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Aute oo o 143
VTE and may be the rst presenting feature of an underlying cancer.
Several mechanisms lead to a prothrombotic state in cancer. This
includes the ability of cancer cells to produce procoagulant/brinolytic
substances and inammatory cytokines and the physical interaction
between tumour cells and blood (monocytes, neutrophils, platelets) or
endothelial cells. Anti-cancer therapy (i.e. surgery, cytotoxic chemo-
therapy, hormone therapy and radiotherapy) and any in-dwelling
access devices (i.e. central venous catheters) further increase the risk.
As in patients without cancer, the management of cancer-associated
VTE primarily involves anticoagulation therapy. However, the choice of
therapy must take into account bleeding risk and possible interactions
with anti-cancer therapies and their side-effects, such as thrombocy-
topenia. In patients with metastatic cancer, anticoagulation therapy will
often be lifelong.
Ectopic hormone production
Some cancers are associated with metabolic abnormalities due to
ectopic production of hormones by tumour cells, including insulin,
ACTH, vasopressin (antidiuretic hormone, ADH), broblast growth fac-
tor (FGF)-23, erythropoietin and parathyroid hormone-related protein
(PTHrP). This can result in a wide variety of presentations, as summa-
rised in Box 7.18
Neurological paraneoplastic syndromes
These form a group of conditions associated with cancer that are
thought to be due to an immunological response to the tumour that
results in damage to the nervous system or muscle (see Box 7.10).
The cancers most commonly implicated are those of the lung, pan-
creas, breast, prostate, ovary and lymphoma. Many are associated
with specic detectable immune biomarkers such as antibodies to
pre-synaptic calcium channels (Lambert–Eaton syndrome), anti-Hu
antibodies (encephalomyelitis) and anti-Yo or anti-Tr antibodies (cere-
bellar degeneration). However, these are not always specic and neg-
ative results do not exclude the diagnosis. The management of these
syndromes is multidisciplinary and includes treatment of the underly-
ing cancer itself and treatment of the syndrome primarily with immu-
nosuppressive agents.
Cutaneous manifestations of cancer
Cancers can present with skin manifestations that are not due to metas-
tases (see Box 7.10). The clinical features and management of these skin
conditions are discussed in Chapter 27
7.18 Ectopic hormone production by tumours
Hormone Consequence Tumours
ACTH Cushing’s syndrome SCLC
Erythropoietin Polycythaemia Kidney, HCC,
FGF-23 Hypophosphataemic
osteomalacia
PTHrP Hypercalcaemia NSCLC (squamous
Vasopressin (ADH) Hyponatraemia SCLC
(ACTH = adrenocorticotrophic hormone; ADH = antidiuretic hormone; FGF = broblast growth
factor; HCC = hepatocellular carcinoma; NSCLC = non-small cell lung cancer; PTHrP =
parathyroid hormone-related protein; SCLC = small cell lung cancer)
cerebellar
haemangioblastoma,
uterine broids
Mesenchymal tumours
cell), breast, kidney
Symptoms from locally advanced cancer or
metastatic sites
Metastatic disease is the major cause of death in cancer patients and the
principal cause of morbidity. For the majority of patients with metastatic
disease the goal of treatment is to control cancer, maintain quality of life,
treat symptoms and prolong life (i.e. ‘palliative treatment’). Patients of PS
3–4 (Box 7.6) or with low albumin plus high inammatory markers often
have a limited prognosis irrespective of anti-cancer treatments. Systemic
anti-cancer therapies have resulted in improved survival for many cancers so that some patients live a good quality life for many years with
metastatic cancer. Treatment of a solitary metastasis or highly treatable
cancers (e.g. germ cell) can be curative.
Brain metastases
Brain metastases occur in 10%–30% of adults and 6%–10% of children with cancer and are an increasingly important cause of morbidity.
Cancers of lung, breast, melanoma and gastrointestinal tract most commonly metastasise to the brain. Most involve the brain parenchyma but
can also affect the meninges, cranial nerves, the blood vessels and other
intracranial structures. In cases of solitary metastasis to the brain, the use
of surgery followed by adjuvant radiotherapy, or alternatively stereotactic
radiotherapy, has been shown to increase survival in patients whose disease is otherwise controlled. Outcomes for patients with more advanced
brain metastases depends on the primary cancer, extent of extracranial
disease and what systemic treatment options are available. For patients
with advanced untreatable cancer and multiple brain metastases, prognosis is often short. Glucocorticoids can improve symptoms, particularly
where there is evidence of peri-lesional oedema. In treatable cancers
whole brain radiotherapy can allow steroid dose to be reduced whilst
systemic therapy is used to treat the remaining cancer. With improved
systemic therapies, including targeted therapies and immunotherapy,
some patients are now living for several years with brain metastases.
Clinical features
Presentation is with headaches and nausea (40%–50%), focal neurological dysfunction (20%–40%), cognitive dysfunction (35%), seizures
(10%–20%) and papilloedema (<10%).
Investigations and management
The diagnosis can be conrmed by CT or contrast-enhanced MRI.
Treatment options include high-dose glucocorticoids for tumour-associated
oedema (dexamethasone 4–12 mg daily depending on amount of oedema),
anticonvulsants for seizures, whole-brain radiotherapy and systemic
anti-cancer therapy. Surgery may be considered for single sites of disease
and can be curative; stereotactic radiotherapy may also be considered for
solitary site involvement or where surgery is more difcult or not possible.
Lung metastases
Lung metastases are common in breast cancer, colon cancer, renal cancer, sarcoma and tumours of the head and neck. The presentation is usually with a lesion on chest X-ray or CT. Solitary lesions require investigation,
as single metastases can be difcult to distinguish from a primary lung
tumour. Patients with two or more pulmonary nodules can be assumed
to have metastases. The approach to treatment depends on the extent
of disease in the lung and elsewhere. For solitary lesions, surgery should
be considered, with a generous wedge resection, or radiofrequency ablation if available. Radiotherapy and systemic anti-cancer therapies can be
used, dependent on the underlying primary cancer diagnosis (Fig. 7.9).
