Chapter 9 Malignant disease
The term ‘malignant disease’ encompasses a wide range of illnesses, including common ones such as lung, breast and colorectal cancer (Table 9.1) as well as rare ones, like the acute leukaemias. Malignant disease is widely prevalent and, in the West, almost one-third of the population will develop cancer at some time during their life. It is second only to cardiovascular disease as the cause of death. Although the mortality of cancer is high, many advances have been made, both in terms of treatment and in understanding the biology of the disease at the molecular level.
|5-year survival (%)|
Most human neoplasms are clonal in origin, i.e. they arise from a single population of precursor or cancer stem cells. This process is typically initiated by genetic aberrations within this precursor cell. Cancer is increasingly common the older we get and can be related to a time dependent accumulation of DNA damage that is not repaired by the normal mechanisms of genome maintenance, damage tolerance and checkpoint pathways. Malignant transformation may result from a gain in function as cellular proto-oncogenes become mutated (e.g. ras), amplified (e.g. HER2) or translocated (e.g. BCR-ABL). However, these mutations are insufficient to cause malignant transformation by themselves. Alternatively, there may be a loss of function of tumour suppressor genes such as P53 that normally suppress growth. Loss or gain of function may also involve alterations in the genes controlling the transcription of the oncogenes or tumour suppressor genes (p. 46). Over subsequent cell divisions, heterogeneity develops with the accumulation of further genetic abnormalities (Fig. 9.1).
The genes most commonly affected can be characterized as those controlling cell cycle checkpoints, DNA repair and DNA damage recognition, apoptosis, differentiation, growth factor receptors and signalling pathways and tumour suppressor genes (Table 9.2). Recognition of critical genetic alterations has enabled extensive development of new targeted drugs such as imatinib that inhibits the growth signals of the abnormal tyrosine kinase BCR/ABL. Proliferation may continue at the expense of differentiation which, together with the failure of apoptosis, leads to tumour formation with the accumulation of morphologically abnormal cells varying in size, shape and cytoplasmic or nuclear maturity.
Control cell cycle checkpoints
Cyclin D1, p15, p16
Growth factor receptors
EGF, VEGF, FGF, BCR/ABL, TGF-B, KIT, L-FLT3
RAS, BRAF, JAK2, NF1, PTCH
Hedgehog signalling pathway
See p. 26
Tumour suppressor genes
P53, Rb, WT1, VHL
Figure 9.2 The hallmarks of cancer: the next generation.Six biological capabilities acquired during the multistep development of human tumours have been identified as shown in figure. Two others have been identified, viz reprogramming of energy metabolism and evading immune destruction.
(From Hanagan D and Weinberg PA The Hallmarks of cancer: the Next Generation. Cell 2011;144:646–474 with permission.)
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)
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.
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.
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.
Neurofibromatosis type 1
Familial adenomatous polyposis (FAP)
Hereditary non-polyposis colon cancer (HNPCC)
MLH1 and MSH2
Hereditary diffuse gastric cancer syndrome
Breast ovary families
Renal cell carcinoma and haemangioblastoma
Multiple endocrine neoplasia type 1
Pituitary, pancreas, parathyroid
Multiple endocrine neoplasia type 2
Thyroid, adrenal medulla
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.
Mouth, pharynx, oesophagus, larynx, lung, bladder, lip
Mouth, pharynx, larynx, oesophagus, colorectal
Bladder, bone marrow
Endometrium, vagina, breast, cervix
Radiotherapy (e.g. mantle radiotherapy)
Carcinoma of breast and bronchus
Skin, lung, bladder, myeloid leukaemia
e.g. leukaemia, thyroid cancer
Hepatitis B virus
Liver (hepatocellular carcinoma)
Hepatitis C virus
Liver (hepatocellular carcinoma)
Human T-cell leukaemia virus
Human papillomavirus types 16, 18
Oral cancer (type 16)
Key messages for a healthy lifestyle for preventing cancer
The incidence of lung cancer in both men and women increased dramatically in the last 25 years worldwide, but is now falling in many developed countries. The association of smoking with lung cancer is indisputable and causative mechanisms have been identified: cigarette tobacco is responsible for one-third of all deaths from cancer in the UK. Smoking not only causes lung cancer, it is also associated with cancer of the mouth, larynx, oesophagus and bladder. Smoking is discussed on page 806.
