopsy specimen; in case of a disparity between the
aspirate and core biopsy, the highest value should be used.
¶ Measured or estimated by validated equations.
Δ If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to
distinguish from solitary plasmacytoma with minimal marrow involvement.
◊ These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The
involved free light chain must be ≥100 mg/L.
§ Each focal lesion must be 5 mm or more in size.

Source: Adapted from Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma
Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15 (12):e538-e548.

neuropathy rarely occurs; if it does, it is USEFUL LABORATORY TESTS
usually in the setting of amyloidosis or
POEMS syndrome. Occasionally, patients n F ull blood count (FBC) and peripheral
may present with headaches or blurred vi- smear
sion due to hyperviscosity.
Apart from the anaemia as described,
other compatible and useful findings on

HANDBOOK OF ONCOLOGY

88 BLOOD, LYMPH AND RELATED CONDITIONS

FBC or smear are: other cytopaenias, rou- n T ests to detect a monoclonal protein
leaux formation (seen in >50%); occasion- Ninety-three percent of patients with MM
ally, plasmacytoid lymphocytes or plasma will have a monoclonal (M) protein which
cells can be seen. is detected by serum-protein electropho-
resis with serum immunofixation.14 Serum
n B one-marrow examination immunofixation is performed as a second-
A bone-marrow examination (BME) is ary test to both confirm the presence of
necessary for the diagnosis of MM and the M-protein, and to determine its type
shows an increase in plasma cells which (IgG being the commonest).
are monoclonal (i.e., they show kappa Figure 1. Bone-marrow aspirate showing an
or lambda light-chain restriction). Plasma increase in the number of plasma cells
cells can usually be readily identified mor- (These plasma cells have fairly normal
phologically on an aspirate (see Figure 1) morphology, but in many cases the plasma cells
and the trephine (see Figure 2) and may show atypical and malignant morphology.)
show abnormal malignant features. A flow
cytometry plasma-cell panel may be use- A plasma cell with an eccentric nucleus,
ful to confirm that the plasma cells are clumped chromatin and a moderate amount
clonal, and may be useful for prognostica- of basophilic cytoplasm with a less basophilic
tion, but, at present, the plasma-cell per- Golgi zone adjacent to the nucleus.
centage on the trephine is the preferred Figure 2. Bone-marrow trephine showing a
method for the enumeration of plasma- diffusely infiltrated marrow with numerous
cell burden.13 At diagnosis, performing cy- plasma cells
togenetics on the bone-marrow aspirate is
useful for prognostication. Routine karyo- Plasma cell with an eccentric nucleus with
typing is typically not useful due to a low “clock-face” chromatin and a prominent
number of metaphases, and a myeloma nucleolus.
fluorescent in situ hybridisation (FISH) pan-
el is preferable.

n Urine analysis
Findings on urine analysis depend on the
cause of kidney damage. Myeloma cast
nephropathy is characterised by casts
formed from precipitated monoclonal light
chains in the distal tubule which may be
sloughed off and seen on microscopy. The
urine dipsticks are often negative for pro-
tein despite a raised urine protein: creati-
nine ratio, because the protein detected is
Bence-Jones protein (i.e., light chains) and
the dipstick is sensitive only for albumin. In
LCCD and amyloidosis AL, the dipsticks
will be positive as these conditions cause
albuminuria. Thus, for accurate urine light-
chain (Bence Jones proteinuria) testing
and quantification, a 24-hour urine sample
for urine protein electrophoresis (UPEP) and
immunofixation is ideally required. Howev-
er, due to the cumbersome collection and
testing method, this test has largely been
superseded in clinical utility by the serum
free light-chain (FLC) assay.

