Tumour immunology

Tumour cells are usually not recognized and killed by the immune system. There are two main reasons. The first is failure to express molecules such as HLA and co-stimulatory B7 molecules that are required for activation of cytotoxic, or ‘killer’, T lymphocytes. Second, tumours may also actively secrete immunosuppressive cytokines and cause a generalized immunosuppression. Successful strategies for tumour vaccines that overcome these obstacles are developing in renal cancer and prostate cancer. The monoclonal antibody ipilimumab against the inhibitory cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) molecule that is expressed after T-cell activation, is used in melanoma (p. 479)

Angiogenesis

For many tumours, there is a progressive slowing of the rate of growth as the tumours become larger. This occurs for many reasons, but outgrowing the blood supply is paramount. New vessel formation (angiogenesis) is stimulated by a variety of peptides produced both by tumour cells and by host inflammatory cells, such as basic fibroblast growth factor (bFGF), angiopoietin 2 and vascular endothelial growth factors (VEGFs), which are stimulated by hypoxia. The anti-VEGF-receptor monoclonal bevacizumab has had some success in colorectal and ovarian cancer.

Invasion and metastasis

Solid cancers spread by both local invasion and by distant metastasis through the vessels of the blood and lymphatic systems. Infiltration into surrounding tissues is associated with loss of cell–cell cohesion, which is mediated by active homotypic cell adhesion molecules (CAMs). Epithelial cadherin (E-cadherin) is expressed by many carcinomas and mutated in some such as familial gastric carcinoma (see p. 252).

Invasion is also determined by the balance of activators to inhibitors of proteolysis. The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumour growth, invasion, metastasis and angiogenesis and are being targeted in new therapeutic drugs for cancer treatment.

Dissemination of tumour cells occurs through intravasation into the vascular and lymphatic vessels and dissemination to distant sites, partly by chance, but also because of specific interactions between receptors and cytokines found on stromal and tumour cells such as TNF, IL-6 and chemokines.

Bone metastasis with osteoclast and osteoblast activation.

Genetic factors

Rather than occurring by somatic mutation in response to mutagens, germline mutations in the genes that predispose to the development of cancer may be inherited and therefore present in all tissues. Examples of such cancer syndromes are given in Table 9.3. Expression of the mutation and hence carcinogenesis, will depend upon the penetrance (due to the level of expression and the presence of other genetic events) of the gene and whether the mutated allele has a dominant or recessive effect. There is a small group of autosomal dominant inherited mutations such as RB (in retinoblastoma), and a small group of recessive mutations (Table 9.3). Carriers of the recessive mutations are at risk of developing cancer if the second allele becomes mutated, leading to ‘loss of heterozygosity’ within the tumour, although this is seldom sufficient as carcinogenesis is a multistep process.

Table 9.3 Familial cancer syndromes

Environmental factors

A wide range of environmental factors have been identified as being associated with the development of malignancy (Table 9.4) and may be amenable to preventative action such as smoking cessation, dietary modification and antiviral immunization (Box 9.1). Environmental factors interact with genetic predisposition. For example, subsequent generations of people moving from countries with a low incidence to those with a high incidence of breast or colon cancer acquire the cancer incidence of the country to which they have moved while northern European people exposed to strong UV radiation have the highest risk of developing melanoma.

Table 9.4 Some causative factors associated with the development of cancer

Geographical distribution

The incidence of cancer across the world is dependent on the local environmental factors, the diet and the genetics of the population (see above) (Figs 9.3, 9.4). Age is also a factor as most cancers occur in those over the age of 65 who comprise 3.3% of the population in Africa compared with 15.2% in Europe. Reproductive patterns also influence breast cancer. Migrating individuals often take on the risks of the local environmental factors.

Figure 9.3 The most common causes of death from cancer worldwide, excluding non-melanoma skin cancers (NMSC) 2002 estimates.

(From: http://info.canceresearchuk.org/cancerstats/world/the-global-picture/)

Figure 9.4 Percentage of all deaths due to cancer in the different regions of the world.

(From: http://info.canceresearchuk.org/cancerstats/world/the-global-picture/)

Other factors

Incidence and mortality are closely linked for cancers for which treatment has yet to make significant improvements such as lung, stomach and liver, while in countries with effective screening programmes, there is an increasing incidence and decreasing mortality for breast, cervix, bowel and prostate cancers.

Asymptomatic detection through screening

Most common cancers start as focal microscopic clones of transformed cells and diagnosis only becomes likely once sufficient tumour bulk has accumulated to cause symptoms or signs. In order to try to make an earlier diagnosis and increase the curative possibilities, an increasing number of screening programmes are being developed which target the asymptomatic or preinvasive stages of the cancer as in cervix, breast and colon or use serum tumour markers as in prostate and ovarian cancers. Genetic screening can be used to target screening to groups at most risk of developing cancer, e.g. BRCA1 positive and breast cancer (see Table 9.3). The aim of screening programmes is to improve individual and/or population survival by detecting cancer at its very early stages when the patient is asymptomatic. This strategy is dependent upon finding tests that are sufficiently sensitive and specific, using detection methods that identify cancer before it has spread and having curative treatments that are practical and consistent with maintenance of a normal lifestyle and quality of life.

Screening is provided to populations, e.g. for breast, cervical and colon cancer in the UK, and also to individuals via annual check-ups, or opportunistic when patients see their doctor for other reasons.

Unfortunately, earlier diagnosis does not necessarily mean longer survival and randomized trials are necessary to prove benefit. With lead time bias, the patient is merely treated at an earlier date and hence the survival appears longer; death still occurs at the same time from the point of genesis of the cancer (Fig. 9.5). With length time bias, a greater number of slowly growing tumours are detected when screening asymptomatic individuals leading to a false impression of an improvement in survival.

Figure 9.5 Lead time bias. Earlier diagnosis, at X, made by screening tests before the clinical diagnosis, at Y, suggests an increased survival time of A + B. The actual survival time (C) remains unchanged.

