Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

The effect of older age on treatment outcomes in women with advanced ovarian cancer receiving chemotherapy: An NRG-Oncology/Gynecologic Oncology Group (GOG-0182-ICON5) ancillary study.

OBJECTIVE: To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction. METHODS: Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared. RESULTS: We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups. CONCLUSIONS: In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986.

The addition of paclitaxel to doxorubicin and cisplatin and volume-directed radiation does not improve overall survival (OS) or long-term recurrence-free survival (RFS) in advanced endometrial cancer (EC): A randomized phase III NRG/Gynecologic Oncology Group (GOG) study.

OBJECTIVES: To determine if the addition of paclitaxel (P) to cisplatin and doxorubicin (CD) following surgical debulking and volume-directed radiation therapy improved long-term, recurrence-free survival (RFS) and overall survival (OS) in patients with advanced-stage endometrial cancer (EC). METHODS: Prospective, randomized GOG trial comparing (CD) (50 mg/m2)/(45 mg/m2) +/- (P) (160 mg/m2) following volume-directed radiation and surgery in advanced EC. A Kaplan-Meier (KM) analysis characterized the relationship between treatment arms and the OS outcome, a log-rank test assessed the independence of treatment with the OS outcome, and the treatment effect on estimated OS was determined using a Cox proportional hazards (PH) model stratified by stage. The PH assumption was assessed using a test of interaction between treatment variable and the natural logarithm of survival time. Adverse events, regardless of attribution, were graded. RESULTS: Since initial publication, 60 deaths occurred, leaving 311 patients alive with 290 (93.8%) recurrence- free. There was no significant decrease in the risk of recurrence or death associated with the CDP treatment regimen stratified for stage (p = 0.14, one-tail). The exploratory analysis for OS and the corresponding homogeneity tests for different effects across subgroups revealed only EFRT and EFRT & GRD status to have significantly different treatment effects (p = 0.027 and p = 0.017, respectively). Second primary malignancies were identified in 17/253 (6.4%) and 19/263 (7.0%) of patients treated with CD and CDP respectively. Breast (2.4%) followed by colon (1%) were the two cancers most frequently diagnosed in this setting. CONCLUSION: No significant difference between treatment arms was identified. Subgroup analysis both in the initial and current reports demonstrated a trend towards improved RFS and OS in patients treated with CDP and EFRT. This long-term analysis of outcomes also identified the necessity of providing on-going cancer screening to patients enrolled in trials.

Does adjuvant chemotherapy dose modification have an impact on the outcome of patients diagnosed with advanced stage ovarian cancer? An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: To determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel. METHODS: Women with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment. RESULTS: A total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19-1.72, P < 0.001) and 1.26 (95% CI, 1.04-1.54, P = 0.021), respectively. Use of G-CSF was more frequent in dose-modified patients with an odds ratio (OR) of 3.63 (95% CI: 2.51-5.26, P < 0.001) compared to dose-unmodified patients. CONCLUSION: Dose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC.

Predictive modeling for determination of microscopic residual disease at primary cytoreduction: An NRG Oncology/Gynecologic Oncology Group 182 Study.

OBJECTIVE: Microscopic residual disease following complete cytoreduction (R0) is associated with a significant survival benefit for patients with advanced epithelial ovarian cancer (EOC). Our objective was to develop a prediction model for R0 to support surgeons in their clinical care decisions. METHODS: Demographic, pathologic, surgical, and CA125 data were collected from GOG 182 records. Patients enrolled prior to September 1, 2003 were used for the training model while those enrolled after constituted the validation data set. Univariate analysis was performed to identify significant predictors of R0 and these variables were subsequently analyzed using multivariable regression. The regression model was reduced using backward selection and predictive accuracy was quantified using area under the receiver operating characteristic area under the curve (AUC) in both the training and the validation data sets. RESULTS: Of the 3882 patients enrolled in GOG 182, 1480 had complete clinical data available for the analysis. The training data set consisted of 1007 patients (234 with R0) while the validation set was comprised of 473 patients (122 with R0). The reduced multivariable regression model demonstrated several variables predictive of R0 at cytoreduction: Disease Score (DS) (p<0.001), stage (p=0.009), CA125 (p<0.001), ascites (p<0.001), and stage-age interaction (p=0.01). Applying the prediction model to the validation data resulted in an AUC of 0.73 (0.67 to 0.78, 95% CI). Inclusion of DS enhanced the model performance to an AUC of 0.83 (0.79 to 0.88, 95% CI). CONCLUSIONS: We developed and validated a prediction model for R0 that offers improved performance over previously reported models for prediction of residual disease. The performance of the prediction model suggests additional factors (i.e. imaging, molecular profiling, etc.) should be explored in the future for a more clinically actionable tool.

Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC. METHODS: Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p-values with genomic control adjustment. RESULTS: The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e-08. No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p-2.144e-08) (rs6256 p-9.774e-07) for PFS and 2 different SNPs were identified (rs295315 p-7.536e-07; rs17693104 p-7.734e-07) which were close to significance for OS. CONCLUSIONS: Using the pre-specified level of significance of 1×10-08, we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers.

Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study.

Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80-0.98) for MS7 compared with 0.69 (0.59-0.80) and 0.71 (0.58-0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival (p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool.

Nomogram for Predicting Individual Survival After Recurrence of Advanced-Stage, High-Grade Ovarian Carcinoma.

OBJECTIVE: To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian-peritoneal-tubal carcinoma and to develop a nomogram to predict individual survival after recurrence. METHODS: We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian-peritoneal-tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated. RESULTS: There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2-92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5-21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy. CONCLUSION: For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival. CLINICAL TRIAL REGISTRATION: ClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.

Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study.

PURPOSE: This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR). EXPERIMENTAL DESIGN: Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib. RESULTS: Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free >6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation. CONCLUSIONS: Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.

Goserelin acetate as treatment for recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

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.

Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: This phase II trial assessed the activity and tolerability of an oral dose of imatinib mesylate 400 mg twice daily in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma. The association between the expression of certain markers and clinical outcome was investigated. PATIENTS AND METHODS: Primary measure of clinical efficacy was progression-free survival (PFS) at 6 months. Mutational analysis of KIT, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay for markers (KIT, platelet-derived growth factor [PDGF] receptor [-R], AKT2, phosphorylated AKT [p-AKT], stem cell factor [SCF], and PDGF) were performed. RESULTS: Fifty-six eligible patients were evaluated. Nine patients were progression free for at least 6 months including one complete responder. The median PFS and survival were 2 and 16 months, respectively. The most common grade 3 and 4 toxicities were neutropenia, GI, dermatologic effects, pain, and electrolyte disturbances. At least one target of imatinib (KIT, PDGFR-alpha, or PDGFR-beta) was expressed in all tumors, and most tumors expressed all three receptors. Higher expression of p-AKT and PDGFR-beta were associated with shorter PFS, and higher IHC scores (% immunopositive cells x staining intensity) of SCF and p-AKT were associated with decreased overall survival. No sequence mutations were detected in the KIT gene. Higher pretreatment plasma concentrations of PDGF-AB, PDGF-BB, and vascular endothelial growth factor (VEGF) were individually associated with shorter PFS and survival. CONCLUSION: Imatinib mesylate was well tolerated but had minimal single-agent activity in patients with recurrent ovarian or primary peritoneal carcinoma. No marker was identified that would predict activity of imatinib; however, tumor p-AKT and plasma VEGF levels were associated with poor outcome.

Phase III randomized trial of intravenous cisplatin plus a 24- or 96-hour infusion of paclitaxel in epithelial ovarian cancer: a Gynecologic Oncology Group Study.

PURPOSE: This study was undertaken to assess if prolonged paclitaxel administration in combination with cisplatin improves overall survival (OS) in epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with suboptimal stage III or IV EOC, fallopian tube, or primary peritoneal cancer were randomly allocated to receive six cycles of cisplatin 75 mg/m2 and either paclitaxel 135 mg/m2 during 24 hours (arm 1) or paclitaxel 120 mg/m2 during 96 hours (arm 2). RESULTS: Planned accrual was 324 patients; 293 were enrolled before the study was closed as a result of a scheduled interim futility analysis. There were 13 ineligible patients; thus, 140 patients in each arm were assessable. In arm 1, 80% of patients completed all six cycles compared with 83% of patients in arm 2. Grade 4 granulocytopenia was more common in arm 1 (79% v 54%; P < .001) whereas grade 3 or worse anemia was more severe in arm 2 (6% v 18%; P < .003). The median progression-free survival was 1.03 years for arm 1 versus 1.05 years for arm 2. The median OS was 2.49 and 2.54 years for arms 1 and 2, respectively. There have been 237 reported deaths. The relative death rate was approximately 12% greater in arm 2 (hazard ratio, 1.12; 95% CI, 0.860 to 1.45). CONCLUSION: Patients with advanced EOC have a relatively poor prognosis. The results of treatment with cisplatin and paclitaxel are not significantly improved by prolonging the paclitaxel infusion from 24 to 96 hours.

Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: a phase II study of the Gynecologic Oncology Group.

OBJECTIVES: To evaluate outcome in patients with clinical stage I/II papillary serous (PS) or clear cell (CC) endometrial carcinoma treated with whole abdominal radiotherapy. METHODS: After total abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic/para-aortic lymph node sampling, and peritoneal washings, eligible patients received radiotherapy (RT) to the abdomen (3000 cGy at 150 cGy/day) with a pelvic boost (1980 cGy at 180 cGy/day). RESULTS: Among 21 PS patients (median age: 68 years), one refused therapy, and another received a non-protocol vaginal boost. In total, eight patients died of disease (DOD) between 9.6 and 35.2 months. Five others died due to protocol treatment (1), toxicity from subsequent chemotherapy (1), intercurrent disease (1), and unknown cause (2). Five-year progression-free survival (PFS) was 38%. Among treated patients who DOD, sites of recurrence included lung (2), lung/vagina (1), abdomen/pelvis (1), vagina (1), and abdomen (2). Among 13 CC patients (median age: 63 years), one received pelvic RT only and died with intercurrent disease. Five others died due to DOD (3), intercurrent disease (1), and unknown cause (1). Five-year PFS was 54%. Among patients who DOD, sites of recurrence included lung (1), vagina (1), and unknown (1). Grade 3/4 toxicities for both histologic groups included gastrointestinal (three grade 4; three grade 3), hematologic (one grade 4), and cutaneous (one grade 3). CONCLUSIONS: Over half of the treatment failures were within the radiation field. Systemic chemotherapy, radiosensitizing chemotherapy, or sequential radiation and chemotherapy should be considered in future adjuvant trials for these patients.

Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study.

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.

Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

PURPOSE: Vinorelbine is being explored by the Gynecologic Oncology Group (GOG) for its possible use in advanced or recurrent squamous cell carcinoma of the uterine cervix. The objective of this Phase II trial was to evaluate a days 1 and 8 every-21-days schedule and determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients with measurable disease and satisfactory baseline bone marrow, liver, and kidney functions were treated with vinorelbine 30 mg/m(2) given on days 1 and 8 every 21 days. A two-stage sampling design was used, proceeding to a second stage accrual if sufficient activity was documented in the first 25 patients. RESULTS: The study did proceed to the second stage and accrued 44 patients. There were six objective responses (one complete, five partial) for a response rate of 13.7% (95% confidence interval: 5.2-27.4%). There were three patients with response in extra-pelvic sites (including the complete response) and three with response in the pelvis. The overall frequency of grades 3 and 4 neutropenia was 41%, whereas neuropathy was reported in 27% and was severe in three. Treatment-related pain, very severe in two instances, was also reported in 27%. CONCLUSION: Vinorelbine has moderate activity in a pretreated population with squamous cell carcinoma of the cervix. Accordingly, vinorelbine in this days 1 and 8 schedule is being studied further in combination with cisplatin by the GOG.

Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to estimate the clinical response rate and toxicity of daily tamoxifen combined with intermittent weekly medroxyprogesterone acetate (MPA). METHODS: This study reports the results of 61 patients with measurable advanced or recurrent endometrial carcinoma enrolled on this study to be treated with tamoxifen 40 mg p.o. daily plus alternating weekly cycles of MPA 200 mg p.o. daily. RESULTS: One patient was excluded and two patients did not receive study treatment. The percent of patients responding (6 complete and 13 partial) was 33% (95% confidence interval [CI]: 21-46%) among 58 eligible patients who received therapy. Median progression-free survival (PFS) was 3 months and median overall survival (OS) was 13 months. CONCLUSION: The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Further investigation of this combination is appropriate.