Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology-Gynecologic Oncology Group Study 240 (NCT 00803062).
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SUBMITTER: Tewari KS
PROVIDER: S-EPMC7907274 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer significantly improves overall and progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240.MethodsEligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0-1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m(2) intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m(2) intravenously over 24 h or 175 mg/m(2) intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m(2) over 3 h on day 1) and topotecan (0·75 mg/m(2) for 30 min on days 1-3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred first. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov, number NCT00803062.FindingsBetween April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not differ significantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI -4·1 to 1·7; p=0·30).InterpretationImprovements in overall survival and progression-free survival attributed to the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life. Patients responding to anti-angiogenesis therapy who maintain an acceptable quality of life could be suitable at progression for treatment with other novel therapies that might confer additional benefit.FundingNational Institutes of Health.
| S-EPMC4479218 | biostudies-literature
Project description:ObjectiveWomen with persistent, recurrent, and/or metastatic cervical cancer have a poor prognosis. Even with the availability of cisplatin plus paclitaxel and bevacizumab, median overall survival (OS) is only 17.0 months, with median post-progression survival of approximately seven months. We studied the therapeutic vaccine, Axalimogene filolisbac (ADXS-HPV), in women who had progressed following at least one prior line of therapy (Gynecologic Oncology Group protocol 265/NCT01266460).MethodsVolunteers ≥18 years with advanced cervical cancer and GOG performance status score of 0 or 1 were eligible for participation in this 2-stage, phase II trial. In stage 1, women received up to three doses of ADXS-HPV (1 × 109 colony-forming units in 250 mL IV over 15 min every 28 days) and were monitored for tumor progression. In stage 2, women were treated until progression, intolerable adverse events (AEs), or voluntary withdrawal of consent. Co-primary endpoints were safety and proportion of volunteers surviving ≥12 months. An estimated, combined (stages 1 + 2) 12-month OS of 35% was calculated from historical GOG cohorts to declare ADXS-HPV sufficiently active in this platinum-pre-treated population. Secondary endpoints were OS and progression-free survival (PFS).ResultsAmong 50 evaluable volunteers, the 12-month OS was 38% (n = 19). Median OS was 6.1 months (95% CI: 4.3-12.1) and median PFS was 2.8 months (95% CI: 2.6-3.0). The most common treatment-related AEs were fatigue, chills, fever, nausea, and anemia. The majority of AEs were grade 1 or 2 and resolved spontaneously or with appropriate treatment.ConclusionAt the dose and schedule studied, ADXS-HPV immunotherapy was tolerable and met the protocol-specified benchmark for activity required to warrant further investigation in volunteers with cervical carcinoma.
| S-EPMC7487015 | biostudies-literature
Project description:BACKGROUND:On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS:In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS:Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION:The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING:National Cancer Institute.
| S-EPMC5714293 | biostudies-literature
Project description:PurposeTo evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma.MethodsEligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m2 over 3 hours day 1, IP cisplatin 75 mg/m2 day 2, and IP paclitaxel 60 mg/m2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22.ResultsA total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm.ConclusionCompared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.
| S-EPMC6544459 | biostudies-literature
Project description:BACKGROUND:Based primarily on studies concerning early-stage tumours (treated surgically), and locally advanced disease (treated with chemoradiation), the prognosis for women with adenocarcinoma (AC) or adenosquamous (AS) carcinoma has been reported to be poorer than those with squamous cell carcinoma (SCCA) of the cervix. It is unclear whether differences in prognosis also persist in the setting of recurrent or metastatic disease treated using chemotherapy doublets with or without bevacizumab. METHODS:Cases were pooled from three Gynaecologic Oncology Group randomised phase III trials of chemotherapy doublets. Pearson's test was used to evaluate response rate (RR) of AC/AS vs SCCA, Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS), and Cox proportional hazards model to estimate the impact of histology on PFS and OS. RESULTS:Of 781 evaluable patients, 77% (N=599) had SCCA and 23% (N=182) AC/AS. There were no significant differences in RRs between histologic subgroups. The adjusted hazard ratio (HR) for death for SCCA vs AC/AS was 1.13 (95% CI 0.93, 1.38 P=0.23). When comparing SC/AS (N=661, 85%) to AC alone (N=120, 15%), the adjusted HR for death was 1.23 (95% CI 0.97, 1.57, P=0.09). CONCLUSIONS:AC/AS and SCCA have similar survival in recurrent or metastatic cervical carcinoma when treated with chemotherapy doublets.
| S-EPMC5785748 | biostudies-literature
Project description:Since 1970, the Gynecologic Oncology Group (GOG) has been at the forefront of evaluating and helping to implement ground breaking and paradigm changing research in the management of cervical cancer. While the most dramatic example of this impact was a series of clinical trials published in 1999 that evaluated chemoradiation therapy versus radiation therapy alone for patients with various clinical scenarios, including both locally advanced as well as post radical hysterectomy patients, investigation has continued to further refine and improve therapy. In 2014, based on the results of GOG protocol 240, bevacizumab became the first approved targeted therapy in a gynecologic cancer in the United States. Most recently, clinical trial work from the GOG is changing the standard of care for all clinical scenarios. Finally, an emphasis on survivorship and special populations are now top priorities.
| S-EPMC6102091 | biostudies-literature
Project description:BACKGROUND:To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma. PATIENTS AND METHODS:This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors. RESULTS:One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (≤1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days). CONCLUSION:Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable. CLINICAL TRIALS IDENTIFIER:NCT00262847.
| S-EPMC4684156 | biostudies-literature
Project description:BackgroundSynuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023).MethodsHigh-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage.ResultsThe overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels.ConclusionsThis largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.
| S-EPMC5360512 | biostudies-literature
Project description:PurposeThe clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive.MethodsPrimary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models.ResultsA total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases.ConclusionMMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors.
| S-EPMC5012715 | biostudies-literature
Project description:PURPOSE:Racial genetic admixture (RGA), a measure to account for ancestral genetic background that correlates with individual's racial classification, could provide insights on causation of racial disparity in endometrial cancer (EC). Our objective is to evaluate the association of RGA with EC outcomes. METHODS:EC patients enrolled onto the GOG-210 protocol were eligible. A randomized subcohort stratified by stage and self-reported race/ethnicity of black or white was used. Genotyping was performed using custom-selected Ancestry Informative Markers to calculate individual admixture estimates of African and European ancestral background. RESULTS:A total of 149 patients were evaluated (self-reported race: 70 black & 79 white). Mean RGA for African ancestry for self-reported black patients was 0.65 (range 0.04-0.86); while mean RGA for European ancestry for self-reported white patients was 0.77 (range 0.12-0.88). Progression-free survival (PFS) analysis using proportional hazards models stratified by stage and race revealed that each 0.10 increase in African ancestry was associated with worse PFS with hazard ratio (HR) of 1.11 (95% CI 0.90-1.37). Each 0.10 increase in European RGA was associated with improved PFS with HR of 0.86 (95% CI 0.69-1.07). Using tertiles of African RGA showed increasing risk of progression of death with increasing African RGA (with 0-5% as reference), HR (95% CIs) for top two tertiles are: 6%-66%: 1.38 (0.64, 2.97), and 67%-86%: 2.27 (0.74, 6.95). CONCLUSION:RGA demonstrated a trend with PFS in self-reported black and white patients with EC. Patients with increased levels of African ancestry showed a trend towards worse survival after stratifying by stage/race.
| S-EPMC4842318 | biostudies-literature