Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group Study.

A randomized clinical trial was conducted in women with stage III ovarian carcinoma (less than or equal to 1 cm residual lesions), using cyclophosphamide plus cisplatin (CP) with or without doxorubicin. There were 349 evaluable patients, of whom 176 received CP while 173 patients received CP plus doxorubicin (CAP). Hematologic toxicity was almost identical. There was no significant difference in progression-free interval (PFI) (median, 22.7 months and 24.6 months), frequency of negative second-look laparotomy (30.2% and 32.8%), or survival (median, 31.2 months and 38.9 months) between CP and CAP, respectively. Thus, doxorubicin in the dose schedule employed does not improve combination chemotherapy of optimal stage III ovarian carcinoma. Several other findings, independent of treatment arm, were of interest. There was a significant difference in PFI and survival by residual disease category (yes v no) and by grade of differentiation (1 v 2 + 3). In multivariate analysis, age, residual disease at entry, cell type (clear cell carcinoma), and time from surgery to initiation of chemotherapy were significant predictors of survival. There was no difference in outcome comparing those who refused second-look with those who had a second-look.

Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.

PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported. PATIENTS AND METHODS: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death. RESULTS: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen. CONCLUSION: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.

Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group.

PURPOSE: To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous (IV) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin. PATIENTS AND METHODS: Patients were randomized to receive either IV paclitaxel 135 mg/m(2) over 24 hours followed by IV cisplatin 75 mg/m(2) every 3 weeks for six courses or IV carboplatin (area under curve 9) every 28 days for two courses, then IV paclitaxel 135 mg/m(2) over 24 hours followed by intraperitoneal (IP) cisplatin 100 mg/m(2) every 3 weeks for six courses. RESULTS: Of the 523 patients who entered this trial, 462 were determined to be assessable, with prognostic factors well balanced between the treatments. Neutropenia, thrombocytopenia, and gastrointestinal and metabolic toxicities were greater in the experimental arm. As a result, 18% of the patients received < or = two courses of IP therapy. Progression-free survival was superior for patients randomized to the experimental treatment arm (median, 28 v 22 months; relative risk, 0.78; log-rank P =.01, one-tail). There was a borderline improvement in overall survival associated with this regimen (median, 63 v 52 months; relative risk, 0.81; P =.05, one-tail). CONCLUSION: An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. Because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm is not recommended for routine use. However, the results provide direction for further clinical investigation in small-volume ovarian cancer.

Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study.

PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study.

PURPOSE: The objective of this study was to determine if groin radiation was superior to and less morbid than groin dissection. METHODS AND MATERIALS: Members of the Gynecologic Oncology Group randomized 58 patients with squamous carcinoma of the vulva and nonsuspicious (N0-1) inguinal nodes to receive either groin dissection or groin radiation, each in conjunction with radical vulvectomy. Radiation therapy consisted of a dose of 50 Gray given in daily 200 centiGray fractions to a depth of 3 cm below the anterior skin surface. RESULTS: The study was closed prematurely when interim monitoring revealed an excessive number of groin relapses on the groin radiation regimen. Metastatic involvement of the groin nodes was projected to occur in 24% of patients based on this Group's previous experience. On the groin dissection regimen, there were 5/25 (20.0%) patients with positive groin nodes. These patients received post-operative radiation. There were five groin relapses among the 27 (18.5%) patients on the groin radiation regimen and none on the groin dissection regimen. The groin dissection regimen had significantly better progression-free interval (p = 0.03) and survival (p = 0.04). CONCLUSION: Radiation of the intact groins as given in this study is significantly inferior to groin dissection in patients with squamous carcinoma of the vulva and N0-1 nodes.

Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study.

PURPOSE: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.

Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes.