Liver metastases
Metastatic cancer in the liver can represent the sole or life-limiting component of disease for many with colorectal cancer, ocular melanoma,
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A B
R
Fig. 7.9
neuro-endocrine tumours (NETs) and, less commonly, other tumour
types. The most common clinical presentations are with right upper
quadrant pain due to stretching of the liver capsule, jaundice, deranged
liver function tests or an abnormality detected on imaging. In selected
cases, resection of the metastasis can be contemplated. In colorectal
cancer, successful resection of metastases improves 5-year survival from
3% to 30%–40%. Other techniques, such as chemoembolisation, radiofrequency ablation or microwave ablation, can also be used, provided
the number and size of metastases remain small. If these are not feasible,
symptoms may respond to systemic anti-cancer therapy (Fig. 7.5).
Bone metastases
Bone is the third most common organ involved by metastasis, after
lung and liver. Bone metastases are a major clinical problem in patients
with myeloma and breast or prostate cancers, but other tumours that
commonly metastasise to bone include those of the kidney and thyroid.
Bone metastases are increasingly seen in other tumour types that do not
classically target bone, due to effective anti-cancer treatments prolonging survival of patients with many cancers. Accordingly, effective management of bony metastases has become a focus in the treatment of
patients with many incurable cancers.
Clinical features
The main presentations are with pain, pathological fractures, spinal
cord compression (see above) and hypercalcaemia. Pain tends to be
progressive and worst at night, and may be partially relieved by activity, but subsequently becomes more constant in nature and is exacerbated by movement. Most pathological fractures occur in metastatic
breast cancer (53%); other tumour types associated with fracture
include the kidney (11%), lung (8%), thyroid (5%), lymphoma (5%) and
prostate (3%).
Investigations and management
The most sensitive way of detecting bone metastases is by isotope bone
scan. This can have false-positive results in healing bone, particularly as
a are response following treatment and false-negative results occur in
multiple myeloma due to suppression of osteoblast activity. Plain X-ray
lms or MRI scans are therefore preferred for any sites of bone pain,
as lytic lesions may not be detected by a bone scan. In patients with a
single lesion, it is especially important to perform a biopsy to obtain a
tissue diagnosis, since primary bone tumours may look very similar to
metastases on X-ray. The main goals of management are:
pain relief
preservation and restoration of function
skeletal stabilisation
local tumour control (e.g. relief of tumour impingement on normal
structure).
Surgical intervention may be warranted where there is evidence of
skeletal instability (e.g. anterior or posterior spinal column fracture) or
an impending fracture (e.g. a large lytic lesion on a weight-bearing bone
with more than 50% cortical involvement). Intravenous bisphosphonates
(pamidronate, zoledronic acid or denosumab) are widely used for bone
metastases and are effective at improving pain and in reducing further
skeletal related events, such as fractures and hypercalcaemia. In certain
types of cancer, such as breast and prostate, hormonal therapy may be
effective. Radiotherapy, in the form of external beam therapy or systemic
radionuclides (strontium treatment), can also help pain. In some settings
(e.g. breast carcinoma), systemic anti-cancer therapy may be used in the
management of bony metastases.
Malignant pleural effusion
This is a common complication of cancer and 40% of all pleural effusions
are due to malignancy. The most common causes are lung and breast
cancers, and the presence of an effusion indicates incurable disease.
The presentation may be with dyspnoea, cough or chest discomfort,
which can be dull or pleuritic in nature. Diagnosis and management of
pleural effusion is discussed on page 494.
Investigations and management
Pleural aspirate is the key investigation and may show the presence of
malignant cells. Malignant effusions are commonly blood-stained and
are exudates with a raised uid to serum LDH ratio (> 0.6) and a raised
uid to serum protein ratio (>0.5). Treatment should focus on palliation of
symptoms and be tailored to the patient's physical condition, treatment
options and prognosis. Aspiration alone may be an appropriate treatment in frail patients with a limited life expectancy. Those who present
with malignant pleural effusion as the initial manifestation of breast cancer, small cell lung cancer, germ cell tumours or lymphoma should have
the uid aspirated and should be given systemic anti-cancer therapy to
try to treat disease in the pleural space. Treatment options for patients
with recurrent pleural effusions include pleurodesis, implanted drainage
catheters, pleurectomy and pleuroperitoneal shunt.
Other common symptoms
Other symptoms that commonly arise from metastatic cancer are:
gastrointestinal obstruction, malignant abdominal ascites, hydronephrosis and cancer cachexia.
Ther ap euti s i oo o 145
Treatment-related toxicities
Whilst most anti-cancer therapies cause some side-effects, most
of these can be managed with supportive medicines at home. Some
patients will develop severe toxicities and an acute assessment will be
needed. Examination of the patient on anti-cancer treatment (p. 128)
should consider the type of anti-cancer treatment, duration since the
last treatment and other concurrent toxicities. Patients on anti-cancer
therapy can deteriorate quickly and prompt assessment and management is required. There may be specic management protocols to help
manage treatment-related toxicities and advice should be sought from
the patient’s cancer centre or acute oncology team.
Therapeutics in oncology
Anti-cancer therapy may be used with either curative or palliative intent,
and this distinction inuences the approach to management of individual
patients. The goal of treatment should be recorded in the medical notes.
Curative therapy is given with the aim of achieving complete remis-
sion. Surgery to remove all macroscopic disease is most frequently
the primary curative intervention. However, in some circumstances
radiotherapy, systemic anti-cancer therapy or a combination of
these may be used with curative, or radical, intent.
Adjuvant therapy is additional therapy given after the primary
curative intervention to lower the risk of disease recurrence.
Radiotherapy and/or systemic anti-cancer therapy may be given
after surgery with the intention of eradicating any micrometastatic
disease that remains.
Neoadjuvant therapy is additional therapy given prior to the primary
curative intervention. Systemic anti-cancer therapy may be administered prior to planned surgery. The principal aim is to lower the
risk of disease recurrence. Any reduction in the volume of disease,
or ‘downstaging’, may also allow less extensive surgery, increase
the likelihood of successful debulking and improve subsequent
surgical morbidity. Direct evaluation of the surgical specimen allows
assessment of the effectiveness of neoadjuvant therapies, guiding
subsequent management and lending this approach to translational
research.
