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Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

ABSTRACT: The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets.Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets.In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m(2) by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m(2) IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m(2) IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients.Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70.

SUBMITTER: Yothers G

PROVIDER: S-EPMC3188282 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

Yothers Greg G O'Connell Michael J MJ Allegra Carmen J CJ Kuebler J Philip JP Colangelo Linda H LH Petrelli Nicholas J NJ Wolmark Norman N

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20110822 28

<h4>Purpose</h4>The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets.<h4>Patients and methods</h4>Other studies have identified patients ...[more]

PMID: 21859995

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Project description:ImportanceOxaliplatin added to fluorouracil plus leucovorin therapy for patients with colon cancer has been shown to provide significant but modest absolute benefit for disease-free survival. However, acute and chronic neurotoxic effects from this regimen underscore the need for markers that predict oxaliplatin benefit.ObjectiveTo test our hypothesis that molecular subtypes of colon cancer would be associated with differential prognosis and benefit from oxaliplatin added to fluorouracil plus leucovorin therapy.Design, setting, and participantsParticipants in the NSABP C-07 trial were divided into discovery (n = 848) and validation (n = 881) cohorts based on the order of tissue block submission. A reestimated centroid using 72 genes was used to determine Colorectal Cancer Assigner subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was examined with a locked-down algorithm for subtype classification and statistical analysis plan. Post hoc analysis included examination of the entire cohort with Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) methods.InterventionsFluorouracil plus leucovorin with or without oxaliplatin.Main outcomes and measuresPercent recurrence-free survival.ResultsAmong 1729 patients, 744 (43%) were female and mean (SD) age was 58 (11) years. Although C-07 participants with stage III disease with an enterocyte subtype showed a statistically significant benefit from oxaliplatin in the discovery cohort (hazard ratio, 0.22 [95% CI, 0.09-0.56]; P = .001 [N = 65]), no statistically significant benefit was observed in the validation cohort (hazard ratio, 0.53 [95% CI, 0.22-1.24]; P = .14 [N = 70]). The stemlike subtype was associated with poor prognosis and lack of benefit from oxaliplatin treatment (HR, 0.99 [95% CI, 0.73-1.34]; P = .96 [N = 367]). Examination of the different subtyping methods shows that all 3 methods robustly identified patients with poor prognosis (stemlike, CCS-3, and CMS-4) in both stage II and III.Conclusions and relevancePatients with stemlike tumors may be appropriate for clinical trials testing experimental therapies because stemlike tumors were robustly identified and associated with a poor prognosis regardless of stage or chemotherapy regimen. The clinical utility of using subtyping for the identification of patients for treatment with oxaliplatin requires validation in independent clinical trial cohorts.Trial registrationclinicaltrials.gov Identifier: NCT00004931.

Project description:BackgroundThe addition of oxaliplatin to adjuvant 5-fluorouracil (5-FU) improves survival of patients with stage III colon cancer in randomized clinical trials (RCTs). However, RCT participants are younger, healthier, and less racially diverse than the general cancer population. Thus, the benefit of oxaliplatin outside RCTs is uncertain.Subjects and methodsPatients younger than 75 years with stage III colon cancer who received chemotherapy within 120 days of surgical resection were identified from five observational data sources-the Surveillance, Epidemiology, and End Results registry linked to Medicare claims (SEER-Medicare), the New York State Cancer Registry (NYSCR) linked to Medicaid and Medicare claims, the National Comprehensive Cancer Network (NCCN) Outcomes Database, and the Cancer Care Outcomes Research & Surveillance Consortium (CanCORS). Overall survival (OS) was compared among patients treated with oxaliplatin vs non-oxaliplatin-containing adjuvant chemotherapy. Overall survival for 4060 patients diagnosed during 2004-2009 was compared with pooled data from five RCTs (the Adjuvant Colon Cancer ENdpoinTs [ACCENT] group, n = 8292). Datasets were juxtaposed but not combined using Kaplan-Meier curves. Covariate and propensity score adjusted proportional hazards models were used to calculate adjusted survival hazard ratios (HR). Stratified analyses examined effect modifiers. All statistical tests were two-sided.ResultsThe survival advantage associated with the addition of oxaliplatin to adjuvant 5-FU was evident across diverse practice settings (3-year OS: RCTs, 86% [n = 1273]; SEER-Medicare, 80% [n = 1152]; CanCORS, 88% [n = 129]; NYSCR-Medicaid, 82% [n = 54]; NYSCR-Medicare, 79% [n = 180]; and NCCN, 86% [n = 438]). A statistically significant improvement in 3-year overall survival was seen in the largest cohort, SEER-Medicare, and in the NYSCR-Medicare cohort (non-oxaliplatin-containing vs oxaliplatin-containing adjuvant therapy, adjusted HR of death: pooled RCTs: HR = 0.80, 95% CI = 0.70 to 0.92, P = .002; SEER-Medicare: HR = 0.70, 95% CI = 0.60 to 0.82, P < .001; NYSCR-Medicare patients aged ?65 years: HR = 0.58, 95% CI = 0.38 to 0.90, P = .02). The association between oxaliplatin treatment and better survival was maintained in older and minority group patients, as well as those with higher comorbidity.ConclusionThe addition of oxaliplatin to 5-FU appears to be associated with better survival among patients receiving adjuvant colon cancer treatment in the community.

