A risk-benefit assessment of amifostine in cytoprotection

Recent advances in chemotherapy have focused on the benefit of high dose re gimens, increasing the dose intensity of conventional chemotherapy and usin g intensified chemotherapy with or without autologous bone marrow rescue. D ose intensity usually increases objective response rates of antineoplastic drugs and might, in some circumstances, improves survival. However, unaccep table acute and/or cumulative toxicity often impairs the proper management of patients, leading to dose reduction or treatment delay, thus reducing th e efficacy and potentially the quality of life of patients. Therefore, cons iderable efforts have been made to manage, to prevent, and to delay many ac ute and cumulative treatment-related toxicities. Amifostine (WR-2721) is a multiorgan cytoprotector which has demonstrated c ytoprotective effects, in vitro and in vivo, against the most common cytoto xic drug-related toxicities and against radiation-induced adverse effects i n healthy tissues. In vitro and in vivo, cytoprotection was observed in sev eral organs including kidney, haematopoietic stem cells, myocardial cells, neural cells, and mucosa, without detectable protection of malignant cells. In addition, in preclinical studies, amifostine appeared to be able to red uce the risk of radiation-induced secondary neoplasms. Phase I studies show ed that nausea/vomiting and hypertension are the dose-limiting toxicities o f amifostine and these may be controlled by reducing the duration of inject ion of amifostine. Phase II and randomised studies have confirmed the effic acy of amifostine in protecting against radiotherapy-induced mucositis, cis platin-induced nephrotoxicity, cyclophosphamide-induced neutropenia and car boplatin-induced thrombocytopenia. Importantly, the cytoprotection of healt hy tissues occurred without any significant deleterious effect on response rate, time to progression, and survival of patients receiving amifostine. However, in addition to the potential quality of life benefit, the most imp ortant question of whether the use of a cytoprotective agent might translat e into the possibility of maintaining the dose intensity of anticancer ther apies has still to be answered. The real benefit of amifostine in the overa ll management of patients with cancer requires additional studies to determ ine whether this chemoprotective approach can be of benefit to patients by increasing response rate, time to progression, and long term survival in pa tients receiving the more recent combination therapies involving new drugs such as the taxanes and oxaliplatin.