Suppression of the production of haemoglobin, white cell series and platelets may occur with many cytotoxic drugs and is a dose-related phenomenon. Severely myelosuppressive chemotherapy is only used when treatment is given with curative intent. Anaemia and thrombocytopenia are managed by blood or platelet transfusions but white cell transfusions have not been successful. Neutropenic patients are therefore managed by the early introduction of broad-spectrum antibiotics intravenously for the prevention and treatment of infection. Initial ‘blind’ therapy should be with a third generation cephalosporin, e.g. ceftazidirne, sometimes combined with an arninoglycoside or a broad-spectrum penicillin; therapy should be reviewed following microbiological results. Haemopoietic growth factors can now reduce the duration of neutropenia
This is a rare side-effect of chemotherapy, usually associated with doxorubicin. It is dose related and can largely be prevented by keeping the total dose within the safe range.
This occurs predominantly with the plant alkaloids and platinum analogues. It is dose related and chemotherapy is usually stopped before the development of a significant polyneuropathy. This is only partially reversible.
A number of cytotoxic drugs, particularly platinum analogues, can potentially cause renal damage but this can usually be prevented by maintaining an adequate diuresis during treatment.
Some anticancer drugs, particularly alkylating agents, may cause sterility which can be irreversible. In males the storage of sperm is an important consideration when chemotherapy is given with curative intent.
Anticancer drugs have mutagenic potential and the development of secondary malignancies, particularly acute leukaemia, is an uncommon but particularly unwelcome long-term side-effect in patients otherwise cured of their malignancies. The alkylating agents are particularly implicated in this very severe complication.
Drug resistance is one of the major obstacles to curing cancer with chemotherapy. Some turn ours have an inherently low level of resistance to currently available treatment and are often cured. These include testicular teratomas, Hodgkin’s disease and childhood acute leukaemia. Solid tumours such as small-cell lung cancer initially appear to be chemosensitive with the majority of patients responding but most patients eventually relapse with resistant disease. In other tumours such as melaoma normal the disease is largely chemoresistant from the start. It is now thought that most resistance occurs as a result of genetic mutation and becomes more likely as the number of tumour cells increases. It has also been shown that anticancer drugs can themselves increase the rate of mutation to resistance. Unfortunately resistance to cytotoxic drugs is often multiple and is known as multidrug rasistance (MDR). An example of this is resistance to anthracyclines (e.g. doxorubicin) which is often associated with resistance to vinca alkaloids and epipodophyllotoxxis. It is thought that this resistance is mediated via increased expression of P-glycoprotein, which mediates an efflux of cytotoxic drugs. A second important mechanism for MDR concerns altered drug binding to topoisoemersa II, an enzyme which is important in bringing about DNA strand breaks in association with cytotoxic drugs. Treating patients as early as possible in the disease, using maximal doses of drugs and combination chemotherapy may help to reduce the likelihood of MDR. Many innovative approaches are currently being examined experimentally.
When a patient first presents with a tumour, it is possible that small amounts of tumour tissue have already spread to the lungs, liver, bone marrow and other sites. This micrometastatic disease consists of relatively few cells with a good blood supply, and might be particularly amenable to the action of anticancer drugs. Therefore, if the primary tumour is removed and the tumour has a great likelihood of relapse, chemotherapy can be given to destroy the residual micrometastatic disease, and the chance of long-term survival and cure might be improved. This was dramatically demonstrated in the childhood renal sarcoma, Wilms’ tumour, when the use of actinomycin D given after nephrectomy resulted in a doubling of the number of children who survived. Chemotherapy used in this way is known as adjuvant therapy, and has been employed in a number of other childhood tumours. In adults adjuvant chemotherapy has been shown to be of value in breast cancer and colon cancer.
Treatment of malignancy in sanctuary sites
A ‘sanctuary site’ is the term used to indicate that metastatic disease has involved a site that is not accessible to conventional drug therapy. An example of this is leukaemic infiltration of the meninges in children with acute lymphoblastic leukaemia. Because of the blood-brain barrier, agents such as vincristine and prednisolone do not enter the subarachnoid space in sufficient quantity to eliminate all the leukaemic cells, and are therefore ineffective in preventing the development of meningeal infiltration. In order to treat these cells, intrathecal chemotherapy and/or cranial irradiation are required.