OVERVIEW OF CANCER

Cancer is not a single disease. There are a huge number of different types of tumour, each with its own characteristic symptoms and prognosis. The one thing all these tumours have in common, however, is their ability to grow in an uncontrolled way and spread with varying speeds through the body. It is this which makes them at once so lethal and so difficult to treat.

Nor is cancer a new disease; evidence of cancerous damage to bones has been found even in human remains dating back into prehistory. Despite this, it is well documented that the prevalence has increased steadily in the past few centuries, and it seems likely that it will continue to do so in the future.

Mortality varies from one type of cancer to another, and improvements in treatment mean that outcomes in some types are very much better than many people realise. The seven year survival rate in primary breast cancer, for example, is now approaching 50%, while there is a greater than 90% cure rate in testicular teratoma (the most common cancer of young males). More than 60% of childhood cancers can now usually be cured. Overall, the five year survival rate for all cancers has increased from 40% in 1965 to 54% in 1985.(1)

It is currently estimated that cancer accounts for some 10% of all deaths worldwide (about 5 million deaths), 22% of all deaths in Europe,(2) and within the UK, some 250,000 new cases occur each year. Of these, just under one-third are cancers of the lung or large bowel, which often present late and may be incurable. (1)

Furthermore, cancer is primarily a disease of the middle-aged and elderly, thus the steadily increasing age of the population means the problem is set to increase still further in the future. The projected increase in cancer deaths in England & Wales between 1980 and the year 2000 is 20% in men and 12% in women. (2)

Causes

The exact causes of cancer are still unknown, even though a wide range of carcinogens have been identified that are known to affect the structure of human DNA. Some cancers have a strong familial link. For these reasons, cancer is sometimes described as a disease of the genes. (3) It is thought that tumour cells have genetic mutations that play a critical role in pathogenesis. We will look therefore at some of the ways in which these mutations come about.

Radiation

To most people, electromagnetic radiation is one of the better known causes of cancer, having become sadly familiar through the aftermath of Hiroshima and Nagasaki. High doses of radiation are lethal to cells (hence the use of radiotherapy against tumours), but lower doses are known to cause genetic changes that promote cancer. In general, however, radiation is probably a relatively rare cause of cancers, the main exception being skin cancers caused by excessive exposure to the UV radiation in sunlight. (4)

The extent to which radiation from sources such as radon in rocks, or the nuclear industry, are associated with cancers is still not known accurately.

Chemical carcinogens

A large and ever-growing number of chemical carcinogens is known. Of these, the most significant for the population in general are the tobacco carcinogens. These are a major cause of mortality throughout the world. The risk of lung cancer rises progressively with increasing cigarette consumption. Tobacco smoking is also a cause of head and neck cancers, such as lip cancer.(5)

Viruses

In animals, a wide variety of oncoviruses have now been identified. In humans, at least two have been studied in detail: the Epstein-Barr virus, which is widespread in Africa and has been shown to be associated with a specific African type of lymphoma; and the hepatitis B virus, which has been linked with a certain kind of liver cancer. (4) In addition, Kaposi's sarcoma may be linked with infection by cytomegalovirus in patients whose immunity has been reduced by AIDS. Such viruses are thought to exert their effects by becoming incorporated into human cell DNA. Specific oncogenes have now been identified in some oncoviruses. These are inserted into the host cell genetic material and, when activated, they cause transformation of the (previously healthy) cell into one with malignant potential.

Genetic causes

It is now accepted that a few cancers are genetic (retinoblastoma, for example). A few others, such as Wilms' tumour, are known to be linked closely with specific genetic abnormalities. Both these examples are rare tumours of children. For the more common cancers, genetic links, if any, are much more complex.

Breast cancer is considered one of the most strongly familial. For women with a close family history of breast cancer, the risk that they will develop breast cancer themselves is 1.2 to 3.0 times greater than for women in general.(6)

The cancer process

Cancers develop from normal body cells that have been transformed such that they behave abnormally. Tumours are formed through the abnormally accelerated division of these cells. To understand what happens in cancer, therefore, it is necessary to compare cancer cells with normal cells.