An effective screening procedure should:

Cervical cancer. The smear test is cheap and safe but requires a well-trained cytologist to identify the early changes (dyskaryosis and cervical intraepithelial neoplasia, CIN). However, developments in liquid cytology and DNA testing for human papillomavirus (HPV) may overcome this. Effective treatment for high-risk preinvasive malignant changes reduces the incidence and mortality from cervical cancer, although there are no randomized trials. Screening will continue to be required despite the introduction of vaccination against HPV infection for women before they become sexually active because the lag time between infection and the appearance of disease can be in the order of 40–50 years.

Breast cancer. The UK NHS Breast Screening Programme (i.e. biplanar mammography every 3 years) for women aged 50–70 years has been shown to reduce mortality from breast cancer in randomized controlled studies. The test is acceptable to most women with 50–75% of women attending for screening when sufficiently educated about the benefits. In North America, there is continuing debate about whether annual mammography from a younger age is more effective.

The cost is estimated to be between £250 000 and £1.3 million per life saved, money which, according to critics of screening, could be used more appropriately in better treatment.

Women from families with BRCA1, BRCA2 and p53 mutations require intensive screening starting at an earlier age when mammography is inaccurate due to greater breast density and MRI scanning is preferred.

Colorectal cancer (CRC). Faecal occult blood is a cheap test for the detection of CRC. Large randomized studies have shown a reduction in cancer-related mortality of 15–33%. However, the false-positive rates are high, meaning many unnecessary colonoscopies (see p. 291). The UK has recently introduced a national screening programme using faecal occult blood in patients aged 60–64 years, in which positive tests have identified that 10% have cancer and 40% adenomas. A randomized trial in Norway has found an increased number of early stage cancers in the screened population but a high incidence of interval cancers between biennial screens.

Colonoscopy is the ‘gold-standard’ technique for the examination of the colon and rectum and is the investigation of choice for high-risk patients. Universal screening strategies have been recommended in the USA, but the shortage of skilled endoscopists, the expense, the need for full bowel preparation and the small risk of perforation make colonoscopy impractical as a population screening tool at present and CT colonography (‘virtual colonoscopy’) (see Fig. 6.5) may become an alternative along with genetic testing and stool DNA tests.

Other population-based screening programmes that are being used or are in trials are:

Prostate cancer. Serum prostate-specific antigen (PSA) can be used for the detection of this cancer, which is on the increase. Many men over 70 have evidence of prostate cancer at post mortem with no symptoms of the disease and it has been suggested that over 75-year-olds should not have screening PSAs. The test must be interpreted with caution due to the natural increase in PSA with age, benign prostatic hypertrophy and with prostatitis. The early results of screening for prostate cancer have varied greatly from no benefit in a low-risk population to a halving of deaths from prostate cancer in a general population study but with no overall reduction in mortality. Currently national screening programmes are not recommended.

Epithelial ovarian cancer. Serum CA125 can be used for the early detection of this cancer and is the subject of ongoing trials. An improvement in survival of a screened population can be shown but at the cost of many unnecessary laparotomies so that further enhancements are being investigated by serial testing and in combination with transvaginal ultrasound scans.

The symptomatic patient with cancer

Patients may offer information of predisposing conditions and family history that alerts the clinician to the likelihood of a cancer diagnosis. Many present with a history of tumour site-specific symptoms, e.g. pain, and physical signs, e.g. a mass, which readily identify the primary site of the cancer. However, some only seek medical attention when more systemic and nonspecific symptoms occur such as weight loss, night sweats, fever, fatigue, recurrent infections and anorexia. These usually indicate a more advanced stage of the disease, except in some paraneoplastic and ectopic endocrine syndromes (see below). Other patients are only diagnosed upon the discovery of established metastases such as the abdominal distension of ovarian cancer, the back pain of metastatic prostatic cancer or the liver enlargement of metastatic gastrointestinal cancer (Table 9.6).

Table 9.6 Symptoms and signs of malignant disease

Paraneoplastic syndromes are indirect effects of cancer (Box 9.2, Fig. 9.6) that are often associated with specific types of cancer and may be reversible with treatment of the cancer. The effects and mechanisms can be very variable. For example in the Lambert–Eaton syndrome (see p. 1152), there is cross-reactivity between tumour antigens and the normal tissues, e.g. the acetylcholine receptors at neuromuscular junctions.

Figure 9.6 Paraneoplastic peripheral neuropathy with wasting of small muscles of the hands.

The coagulopathy of cancer may present with thrombophlebitis, deep venous thrombosis and pulmonary emboli, particularly in association with cancers of pancreas, stomach and breast. Some 18% of patients with recurrent pulmonary embolus will be found to have an underlying cancer and many cancer patients are at increased risk of venous thromboembolism (VTE) following diagnosis. Trousseau’s syndrome – superficial thrombophlebitis migrans – refers to this process in the superficial venous system. All patients with active cancer admitted to hospital are at high risk of VTE and should be given prophylaxis with subcutaneous LMW heparin in the absence of any contraindications (see p. 429). Dabigatran, an oral direct thrombin inhibitor, is an alternative therapy.

Other symptoms are related to peptide or hormone release, e.g. carcinoid or Cushing’s syndrome.

Cachexia of advanced cancer is thought to be due to release of chemokines such as tumour necrosis factor (TNF), as well as the fact that patients have a loss of appetite. The unexplained loss of >10% of body weight in a patient should always stimulate a search for an explanation.

Cancer-associated immunosuppression can lead to reactivation of latent infections such as herpes zoster and tuberculosis.

Reactivated herpes zoster (Shingles).

Aims of treatment

Optimal cancer treatment is delivered by a multidisciplinary team which coordinates the delivery of the appropriate anticancer treatment (surgery, chemotherapy, radiotherapy and biological/endocrine therapy), supportive and symptomatic care and psychosocial support. While all members will have the patient’s care as their central concern, someone, often the oncologist, has to take responsibility for the coordination of the many professionals involved.

The organization across multiple departments and coordination from primary to secondary and tertiary care has become known as a patient pathway. Establishment of agreed patient pathways has enabled more effective and timely delivery of care and post-treatment rehabilitation. The aim is to provide optimal treatment and for the patient to experience seamless and high quality care and to allow audit and continuing improvement against agreed standards. Central to this endeavour is the involvement of the patient, through education as to the nature of their disease and the treatment options available. An informed choice can then be made, even if in the end it is simply to abide by the decisions made by the professionals. Good communication embodies a humane approach which preserves hope at an appropriate level through empathy and understanding of the patient’s position (see p. 14).

