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Therapeutics 243
dromes. For patients at high risk of bleeding, unfractionated heparin (which
requires monitoring by measurement of APPT) is more suitable than LMWH
because its effect can be terminated rapidly by stopping the infusion. Refer
to National Formulary for dosing for both unfractionated and low molecular
weight heparin.
Side effects
• Haemorrhage.
• Thrombocytopenia, which is immune mediated and does not usually
develop until after 5–14 days after first exposure; it may be complicated
by thrombosis. Platelet counts are recommended for patients receiving
heparin for more than 5 days. Heparin should be stopped immediately and
not repeated in those who develop thrombocytopenia or a 50% reduction of
platelet count.
• Hyperkalaemia due to aldosterone secretion.
• Osteoporosis after prolonged use.
Cautions/contraindications
Contraindicated with active bleeding, acquired or inherited bleeding disorders,
thrombocytopenia (platelets <75 × 109/L), recent cerebral haemorrhage,
severe liver disease, severe untreated hypertension (>230/120 mmHg),
recent surgery to eye or nervous system, history of heparin-induced thrombocytopenia, lumbar puncture/epidural within the past 4 hours or expected
within the next 12 hours, acute stroke (discuss with stroke consultant).
Oral anticoagulants
Mechanism of action
Warfarin, a coumarin, inhibits vitamin K-dependent γ-carboxylation of
coagulation factors II, VII, IX and X, thus leading to biologically inactive forms.
Monitoring is by measurement of the INR.
Indications
Prophylaxis of embolization in atrial fibrillation, cardioversion, dilated
cardiomyopathy and mechanical prosthetic aortic or mitral valve insertion;
prophylaxis and treatment of venous thrombosis and pulmonary embolism (see
Table 5.19 for specific INR targets). It takes at least 48–72 hours for warfarin’s
anticoagulant effect to develop fully. All patients starting warfarin should be
given an anticoagulant treatment booklet (advice on treatment, recording of INR
and dosing) and be advised to avoid cranberry juice (increases INR).
Preparations and dose
Warfarin. For rapid anticoagulation in venous thromboembolism, starting
dose is 10 mg on days 1 and 2 with subsequent doses adjusted according
tothe INR. A lower dose (5 mg) is used in patients >60 years, body weight
<50 kg, baseline INR >1.4 or patients taking interacting drugs which inhibit the
244 Haematological disease
metabolism of warfarin. Slow induction of warfarin (1 mg daily for a week) is used
for patients in atrial fibrillation with subsequent dosing dependent on the INR.
Maintenance dose – usually 3–9 mg daily by mouth taken at the same
time each day. Daily monitoring of the INR in the early days of treatment, then
at longer intervals depending on response.
Side effects
Skin necrosis in patients with protein C or protein S deficiency may occur
soon after starting treatment.
Haemorrhage; management is based on the INR and whether there is
major or minor bleeding:
• Major bleeding (intracranial, intraperitoneal, intraocular, muscular
compartment syndrome or life-threatening from any orifice); stop
warfarin, give phytomenadione (vitamin K1) 5 mg by slow i.v. injection,
and prothrombin complex concentrate 30–50 units/kg or FFP (15 mL/kg).
• INR >8, no bleeding or minor bleeding, stop warfarin. Give vitamin K, 500 μg
by slow i.v. injection or 5 mg by mouth if there are risk factors for bleeding.
• Any other INR > target range, stop warfarin and restart when INR <5.
Contraindications
• Underlying abnormalities of haemostasis (e.g. haemophilia,
thrombocytopenia)
• Hypersensitivity to warfarin or any of the excipients
• After an ischaemic stroke for 2–14 days, depending on the size of infarct
and blood pressure
• Surgery: stop warfarin 3 days prior to surgery if there is a risk of severe
bleeding. In most instances, warfarin can be restarted post-operatively
as soon as the patient starts oral intake. Warfarin does not need to be
stopped before tooth extraction provided INR <3.