Palliative therapy is primarily used to treat patients with metastatic
disease, or where curative treatment is not possible. The goal is to
control cancer, with the aim of improving or maintaining quality of
life, treating and preventing symptoms and improving survival. The
choice of therapy depends on the clinical situation and a careful
evaluation of the risks and benets of the intervention.
Surgical treatment
Surgery has a pivotal role in the management of cancer. It is the main
curative management of most solid cancers. In early localised cases of
colorectal, breast and lung cancer, cure rates are high with surgery. There
is evidence that outcome is related to surgical expertise, and most multidisciplinary teams include surgeons experienced in the management of
a particular cancer. There are some cancers for which surgery is one of
two or more options for primary management, and the role of the MDT is
to recommend appropriate treatment for an individual patient. Examples
include prostate and transitional cell carcinoma of the bladder, in which
radiotherapy and surgery may be equally effective. Specialised surgical,
or interventional radiology techniques may also be employed with curative intent. Radiofrequency ablation, microwave ablation or cryotherapy
may be used to treat small renal cell carcinomas or hepatocellular carcinomas. Surgery has less of a role in lymphoma, high-grade neuro-endocrine tumours or small cell cancer, where systemic anti-cancer therapy is
the main treatment used.
Surgical procedures are often the quickest and most effective way
of palliating symptoms in patients with metastatic disease. Examples
include the treatment of faecal incontinence with a defunctioning
colostomy; xation of pathological fractures; decompression of spinal cord
compression; and the treatment of fungating skin lesions by ‘toilet’ sur-
gery. Debulking cytoreductive surgery may improve survival in some can-
cers, including renal cell carcinoma and ovarian cancer. In very selected
cases, such as patients with oligometastatic disease, resection of metas-
tases may improve survival and reduce the need for other therapies.
Radiotherapy
Radiotherapy (radiation therapy) involves treating the cancer with ionis-
ing radiation such as X-rays, gamma rays, electrons or charged atoms.
Ionising radiation kills cancer cells by two mechanisms; directly damag-
ing cancer DNA or indirectly by triggering the formation of very reactive
molecules (free radicals) that also damage cancer DNA.
Two main types of radiation therapy exist: external beam radiotherapy,
and brachytherapy (internal radiotherapy). External beam radiotherapy is
most commonly delivered by a linear accelerator, which produces electron or photon beams. As normal tissues can also be damaged by radiotherapy, treatments are planned to ensure maximum exposure of the
tumour and minimal exposure of surrounding normal tissues. Improved
localisation of the target volume, or tumour, can be achieved by the
use of surgical clips at the site of resection and fusion of radiotherapyplanning CT scans with diagnostic MRI or PET-CT scans. Treatmentplanning software controls the size and shape of the beam. Intensity
modulated radiotherapy (which allows for more homogeneous dose
distribution), and volumetric radiotherapy (in which the shape of the radiation beam is designed to closely t the tumour), have largely replaced
conventional methods that use a limited number of square or rectangular
beams. Stereotactic radiotherapy is a highly targeted method to deliver
focused radiation beams from many different angles which converge
on the tumour to deliver high doses precisely. Proton therapy uses a
cyclotron to produce beams of high-energy protons, which deposit their
radiation dose by a means that allows further sparing of normal tissues.
Brachytherapy, or internal radiation therapy, involves the direct application of a radioactive source onto or into a tumour. This allows the delivery of a high, localised dose of radiation. Brachytherapy is a common
treatment for cancers of the prostate, uterus and cervix. Most commonly,
an applicator device is used to deliver a radioactive source to the tumour
for a set time, typically 10–20 minutes. In other cases, such as in prostate
cancer, small radioactive seeds may be permanently placed, releasing
radiation slowly over several months. Radioactive liquid treatments, such
223
as
radium for bone metastases from prostate cancer or
thyroid cancers are other examples of internal radiation therapy.
Biological differences between normal and tumour tissues are
exploited to obtain therapeutic benet. Fundamental to this is fractionation, which entails delivering the radiation as a number of small doses on
a daily basis. This allows normal cells to recover from radiation damage
but recovery occurs to a lesser degree in malignant cells. Fractionation
regimens vary depending on the tumour being treated, the total radiation dose to be delivered and the intent of treatment. Curative, or radical treatments typically deliver a higher overall dose in 20–35 fractions
over 4–7 weeks. For palliative treatments a smaller dose given over 1–10
fractions is usually adequate. Malignant tissues vary widely in their sensitivity to radiotherapy. Germ cell tumours and lymphomas are extremely
radiosensitive, and relatively low doses are adequate for cure. However,
most other cancers require higher doses. Normal tissue also varies in its
radiosensitivity, with the central nervous system, small bowel and lung
being among the most sensitive.
The side-effects of radiotherapy depend on the site being treated, the
tissue’s radiosensitivity and the dose delivered. For example, skin reactions are common with high-dose radical head and neck cancer treatments, or proctitis and cystitis with treatment to the bladder or prostate.
These acute reactions typically settle within a few weeks after treatment.
Late effects of radiotherapy develop more than 6 weeks after treatment
and occur in 5%–10% of patients. Examples include brachial nerve
damage and subcutaneous brosis after breast cancer treatment. There
131
iodine for
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is also a risk of inducing new cancer after radiotherapy, which varies
depending on the site treated and on whether the patient has had other
treatment such as cytotoxic chemotherapy.
Systemic anti-cancer therapy
Systemic anti-cancer therapy (SACT) is a collective term to describe the
growing number of differing drug therapies used to treat cancer. These
drugs reach throughout the body to treat cancer cells wherever they may
Precursors
Antifolates
Purine
biosynthesis
Ribonucleotides
Deoxyribonucleotides
be. Increasingly, treatment is tailored to a patient’s particular cancer and
its molecular prole, allowing more personalised therapy.