A curative approach

For most solid tumours local control is necessary, but not sufficient, for cure because of the presence of systemic (microscopic) disease, while haematological cancers are usually disseminated from the outset. Improvement in the rate of cure of most cancers is thus dependent upon earlier detection to increase the success of local treatment and effective systemic treatment. The likelihood of cure of the systemic disease depends upon the type of cancer and its expression of appropriate treatment targets, its drug sensitivity and tumour bulk (microscopic or clinically detectable). A few rare cancers are so chemosensitive that even bulky metastases can be cured, e.g. leukaemia, lymphoma, gonadal germ cell tumours and choriocarcinoma. For most common solid tumours such as lung, breast and colorectal cancer, there is no current cure of bulky (clinically detectable) metastases, but micrometastatic disease treated by adjuvant systemic therapy (see below) after surgery can be cured in 10–20% of patients.

A palliative approach

When cure is no longer possible, palliation, i.e. relief of tumour symptoms, preservation of quality of life and prolongation of life, is possible in many cancers in proportion to their drug and radiation sensitivity. There is on average a 2–18-month prolongation in median life expectancy with treatments for solid tumours (see specific tumour types for details) and up to 5–8 years for some leukaemias and lymphomas, with those with the most responsive tumours experiencing the greatest benefit. The development of more effective chemotherapeutic drugs, targeted biological agents and better supportive care has done much to reduce the side-effects of systemic therapy and to improve the cost/benefit ratio for the patient receiving palliative treatment. In addition, through early assessment during treatment, it is possible to stop if no evidence of benefit is demonstrable early on, so as to minimize exposure to toxic and unsuccessful treatment.

Assessments before treatment

Assessing the benefits of treatment

A measurable response to treatment can serve as a useful early surrogate marker when assessing whether to continue a given treatment for an individual patient. Trials to assess response to treatment in advanced disease have identified active agents for use in the more curative setting of adjuvant treatment of early stage disease

Response to treatment can be subjective or objective.

A subjective response is one perceived by the patient in terms of, for example, relief of pain and dyspnoea, or improvement in appetite, weight gain or energy. Such subjective response is a major aim of most palliative treatments. Quantitative measurements of these subjective symptoms (Patient Reported Outcome Measures, PROMs) form a part of the assessment of response to chemotherapy, especially in those situations where cure is not possible and where the aim of treatment is to provide prolongation of good-quality life. In these circumstances, measures of quality of life enable an estimate of the balance of benefit and side-effects to be made.

Chemotherapy radiological response. Bone metastasis responding to chemotherapy with sclerotic new bone formation. (a) Tumour (arrow). (b) Following radiotherapy.

An objective response to treatment is assessed clinically and radiologically. The term ‘remission’ is often used synonymously with ‘response’, which if complete, means an absence of detectable disease without necessarily implying a cure of the cancer. The terms used to evaluate the responses of tumours are given in Box 9.3. For a complete response all previous clinical abnormalities should have resolved and this needs to be confirmed by clinical examination or sampling of the primary disease site, e.g. by bone marrow examination in leukaemia. Where a tumour marker exists, such as a paraprotein in myeloma or β-hCG in testicular cancer, reductions in the level of tumour markers are useful surrogates for evidence of tumour response. They are also useful predictors for disease recurrence. Radiologically, a complete response, is the complete disappearance of all detectable disease and a partial response, defined since 1999 by the Response Evaluation Criteria in Solid Tumors (RECIST) convention, is a ≥30% reduction in the sum of all measurable lesion diameters.

The final assessment of treatment outcome is the impact of the therapy on remission duration and survival, i.e. the cure rate. Such survival figures are increasingly incorporating quality of life assessments and a health economic assessment to calculate the number of quality adjusted life years (QALY) gained for the cost of the treatment and judgements made about health system affordability.

When counselling, the individual patient’s interpretation of the trial evidence for benefit must be adjusted for the degree to which they resemble the population from which it is derived and the cost interpreted in view of their co-morbidities and lifestyle choices.

Classification of cytotoxic drugs (Table 9.9)

Side-effects of chemotherapy

Chemotherapy carries many potentially serious side-effects and should be used only by trained practitioners; however, an appreciation of its common potential side-effects is necessary for any general physician who is called to see a cancer patient on chemotherapy. The five most common side-effects are vomiting, hair loss, tiredness, myelosuppression and mucositis (Table 9.10). Side-effects are much more directly dose related than anticancer effects and it has been the practice to give drugs at doses close to their maximum tolerated dose, although this is not always necessary to achieve their maximum anticancer effect. Common combination chemotherapeutic regimens are shown in Table 9.11.

Table 9.10 Side-effects of chemotherapy

Table 9.11 Some common chemotherapy regimens

Note: Some abbreviations are related to trade names.

Extravasation of intravenous drugs. Cytotoxic drugs should only be given by trained personnel. They cause severe local tissue necrosis if leakage occurs outside the vein. Stop the infusion immediately and institute local measures, e.g. aspirate as much of the drug from the cannula, infiltrate area with 0.9% saline and apply warm compresses. Antihistamines and corticosteroids may give symptomatic relief. Dexrazoxane is used for anthracycline extravasation.

Nausea and vomiting. The severity of this common side-effect varies with the cytotoxic and it can be eliminated in 75% of patients by using modern antiemetics. Nausea and vomiting are particular problems with platinum analogues. A stepped policy with antiemetics such as metoclopramide and domperidone followed by 5-HT₃ serotonin antagonists (e.g. ondansetron, granisetron) combined with dexamethasone should be used to match the emetogenic potential of the chemotherapy. Aprepitant, a neurokinin receptor antagonist, is helpful in preventing acute and delayed nausea and vomiting. It is used with dexamethasone and a 5-HT₃ antagonist. Drugs such as cyclizine, haloperidol and levomepromazine and benzodiazepines can be used to control persistent nausea.

