Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study.

PURPOSE: To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m(2)) or 24-hour infusion paclitaxel (200 mg/m(2)) or the combination of paclitaxel (135 mg/m(2)) followed by cisplatin (75 mg/m(2)). PATIENTS AND METHODS: After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS: Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P <.001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P <.001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0. 929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P =.31). CONCLUSION: Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option.

Intraperitoneal alpha-interferon alternating with cisplatin in residual ovarian carcinoma: a phase II Gynecologic Oncology Group study.

OBJECTIVE: The aim of this study was to study the combination of intraperitoneal alpha-interferon and cisplatin administered second-line in an alternating sequence in small volume residual epithelial ovarian cancer after second-look surgery and the activity of this combination based on prior response to first-line platinum compounds. METHODS: Sixty-two patients with minimal residual (<0.5 cm) epithelial ovarian cancer at reassessment laparotomy were entered into a multicenter trial of intraperitoneal alpha-interferon alternating with cisplatin given for eight cycles unless disease progression or unacceptable toxicity occurred. The patients were considered favorable if they were platinum-sensitive and/or relapsed 6 months or longer after completing treatment. Another reassessment laparotomy was performed within 12 weeks of completion of treatment in patients who were in clinical remission. RESULTS: Fifty-four patients were clinically evaluable and 18 were surgically reassessed, 5 of whom had a negative reassessment operation (20% complete response and 8% partial response). Of the 54 patients evaluable for toxicity, the most common adverse effects of more than grade 2 were gastrointestinal in 13 (47%), neutropenia in 9 (17%), and leukopenia in 6 (12%). Grade 4 toxicity was seen in 10 instances: 4 gastrointestinal, 2 neutropenia, 2 thrombocytopenia, 1 wound infection, and 1 allergic reaction. CONCLUSIONS: alpha-Interferon and cisplatin are active agents in favorable patients with minimal residual epithelial ovarian cancer at second-look. The combination of the two drugs administered in an alternating sequence appears to be associated with more side effects than when either drug is administered alone. The combination produced response rates similar to those seen when either drug is given alone.

Neuroendocrine small cell uterine cervix cancer in pregnancy: long-term survival following combined therapy.

A 22-year-old woman carrying twin gestations at 30 weeks presented with preterm labor and a prolapsing cervical mass. Following Cesarean section birth, she was treated with multiagent chemotherapy followed by pelvic radiotherapy for a Stage IIA small cell cancer of the uterine cervix. She is without evidence of disease 5.5 years after diagnosis and is the first reported long-term survivor of a small cell cervical carcinoma diagnosed during pregnancy.

Hydroxyurea, 5-fluorouracil infusion, and cisplatin adjunct to radiation therapy in cervical carcinoma: a phase I-II trial of the Gynecologic Oncology Group.

BACKGROUND: In a previous study, the Gynecologic Oncology Group (GOG) compared hydroxyurea (HDXR) and the combination of cisplatin (C) and 5-fluorouracil (5-FU) infusion as potentiators of radiation therapy. This study was undertaken to determine whether these two regimens could be combined, concurrent with pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: The GOG entered 75 eligible and evaluable patients on a Phase I-II evaluation of HDXR, C, and 5-FU as adjuncts to radiation therapy for locally advanced carcinoma of the cervix. All patients had histologically verified primary disease and confirmed negative para-aortic lymph nodes. Eligibility was limited to clinical stage IIB through IVA. HDXR was given orally, twice weekly at a dose of 2.5 g/m2; C on Days 1 and 29 at 50 mg/m2; and 5-FU by 96-hr infusion on Days 2-5 and 30-33 at a starting dose of 800 mg/m2. RESULTS: Forty-eight (64%) patients had stage IIB disease, 25 (33%) had stage IIIB, and 2 had stage IVA tumors. Primary tumors 4 cm or less in size were present in 15 patients, between 4 and 6 cm were in 27 patients, and larger than 6-cm were observed in 33 patients. Grade 3/4 acute toxicity was experienced by 41 (54.7%) patients. These acute toxicities caused delays in prescribed radiation therapy of more than 1 week in 14 (18.9%) and low doses of drug in 16 (21.3%), and only 26 (34.7%) patients had the scheduled dose escalation of 5-FU on their second course. Clinical response was excellent with complete and partial response rate of 93.3%. Median time to progression has not been reached. CONCLUSION: Although this dose and schedule could be successfully administered, the delays in therapy should be avoided by a lower starting dose of hydroxyurea. Stomatitis was not a dose-limiting toxicity. These results have formed the basis of a phase III trial comparing this regimen to two other chemoradiation regimens.

