Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: Cisplatin-based combination chemotherapy is considered standard treatment for advanced/recurrent cervical carcinoma; however, the majority of patients do not respond. This study was undertaken to identify the prognostic factors and develop a model predictive of (non-) response to chemotherapy. METHODS: Four-hundred twenty-eight patients with advanced cervical cancer who received a cisplatin-containing combination in three Gynecologic Oncology Group (GOG) protocols (110, 169 and 179) were evaluated for baseline clinical characteristics and multivariate analysis was conducted to identify factors independently prognostic predictive of response using a Logistic regression model. A predictive model was developed and externally validated using an independent GOG protocol (149) data. RESULTS: Multivariate analysis identified five factors (African-American, performance status [PS] >0, pelvic disease, prior radiosensitizer and time interval from diagnosis to first recurrence <1 year) independently prognostic of poor response. A simple prognostic index was derived based on the total number of risk factors. When patients were classified into three risk groups (low risk: 0-1 factor; mid risk: 2-3 factors; high risk: 4-5 factors), patients with 4-5 risk factors were estimated to have a response rate of only 13%, and median progression-free and overall survival of 2.8 months and 5.5 months, respectively. The accuracy of the index was supported by both internal and external datasets. CONCLUSIONS: A simple index based on five prognostic factors may have utility in clinical practice to identify the women who are not likely to respond to the cisplatin-containing regimens. This subgroup of patients should be considered for non-cisplatin chemotherapy or investigational trials.

Influence of race on tolerance of platinum-based chemotherapy and clinical outcomes in women with advanced and recurrent cervical cancer: a pooled analysis of 3 Gynecologic Oncology Group studies.

OBJECTIVE: This study was undertaken to compare toxicity and outcomes from cisplatin-based combination chemotherapy for black and white women with advanced /recurrent cervical cancer. STUDY DESIGN: Frequencies of grade 3 and 4 toxicities, response, and survival were compared by race using data from 3 Gynecologic Oncology Group studies. RESULTS: Black women experienced significantly less grade 3 and 4 neutropenia (63% vs 82%), leukopenia (58% vs 79%), thrombocytopenia (10% vs 23%), and adverse events of any nature (84% vs 93%) compared with white women. Black patients were not at increased risk of disease progression (adjusted relative risk, 1.11; 95% confidence interval, 0.88-1.38; P = .382) or death (adjusted relative risk, 1.02; 95% confidence interval, 0.82-1.26; P = .893). CONCLUSION: Cisplatin-based chemotherapy delivered in a protocol setting for advanced/recurrent carcinoma of the cervix appears better tolerated by black women.

Phase II evaluation of 9-aminocamptothecin (9-AC, NSC #603071) in platinum-resistant ovarian and primary peritoneal carcinoma: a Gynecologic Oncology Group Study.

OBJECTIVE: To estimate the antitumor activity of 9-aminocamptothecin (9-AC) in patients with recurrent platinum-"resistant" ovarian cancer; and to determine the nature and degree of toxicity of 9-AC in this cohort of patients. METHODS: A multicenter phase II study was conducted by the Gynecologic Oncology Group (GOG). Patients were to receive 9-AC (colloidal dispersion) 25 microg/m(2)/h (600 microg/m(2)/day) IV over 120 h (5 days) beginning days 1 and 8. Dose adjustment was permitted for toxicity. This schedule was repeated every 21 days until disease progression or unacceptable adverse events. Hematopoietic growth factor support was used as necessary. RESULTS: From January 1999 to December 2000, 29 member institutions of the GOG enrolled 58 patients. Two patients received no therapy; thus, 56 (97%) were evaluable. Median age was 61 (range: 33-81) years. A median of four (range: 1-32) courses of 9-AC was administered. The most frequent grade 3 or 4 toxicities were neutropenia in 46%, leukopenia in 37%, gastrointestinal in 29%, anemia in 25%, and thrombocytopenia in 21%. There was one possible treatment-related death. There were four (7%) complete and four (7%) partial responses, for an overall response rate of 14%. Eighteen (32%) patients had stable disease, 22 (39%) progressed, and response could not be assessed in 8 (14%). CONCLUSION: The 9-AC at this dose and schedule showed limited activity comparable to that seen with other agents in platinum-resistant ovarian or primary peritoneal cancer.

Intraperitoneal cisplatin with intraperitoneal gemcitabine in patients with epithelial ovarian cancer: results of a phase I/II Trial.