Hair, skin and nails. Many but not all cytotoxic drugs are capable of causing hair loss. Scalp cooling can sometimes be used to reduce hair loss but in general this side-effect can only be avoided by selection of drugs where this is possible. Hair regrows on completion of chemotherapy. Nails will demonstrate banding reflecting periods of cessation of growth during each chemotherapy cycle and skin toxicity may be particularly pronounced with 5FU, capecitabine and docetaxel (Fig. 9.9).

Figure 9.9 Hands showing palmar–plantar skin toxicity.

Nail growth cessation with each drug cycle (Beau’s lines).

Fatigue is often significant and may continue beyond completion of therapy. Other problems such as anaemia or depression may exacerbate this. Attention should be paid to nutrition, hydration, sleep hygiene, gentle exercise, task prioritization, pacing, realistic target setting and scheduling rest within the day.

Bone marrow suppression and immunosuppression. Suppression of the production of red blood cells, white blood cells and platelets occurs with most cytotoxic drugs and is a dose-related phenomenon (Fig. 9.10). Severely myelosuppressive chemotherapy may be required if treatment is to be given with curative intent despite the potential for rare but fatal infection or bleeding. Anaemia and thrombocytopenia are managed by red cell or platelet transfusions. (Neutropenic infection is discussed on p. 448.) The risk of infective problems can be ameliorated by the use of prophylactic antimicrobials, such as ciprofloxacin, or the use of GCSF as primary prophylaxis in those chemotherapy regimens with a significant risk of febrile neutropenia or those patients on less intensive therapies who are at higher risk due to age or co-morbidity.

Figure 9.10 Cyclical myelosuppression from chemotherapy (arrows).

Mucositis. This common side-effect of chemotherapy reflects the sensitivity of the mucosa to antimitotic agents. It causes severe pain in the oropharyngeal region and problems with swallowing and nutrition. Mucositis can be generalized throughout the intestinal tract when it can cause life-threatening diarrhoea. Treatment is with antiseptic and anti-candidal mouthwash and, if severe, fluid and antibiotic support, as the mucosa is a portal for entry of enteric organisms. Palifermin, a recombinant keratinocyte derived growth factor, may ameliorate severe chemotherapy and radiotherapy induced mucositis.

Other toxicities

Cardiotoxicity. This is a rare side-effect of chemotherapy, usually associated with anthracyclines such as doxorubicin, and can present as an acute arrhythmia during administration or cardiac failure due to cardiomyopathy after chronic exposure. This effect is dose-related and can largely be prevented by restricting the cumulative total dose of anthracyclines within the safe range (equivalent to 450 mg/m² body surface area cumulative doxorubicin dose). The risk of anthracycline cardiomyopathy is also dependent on other treatments such as trastuzumab or radiotherapy as well as other cardiac risk factors such as hypertension, smoking and hypercholesterolaemia. Cardiotoxicity can also be reduced by using the analogue epirubicin or by reducing peak drug concentrations through delayed release preparations such as liposomal doxorubicin. 5-Fluorouracil and its prodrug capecitabine can cause cardiac ischaemia.

Anthracycline dilated cardiomyopathy with congestive heart failure.

Neurotoxicity. This occurs predominantly with the vinca alkaloids, taxanes and platinum analogues (but not carboplatin). It is dose-related and cumulative. Chemotherapy is usually stopped before the development of a significant polyneuropathy, which once established is only partially reversible. Vinca alkaloids such as vincristine must never be given intrathecally as the neurological damage is progressive and fatal.

Nephrotoxicity. Cisplatin (but not oxaliplatin or carboplatin), methotrexate and ifosfamide can potentially cause renal damage. This can usually be prevented by maintaining an adequate diuresis during treatment to reduce drug concentration in the renal tubules and careful monitoring of renal function.

Sterility and premature menopause. Some anticancer drugs, particularly alkylating agents, but also anthracyclines and docetaxel, may cause gonadal damage resulting in sterility and in women the loss of ovarian oestrogen production, which may be irreversible.

In males, the storage of sperm prior to chemotherapy should be offered to the patient when chemotherapy is given with curative intent.

In females, collection of oocytes to be fertilized in vitro and cryopreserved as embryos for subsequent implantation is most successful; however it is also possible to collect and freeze by vitrification of unstimulated oocytes. Cryopreservation of ovarian tissue and retrieval of viable oocytes for subsequent fertilization is still experimental. The recovery of gonadal function is dependent upon the status before treatment and in women this is mostly related to age since menarche, with those under the age of 40 having significantly more ovarian reserve.

Secondary malignancies. Anticancer drugs have mutagenic potential and the development of secondary malignancies, predominantly acute leukaemia, is an uncommon but particularly unwelcome long-term side-effect in patients otherwise cured of their primary malignancies. The alkylating agents, anthracyclines and epipodophyllotoxins are particularly implicated in this complication.

Haemopoietic stem cell transplantation (HSCT)

HSCT is used in a range of malignancies and some non-malignant disorders such as sickle cell disease. It relies on the ability of transfused haemopoietic stem cells to repopulate the marrow niche that has been rendered temporarily or permanently hypoplastic from chemotherapy with or without additional radiotherapy. Such procedures vary in the source of the stem cells and in the type and intensity of the preparatory conditioning regimen (Box 9.4).

Biological therapies

Targeted therapies

Theoretical background

Radiation delivers energy to tissues, causing ionization and excitation of atoms and molecules. The biological effect is exerted through the generation of single- and double-strand DNA breaks, inducing apoptosis of cells as they progress through the cell cycle and through the generation of short-lived free radicals, particularly from oxygen, which damage proteins and membranes. The generation of free radicals depends upon the degree of oxygenation/hypoxia in the target tissues. This can affect the biological effect by up to threefold and is the subject of continuing research for hypoxic cell sensitizers to overcome the reduced efficacy of radiation for hypoxic tumours. Hypoxia, however, may also drive a more malignant potential further, so reduced efficacy is only part of the solution to the hypoxia problem.

