BMA Concise Guide to Medicine & Drugs

MALIGNANT AND IMMUNE DISEASE

New cells are continuously needed by the body to replace those that wear out and die naturally and to repair injured tissue. Normally, the rate at which cells are created is carefully regulated. However, sometimes abnormal cells are formed that multiply uncontrollably. They may form lumps of abnormal tissue. These tumours are usually confined to one place and cause few problems; these are benign growths, such as warts. In other types of tumour the cells may invade or destroy the structures around the tumour, and abnormal cells may spread to other parts of the body, forming satellite or metastatic tumours. These are malignant growths, also called cancers.

Opposing the development of tumours is the body’s immune system. This can recognize as foreign not only invading bacteria and viruses but also transplanted tissue and cells that have become cancerous. The immune system relies on different types of white blood cells produced in the lymph glands and the bone marrow.

TYPES OF CANCER

Uncontrolled multiplication of cells leads to the formation of tumours that may be benign or malignant. Benign tumours do not spread to other tissues; malignant (cancerous) tumours do, however.

Carcinomas affect the skin and cells in the tissue lining internal organs.

Sarcomas affect muscles, bones, and fibrous tissues and lining cells of blood vessels.

Leukaemia affects white blood cells.

Lymphomas affect the lymph glands.

WHAT CAN GO WRONG

A single cause for cancer has not been identified, and an individual’s risk of developing cancer may depend both upon genetic predisposition (some families seem prone to cancers of one or more types) and upon exposure to external risk factors, known as carcinogens. These include tobacco smoke, which increases the risk of lung cancer, and ultraviolet light, which makes skin cancer more likely in those who spend long periods in the sun. Long-term suppression of the immune system by disease (as in AIDS) or by drugs – for example, those given to prevent rejection of transplanted organs – increases the risk of developing infections and also certain cancers. This demonstrates the importance of the immune system in removing abnormal cells with the potential to cause a tumour.

Overactivity of the immune system may also cause problems. It may respond excessively to an innocuous stimulus, as in hay fever (see Allergy), or may mount a reaction against normal tissues (autoimmunity), leading to disorders known as autoimmune diseases. These include rheumatoid arthritis, systemic lupus erythematosus, pernicious anaemia, and some forms of hypothyroidism. Immune system activity can also be troublesome following a transplant, when it may lead to rejection of the foreign tissue. Medication is then needed to damp down the immune system and enable the body to accept the foreign tissue.

WHY DRUGS ARE USED

In cancer treatment, conventional chemotherapy involves using cytotoxic (cell-killing drugs) to eliminate abnormally dividing cells. These slow the growth rate of tumours and sometimes lead to their complete disappearance. Because these drugs act against all rapidly dividing cells, they also reduce the number of normal cells, including blood cells, being produced from bone marrow. This can produce serious adverse effects, such as anaemia and neutropenia in cancer patients, but it can be useful in limiting white cell activity in autoimmune disorders. Newer anticancer drugs are more selective in the cells they target. For example, trastuzumab (Herceptin) targets a specific protein produced by certain types of breast cancer cells.

Other drugs that have immunosuppressant effects include corticosteroids, azathioprine, and ciclosporin, which are used after transplant surgery. No drugs are yet available that directly stimulate the entire immune system.

However, growth factors may be used to increase the number and activity of some white blood cells, and antibody infusions may help those with deficient production or be used against specific targets in organ transplantation and cancer.

MAJOR DRUG GROUPS

· Anticancer drugs

· Immunosuppressant drugs

· Drugs for HIV and AIDS

Anticancer drugs

Cancer is a general term that covers a wide range of disorders, ranging from the leukaemias (blood cancers) to solid tumours of the lung, breast, and other organs. In all cancers, a group of cells escape from the normal controls on cell growth and multiplication. As a result, the malignant (cancerous) cells begin to crowd out the normal cells and a tumour develops. Cancerous cells are frequently unable to perform their usual functions, and this may lead to progressively impaired function of the organ or area concerned. Cancers may develop from cells of the blood, skin, muscle, or any other tissue.

Malignant tumours spread into nearby structures, blocking blood vessels and compressing nerves and other structures. Fragments of the tumour may become detached and carried in the bloodstream to other parts of the body, where they form secondary growths (metastases).