PURPOSE: The aims of this study were to determine the dose and schedule of i.p. cisplatin with i.p. gemcitabine in patients with persistent disease at second-look assessment, the toxicity of this regimen, and the time to treatment failure and overall survival. EXPERIMENTAL DESIGN: We performed a Phase I/II evaluation of i.p. cisplatin at 75 mg/m(2) on day 1 with planned gemcitabine at 500, 750, 1000, or 1250 mg/m(2) i.p. on days 1, 8, and 15 on a 28-day schedule for four courses. Eligible patients completed surgical cytoreduction followed by adjuvant platinum-based chemotherapy. They had second-look assessment showing microscopic or macroscopic (< or =1 cm) disease, followed by i.p. port placement. RESULTS: The Phase I dose-limiting toxicity was grade 3 thrombocytopenia at day 15 on dose level 1 (n = 5). The protocol was amended, and the Phase II portion accrued to 30 patients, who were given i.p. cisplatin (75 mg/m(2)) on day 1 and gemcitabine at 500 mg/m(2) on days 1 and 8 on a 21-day schedule for four courses. Nine patients were removed from the study: one each for hypersensitivity, cellulitis, and i.p. port malfunction; two for progression of disease; and four for renal toxicity. Other toxicities included grade 3 nausea (7%) and transient grade 3 neuropathy (3%). Grade 1 or 2 neuropathy was frequently seen (80%). Five patients (17%) returned to the operating room at a median of 6 months (range, 1-20 months) after i.p. therapy for evaluation of abdominal pain; two patients had recurrence, and all had areas of fibrous tissue with encasement of the bowel. In two patients, the fibrous tissue was causing partial bowel obstruction. No other patients had symptoms prompting surgical exploration. Pharmacokinetic (PK) studies showed a median area under the curve (AUC) i.p. of 3041 h. micro M (range, 676-5702 h. micro M) and AUC in plasma of 4.0 h. micro M (range, 0.92-8.2 h. micro M) reached between 120 and 240 min; the pharmacological advantage was 759-fold (range, 217-1415-fold) for i.p. versus plasma drug levels. The mean residence time of gemcitabine with i.p. administration was 4.7 h. The median time to progression of the intent to treat population was 15.93 months (95% confidence interval, 9.13-25.9 months), with a median overall survival of 43.5 months [95% confidence interval, (34.66- infinity)]. No statistical differences were seen with respect to overall survival if patients were grouped in terms of optimal debulking or not (median not reached versus 34.8 months, respectively; P = 0.16) or whether visible disease was present or not at the start of i.p. therapy (34.8 versus 47.7 months; P = 0.47). With regard to time to treatment failure, a statistical difference favored patients with optimal versus nonoptimal primary debulking (25.2 versus 10.2 months, respectively; P = 0.03). CONCLUSIONS: The median time to treatment failure and overall survival of 15.9 months and 43.5 months, respectively, are consistent with our historical data in patients receiving i.p. platinum-based regimens for consolidation. The fibrotic changes seen in explored patients suggest local toxicity of this combination. The absolute benefit of i.p. consolidation requires randomized trials to assess efficacy.

A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study.

BACKGROUND: Despite their low risk for recurrence, many women with endometrial adenocarcinoma receive postoperative radiation therapy (RT). This study was developed to determine if adjunctive external beam irradiation lowers the risk of recurrence and death in women with endometrial cancer International Federation of Gynaecology and Obstetrics (FIGO) stages IB, IC, and II (occult disease). METHODS: Four hundred forty-eight consenting patients with "intermediate risk" endometrial adenocarcinoma were randomized after surgery to either no additional therapy (NAT) or whole pelvic radiation therapy (RT). They were followed to determine toxicity, date and location of recurrence, and overall survival. A high intermediate risk (HIR) subgroup of patients was defined as those with (1) moderate to poorly differentiated tumor, presence of lymphovascular invasion, and outer third myometrial invasion; (2) age 50 or greater with any two risk factors listed above; or (3) age of at least 70 with any risk factor listed above. All other eligible participants were considered to be in a low intermediate risk (LIR) subgroup. RESULTS: Three hundred ninety-two women met all eligibility requirements (202 NAT, 190 RT). Median follow-up was 69 months. In the entire study population, there were 44 recurrences and 66 deaths (32 disease or treatment-related deaths), and the estimated 2-year cumulative incidence of recurrence (CIR) was 12% in the NAT arm and 3% in the RT arm (relative hazard (RH): 0.42; P=0.007). The treatment difference was particularly evident among the HIR subgroup (2-year CIR in NAT versus RT: 26% versus 6%; RH=0.42). Overall, radiation had a substantial impact on pelvic and vaginal recurrences (18 in NAT and 3 in RT). The estimated 4-year survival was 86% in the NAT arm and 92% for the RT arm, not significantly different (RH: 0.86; P=0.557). CONCLUSIONS: Adjunctive RT in early stage intermediate risk endometrial carcinoma decreases the risk of recurrence, but should be limited to patients whose risk factors fit a high intermediate risk definition.