From 1977 to 1984, 114 eligible patients with invasive squamous cell carcinoma of the vulva and positive groin nodes after radical vulvectomy and bilateral groin lymphadenectomy were randomized to receive either radiation therapy or pelvic node resection. Fifty-three of the 59 patients randomized to radiation therapy received a 4500- to 5000-rad tumor dose in five to 6.5 weeks bilaterally to the groins and to the midplane of the pelvis even if only unilateral positive groin nodes had been detected; no radiation was given to the central vulvar area. Fifty-three of the 55 patients randomized to further surgery had pelvic node resection performed on the side containing positive groin nodes either unilaterally or bilaterally. Acute and chronic morbidity was similar for both regimens. The two major poor prognostic factors were clinically suspicious or fixed ulcerated groin nodes and two or more positive groin nodes. The difference in survival for the 114 evaluable patients was significant, favoring the adjunctive radiation therapy group (P = .03). The estimated two-year survival rates were 68% for the radiation therapy group and 54% for pelvic node resection group. The most dramatic survival advantage for radiation therapy was in patients who had either of the two major poor prognostic factors present; at this time, the benefit of radiation therapy for the remaining patients is uncertain. In this randomized prospective study, the addition of adjunctive groin and pelvic irradiation therapy after radical vulvectomy and inguinal lymphadenectomy proved superior to pelvic node resection.

Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group.

Although cure rates are high, the morbidity of radical operation for carcinoma of the vulva is substantial. Between 1983-1989, member institutions of the Gynecologic Oncology Group entered 155 patients in a prospective evaluation of modified radical hemivulvectomy and ipsilateral inguinal lymphadenecctomy for clinical stage I vulvar cancer. Only patients with neoplastic thickness of 5 mm or less, without vascular space invasion, and negative inguinal lymph nodes were eligible for this study. There have been 19 recurrences and seven deaths from disease among the 121 eligible and evaluable patients. Patients whose disease recurred on the vulva were frequently (eight of ten patients) salvaged by further operation. Five of the seven deaths due to cancer occurred among patients whose first recurrence was in the groin. Acute and long-term morbidity as well as hospital stay were each less than in the Group's previous experience in a comparable patient population treated with radical vulvectomy and bilateral inguinal-femoral lymphadenectomy. There was a significantly increased risk of recurrence but not death when compared with these same historic controls. Modified radical hemivulvectomy and ipsilateral inguinal lymphadenectomy is an alternative to traditional radical operation for these selected patients with stage I carcinoma of the vulva. The number of patients who experienced recurrence in the operated groin is of concern and may be attributable to the decision to leave the femoral nodes intact.

Teniposide (VM-26) in patients with advanced endometrial carcinoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-two evaluable patients with advanced endometrial cancer were treated with teniposide 100 mg/m2/week administered as a 30-60-minute infusion. Escalations of 20 mg/m2/week to a maximum dose of 160 mg/m2 were performed in patients without toxicity. Seventeen of the 22 patients had prior chemotherapy. Two patients had a partial response (95% upper confidence bound for response: 25.9%). Toxicity was minimal. Four patients had white blood cell counts of less than 2,000/mm3 but only two with less than 1,000/mm3. Only one patient had a platelet count between 25,000 and 50,000, and no bleeding or septic episodes were noted. Four patients had mild nausea, and eight mild nausea and vomiting. Teniposide displays no major activity in patients with advanced endometrial cancer who have had prior chemotherapy.

Mitoxantrone in the treatment of advanced vulvar and vaginal carcinoma. A gynecologic oncology group study.

Nineteen evaluable patients with advanced carcinoma of the vulva or vagina were treated with mitoxantrone, 12 mg/m2, every 3 weeks. All patients had good performance status and measurable disease and only nine had received prior chemotherapy. No complete or partial responses were noted. The major toxicity was myelosuppression; other toxicity was mild, and no cardiac toxicity or drug deaths occurred. The median progression-free interval was 1.3 months for patients with vulvar cancer and 1.6 months for patients with vaginal cancer. Median survival was 3.2 months for patients with vulvar cancer and 2.7 months for patients with vaginal cancer. Mitoxantrone displays no activity in patients with advanced carcinoma of the vulva or vagina.

Mitoxantrone in the treatment of advanced uterine sarcoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-nine evaluable patients with metastatic or recurrent leiomyosarcoma or malignant mixed mesodermal tumors of the uterus were treated with mitoxantrone 12 mg/m2 every 3 weeks. All patients had good performance status and measurable disease. Nineteen had prior chemotherapy but only five had prior doxorubicin. No complete or partial responses were seen in 12 patients with leiomyosarcoma (95% confidence interval for a response of 0-22%) or 17 patients with mixed mesodermal tumors (95% confidence interval for a response of 0-16%). The median progression-free interval for patients with leiomyosarcoma was 1.4 months and the median survival 4.1 months. The median progression-free interval for patients with mixed mesodermal was 1.4 months and median survival 4.0 months. Mitoxantrone does not appear to be very active against leiomyosarcoma or mixed mesodermal tumors as second-line therapy.

