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Purpose . To determine the feasibility of administering a minimum of four cycles of carboplatin, paclitaxel, and gemcitabine (CPG) every 21 days without excessive dose modification or cycle delay in patients with previously untreated epithelial ovarian cancer or primary peritoneal cancer. Methods . Paclitaxel 175 mg/m 2 was given over 3 h followed by carboplatin concentration time curve (AUC) 5 (day 1) and gemcitabine 1 g/m 2 (days 1 and 8) in the first cohort. A second cohort received paclitaxel 135 mg/m 2 over 3 h followed by carboplatin AUC 5 (day 1) and gemcitabine 800 mg/m 2 (days 1 and 8). A maximum of eight cycles was administered. Results . Fourteen patients received 89 cycles during the first cohort. Seven patients experienced 19 hematologic dose-limiting events (DLEs) within the first four cycles, including grade 4 thrombocytopenia ( n = 9), febrile neutropenia ( n = 3), and omission of gemcitabine on day 8 ( n = 7). This exceeded the threshold for nonfeasibility. In the second, less intense regimen, 36 patients were entered. Thirty-one evaluable patients received a total of 200 and median of 6 (range: 2–8) cycles. Thirteen of the thirty-one had 27 DLEs within the first four cycles including grade 4 thrombocytopenia ( n = 5), prolonged grade 4 neutropenia ( n = 2), febrile neutropenia ( n = 2), and omission of day 8 gemcitabine ( n = 18). There was one patient death secondary to a wound abscess and febrile neutropenia. Myelosuppression as expected was the dose-limiting toxicity. Conclusion . The schedule of paclitaxel 135 mg/m 2 (day 1, 3 h), carboplatin AUC 5 (day 1), and gemcitabine 800 mg/m 2 (days 1 and 8) is feasible, with an acceptable toxicity profile.

Objective A phase II study was conducted to determine the efficacy of oxaliplatin therapy in patients with previously treated squamous cell carcinoma of the cervix. Methods Eligible patients were to have measurable disease and not more than one prior chemotherapy regimen that could include carboplatin or cisplatin but not oxaliplatin. Oxaliplatin 130 mg/m 2 was administered intravenously over 2 h. This treatment was repeated every 21 days until progression of disease or adverse effects prohibited further therapy. Results Twenty-eight patients were entered onto this study, of whom 24 were evaluable for toxicity and 22 were evaluable for response; 23/24 evaluable patients had had prior platinum. There were two (8.3%) responses. One patient achieved a complete response which lasted 2.2 months, and a second patient attained a partial response which lasted 3.2 months. Nine (37.5%) patients had stable disease with a median duration of 7.6+ (3.1–21.2) months. The most frequently reported drug-related toxicities consisted of anemia, nausea and vomiting, and neurotoxicity. Three (12.5%) patients had a grade 3 allergic response that was infusion-related and was largely resolved by increasing infusion time. Conclusions Oxaliplatin has limited activity in patients with persistent or recurrent squamous cell carcinoma of the cervix at the dose and schedule tested.

Objective To estimate the antitumor activity of paclitaxel (Taxol) in patients with persistent or recurrent endometrial carcinoma who have failed prior chemotherapy. To determine the nature and degree of toxicity of paclitaxel in this group of patients. Methods Paclitaxel was administered as a 3-h infusion at an initial dose of 200 mg/m 2 every 21 days or 175 mg/m 2 for patients with prior pelvic radiation therapy. Dose modifications were based on nadir toxicity, both hematologic and nonhematologic, and were accomplished by dose level adjustments. The dose levels were 200, 175, 135, and 110 mg/m 2 . Patients were evaluable for response after receiving one dose of paclitaxel and living 3 weeks. They were evaluable for toxicity after receiving any paclitaxel. Results Of the 44 patients evaluable for response, three patients (6.8%) achieved a complete response and nine patients (20.5%) had a partial response for an overall response rate of 27.3%. The 95% confidence interval for the true response rate was 15–42.8%. The median number of courses of paclitaxel to response was 2 (range: 1–4) and the median response duration was 4.2 months. The median overall survival was 10.3 months. Of 48 patients evaluable for toxicity, 28 experienced at least one episode of grade 3 or 4 neutropenia, with one treatment-related death. There were four patients who developed grade 3 neurotoxicity in this group of previously treated patients, most of whom had received cisplatin-containing chemotherapy. There was virtually no cardiac toxicity and only 3 of 48 patients experienced grade 3 or 4 gastrointestinal symptoms. Conclusions Paclitaxel is an active agent in the treatment of endometrial cancer in patients who have had prior chemotherapy.

