John A. Blessing

Ten-year follow-up of patients receiving cisplatin, doxorubicin, and cyclophosphamide chemotherapy for advanced epithelial ovarian carcinoma.

Fifty-six patients were randomly assigned to receive either one-day cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy (PAC-I) or five-day PAC (PAC-V) for advanced epithelial ovarian carcinoma. Follow-up has been 120+ months or to death. Ninety-one percent had either suboptimal stage III or stage IV disease and 55% had grade 2 or 3 lesions. Two patients died of toxicity and were free of disease at autopsy. A third patient died of congestive heart failure with no disease at 103 months. Additionally, eight patients had a negative second-look laparotomy, and three (37.5%) are alive with no evidence of disease (NED) 133 to 144 months after diagnosis. Five patients (62.5%) died of disease 2 to 123 months after negative second-look. Patients with optimal stage III disease had a longer median progression-free interval (PFI) and survival (33.3 and 44.5 months, respectively) than those with suboptimal or stage IV disease (16.4 and 22.5 months, respectively), and the difference in median PFI is significant (P less than .02). Patients with ascites at diagnosis had a shorter median PFI and survival (14.7 and 18 months) than those without ascites (30.0 and 33.0 months). Both differences were significant (PFI, P less than .04; survival, P = .005). PAC produces response rates that are superior to those obtained historically with single-agent alkylating therapy. Late recurrences after negative second-look laparotomy suggest that 5-year survival data may be inadequate in ovarian carcinoma.

A Phase II Trial of 5-Fluorouracil and High-Dose Leucovorin in Recurrent Epithelial Ovarian Carcinoma: A Gynecologic Oncology Group Study

In this series 49 patients with epithelial ovarian carcinoma previously treated with platinum-based chemotherapy received leucovorin 200 mg/m2 i.v. bolus followed by 5-fluorouracil at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses and subsequent courses were given every 5 weeks. Of this group, 47 patients were evaluable for toxicity and 44 for response. Of the patients evaluable for response, 15 were considered platinum-sensitive and 29 were platinum-refractory. The overall response rate was 6/44 (13.6%). There were two complete responders (4.5%) and four partial responders (9.1%). In the platinum-sensitive patients, there was one complete response, yielding a response rate of 6.6%, whereas in the platinum-refractory patients, there were four partial responses and one complete response for a response rate of 17.2%. Five responses were in the pelvis and there was one response at an extrapelvic site in the abdominal mesentery. The median number of courses delivered was three (range: 1–10). The major adverse effect was myelosuppression with 16/47 (34.0%) experiencing granulocy-topenia < 1.000/mm3. The median white blood count nadir for the patients experiencing any leukopenia was 2,700 (range: 400–3,900/mm3). There was one episode of grade 3 thrombocytopenia. Grade 3 intestinal toxicity was seen in seven patients (14.9%). There were no treatment-related deaths. In this previously treated population, 5-fluorouracil with high-dose leucovorin exhibited activity of interest in the platinumrefractory population and warrants further investigation.

A phase II evaluation of mitolactol in patients with advanced squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study

Sixty patients with advanced squamous cell carcinoma of the cervix (SCC) who had received no prior chemotherapy were entered onto a study of mitolactol (dibromodulcitol [DBD]). The drug was administered orally at an initial dose of 180 mg/m2 per day for 10 days and repeated every 4 weeks. There were 55 evaluable patients, of whom one (2%) had a complete response (CR), and 15 (27%) had a partial response (PR), (CR plus PR, 29%). A 95% confidence interval for the true response rate is 18.8% to 42.1%. Myelosuppression was appreciable at this dose and schedule, with 13 patients experiencing life-threatening thrombocytopenia and two drug-related deaths. The level of activity in this disease encourages us to determine a tolerable dose of this drug in combination with cisplatin for further study.

Echinomycin in recurrent and metastatic endometrial carcinoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-one evaluable patients with recurrent or metastatic endometrial carcinoma were treated with 1,500 μg/m2 of echinomycin every 3 weeks. All patients had received prior chemotherapy. There was one complete response (5%), 95% confidence interval for response is 0.9–22.7%. The major toxicity was nausea and vomiting which was moderate to severe in 42% of patients. Myelosuppression was minimal. Echinomycin, in this dose and schedule, displays minimal activity in patients with advanced endometrial carcinoma who have had prior chemotherapy.