Cytotoxic chemotherapy
Cytotoxic chemotherapy drugs work by interfering with the processes
involved in cell division. They are sub-classied by their mode of action
(Fig. 7.10). Cytotoxic chemotherapies have their greatest activity in proliferating cells and this provides the rationale for their use in the treatment
Precursors
Pyrimidine
biosynthesis
Fluoropyrimidines
Nucleoside analogues
Mechanism
of action
Examples
Anthracyclines
Bleomycin
Actinomycin D
Antimetabolites
Alkylating
agents
Alkaloids
Topoisomerase
inhibitors
Antitumour
antibiotics
Antifolates Fluoropyrimidines Nucleoside
Inhibit
dihydrofolate
reductase and
so purine and
pyrimidine
synthesis
Methotrexate 5-Fluorouracil,
Inhibit thymidylate
synthase and so
pyrimidine synthesis
capecitabine
analogues
Incorporated
into DNA
during
synthesis,
leading to
irreparable
errors
Gemcitabine,
fludarabine
DNA
RNA
(transfer, messenger,
ribosomal)
Proteins
Enzymes Microtubules
Nitrogen
mustards
Form covalent
cross-links between
DNA molecules by
adding an alkyl
group to DNA
Cyclophosphamide,
ifosfamide
Platinum
agents
Form inter-/
intra-strand
cross-links
between DNA
molecules,
not by adding
an alkyl group,
so considered
alkylating-like
agents
Cisplatin,
carboplatin,
oxaliplatin
Topoisomerase
I/II inhibitors
Prevent re-ligation
of DNA strands by
topoisomerase I/II
Etoposide (II);
topotecan,
irinotecan (I)
Nitrogen mustards
Platinum agents
Topoisomerase I
inhibitors
Topoisomerase II
inhibitors
Mitotic inhibitors
Microtubule
aggregators
Mitotic
inhibitors
Bind tubulin,
blocking
microtubule
formation
Vinca alkaloids:
vincristine,
vinblastine,
vinorelbine
Microtubule
aggregators
Stabilise the
microtubule
polymer
preventing its
disassembly
Taxanes:
paclitaxel,
docetaxel
Others –
acting on DNA
1. Intercalate with DNA
and inhibit the
progression
of topoisomerase I
2. Induce DNA strand
breaks by oxidative
damage
3. Bind to DNA
to prevent
transcription
1. Anthracyclines:
epirubicin, doxorubicin
2. Bleomycin
3. Actinomycin D
Fig. 7.10
Commonly used cytotoxic chemotherapy agents and their mechanisms of action.
of cancer. However, they are not specic for cancer cells and the sideeffects of treatment are largely a result of their antiproliferative actions in
normal tissues such as the bone marrow, skin and gut (p. 129). Other
organs, such as the heart, kidney and peripheral nervous system, may
also be affected by some cytotoxic drugs.
The choice of cytotoxic chemotherapy agent, or combination of
treatments, is determined by the cancer type. The dosing schedule is
determined by the choice of treatments and recovery of normal tissues,
usually the bone marrow. For most common cytotoxic chemotherapy
regimens the treatment is administered in cycles. A course of treatment
may constitute a pre-dened number of cycles, or may continue indenitely until evidence of disease progression or until limiting side-effects.
Supportive therapy is used to enable patients to tolerate therapy and
achieve benet. Nausea and vomiting are common, but with modern
antiemetics, regimens such as the combination of dexamethasone and
highly selective 5-hydroxytryptamine (5-HT3, serotonin) receptor antagonists such as ondansetron, most patients now receive cytotoxic chemotherapy without any signicant problems. Myelosuppression is common
to almost all cytotoxics and this not only limits the dose of drug but also
can cause life-threatening complications. The risk of neutropenia can
be reduced with the use of specic growth factors that accelerate the
repopulation of myeloid precursor cells. The most commonly employed
is G–CSF, which is widely used in conjunction with cytotoxic chemotherapy regimens that induce a high rate of neutropenia.
Deregulating
cellular
energetics:
aerobic glycolysis
inhibitors
Resisting
cell death:
BCL-2 inhibitors
Genome instability
and mutation:
PARP inhibitors
Ther ap euti s i oo o 147
Sustaining
proliferative
signalling:
EGFR, HER2
and BRAF
inhibitors
Inducing
angiogenesis:
VEGF inhibitors
Evading growth
suppressors:
CDK4/6
inhibitors
immunotherapy
Activating
invasion and
metastases:
HGF/c-MET
inhibitors
Avoiding
immune
destruction:
checkpoint
inhibitors as
Enabling
replicative
immortality:
telomerase
inhibitors
Tumour-
promoting
inflammation:
selective anti-
inflammatory
agents
7
Hormone therapy
Hormones are important cell-signalling molecules and, in some cancers,
may be key drivers of tumour growth. Blocking hormonal signalling pathways in these cancers may be a very effective treatment strategy.
Approximately 80% of breast tumours are positive for expression of
the oestrogen receptor (ER). Assessment of ER status is now standard
in the diagnostic workup of breast cancer. Drugs that reduce oestrogen
levels or block the effects of oestrogen on the receptor are widely used in
the management of ER-positive breast cancer. Adjuvant hormone therapy may reduce the risk of relapse and death at least as much as cytotoxic chemotherapy and in advanced cases can induce stable disease
and remissions that may last months to years, with acceptable toxicity.
Hormonal manipulation may be effective in other cancers. In prostate
cancer, hormonal therapy (e.g. luteinising hormone releasing hormone
(LHRH) analogues such as goserelin and/or anti-androgens such as
bicalutamide) aimed at reducing androgen levels can provide good longterm control of advanced disease. The side-effects of hormone therapies
are linked to their hormonal targets.
Targeted therapies
Advances in knowledge about the molecular basis of cancer have
resulted in the development of treatments to target specic genes and
proteins that are involved in the growth and survival of cancer cells
(Fig. 7.11). These signalling pathways may have broad importance to a
range of cancer types or be specic to certain cancers. They may not
be important in all tumours of the same cancer type, requiring specic
molecular testing to predict whether the patient may benet.
Targeted therapies are broadly divided into two groups: monoclonal
antibodies (-mab) and small molecule inhibitors (-ib). The -mab family are
typically utilised for targets that are overexpressed on the outside of the
cancer cell. The -ib family typically target processes within the cell, such
as the cytoplasmic tyrosine kinase, and are designed to be small enough
to enter the cell.
A wide range of targeted therapies are now used routinely in oncological practice. Some of these are described below. The side effects
of targeted therapies are determined by the molecular pathway being
targeted (p. 129).