The radiation effect will also depend upon the intensity of the radiation source, measured as the linear energy transfer or frequency of ionizing events per unit of path, which is subject to the inverse square law as the energy diminishes with the distance from the source. The depth of penetration of biological tissues by the photons depends upon the energy of the beam. Low-energy photons from an 85 kV source are suitable for superficial treatments, while high-energy 35 MV sources produce a beam with deeper penetration, less dose at the initial skin boundary (skin sparing), sharper edges and less absorption by bone. Superficial radiation may be also delivered by electron beams from a linear accelerator that has had the target electrode that generates the X-rays removed.

The radiation dose is measured in Gray (Gy), where 1 Gray = 1 joule (J) absorbed per kilogram of absorbing tissue. The biological effect is dependent upon the dose rate, duration, volume irradiated and the tissue sensitivity. Sensitivity to photon damage is greatest during the G2–M phase of the cell cycle and is also dependent upon the DNA repair capacity of the cell.

Types of radiation therapy

External beam (or teletherapy) from a linear accelerator source produces X-rays. The energy is transmitted as photons and is the most commonly used form of radiotherapy. Cobalt-60 generators can also provide γ-rays and high-energy photons, but are being gradually phased out. Most external beam treatments that are given with curative intent are delivered in 1.5–2 Gy fractions daily for 5 days per week.

Fractionation is the delivery of the radiation dose in increments separated by at least 4–6 hours to try to exploit any advantage in DNA repair between normal and malignant cells.

Hyperfractionation is when more than one fraction per day is given and this approach has been shown to improve outcome in head and neck and lung cancer. The treatment can also be accelerated, i.e. the total dose is given in a shorter overall time. For example a standard curative treatment taking 6.5 weeks can be accelerated so that the same dose is delivered in 5.5 weeks. Radiation dose is thus described by three factors:

Brachytherapy is the use of radiation sources in close contact with the tissue to provide intense exposure over a short distance to a restricted volume. Such techniques have been used to treat localized breast, prostatic and cervical carcinoma.

Systemic radionuclides, e.g. iodine-131, or radioisotope-labelled monoclonal antibodies (e.g. anti-CD20 for lymphoma) and hormones (e.g. somatostatin for carcinoid tumours), can be administered by intravenous or intracavitary routes to provide radiation targeted to particular tissue uptake via surface antigens or receptors.

Clinical application of radiation therapy

Radiotherapy treatment planning involves both detailed physics of the applied dose and knowledge of the biology of the cancer and whether the intention is to treat the tumour site alone, or include the likely loco-regional patterns of spread. Normal tissue tolerance will determine the extent of the side-effects and therefore the total achievable dose. A balanced decision is made according to the curative or palliative intent of the treatment and the likely early or late side-effects.

The cancers for which radiotherapy is usually employed in a primary curative approach, when the tumour is anatomically localized, are listed in Table 9.13, along with those in which radiotherapy has curative potential when used in addition to surgery (adjuvant radiotherapy). Palliative treatments are frequently used to provide relief of symptoms to improve quality if not duration of survival (Box 9.5). Palliative treatment is usually given in as few fractions as possible over as short a time as possible. Radiotherapy planning, by the use of CT scanning guidance, has been complemented by the introduction of 3-dimensional planning and intensity modulated radiotherapy (IMRT) which can deliver curved dose distributions to enable an improved therapeutic ratio. This allows a greater differential in dose between the tumour and critical normal structures, in turn allowing dose escalation or a reduced risk of toxicity. 4D radiotherapy planning is also becoming widely used varying radiation dose over time, e.g. the respiratory cycle during lung cancer treatment. Stereotactic focused irradiation using the γ-knife or Cyberknife can concentrate gamma radiation from multiple sources onto a small volume to generate an ablative dose for treating tumours of the CNS and isolated metastases.

Table 9.13 Curative radiotherapy treatment

Combination chemoradiotherapy

The local efficacy of radiotherapy can be increased by the simultaneous but not serial addition of chemotherapy with agents such as cisplatin, mitomycin and 5FU for cancers of the head and neck, lung, oesophagus, stomach, rectum, anus and cervix. Reduced local recurrence rates have translated into survival benefits and further research is investigating the concurrent use of biological agents (e.g. epidermal growth factor receptor inhibitors) with radiation.

Side-effects of radiotherapy

Early radiotherapy side-effects may occur within days to weeks of treatment when they are usually self-limiting but associated with general systemic disturbance (Table 9.14). The side-effects will depend upon tissue sensitivity, fraction size and treatment volume and are managed with supportive measures until normal tissue repair occurs. The toxicity may also be enhanced by exposure to other radiation-sensitizing agents, especially some cytotoxics, e.g. bleomycin, actinomycin, anthracyclines, cisplatin and 5-fluorouracil.

Table 9.14 Side-effects of radiotherapy

Later side-effects occur from months to years later, unrelated to the severity of the acute effects because of their different mechanism. Late effects reflect both the loss of slowly proliferating cells and a local endarteritis which produces ischaemia and proliferative fibrosis. The risks of late side-effects are related to the fraction size and total dose delivered to the tissue.

Growth may be arrested if bony epiphyses are not yet fused and are irradiated, leading to distorted skeletal growth in later life.

Secondary malignancies following radiotherapy may appear 10–20 years after the cure of the primary cancer. Haematological malignancies tend to occur sooner than solid tumours from the irradiated tissues. The latter are very dependent upon the status of the tissue at the time of treatment, e.g. the pubertal breast is up to 300 times more sensitive to malignant transformation than the breast tissues of a woman in her thirties. Patients who smoke are more liable to develop lung cancer. Treatment of these secondary cancers can be successful providing there is normal bone marrow to reconstitute the haemopoietic system or the whole tissue at risk can be resected (e.g. thyroid after mantle radiotherapy for lymphoma).

Aetiology

In the majority of patients, this is unknown but several factors have been associated:

Clinical features

The majority of patients with acute leukaemia, regardless of subtype, present with symptoms reflecting inadequate haematopoiesis secondary to infiltration of the bone marrow by leukaemic cells, symptoms due to tissue infiltration by leukaemic cells, the consequences of a high WBC or substance release from the tumour cells (Table 9.18).