Ifosfamide alone and in combination in the treatment of refractory malignant gestational trophoblastic disease

OBJECTIVEnWe attempted to evaluate the use of ifosfamide either alone or in combination in patients with refractory malignant gestational trophoblastic disease.nnnSTUDY DESIGNnOur study comprised, in part, a phase II multiinstitutional trial of ifosfamide in refractory gynecologic malignancies and, in part, a review of institutional experience with ifosfamide in combination chemotherapy.nnnRESULTSnSingle-agent ifosfamide produced a significant response in titer in one of two patients with refractory choriocarcinoma. Ifosfamide with etoposide and cisplatin (also known as VIP) resulted in significant response in human chorionic gonadotropin titers in three patients with highly refractory metastatic gestational trophoblastic disease and one cure in this group of patients.nnnCONCLUSIONnIfosfamide has activity in refractory choriocarcinoma and, when combined with etoposide and cisplatin (VIP), may be curative.

Methotrexate in advanced endometrial carcinoma. A Phase II trial of the Gynecologic Oncology Group

Thirty-three patients with advanced or metastatic endometrial carcinoma were entered in a Phase II trial utilizing methotrexate, 40 mg/m2 intravenously on a weekly basis. Almost all patients had prior total abdominal hysterectomy and almost two-thirds prior pelvic irradiation. No patient had prior chemotherapy. There was one complete and one partial response, for a complete and partial response rate of 6% (95% confidence intervals for a response of 1.7 to 19.6%). Toxicity was mild, with major adverse effects being nausea and vomiting and myelosuppression. One death may have been drug related. Methotrexate displays minimal clinical activity in patients with advanced or recurrent endometrial carcinoma who have received no prior chemotherapy.

5-fluorouracil and low-dose leucovorin in the treatment of recurrent squamous cell carcinoma of the cervix. A phase II trial of the Gynecologic Oncology Group.

Twenty-eight patients with recurrent squamous carcinoma of the cervix not amenable to cure by further surgery or radiation therapy were entered into a Phase II trial utilizing i.v. leucovorin 20 mg/m2 followed by 5-fluorouracil 425 mg/m2 administered daily for 5 days every 4 weeks for the first two courses and then every 5 weeks. One patient never received therapy, and three are inevaluable for response; therefore, 27 patients were evaluable for toxicity and 24 for response. Twenty-three patients had received prior radiotherapy, and 16 had received prior chemotherapy. There was one partial response 4.2% (95% confidence intervals for a response of 0 to 21%). Although toxicity was acceptable with 11 of 27 (41%) grade 3 or 4 leukopenia, 1 of 27 (4%) grade 3 thrombocytopenia, and 3 of 27 (11%) grade 3 or 4 gastrointestinal toxicity, this dose schedule of 5-fluorouracil and leucovorin has minimal activity in recurrent squamous carcinoma of the cervix.

Echinomycin (NSC 526417) in squamous-cell carcinoma of the cervix. A phase II trial of the Gynecologic Oncology Group.

Twenty-eight evaluable patients with advanced or recurrent squamous-cell carcinoma of the cervix were treated with 1,500 μg/m2 of echinomycin every 4 weeks. All patients had prior chemotherapy. Two patients had partial responses (7% response, 95% confidence interval for response of 1 to 24%). The major toxicity was nausea and vomiting. Myelosup- pression and other toxicity were modest. Echinomycin, at this dose and schedule, displays minimal activity in patients with squamous-cell carcinoma of the cervix who have had prior chemotherapy.

ICRF-159 (Razoxane) in Patients with Advanced Adenocarcinoma of the Endometrium A Gynecologic Oncology Group Study

Twenty-seven patients with advanced adenocarcinoma of the endometrium were accessioned into this Phase II study evaluating the efficacy of ICRF-159 (razoxane) as second-line chemotherapy between February 1981 and September 1983. One patient was ineligible because of an undocumented primary. One patient was inevaluable because of concurrent use of adjunctive therapy and one patient had an inadequate trial. Twenty-four evaluable patients with measurable disease were given ICRF-159 orally at a starting dose of 1.5 g/m2 weekly until response could be determined. Grade 4 hematologic adverse effects were the only significant toxicity. There was no evidence of tumor response in any of the patients. Fourteen patients had stable disease and 10 had progressive disease. No activity was noted in advanced adenocarcinoma of the endometrium with ICRF-159 administered in the above dose and schedule.

Echinomycin (NSC 526417) in advanced ovarian cancer. A phase II trial of the Gynecologic Oncology Group.

Twenty-two patients with recurrent carcinoma of the ovary progressive after initial chemotherapy (21 with cisplatin-based treatment) were entered on a phase II trial utilizing Echinomycin at a dosage of 1,500 μg/m2 every 4 weeks. There were two complete responders and no partial responders (9% response, 95% confidence intervals for complete and partial responses of 1–29%). Major toxicity was modest and consisted mainly of nausea and vomiting. Echinomycin displays minimal activity as salvage therapy in women with advanced ovarian cancer at this dose and schedule.