Project description:ImportanceGiven recently published results of a 750-patient adjuvant sunitinib trial showing improved disease-free survival (DFS), the appropriate strategy for treating high-risk patients is unclear. We sought to determine whether there is improved disease-free survival benefit to taking the active drug in patients with high-risk (pT3, pT4, node-positive) clear cell renal cancer (ccRCC) in the ASSURE trial (adjuvant sunitinib or sorafenib vs placebo in resected unfavorable renal cell carcinoma [RCC]), the largest adjuvant trial published to date.ObjectiveTo evaluate DFS and overall survival (OS) in ccRCC high-risk patients randomized to sunitinib or sorafenib vs placebo among patients with stages comparable to other high-risk adjuvant trials.Design, setting, and participantsThe DFS and OS at 10 years postactivation were calculated for 1069 patients in US and Canadian cooperative groups with high-risk patients who had ccRCC histology and pT3, pT4, or node-positive disease accrued between 2006 and 2010 to the double-blind randomized placebo-controlled phase 3 trial. Outcome analyses by dose quartiles of these patients receiving sunitinib or sorafenib were also performed.InterventionsPatients received 1 year of adjuvant sunitinib (50 mg), sorafenib (800 mg) daily, or equivalent placebo. The study was amended for patient intolerance to sunitinib (37.5 mg), sorafenib (400 mg) daily, or equivalent placebo with mandatory dose escalation if no serious adverse effects were experienced.Main outcomes and measuresDisease-free survival, defined as time from randomization to recurrence, second primary cancer, or death.ResultsOf 1069 patients, 358 (243 [67.9%] men, 115 [32.1%] women) received sunitinib, 355 (248 [69.9%] men, 107 [30.1%] women) received sorafenib, and 356 (254 [71.3%] men, 102 [28.7%] women) received placebo as adjuvant therapy. The mean (SD) age for each group was 58.3 (10.6) years, 56.8 (10.3) years, and 57.5 (10.4) years, respectively. Five-year DFS rates were 47.7%, 49.9%, and 50.0%, respectively for sunitinib, sorafenib, and placebo (HR, 0.94 for sunitinib vs placebo; and HR, 0.90; 97.5% CI, 0.71-1.14 for sorafenib vs placebo), with 5-year OS of 75.2%, 80.2%, and 76.5% (HR, 1.06; 97.5% CI, 0.78-1.45; P = .66, sunitinib vs placebo; and HR, 0.80; 97.5% CI, 0.58-1.11; P = .12 for sorafenib vs placebo). There was no difference by dose quartile.Conclusions and relevanceNeither prognostic category of the tumor nor dose intensity of therapy altered the lack of difference in DFS or OS in this population of patients with high-risk ccRCC.Trial registrationclinicaltrials.gov Identifier: NCT00326898.

Project description:Response to oxaliplatin-based adjuvant chemotherapy varies among patients with stage II and III colon cancer; however, genetic alterations associated with this response remain incompletely characterized. A three-stage analytical framework, including the discovery, validation, and replication stages, was designed to explore genetic alterations modulating response to oxaliplatin-based chemotherapy in adjuvant setting among patients with stage II and III colon cancer receiving complete resection of tumor. Except for several somatic mutated genes, such as ARSD and ACE, showing less definitive associations with response to oxaliplatin-based adjuvant chemotherapy, we found stable associations of rs6891545C > A polymorphism in SLF1 gene, a key component of DNA damage response system, with the response across all three stages. Patients with rs6891545 A allele had significantly lower risk of poor responsiveness to oxaliplatin-based adjuvant chemotherapy at both discovery and validation stages, compared with ones possessing wild homozygous genotype CC (discovery stage: odds ratio, 0; 95% CI, 0-0.48; P = .005; validation stage: odds ratio, 0.33; 95% CI, 0.11-0.99; P = .048). In the replication cohort, rs6891545 A allele was confirmed to be strongly associated with improved DFS (hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .007). Notably, the improvement persisted after controlling for sex, age, tumor location, differentiation, and stage (hazard ratio, 0.42; 95% CI, 0.22-0.80; P = .009). Moreover, in silico analysis unraveled strong impact of rs6891545 A allele on local secondary structure of SLF1 mRNA, possibly leading to low SLF1 protein expression. We conclude that the rs6891545C > A polymorphism may serve as an independent marker of response to oxaliplatin-based adjuvant chemotherapy in patients with stage II and III colon cancer, with improved clinical benefit observed in patients with the A allele possibly attributable to low expression of SLF1 protein resulting in deficient DNA repair capacity.

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Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

Publications

Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

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