• Severe uncontrolled hypertension
• Active peptic ulceration
• Severe liver disease
• Pregnancy: teratogenic in first trimester and risk of placental or
fetal haemorrhage in third trimester. Warfarin can be used during
breastfeeding.
Drug interactions. Many drugs interact with warfarin (check British
National Formulary for full list) and the patient’s INR should be measured
frequently whenever any drug is added to, or withdrawn from, the patient’s
therapeutic regimen. Warfarin activity is particularly increased by alcohol,
allopurinol, amiodarone, aspirin and other NSAIDs, omeprazole, ciprofloxacin,
clofibrate, co-trimoxazole, dipyridamole, macrolide antibiotics such as
clarithromycin, metronidazole, statins, tamoxifen and levothyroxine. Warfarin
activity is particularly decreased by carbamazepine, rifampicin, rifabutin,
griseofulvin and some herbal remedies, e.g. St John’s wort. Warfarin
activity may be increased or decreased by phenytoin, corticosteroids and
Therapeutics 245
colestyramine. Other drugs co-administered with warfarin increase the risk
of bleeding and should be avoided, i.e. antiplatelet drugs (p. 240), NSAIDs and
the antidepressant drugs serotonin selective reuptake inhibitors.
Direct oral anticoagulants (DOACs)
Mechanism of action
These orally active drugs directly inhibit either thrombin (e.g. dabigatran)
or factor Xa (e.g. rivaroxaban, apixaban, edoxaban). DOACs have a much
broader therapeutic window than warfarin, have fewer drug interactions
(aside from stronger inducers and inhibitors of P-glycoprotein and CYP3A4)
and offer the prospect of fixed drug dosing without the need for regular monitoring. Dose amendment is recommended with some DOACs in relation to
patient age, weight and renal/liver function. If monitoring is required, specific
drug levels must be measured as INR is not helpful.
• Edoxaban and dabigatran are preceded by parenteral anticoagulation
(such as LMWH) for 5 days. There is a straight switch from LMWH to
edoxaban or dabigatran on day 6 with no overlap.
• Apixaban and rivaroxaban do not require parenteral anticoagulation
and the DOAC is used alone from the outset, albeit at a higher initial
dose, for 7 and 21 days, respectively.
Preparations and indications
Dagibatran, apixaban, edoxaban and rivaroxaban are all licensed for prevention of stroke in non-valvular atrial fibrillation, treatment of venous
thromboembolism, prevention of thrombosis in hip and knee replacement surgery and prevention of recurrent DVT and PE. DOACs are not recommended in
antiphospholipid syndrome, due to an increased risk of recurrent thrombosis.
All require dose adjustment depending on the degree of renal impairment (see
National Formulary). None of the factor Xa inhibitors are recommended if the
creatinine clearance is less than 15 mL/min. Dabigatran should be avoided if
the creatinine clearance is below 30 mL/min and dose reductions are needed
if used in conjunction with verapamil or amiodarone. Rivaroxaban should be
taken with food (efficacy is reduced on an empty stomach).
Side effects
DOACs have higher rates of gastrointestinal haemorrhage but lower rates of
intracranial haemorrhage than warfarin. Specific antidotes are now available.
If bleeding occurs on DOACs, partial anticoagulant reversal can be achieved
using prothrombin complex concentrates. All agents have relatively short
half-lives (<14 hours) and will wear out of the circulation relatively quickly.
Contraindications
Patients with significant hepatic dysfunction or renal impairment may not be
good candidates for these drugs because of their hepatic and renal excretion.
246 Haematological disease
Fibrinolytic drugs
Mechanism of action
Fibrinolytic drugs hydrolyse a peptide bond in plasminogen to yield the active
enzyme, plasmin, which promotes clot lysis.
Indications
• Acute myocardial infarction within 12 hours of symptom onset
• Selected cases of venous thromboembolism
• Massive pulmonary embolism with hypotension
• Acute ischaemic stroke within 4.5 hours of symptom onset.