Division and differentiation of normal cells

All the cells of the human body are derived from the repeated division of a single cell, the original fertilised egg or zygote. Every body cell (except sex cells or gametes) contains identical copies of all the genes that were present in that zygote. Yet the body has a variety of different types of cell, many of which are highly specialised.

The reason for this is that dividing cells are also subject to a process called differentiation. This involves the selective activation of certain genes, but the repression of others. The most highly differentiated cells of the body are the most specialised (e.g. muscle cells or nerve cells). These serve highly specific, complex functions, but have limited potential to divide further and form new cells. Other cells, called stem cells, are unspecialised, but divide repeatedly to form new cells to replace others as they die. This is a process that continues throughout life, providing constant replacement of white blood cells as they become exhausted and die.

Except in the gonads, body cells divide by the process of mitosis - splitting into two identical offspring. Dividing cells pass through a series of stages, the cell cycle, which is the same for all cell types, although the length of time needed for completion of the cycle varies from one type of cell to another. In cells that need frequent replacement and therefore divide rapidly, such as certain cells of the gut lining, the cell cycle time is usually about 24 to 48 hours. (3)

The speed of cell cycling is subject to a whole range of natural control factors including:

• various chemical growth factors and hormones (e.g. certain peptides and steroids)
• contact with other cells, and availability of nutrients or oxygen
• degree of cell differentiation

Most normal cells are programmed to die after a certain number of divisions. Equally importantly, they have what could be described as a sense of their proper place in the body, and will not usually divide if they become transplanted into another part of the body accidentally. Epidermal cells, for example, normally divide very rapidly, but they do not do so if they are displaced into a deeper tissue such as a muscle (as might perhaps happen during accidental wounding or surgery).

Cancer cells

The genetic changes needed to cause transformation of a normal cell into a cancer cell are very small. Thus, cancer cells contain DNA that is almost completely identical to that of normal cells. They differ from normal cells, however, in that they no longer respond to the normal growth control mechanisms. Specifically, they:

• need fewer growth factors to facilitate division, and do not respond to the normal chemical checks
• divide unrestricted by a lack of space
• often show less differentiation than normal cells.
• are able to continue dividing almost indefinitely
• are able to detach from their original site and travel in the lymph or bloodstream to other, distant sites where they become attached and continue dividing (a process known as metastasis)

The ability of cancer cells to metastasise is one of the main reasons why cancer is so difficult to eradicate completely.

Tumour development and spread

Tumours or neoplasms form when mitotic division occurs at a rate faster than is needed for normal cell replacement. Their overall rate of growth therefore depends on several factors:

• the proportion of cells that are actively dividing (the growth fraction)
• the cell cycle time
• the rate of cell loss

In general (but not always), tumours that enlarge only relatively slowly are more likely to be benign than malignant.

Malignancy

Malignant tumours are thought to develop from a single transformed cell, and are sometimes described therefore as monoclonal. As tumour growth progresses, the DNA of the cancer cells becomes unstable, tending to break up and rearrange itself spontaneously. The cells containing this new, altered DNA divide further, so forming new types of tumour cells each with slight genetic differences from the other. At this stage, the tumour may be described as heterogeneous.

Heterogeneity is significant because the various different cell sub-populations have differing speeds of cell cycling, degrees of invasiveness, metastatic potential, etc. As a result, some parts of the tumour grow rapidly, crowding out and destroying other, slower-growing parts. It is this tissue destruction and death (necrosis) that leads to many of the most distressing aspects of malignant cancers, such as bleeding, ulceration, disfigurement and pain.

Invasion and metastasis

As a tumour gets bigger, it may start to invade the tissues surrounding it. With increasing heterogeneity, invasiveness may also increase, as groups of cells form that are more mobile and more able to produce proteolytic enzymes or other destructive chemicals. Generally, invasion tends to follow a path of least resistance, extending first into loosely organised tissues and only later into denser or encapsulated structures.

Invasion of lymphatic and blood vessels allows metastasis to occur. Cells from the primary tumour cells detach and travel in the lymph or bloodstream to become attached in the capillary bed of another organ or tissue. If conditions are right, they may grow there to form secondary tumours or metastases

Generally, metastasis is a late stage in tumour development and each type of cancer has its own particular pattern of secondary formation. For example, both lung and breast cancers commonly metastasise to the bones and brain. In advanced cancers of all types, metastases are a major source of pain and distress.