Comparison of combination therapy with paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with suboptimal stage III and stage IV ovarian cancer: a Gynecologic Oncology Group study.

This prospective study compared the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin with the standard therapy of cyclophosphamide/cisplatin in women with suboptimal stage III and stage IV ovarian cancer. Of the initial 410 women who presented with advanced disease and greater than 1 cm residual masses after initial surgery, 386 met all eligibility criteria and were randomly assigned to receive a regimen of cisplatin 75 mg/m2 and cyclophosphamide 750 mg/m2 or cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 delivered over 24 hours. Dosage reductions were permitted in the event of significant toxicity. Among 216 patients with measurable disease, responses were reported in 73% of those receiving cisplatin/paclitaxel and in 60% of those receiving cisplatin/cyclophosphamide. Median progression-free survival was significantly longer (P < .001) in the group treated with cisplatin/paclitaxel, compared with those receiving cisplatin/cyclophosphamide (17.9 v 12.9 months, respectively).

Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group).

Administration of an alkylating agent plus a platinum coordination complex is standard therapy for advanced epithelial ovarian cancer in the United States. The most commonly used combination is cyclophosphamide/ cisplatin; however, the benefit of this combination in overall survival has not been compelling. We report a prospective comparison of this regimen versus a combination of cisplatin with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a new and well-tolerated agent with documented activity in cisplatin-refractory ovarian cancer. Three hundred eighty-six patients with advanced ovarian cancer and greater than 1 cm residual masses following initial surgery were randomly assigned to receive a regimen of cisplatin (75 mg/m2) and cyclophosphamide (750 mg/m2), or cisplatin (75 mg/m2) and paclitaxel (135 mg/m2), delivered over 24 hours. Dose reductions in cyclophosphamide or paclitaxel were permitted for significant toxicity. In 216 patients with measurable disease, responses were reported in 73% of those randomized to the cisplatin/paclitaxel arm and in 60% randomized to the cisplatin/cyclophosphamide arm. Progression-free survival was significantly longer (P < .001) with cisplatin/paclitaxel (median, 12.9 v 17.9 months). Overall survival was also significantly longer (P < .001) with cisplatin/paclitaxel (median, 37.5 v 24.4 months). Incorporating paclitaxel into first-line therapy for patients with suboptimally debulked stage III and stage IV ovarian cancer can increase the duration of the progression-free interval and extend overall survival while maintaining an acceptable toxicity profile.

Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.

BACKGROUND: Chemotherapy combinations that include an alkylating agent and a platinum coordination complex have high response rates in women with advanced ovarian cancer. Such combinations provide long-term control of disease in few patients, however. We compared two combinations, cisplatin and cyclophosphamide and cisplatin and paclitaxel, in women with ovarian cancer. METHODS: We randomly assigned 410 women with advanced ovarian cancer and residual masses larger than 1 cm after initial surgery to receive cisplatin (75 mg per square meter of body-surface area) with either cyclophosphamide (750 mg per square meter) or paclitaxel (135 mg per square meter over 24 hours). RESULTS: Three hundred eighty-six women met all the eligibility criteria. Known prognostic factors were similar in the two treatment groups. Alopecia, neutropenia, fever, and allergic reactions were reported more frequently in the cisplatin-paclitaxel group. Among 216 women with measurable disease, 73 percent in the cisplatin-paclitaxel group responded to therapy, as compared with 60 percent in the cisplatin-cyclophosphamide group (P = 0.01). The frequency of surgically verified complete response was similar in the two groups. Progression-free survival was significantly longer (P < 0.001) in the cisplatin-paclitaxel group than in the cisplatin-cyclophosphamide group (median, 18 vs. 13 months). Survival was also significantly longer (P < 0.001) in the cisplatin-paclitaxel group (median, 38 vs. 24 months). CONCLUSIONS: Incorporating paclitaxel into first-line therapy improves the duration of progression-free survival and of overall survival in women with incompletely resected stage III and stage IV ovarian cancer.