Preparations and dose
Alteplase. Acute myocardial infarction within 12 hours of symptom
onset: 15 mg by i.v. injection, followed by i.v. infusion of 50 mg (in patients
<65 kg, 0.75 mg/kg) over 30 minutes, then 35 mg (<65 kg, 0.5 mg/kg) over
60 minutes. For acute myocardial infarction, 6–12 hours within symptom
onset 10 mg by i.v. injection, followed by i.v. infusion of 50 mg over 60
minutes, then four infusions each of 10 mg over 30 minutes; maximum total
dose 1.5 mg/kg in patients <65 kg.
Massive pulmonary embolism with hypotension: 10 mg by i.v. injection
over 1–2 minutes, followed by i.v. infusion of 90 mg over 2 hours; max 1.5
mg/kg in patients <65 kg.
Acute ischaemic stroke, 900 μg/kg (max 90 mg) over 60 minutes by i.v.
infusion; initial 10% given by i.v. injection. Start as soon as possible (‘time is
brain’) and given up to 4.5 hours after symptom onset.
Side effects
The main disadvantage is the indiscriminate activation of plasminogen both
in clots and in the circulation, leading to an increased risk of haemorrhage.
Other side effects are cardiac arrhythmias during reperfusion of the myocardium, hypotension and allergic reactions (bronchospasm, urticaria) with
streptokinase.
Contraindications
Gastrointestinal or genitourinary bleeding (within the previous 21 days), aortic
dissection, severe uncontrolled hypertension (systolic blood pressure >180
mmHg, diastolic blood pressure >110 mmHg), intracranial aneurysm, recent
major trauma/surgery/head injury (within the previous 14 days) or invasive
diagnostic procedure (within the last 7–10 days), recent stroke (other
than acutely in ischaemic stroke), bleeding disorders, pregnancy or recent
obstetric delivery, INR >1.7 if on warfarin.
6
Malignant disease is common and is the second most common cause of
death after cardiovascular disease. Most tumours arise from genetic mutations within a single population of precursor stem cells and over subsequent
cell divisions there is an accumulation of further abnormalities. The genes
most commonly affected are those that control cell cycle checkpoints, DNA
repair and DNA damage recognition, apoptosis, differentiation and growth
signalling. Gene mutations may be:
• Germline: e.g. mutations in BRCA1 and BRCA2 account for most cases
of familial breast cancer. The protein product of these mutated genes is
unable to bind to the DNA repair enzyme Rad51 to make it functional in
repairing DNA breaks.
• Somatic: in response to environmental carcinogens, e.g. smoking.
Malignant disease
DIAGNOSIS OF MALIGNANCY
The diagnosis of malignancy is made by:
• Screening in an asymptomatic person with the aim of detecting cancer at
an earlier stage than symptomatic presentation and hopefully therefore
achieving a better outcome. This is undertaken by population screening or
individual screening of at-risk individuals. In the UK, population screening
programmes are established for breast, cervical and colon cancer. Individual
screening programmes are established for persons with a higher-thanaverage risk, usually because of family history, e.g. colonoscopy in persons
with a family history of colon cancer at a young age.
• Surveillance in a patient with a disease that places them at higher risk
of developing malignancy, e.g. liver ultrasound and measurement of
serum α-fetoprotein in a patient with cirrhosis with the aim of detecting
hepatocellular carcinoma at an earlier stage than symptomatic presentation.
• Investigation in a symptomatic patient. Symptoms are the result of:
• The primary tumour
• Metastases
• The coagulopathy of cancer may cause deep venous thromboses
and pulmonary emboli, particularly in association with cancers of the
pancreas, stomach and breast.
• Paraneoplastic symptoms. These are a consequence of the cancer
but are not due to the local presence of the cancer and may be
mediated by hormones or cytokines secreted by the cancer (e.g.
ectopic adrenocorticotrophic hormone [ACTH] secretion in small cell
248 Malignant disease
lung cancer) or an immune response directed against the cancer,
e.g.dermatomyositis.
