Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: A Commentary

2005 ◽  
Vol 23 (34) ◽  
pp. 8564-8565 ◽  
Author(s):  
Judith Abrams
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Free Survival ◽  
End Point ◽  
Disease Free ◽  
Cancer Studies

scholarly journals Bevacizumab in Stage II-III Colon Cancer: 5-Year Update of the National Surgical Adjuvant Breast and Bowel Project C-08 Trial

2013 ◽  
Vol 31 (3) ◽  
pp. 359-364 ◽  
Author(s):  
Carmen J. Allegra ◽  
Greg Yothers ◽  
Michael J. O'Connell ◽  
Saima Sharif ◽  
Nicholas J. Petrelli ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Free Survival ◽  
National Surgical Adjuvant Breast ◽  
End Point ◽  
Bowel Project ◽  
Modified Folfox6 ◽  
Disease Free

PurposeThe National Surgical Adjuvant Breast and Bowel Project trial C-08 was designed to investigate the safety and efficacy of adding bevacizumab to fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) for the adjuvant treatment of patients with stage 2-3 colon cancer. Our report summarizes the primary and secondary end points of disease-free and overall survival, respectively, with 5 years median follow-up time.Patients and MethodsPatients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group). The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point.ResultsOf 2,673 analyzed patients, demographic factors were well-balanced by treatment. With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P = .35). Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 1.25-year landmark (time-by-treatment interaction P value <.0001). The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P = .56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P = .99).ConclusionBevacizumab for 1 year with modified FOLFOX6 does not significantly prolong DFS or OS in stage 2-3 colon cancer. We observed no evidence of a detrimental effect of exposure to bevacizumab. A transient effect on disease-free survival was observed during bevacizumab exposure in the study's experimental arm.

Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: Individual Patient Data From 20,898 Patients on 18 Randomized Trials

2005 ◽  
Vol 23 (34) ◽  
pp. 8664-8670 ◽  
Author(s):  
Daniel J. Sargent ◽  
Harry S. Wieand ◽  
Daniel G. Haller ◽  
Richard Gray ◽  
Jacqueline K. Benedetti ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Individual Patient Data ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
End Point ◽  
Disease Free

Purpose A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

Re-Evaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials

2021 ◽  
Author(s):  
Jun Yin ◽  
Mohamed E Salem ◽  
Jesse G Dixon ◽  
Zhaohui Jin ◽  
Romain Cohen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Surrogate Endpoint ◽  
Free Survival ◽  
A Value ◽  
Deficient Mismatch Repair ◽  
Disease Free

Abstract Background Disease-free survival with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence, in patients who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from nine randomized studies conducted between 1998 and 2009 were included; three trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18,396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (pT1-3 & pN1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high/deficient mismatch repair tumors. Trial level correlation between 3-year DFS and 5-year OS remained strong (R2 =0.82, 95% CI = 0.67 to 0.98; R2 =0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusion Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

Endpoints in adjuvant trials: A systematic review of the literature in colon cancer and proposed definitions for future trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4018-4018
Author(s):  
M. E. Buyse ◽  
K. J. Punt ◽  
C. H. Köhne ◽  
P. Hohenberger ◽  
R. Labianca ◽  
...  
Keyword(s):  
Systematic Review ◽  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Review Of The Literature ◽  
Free Survival ◽  
Medical Oncologists ◽  
Starting Point ◽  
Definition Of ◽  
Disease Free

4018 Background: Disease-free survival (DFS) is the primary endpoint of most trials testing adjuvant treatments. However many other endpoints are used. There is much confusion about these endpoints since different definitions were used among trials, or no definitions were provided at all. Moreover there is no consensus on either the definition of each endpoint or on the most relevant among these endpoints. This creates difficulties when comparing the results of various trials. Methods: Adjuvant trials in colon cancer were used as a model. A systematic review was performed on published adjuvant studies in colon cancer from 1997–2006, and the definitions of endpoints other than overall survival (OS) were recorded. A panel of medical oncologists, surgical oncologists, and a statistician, all with expertise in randomised trials in colorectal cancer, aimed to reach consensus on the definition of the various endpoints as well as to select the most relevant among these. Results: A total of 52 studies were identified. In addition to overall survival 8 other endpoints were used, and both the definition of these endpoints as well as the starting point differed considerably among these studies. No definition was provided for the endpoint in 19 (37%) studies and for the starting point in 30 (58%) studies. The panel reached consensus on the definition of each endpoint ( table ), and agreed that DFS, defined as the time from randomisation to any event irrespective of cause was considered to be the most relevant endpoint for adjuvant studies. The date of randomisation was considered to be the most appropriate starting point. Conclusions: The proposed guideline will help in the design of future adjuvant studies in colon cancer, and will achieve the uniformity required to facilitate cross-study comparisons. It may serve as a model for adjuvant studies in other solid tumors. [Table: see text] No significant financial relationships to disclose.