A phase II trial of medroxyprogesterone acetate in epithelial ovarian cancers. A Gynecologic Oncology Group study.

Twenty-four evaluable patients with advanced or recurrent epithelial ovarian carcinoma who progressed on platinum-containing combination chemotherapy were treated with medroxyprogesterone acetate (C.T. Provera) 50 mg orally three times a day until progression of disease. One patient had a partial response (4.2%), 9 patients had stable disease (37.5%), and 14 (58.3%) had increasing disease. The 95% upper confidence limit for response is less than or equal to 18.3%. There was no toxicity associated with its use. C.T. Provera has limited activity in patients with epithelial ovarian cancer who have failed combination chemotherapy.

Adriamycin chemotherapy for malignant mixed mesodermal tumor of the ovary. A Gynecologic Oncology Group Study.

Malignant mixed mesodermal tumor (MMMT) of the ovary is a rare, but usually fatal, cancer for which there exists no proven postsurgical therapy. The Gynecologic Oncology Group has evaluated adriamycin in this disease at a dose of 75/m2. Among 10 evaluable cases with measurable disease there was one partial response and no complete responses. Of 21 cases with nonmeasurable tumor four remain clinically free of cancer from 2 to 45 months. There were two treatment-related deaths. We conclude that adriamycin alone as first-line chemotherapy in patients with MMMT of the ovary is not sufficiently active to be clinically useful.

Teniposide (VM-26) in patients with non-squamous-cell carcinoma of the cervix. A phase II trial of the Gynecologic Oncology Group.

Twenty-three evaluable patients with non-squamous-cell carcinoma of the cervix were treated with teniposide 100 mg/m2 per week administered as a 30-60 min infusion. Escalations of 20 mg/m2 per week to a maximum dose of 160 mg/m2 were performed in patients without toxicity. Thirteen of the 23 patients had no prior chemotherapy. One patient had a partial response (95% confidence intervals for response less than or equal to 19%). Toxicity was minimal. Seven patients had white blood cell counts of less than 2,000/mm3 but only one had less than 1,000/mm3. No patients had platelet counts less than 50,000/mm3, and no bleeding or septic episodes were noted. Two patients had mild nausea and seven had mild nausea and vomiting. Teniposide displays no major activity in patients with non-squamous-cell cervical cancer.

Carcinoma of the cervix treated with chemotherapy and radiation therapy. Cooperative studies in the Gynecologic Oncology Group.

Since its inception in 1970, the Gynecologic Oncology Group (GOG) has pursued a series of Phase II and III cooperative clinical investigations of the combination of cytotoxic chemotherapy and radiation therapy for patients with locally advanced carcinoma of the cervix. After an initial randomized trial indicated that hydroxyurea was superior to placebo, subsequent studies have evaluated whether the hypoxic sensitizer, misonidazole, or the combination of cisplatin with infusional 5-fluorouracil were superior to hydroxyurea. Other studies have evaluated concurrent chemotherapy with extended field radiation for patients with metastatic disease in their paraaortic nodes. The GOG will continue to attempt to identify and develop superior adjuncts to radiation therapy for this patient population.

Clinical-pathologic study of stage IIB, III, and IVA carcinoma of the cervix: extended diagnostic evaluation for paraaortic node metastasis--a Gynecologic Oncology Group study.