• Non-specific effects such as weight loss, tiredness and lethargy.
Investigations
• To confirm the presence of malignancy in a patient with suspicious
symptoms or signs. This is by radiological imaging (with the specific
test depending on the site) and biopsy of a suspicious lesion (e.g. at
endoscopy) with histological examination and tissue tumour markers.
Serum tumour markers (Table 6.1) are intracellular proteins or cell
surface glycoproteins released into the circulation and may be present
in higher than usual concentration in patients with cancer. In many
cases they are requested inappropriately as most tumour markers are
neither sensitive nor specific for a particular malignancy and can also
be raised in benign conditions. Serum tumour markers are mainly used
in monitoring response to treatment. Biopsy is necessary to confirm the
tissue diagnosis and to inform treatment decisions.
• To stage the cancer once diagnosed. Staging the cancer will divide the
patients into groups of different prognoses, which can guide treatment
selection. The staging systems vary according to tumour type and may
be site specific (see Hodgkin’s lymphoma) or the TNM (tumour, node,
metastasis) classification which can be adapted for application to most
common cancers.
• To assess a patient’s suitability for treatment, their general state of
health (‘performance status’) needs to be considered. Performance status
is of great prognostic significance and reflects the effects of the cancer
on the patient’s functional capacity.
Table 6.1 Serum tumour markers
α-Fetoprotein
β-Human chorionic gonadotrophin
(β-hCG)
Prostate-specific antigen (PSA) Prostate cancer
Carcinoembryonic antigen (CEA) Colorectal cancer. May also be raised in
CA-125 Ovarian cancer. May also be raised in
CA19-9 Upper gastrointestinal malignancies
CA15-3 Breast cancer
Osteopontin Many cancers including mesothelioma
Hepatocellular carcinoma and
non-seminomatous germ cell tumour
of the gonads
Choriocarcinomas, germ cell tumours
(testicular) and lung cancer
other gastrointestinal malignancies
breast, cervical, endometrial and
gastrointestinal malignancies
Diagnosis of Malignancy 249
Cancer treatment
The management of patients with cancer must be coordinated by a multidisciplinary team (MDT), which may include a surgeon, oncologist, radiologist,
histopathologist, physician, specialist nurse and other allied healthcare
professionals, e.g. dietician. Discussion with patients about the treatment
plan at each step will allow them to make a fully informed choice about their
management. Not all treatment intent will be curative. In indolent disease,
treatments are focused on slowing progression or managing symptoms and
complications. Performance status or frailty scores are helpful in estimating
how well patients may tolerate a particular treatment. Potential side effects
and complications of treatment must be balanced against the likelihood of a
favourable outcome.
In some solid tumours, treatment (chemotherapy, radiotherapy or
hormone) is given after the primary treatment, e.g. surgical resection, where
dissemination is undetectable but patients are at risk of micrometastases.
This is called adjuvant therapy. Neoadjuvant therapy is given before the
primary treatment to shrink the tumour in order to improve the efficacy
of the local excision and to treat micrometastases as soon as possible. If
effective, these treatments should lead to an increased chance of cure or
overall disease-free survival.
Treatments are guided by a large volume of clinical trial evidence and
often patients can be offered enrolment into clinical trials of novel agents.
Chemotherapy
There are many chemotherapy drugs in common use. These drugs directly
damage DNA and/or RNA and kill cells by promoting apoptosis and sometimes cell necrosis. They therefore affect not only tumour cells but also the
rapidly dividing normal cells of the bone marrow, gastrointestinal tract and
germinal epithelium.
Side effects include tiredness, bone marrow suppression (leading to
anaemia, thrombocytopenia and neutropenia), mucositis (causing mouth
ulceration), hair loss (alopecia) and sterility. Side effects are much more
directly dose related than anticancer effects. To minimize side effects,
chemotherapy is given at intervals to allow some recovery of normal cell
function between cycles. Nausea and vomiting may be severe with some
drugs, such as cisplatin, and are related to the direct actions of cytotoxic
agents on the brainstem chemoreceptor trigger zone. Antiemetics such as
metoclopramide (p. 134) and domperidone (p. 134) are used initially, but the
serotonin (5-hydroxytryptamine) type 3 (5-HT3) antagonists (ondansetron and
granisetron) combined with dexamethasone are used for severe vomiting.
