Complications of cytotoxic therapy- part 2

Summary
Chemotherapy can cure some cancers, but it has many adverse effects which can affect any system of the body. Some may not appear until after treatment is completed. As more people are being treated as outpatients, general practitioners need to be aware of the toxicities. While some adverse effects can be treated symptomatically, others may be lifethreatening. Less common, but nonetheless significant, adverse effects include hypersensitivity reactions, ocular, cardiac, pulmonary, hepatic, renal, neurological and vascular toxicities.

Hypersensitivity reactions
Apart from the nitrosoureas and dactinomycin, most antitumour drugs can cause hypersensitivity reactions e.g. colaspase, mitomycin, paclitaxel, cisplatin, procarbazine and anthracyclines. These reactions are usually type I. The IgE mediated mast cell release of neurogenic vasoactive substances can cause urticaria, angioedema, rash, bronchospasm, abdominal cramping, pain in the extremities, agitation, anxiety and hypotension. Haemolytic anaemia (complement mediated), immune complex deposition (Ag-Ab complex mediated) and contact dermatitis (T lymphocytes mediated) are less common. (See also the wall chart 'Medical management of severe anaphylactoid and anaphylactic reactions', insert to Australian Prescriber Vol. 17 No. 4 1994.)

Ocular toxicity
As cytotoxics are used more and patients survive longer, more ocular adverse effects are being recognised (Table 1). The ocular toxicity may be reversible if it is recognised early and the dose is decreased or the drug discontinued.

Cardiotoxicity
Doxorubicin, mitoxantrone, cyclophosphamide, fluorouracil and paclitaxel are cardiotoxic. Doxorubicin may cause acute effects (within hours) including supraventricular tachyarrhythmias, ECG changes, atrial and ventricular ectopy, and, rarely, fatal ventricular dysrhythmia. Subacute (within days to weeks) toxic myocarditis or pericarditis is rare.

Chronic (within weeks to months) toxicity is the most important and is related to the cumulative dose of doxorubicin. The risk of congestive cardiac failure is 0.1-7% with doses of <550mg/m2 (body surface area), rising linearly to 50% probability at doses >1000mg/m2. Thus, in common practice, treatment with doxorubicin is usually discontinued after patients have received a lifetime dose of 550 mg/m 2 (i.e. 6-8 months of therapy). Congestive cardiac failure in this setting is lethal in 30-60% of patients. The cardiotoxicity of doxorubicin is increased by both previous or current radiotherapy to the chest. Gated heart pool scans can be used to detect early cardiotoxicity.

Mitoxantrone is an anthraquinone structurally similar to the anthracyclines. It causes less mucositis, less nausea and vomiting, and less alopecia than doxorubicin, and is significantly less cardiotoxic. The risk for cardiotoxicity does not increase until a cumulative dose of 160 mg/m2 is reached (this is equivalent to 800 mg/m2 of doxorubicin).

The cardiotoxicity which occurs in 1-2% of patients treated with fluorouracil is probably caused by coronary artery spasm. Presentations include angina, myocardial infarction, atrial fibrillation, atrial flutter, tachycardia and hypotension. A higher incidence (4.5%) occurs in patients with a history of ischaemic cardiomyopathy.

Paclitaxel (an antimicrotubule agent) may cause hypersensitivity reactions with concomitant hypotension and dysrhythmias. The hypotension is probably related to the paclitaxel's vehicle, a polyoxyethylated castor oil called cremophor EL. It is essential to premedicate a patient receiving paclitaxel with corticosteroids and antihistamines. Cardiac monitoring is warranted during the first infusion.

Pulmonary toxicity
The patient with progressive dyspnoea, pulmonary infiltrates and fever is a diagnostic dilemma. The cause may be infection, neoplastic involvement, intrapulmonary haemorrhage (especially if the patient is thrombocytopenic) or treatment-related pulmonary toxicity.

There are at least 40 drugs which may produce adverse pulmonary effects. The more common ones are bleomycin, busulfan, mitomycin, BCNU, arabinoside, IL2 and methotrexate. The clinical features are dyspnoea, cough, pulmonary infiltrates, basal inspiratory crackles, and, rarely, pleural friction rub, pleural effusions, pulmonary fibrosis and eosinophilia.

Although the diffusing capacity for carbon monoxide is often used to monitor potential pulmonary toxicity, in many patients the deterioration is sudden, severe, and may occur many months after completing therapy. Once toxicity is diagnosed, the drug must be discontinued and corticosteroids started. Despite this, morbidity and mortality are considerable.

Hepatotoxicity
Potential causes of hepatic abnormality in patients with cancer include: hepatic metastases, preexisting liver disease, other hepatotoxic medications (e.g. high-dose allopurinol), coexisting medical conditions and infections.

