This account describes the main groups of drugs (see p. 510) but it is important to understand the overall context in which systemic therapy is offered to patients.

Systemic cancer therapy

Cancers originating from different organs of the body differ in their initial behaviour and in their response to treatments (Table 31.1). Primary surgery and/or radiotherapy to a localised cancer offer the best chance of cure for patients. Drug treatments offer cure only for certain types of cancer, often characterised by their high proliferative rate, e.g. lymphoma, testicular cancer, Wilms’ tumour. More often, systemic therapy offers prolongation of life from months to many years and associated improvements in quality of life, even if patients ultimately die from their disease.

Table 31.1 Degree of benefit achieved with systemic therapy for common cancers

Curable: chemosensitive cancers	Improved survival: some degree of chemosensitivity	Equivocal survival benefit: chemoresistant cancers
Teratoma	Colorectal cancer	Sarcoma
Seminoma	Small cell lung cancer	Bladder cancer
High-grade non-Hodgkin’s lymphoma	Ovarian cancer	Melanoma
Hodgkin’s lymphoma	Breast cancer	Renal cancer Insensitive to cytotoxic chemotherapy but now can be controlled temporarily with oral VEGF2 and mTOR inhibitors
Wilms’ tumour	Cervical cancer	Primary brain cancers
Acute myeloblastic leukaemia	Endometrial cancer	Nasopharyngeal carcinoma
Acute lymphoblastic leukaemia in childhood	Gastro-oesophageal cancer Cholangiocarcinoma and gall bladder cancer	Hepatoma Insensitive to cytotoxic chemotherapy but now can be controlled temporarily with oral VEGF inhibitors
	Myeloma
	Pancreatic cancer
	Low-grade non-Hodgkin’s lymphoma
	Non-small cell lung cancer
	Adult acute lymphoblastic leukaemia

Use of drugs as adjuvant therapy attempts to eradicate residual microscopic cancer by treating patients after their primary surgery. This strategy has improved overall survival for patients after surgical resection of primary breast, colorectal and gastric cancer. In some situations, drugs are administered prior to surgery (neoadjuvant therapy), primarily to shrink large, locally advanced disease to subsequently enable surgical resection. Many patients with cancer are not cured by their primary treatment due to the presence of micrometastatic disease; the disease often returns months or years later even though at the time of completing their initial treatment there was no visible evidence of cancer. Clearly, this is a limitation of current standard techniques used to identify residual disease. Currently, radiological techniques cannot clearly visualise lesions smaller than 5 mm in most organs, which equates to over many million cancer cells.

Palliative therapy, offered to patients with advanced, incurable cancer, aims both to increase survival and to improve quality of life by symptom control. Despite significant improvements in cancer outcomes in the last 5–10 years, there remain a number of types of cancer that are poorly responsive to currently available drugs. Patients with chemoresistant cancers who are fit enough and willing may be offered experimental treatments within Phase 1 or 2 clinical trials.

Most treatments currently available are associated with unwanted effects of varying degrees of severity. The risk of causing harm must be weighed against the potential to do good in each individual case. Systemic therapy aims to kill malignant cells or modify their growth but leave the normal cells of the host unharmed or, more usually, temporarily harmed but capable of recovery. When there is realistic expectation of cure or extensive life prolongation, then to risk more severe drug toxicity is justified. For example, the treatment of testicular cancer with potentially life-threatening platinum-based combination chemotherapy regimens offers a greater than 85% chance of cure, even for those with extensive, metastatic disease.

Where expectation is confined to palliation in terms of modest life prolongation of less certain quality, then the benefits and risks of treatment must be judged carefully. Palliative treatments should involve low risk of adverse effects, e.g. 5-fluorouracil-based chemotherapy for advanced colorectal cancer is well tolerated by most patients, while improving survival by around 1–2 years. A modern prerequisite of cancer chemotherapy Phase 3 trials is concomitantly and objectively to assess patient quality of life while on drug therapy. This helps clinicians and nurses to explain the potential benefits and harm of treatment to patients and their families, who may themselves hold strong views about the quality and quantity of life.