Cancer symptoms and progression

Each type of cancer has its own set of symptoms but, frequently, these are not detectable until the cancer is already fairly advanced. In most cases, the earlier the diagnosis, the better the prognosis. Small (2cm or less in diameter), localised tumours are often highly curable. (4)

For this reason, there are national screening programmes against certain common cancer types. The main ones are cervical and breast cancers, where the key tests (pap smears and mammography) are non-invasive and technically relatively easy to perform. However, a large proportion of cancers are still detected by accident, perhaps during a medical examination for something else.

As far as possible, the general public is encouraged to be alert for possible signs of cancer themselves. For example, the following warning signals are highlighted and publicised widely by the American Cancer Society(4):

• a change in bowel or bladder habits
• a sore that does not heal
• unusual bleeding or discharge
• thickening of a lump in breast or elsewhere
• indigestion or difficulty in swallowing
• an obvious change in wart or mole
• a nagging cough or hoarseness

These result mainly from localised tissue damage, or pressure exerted by the enlarging tumour on nearby organs. Even in the early stages, however, there may be other, more general symptoms that are changes due to cancer.

Other, non-specific, changes that may be signs of cancer include:

• loss of appetite
• weakness
• weight loss
• drowsiness
• nausea and vomiting
• skin changes
• fever
• muscle wasting
• sweats, especially at night
• hormone changes

Pain is the symptom that many people associate with cancer, particularly with the advanced stages of the disease. This association is justified; although pain is not usually a feature of cancer in the early stages, it tends to increase steadily as the disease progresses. Thus, in advanced cancer, the majority of patients have pain which is usually severe and prolonged. Other major symptoms of advanced cancer depend to some degree on the type of cancer involved (e.g. dyspnoea and cough are especially likely in lung cancer). Distressing symptoms common in all types, however, include weight loss, anorexia, weakness and insomnia.

Diagnosis

A diagnosis of cancer is never based on symptoms alone. A full patient history is needed, including questions about occupation and habits such as smoking. The doctor will also look for specific signs of disease, such as palpable lymph nodes, enlargement of the liver, abnormal chest sounds, etc.

Further, more specific, investigations are carried out subsequently. The exact choice of technique depends upon the body site or sites thought to be involved.

Histological typing, grading and staging

Histological typing, grading and staging, form a routine part of all cancer diagnoses. They are important because they determine the prognosis for the patient, and are the key influence on treatment decisions.

There are many different types of tumour, classified histologically according to their degree of malignancy and the tissue in which the tumour has originated. Carcinoma and sarcoma are commonly used names you may encounter. Carcinomas are malignant tumours that originate in epithelial tissues such as skin or mucous membranes, while sarcomas are malignant tumours that originate in connective tissues.

Lymphomas are malignancies of the lymphatic system, while leukaemias are malignancies of the tissues that produce blood cells. These are often treated separately from carcinomas and sarcomas on the basis of their structure - carcinomas and sarcomas are described as "solid" tumours, while leukaemias are defined as "non-solid" tumours. Lymphomas straddle these two classifications. A tumour's structure to some extent determines its treatment. Thus, solid tumours that have not yet metastasised may be sensitive to localised treatments such as surgery or radiotherapy, but non-solid leukaemias need systemic treatment with, for example, chemotherapy. Lymphomas are generally managed surgically, but may respond to a combination of radiotherapy and chemotherapy.

Tumour grading

The grading of a tumour is an estimate of its degree of differentiation, as determined by histological examination. It is important because, generally speaking, the degree of differentiation is an indication of the degree of malignancy. Usually, four different grades are recognised:

• Grade 1, well differentiated
• Grade 2, moderately well differentiated
• Grade 3, poorly differentiated
• Grade 4, very poorly differentiated (4)

Staging of malignant disease

In cases where a tumour is found to be malignant, staging is the diagnostic step that evaluates the overall extent of spread of the cancer. It provides the key to subsequent therapeutic decisions and a guide to prognosis. In many solid tumours, including some lung cancers and those of the breast, head, neck, and genito-urinary system, a system called the Tumours, Nodes and Metastases (TNM) system is generally used.

