12 Cancer
Concepts of cancer chemotherapy
Cancer
Cancers are malignant neoplasms (new growths). Despite their variability, cancers share the characteristics of:
Cancers account for 20–25% of deaths in the Western world; attempts to cure or palliate cancer use three principal methods: surgery, radiotherapy and chemotherapy. These methods are not mutually exclusive, often being used in combination, e.g. adjuvant chemotherapy after surgical removal of a tumour.
Chemotherapy
Cancer chemotherapy is the use of drugs to inhibit the rate of growth of, or to kill, cancerous cells while having minimal effects on non-neoplastic host cells.
In a fashion similar to antimicrobial chemotherapy, the ideal anti-cancer drugs target malignant cells in preference to non-malignant cells. This is achieved by exploiting the molecular differences between them.
Mr Collins is a 60-year-old delivery man, who presents with a 6-week history of passage of fresh blood from his anus and diarrhoea (he is normally slightly constipated). He also admits to low appetite, significant weight loss and feeling fatigued. He is referred for investigative colonoscopy, which reveals an abnormal growth in the descending colon. A biopsy reveals adenocarcinoma of the colon. Staging CT scans show no other areas of disease. He is managed by surgical resection of the tumour. Following this he undergoes adjuvant chemotherapy consisting of six cycles of 5-fluorouracil.
The most striking difference between cancerous and non-cancerous cells is their accelerated rate of cell division. This remains the main target for therapeutic intervention at present, though newer drugs are being developed which recognize other molecular differences.
The chemotherapeutic techniques currently used include:
Cancers differ in their sensitivity to chemotherapy, from the very sensitive (e.g. lymphomas, testicular carcinomas) where complete clinical cures can be achieved, to the resistant (generally solid tumours, e.g. colorectal, squamous cell bronchial carcinoma).
A diagnosis of cancer carries a significant social and emotional impact. Hair loss and sickness are more often the initial concern for patients, rather than other potentially serious side-effects of chemotherapy. Nausea and vomiting should be taken seriously in cancer management, as these can have a devastating impact on quality of life; antiemetic drugs are discussed in Chapter 8.
Cytotoxic chemotherapy
Mechanisms of action
Most cytotoxic drugs affect DNA synthesis. They can be classified according to their site of action on the process of DNA synthesis within the cancer cell (Fig. 12.1). Cytotoxic drugs are therefore most active against actively cycling/proliferating cells, both normal and malignant, and least active against non-dividing cells.
Some drugs are only effective at killing cycling cells during specific parts of the cell cycle. These are known as phase-specific drugs (Fig. 12.2). Other drugs are cytotoxic towards cycling cells throughout the cell cycle (e.g. alkylating agents) and are known as cycle-specific drugs.
Selectivity
Cytotoxic drugs are not specifically toxic to cancer cells, and the selectivity they show is marginal at best.
Cytotoxic drugs affect all dividing tissues, both normal and malignant, and thus are likely to have general toxic side-effects (see Fig. 12.4). The side-effects of cytotoxic drugs are most often related to the inhibition of division of non-cancerous host cells, namely in the gut, in the bone marrow and in the reproductive and immune systems.
Relative selectivity can occur with some cancers because:
Knowledge of these principles and knowing that cytotoxic drugs kill a constant fraction, not a constant number, of cells, lays down the foundation for chemotherapeutic dosing schedules (Fig. 12.3).
Resistance to cytotoxic drugs
Genetic resistance to cytotoxic drugs can be inherent to the cancer cell line or acquired during the course of chemotherapy, as a result of selection imposed by the chemotherapeutic agent.
Mechanisms of genetic resistance to cytotoxic drugs
The mechanisms of genetic resistance to cytotoxic drugs include:
Some tumours are relatively resistant to chemotherapy because they exist in so-called ‘pharmacological sanctuaries’. These occur when a tumour is in a privileged compartment, e.g. inside the blood–brain barrier, or in large solid tumours when poor blood supply and diffusion limit the penetration of the drug.
In clinical practice, cancers may be treated more successfully with combinations of cytotoxic drugs simultaneously, for example FEC (5-flourouracil, epirubicin and cyclophosphamide) for breast cancer. The theory is that multiple attacks with cytotoxic agents acting at different biochemical sites will increase efficacy while reducing the likelihood of resistance.
Cytotoxic agents
Cytotoxic agents, the major group of anticancer drugs, include the:
Mrs Overton, 58 years old, presents to her GP following increasing vague abdominal pain and discomfort for the past 4 months and abdominal distension for the past 1 month. She is referred to accident and emergency and admitted. A CT scan is done and an ascitic drain inserted, from which a sample of the fluid is sent to cytology. CT shows ovarian and omental masses. Cytological examination of ascitic fluid indicates adenocarcinoma.
Laparotomy is done allowing peritoneal biopsy which shows ovarian malignancy. Mrs Overton’s management includes removal of her uterus, ovaries and omentum. After surgery she is started on a 6-month course of carboplatin and paclitaxel.
Alkylating agents
Examples of alkylating agents include melphalan, cyclophosphamide and chlorambucil.
Mechanism of action
Alkylating agents act via a reactive alkyl group that reacts to form covalent bonds with nucleic acids. There follows either cross-linking of the two strands of DNA, preventing replication, or DNA strand breakage (see Fig. 12.1).
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