Alcohol is associated with cancers of the upper respiratory and gastrointestinal tracts, and it also interacts with tobacco in the aetiology of these tumours. It may be associated with an increased risk of breast cancer.
Dietary factors have been attributed to account for one-third of cancer deaths, although it is often difficult to differentiate these from other epidemiological factors. For example, the incidence of stomach cancer is particularly high in the Far East, while breast and colon cancers are more common in the Western, economically more developed countries. Many associations have been observed without a causative mechanism being identified between the incidence of cancer and the consumption of dietary fibre, red meat, saturated fats, salted fish, vitamin E, vitamin A and many others. Food and its role in the causation of gastrointestinal cancer is discussed in Chapter 5 (see p. 218). Increasing levels of obesity in the developed world have been associated with increases in women of cancers associated with oestrogenic stimulation of the breast and endometrium.
Ultraviolet light is known to increase the risk of skin cancer (basal cell, squamous cell and melanoma). The incidence of melanoma is therefore particularly high in the white Anglo-Celtic population of Australia, New Zealand and South Africa, where exposure to UV light is combined with a genetically predisposed population.
Occupational factors. In 1775, Percival Pott described the association between carcinogenic hydrocarbons in soot and the development of scrotal epitheliomas in chimney sweeps. The principal causes now are asbestos (lung and mesothelial cancer) and polycyclic hydrocarbons from fossil fuel combustion (skin, lung, bladder cancers). Organic chemicals, such as benzene, may cause the development of bone marrow conditions such as myelodysplastic syndrome or acute myeloid leukaemia.
The geographical distribution of a rare malignancy suggests that it might be caused by, or associated with, an infective agent. Chronic persistent infection provides growth stimulation while many viruses contain transforming viral oncogenes.
T-cell leukaemia, seen almost exclusively in residents of the southern island of Japan and in the West Indies, is caused by infection with the locally endemic retrovirus HTLV-1 (human T-cell leukaemia virus) and integration of the oncogene, TAX, into the cellular genome.
Hepatocellular carcinoma occurs in patients with hepatitis B and C virus infections and Burkitt’s lymphoma and nasopharyngeal carcinoma are associated with the Epstein–Barr virus. EBV is also linked with Hodgkin’s lymphoma (see p. 459).
The incidence of cervical cancer had increased among younger women in association with sexually transmitted HPV (human papillomavirus) infection types 16 and 18, for which an effective vaccine is now available.
Bacterial infection with Helicobacter pylori predisposes to the development of gastric cancer and gastric lymphoma, while Schistosoma japonicum infection predisposes to the development of squamous cell carcinomas in the bladder.
Oestrogens have been implicated in the development of vaginal, endometrial and breast carcinoma. Certain cytotoxic drugs given, e.g. for Hodgkin’s lymphoma (see later) are themselves associated with an increased incidence of secondary acute myelogenous leukaemia (AML), bladder and lung cancer. Androgens have been associated with both benign and malignant liver tumours.
Accidental. The nuclear disasters of Hiroshima, Nagasaki and Chernobyl led to an increased incidence of leukaemia after 5–10 years in the exposed population as well as increased incidences of thyroid and breast cancer. Radiation workers are at an increased risk of malignancy due to occupational exposure unless precautions are taken to minimize this using personal and environmental shielding and to record and limit the amount of personal exposure.
Diagnostic. Imaging procedures involving radiation exposure are associated with an increased risk of cancer. This risk is cumulative, dose dependent and time dependent, i.e. children are at higher risk than adults. The cancer risk of various common investigations is shown in Table 9.5. All doctors should strive to minimize diagnostic exposure to radiation where possible using alternative modalities such as ultrasound or MRI. Good documentation of radiation doses is required. This is particularly so in children and pregnant women.
Whole body CT
Percutaneous coronary intervention
Myocardial perfusion imaging
UK background radiation is 2.6 mSv per year. 1 mSv carries a lifetime cancer risk of 1 in 17 500 and 5 mSv a risk of 1 in 3500.