Gemcitabine in cervical cancer.

OBJECTIVE: Recurrent and advanced cervical cancers are associated with high mortality and a lack of effective treatment options, especially for women who are poor candidates for surgery or radiation therapy. The broad clinical effectiveness and low toxicity of gemcitabine in other human malignancies suggest that it might be useful in treating cervical tumors. METHODS: Fifteen phase I/II clinical trials on the use of gemcitabine, both as a single agent and in combination with cisplatin, in patients with recurrent or advanced carcinoma of the cervix were reviewed. Data from studies in which gemcitabine was used in combination with radiotherapy for induction therapy and with cisplatin for neoadjuvant chemotherapy were also evaluated. RESULTS: Although single-agent gemcitabine was generally inferior to cisplatin, when used concurrently with cisplatin and/or radiation therapy, objective response rates were high and survival was prolonged. The drug also showed promise when used with cisplatin as neoadjuvant therapy. CONCLUSIONS: Initial studies suggest that gemcitabine may be useful in the management of recurrent or advanced cervical cancer when used concurrently with cisplatin. Accordingly, a large phase III study will compare cisplatin/gemcitabine with the current standard, and further evaluation of gemcitabine appears to be warranted in conjunction with radiotherapy and in the neoadjuvant setting.

Treatment of ovarian cancer: new strategies.

OBJECTIVES: The objective was to review the progress made in gene- and molecular-based management of ovarian cancer over the past decade and the future direction of targeted therapies. METHODS: Research studies, review articles, and scientific meeting abstracts published between 1994 and 2002 were reviewed and analyzed. RESULTS: Significant progress has been made in understanding the molecular biology of ovarian cancer and the role that single-nucleotide polymorphisms, tumor suppressor genes, and oncogenes play in promoting tumor cell growth and proliferation. Strategies have been developed to correct gene defects or single out ovarian cancer cells for destruction. Molecular-based therapies are now under development to specifically target receptors and signal transduction pathways that control cell proliferation and apoptosis, angiogenesis, cellular adhesion, and cell motility in ovarian tumors. CONCLUSIONS: The end product of this intense investigation will be new targeted therapies that offer the hope of improving the medical management of ovarian cancer while being significantly less toxic to normal cells.

Extraovarian peritoneal serous papillary carcinoma: a phase II trial of cisplatin and cyclophosphamide with comparison to a cohort with papillary serous ovarian carcinoma-a Gynecologic Oncology Group Study.

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/m(2) and cyclophosphamide 750 mg/m(2) 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 tended to be older that those with EPSPC 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.

Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study.

PURPOSE: Phase II trial reports have suggested that the addition of bleomycin to the combination of cisplatin and ifosfamide may improve response rates and possible survival in squamous carcinoma of the cervix. This study prospectively evaluates the combination of bleomycin to this regimen in women with histologically proven advanced recurrent or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Eligible women were randomized to receive either cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CI) versus bleomycin 30 units over 24 hours on day 1 followed by cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CIB). Three hundred three women were enrolled onto this trial, of which 287 were assessable. RESULTS: There were no significant differences between CI and CIB with regard to response rates (32% v 31.2%, respectively), progression-free survival (PFS), or overall survival. PFS and survival were associated with initial performance status (PS). Patients with a PS of 0 experienced a lower rate of failure (P =.013) and a lower risk of death (P =.009) compared with patients with PS of 2. The most frequent grade 3/4 toxicities were leukopenia, neutropenia, anemia, thrombocytopenia, and nausea and vomiting. Neither regimen was associated with a significant increase in incidence of these toxicities. CONCLUSION: The CI regimen was virtually identical to CIB with regard to response rate, PFS, survival, and toxicity profile. Thus, the addition of bleomycin in the dose-schedule employed to cisplatin and ifosfamide did not improve outcome in patients with advanced cervical cancer.