Preliminary analysis of the behavior of stage I ovarian serous tumors of low malignant potential: a Gynecologic Oncology Group study.

PURPOSE: From December 1983 through February 1992, a prospective study designed to determine the clinical course of patients with ovarian tumors of low malignant potential (LMP) was conducted by the Gynecologic Oncology Group (GOG). MATERIALS AND METHODS: This protocol was developed to evaluate the following (1) the biologic behavior of ovarian LMP tumors, (2) the effectiveness of melphalan chemotherapy in patients with clinically detectable residual disease after surgical staging and in patients whose tumors progress or recur after surgical therapy, and (3) the response rate to cisplatin in those who failed to respond to melphalan therapy. The study group consisted of 146 assessable patients with stage I serous LMP tumors. All of these women had the affected ovary (or ovaries) removed, and a complete staging operation was performed in each case. While 123 patients had a total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO), 21 retained the uterus and one normal-appearing ovary and fallopian tube. No adjuvant chemotherapy or radiation therapy was administered to any patients in the stage I study group. RESULTS: The median follow-up time was 42.4 months (range, 1.6 to 108). Thus far, no patient with a stage I ovarian serous LMP tumor has developed recurrent disease. CONCLUSION: Stage I ovarian serous LMP tumors rarely, if ever, recur. Limited resection, after meticulous surgical exploration, is adequate therapy for women of reproductive age.

New therapeutic approaches in gynecologic oncology.

Early-stage epithelial ovarian cancer, although elusive in screening programs, is readily controlled by resection and limited duration chemotherapy. Extensive cytoreductive surgery and multiagent chemotherapy, now including paclitaxel, show significant, although still modest, improvement in the survival of advanced-stage epithelial cancer. The role of radiation therapy for intermediate risk and advanced-stage endometrial cancer is debatable. Tailored hysterectomy for early-stage cervical cancer is replacing radiation therapy in many instances, whereas advanced cancer is being treated with combination chemoradiation. Smaller, less disfiguring procedures are being used successfully for vulvar squamous cell cancers and melanomas.

Malignant melanoma of the vulva treated by radical hemivulvectomy. A prospective study of the Gynecologic Oncology Group.

BACKGROUND: Beginning in 1983, the Gynecologic Oncology Group (GOG) conducted a prospective clinicopathologic study of primary malignant melanoma of the vulva. The objectives of this study were to determine the relationship of histopathologic parameters and microstaging to the International Federation of Gynaecology and Obstetrics (FIGO) staging and prognosis. METHODS: All patients with primary untreated malignant melanoma of the vulva and no history of previous or subsequent other primary invasive malignancy were eligible for study entry. All patients were required to have modified radical hemivulvectomy as minimal therapy. Groin dissection was optional. Histopathologic specimens were reviewed for capillary space involvement, Clark's level, Breslow's depth of invasion, cell type, and melanin distribution. Patient characteristics were analyzed in their relationship to groin node status and recurrence-free interval. RESULTS: Between 1983 and 1990, 81 patients were entered in the study. Of these, 71 were evaluable. Thirty-four patients underwent radical hemivulvectomy, and 37 patients underwent radical vulvectomy. In addition, 56 patients underwent groin node dissection. The factors that were independently correlated with groin node status were: capillary lymphatic space involvement (p = 0.0001) and central primary tumor location (i.e., bilateral/clitoral/T3) (P = 0.003). The other factors that were significant--clinical tumor size, vulvar staging (FIGO), GOG performance status, and Breslow's depth of invasion--were not independent predictors of positive nodes. The factor with the highest significant correlation with recurrence-free interval was the 1992 staging system of the American Joint Committee on Cancer (AJCC) for malignant melanoma of the skin. Using multiple regression, AJCC stage was the only independent prognostic factor. In the absence of AJCC stage, Breslow's depth of invasion was the most prognostic. CONCLUSION: The biologic behavior of vulvar melanoma is similar to other nongenital cutaneous malignant melanoma.

Primary malignant melanoma of the uterine cervix: two case reports and a century's review.