Modified from: Smith-Bindman R, Lipson J, Marcus R et al. Archives of Internal Medicine 2009; 169:2078–2086 and Fazel R, Krumholz HM, Wang Y et al. New England Journal of Medicine 2009; 361:849–857.
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.
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.
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.
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.
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.
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.
Menon U, Gentry-Maharaj A, Hallett R et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet. Oncology 2009; 10:327–340.
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).
|Degree of spread||Anatomical location||Examples of clinical problems|
Thyroid nodule, pigmented naevus, breast lump, abdominal mass, testicular mass
Local infiltration of skin
Dermal nodules, peau d’orange, ulceration
Local infiltration of nerve
Neuropathic pain and loss of function
Local infiltration of vessel
Venous thrombosis, tumour emboli, haemorrhage, e.g. GI
Obstruction of viscera or duct
Small or large bowel obstruction, dysphagia, SVC obstruction
Supraclavicular fossa, Virchow’s node, lymphoedema
Mediastinum – SVC obstruction, porta hepatis – obstructive jaundice, para-aortic nodes and back pain
Pleuritic pain, cough, shortness of breath, lymphangitis and respiratory failure, recurrent pneumonia
RUQ pain, anorexia, fever, raised serum liver enzymes, jaundice
Headache and vomiting of raised intracranial pressure, focal deficit, coma, seizure
Bone pain, cord compression, fracture, hypercalcaemia
Effusion, pain, shortness of breath
Ascites, Krukenberg tumours
Addison’s disease (hypoadrenalism)
Sister Mary Joseph’s nodule
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.
Lung (small-cell) lymphoma
Peripheral sensory neuropathy
Lung (small-cell), breast and ovary lymphoma
Lung (particularly small-cell) lymphoma
Breast, lung (small-cell)
Stiff person syndrome
Breast, lung (small-cell)
Limbic, hypothalamic, brain stem encephalitis
Ectopic ACTH secretion
Renal, breast, myeloma, lymphoma
Hypertrophic pulmonary osteoarthropathy
Lung and upper GI
Gastric, lung (non-small cell)
Non-Hodgkin’s lymphoma, CLL
Renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma
SIADH, syndrome of inappropriate antidiuretic hormone secretion; ACTH, adrenocorticotrophic hormone; CLL, chronic lymphocytic leukaemia; DIC, disseminated intravascular coagulation; NMDAR, N-methyl-D-aspartate receptors.
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.
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.
Tumour markers are intracellular proteins or cell surface glycoproteins released into the circulation and detected by immunoassays. Examples are given in Table 9.7. Values in the normal range do not necessarily equate with the absence of disease and a positive result must be corroborated by histology as these markers can be seen in many benign conditions. They are most useful in the serial monitoring of response to treatment. As discussed in subsequent sections, a proportion of low-grade B-cell lymphomas and a majority of cases of myeloma will produce a monoclonal paraprotein of intact immunoglobulin molecule or light chains. This acts as a valuable tumour marker in the diagnosis and assessment of response.
Hepatocellular carcinoma and non-seminomatous germ cell tumours of the gonads
β-Human chorionic gonadotrophin (β-hCG)
Choriocarcinomas, germ cell tumours (testicular) and lung cancers
Prostate-specific antigen (PSA)
Carcinoma of prostate
Carcinoma embryonic antigen (CEA)
Gastrointestinal cancers, particularly pancreatic cancer
Many cancers including mesothelioma
M-band (Ig or light chain)
Myeloma, chronic lymphocytic leukaemia, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, amyloid
Radiological investigation by experts is required at various stages: at initial diagnosis and staging of the disease, during the monitoring of treatment efficacy, at the detection of recurrence and for the diagnosis and treatment of complications.
The choice of investigations needs to be guided by the patient’s symptoms and signs, site and histology of the cancer, the curative or palliative potential of treatment and the utility of the information in guiding treatment. The investigations are described under each tumour type.
Contrast agents are used for increased structural discrimination and can be further enhanced with functional specificity for metabolically active tissue with 19fluorodeoxy-glucose uptake and CT-positron emission tomography (CT-PET scan) as used extensively in head and neck cancer, lung cancer and lymphoma. Radionuclide imaging of sentinel lymph nodes is used to guide lymphatic surgery in breast cancer and melanoma. Tumour targeted contrast agents can improve detection rates such as the radiolabelled MAb rituximab for lymphoma or radiolabelled small molecules such as octreotide for neuroendocrine tumours. Research into the use of reporter agents which become visible only upon activation within the tumour environment holds the promise of greater sensitivity and specificity in the future.