There is a spectrum of hepatic toxicities. Mild and usually clinically insignificant elevation of transaminases are common, but life-threatening hepatic necrosis may be seen with dacarbazine, methotrexate, 6-mercaptopurine and L-asparaginase. Other adverse effects include fatty change, cholestasis (6-mercaptopurine), fibrosis and cirrhosis (methotrexate), peliosis hepatis, second neoplasm, venoocclusive disease, sclerosing cholangitis and nodular regenerative hyperplasia.

Renal and electrolyte abnormalities
Cytotoxics can induce renal impairment, tubular and glomerular dysfunction, urate nephropathy and rapid tumour lysis syndrome. Rapid tumour lysis syndrome occurs in the presence of massive cell death which results in hyperkalaemia, hyperphosphataemia, hypocalcaemia and hyperuricaemia. It may require haemodialysis.

Urate may precipitate in the distal tubule (uric acid nephropathy) during the treatment of tumours which are readily responsive to chemotherapy (lymphomas, leukaemias). A random urinary urate to creatinine ratio >1 is specific for the diagnosis. Prevention includes maintaining an adequate urinary output, alkalinisation of urine and giving allopurinol before starting chemotherapy.

Cisplatin may cause hypomagnesaemia in 1-10% of patients, proximal tubular defects, hypocalcaemia and renal sodium wasting. Patients may present with muscle irritability or cramps. Aminoglycosides may increase its toxicity, even when given after cisplatin administration. Prevention involves the infusion of intravenous fluids and mannitol. Management of acute toxicity requires either discontinuation of the drug or dosage reduction. Dialysis is not effective in reversing acute renal failure. Hypomagnesaemia, sodium and water wasting require judicious replacement therapy.

Mitomycin has been associated with the haemolytic uraemic syndrome, a syndrome of renal failure and microangiopathic haemolytic anaemia. Ifosfamide causes haematuria (it is essential to use mesna, a uroprotective agent) and a proximal tubular defect. Cyclophosphamide may cause haemorrhagic cystitis, hyponatraemia and the syndrome of inappropriate ADH secretion (SIADH).

Neurotoxicity
Distinguishing drug toxicity from other metastatic or nonmetastatic neurological complications of cancer is sometimes difficult. Direct toxicity to the peripheral nervous system may be acceptable if it is reversible and not severe (e.g. some cases of vincristine neuropathy). Significant but reversible central nervous system toxicity usually requires treatment to be stopped or a reduction in dose. If the toxicity is likely to be irreversible, treatment is usually stopped.

Vascular toxicity
Vascular toxicities are heterogeneous, the precise mechanism is uncertain and a cause effect relationship often cannot be proven in every case (Table 2).

Second malignancies
All alkylating agents (particularly melphalan) have been associated with both myelodysplastic syndrome (MDS) and acute nonlymphoblastic leukaemia (ANLL). MDS is usually characterised by cytopenias and occurs before acute leukaemia develops. The median time from starting chemotherapy to overt leukaemia is 3-4 years. Cytogenetic abnormalities occur in 90% (especially chromosomes 5 and 7). Therapy for ANLL is usually unsuccessful.

ANLL related to alkylating agents has been reported in patients with multiple myeloma, Waldenstrom's macroglobulinaemia, Hodgkin's disease, lymphocytic lymphoma, cancer of ovary and breast, and even in nonneoplastic diseases.

Lymphocytic lymphoma has occurred in patients with Hodgkin's disease treated with both chemotherapy and radiotherapy (4.4%), connective tissue disorders (especially dermatomyositis, SLE), and prolonged immuno suppression of renal or cardiac allograft recipients with cyclosporin or azathioprine. The incidence of solid tumours may be slightly increased following cytotoxic chemotherapy, although the relationship is not clear. Long term use of tamoxifen has been associated with an increase in endometrial cancer.

Conclusion
Almost all of the currently available cytotoxic drugs have been selected for their activity against proliferating cells. Unfortunately, this does not discriminate between neoplastic cells and normal cells undergoing rapid division. Cytotoxics may cause specific organ toxicities and give rise to a whole spectrum of rare, unpredictable or idiosyncratic reactions. Toxicity of treatment will continue to be a significant problem until therapies are developed which destroy the malignant cells selectively.

Further reading
Adverse effects of treatment. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer principles and practice of oncology. 4th ed. Philadelphia: Lippincott, 1993:2338-2416.

Management of drug toxicity. In: Perry MC, editor. The chemotherapy source book. Baltimore: Williams & Wilkins, 1992:498-753.

Lieschke GJ. Granulocyte colony stimulating factor (GCSF). Aust Prescr 1994;17:96-9.