Chemotherapy drugs may themselves cause cancer, particularly acute
leukaemia presenting years after treatment. Some side effects are specific
to one class of drug, e.g. cardiotoxicity with the anthracyclines (such as
doxorubicin) and neurotoxicity and nephrotoxicity with cisplatin.
250 Malignant disease
Radiotherapy
Radiation induces strand breaks in DNA and apoptosis. The complications of
radiotherapy depend on the radiosensitivity of normal tissue in the path of the
radiation field. There may be damage to the skin (erythema and desquamation), gut (nausea, mucosal ulceration and diarrhoea), testes (sterility) and
bone marrow (anaemia, leucopenia). General side effects are lethargy and
loss of energy.
Endocrine therapy
This is used in the treatment of breast and prostate cancer to block the effects
of oestrogens and androgens which may act as growth factors. Tamoxifen is
a mixed agonist and antagonist of oestrogen on the oestrogen receptor and
is used as an adjuvant therapy in breast cancer and in advanced metastatic
breast disease. Aromatase inhibitors, e.g. anastrozole, letrozole and exemestane, block the conversion of androgens (synthesized by the adrenal glands)
to estrone in the subcutaneous fat of post-menopausal women. They have
greater efficacy than tamoxifen in the treatment of metastatic breast cancer
and equal efficacy in the adjuvant setting. Gonadotropin-releasing hormone
(GnRH) agonists (e.g. goserelin), which lower levels of circulating androgens,
and androgen receptor blockers (e.g. flutamide), are both used in the treatment of prostate cancer.
Biological therapy
This group includes a range of protein molecules, from small peptide chemokines and larger cytokines to complex antibody molecules, made available
by genetic engineering.
• Interferons, such as interferon alfa, have antiproliferative activity and
stimulate humoral and cell-mediated immune responses to the tumour.
• Interleukins have widespread activity in coordinating cellular activity in
many organs. Interleukin-2 is used in renal cell carcinoma and melanoma.
• Tyrosine kinase inhibitors (imatinib, sunitinib, sorafenib) have diverse
effects on cell growth, differentiation and metabolism.
• Anti-growth factor agents, e.g. bevacizumab (antivascular endothelial
growth factor receptor) and cetuximab (antiepidermal growth factor
receptor), are added to chemotherapy to improve response.
• Anti-CD20 (rituximab) inhibits CD20 on B cells, thus inhibiting the
development and differentiation of B cells into plasma cells. Anti-CD52
(alemtuzumab) inhibits CD52 expressed on T and B lymphocytes and
monocytes.
• Immune checkpoint inhibitors interfere with the relationship between
T cells and tumour cells to overcome the common problem of immune
tolerance. Ipilimumab is a monoclonal antibody used in the treatment of
melanoma. The inhibitors of the programmed death (PD-1) receptor are
used in metastatic melanoma.
Myeloablative Therapy and HSCT 251
• Proteasome inhibitors cause apoptosis in cancer cells. Bortezomib (the
first of these agents to reach clinical practice) is used in myeloma and
some types of non-Hodgkin’s lymphoma (NHL).
• Haemopoietic growth factors such as erythropoietin and granulocyte
colony-stimulating factor (G-CSF) are used to treat anaemia or to reduce
the duration of neutropenia following chemotherapy.