Epidermal growth factor receptor (EGFR) is an important transmembrane signalling protein. Mutations in the EGFR gene lead to overexpression of the EGFR protein or constitutive activation of the cell-signalling
Fig. 7.11 Examples of targeted anti-cancer therapies and their actions in
relation to the Hallmarks of Cancer. (For abbreviations see text.)
pathway, leading to uncontrolled cell division, in several cancer types.
Approximately 15% of lung adenocarcinomas have activating mutations
of EGFR, which may be targeted with drugs such as getinib, erlotinib or
osimertinib. The latter of these agents has been designed to overcome
a particular mutation (i.e. T790M) responsible for 50% of resistance to
older EGFR inhibitors. In colorectal cancer drugs such as cetuximab and
panitumumab are active in patients where molecular testing does not
detect resistance inferred by mutations in the RAS/RAF family of genes.
Vascular endothelial growth factor receptor (VEGFR) inhibitors such
as sunitinib, pazopanib and cabozantinib have been a pillar of renal cell
carcinoma treatment for over a decade. Activation of members of the
VEGFR family play an important role in tumour angiogenesis. VEGFR
small molecule inhibitors are commonly used in the management of
hepatocellular carcinoma and thyroid cancer. Bevacizumab, a monoclonal antibody therapy targeted at VEGF-A, is active in a number of cancers, including ovarian, colorectal and breast.
HER2 is a member of the epidermal growth factor receptor family.
Amplication or over-expression of HER2 is found in breast, gastric, pancreatic, lung and some uterine cancers. Approximately 20% of breast
cancers are HER2-positive, where it is associated with increased risk of
recurrence and poor prognosis. Several agents have been developed to
target HER2, including trastuzumab and pertuzumab. The agent trastuzumab emtansine is an antibody-drug conjugate consisting of trastuzumab covalently linked to the cytotoxic chemotherapy agent emtansine
which is delivered specically to the HER2-positive breast cancer cell.
Immunotherapy
The term immunotherapy encompasses a range of anti-cancer therapies that work by harnessing the immune system to attack cancer cells.
Cytokines, such as interferon alpha and interleukin-2, have been used
with some success in melanoma and renal cell carcinoma. However, in
recent years the development of other immunotherapy treatments has
revolutionized the management of several cancer types.
Immune checkpoints are key regulators of the immune system
which work to prevent the immune response from attacking normal
healthy cells. Cancers may co-opt this mechanism to evade immune
destruction. Targeted therapies that inhibit these checkpoint molecules
(CTLA4, PD-1) or their ligands (PD-L1) (Fig. 7.12) are now licensed in
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A
B
Anti-PD-L1
Anti-PD-1
PD-L1
PD-1
Tumour cell
PD-1
Tumour cell
T cell
death
PD-L1
T cell
Antigen
T-cell receptor
T-cell
inhibited
Antigen
T-cell receptor
T-cell
activated
T-cell effector
function
T-cell
proliferation
7.19 Response evaluation criteria in solid tumours (RECIST)
Response Criteria
Complete response (CR) Disappearance of all target lesions
Partial response (PR) At least a 30% decrease in the sum of the
longest diameter (LD) of target lesions,
taking as reference the baseline sum LD
Progressive disease (PD) At least a 20% increase in the sum of the
LD of target lesions, taking as reference
the smallest sum LD recorded since
the treatment started and at least 5 mm
increase or the appearance of one or more
new lesions
Stable disease (SD) Neither sufcient shrinkage to qualify for
PR nor sufcient increase to qualify for PD,
taking as reference the smallest sum LD
since the treatment started
or biochemical monitoring are commonly used to determine whether
a treatment is being effective. Uniform criteria have been established
to measure these, including the response evaluation criteria in solid
tumours (RECIST, Box 7.19) and common toxicity criteria (e.g. common
terminology criteria for adverse events (CTCAE)). This allows clinicians to
inform patients accurately about the prognosis, effectiveness and toxicity
of systemic anti-cancer therapy and empowers patients to take an active
role in treatment decisions.
Fig. 7.12
activation and tumour cell death. (PD-1 = programmed cell death protein 1;
PD-L1 = programmed cell death ligand 1)
the management of many cancers, including melanoma, renal cell carcinoma, lung, bladder, head and neck, and, more broadly, any cancers
demonstrating microsatellite instability. Checkpoint inhibitor immunotherapies may be used alone, or in combination with other checkpoint inhibitor immunotherapies, targeted therapies or cytotoxic chemotherapy.
Adoptive cell therapy, also known as cellular immunotherapy, is increasingly being used, particularly in haematological malignancies. Immune
cells isolated from either the patient’s tumour or bloodstream may be activated and expanded, before being infused back into the patient to attack
cancer cells (i.e. tumour inltrating lymphocyte (TIL) therapy). The immune
cells may also be genetically modied to improve the likelihood that they
identify the cancer cells (i.e. engineered T-cell (TCR) therapy, chimeric
antigen receptor T-cell (CAR-T) therapy). Cancer treatment vaccines are
also in development. These aim to boost the immune system’s ability to
recognise and destroy antigens using a number of different techniques.
Immunotherapy treatment is likely to become more prevalent in
the future for many types of cancers and indications. In patients with
advanced or metastatic disease a key observation has been the potential for durable treatment responses. For example, average survival for
patients with metastatic melanoma has improved from 6–8 months in the
pre-immunotherapy era to over 5 years with the use of combination antiCTLA4 and anti-PD-1 checkpoint inhibitors in clinical trials. However,
many patients do not respond and others are affected by potentially
life-threatening immune-related adverse events (see above).
Late toxicity of therapy
The late toxicities of treatment for cancer are particularly important
for patients where multimodality therapy is given with curative intent,
where the patient is young and as more patients are living longer.
This can cause considerable morbidity: for example, radiotherapy
can retard bone and cartilage growth, impair intellect and cognitive
function, and cause dysfunction of the hypothalamus, pituitary and
thyroid glands. Late consequences of cytotoxic chemotherapy include
heart failure due to cardiotoxicity, pulmonary brosis, nephrotoxicity
and neurotoxicity.
Premature gonadal failure can result from cytotoxic chemotherapy
or radiotherapy and leave a patient subfertile. Patients should be made
aware of this before treatment is initiated, as it may be possible to store
sperm for male patients before treatment starts; this should always be
offered, if practical. Egg storage or embryo banking after in vitro fertilisation may be an option for young women. Sterility develops at higher
radiotherapy doses but erectile dysfunction is seen in patients receiving
high radiotherapy doses to the pelvis, as in prostate cancer. Additional
social or psychological support may be required to address these issues.