HANDBOOK OF ONCOLOGY

Multiple Myeloma 89

In patients with a high clinical suspicion PROGNOSIS TREATMENT APPROACHES
of MM but a normal SPEP, the serum-free
light-chain (FLC) assay should be per- The prognosis of myeloma depends on
formed. The serum FLC test detects light patient factors (age, comorbidities), stag-
chains (kappa or lambda) and will show ing (B2-microglobulin and albumin are
abnormality in the ratio of kappa to lamb- used as surrogate markers for tumour
da in 60% of MM patients who do not have burden which in myeloma corresponds
an M-protein on SPEP.15 The SFL has obvi- to staging), disease biology (cytogenetic
ated the need for the urine Bence-Jones abnormalities) and the response to initial
protein in many patients.16 There is a small treatment. The revised International Stag-
fraction of MM patients who do not have ing Score (R-ISS) is the most widely used
an M protein detectable by any of these staging system and combines measures
methods (“non-secretors”). of tumour burden with disease biology to
identify three stages with variable overall
A total protein test has been aptly survival rates (see Table 2).18
called “poor man’s SPEP” and in a poor-
resource setting is a useful initial screening TREATMENT AND REFERRAL
test when performed in the setting of clini- GUIDELINES
cal suspicion for MM (such as back pain GENERAL MANAGEMENT
or a normocytic anaemia). However, in
patients with decreased albumin, early Patients with MM should be referred for
disease or low/non-secretory disease, this management to an oncologist or haema-
may result in a normal total protein level tologist. However, the role of the general
and a falsely normal result. Thus, in any pa- practitioner to diagnose, stabilise and ap-
tient with a strong suspicion of myeloma, propriately manage the complications of
a full work-up and referral to a specialist myeloma is of critical importance. Patients
centre is required. with myeloma may be frail and appear
terminally unwell at diagnosis (often with
n Imaging a history of deterioration and decreased
Imaging is an important part of the diag- mobility over months) and yet, despite the
nosis of myeloma. Cross-sectional imaging incurable nature of the disease, many of
(whole-body, low-dose CT without con- them can have a good quality of life for
trast, PET/CT or MRI) is more sensitive to years following diagnosis with therapy.
detect lytic lesions than XR, but due con- MGUS does not require treatment. The
sideration needs to be given to cost and follow-up of MGUS can be performed by
exposure to radiation and drugs that may a general practitioner. Current recom-
be nephrotoxic (gadolinium and contrast). mendations are to repeat a SPEP in six
Patients for whom cross-sectional imag- months in all patients with MGUS and then
ining should be performed are patients further follow-up, depending on the risk
with SMM and solitary plasmacytoma in of the progression of MGUS: patients with
whom lytic lesions would “up-stage” the low-risk MGUS (an M-protein of <1.5g/dL,
diagnosis to MM; and patients with MGUS IgG subtype and normal FLC ratio) may
and bone pain. Whole-body low-dose CT be followed up with history and examina-
without contrast is preferred for its con- tion alone.19 All other patients with MGUS
venience and lower cost.17 An important are followed with annual serum and uri-
differential cause for lytic bone lesions and nary M-protein, FBC, creatinine and serum
hypercalcaemia is metastatic carcinoma, calcium. Features considered “red flags”
and a subset of these patients may have in these patients are bone pain, fatigue,
an incidental MGUS. If the bone-marrow constitutional symptoms, bleeding, lym-
examination is not in keeping with myelo- phadenopathy or splenomegaly.
ma, a useful investigation is a biopsy of the
lytic bone lesion. Patients with SMM and plasmacytoma
require a thorough investigation to ex-
clude MM, including cross-sectional imag-
ing studies and FLC assay. These patients

HANDBOOK OF ONCOLOGY

90 BLOOD, LYMPH AND RELATED CONDITIONS

Table 2. The international staging system (R-ISS) for multiple myeloma

Stage Criteria 5 year overall
survival (%)

I Beta-2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL 82

II Not R-ISS I or III 62

III Beta-2-microglobulin ≥5.5 mg/L and either high LDH or 40

high-risk chromosomal abnormalities by I-FISH (defined as

presence of del (17p) and/or translocation t(4;14) and/or

translocation t(14;16))