Primary malignant cervical melanoma is diagnosed by the presence of junctional melanocytic abnormality and the absence of distant metastasis. Amelanotic and poorly differentiated tumors can often be diagnosed with the HMB-45 immunoperoxidase stain which is very specific for melanoma. Early reported cases were treated with simple excision followed many times by radiation therapy. Radical hysterectomy, pelvic lymphadenectomy, and partial vaginectomy have been advocated by some contemporary investigators. Radiation can be used as adjuvant or palliative treatment; its efficacy is not well established. Few patients have been treated with modern chemotherapy. No patient has been treated with immunotherapy. Primary malignant cervical melanoma carries a very poor prognosis. Most patients succumb from their disease within 2 years. One patient has survived 14 years. The small number of reported cases makes it difficult to evaluate the efficacy of any treatment modality.

Whole-abdominal radiotherapy for patients with minimal residual epithelial ovarian cancer.

Sixteen patients with advanced epithelial ovarian cancer who were treated with cytoreductive surgery followed by multiagent chemotherapy were found to have residual tumor masses less than 2 cm in greatest diameter at reexploration and were treated with whole-abdominal radiation (19-31 Gy). Thirteen patients also received pelvic boosts to a total pelvic dose of 41-53.7 Gy. Radiotherapy was completed in all but 2 patients after treatment delays in 7 patients. Early treatment complications included myelosuppression in 11 patients, diarrhea in 3, and a self-limited small bowel obstruction in one. Delayed complications were severe and included 9 patients with radiation enterocolitis, 8 of whom required intestinal resection or diversion. One additional patient with radiation cystitis required instillation of formalin to control bleeding. Two patients are without evidence of disease 28 and 30 months following radiotherapy, while the remaining 14 patients have recurred after a median progression-free interval of 9 months (range 1-30 months). All patients who recurred failed within the treatment field and died of cancer after a median interval of 19 months following radiotherapy and 9 months after documentation of progression. These data suggest that few patients with persistent ovarian cancer following surgery and chemotherapy will be salvaged with radiotherapy.

Concordance of combination and single agent chemosensitivity prediction in ovarian carcinoma using the subrenal capsule xenograft assay (SRCA).

The tumors from 62 patients with advanced ovarian adenocarcinoma were assayed by the subrenal capsule xenograft assay (SRCA) for sensitivity to doxorubicin (A), cis-platinum (P), and cyclophosphamide (C), individually and in combination. In some instances only one or two of the individual drugs were assayed; however, the combination, CAP, was always tested. All patients received an optimal surgical debulking (absence of any residual tumor masses greater than or equal to 2 cm) followed by chemotherapy with CAP. Forty-two tumors were predicted to be sensitive to CAP by the SRCA; 51 of 71 (72%) individually tested drugs agreed with this determination. Twenty-one tumors were predicted to be resistant to CAP and 32 of 36 (89%) individually tested drugs agreed with this determination. In this preliminary study, 11 patients had surgically documented partial responses to CAP chemotherapy. All of these patients had tumors which prospectively tested as sensitive to CAP in the SRCA: 13 of 18 (72%) of separately tested drugs were in concordance with this sensitivity. Fourteen patients failed CAP therapy and three of these failures were predicted prospectively by the SRCA: 9 of 9 (100%) of separately tested drugs were in concordance. Thus, there is an overall concordance of 82% (22/27) between the individual components of a combination chemotherapy and the combination therapy itself. It would seem that extrapolations of sensitivity or resistance can be made from the individual components.

Rotated hypoplastic hemipelvis: a cause of obstructive dyspareunia.

Repeat Chiari innominate osteotomy in a young woman with traumatic monoplegia and subsequent hypoplasia of the hemipelvis and leg resulted in rotation of the pubic ramus into the vagina, causing obstructive dyspareunia. Resection of the inferior pubic ramus through a transperineal approach allowed successful intromission with resolution of her dyspareunia.

Prophylactic mezlocillin in radical hysterectomy.

The role of prophylactic antibiotics in radical hysterectomy patients was studied in a double-blind randomized prospective study of mezlocillin (Mezlin, Miles Pharmaceuticals), a broad-spectrum semisynthetic penicillin, compared to placebo. Thirty evaluable patients received 4 g mezlocillin or saline placebo intravenously one-half hour before surgery, a second dose four to six hours later, and a final dose six hours after that. The rate of wound infection, postoperative use of additional antibiotics, fever index, and the incidence of standard febrile morbidity were all significantly lower in the mezlocillin group. Short-term perioperative prophylactic antibiotics are indicated in patients undergoing radical hysterectomy.