Rationale for cytotoxic chemotherapy

The narrow therapeutic index of cytotoxic agents means that escalation of drug doses is constrained by damage to normal cells and the maximum doses that patients can tolerate are often suboptimal to achieve total cancer cell killing. Even so, cytotoxic chemotherapy agents remain the mainstay of systemic anticancer treatment, as an understanding of their pharmacology has enabled clinicians to exploit the benefits of these drugs (see below).

The very real limitations of cytotoxic chemotherapy have forced a concentration of cancer research on trying to understand the carcinogenic process, the aim being to identify specific molecular targets that can be exploited to develop novel therapeutic approaches. So-called targeted therapies are now well-established groups of anticancer drugs.

Classes of cytotoxic chemotherapy drugs

Cytotoxic chemotherapy drugs exert their effect by inhibiting cell proliferation. All proliferating cells, whether normal and malignant, cycle through a series of phases of: synthesis of DNA (S phase), mitosis (M phase) and rest (G₁ phase). Non-cycling cells are quiescent in G₀ phase (Fig. 31.1).

Fig. 31.1 The cell cycle. Most cytotoxic drugs inhibit the processes of DNA replication or mitosis.

Cytotoxic drugs interfere with cell division at various points of the cell cycle, in particular G₁/S phase (e.g. synthesis of nucleotides from purines and pyrimidines), S phase (preventing DNA replication) and M phase (e.g. blocking the process of mitosis).

They are thus all potentially mutagenic. Cytotoxic drugs ultimately induce cell death by apoptosis,² a process by which single cells are removed from living tissue by being fragmented into membrane-bound particles and phagocytosed by other cells. This occurs without disturbing the architecture or function of the tissue, or eliciting an inflammatory response. The instructions for apoptosis are built into the cell’s genetic material, i.e. ‘programmed cell death’.³

In general, cytotoxics are most effective against actively cycling cells and least effective against resting or quiescent cells. The latter are particularly problematic in that, although inactive, they retain the capacity to proliferate and may start cycling again after a completed course of chemotherapy, often leading later to rapid regrowth of the cancer.

Cytotoxic drugs can be classified as either:

• cell cycle non-specific: these kill cells whether they are resting or actively cycling (as in a low growth fraction cancer such as solid tumours), e.g. alkylating agents, doxorubicin and allied anthracyclines, or

• cell cycle (phase) specific: these kill only cells that are actively cycling, often because their site of action is confined to one phase of the cell cycle, e.g. antimetabolite drugs.

Table 31.2 provides a summary of the key groups of anticancer drugs, their common toxicities and main treatment applications.

Table 31.2 Principal classes of cytotoxic drug, their common toxicities and examples of clinical use