I-FISH = interphase fluorescence in situ hybridisation; LDH = lactate dehydrogenase

Source: Adapted from Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple
myeloma: a report from International Myeloma Working Group. J Clin Oncol. 33:2863-2869.

are best followed up by an oncologist or oedematous, a loop diuretic may be
haematologist for close monitoring and a used. The routine use of loop diuretics in
decision for when to initiate therapy. hypercalcaemia (with hyperhydration)
has largely fallen out of favour with avail-
The complications of MM frequently ability of the bisphosphonates.20 Zoledron-
seen that require specific treatment are ic acid is given IV at a dose of 4 mg over
hypercalcaemia, renal insufficiency, in- 15 minutes, and pamidronate IV at a dose
fection and skeletal lesions. Details on the of 60-90 mg over 2 hours. The dose and/
management of these conditions follows. or duration of administration of zoledronic
Patients with MM are at an increased acid needs to be adjusted for renal failure,
thrombotic risk and when admitted to hos- and in patients who present with acute re-
pital, prophylactic anticoagulation is ad- nal failure, pamidronate is preferred.
vised in the absence of contra-indications.
n Renal insufficiency
n Hypercalcaemia The treatment of renal insufficiency de-
The treatment depends on the level of pends on the underlying cause, with cor-
calcium, and the patient’s symptoms. For rection of hydration status and electrolytes
mild cases of hypercalcaemia (e.g., calci- and avoidance of nephrotoxins (NSAIDs).
um <3mmol/ L) hydration (preferably with Hydration should be carefully monitored
normal saline) and treatment with corti- and matched to output when a patient
costeroids is recommended. Note that is fluid-replete. In the presence of indica-
steroids may affect the findings on bone- tions for referral, dialysis patients should be
marrow biopsy and in these patients with referred promptly. Acute renal failure due
mild hypercalcaemia, a bone-marrow ex- to light-chain cast nephropathy is best
amination is preferably performed before treated by treatment of the myeloma with
steroid therapy. a dexamethasone-containing regimen.

In moderate to severe hypercalcaemia, n S keletal lesions
treatment includes hydration, corticoster- Skeletal lesions can result in bone pain,
oids as above, and bisphosphonates such pathological fractures and spinal cord
as zoledronic acid or pamidronate. Hydra- compression, all of which are best man-
tion is critically important as these patients aged by a specialist-led multidisciplinary
are typically very dehydrated. A reason- team. Patients with myeloma should be
able regimen is to give isotonic saline at encouraged to remain as active as pos-
200-300 ml/hour that is then adjusted to sible in order to maintain bone density
maintain the urine output at 100-150 ml/ and take vitamin D supplementation as
hour. Saline therapy requires careful moni- preventive measures. Bisphosphonate
toring, especially in patients with impaired
renal function. If a patient becomes