TNM staging (4)

The extent of disease is given a class within each of the three components:

• Size or local invasiveness of the primary tumour (T)
  Five classes, ranging from T0 (no gross evidence of a tumour, microscopic evidence of malignant change) through to T4 (a massive tumour extending into another organ, nerve, artery or vein; evidence of bone destruction sometimes present)
• Spread to lymph nodes (N)
  Five classes ranging from N0 (no evidence of cancer in lymph nodes) through to N4 (distant nodes involved)
• Presence of metastases (M)
  Four classes, ranging from M0 (no evidence of metastases) through M1 (a single metastasis) and M2 (multiple metastases confined to a single organ system), to M3 (metastases in multiple organ systems)

For example, a breast tumour staged T1 N0 M0 is a primary tumour confined to the breast only, with no evidence of invasion into surrounding tissues, no nodal involvement, and no metastases. Such a tumour has a relatively good prognosis. The same tumour with even a single metastasis present (M1) would have a much poorer prognosis.

For other tumours, including ovarian and cervical cancers, small cell carcinoma of the lung, cancer of the colon, leukaemias and lymphomas, the TNM system is less useful and other staging systems are used.

Assessment of patient's status

The patient's overall condition is also critical to cancer prognosis, and treatment decisions are made in its light. In a fairly fit forty-year old, for example, intensive chemotherapy or major surgery might be worth trying, even when a highly aggressive or resistant cancer is present. For a frail 85-year old patient, the possible benefits of such treatment are more questionable when weighed against the inevitable side effects of the chemotherapy, or the postoperative trauma of the surgery.

Many doctors make these assessments without formalising them in any way, although various standards exist. The Karnofsky performance status is one example. However, it is currently being replaced by the WHO performance guidelines, which are simpler to use and more widely accepted:
0 - able to carry out all normal activity without restriction
1 - restricted in physically strenuous activity, but ambulatory and able to carry out light work
2 - ambulatory and capable of all self-care activity, but unable to carry out any work; up and about more than 50% of waking hours
3 - capable of only limited self-care; confined to bed or chair more than 50% of waking hours
4 - completely disabled, cannot carry out any self-care; totally confined to bed or chair

Some common cancers

This section is intended to provide an outline of the prevalence and likely prognosis of the cancers that pose the greatest problems in the UK. You will notice that, in general, those that are most common are also those with the worst prognoses. For the most part, it is only the rarer cancers that respond well to treatment.

Lung cancer

Lung cancer is the biggest killer of all the cancers in the UK, accounting for some 40,000 deaths annually. The most important cause is cigarette smoking, but industrial carcinogens are factors in some groups of patients (e.g. asbestos workers).

The average age of onset is about 60 years, and men and women are equally susceptible. Lung cancer is rare in people younger than 30 years.(9)

Four main types of lung cancer are recognised, (9) but for practical purposes lung cancers are often classed into only two main categories, small cell carcinomas and non-small cell carcinomas. Both categories have generally poor prognoses.

In small cell carcinomas, treatment achieves 5-year survival rates of around 14% to 35%, while in non-small cell carcinomas, 5-year survival is only about 8-10%. (9)

Lung cancers often metastasise to the bones and brain, and also to the liver. Bone metastases are painful, leading to rapidly progressive disablement and patient deterioration.

Breast cancer

Breast cancer is the most common cancer in British women, particularly Scottish women, due to their greater incidence of cigarette smoking. The course of breast cancer is very unpredictable, depending on the extent of the disease at diagnosis. For example, as has been mentioned, the seven year survival rate for non-metastatic primary breast tumours is now approaching 50%, but the disease cannot always be caught at this stage. Late diagnoses and long term recurrences or metastases mean that the majority of breast cancer patients still die eventually from their cancer or its complications.

Risk from breast cancer in women below the age of 35 is low, but it increases steadily year by year after that (6) and, whilst the UK has a national breast screening programme designed to detect lumps as early as possible, its value is much debated.