Infertility and pubertal delay are potential late effects of therapy in children, especially boys.
Second malignancies may be induced by cancer treatment and
occur at greatest frequency following chemoradiation. Secondary
acute leukaemia (mostly AML) can occur 1–2 years after treatment
with topoisomerase II inhibitors, or 2–5 years after treatment with
alkylating agents. The most common second malignancy within a
radiation eld is osteosarcoma but others include soft tissue sarcoma
and leukaemia.
Cancer clinical trials
Evaluation of treatment
In advanced or metastatic cancer the evaluation of treatment is an
ongoing process and includes assessments of treatment response, toxicity and quality of life. Clinical evaluation alongside radiological imaging
Cancer clinical trials are embedded within routine practice in oncology. Close collaboration with laboratory scientists, active recruitment
of cancer patients into clinical trials and robust translational research
have led to many new cancer treatments, personalised therapies and a
transformation of cancer management over the last 20 years. As many
Spe if i a ers 149
anti-cancer drugs are expected to have toxicities, which may ultimately
limit the deliverable dose, clinical trials in cancer differ from trials of other
medicines.
Phase I cancer clinical trials take treatments of interest from labor-
atory studies and test them in patients with advanced cancer for
whom no other standard anti-cancer treatment exists. Phase I trials
assess the safety of a treatment and identify an optimal dose and
dosing schedule. Initial doses are very low and each sequential
cohort of patients receives a higher dose. Doses are escalated in
controlled cohorts of 1–6 patients, according to toxicities, pharmacokinetics and pharmacodynamics, until the maximum tolerated
dose is reached.
Phase II cancer clinical trials treat patients with specic cancers of
interest with the trial drug, using the dose established in phase I
trials. Phase II trials may be randomised or non-randomised but will
recruit enough patients to further assess the safety of the treatment
and whether it results in enough anti-cancer activity in a specic
cancer to develop the drug further by way of phase III trials.
Phase III cancer trials are large, multi-centre randomised controlled
trials to compare the new treatment of interest with the current
established therapy for this indication. Cancer response, toxicity,
quality of life and survival data will usually be assessed. Phase III
trials may also compare current standard treatment with a different
treatment, either looking for improved outcome or improved quality
of life with non-inferior outcome. If a treatment is deemed to be safe
and effective it will be licensed for clinical use.
Phase IV trials involve the continuing safety surveillance of a treat-
ment after it receives a licence for clinical use. This can be particularly useful to detect any rare or long-term adverse effects in a much
larger population and longer time period than was possible during
Phase I–III trials.
Specic cancers
As cancer management becomes more complex and personalised, and
incorporates multi-modality treatment approaches, oncology teams are
increasingly subspecialised and work as part of tumour-specic multidisciplinary teams. The diagnosis and management of specic cancers are
discussed in more detail elsewhere in the book (Box 7.20). Here we discuss the pathogenesis, clinical features, investigation and management
of some common tumours that are not covered elsewhere.
Breast cancer
Globally, the incidence of breast cancer is second only to that of lung
cancer, and the disease represents the leading cause of cancer-related deaths among women. Invasive ductal carcinoma with or without ductal carcinoma in situ (DCIS) is the most common histology,
accounting for 70%, whilst invasive lobular carcinoma accounts for
most of the remaining cases. DCIS constitutes 20% of breast cancers
detected by mammography screening. It is multifocal in one-third of
women and has a high risk of becoming invasive (10% at 5years following excision only). Pure DCIS does not cause lymph node metastases, although these are found in 2% of cases where nodes are
examined, owing to undetected invasive cancer. Lobular carcinoma in
situ (LCIS) is a predisposing risk factor for developing cancer in either
breast (7% at 10 years). The survival for breast cancer by stage is
outlined in Box 7.21
Pathogenesis
Both genetic and hormonal factors play a role: about 5%–10% of breast
cancers are hereditary and occur in patients with mutations of BRCA1,
BRCA2, AT or TP53 genes. Prolonged oestrogen exposure associated
with early menarche, late menopause and use of hormone replacement
therapy (HRT) has been associated with an increased risk. Other risk
7.20 Specic cancers covered in other chapters
Bladder cancer p. 607
Colorectal cancer p. 826
Familial cancer syndromes p. 55
Gastric cancer p. 817
Hepatocellular carcinoma p. 901
Leukaemia p. 963
Lung cancer p. 528
Lymphoma p. 971
Mesothelioma p. 546
Myeloma p. 976
Oesophageal cancer p. 809
Pancreatic cancer p. 855
Prostate cancer p. 610
Renal cancer p. 606
Seminoma p. 611
Skin cancer p. 1082
Teratoma p. 611
Thyroid cancer p. 665
7.21 Five-year survival rates for breast cancer by stage
Tumour stage Stage denition 5-year survival (%)
I
Tumour <2 cm, no lymph
98
nodes
II Tumour 2–5 cm and/or
90
mobile axillary lymph nodes
III Chest wall or skin xation
72
and/or xed axillary lymph
nodes
IV Metastasis 26
factors include obesity, alcohol intake, nulliparity and late rst pregnancy.
There is no denite evidence linking use of the contraceptive pill to
breast cancer.
Clinical features
Breast cancer usually presents as a result of mammographic screening or as a palpable mass with nipple discharge in 10% and pain
in 7% of patients. Less common presentations include inammatory
carcinoma with diffuse induration of the skin of the breast, and this
confers an adverse prognosis. Around 40% of patients will have axillary nodal disease, with likelihood correlating with increasing size of
the primary tumour. Distant metastases are infrequently present at
diagnosis and the most common sites of spread are bone (70%), lung
(60%), liver (55%), pleura (40%), adrenals (35%), skin (30%) and brain
(10%–20%).