Table 9.18 Symptoms and signs of leukaemia

Investigations

Confirmation of diagnosis (Fig. 9.13)

Blood count. Hb low, WBC raised usually (sometimes low), platelets low.

Blood film. Blast cells almost invariably seen (Fig. 9.13a), lineage may be identified morphologically, e.g. presence of Auer rods is consistent with a diagnosis of AML (Box 9.7).

Bone marrow aspirate. Increased cellularity, reduced erythropoiesis, reduced megakaryocytes. Replacement by blast cells >20% (often approaching 100%) (Fig. 9.13b). Lineage confirmation by immunophenotyping, e.g. AML – CD33 or CD13, B lineage ALL – CD10 and CD19 and T lineage – CD3. Cytogenetic FISH analysis in real-time PCR and molecular genetics for prognostication.

Chest X-ray. Mediastinal widening often present in T lymphoblastic leukaemia.

Cerebrospinal fluid examination. Performed in all patients with ALL, as the risk of CNS involvement is high. It is less critical in AML.

Coagulation profile to exclude presence of DIC (raised PT, APTT, reduced fibrinogen, increased fibrinogen degradation products, e.g. D-dimers).

Figure 9.13 Acute leukaemia. (a) Peripheral blood film showing characteristic blast cells. The arrow points to the abnormal blast cell. (b) Bone marrow aspirate showing particle with increased cellularity.

(Courtesy of Dr Manzoor Mangi.)

 Box 9.7

Characteristics of blast cells

A blast is an immature precursor of myeloid cells (myeloblasts) or lymphoid cells (lymphoblast)

Bigger than normal counterpart

Immature nucleus (nucleolus, open chromatin)

Cytoplasmic appearances often atypical

Rarely ever seen in normal individuals

If present, are highly suggestive of an acute leukaemia or a chronic disorder that is beginning to transform into an acute disease, e.g. transformed MPN, MDS-RAEB, CML blast crisis.

For planning therapy

Biochemistry, serum urate, renal and liver biochemistry.

Cardiac function; ECG and direct tests of left ventricular function, e.g. echocardiogram (see p. 685).

Principles of management

Untreated acute leukaemia is invariably fatal, most often within a few months, though with judicious palliative care, it may be extended to perhaps a year. Treatment with curative intent may be successful, or may fail, either because the leukaemia does not respond (i.e. refractory to treatment), because the disease returns after an initial favourable response (relapse) or because the patient succumbs to complications of the therapy (treatment-related mortality). At initial presentation, acute leukaemias range from being probably curable (e.g. childhood ‘good risk’ ALL) through to probably incurable (e.g. AML with adverse cytogenetic features in the elderly). Since curative treatment carries considerable morbidity and potential mortality, it is essential that the ‘risk/benefit’ ratio is clearly understood by physician and patient alike.

Palliative therapy

Every attempt should be made to ensure that the patients are at home as much as possible, while making available the full range of supportive care. Palliation may well include both low-dose chemotherapy and irradiation in addition to blood product support and antimicrobials.

Curative therapy

The decision to treat with curative intent, particularly if successful, implies severe disruption of normality for the patient and family for at least 6 months and often up to a year. In the short term, it may demand transfer to another hospital, as acute leukaemia should only be treated in units seeing at least 10 such cases per year. It is highly likely to involve admission to hospital for up to a month in the first instance, with further, partly predictable, subsequent admissions of several days’ to weeks’ duration, requiring discussions and decisions about work or education.

The decision to treat with curative intent implies that cure is possible and that the chance of cure justifies the risks of the therapy. It does not imply that cure is guaranteed or even expected. The failure rate may be high and the patient must know that he or she will be told if cure becomes an unrealistic goal.

Active therapy

Supportive care

This forms the basis of treatment whether for cure or palliation:

Avoidance of symptoms of anaemia (haemoglobin >80–100 g/L) – repeated transfusion of packed red cells (sometimes irradiation of cells is required)

Prevention or control of bleeding (platelet count <10 × 10⁹/L in the stable and <20 × 10⁹/L in the septic patient or <50 if a procedure is planned, e.g. a lumbar puncture). Coagulation abnormalities should be corrected with FFP to keep APTR/INR <1.5 × normal and with cryoprecipitate to keep the fibrinogen level >1.5 g/dL. Norethisterone is given to women of menstrual age to avoid menorrhagia during their thrombocytopenic phase.

Leucopheresis may be required to reduce the white cell count rapidly before the chemotherapy has started to be effective.

Treatment of infection (see Box 9.6):

– Prophylactically. Education of patients, relatives and staff about hand washing and isolation facilities. Selected antibiotics, antifungals, antivirals and Pneumocystis jiroveci prophylaxis may be required.

– Therapeutically. Management of fever with protocol/algorithm of antibiotic and antifungal combinations.

Control of hyperuricaemia with hydration, prophylactic allopurinol and occasionally rasburicase (see p. 479).

Indwelling venous devices, e.g. Hickman line, are required to allow easy access to the blood for tests and administration of therapy. Sperm banking is offered to postpubertal men and oocyte collection to women, if there is time before treatment.

Specific treatment

The initial requirement of therapy is to return the peripheral blood and bone marrow to normal (complete remission; CR). This ‘induction chemotherapy’ is tailored to the particular leukaemia and the individual patient’s risk factors. Since this treatment is not leukaemia specific but also impairs normal bone marrow function, it leads to a major risk of life-threatening infection, which increases the risk of early death in the short term.

Successful remission induction is always followed by further treatment (consolidation). The details of this are determined by the type of leukaemia, the patient’s risk factors and the patient’s tolerance of treatment. Recurrence is almost invariable if ‘consolidation’ therapy is not given. This reflects the lack of sensitivity of the definition of ‘complete remission’, which has been solely morphological. Cytogenetics and molecular genetic techniques can however identify residual leukaemic cells not detected morphologically and they are highly predictive of recurrence. Recommendations have recently been made to modify the definition of remission to reflect this. Failure to achieve morphological CR with two cycles of therapy (‘refractory’) carries almost as bad a prognosis as the untreated leukaemia. If CR can be achieved, e.g. by new experimental approaches, cure may still be possible with stem cell transplantation (see p. 444). A small proportion of patients with refractory disease may also be cured by a myeloablative allograft.