The most important aetiological factor appears to be a close family history of breast cancer. However, hormonal factors may also be important. It is well established, for example, that breast cancers are often oestrogen-sensitive.(6) There is also some evidence that breast cancer is linked with both cancer of the uterus and certain cancers of the salivary glands. (4)

The risk of metastasis in breast cancer continues for 20 years or more after apparently successful treatment. (6) In the many cases where breast cancer eventually proves fatal, bone and brain metastases often contribute to prolonged, painful, and disabling illness.

Cancers of the colon and rectum

Cancers of the colon and rectum are relatively common, affecting men and women almost equally. Most patients are over 50 years old. The typical Western diet (low in fibre, high in animal fat) is widely regarded as an important aetiological factor. (10) Generally, the prognosis is relatively poor, with 5-year survival rates of only about 50%. Metastatic spread typically involves the liver. (10)

Prostatic cancer

Prostatic cancer has a very high incidence in older men - it is sometimes said that all men will develop it if they live long enough. (11) Five year survival rates of around 60% to more than 80% have been reported for early stage prostatic cancers, but early diagnosis is very unusual. In general, the combination of patient age and late diagnosis makes prostatic cancer an important cause of mortality. (11) Frequently, bony metastases are already present at diagnosis.

Leukaemias and lymphomas

Leukaemias are cancers of the bone marrow cells that form blood cells. There are several different types, each affecting a different age group of people.

Prognosis varies from one type to another. Childhood leukaemias, in particular, respond very well to treatment and are one of the cancer success stories of recent years. Treatment of acute and chronic leukaemia can be very different, and prognosis will depend very much on the state of the disease at diagnosis.

Lymphomas are malignancies of the lymphatic system, and are divided into Hodgkin's disease and non-Hodgkin's lymphomas, depending on the cell type seen on biopsy.

Hodgkin's disease is the less common of the two types, but responds well to treatment and has the better prognosis. Five-year and even ten-year survival rates of up to 96% have been reported. (12) There are various non-Hodgkin's lymphomas, which can be divided into low grade (less malignant) and high grade (more malignant) types. In general, lymphomas are highly chemo-sensitive and radio-sensitive. However, in some types remission periods are very short.

Management
The patient and the family

The distress caused by cancer is difficult to appreciate fully if you have never suffered directly, or nursed someone dear to you. There is an intense need for support from family, friends, and health professionals. Patients and their families experience a constantly-changing mix of emotions: fear; hope; denial; anger; depression. As the disease progresses, they may come eventually to an acceptance of dying, but this acceptance is seldom achieved unless physical and psychological problems are dealt with.

Three main types of problem are faced by patients, and these increase with disease severity:

• disease symptoms
• treatment side effects
• psychological and spiritual problems raised by the knowledge or fear that death is close

For the patient's family, it is not only the emotions of the situation that need attention. There will also be practical issues, such as training in the daily nursing care, that need to be addressed. The total care of cancer patients involves many medical, paramedical, and nursing staff.

Specialist oncology team

The specialist oncology team is the usual source of potentially curative radiotherapy and chemotherapy. As cancer progresses, however, the input of the specialists usually declines.

In the UK, most cancer treatment is prescribed by radiotherapists, who may also be called clinical oncologists. However, the number of medical oncologists, trained in the use of cytotoxic agents, is growing steadily.

The GP

The role of the patient's GP becomes increasingly important as care becomes terminal. In an average-sized practice of 7,200 patients, around half of the 50 or so deaths each year are likely to be caused by cancer - one third of these by lung cancer. (13) Hence, palliative care of cancer patients forms an important aspect of the GP's workload.

Macmillan and Marie Curie nurses

Macmillan nurses are funded partly by the NHS and partly through charitable funding (e.g. the Cancer Relief Macmillan Fund). The majority of Macmillan nurses (about 750) are involved in the home care of cancer patients, but there are also around 200 who work in hospital. They are specially trained to offer counselling to cancer patients and relatives, and are an important source of advice to GPs, patients, their families, and district nurses, especially with respect to pain control and symptomatic relief.

Marie Curie nurses are another source of part-time home care for cancer patients. They are funded by the Marie Curie Foundation and primarily provide respite for carers and overnight care for patients in their own homes.

Specialist palliative care physicians and pain relief clinics

The numbers of specialist palliative care physicians is growing. Such specialists are able to advise other healthcare professionals on symptom control in any patient, but they have particular expertise in the care of the dying. In addition, there are also specialist pain relief clinics. These are not only intended for cancer patients, but also provide care for patients with other forms of chronic and severe pain.