Many different factors, or a combination of them, can provoke cancerous changes in cells. These factors include an individual’s genetic background, impairment or failure of the immune system, and exposure to cancer-causing agents (carcinogens). Known carcinogens include strong sunlight, tobacco smoke, radiation, certain chemicals, viruses, and dietary factors.

Treating cancer is a complicated process that depends on the type of cancer, its stage of development, and the patient’s condition and wishes. Any of the following treatments may be used alone or in combination with the others: surgery, radiation treatment, and drug therapy.

Until recently, drug treatment of cancer relied heavily on hormonal drugs and cytotoxic agents (usually referred to as chemotherapy). Hormone treatments are suitable for only a few types of cancer and cytotoxic drugs, although valuable, can have severe side effects because of the damage that they do to normal tissues. In recent years, as understanding of cancer biology has increased, new anticancer drugs have been developed. These drugs include cytokines, such as interferon and interleukin-2, that stimulate the immune system to attack certain cancers, and monoclonal antibodies and growth factor inhibitors that attack the cancer cells much more selectively.

WHY THEY ARE USED

Cytotoxic drugs can cure rapidly growing cancers and are the treatment of choice for leukaemias, lymphomas, and certain cancers of the testis. They are less effective against slow-growing solid tumours, such as those of the breast and bowel, but they can relieve symptoms and prolong life when given as palliative chemotherapy (treatment that relieves symptoms but does not cure the disease). Adjuvant chemotherapy is increasingly being used after surgery, especially for breast and bowel tumours, to prevent regrowth of the cancer from cells left behind after surgery. Neoadjuvant, or primary chemotherapy may sometimes be used before surgery to reduce the size of the tumour.

Hormone treatment is offered in cases of hormone-sensitive cancer, such as breast, uterine, and prostatic cancers, where it can be used to relieve disease symptoms or provide palliative treatment in advanced disease. Cytokines, monoclonal antibodies, and growth factor inhibitors are increasingly used alongside or instead of conventional chemotherapy. Sometimes these can be curative but often they produce or prolong disease remission.

Most anticancer drugs, especially cytotoxic drugs, have side effects, which are sometimes severe, and so treatment decisions have to balance possible benefits against the side effects.

Often a combination of several drugs is used. Special regimes of different drugs that are used together and in succession have been devised to maximize their activity and minimize the side effects.

Certain anticancer drugs are also used for their effect in suppressing immune system activity.

HOW THEY WORK

Anticancer drugs work in many different ways. The main groups of drugs and how they work are described here.

Cytotoxic drugs There are several classes of cytotoxic drugs, including the alkylating agents, antimetabolites, taxanes, and cytotoxic antibiotics. Each class has a different mechanism of action, but all act by interfering with basic processes of cell replication and division. They are particularly potent against rapidly dividing cells. These include cancer cells but also certain normal cells, especially those in the hair follicles, gut lining, and bone marrow. This explains their side effects and why treatment needs careful scheduling.

Hormone therapies Hormone treatments act by counteracting the effects of the hormone that is encouraging growth of the cancer. For example, some breast cancers are stimulated by the female sex hormone oestrogen; the action of oestrogen is opposed by the drug tamoxifen. Other cancers are damaged by very high doses of a particular sex hormone. An example is medroxyprogesterone, a progesterone that is often used to halt the spread of endometrial cancer.

Cytokines The cytokines, interferon alfa and interleukin-2, stimulate the immune system to attack certain cancers. The mechanisms responsible for this action are not entirely understood.

Monoclonal antibodies Antibodies are a fundamental building block of the immune system. They recognize and bind very specifically to foreign proteins on the surface of bacteria, viruses, and parasites, marking them out for destruction by other parts of the immune system. Monoclonal antibodies are produced in tissue culture using cells genetically engineered to make antibodies against a particular target protein. If the target is carefully selected, the antibodies can be used to identify cancer cells for destruction. If the target is found only on cancer cells, or on the cancer cells and the normal tissue from which it arose, the damage to healthy tissues during treatment is limited.

Monoclonal antibodies are being used increasingly in cancer treatment. Examples include trastuzumab (Herceptin), which binds to a protein produced by certain types of breast cancer cells, and alemtuzumab and rituximab, which recognize different types of proteins on white blood cells and are used to treat leukaemias and lymphomas. These antibodies are very specific for certain types of cancer, and they cause little of the toxicity of conventional chemotherapy. They can, however, cause allergy-type reactions, especially at the beginning of treatment.