Acute myeloid leukaemia (AML)

In AML, the prognosis is dependent on a range of key variables, the two main ones being age and cytogenetics (Fig. 9.14; Table 9.19).

Figure 9.14 Prognosis related to cytogenetics and molecular data in AML Outcome of younger adults with AML treated in the MRC AML10 and AML12 trials stratified according to cytogenetic and molecular abnormalities.

(Reproduced with permission from Smith ML, Hills RK, Grimwade D. Independent prognostic variables in acute myeloid leukaemia. Blood Reviews 2011; 25(1):39–51.)

Table 9.19 AML risk factors

Good risk	Poor risk
De novo disease Favourable cytogenetics t(15; 17) t(8; 21) or inv(16) or its variant t(16; 16) CEBPA biallelic mutation NPM1 mutation with FLT3 wild type

Age >60

Male

Secondary disease, e.g. prior MDS or MPN

High WBC

Adverse cytogenetics: -5, del(5q), -7, abnormal 3q26 or a complex karyotype

FLT3 internal tandem duplication mutation

MRD positivity

Treatment with curative intent is undertaken in the majority of adults below the age of 60 years, provided there is no significant co-morbidity. Treatment success reflects the cytogenetic pattern. Those at ‘low risk’ are treated with moderately intensive combination chemotherapy. This always includes an anthracycline such as daunorubicin and cytosine arabinoside (cytarabine) and consolidation with a minimum of four cycles of treatment given at 3–4-week intervals. Patients with low-risk disease do not benefit from allogeneic stem cell transplantation during their first complete remission because the risks outweigh benefits. Those at ‘intermediate risk’ are a heterogeneous group. When possible, they should be given consolidation chemotherapy after an initial remission has been achieved followed by allogeneic transplantation only in those who are deemed at increased risk of relapse because of other risk factors, e.g. mutational data. Patients with high-risk disease should proceed to a stem cell transplant in CR1 because they respond poorly to conventional chemotherapy and have a high risk of relapse.

Complete remission (CR) will be achieved in about 80% of patients under the age of 60. Failure is due to either resistant leukaemia (10%) or death due to infection or bleeding (10%). Approximately 50% of those entering complete remission will be cured (i.e. approximately 40% overall) although this varies from 60–70% in the favourable cytogenetic group to 10–20% in the adverse cytogenetic group.

The initial treatment of the older patient is much more contentious. Older patients tolerate cytotoxic therapy less well than younger patients due to co-morbidities and their disease is often more aggressive in its biology, e.g. adverse cytogenetics are more common with increasing age. Reduced intensity allogeneic transplantation is increasingly being used for this group but is limited by the toxicity of this treatment.

The management of recurrence is undertaken on an individual basis, since the overall prognosis is very poor despite the fact that second remissions may be achieved. Long survival following recurrence is rarely achieved without allogeneic transplantation. Experimental therapy should be considered. The use of minimal residual disease monitoring may allow the detection of a subgroup of patients during initial therapy who require treatment intensification, e.g. allograft, as well as patients in CR who are at the early stages of relapse and need preemptive therapy before frank marrow relapse occurs.

Newer agents that target the FLT3 mutation, present in a significant proportion of cases of AML, are in clinical trials in conjunction with conventional chemotherapy. Other novel therapies that are being considered in AML include chemotherapy labelled monoclonal antibodies (gemtuzumab ozogamicin) and hypomethylating agents (azacytidine).

Acute promyelocytic leukaemia (APML)

This is a variant of AML, occurring in 10–15% of cases, that is characterized by the translocation t(15; 17) and with particular morphological features. There is an almost invariable coagulopathy, which was a major cause of early death. The empirical discovery that all-trans-retinoic acid (ATRA) causes differentiation of promyelocytes and rapid reversal of the bleeding tendency was a major breakthrough. APML is treated with ATRA combined with several courses of chemotherapy. Complete remission and molecular remission occur in at least 90% of younger adults with APML and at least 70% will expect to be cured. Transplantation may be necessary either if the leukaemia is not eliminated at the molecular level, or following recurrence and reinduction therapy. Arsenic trioxide, which induces apoptosis via activation of the caspase cascade (see p. 33), is used with resistant or relapsed disease and is under investigation as first-line therapy.

Acute lymphoblastic leukaemia (ALL)

This condition may present in leukaemic phase with significant marrow involvement (ALL) or may present as localized disease, typically a mediastinal mass (lymphoblastic lymphoma). The tumour cells in each condition are indistinguishable and similar therapies are therefore used. The overall strategy for the treatment of ALL differs in detail from that for AML. Remission induction is undertaken with combination chemotherapy including vincristine, a glucocorticoid, an anthracycline and asparaginase. Once remission is achieved, the details of consolidation will be determined by the anticipated risk of failure. Intensive consolidation of remission with variable numbers of chemotherapy cycles comprising cytotoxics with different mechanisms of action has been standard practice, including the administration of high-dose methotrexate. In those patients with high-risk features (see below) or an HLA-matched sibling donor, allogeneic transplantation is recommended upon achieving first complete remission (CR1).

A major difference between therapy for ALL and AML is the need for central nervous system directed therapy. Prophylaxis should be given with intrathecal chemotherapy under platelet cover if necessary, as soon as blasts are cleared from the blood. Depending upon risk this may be continued for up to 2 years and complemented by high doses of systemic cytosine arabinoside (cytarabine) or methotrexate. Cranial irradiation was previously given to all patients to reduce the risk of relapse within the central nervous system; some risk adapted strategies reserve this only for those patients at very high risk.

Additionally, after intensive induction and consolidation, maintenance therapy for 2 years is required to reduce the risk of disease recurrence. This typically comprises 2 years of treatment with methotrexate and mercaptopurine, although more intensive regimens are used by many groups.

Prognosis

The prognosis (Fig. 9.15) of ALL in childhood is now excellent: complete remission is achieved in almost all, with up to 80% being alive without recurrence at 5 years. Failure occurs most frequently in those with high presentation blast counts or a t(9;22) translocation. Current treatment strategies are to lessen therapy for ‘good risk’ children in order to avoid some of the long-term consequences of therapy such as avascular necrosis of bone, infertility, neurotoxicity and cardiotoxicity.