Hospice directors and staff

Hospices are non-hospital institutions that provide palliative care for patients who do not want or need the high-tech facilities of a hospital. The emphasis is on facilitating patient autonomy and providing a home-like environment as far as possible.

Originally, the hospice movement was funded entirely from donations, but there is now some NHS provision. Frequently, hospices have home care teams attached, who provide support and advice to patients and carers in the community.

Geriatricians

As we have seen, many cancers are conditions of old age. Geriatricians in the UK therefore have an important role in the management of many cancers.

Overview of anticancer treatment options

Anticancer treatments can be defined as treatments for cancer that have been developed with the aim of being curative. They have acknowledged side-effects but these are usually felt to be tolerable if cure (or even partial cure) is successfully achieved. In practice, however, even these "curative" treatments are not always curative as such. Anticancer treatment efficacies are usually measured in terms of five-year or seven-year survival rates.

The anticancer treatment options available include:

• surgery
• chemotherapy
• radiotherapy
• hormone therapy (limited mainly to cancers of the breast and prostate)

Anticancer treatments are even used sometimes in advanced cancers, where there is little or no chance of cure. In these cases, the treatment emphasis changes away from "cure at almost any cost" towards treatment practices that concentrate on controlling or reducing the symptoms of the disease, or the side-effects of treatments. Pain, nausea, vomiting, and constipation, are by far the most troublesome of these. This symptomatic care develops into the wider area of palliative medicine, which encompasses many more aspects than symptom control.

Curative and palliative therapy

The choice between curative or palliative care is not straightforward. It must be based on a wide range of factors, including:

• a clinical assessment of the tumour stage and prognosis
• the likely side-effects of "curative" treatment (if this is still possible)
• the patient's overall condition, age and nutritional status
• the presence of complications such as infections
• the degree of robustness or frailty of the patient
• emotional factors.

An individual decision must be made for each patient, with the situation changing subtly as the disease progresses. There is no single, definable cut-off point when palliative care takes over entirely from curative.

A fact that is sometimes overlooked is that the patient's view may be very different from the doctor's (or even from that of other lay people). For example, one study showed recently that patients were prepared to opt for intensive treatments such as radical chemotherapy even when they were told that the treatment offered only a 1% chance of achieving an additional lifespan of 12 months, and only a 10% chance of alleviating their symptoms.(14)

In practice, the switch from curative to palliative treatment often comes when prognosis is estimated at six months or less. (15)

Surgery

Surgery is the primary treatment for localised solid tumours, where it is potentially curative, depending on the rate and pattern of tumour growth. The surgeon may excise not just the tumour itself, but also parts of the surrounding tissue and/or lymph nodes in case these were involved as well.(16)

Increasingly, there is concern about micro-metastases that early investigations may have missed. In addition, tumours sometimes regrow at the primary site, perhaps from cancer tissue that has been inadvertently left behind. For these reasons, chemotherapy is used more and more as an adjunct to surgery, even in tumours that seem very localised.

In more extensive disease, where the primary tumour is very invasive or metastases are already present, surgery to remove all diseased tissue is no longer feasible. In these cases, therefore, surgery is usually confined to removal of the primary tumour only, while chemotherapy and radiotherapy are directed against the wider spread of disease.

Laser surgery is a technique that is sometimes used curatively, but is considered especially useful for the palliation of certain advanced tumours. It is used, for example, against tumours located deep in the bronchi, to alleviate airways obstruction and improve patients' breathing. Laser surgery has also been used successfully in advanced oesophageal and colorectal tumours, to maintain flow of the gut lumen. (16)

Curative radiotherapy

When used against primary tumours, radiotherapy is primarily intended to be curative. In these situations, the dosage is usually fractionated (i.e. the total dose is divided into many smaller doses, given repeatedly on a regular basis, usually daily). This is done mainly in order to exploit the difference in recovery rate between normal and tumour cells.

One regimen of fractionated radiotherapy is known as multiple daily fractions, where a small dose is given daily over 2-3 weeks. Multiple fractions daily is a newer regimen being tried in some centres, where 2 or 3 doses are given in every 24 hours.