Growth factor inhibitors The growth of cells is controlled by a complex network of growth factors that bind very specifically to receptor sites on the cell surface. This triggers a complex series of chemical reactions that transmit the “grow” message to the nucleus, triggering cell growth and replication. In many cancers, this system is faulty and there are either too many receptors on the cell surface or other abnormalities that result in inappropriate “grow” messages. The extra or abnormal cell surface receptors can be used as targets for monoclonal antibodies.

Other defects in this system are being used as the basis for other new drugs. For example, imatinib very selectively interferes with an abnormal version of an enzyme found in certain leukaemic cells. This abnormal enzyme results in the cell nucleus receiving a “grow” signal continuously, resulting in the uncontrolled growth of cancer. By stopping the enzyme working, it is possible to selectively “turn off” the growth of the abnormal cells. Imatinib is proving successful in treating certain types of leukaemia, with few serious side effects.

Another new area of cancer treatment is the use of drugs that inhibit the growth of new blood vessels to tumours (anti-angiogenesis agents), thereby depriving the tumours of the nutrients and oxygen they need to grow. One example is bevacizumab, a monoclonal antibody that blocks vascular endothelial growth factor (VEGF), a protein produced by certain tumours that promotes blood vessel growth. Bevacizumab is used to treat advanced cancer of the bowel, breast, lung, or kidney. Other new drugs are being developed that work in similar ways.

HOW THEY AFFECT YOU

Cytotoxic drugs are generally associated with more side effects than other anticancer drugs. At the start of treatment, adverse effects of the drugs may be more noticeable than benefits. The most common side effect is nausea and vomiting, for which an anti-emetic drug will usually be prescribed. Effects on the blood are also common. Many cytotoxic drugs cause hair loss because of their effect on the hair follicle cells, but the hair usually starts to grow back after chemotherapy has been completed. Individual drugs may produce other side effects.

Cytotoxic drugs are, in most cases, administered in the highest doses that can be tolerated in order to kill as many cancer cells as quickly as possible.

The unpleasant side effects of intensive chemotherapy, combined with a delay of several weeks before any beneficial effects are seen and the seriousness of the underlying disease, often lead to depression in those who are receiving anticancer drugs. Specialist counselling, support from family and friends, and, in some cases, treatment with antidepressant drugs may be helpful.

SUCCESSFUL CHEMOTHERAPY

Not all cancers respond to treatment with anticancer drugs. Some cancers can be cured by drug treatment. In other cancers, drug treatment can slow or temporarily halt the disease’s progress. In certain cases, drug treatment has no beneficial effect but other treatments, such as surgery, often produce significant benefits. The main cancers that fall into each of the first two groups are described here:

Cancers that can often be cured by drugs

· Some cancers of the lymphatic system (including Hodgkin’s disease)

· Acute leukaemias (forms of blood cancer)

· Choriocarcinoma (cancer of the placenta)

· Germ cell tumours (cancers affecting sperm and egg cells)

· Wilms’ tumour (a rare form of kidney cancer that affects children)

· Cancer of the testis

Cancers in which drugs may produce worthwhile benefits

· Breast cancer

· Ovarian cancer

· Some leukaemias

· Multiple myeloma (a bone marrow cancer)

· Many types of lung cancer

· Head and neck cancers

· Cancer of the stomach

· Cancer of the prostate

· Some cancers of the lymphatic system

· Bladder cancer

· Endometrial cancer (cancer affecting the lining of the uterus)

· Cancer of the large intestine

· Cancer of the oesophagus

· Cancer of the pancreas

· Cancer of the cervix

Successful drug treatment of cancer usually requires repeated courses of anticancer drugs because the treatment needs to be halted periodically to allow the blood-producing cells in the bone marrow to recover.

RISKS AND SPECIAL PRECAUTIONS

All cytotoxic anticancer drugs interfere with the activity of noncancerous cells and, for this reason, they often produce serious adverse effects during long-term treatment. In particular, these drugs often adversely affect rapidly dividing cells such as the blood-producing cells in the bone marrow. The numbers of red and white cells and the number of platelets (particles in the blood responsible for clotting) may all be reduced. In some cases, symptoms of anaemia (weakness and fatigue) and an increased risk of abnormal or excessive bleeding may develop as a result of treatment with anticancer drugs.

