PURPOSE:Because toxicities associated with chemotherapy and radiotherapy canadversely affect short- and long-term patient quality of life, can limitthe dose and duration of treatment, and may be life-threatening, specificagents designed to ameliorate or eliminate certain chemotherapy andradiotherapy toxicities have been developed. Variability in interpretationof the available data pertaining to the efficacy of the three United StatesFood and Drug Administration–approved agents that have potentialchemotherapy- and radiotherapy-protectant activity—dexrazoxane,mesna, and amifostine—and questions about the role of theseprotectant agents in cancer care led to concern about the appropriate useof these agents. The American Society of Clinical Oncology sought toestablish evidence-based, clinical practice guidelines for the use ofdexrazoxane, mesna, and amifostine in patients who are not enrolled onclinical treatment trials. METHODS: A multidisciplinary Expert Panelreviewed the clinical data regarding the activity of dexrazoxane, mesna,and amifostine. A computerized literature search was performed usingMEDLINE. In addition to reports collected by individual Panel members, allarticles published in the English-speaking literature from June 1997through December 1998 were collected for review by the Panel chairpersons,and appropriate articles were distributed to the entire Panel for review.Guidelines for use, levels of evidence, and grades of recommendation werereviewed and approved by the Panel. Outcomes considered in evaluating thebenefit of a chemotherapy- or radiotherapy-protectant agent includedamelioration of short- and long-term chemotherapy- or radiotherapy-relatedtoxicities, risk of tumor protection by the agent, toxicity of theprotectant agent itself, quality of life, and economic impact. To theextent that these data were available, the Panel placed the greatest valueon lesser toxicity that did not carry a concomitant risk of tumorprotection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed asdetailed in these guidelines, is recommended to decrease the incidence ofstandard-dose ifosfamide-associated urothelial toxicity. (2) There isinsufficient evidence on which to base a guideline for the use of mesna toprevent urothelial toxicity with ifosfamide doses that exceed 2.5g/m2/d. (3) Either mesna or forced saline diuresis isrecommended to decrease the incidence of urothelial toxicity associatedwith high-dose cyclophosphamide use in the stem-cell transplanta-tionsetting. Dexrazoxane: (1) The use of dexrazoxane is not routinelyrecommended for patients with metastatic breast cancer who receive initialdoxorubicin-based chemotherapy. (2) The use of dexrazoxane may beconsidered for patients with metastatic breast cancer who have received acumulative dosage of 300 mg/m2 or greater of doxorubicin inthe metastatic setting and who may benefit from continueddoxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvantsetting is not recommended outside of a clinical trial. (4) The use ofdexrazoxane can be considered in adult patients who have received more than300 mg/m2 of doxorubicin-based therapy for tumors other thanbreast cancer, although caution should be used in settings in whichdoxorubicin-based therapy has been shown to improve survival because ofconcerns of tumor protection by dexrazoxane. (5) There is insufficientevidence to make a guideline for the use of dexrazoxane in the treatment ofpediatric malignancies, with epirubicin-based regimens, or with high-doseanthracycline-containing regimens. Similarly, there is insufficientevidence on which to base a guideline for the use of dexrazoxane inpatients with cardiac risk factors or underlying cardiac disease. (6)Patients receiving dexrazoxane should continue to be monitored for cardiactoxicity. Amifostine: (1) Amifostine may be considered for the reduction ofnephrotoxicity in patients receiving cisplatin-based chemotherapy. (2)Although amifostine may be considered for the reduction of neutropenia inpatients receiving alkylating agents, chemotherapy dose reduction or growthfactor use should be considered as an alternative to the use of amifostine.(3) Present data are insufficient to recommend the use of amifostine forprotection against thrombocytopenia or the routine use of amifostine toprevent cisplatin-associated neurotoxicity or ototoxicity. Similarly,present data are insufficient to support the use of amifostine for theprevention of paclitaxel-associated neurotoxicity. (4) Use of amifostinemay be considered to decrease the incidence of acute and late xerostomia incertain patients undergoing fractionated radiation therapy in the head andneck region, although present data are insufficient to recommend the use ofamifostine to prevent radiation therapy–associated mucositis. Detailsregarding dose and management of amifostine side effects, includinghypotension, are included in the guidelines. Further research is warrantedto further define the role of these chemotherapy- andradiotherapy-protectant agents in the care of cancerpatients.
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