Accurate laboratory predictions of the clinical response of patients with advanced ovarian cancer to treatment with cyclophosphamide, doxorubicin, and cisplatin.

Seventy-six patients with advanced ovarian cancer treated with cyclophosphamide, doxorubicin, and cisplatin (CAP) at 3-week intervals were tested for the response of their tumors to treatment with CAP in the subrenal capsule tumor implant assay. Thirty-four of the patients' tumors were assayed prospectively before clinical treatment and 33 were assayed retrospectively, after clinical treatment with CAP. Nine of the patients' tumors were assayed both prospectively and retrospectively. All of the patients underwent a tumor debulking laparotomy. Of the patients with clinically measurable residual disease, 17 had a partial response of at least 50% regression of disease, and 11 had a progression of disease. Of the patients with known residual but nonmeasureable disease, 7 had surgically verified complete responses, 8 at least 50% regression, and 23 had progression of disease: 10 had no evidence of disease clinically but had not had surgical confirmation. Twenty-six of the tumors were adenocarcinomas not otherwise specified (2 grade I, 2 grade II, and 22 grade III), 39 were serous adenocarcinomas (7 grade I, 9 grade II, and 23 grade III), 7 were endometrioid adenocarcinoma (all grade III), 3 were mucinous adenocarcinomas (1 each of grade I, II, and III) and 1 was an adenosquamous carcinoma (grade III). Thirty-four of the patients failed the therapy. The subrenal capsule (SRC) assay predicted 21 of these failures (4 prospective and 17 retrospective). Thirty-two of the patients responded to CAP chemotherapy. The SRC assay accurately predicted the clinical regression of the tumors of 22 of the patients (15 prospective and 7 retrospective). Second-look laparotomy confirmed 7 patients with no evidence of disease, 5 patients with minimal disease, and 5 patients with a greater than 50% reduction of their disease. The SRC assay predicted the response of all these patients except 2 with partial responses to chemotherapy. Thus, while the overall positive predictive value of the SRC assay in this study is 65%, it is 100% for those patients whose tumors respond completely and for those who have minimal residual disease after CAP chemotherapy.

Malignant ovarian germ cell tumors: a review of thirty-six cases.

Thirty-six patients with malignant ovarian germ cell tumors were treated between 1972 and 1983, including 16 with immature teratoma, five with endodermal sinus tumor, seven with dysgerminoma, and eight with mixed germ cell tumors. The median age at presentation was 18 years and mean primary tumor diameter was 18 cm. Twenty-five of the 27 patients who were treated with multiple-agent chemotherapy underwent second-look procedures, only two of which revealed persistent malignancy. No patients have developed recurrence after a negative second-look operation. Two of the three patients with failure of initial chemotherapeutic regimens had complete remissions with second regimens. Two patients have died of malignancy, one who presented with a Stage IA mixed germ cell tumor and one noncompliant patient with a Stage IA, grade 2 immature teratoma. The other 34 patients are alive without evidence of disease from 21 to 141 months, with a median follow-up of 68 months. These data confirm that multiple-agent chemotherapy has dramatically improved the prognosis for patients with malignant nondysgerminomatous ovarian germ cell tumors.

Action of 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin) against untreated human ovarian cancers in the murine xenograft assay.

The activity of 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin) was determined in nine untreated human ovarian cancer specimens, using the murine subrenal capsule xenograft assay. Tumor cytotoxic effect was demonstrated in seven out of the nine tumors implanted. The drug was well tolerated by the test animals. Tiazofurin may prove to be an effective chemotherapeutic agent in the treatment of ovarian cancer.

A simplified method for right atrial catheter insertion.

Using the technique described, Hickman catheters can be inserted by a single operator at low cost and risk. The simplicity of insertion and removal with this method makes the use of this device preferable to standard temporary central venous catheters in most instances.

Hydrocele of the canal of Nuck. A report of four cases.

Hydrocele formation in the incompletely obliterated processus vaginalis (canal of Nuck) is an uncommon and infrequently reported finding in women. Approximately one-third of cases are associated with inguinal herniae. Surgical exploration permits excision of the hydrocele and repair of any coexisting fascial defect.