Preliminary Evidence of Benefit From Amifostine for Cytoprotection in Patients With Cervical Cancer

CHICAGO-"There is a need for toxicity reduction in cervical cancer patients and some preliminary evidence that amifostine(Drug information on amifostine) may be beneficial," notes William Small, Jr., MD, associate professor of clinical radiology, division of radiation oncology at Northwestern University Medical School. He discussed Radiation Therapy Oncology Group (RTOG) plans to add an amifostine (Ethyol) arm to the ongoing RTOG C-0116 study of extended-field external irradiated (EFER) and intracavitary radiotherapy and chemotherapy in cervical cancer patients with positive para-aortic or high common iliac lymph nodes. Dr. Small said that while the incidence of cervical cancer in the US has dropped from 12,200 in 2000 to a predicted 10,520 in 2004, "treatment-associated severe and fatal toxicities are much higher than most of us realize." Chemoradiotherapy is now the de facto standard of care but is associated with high rates of acute grade 3 or 4 toxicities. In the RTOG 90-01 study, for example, patients had significant nausea/vomiting (14% grade 3 and 3% grade 4), bowel and rectal problems (12% grade 3 and 5% grade 4), and hematologic toxicity (57% grade 3 and 16% grade 4). In the GOG (Gynecologic Oncology Group)- 120 trial of pelvic RT combined with cisplatin (Platinol) vs cisplatin/ fluorouracil(Drug information on fluorouracil)/hydroxyurea vs hydroxyurea, both cisplatin(Drug information on cisplatin) arms improved survival. Yet, this benefit came at the cost of leukopenia (21% grade 3 and 2% grade 4) and gastrointestinal (10% grade 3 and 5% grade 4) and genitourinary toxicity (3% grade 3 and 2% grade 4). Cervical cancer patients who have metastases to the para-aortic lymph nodes can be cured with extended-field RT despite secondechelon lymph node metastases- but at the expense of high RT toxicity, Dr. Small said. "Given the positive results of combined therapy in pelvic-only disease, combination extended-field RT and chemotherapy in para-aortic node positive patients appears to be indicated," he noted. Extended-field RT alone produced local control of about 55% and 5-year survival of about 30% in these patients, but nearly one in four patients had some type of grade 4 toxicity. RTOG C-0116
"RTOG C-0116 is a prospective clinical trial designed to test the hypothesis that amifostine can reduce radiotherapy and chemotherapy toxicity in treatment of cervical cancer. Eligibility includes patients with para-aortic metastases, as this patient population is believed to be at highest risk for treatment mortality," Dr. Small said. The trial has two phases, the first being treatment with extended- field RT, brachytherapy, and concurrent cisplatin without amifostine. This arm was designed to obtain a good estimate of the true toxicity of extended-field RT and concurrent cisplatin because the investigators believed there was no adequate historical control. That phase has been completed (with 26 patients), and grade 3 or 4 toxicity was 77% (excluding grade 3 leukopenia). This toxicity level was higher than anticipated in the study protocol, according to which the study would continue to phase II, with addition of amifostine, if the grade 3/4 toxicity was 30% to 62.5%. "In our experience without amifostine, we were uncommonly able to give patients the full planned six doses of chemotherapy," Dr. Small said. Per protocol, the investigators are seeking a study amendment to permit continuation of the study. They hope to treat 18 to 20 patients in the second phase of the study, with amifostine cytoprotection added, and to report efficacy data by next year.