Reduction in the number of white blood cells may result in an increased susceptibility to infection. A simple infection such as a sore throat may be a sign of depressed white cell production in a patient taking anticancer drugs, and it must be reported to the doctor without delay. In addition, wounds may take longer to heal, and susceptible people can develop gout as a result of increased uric acid production due to cells being broken down.

Because of these problems, anticancer chemotherapy is often given in hospital, where the adverse effects can be closely monitored. Several short courses of drug treatment are usually given, thus allowing the bone marrow time to recover in the period between courses (see Successful chemotherapy). Blood tests are performed regularly. When necessary, blood transfusions, antibiotics, or other forms of treatment are used to overcome adverse effects. When relevant, contraceptive advice is given early in treatment because most anticancer drugs can damage a developing baby. In some cases, eggs or sperm may be harvested before chemotherapy for later IVF after the chemotherapy is completed. In addition to these general effects, individual drugs may have adverse effects on particular organs. These are described under individual drug profiles in Part 2.

By contrast, other anticancer drugs, such as hormonal drugs, antibodies, and growth factor inhibitors are much more selective in their actions and they generally have less serious side effects.

COMMON DRUGS

Alkylating agents Chlorambucil, Cyclophosphamide, Melphalan

Antimetabolites Azathioprine, Capecitabine, Cytarabine, Fluorouracil, Mercaptopurine, Methotrexate

Cytotoxic antibiotics Doxorubicin, Epirubicin

Hormone treatments Anastrozole, Bicalutamide, Cyproterone, Flutamide, Goserelin, Letrozole, Leuprorelin, Medroxyprogesterone, Megestrol, Tamoxifen

Cytokines Interferon alfa, Interleukin-2

Taxanes Docetaxel, Paclitaxel

Monoclonal antibodies Alemtuzumab, Bevacizumab, Rituximab, Trastuzumab

Growth factor inhibitors Imatinib

Other drugs Carboplatin, Cisplatin, Etoposide, Irinotecan

Immunosuppressant drugs

The body is protected against attack from bacteria, fungi, and viruses by the specialized cells and proteins in the blood and tissues that make up the immune system. White blood cells known as lymphocytes either kill invading organisms directly or produce special proteins (antibodies) to destroy them. These mechanisms are also responsible for eliminating abnormal or unhealthy cells that could otherwise multiply and develop into a cancer.

In certain conditions it is medically necessary to damp down the activity of the immune system. These include a number of autoimmune disorders in which the immune system attacks normal body tissue. Autoimmune disorders may affect a single organ – for example, the kidneys in Goodpasture’s syndrome or the thyroid gland in Hashimoto’s disease – or they may result in widespread damage, for example, in rheumatoid arthritis or systemic lupus erythematosus.

Immune system activity may also need to be reduced following an organ transplant, when the body’s defences would otherwise attack and reject the transplanted tissue.

Several types of drugs are used as immunosuppressants: anticancer drugs, corticosteroids, ciclosporin, and monoclonal antibodies.

WHY THEY ARE USED

Immunosuppressant drugs are given to treat autoimmune disorders, such as rheumatoid arthritis, when symptoms are severe and other treatments have not provided adequate relief. Corticosteroids are usually prescribed initially. The pronounced anti-inflammatory effect of these drugs, as well as their immunosuppressant action, helps to promote healing of tissue damaged by abnormal immune system activity. Anticancer drugs such as methotrexate may be used in addition to corticosteroids if these do not produce sufficient improvement or if their effect wanes (see also Antirheumatic drugs).

Immunosuppressant drugs are given before and after organ and other tissue transplants. Treatment may have to be continued indefinitely to prevent rejection. Various drugs and drug combinations are used, depending on which organ is being transplanted and the underlying condition of the patient. However, ciclosporin, along with the related drug tacrolimus, is now the most widely used drug for preventing organ rejection. It is also increasingly used to treat autoimmune disorders. It is often used in combination with a corticosteroid or the more specific drug mycophenolate mofetil.

Monoclonal antibodies, which destroy specific cells of the immune system, are also used to aid transplantation and are increasingly being used to treat autoimmune disorders. For example, adalimumab is used to treat certain types of arthritis while rituximab is also used for systemic lupus erythematosus and vasculitis.

HOW THEY WORK

Immunosuppressant drugs reduce the effectiveness of the immune system, either by depressing the production of lymphocytes or by altering their activity.