HANDBOOK OF ONCOLOGY

Multiple Myeloma 91

therapy has been shown to significantly re- determined by the M-protein; this is fol- TREATMENT APPROACHES
duce the number of skeletal events (path- lowed either by no therapy (with restart-
ological fracture, lytic lesions) and improve ing of treatment when the M-protein rises
pain control from skeletal-related pain.21 significantly) or with single-agent mainte-
nance therapy.
n I nfection
It is recommended that patients with MM re- Although myeloma is presently consid-
ceive the annual flu vaccine as well as a sin- ered an incurable disease, patients may
gle pneumococcal vaccine at the time of have a good quality of life for a num-
diagnosis, although the evidence for this is ber of years with treatment and conse-
weak.22 Infection should be treated prompt- quently, early diagnosis with appropriate
ly with broad-spectrum antibiotics. Patients treatment of complications and specialist
with recurrent, severe infections and hy- referral is of critical importance. The de-
pogammaglobulinaemia may benefit from velopment of new drugs that show an en-
immunoglobulin replacement with IVIG. hanced ability to induce a remission, with
lower toxicity, is promising and has led to
DISEASE-SPECIFIC TREATMENT a significant increase in both progression-
FOR MYELOMA free and overall survival, but their use is lim-
ited by prohibitive costs.
Disease-specific treatment for MM is per-
formed by oncologists and haematolo- REFERENCES
gists. Patients are evaluated pre-treatment
for eligibility for autologous haematopoi- 1. Schonfeld SJ, Erdmann F, Wiggill T, et al.
etic cell transplantation (HCT), depending Hematologic malignancies in South Africa
on the age, comorbidities and functional 2000-2006: analysis of data reported to the
testing. When compared with chemo- National Cancer Registry. Cancer Med.
therapy alone, intensified chemotherapy 2016;5(4):728-738. doi:10.1002/cam4.597.
followed by HCT prolongs both event-
free and overall survival in patients with 2. Kyle RA, Therneau TM, Rajkumar SV, et al. Inci-
MM and remains the standard of care for dence of multiple myeloma in Olmsted Coun-
younger patients (less than 70 years) with ty, Minnesota. Cancer. 2004;101(11):2667-
newly diagnosed MM.22 2674. doi:10.1002/cncr.20652.
Transplant-eligible patients are typically
given induction chemotherapy with a 3. Sant M, Allemani C, Tereanu C, et al. In-
two- or three-drug combination that typi- cidence of hematologic malignancies
cally includes a corticosteroid, an immu- in Europe by morphologic subtype: re-
nomodulatory agent such as lenalidomide sults of the HAEMACARE project. Blood.
and/or a proteasome inhibitor such as 2010;116(19):3724-3734. doi:10.1182/blood-
bortezomib and/or a chemotherapeutic 2010-05-282632.
agent such as cyclophosphamide or an
anthracycline. Patients are typically given 4. Waxman AJ, Mink PJ, Devesa SS, et al. Racial
four to six cycles of this combination and disparities in incidence and outcome in mul-
when an adequate response has been tiple myeloma: a population-based study.
achieved (as determined by the decrease Blood. 2010;116(25):5501-5506. doi:10.1182/
in M-protein) are offered an autologous blood-2010-07-298760.
transplant. Post-transplant, some specialists
will treat with maintenance therapy. 5. Kyle RA, Gertz MA, Witzig TE, et al. Review
of 1027 Patients with Newly Diagnosed Mul-
Transplant-ineligible patients are given tiple Myeloma. Mayo Clin Proc. 2003;78
an initial combination of dexamethasone, (1):21-33. doi:10.4065/78.1.21.
melphalan and an immunomodulatory
agent or proteasome inhibitor. Treatment 6. Groot JJB de, Webb MJ, Raubenheimer JE,
is continued for 12-18 months until the pa- et al. Concomitant HIV infection in newly
tient reaches a stable plateau phase as diagnosed multiple myeloma patients is
hard to recognise and should be tested
for routinely in areas of high endemicity.
South African Med J. 2017;107(9):781-787.
doi:10.7196/SAMJ.2017.v107i9.12360.

7. Dal Maso L, Franceschi S. Epidemiology
of non-Hodgkin’s lymphomas and other
haemolymphopoietic neoplasms in people
with AIDS. Lancet Oncol. 2003;4(2):110-119.
doi:10.1016/S1470-2045(03)00983-5.