Palliative radiotherapy

Radiotherapy is sometimes used in the palliation of cancers to alleviate symptoms by reducing tumour size. It may be directed against the primary tumour or against secondary metastases. Even a single dose of radiation can provide good palliation and may be used in the treatment of painful bone metastases. In planning a course of radiotherapy, factors such as:

• the patient's progress
• how far they live from the unit
• the severity of their pain

need to be considered as well, as their tumour factors.

Side-effects

Radiation affects healthy as well as cancerous tissue, and radiotherapy therefore can have a variety of unpleasant side-effects which will depend on the site (field) irradiated and the dose given. Although malaise and weakness are often a problem, site-specific side-effects, such as the following, are nearly always self-limiting:

• nausea and vomiting
• diarrhoea
• suppression of bone marrow (see below)
• hair loss (alopecia).

Consequently, potential side-effects are also a factor in planning radiotherapy.

Bone marrow toxicity

Bone marrow toxicity carries with it the danger of blood cell shortages. Deficiency of white blood cells is dangerous because it seriously impairs a patient's immunity, increasing the danger of infection, while deficiency of other blood cell types may lead to bleeding problems or symptoms of anaemia. When used at high "curative" doses, chemotherapy sometimes causes such severe bone marrow toxicity that patients must be looked after in isolation units to protect them against infection.

In addition, very high dose chemotherapy will sometimes be combined with a bone marrow transplant, either with the patient's own bone marrow (autologous) or from a donor (allogeneic).

Chemotherapy

Chemotherapy is the use of drugs to inhibit cancer cell growth. At one time, it was restricted to use only in the metastatic stages of disease, but now it is widely used as an adjunct to surgery or radiotherapy of the primary tumour, to prevent micro-metastases forming and spreading.

Although the first use of chemotherapy was in 1942 (nitrogen mustard),(18) the real "explosion" in anti-cancer drugs took place in the 1960s and subsequently.

The speciality of medical oncology, the science of using these drugs, continues to grow in Britain. A huge range of different agents is now available. The success of chemotherapy varies greatly. In testicular cancer, for example, the cure rate is now over 90%. (1) However, this is one of the rarer cancers (although it is still the most common malignancy of younger men). In general, the most common cancers are the least responsive.

The relief of pain, dyspnoea, and other symptoms of malignant disease can be achieved by shrinkage of the tumour. Chemotherapy can be of help in this respect, even if life will not be prolonged. Patients will benefit if reduction of tumour mass opens a bronchus or unblocks the bowel, reduces pain, or relieves pressure on tissues and organs.

Chemotherapy dosage regimens

Like radiotherapy, chemotherapy works because it is cytotoxic - its aim is to kill the actively dividing tumour. Like radiotherapy, therefore, it must usually be given in divided doses over a period of days or weeks, in order to allow recovery of normal cells.

The main problem is that drug treatment is systemic, rather than localised like radiotherapy. Thus, the drugs used affect the whole body, not just the tumour site. Certain body tissues, particularly those of the bone marrow or gut lining, are even more rapidly-dividing than tumour cells and this makes them very vulnerable to the drugs' cytotoxic effects. In practice, therefore, the risk of bone marrow toxicity limits the chemotherapy dosage that can be given.

Combination chemotherapy

The heterogeneity of malignant tumours can sometimes make them quite difficult to treat when only a single drug is used. Small sub-populations of cells may occur that are resistant to therapy and are able to regrow. For this reason, combinations of several drugs, active against cells in different stages of the cell cycle, are often used becauses this helps to maximise the combination's effect.

Side-effects

Chemotherapy can have many unpleasant acute effects. Different chemotherapy agents have different side-effects but some of the most common are:

• bone marrow toxicity
• alopecia
• skin rashes
• sore mouths and throats (including ulcerations) linked to epithelial sensitivity
• fatigue
• diarrhoea
• nausea and vomiting.

It is important to note that these side-effects can be minimised, providing care is taken to select the optimum agent for each patient. Long-term side effects such as infertility, pulmonary fibrosis, carcinogenesis, cardiac damage, and hepatotoxity, are sometimes an issue in people who have been cured successfully with chemotherapy (e.g. children cured of leukaemia). Generally, however, the main issues relating to chemotherapy side effects are the patient's capacity to withstand them, and the limits this places on the use of chemotherapy in frail patients with advanced disease.