HOW THEY AFFECT YOU

When immunosuppressants are given to treat an autoimmune disorder, they reduce the severity of symptoms and may temporarily halt the progress of the disease. However, they cannot restore major tissue damage.

Immunosuppressant drugs can produce a variety of unwanted side effects. The side effects caused by corticosteroids are described in more detail. Anticancer drugs, when prescribed as immunosuppressants, are given in low doses that produce only mild side effects. They may cause nausea and vomiting, for which an anti-emetic drug may be prescribed. Hair loss is rare and regrowth usually occurs when the drug treatment is discontinued. Ciclosporin may cause increased growth of facial hair, swelling of the gums, and tingling in the hands.

RISKS AND SPECIAL PRECAUTIONS

All of these drugs may produce potentially serious adverse effects. By reducing the activity of the patient’s immune system, immunosuppressant drugs can affect the body’s ability to fight invading microorganisms, thereby increasing the risk of serious infections. Because lymphocyte activity is also important for preventing the multiplication of abnormal cells, there is an increased risk of certain types of cancer. A major drawback of anticancer drugs is that, in addition to their effect on the production of lymphocytes, they interfere with the growth and division of other blood cells in the bone marrow. Reduced production of red blood cells can cause anaemia; when the production of blood platelets is suppressed, blood clotting may be less efficient.

Although ciclosporin is more specific in its action than either corticosteroids or anticancer drugs, it can cause kidney damage and, in too high a dose, may affect the brain, causing hallucinations or seizures. Ciclosporin also tends to raise blood pressure, and another drug may be required to counteract this effect (see Antihypertensive drugs).

COMMON DRUGS

Anticancer drugs Azathioprine, Chlorambucil, Cyclophosphamide, Methotrexate

Corticosteroids

Antibodies Adalimumab, Anti-lymphocyte globulin, Basiliximab, Infliximab, Rituximab

Other drugs Ciclosporin, Mycophenolate mofetil, Tacrolimus

Drugs for HIV and AIDS

The disease AIDS (acquired immune deficiency syndrome) is caused by infection with the human immunodeficiency virus (HIV). This virus invades certain cells of the immune system, particularly the white blood cells called T-helper lymphocytes (or CD4 cells), which normally activate other immune cells to fight infection. HIV kills T-helper lymphocytes, so that the body cannot fight the virus or subsequent infections. In recent years the number of drugs to treat HIV has increased considerably, as well as knowledge about how best to use them in combination.

WHY THEY ARE USED

Drug treatments for HIV infection can be divided into treatment of the initial infection with HIV and treatment of diseases and complications associated with AIDS.

Drugs that act directly against HIV are called antiretrovirals. The two most common groups work by interfering with enzymes vital for virus replication. The first inhibit an enzyme called reverse transcriptase. They are divided according to their chemical structure into nucleoside inhibitors (also called nucleoside analogues), nucleotide inhibitors (nucleotide analogues), and non-nucleoside inhibitors. The second group interfere with an enzyme called protease. Entry, or fusion, inhibitors are a new group that interfere with the entry of the virus into the cell. Further groups are being developed: integrase inhibitors to prevent the virus from injecting its genetic material into the cell nucleus; and other drugs to target the receptor sites the virus relies on for entry into cells.

Antiretrovirals are much more effective in combination. Treatment usually starts with two nucleoside transcriptase inhibitors plus a non-nucleoside drug or protease inhibitor. If combination, or highly active antiretroviral therapy (HAART), is started before the immune system is too damaged, it can dramatically reduce the level of HIV in the body and improve the outlook for HIV-infected people, but it is not a cure and such people remain infectious.

The mainstay of drug treatment for AIDS-related diseases are antimicrobial drugs for the bacterial, viral, fungal, and protozoal infections to which people with AIDS are particularly susceptible. These drugs include antituberculous drugs, co-trimoxazole for pneumocystis pneumonia, and ganciclovir to treat cytomegalovirus (CMV) infection.

DK

COMMON DRUGS

Nucleoside reverse transcriptase inhibitors (nucleoside analogues) Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Zidovudine (AZT)/ lamivudine

Nucleotide reverse transcriptase inhibitor (nucleotide analogue) Tenofovir

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz, Nevirapine

Protease inhibitors (PIs) Atazanavir, Fosamprenavir, Lopinavir/ritonavir, Nelfinavir, Saquinavir, Tipranavir

Fusion inhibitor Enfuvirtide