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
Myeloablative therapy is the term used for treatment that employs high-dose
chemotherapy or chemotherapy plus radiation, with the aim of clearing
the bone marrow completely of both benign and malignant cells. Without
bonemarrow replacement or ‘transplantation’, the patient would die of bone
marrow failure. Approaches to restore bone marrow function include the
following:
• Allogeneic bone marrow transplantation (BMT): Bone marrow or
peripheral blood stem cells from another individual, usually a human
leucocyte antigen (HLA)-identical sibling, are infused intravenously
following myeloablative therapy. Immunosuppression is required to
prevent host rejection and graft-versus-host disease (GVHD). The latter
is a syndrome in which donor T lymphocytes infiltrate the skin, gut and
liver, causing a maculopapular rash, diarrhoea and liver necrosis. This
occurs in 30%–50% of transplant recipients and is potentially fatal in
some cases. Following allogeneic BMT the blood count usually recovers
within 3–4 weeks. The mortality rate is 20%–40%, depending on the
person’s age, and is often a result of infection or GVHD.
• Autologous (the patient acts as his or her own source) stem cells: These
are collected from bone marrow or peripheral blood before myeloablative
chemotherapy and stored and reinfused afterwards. The main advantage is
the short time for blood count recovery because peripheral blood progenitor
cells are more differentiated. This technique has been particularly effective
in relapsed leukaemias, lymphomas, myeloma and germ cell tumours.
• Syngeneic: Donor cells are taken from an identical twin.
• From umbilical cord blood: This is increasingly being used for adult and
childhood leukaemia.
Oncological emergencies
These arise as a result of the tumour itself or as a complication of treatment.
Neutropenic sepsis is the most common cause of attendance in
the emergency department for any cancer patient and must be always
considered in any patient who is unwell within a month of chemotherapy.
This is discussed on page 205.
252 Malignant disease
Superior vena cava obstruction can arise from any upper mediastinal
mass but is most commonly associated with lung cancer and lymphoma.
Presentation is with difficulty breathing and/or swallowing, oedematous
facies and arms, and venous congestion in the neck with dilated veins in the
upper chest and arms. Treatment is with immediate steroids, vascular stents,
radiotherapy and chemotherapy for sensitive tumours.
Acute tumour lysis syndrome occurs as a result of treatment producing
massive and rapid breakdown of tumour cells, leading to increased serum level
of urate, potassium and phosphate with secondary hypocalcaemia. It is most
commonly seen as a complication of treatment of acute leukaemia and highgrade lymphoma unless preventative measures are taken. Hyperuricaemia and
hyperphosphataemia result in acute kidney injury through urate and calcium
phosphate deposition in the renal tubules. Prevention and treatment is with
allopurinol (p. 299), rasburicase (urate oxidase) and high fluid loads, e.g. 4–5
L daily by intravenous infusion prior to, and continuing during, chemotherapy.
Spinal cord compression (p. 755), hypercalcaemia (p. 634), pulmonary
embolus (p. 466) and raised intracranial pressure (p. 749) are discussed
elsewhere.
The leukaemias
The leukaemias are malignant neoplasms of the haemopoietic stem cells,
characterized by diffuse replacement of the bone marrow by neoplastic
cells. In most cases, the leukaemic cells spill over into the blood, where they
may be seen in large numbers. The cells may also infiltrate the liver, spleen,
lymph nodes and other tissues throughout the body. They are relatively rare
diseases with an overall incidence of 10 per 100 000 per year.
General classification. The characteristics of leukaemic cells can
be assessed by light microscopy, expression of cytosolic enzymes and
expression of surface antigens. Leukaemia can be divided into acute or
chronic on the basis of the speed of evolution of the disease. Each of these is
then further subdivided into myeloid or lymphoid, according to the cell type
involved. Myeloid disorders arise from bone marrow lineages that produce
granulocytes, red cells or platelets. Lymphoid disorders arise from either
B- or T-cell lineages:
• Acute myeloid leukaemia (AML)
• Acute lymphoblastic leukaemia (ALL)
• Chronic myeloid leukaemia (CML)
• Chronic lymphocytic leukaemia (CLL).
Aetiology
Like all cancers, haematological malignancies are caused by genetic
changes within a normal cell, leading to a clonal population. Several factors
are associated with an increased risk of such genetic change.