The diagnosis of cancer may be suspected by both patient and doctor but advice about treatment can usually only be given on the basis of a tissue diagnosis. This may be obtained by endoscopic, radiologically-guided or surgical biopsy or on the basis of cytology (e.g. lung cancer diagnosed by sputum cytology). Malignant lesions can be distinguished morphologically from benign ones by the pleiomorphic nature of the cells, increased numbers of mitoses, nuclear abnormalities of size, chromatin pattern and nucleolar organization and evidence of invasion into surrounding tissues, lymphatics or vessels. The degree of differentiation (or conversely of anaplasia) of the tumour has prognostic significance: generally speaking, more differentiated tumours have a better prognosis than poorly-differentiated ones. In some tumours where the surgical procedure will vary depending on the presence of malignancy, an intraoperative histological opinion can be rapidly obtained using a tissue sample processed using ‘frozen section’ techniques, which requires the availability of a histopathologist. This obviates the need for the sample to be paraffin embedded, which takes hours to days.
Tissue tumour markers. Immunocytochemistry, using monoclonal antibodies against tumour antigens, is very helpful in differentiating between lymphoid and epithelial tumours and between some subsets of these, for example T- and B-cell lymphomas, germ cell tumours, prostatic tumours, neuroendocrine tumours, melanomas and sarcomas. However, there is much overlap in the expression of many of the markers and some adenocarcinomas and squamous carcinomas do not bear any distinctive immunohistochemical markers that are diagnostic of their primary site of origin.
Molecular markers of genetic abnormalities have long been available in the haematological cancers and are increasingly available in solid cancers. For example, fluorescent in situ hybridization (FISH, see p. 40) can be used to look for characteristic chromosomal translocations, e.g. in lymphoma and leukaemia, as well as deletions or amplifications, e.g. in breast cancer (see genetic basis of cancer, p. 45). Tissue microarrays can identify patterns of multiple genomic alterations and single nucleotide polymorphisms (SNPs), e.g. in breast cancer and lymphoma (see p. 35), and RNA assays with RT-PCR can be used to identify tissue of origin with prognostic and predictive relevance.
Genomics and proteomics are being investigated in order to target new (and expensive) therapies, e.g. imatinib in CML and GIST, trastuzumab and lapatinib in breast cancer and erlotinib in lung cancer.
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).
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.
This is defined as treatment given, in the absence of macroscopic evidence of metastases, to patients at risk of recurrence from micrometastases, following treatment given for the primary lesion. ‘Neoadjuvant’ therapy, alternatively, is given before primary surgery, to both shrink the tumour to improve the local excision and treat any micrometastases as soon as possible.
Micrometastatic spread by lymphatic or haematological dissemination often occurs early in the development of the primary tumour and can be demonstrated by molecular biological methods capable of detecting the small numbers (1 in 106) of circulating cells. Studies correlating prognosis with histological features of the primary cancer, e.g. differentiation, invasion of blood vessels or regional lymph nodes and molecular markers, e.g. Her2 in breast cancer, enable risk stratification and increasing individualization of therapy.
The success of adjuvant treatment across many tumour types relies upon careful selection of patients according to defined risk criteria and the reduction of treatment toxicity to reach a balanced risk/benefit ratio. Relative risk reductions in the order of 12–33% and absolute improvements in 5–10-year survival of 5–25% (dependent upon the pre-existing risk) have been achieved in common epithelial cancers such as lung, bowel, breast and prostate, with greater absolute improvements in the more sensitive germ cell tumours.
While these improvements currently translate into many lives saved from common diseases at a public health level, the majority who receive such treatment do not benefit because they were already cured, or because the cancer is resistant to the treatment. Better tests, e.g. gene arrays and circulating tumour cells, are being developed to identify those with the micrometastases who really need treatment. On an individual patient basis the decision on whether adjuvant treatment will be worthwhile must include consideration of other factors such as the patient’s life expectancy, concurrent medical conditions and lifestyle priorities.