Adverse Effects Of Chemotherapy

Principal adverse effects (see Table 30.3) are manifest as, or follow damage to, the following:

• Nausea and vomiting

• Bone marrow and lymphoreticular system: pancytopenia and immunosuppression (depression of both antibody and cell-mediated immunity), leading to opportunistic microbial infection

• Gut epithelium and other mucosal surfaces: diarrhoea, mouth ulcers

• Hair: alopecia due to effect on hair bulb (recovers 2-6 months after ceasing treatment); prevention by scalp hypothermia helps with certain drugs, e.g. vindesine

• Delayed wound healing

• Local toxicity if extravasation occurs

• Specific organ damage

• Germ cells and reproduction: sterility, teratogenesis, mutagenicity

• Second malignancies.

The first six occur immediately or in the short term and are liable to be troublesome with any vigorously pursued regimen.

Nausea and vomiting. This is common, can be extremely severe and prolonged and cause patients to refuse treatment. Effective management is of the utmost importance. Vomiting may be immediate, commonly beginning in 1-5 hours, or may be delayed, lasting several days, depending on the agent. Since emetogenicity is largely predictable, preventive action can be taken. The most effective drugs are competitive antagonists at serotonin (5-HT3) receptors (ondansetron) and at the dopamine D2-receptor (metoclopramide). They may be used in combination with a benzodiazepine (anxiety is a major factor in promoting emesis when the patient knows that it will occur, as with cisplatin), or dexamethasone, which benefits by an unknown mechanism. Other effective agents include prochlorperazine, domperidone and nabilone.

Combinations, e.g. benzodiazepine plus dexamethasone, plus a 5-HT3 (ondansetron) or dopamine D2-receptor blocker (metoclopramide) are often more effective than a single drug.

Routes of administration are chosen as common-sense counsels, e.g. prophylaxis may be intravenous or oral, but when vomiting occurs injections and suppositories are available.

Bone marrow suppression is the single most important dose-limiting factor with cytotoxic agents. Repeated blood monitoring is essential and transfusion of any/all formed elements of the blood may be needed, e.g. platelet transfusion for thrombocytopenic bleeding or where the platelet count falls below 10 x 109/1. Cell growth factors, e.g. the natural granulocyte colony stimulating factor (filgrastim), are effective in neutropenia.

Septicaemia is often an opportunistic infection by Gram-negative bacteria from the patient's own flora, e.g. from the gut, which has been injured by the drugs. Vigorous antimicrobial prophylaxis and therapy, often in combination, are used. Infections with virus (herpes zoster), fungus (candida) and protozoa (pneumocystis) are also prominent. Fever in a patient under this treatment requires collection of samples for microbiological studies and urgent treatment.

Immune responses. Vigorous and prolonged chemotherapy can impair the immune responsiveness of patients for as long as 3 years after ceasing therapy. Purine analogues (e.g. fludarabine), high dose chemoradiotherapy and allogeneic bone marrow transplant produce profound immunosuppression with significant risk of opportunistic infection (e.g. herpes zoster, Pneumocystis carinii pneumonia) and third party graft-versus-host disease following unirradiated blood transfusion. Use of living vaccines is contraindicated.

Gonadal cells and reproduction. Sterility may occur. The mutagenic effects of anticancer drugs mean that reproduction should be avoided during and for several months after therapy (but both men and women have reproduced normally whilst undergoing chemotherapy). When treatment may cause permanent sterility, men are offered the facility for prior storage of sperm. Cryopreservation of ovarian tissue is now also feasible. Most cytotoxic drugs are teratogenic and should not be used during pregnancy. Contraceptive advice should be given before cancer chemotherapy begins.

Urate nephropathy. Rapid destruction of malignant cells releases purines and pyrimidines, which are converted to uric acid and may crystallise in and block the renal tubule (urate nephropathy). In practice this occurs only when there is a large cell mass and the tumour is very sensitive to drugs, e.g. acute leukaemias and high-grade lymphomas. High fluid intake, alkalinisation of the urine and use of allopurinol (p. 296) during the early stages of chemotherapy avert this outcome.