Three hundred twenty patients were entered into GOG Protocol 63, a clinical-pathologic study of stage IIB, III, and IVA cervical carcinoma. Following the completion of FIGO staging prerequisites, patients had computerized tomography (CT), a lymph-angiogram (LAG), and an ultrasound (US) of the aortic area. If any study was positive, a cytologic or histologic evaluation by fine-needle aspiration or selective paraaortic lymphadenectomy was performed. Paraaortic node dissection was mandated for patients with negative extended staging studies. Results of extended staging evaluations were compared with histologic or cytologic results. Two hundred sixty-four patients were eligible and evaluable. One hundred sixty-seven patients (63%) were stage IIB, 89 (34%) were stage III, and 8 (3%) were stage IVA. Positive paraaortic nodes occurred in 21% of stage IIB, 31% of stage III, and 13% of stage IVA. LAG sensitivity was 79% with a specificity of 73%. Sensitivity of CT and US was 34 and 19%, respectively, with specificities of 96 and 99%, respectively. The frequency of false-negative results with LAG for patients with stage IIB disease was 6%. This decrease is consistent with a stable sensitivity and specificity. These findings suggest that a negative LAG may be adequate to eliminate surgical staging in subgroups with low risk of metastasis to the aortic nodes. Until new noninvasive testing methods are developed, LAG appears to be the most reliable noninvasive examination to evaluate spread of cervical cancer to aortic nodes.

Mitoxantrone in the treatment of advanced non-squamous carcinoma of the cervix (a phase II trial of the gynecologic oncology group).

Twenty-five evaluable patients with advanced non-squamous carcinoma of the uterine cervix were treated with mitoxantrone 12 mg/m2 every three weeks. All patients had good performance status and measurable disease and only 11 had received prior chemotherapy. One complete and one partial response were noted among 15 patients with no prior chemotherapy while no responses were seen in 11 previously treated patients. The major toxicity was myelosuppression; other toxicity was mild. The median progression-free interval was 2.1 months and median survival 4.3 months. Mitoxantrone displays minimal activity in patients with advanced non-squamous carcinoma of the cervix.

Phase III study on the treatment of women with cervical cancer, stage IIB, IIIB, and IVA (confined to the pelvis and/or periaortic nodes), with radiotherapy alone versus radiotherapy plus immunotherapy with intravenous Corynebacterium parvum: a Gynecologic Oncology Group Study.

A report on a study conducted under the auspices of the Gynecologic Oncology Group on the treatment of women with advanced carcinoma of the uterine cervix (stages IIB, IIIB, IVA) with radiotherapy alone versus radiotherapy plus immunotherapy (intravenous Corynebacterium parvum) is presented. There were 283 patients considered evaluable for analysis. Of these, 135 patients were randomized to radiotherapy plus C. parvum (120 patients received at least one course) and 148 were randomized to radiotherapy only. The two treatment regimens were similar for those adverse effects commonly associated with radiation therapy but for hematologic toxicity and fever and/or chills were significantly more frequent among those patients who received C. parvum. There was no statistical difference in the treatment regimens with regard to survival or progression-free interval. Of the 42 patients with positive periaortic nodes, 19% were alive at 3 years. No therapeutic value was demonstrated by combining C. parvum therapy with traditional radiation therapy in advanced cervical cancer. Because of the greater frequency of adverse effects in those patients receiving C. parvum, the further use of C. parvum at this dose and schedule does not appear to be indicated for treating cervical cancer patients.

Experience with the use of generalized data base management systems in cooperative group clinical trials (a project of the Gynecologic Oncology Group).

Roswell Park Management Information System (RPMIS) is a formatted video-based system of programs for file creation, data entry, editing, updating, retrieval, and report generation. It has been utilized in more than 800 intrainstitutional research studies at Roswell Park. The Gynecologic Oncology Group (GOG) is a multiinstitutional, multidisciplinary cooperative group. Its clinical trials encompass the planning, initiation, execution, analysis, and presentation of results of management and treatment of patients with gynecologic cancer. The GOG Statistical Office, located at Roswell Park Memorial Institute, is responsible for data management and analysis of all patients entered into GOG protocols. Present annual accrual is approximately 2000 patients per year; 38 protocols are actively accruing patients while follow-up continues on 14 studies that are closed to patient entry. A previous paper (J Med Syst 7:235-242, 1983) described a time study comparing use of RPMIS and a paper batch processing system in GOG data management. The time study results and potential advantages of RPMIS warranted a gradual total conversion to this system. Presently GOG maintains 43 separate, self-contained applications of RPMIS and routinely develops a new system in conjunction with each new study initiated. This paper documents GOG experience with RPMIS during the past 4 years.