Figure 9.15 Overall survival in 2628 children of different ages with newly diagnosed ALL participating in consecutive studies conducted at St Jude Children’s Research Hospital from 1962 to 2005.

(From Pui C-M, Robinson LL, Lock T. Acute lymphoblastic leukaemia. Lancet 2008; 371:1030–1043, Figure 3, with permission.)

The situation is far less satisfactory for adults, the prognosis getting worse with advancing years. Co-morbidity and t(9; 22) translocation increases in frequency with age. Overall, the complete remission rate is 70–80%. Disease that is refractory to first-line therapy carries a very poor prognosis. Between 30% and 40% of patients continue in durable first remissions, resulting in approximately 25–30% overall patient cure. Increasing numbers of patients are being transplanted for this condition, including those with sibling donors and those high-risk patients with an available unrelated donor. Imatinib used in conjunction with chemotherapy increases the response rate and quality of response in patients with the t(9;22) translocation and ALL. As with AML, most recurrences occur within the first 3 years and the outcome is extremely poor. Second remissions, though usually achieved, are rarely durable except following allogeneic transplantation. Isolated extramedullary recurrences, however, may be cured.

FURTHER READING

Diller L. Adult primary care after childhood acute lymphoblastic leukemia. N Engl J Med 2011; 365:1417–1424.

Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008; 371:1030–1043.

Chronic myeloid leukaemia (CML)

Chronic myeloid leukaemia (CML), which accounts for about 14% of all leukaemias, is one of the family of myeloproliferative neoplasms (MPNs) and is almost exclusively a disease of adults with the peak of presentation being between 40 and 60 years. It is defined by the presence of the Philadelphia chromosome (Fig. 9.16), either demonstrated cytogenetically (95%) or molecularly (5%). Unlike the acute leukaemias which are either rapidly reversed or rapidly fatal, CML has a more slowly progressive course, which if not initially cured, will be followed eventually by ‘blast crisis’ transformation to acute leukaemia (75% myeloid, 25% lymphoid) or myelofibrosis with death in a median of 3–4 years.

Figure 9.16 The Philadelphia chromosome (Ph). (a) The long arm (q) of chromosome 22 has been shortened by the reciprocal translocation with chromosome 9. (b) The Philadelphia chromosome is formed by a reciprocal translocation of part of the long arm (q) of chromosome 22 to chromosome 9. It is seen in 90–95% of patients with chronic myeloid leukaemia. The karyotype is expressed as 46XX, (9;22)(q34;q11).

Investigations

Blood film showing blast cells in CML.

Blood count. Hb low (normochromic and normocytic) or normal, WBC raised (usually >100 × 10⁹/L), platelets low, normal or raised.

Blood film. Neutrophilia with the whole spectrum of mature myeloid precursors. Elevated basophils and eosinophils. Increased numbers of blasts are suggestive of accelerated phase or blast crisis.

Bone marrow aspirate. Increased cellularity, increased myeloid precursors. Cytogenetics reveals t(9; 22) translocation (the Philadelphia chromosome) (Fig. 9.16b).

Fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) are used to demonstrate the cytogenetic/molecular abnormality. These are also used to quantitatively monitor response to therapy.

Chronic lymphocytic leukaemia (CLL)

This is the most common leukaemia, occurring predominantly in later life and increasing in frequency with advancing years (median age of presentation between 65 and 67 years). It results from the clonal expansion of small lymphocytes and is almost invariably (95%) B cell in origin. The majority of patients are asymptomatic, identified as a chance finding on a blood count performed for another indication. Other patients, however, present with the features of marrow failure or immunosuppression. The median survival is about 10 years and prognosis correlates with clinical stage at presentation (Table 9.21). A number of cytogenetic and molecular abnormalities are now recognized as being of prognostic significance (see below). This condition may present in leukaemic phase with significant marrow involvement (CLL) or may present as localized disease (small lymphocytic lymphoma, SLL). The tumour cells in each condition are indistinguishable and a similar therapeutic approach is therefore used. A pre-malignant condition, monoclonal B cell lymphocytosis (MBL) exists where there are less than the 5 × 10⁹/L B-cells required for a diagnosis of CLL. Some of these have CLL phenotype and may progress to CLL.

Prognostic biomarkers

The clinical course of CLL is variable. Several markers are used to supplement clinical stage and have been shown to predict progression and survival. Variations in predictor cut-off levels have limited their widespread application.

Cytogenetic abnormalities are detected in >90% of cases. Patients with an isolated deletion of 13q have an excellent prognosis, in contrast to those with either 11q deletion or 17p deletion (the sites of the tumour suppressor genes ATM and TP53, respectively) who tend to have a rapidly evolving clinical course. In those tumours that demonstrate a high level of mutation within the variable region of the rearranged immunoglobulin heavy chain (IgVH), the clinical course is more indolent than those where the IgVH sequence more closely resembles that of the germline. Expression of ZAP70, a 70 kDa tyrosine kinase protein, correlates well with mutational status. Patients with <20% expression of ZAP70 have median 10-year survival of >50%; in >20% expression the median survival was <5 years. High expression of CD38 on leukaemic cells may also indicate adverse prognosis.

Fluorescence in situ hybridization photomicrograph of a patient with CLL. (a) 17p (green probe) and 11q (red probe) shows two green signals (TP53 deletion) with normal diploid complement of 11q. (b) 12 centromere (green probe) and 13q14 (red probe) shows three green signals (trisomy 12) with normal diploid complement of 13q.

(Courtesy of Debra Lillington, Barts and the London NHS Trust.)

Hairy cell leukaemia (HCL)

HCL is a clonal proliferation of abnormal B (or very rarely T) cells which, as in CLL, accumulate in the bone marrow and spleen. It is a rare disease, median age at presentation is 52 years old and the male to female ratio is 4 : 1. The bizarrename relates to the appearance of the cells on a blood film and in the bone marrow – they have an irregular outline owing to the presence of filament-like cytoplasmic projections.