Overall survival (OS) and updated disease-free survival (DFS) results of the NSABP C-08 trial assessing bevacizumab (B) in stage II and III colon cancer.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 3508-3508 ◽  
Author(s):  
C. J. Allegra ◽  
G. A. Yothers ◽  
M. J. O'Connell ◽  
S. Sharif ◽  
N. J. Petrelli ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Free Survival ◽  
Disease Free

Cochrane systematic review and meta-analysis of adjuvant chemotherapy for stage II colon cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3548-3548
Author(s):  
Brandon Matthew Meyers ◽  
Humaid Obaid Al-Shamsi ◽  
Alvaro Tell Figueredo
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Cochrane Systematic Review ◽  
Free Survival ◽  
Stage Ii Colon Cancer ◽  
Disease Free

3548 Background: Colon cancer is potentially curable by surgery in the early stages of the disease. Adjuvant chemotherapy improves disease-free and overall survival in patients with stage III disease, but the magnitude of benefit in stage II colon cancer is less clear. A previous Cochrane systematic review and meta-analysis (SR/MA) found improved disease-free, but not overall survival (Figueredo et al., 2008). An updated SR/MA was performed to determine the effects of adjuvant chemotherapy on disease-free and overall survival in patients with stage II colon cancer. Methods: Relevant databases (MEDLINE, EMBASE, and Cochrane) were independently searched by all authors, using the same search strategy employed in the original study (1/1988 to 9/2012). Randomized trials containing data on stage II colon cancer patients undergoing adjuvant 5-fluorouracil (5FU) chemotherapy versus observation were included. Pooled results were expressed as hazard ratios (HR) whenever possible, or risk ratios (RR), with 95% confidence intervals (95%CI) using a random effects model. Results: Seven studies were identified, and included in the final SR/MA. Six of the 7 studies were included in the disease-free survival analysis (n=4587). Adjuvant 5FU was associated with better disease-free survival (RR 0.84 (95%CI 0.75-0.94)). All 7 studies (n=5353) were included in the overall survival analysis showing an improvement with adjuvant 5FU (HR 0.87 (95%CI 0.78-0.97)). There was no evidence of heterogeneity across the studies (I2 = 0% for all analyses). Conclusions: In stage II colon cancer, adjuvant 5FU chemotherapy statistically improves both disease-free and overall survival. Our SR/MA demonstrates, for the first time, an overall survival advantage with adjuvant chemotherapy in stage II colon cancer.

Adjuvant Therapy for Stage II Colon Cancer: A Systematic Review From the Cancer Care Ontario Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group

2004 ◽  
Vol 22 (16) ◽  
pp. 3395-3407 ◽  
Author(s):  
Alvaro Figueredo ◽  
Manya L. Charette ◽  
Jean Maroun ◽  
Melissa C. Brouwers ◽  
Lisa Zuraw
Keyword(s):  
Systematic Review ◽  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Therapy ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Free Survival ◽  
Stage Ii Colon Cancer ◽  
Disease Free

Purpose To develop a systematic review that would address the following question: Should patients with stage II colon cancer receive adjuvant therapy? Methods A systematic review was undertaken to locate randomized controlled trials comparing adjuvant therapy to observation. Results Thirty-seven trials and 11 meta-analyses were included. The evidence for stage II colon cancer comes primarily from a trial of fluorouracil plus levamisole and a meta-analysis of 1,016 patients comparing fluorouracil plus folinic acid versus observation. Neither detected an improvement in disease-free or overall survival for adjuvant therapy. A recent pooled analysis of data from seven trials observed a benefit for adjuvant therapy in a multivariate analysis for both disease-free and overall survival. The disease-free survival benefits appeared to extend to stage II patients; however, no P values were provided. A meta-analysis of chemotherapy by portal vein infusion has also shown a benefit in disease-free and overall survival for stage II patients. A meta-analysis was conducted using data on stage II patients where data were available (n = 4,187). The mortality risk ratio was 0.87 (95% CI, 0.75 to 1.01; P = .07). Conclusion There is preliminary evidence indicating that adjuvant therapy is associated with a disease-free survival benefit for patients with stage II colon cancer. These benefits are small and not necessarily associated with improved overall survival. Patients should be made aware of these results and encouraged to participate in active clinical trials. Additional investigation of newer therapies and more mature data from the presently available trials should be pursued.

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