Amifostine Pretreatment for Protection Against Cyclophosphamide-Induced and Cisplatin-Induced Toxicities
Purpose: Serious cumulative toxicity is a well-recognized consequence of chemotherapy. Amifostine, an organic thiophosphate, has demonstrated the ability to protect selectively a broad range of normal, but not neoplastic, tissues from the cytotoxic effects of chemotherapy and radiotherapy. This study was designed to determine if amifostine could reduce the serious toxicities associated with cyclophosphamide and cisplatin (CP), without reducing antitumor efficacy in patients with ovarian cancer.
Patients and Methods: Two hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide (1,000 mg/m2 ) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2 ) every 3 weeks for six cycles. The occurrence of hematologic, renal, neurologic, and ototoxicity was evaluated. Antitumor efficacy was assessed by pathologic tumor response and survival.
Results: Pretreatment with amifostine before each cycle of chemtherapy resulted in a reduction of cumulative taxicities. Hematologic toxicity consisted of grade 4 neutro-penia associated with fever and/or infection that required antibiotic therapy (P =0.005), days in hospital (P =0.019), and days on antibiotics (P =0.031). Platinum-specific toxicities consisted of protracted serum creatinine levations (P=0.004), 2 40% reduction from baseline in creatinine clearance (P =0.001), and severity of neurologic toxicity (P= 0.029). Twenty-four percent of CP patients compared with 9% of amifostine plus CP patients discontinued therapy because of protocol-specified toxicity (P =0.002). Pathologic tumor response rates were 37% with amifostine and 28% in controls, with comparable median survival times of 31 months. Amifostine was generally well tolerated; the principal side effects were emesis and a transient decrease in blood pressure.
Conclusion: Pretreatment with amifostine reduces the cumulative hematologic, renal, and neurologic toxicities associated with the CP regimen, with no reduction in antitumor efficacy.
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