Objective To evaluate the effectiveness and toxicity of mifepristone in patients with ovarian, peritoneal and fallopian tube cancers. Methods Patients with confirmed epithelial ovarian, peritoneal and fallopian tube cancers which were persistent or recurred in less then 1 year after primary chemotherapy were entered into this study. Patients were given mifepristone 200 mg by mouth daily for a 28 day cycle. The medication was stopped for unacceptable toxicity or tumor progression. Results Twenty-four patients were entered into the study. Twenty-two patients were evaluable for response. Only one patient had a partial response for a response rate of only 4.5% (90% confidence interval: 0.2%, 19.8%). Conclusion Mifepristone has not proven to be an effective agent in the treatment of patients with recurrent or persistent ovarian, peritoneal and fallopian tube cancers.

Purpose After initial surgery, there has been no established consensus regarding adjunctive therapy for patients with uterine carcinosarcoma (CS). This study was designed to compare patient outcome following treatment with adjuvant whole abdominal irradiation (WAI) versus (vs.) chemotherapy for patients with this rare group of female pelvic malignancies. Patients and methods Eligible, consenting women with stage I–IV uterine CS, no more than 1 cm postsurgical residuum and/or no extra-abdominal spread had their treatments randomly assigned as either WAI or three cycles of cisplatin (C), ifosfamide (I), and mesna (M). Results 232 patients were enrolled, of whom 206 (WAI=105; CIM=101) were deemed eligible. Patient demographics and characteristics were similar between arms. FIGO stage (both arms) was: I=64 (31%); II=26 (13%); III=92 (45%); IV=24 (12%). The estimated crude probability of recurring within 5 years was 58% (WAI) and 52% (CIM). Adjusting for stage and age, the recurrence rate was 21% lower for CIM patients than for WAI patients (relative hazard [RH]=0.789, 95% confidence interval [CI]: (0.530–1.176), p =0.245, 2-tail test). The estimated death rate was 29% lower among the CIM group (RH=0.712, 95% CI: 0.484–1.048, p =0.085, two-tail test). Conclusion We did not find a statistically significant advantage in recurrence rate or survival for adjuvant CIM over WAI in patients with uterine CS. However, the observed differences favor the use of combination chemotherapy in future trials.

Purpose To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. Patients and Methods Eligible patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. Results Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n= 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. Conclusion C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.

Objectives The goals of this study were first, to assess the clinical effectiveness of cisplatin and cyclophosphamide in a phase II study involving a well-defined group of women with extraovarian peritoneal serous papillary carcinoma (EPSPC); and second, to compare these results with those of a group of patients with papillary serous ovarian carcinoma (PSOC) who received identical therapy. Methods After primary surgery, patients were treated with cisplatin 75 mg/m2 and cyclophosphamide 750 mg/m2 every 21 days for six cycles. Patient demographics, tumor characteristics, clinical and surgical response to treatment, progression-free survival, and overall survival were evaluated. These patients were then compared with patients with PSOC who received identical treatment on a separate protocol. Results Women with a diagnosis of EPSPC tended to be older than those with PSOC (median age: 65.8 years vs 60.3 years, P = 0.04). The estimated probability of clinical response (complete and partial) to the treatment regimen for EPSPC was 65% (95% confidence interval [CI]: 41–85%) compared with 59% (95% CI: 47–71%) for women with PSOC. Surgical complete responses were similar (20% vs 19%) in the two patient groups. Additionally, the death rates did not significantly differ between the two groups (hazard ratio: 1.25, 95% CI: 0.834–1.88). Conclusion Women with EPSPC and PSOC exhibit a similar probability of response to cisplatin and cyclophosphamide and a similar overall survival. Based on these findings and the fact that results of ovarian cancer trials are frequently extrapolated to patients with EPSPC, it is reasonable to include EPSPC patients in future large-scale treatment trials involving patients with advanced ovarian cancer.

This Gynecologic Oncology Group (GOG) study was designed to estimate the activity of goserelin acetate as treatment for advanced and recurrent endometrial carcinoma. Forty evaluable patients received monthly treatment with goserelin acetate at a dose of 3.6 mg, given subcutaneously. Standard GOG response and adverse effects criteria were used. The median age of patients was 71 years. Seventy-one percent of patients had received prior radiation therapy; 18% of patients were reported to have received prior progestational therapy for endometrial cancer. One patient had received prior chemotherapy. There were two complete responses (5%) and three partial responses (7%). One response occurred in a patient who previously did not respond to progestin therapy after having achieved a response. The overall response rate was 11% (95% CI: 4-27%). Median progression-free survival was 1.9 months and median overall survival was 7.3 months. No severe or life-threatening toxicities occurred because of goserelin. Deep venous thrombosis developed in two patients. This study confirmed the limited activity of goserelin acetate in endometrial carcinoma, with only one response in a patient previously treated with hormonal therapy. The activity is insufficient to warrant further study of the single agent at this time. Elucidation of the mechanism of action of this drug may allow more effective use in conjunction with other agents in the future.