Drug class	Common toxicities	Examples of clinical use
Cytotoxic drugs
Alkylating agents	Nausea and vomiting, bone marrow depression (delayed with carmustine and lomustine), cystitis (cyclophosphamide, ifosfamide), pulmonary fibrosis (especially busulfan). Male infertility and premature menopause may occur. Myelodysplasia and secondary neoplasia	Widely used in the treatment of both haematological and non-haematological cancers, with varying degrees of success
Platinum drugs	Bone marrow depression, nausea and vomiting, allergy reaction (esp. carboplatin), nephrotoxicity, hypomagnesaemia; hypocalcaemia; hypokalaemia; hypophosphataemia; hyperuricaemia (all as a consequence of renal dysfunction, primarily associated with cisplatin); Raynaud’s disease; sterility; teratogenesis; ototoxicity (cisplatin); peripheral neuropathy; cold dysaesthesia and pharyngolaryngeal dysaesthesia (oxaliplatin)	Testicular cancers, ovarian cancer; oxaliplatin acts synergistically with 5FU and is licensed in combination with 5FU to treat both advanced and early stages of colorectal cancer
Nucleoside analogues, e.g. cytarabine, gemcitabine, fludarabine	Bone marrow depression, mainly affecting platelets; mild nausea and vomiting; diarrhoea; anaphylaxis; sudden respiratory distress with high doses (cytarabine); rash, fluid retention and oedema; profound immunosuppression with fludarabine	Cytarabine is used in haematological regimens; gemcitabine is used for pancreatic cancer, bladder cancer and some other solid tumours; fludarabine is active in chronic lymphatic leukaemia and lymphoma
Taxanes	Nausea and vomiting, hypersensitivity reactions, bone marrow depression, fluid retention; peripheral neuropathy; alopecia; arthralgias; myalgias; cardiac toxicity; mild GI disturbances; mucositis	Breast and gynaecological cancers; recent evidence that docetaxel improves survival in advanced prostate cancer
Anthracyclines	Nausea and vomiting, bone marrow depression; cardiotoxicity (may be delayed for years); red-coloured urine; severe local tissue damage and necrosis on extravasation; alopecia; stomatitis; anorexia; conjunctivitis; acral (extremities) pigmentation; dermatitis in previously irradiated areas; hyperuricaemia	Common component of many chemotherapy regimens for both haematological and non-haematological malignancies
Antimetabolites, e.g. 5-fluorouracil, methotrexate	Nausea and vomiting; diarrhoea; mucositis, bone marrow depression, neurological defects, usually cerebellar; cardiac arrhythmias; angina pectoris, hyperpigmentation, hand–foot syndrome, conjunctivitis	Commonly used in haematological and non-haematological malignancies
Topoismerase I inhibitors	Nausea and vomiting; cholinergic syndrome; hypersensitivity reactions; bone marrow depression; diarrhoea; colitis; ileus; alopecia; renal impairment; teratogenic	Irinotecan is effective in advanced colorectal cancer; topotecan is used in gynaecological malignancies
Mitotic spindle inhibitors (vinca alkaloids)	Nausea and vomiting; local reaction and phlebitis with extravasation, neuropathy, bone marrow depression; alopecia; stomatitis; loss of deep tendon reflexes; jaw pain; muscle pain; paralytic ileus	Commonly used in haemato-oncology regimens
Hormones
Tamoxifen	Hot flushes; transiently increased bone or tumour pain; vaginal bleeding and discharge; rash; thromboembolism; endometrial cancer	Oestrogen receptor-positive, advanced and early stage breast cancer
Aromatase inhibitors	Nausea; dizziness; rash; bone marrow depression; fever; masculinisation	Equivalence with tamoxifen suggested
Medroxyprogesterone acetate	Menstrual changes; gynaecomastia; hot flushes; oedema, weight gain; hirsutism; insomnia; fatigue; depression; thrombophlebitis and thromboembolism; nausea; urticaria; headache	Third-line therapy for slowly progressive breast cancer in postmenopausal women
Flutamide	Nausea; diarrhoea; gynaecomastia; hepatotoxicity	Prostate cancer
Goserelin	Transient increase in bone pain and urethral obstruction in patients with metastatic prostatic cancer; hot flushes; impotence; testicular atrophy; gynaecomastia	Prostate cancer
Leuprolelin (LHRH analogue)	Transient increase in bone pain and ureteral obstruction in patients with metastatic prostatic cancer; hot flushes, impotence; testicular atrophy; gynaecomastia; peripheral oedema	Prostate cancer
Immunotherapy
BCG (bacille Calmette-Guérin)	Bladder irritation; nausea and vomiting; fever; sepsis, granulomatous pyelonephritis; hepatitis; urethral obstruction; epididymitis; renal abscess	Localised bladder cancer
Interferon-α	Fever; chills; myalgias; fatigue; headache; arthralgias, bone marrow depression; anorexia; confusion; depression; psychiatric disorders; renal toxicity; hepatic toxicity; rash	Renal cancer
Interleukin-2	Fever; fluid retention; hypotension; respiratory distress; rash; anaemia, thrombocytopenia; nausea and vomiting; diarrhoea, capillary leak syndrome, nephrotoxicity; myocardial toxicity; hepatotoxicity; erythema nodosum; neuropsychiatric disorders; hypothyroidism; nephrotic syndrome	Renal cancer
Trastuzumab (Herceptin)	Fever; chills; nausea and vomiting; pain; hypersensitivity and pulmonary reactions, bone marrow depression; cardiomyopathy; ventricular dysfunction; congestive cardiac failure; diarrhoea	Advanced and early stage breast cancer, combined with cytotoxic chemotherapy
Rituximab (MabThera)	Hypersensitivity reaction, bone marrow depression, angioedema, precipitation of angina or arrhythmia with pre-existing heart disease	Non-Hodgkin’s lymphoma