Investigations
Following clinical examination, patients should undergo imaging with mammography or ultrasound evaluation, and a biopsy using ne needle aspiration for cytology or core biopsy for histology. Histological assessment
should be carried out to assess tumour type and to determine oestrogen
and progesterone receptor (ER/PR) status and HER2 status. If distant
spread is suspected, CT of the thorax and abdomen and an isotope bone
scan are required. Molecular subtyping is being used to classify tumours
into four major subtypes: luminal A, luminal B, HER2 type and basal-like
7
150 O ncO l Og y
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(often called ‘triple negative’, as these tumours are ER-, PR- and HER2negative). This may allow more targeted selection of therapies in future.
Management
Surgery is the mainstay of curative treatment. This can range from a
lumpectomy, where only the tumour is removed, to mastectomy, where
the whole breast is removed. Breast-conserving surgery is as effective as
mastectomy if complete excision with negative margins can be achieved.
Lymph node sampling is performed at the time of surgery.
There is signicant evidence to support the use of additional therapies
to reduce the risk of breast cancer recurrence. Adjuvant radiotherapy is
given to reduce the risk of local recurrence. In those patients considered
at high risk of recurrence (i.e. tumour of >1 cm, ER-negative disease or the
presence of involved axillary lymph nodes) cytotoxic chemotherapy may
be offered. In patients with HER2-positive breast cancer adjuvant trastuzumab, a humanised monoclonal antibody to HER2, may be used alongside standard cytotoxic chemotherapy. These treatments are increasingly
being used in the neoadjuvant setting, with the aim of achieving a complete
pathological response when the cancer is resected, often with a more
organ-preserving surgical procedure. In patients with ER-positive tumours
adjuvant hormonal therapy may gain additional disease-free and overall
survival benets. Patients at low risk of recurrence (i.e. small, ER-positive
disease) may require only adjuvant hormonal therapy. In post-menopausal
women adjuvant bisphosphonate therapy may also be used.
The treatment of metastatic breast cancer is complex. Radiotherapy
may be used to palliate painful bone metastases. SACT decisions are
made with consideration of ER status, HER2 status, the distribution
of metastatic disease and previous neo/adjuvant treatment, alongside
assessments of performance status (PS) and comorbidities. For example, in a post-menopausal patient with ER-positive, HER2-negative
bone-only metastatic disease who is PS 0, hormonal therapy (i.e. an
aromatase inhibitor) in combination with a CDK4/6 targeted therapy
(i.e. palbociclib, abemaciclib or ribociclib) may be used as rst-line
treatment. In a similar patient with additional symptomatic liver metastases, cytotoxic chemotherapy may be more appropriate.
Ovarian cancer
Ovarian cancer is the most common gynaecological tumour in Western
countries. Most ovarian cancers are epithelial in origin (90%), and up
to 7% of women with ovarian cancer have a positive family history.
Patients often present late in ovarian cancer with vague abdominal discomfort, low back pain, bloating, altered bowel habit and weight loss.
Occasionally, peritoneal deposits are palpable as an omental ‘cake’ and
nodules in the umbilicus (Sister Mary Joseph nodules).
Pathogenesis
Genetic and environmental factors play a role. The risk of ovarian cancer
is increased in patients with BRCA1 or BRCA2 mutations, and Lynch
type II families (a subtype of hereditary non-polyposis colon cancer,
HNPCC) can have ovarian, endometrial, colorectal and gastric tumours
due to mutations of mismatch repair enzymes. Advanced age, nulliparity,
ovarian stimulation and European descent all increase the risk of ovarian
cancer, while suppressed ovulation appears to protect, so pregnancy,
prolonged breastfeeding and the contraceptive pill have all been shown
to reduce the risk of ovarian cancer.
Surgery should include removal of the tumour along with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy.
Even in advanced disease, surgery is undertaken to maximally debulk the
tumour and is followed by cytotoxic chemotherapy, typically using carboplatin and paclitaxel. Bevacizumab, a targeted therapy against VEGFR,
is indicated for patients with high-grade tumours that are suboptimally
debulked or those with a more aggressive biological pattern. Subsequent
treatment decisions are made with consideration of response to rst-line
cytotoxic chemotherapy and germline BRCA mutation status. Options
include further platinum/paclitaxel combination, liposomal doxorubicin or
targeted therapy against poly-ADP ribose polymerase (PARP, e.g. olaparib, niraparib or rucaparib).
The serum tumour marker CA-125 and clinical examination may be
used to monitor treatment response in ovarian cancer, with CT imaging
for those with suspected progressive disease.
Endometrial cancer
Endometrial cancer accounts for 4% of all female malignancies, producing a 1 in 73 lifetime risk. The majority of patients are post-menopausal,
with a peak incidence at 50–60 years of age. Mortality from endometrial cancer is currently falling. The most common presentation is with
post-menopausal bleeding, which often results in detection of the disease before distant spread has occurred.
Pathogenesis
Oestrogen plays an important role in the pathogenesis of endometrial
cancer, and factors that increase the duration of oestrogen exposure,
such as nulliparity, early menarche, late menopause and unopposed HRT,
increase the risk. Endometrial cancer is 10 times more common in obese
women and this is thought to be due to elevated levels of oestrogens.
Investigations
The diagnosis is conrmed by endometrial biopsy.
Management
Surgery is the treatment of choice and is used for staging. A hysterectomy and bilateral salpingo-oophorectomy are performed with peritoneal
cytology and, in some cases, lymph node dissection. Where the tumour
extends beyond the inner 50% of the myometrium or involves the cervix and local lymph nodes, or there is lymphovascular space invasion,
adjuvant pelvic radiotherapy is recommended. Cytotoxic chemotherapy
is used as adjuvant therapy, and hormonal therapy and cytotoxic chemotherapy are used to palliate symptoms in recurrent disease.
Cervical cancer
Cervical cancer is the fourth most common cancer in women and the
leading cause of death from gynaecological cancer worldwide. The
incidence is decreasing in high-income industrialised countries but continues to rise in low- and middle-income nations. The most common
presentation in the UK is with an abnormal smear test, but with locally
advanced disease the presentation is with vaginal bleeding, discomfort,
discharge or symptoms attributable to involvement of adjacent structures, such as bladder, or rectal or pelvic wall. Occasionally, patients
present with distant metastases to bone and lung.
Investigations
Initial workup for patients with suspected ovarian cancer includes imaging in
the form of ultrasound and CT. Serum levels of the tumour marker CA-125
are often measured. Surgery plays a key role in the diagnosis, staging and
treatment of ovarian cancer, and in early cases, palpation of viscera, peritoneal washings and biopsies are generally performed to dene disease extent.