8. Grulich AE, van Leeuwen MT, Falster MO, et
al. Incidence of cancers in people with HIV/

HANDBOOK OF ONCOLOGY

92 BLOOD, LYMPH AND RELATED CONDITIONS

AIDS compared with immunosuppressed concordant and discordant free light chain
transplant recipients: a meta-analysis. ratios. Blood. 2009;114(1):38-39. doi:10. 1182/
Lancet. 2007;370(9581):59-67. doi:10.1016/ blood-2009-02-205807.
S0140-6736(07)61050-2. 16. McTaggart MP, Lindsay J, Kearney EM. Re-
9. Landgren O, Kyle RA, Pfeiffer RM, et al. placing urine protein electrophoresis with
Monoclonal gammopathy of undeter- serum free light chain analysis as a first-line
mined significance (MGUS) consistently test for detecting plasma cell disorders of-
precedes multiple myeloma: a prospec- fers increased diagnostic accuracy and
tive study. Blood. 2009;113(22):5412-5417. potential health benefit to patients. Am
doi:10.1182/blood-2008-12-194241. J Clin Pathol. 2013;140(6):890-897. doi:10.
10. R ajkumar SV. Prevention of progression 1309/AJCP25IHYLEWCAHJ.
in monoclonal gammopathy of unde- 17. Regelink JC, Minnema MC, Terpos E, et al.
termined significance. Clin Cancer Res. Comparison of modern and conventional
2009;15(18):5606-5608. doi:10.1158/1078- imaging techniques in establishing multiple
0432.CCR-09-1575. myeloma-related bone disease: a system-
11. Kyle RA, Therneau TM, Rajkumar SV, et al. atic review. Br J Haematol. 2013;162(1):50-
Prevalence of Monoclonal Gammopathy 61. doi:10.1111/bjh.12346.
of Undetermined Significance. N Engl J 18. Palumbo A, Avet-Loiseau H, Oliva S, et al.
Med. 2006;354(13):1362-1369. doi:10.1056/ Revised international staging system for
NEJMoa054494. multiple myeloma: a report from interna-
12. Rajkumar SV, Dimopoulos MA, Palumbo A, tional myeloma working group. J Clin On-
col. 2015;33(26):2863-2869. doi:10.1200/
et al. International Myeloma Working JCO.2015.61.2267.
19. Go RS, Vincent Rajkumar S, Affiliations A.
Group updated criteria for the diagno- How I manage monoclonal gammopathy
of undetermined significance. Blood. 2017
sis of multiple myeloma. Lancet Oncol. Jan; 131(2):163-173. doi:10.1182 blood-2017-
09-807560.
2014;15(12):e538-e548. doi:10.1016/S1470- 20. LeGrand SB, Leskuski D, Zama I. Narrative
2045(14)70442-5. Review: Furosemide for hypercalcemia: an
13. Rawstron AC, Orfao A, Beksac M, et al. AND unproven yet common practice. Ann Intern
Report of the European Myeloma Network Med. 2008;149(4):259. doi:10.7326/0003-
on multiparametric flow cytometry in multiple 4819-149-4-200808190-00007.
myeloma and related disorders. Haemato- 21. Mhaskar R, Kumar A, Miladinovic B, et al.
logica. 2008;93(3):431-438. doi:10.3324/hae- Bisphosphonates in multiple myeloma: an
matol.11080. updated network meta-analysis. Cochrane
14. Sasson SC, Mcgill K, Wienholt L, et al. Com- Database Syst Rev. 2017 December. doi:10.
parison of the Freelite serum free light chain 1002/14651858.CD003188.pub4.
(SFLC) assay with serum and urine electro- 22. Alemu A, Richards JO, Oaks MK, et al. Vac-
phoresis/immunofixation and the N Latex cination in multiple myeloma: review of
FLC assay. Pathology. 2015 Oct;47(6):564-9. current literature. Clin Lymphoma Myelo-
doi:10.1097/PAT.0000000000000316. ma Leuk. 2016;16(9):495-502. doi:10.1016/J.
15. Singhal S, Vickrey E, Krishnamurthy J, et al. CLML.2016.06.006.
The relationship between the serum free
light chain assay and serum immunofixa-
tion electrophoresis, and the definition of

HANDBOOK OF ONCOLOGY