TABLE 30.3 Adverse effects of some cytotoxic drugs, hormones and biological agents (reproduced and adapted by courtesy of the Medical Letter on Drugs and Therapeutics, New York)

Drug

Dose-limiting effects are in bold type

Cytotoxic agents

Asparaginase

Bleomycin Busutfan

Carboplatin Carmustine

Chlorambucil Ci splat í'fí

Cyclophosphamide C y carabine

Dacarbazine

Daccinomycin

Datinorubicin

Docetaxel

Acute toxicity

Nausea and vomiting; fever, chills; headache; hypersensitivity; anaphylaxis; abdominal pain; hyperglycaemia leading to coma

Nausea and vomiting; fever; anaphylaxis and other allergic reactions; phlebitis at injection site

Nausea and vomiting; rarely diarrhoea

Nausea and vomiting

Nausea and vomiting; local phlebitis

Nausea and vomiting; seizures

Nausea and vomiting; diarrhoea,anaphylactic reactions

Nausea and vomiting; Type I (anaphylactoid) hypersensitivity; facial burning with i.v. administration; visual blurring

Nausea and vomiting; diarrhoea; anaphylaxis; sudden respiratory distress with high doses

Nausea and vomiting; diarrhoea; anaphylaxis, pain on administration

Nausea and vomiting; hepatic toxicity with ascites: diarrhoea: severe local tissue damage and necrosis on extravasation; anaphylactic reaction

Nausea and vomiting; diarrhoea; red urine (not haematuria); severe local tissue damage and necrosis on extravasation; transient ECG changes; anaphylactoid reaction

Nausea and vomiting; hypersensitivity reactions

Delayed toxicity

CNS depression or hyperexcitability;acute haemorrhagic pancreatitis; coagulation defects; thrombosis; renal damage; hepatic damage Pneumonitis and pulmonary fibrosis; rash and hyperpigmentation; stomatitis; alopecia; Raynaud's phenomenon; cavitating granulomas; haemorrhagic cystitis

Bone marrow depression; pulmonary infiltrates and fibrosis; alopecia;gynaecomastia;ovarian failure; hyperpigmentation; azoospermia; leukaemia: chromosome aberrations;cataracts; hepatitis; seizures and veno-occlusive disease with high doses

Bone marrow depression; peripheral neuropathy (uncommon); hearing loss: transient cortical blindness; haemolytic anaemia Delayed leukopenia and thrombocytopenia

(may be prolonged); pulmonary fibrosis (may be irreversible); delayed renal damage; reversible liver damage; leukaemia; myocardial ischaemia

Bone marrow depression; pulmonary infiltrates and fibrosis; leukaemia; hepatic toxicity; sterility Renal damage; ototoxicity; bone marrow depression; haemolysis: hypomagnesaemia; peripheral neuropathy: hypocalcaemia; hypokalamia; Raynaud's disease; sterility: teratogenesis: hypophosphataemia; hypcru ricaemia Bone marrow depression; alopecia; haemorrhagic cystitis;sterility {may bo temporary); pulmonary infiltrates and fibrosis; hyponatremia; leukaemia; bladder cancer; inappropriate antidiuretic hormone secretion: cardiac toxicity Bone marrow depression; conjunctivitis; mcgaloblastosis; oral ulceration; hepatic damage: fever; pulmonary oedema and central and peripheral neurotoxicity with high doses; rhabdomyolysis; pancreatitis when used with asparaginase; rash

Bone marrow depression; alopecia;flu-like syndrome: renal impairment; nepatic necrosis; facial flushing: paraesthesiae; photosensitivity; urticarial rash

Stomatitisj oral ulceration; bone marrow depression; alopecia folliculitis;dermatitis in previously irradiated areas

Bone marrow depression; cardiotoxicity (may be delayed for years); alopecia; stomatitis; anorexia; diarrhoea; fever and chills; dermatitis in previously irradiated areas; skin and nail pigmentation; photosensitivity

Bone marrow depression;fluid retention; peripheral neuropathy; alopecia; arthralgias; myalgias; cardiac toxicity; mild Gl disturbances; mucositis

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