Phase I escalation of gemcitabine combined with protracted oral etoposide in gynecologic malignancies - A Gynecologic Oncology Group study

Objective: Although improvements have been made in the management of patients with advanced ovarian cancer, long-term survivors are still uncommon. Gemcitabine and prolonged oral etoposide have shown reproducible single-agent activity in patients with platinum/paclitaxel-resistant ovarian cancer. This, combined with preclinical synergism, prompted the Gynecologic Oncology Group to determine the maximum tolerated dose (MTD) of this combination. Methods: Eligible patients had recurrent epithelial ovarian cancer, primary papillary peritoneal, or fallopian tube carcinoma. All had received prior platinum/paclitaxel-based chemotherapy and had adequate hepatic, renal and bone marrow function. Oral etoposide was administered at 50 mg/m(2) for ten days, with three proposed dose levels for gemcitabine on days 1 and 8: 400, 550 and 700 mg/m(2). Cycles were to be repeated every 28 days. Three patients were to enter at each dose level. Results: Patients were enrolled only to dose level 1 as this dose exceeded MTD. Of six patients initially enrolled, one was removed after three days with fever, ascites and decreased albumin believed not to be treatment related. Five patients were evaluable for toxicity and response. One of the first three patients developed dose limiting toxicity (DLT) manifested as grade 4 neutropenia. A second DLT (neutropenic fever and thrombocytopenia associated with bleeding) occurred among the next three patients; therefore, MTD was reached at dose level 1. Grade 4 toxicities included episodes of neutropenia (4) and thrombocytopenia (3). No objective response was observed. Conclusions: Oral etoposide and gemcitabine at this dose and schedule was associated with substantial toxicity in this population. Patients who are previously treated with platinum/paclitaxel-based chemotherapy may be at particular risk for toxicity.