Objective. A phase II study of Mifepristone (RU486) was conducted in patients with ovarian cancer whose tumors were resistant to cisplatin and paclitaxel, alone or in combination. Patients and Methods. Forty-four patients were accrued into this study. All had ovarian cancer that had become resistant to cisplatin and paclitaxel. Patients received Mifepristone 200 mg orally on a daily basis. Patients were followed by tumor size or CA-125 levels when there was no measurable disease. A dose reduction of Mifepristone was to occur in the event of grade 3/4 hematologic, GI, or liver toxicity, creatinine >2.5%, and grade 4 peripheral neuropathy. Results. Thirty-four patients were evaluable for response. Nine (26.5%) of these patients had a response to Mifepristone. Three(9%) patients had a complete response, and six (17.5%), a partial response. The response of one patient in each group was measured by CA-125 levels while the remainder had measurable disease. The response lasted 1 to 4 months in all but one patient. One patient continues to respond after more than 3 years. The major toxic effect was a rash and this was the major reason patients were removed from the study. Conclusion. Mifepristone has activity against ovarian cancer resistant to cisplatin and paclitaxel. The drug is well tolerated. Further studies need to be performed when this drug becomes more widely available in the United States.

a Cooper University Hospital, Camden, NJ 08103, USA b Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA c Abington Memorial Hospital, Abington, PA 19001, USA d The Hospital of Central Connecticut, New Britain, CT 06050, USA e Maine Medical Center, Portland, ME 04102, USA f Rush-Presbyterian St. Lukes Medical Center, Chicago, IL 60612, USA g University of Oklahoma, Oklahoma City, OK 73190, USA

Site of recurrence and survival data were reviewed for 96 patients with FIGO stage IB cervical carcinoma treated between July 1978 and December 1986 with radical surgery (N = 55), radiation therapy (N = 30), or combination therapy (N = 11). There were 21 patients (21.8%) who suffered recurrences. After radiation 10 of 30 (33.3%) patients recurred versus 11 of 55 (20%) after radical surgery alone. Recurrences were observed in 6 of 14 (42.8%) patients with positive nodes, 11 of 61 (18%) patients with negative nodes, and 4 of 21 (19%) patients with unknown nodal status. The first manifestation of recurrence was central in 3, locoregional in 9, and distant in 9. The median disease-free interval (DFI) was 11 months for surgical and 10.5 months for irradiated patients. The 2-year disease-free survival was 83.6% for surgical patients and 73.3% for irradiated patients. The risk of distant metastases was 3 of 55 (5.4%) following radical surgery and 6 of 30 (20%) after radiation (P = 0.04). The median time to pelvic recurrence was 10 months and that for distant recurrence was 20 months (P less than 0.05). The median time to pelvic relapse was 9.5 months for radical surgery patients and 10 months for irradiated patients. The median time to distant recurrence was 20 months for radical surgery patients and 16.5 months for irradiated patients. Median survival in those who died of disease after a recurrence confined to the pelvis was 15 months versus 8 months for those with a distant recurrence (P less than 0.05). Our data confirm that (1) site of relapse is influenced by primary therapeutic modality and (2) pelvic recurrence manifests before distant recurrence; however, median DFI for all recurrences as well as for the subsets of pelvic and distant relapses is independent of primary modality. We suggest that an understanding of the natural history of cervical cancer recurrence will allow optimal use of resources in the follow-up of patients to detect recurrence.

Eighty-five patients underwent a surgical staging procedure during a 2-year period. Fifty-eight of these patients were evaluated in relation to the histologic grade of their squamous carcinoma of the cervix. An increased incidence of extrapelvic lymph node metastasis is associated with poorly differentiated tumors and with parametrial extension of the primary tumor regardless of histologic grade. Surgical staging is suggested for patients with parametrial extension of their tumor or for patients with poorly differentiated tumors.

Thirty-six patients with primary ovarian carcinoma who had 42 second-look procedures performed are reported. Twenty-three patients had no tumor found at the second-look celiotomy and were given no further treatment. Thirteen patients had tumor at the second-look procedure and were continued on therapy. Six patients have died with disease and all had a positive second-look celiotomy. Two patients have died with leukemia but with no evidence of ovarian cancer, one after a negative second-look and the other a negative third-look. No patient with a negative second-look celiotomy has died with disease. A correlation with respect to the findings at the second-look was found with respect to the stage of disease and the amount of residual tumor at the initial surgery. The use of the second-look celiotomy in patients with disease in the early stages and in patients treated with irradiation is discussed, along with the utilization of the laparoscopy.