Hormone therapy

Hormone therapy is now used widely in cancers of the breast and prostate, although its application in other conditions is limited. In some types of breast cancer, for example, it is known that oestrogen receptors are present, and that suppression of natural oestrogen production through oophorectomy is sometimes an effective treatment. These days, anti-oestrogens such as tamoxifen are the treatment of choice in post-menopausal women with breast cancer that has already metastasised and made surgery impractical. Permanent regression is sometimes achieved and the side-effects are considered relatively minimal.(6) Maintenance doses may be needed for many years and therapy is often supervised by GPs.

Similarly, prostatic cancer often responds to the suppression of natural testosterone production by orchidectomy, but alternative hormonal drug therapies have now replaced this drastic course of action.

Examples of hormonal drug therapies for prostatic cancer are

• GRH analogues, for example goserelin (Zoladex)
• stilboestrol, for example Apstil
• cyproterone acetate, for example Cyprostat

Management of common cancers
Lung Cancer

Some non-small cell carcinomas may be surgically resectable, otherwise "radical radiotherapy" may be curative. Small cell carcinomas, by contrast, are usually very chemo-sensitive, although they have very short remission periods. Recent evidence has also shown that chemotherapy can provide useful symptom relief in some patients with non-small cell lung cancer. Radiotherapy may be helpful where surgery is not appropriate, and this may also provide relief from symptoms due to bony metastases in patients with both non-small cell and small cell cancer.

Breast cancer

With newly diagnosed breast cancer there are a number of options available:

• chemotherapy; e.g. in pre-menopausal women, tamoxifen is increasingly becoming the drug of choice
• surgery; for those patients for whom surgical treatment is appropriate, a traditional radical mastectomy has been largely replaced by the less drastic lumpectomy, with post-operative radiotherapy being given if there is evidence of lymphatic spread
• if metastases are present, treatment with chemotherapy or hormonal therapy is used with or without surgery, depending on the size and spread of the primary tumour
• adjuvant chemotherapy may also be used to prevent the spread of micrometastases.

In inoperable, widespread or recurrent disease, radiotherapy may be given to reduce tumour mass, heal ulceration, and control bleeding and discharge.

Bone and brain metastases are often helped by local irradiation. Chemotherapy may also be used to slow down the spread.

Cancers of the colon and rectum

In large bowel cancer, the main treatment is the surgical excision of the affected part of the bowel, and a stoma may be required. In addition, palliative radiotherapy and chemotherapy can often provide good symptom control in cases of metastatic disease.

Prostatic cancer

Surgical prostatectomy is potentially curative in the early stages of disease, but patients are often too old and frail, or the disease is frequently too advanced, for this to be possible. Local radiotherapy is also used sometimes, initially for the primary tumour and later for bony metastases. Once metastases are present, hormone therapy is the usual course of treatment.

Leukaemias and lymphomas

These are treated mainly by chemotherapy, and the technique of bone marrow transplantation is now allowing higher doses to be given effectively in some types. The technique is to give the patient chemotherapy first, followed by total body irradiation, and then a bone marrow transplant to replace the damaged bone marrow. Immuno-suppressive drugs are needed to prevent bone marrow rejection, and the procedure may be a cause of treatment-associated death.

Summary

By now you should have an understanding of the disease processes involved in malignant cancer. The clinical consequences of the disease vary according to tumour location and metastatic spread, but pain, inflammation, and loss of function are common denominators.

The management of cancer can be divided into curative approaches aimed at eradicating the tumour, and treatments intended to relieve the symptoms of the disease process itself, or those resulting from side-effects of the anti-cancer therapies. In practice, however, the two approaches are usually combined until poor prognosis, coupled with weakened patient state, makes aggressive treatment unacceptable.

Pain remains the major concern of patient and professional alike. The significance of this relates not just to the obvious distress and unpleasantness but to deeper issues, for example, family stress, psychological factors, and spiritual dilemmas. This topic is explored in depth in the next booklet, Cancer Pain and its Management.

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