Management
In early disease, surgery followed by adjuvant cytotoxic chemotherapy
with carboplatin, or carboplatin plus paclitaxel, is the treatment of choice.
Pathogenesis
Almost all cases of cervical cancer are linked to high-risk human papillomaviruses (HPV), transmitted through sexual contact. This has underpinned the introduction of programmes to immunise adolescents against
HPV in an effort to prevent up to 90% of cervical cancer.
Investigations
Diagnosis is made by smear or cone biopsy. Further examination may
require cystoscopy and exible sigmoidoscopy if there are symptoms referable to the bladder, colon or rectum. In contrast to other gynaecological
Fu rt he r i f o rm at io 151
malignancies, cervical cancer is a clinically staged disease, although MRI
is often used to characterise the primary tumour. CT of the chest, abdomen and pelvis is performed to look for metastases in the lungs, liver and
lymph nodes, and to exclude hydronephrosis and hydroureter.
Management
This depends on the stage of disease. Pre-malignant disease can be
treated with laser ablation or diathermy, whereas in microinvasive disease a large loop excision of the transformation zone (LLETZ) or a simple
hysterectomy is employed. Invasive but localised disease requires radical surgery, while cytotoxic chemotherapy and radiotherapy, including
brachytherapy, may be given as primary treatment, especially in patients
with adverse prognostic features such as bulky or locally advanced disease, or lymph node or parametrium invasion. In metastatic disease,
platinum-based cytotoxic chemotherapy may be benecial in improving
symptoms but does not increase survival signicantly.
Head and neck tumours
Head and neck cancers are typically squamous tumours that arise in
the nasopharynx, hypopharynx and larynx. They are most common in
older adult males but oropharyngeal cancers now occur with increasing
frequency in a younger cohort of patients, including in women. The rising
incidence of oropharyngeal cancers, especially in high-income countries,
is thought to be secondary to HPV infection. Presentation depends on
the location of the primary tumour and the extent of disease. For example, early laryngeal cancers may present with hoarseness, while more
extensive local disease may present with pain due to invasion of local
structures or with a lump in the neck. Patients who present late often
have pulmonary symptoms, as this is the most common site of distant
metastases (Box 7.22).
Pathogenesis
The tumours are strongly associated with a history of smoking and
excess alcohol intake, but other recognised risk factors include Epstein–
Barr virus for nasopharyngeal cancer and HPV infection for oropharyngeal tumours.
Investigations
Careful inspection of the primary site is required as part of the staging
process, and most patients will require endoscopic evaluation and examination under anaesthesia. Tissue biopsies should be taken from the most
accessible site. CT of the primary site and the thorax is the investigation of
choice for visualising the tumour, while MRI may be useful in certain cases.
Management
In general, the majority of patients with early or locally advanced disease
are treated with curative intent. In localised disease where there is no
involvement of the lymph nodes, long-term remission can be achieved in
up to 90% of patients with surgery or radiotherapy. The choice of surgery
versus radiotherapy often depends on patient preference, as surgical
treatment can be mutilating with an adverse cosmetic outcome. Patients
with lymph node involvement are treated with a combination of surgery
and radiotherapy (often with a radiosensitising agent such as cisplatin
or cetuximab), and this produces long-term remission in approximately
60%–70% of patients. Recurrent or metastatic tumours may be palli-
ated with further surgery or radiotherapy to aid local control, or systemic
cytotoxic chemotherapy or immunotherapy may be used. Second malig-
nancies are common (3% per year) following successful treatment for pri-
mary disease, and all patients should be encouraged to give up smoking
and drinking alcohol to lower their risk.
Survivorship
Advances in cancer prevention, diagnosis and treatment mean that
more people are surviving cancer. Cancer survival has doubled in the last
40years in the UK. There are an estimated 2 million people living with, or
beyond, cancer in the UK today and 50% of those diagnosed with can-
cer will survive their disease for 10 years or more. Cancer survivorship
has at least two common meanings:
completing treatment for cancer and having no signs of cancer after
nishing treatment
living with, through and beyond cancer, thus including people who
receive curative treatment and people who receive intermittent
anti-cancer treatment to control their cancer over a longer time.
Many people feel that life is never the same after a cancer diagnosis. There are often long-lasting physical, social and emotional consequences of both cancer and its treatment. These start at diagnosis and
last through rst treatment (acute survivorship), continue through and
beyond cancer treatments (extended survivorship) and can be longlasting, even when risk of cancer recurrence is low (permanent survivorship). An increasing awareness of survivorship, the impact of a cancer
diagnosis and its wide-ranging effects on patients has highlighted the
need for holistic and patient-centred care, support and services throughout and after cancer treatment.
7
7.22 Common presenting features by location in head and
neck cancer
Hypopharynx
Dysphagia
Odynophagia
Mouth and tongue
Non-healing ulcers Ipsilateral otalgia
Nasal cavity and sinuses
Discharge (bloody) or obstruction
Nasopharynx
Nasal discharge or obstruction
Conduction deafness
Atypical facial pain
Oropharynx
Dysphagia
Pain
Salivary gland
Painless swelling Facial nerve palsy
Referred otalgia
Enlarged lymph nodes
Diplopia
Hoarse voice
Horner syndrome
Otalgia
Further information
Books and journal articles
Cassidy J, Bissett D, Spence RAJ, etal. Oxford handbook of oncology, 4th edn.
Oxford: Oxford University Press; 2015.
Hanahan D, Weinberg RA. The hallmarks of cancer: perspectives for cancer
medicine. In: Kerr DJ, Haller DG, van de Velde CJH, Baumann M, eds. Oxford
textbook of oncology, 3rd edn. Oxford: Oxford University Press; 2016. Oxford
Medicine Online DOI: 10.1093/med/9780199656103.003.0001.
Tobias J, Hochhauser D. Cancer and its management, 7th edn. Chichester:
Wiley–Blackwell; 2014.
Websites
cancer.org American Cancer Society: clinical practice guidelines
ctep.cancer.gov/reporting/ctc.html Common toxicity criteria
info.cancerresearchuk.org/cancerstats/ Cancer statistics that can be sorted by
type or geographical location
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