scholarly journals The validation of surrogate end points by using data from randomized clinical trials: a case-study in advanced colorectal cancer

2004 ◽  
Vol 167 (1) ◽  
pp. 103-124 ◽  
Author(s):  
Tomasz Burzykowski ◽  
Geert Molenberghs ◽  
Marc Buyse
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Advanced Colorectal Cancer ◽  
End Points ◽  
Using Data

scholarly journals Evaluation of Continuous Tumor-Size–Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer

2019 ◽  
Vol 2 (9) ◽  
pp. e1911750
Author(s):  
Tomasz Burzykowski ◽  
Elisabeth Coart ◽  
Everardo D. Saad ◽  
Qian Shi ◽  
Dirkje W. Sommeijer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Tumor Size ◽  
Randomized Clinical Trials ◽  
End Points

Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. Advanced Colorectal Cancer Meta-Analysis Project.

1994 ◽  
Vol 12 (5) ◽  
pp. 960-969 ◽  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Regression Model ◽  
Randomized Clinical Trials ◽  
Tumor Response ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Meta Analysis ◽  
Biochemical Modulation

PURPOSE Even though fluorouracil (5FU) remains the standard treatment of advanced colorectal cancer, almost 90% of patients treated with 5FU alone do not achieve an objective response to chemotherapy. Biochemical modulation of 5FU by methotrexate (MTX) is an attempt to increase the sensitivity of tumor cells to 5FU. However, despite the inclusion of several hundreds of patients in randomized clinical trials, no definitive evidence is available on the clinical benefit of 5FU/MTX over 5FU alone. A meta-analysis was performed to assess this benefit objectively and quantitatively for tumor response rate and overall survival. DESIGN The meta-analysis was based on individual data of 1,178 patients included in eight randomized clinical trials comparing 5FU alone with 5FU/MTX. Patient data were provided by all principal investigators. The analyses were performed by an independent secretariat, and then discussed with all collaborators. RESULTS Tumor response rate was 10% for patients allocated to 5FU alone (complete response [CR] rate, 2%; partial response [PR] rate, 8%) compared with 19% for patients allocated to 5FU/MTX (CR rate, 3%; PR rate, 16%). This difference was highly significant, with an overall response odds ratio (OR) of 0.51 (95% confidence interval [CI], 0.37 to 0.70) (P < .0001). Median overall survival times were 9.1 months and 10.7 months in the 5FU-alone and 5FU/MTX groups, respectively. This difference was also statistically significant, with an overall survival OR of 0.87 (95% CI, 0.77 to 0.98) (P = .024). Logistic regression model and Cox regression model showed that performance status and randomized treatment were the only two significant predictors of tumor response and survival. CONCLUSION It is concluded that the modulation of 5FU by MTX doubles the response rate to 5FU, and yields a small improvement in survival.

scholarly journals First-Line Maintenance Treatment in Metastatic Colorectal Cancer (mCRC): Quality and Clinical Benefit Overview

2021 ◽  
Vol 10 (3) ◽  
pp. 470
Author(s):  
Marta Martín-Richard ◽  
Maria Tobeña
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Clinical Benefit ◽  
Maintenance Treatment ◽  
Randomized Clinical Trials ◽  
Line Treatment ◽  
First Line ◽  
Design Quality ◽  
Primary Endpoints ◽  
First Line Treatment

Different strategies of maintenance therapy (sequential CT, intermittent CT, intermittent CT and MAbs, or de-escalation MAbs monotherapy) after first-line treatment are undertaken. Many randomized clinical trials (RCT), which evaluated these approaches, suffer from incorrect design, heterogenous primary endpoints, inadequate size, and other methodology flaws. Drawing any conclusions becomes challenging and recommendations are mainly vague. We evaluated those studies from another perspective, focusing on the design quality and the clinical benefit measure with a more objective and accurate methodology. These data allowed a clearer and more exact overview of the statement in maintenance treatment.

The impact of data errors on the outcome of randomized clinical trials

2017 ◽  
Vol 14 (5) ◽  
pp. 499-506 ◽  
Author(s):  
Marc Buyse ◽  
Pierre Squifflet ◽  
Elisabeth Coart ◽  
Emmanuel Quinaux ◽  
Cornelis JA Punt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Randomized Clinical Trials ◽  
Systematic Errors ◽  
Age Related Macular Degeneration ◽  
Random Errors ◽  
Significant Treatment ◽  
Age Related ◽  
The Impact

Background/aims Considerable human and financial resources are typically spent to ensure that data collected for clinical trials are free from errors. We investigated the impact of random and systematic errors on the outcome of randomized clinical trials. Methods We used individual patient data relating to response endpoints of interest in two published randomized clinical trials, one in ophthalmology and one in oncology. These randomized clinical trials enrolled 1186 patients with age-related macular degeneration and 736 patients with metastatic colorectal cancer. The ophthalmology trial tested the benefit of pegaptanib for the treatment of age-related macular degeneration and identified a statistically significant treatment benefit, whereas the oncology trial assessed the benefit of adding cetuximab to a regimen of capecitabine, oxaliplatin, and bevacizumab for the treatment of metastatic colorectal cancer and failed to identify a statistically significant treatment difference. We simulated trial results by adding errors that were independent of the treatment group (random errors) and errors that favored one of the treatment groups (systematic errors). We added such errors to the data for the response endpoint of interest for increasing proportions of randomly selected patients. Results Random errors added to up to 50% of the cases produced only slightly inflated variance in the estimated treatment effect of both trials, with no qualitative change in the p-value. In contrast, systematic errors produced bias even for very small proportions of patients with added errors. Conclusion A substantial amount of random errors is required before appreciable effects on the outcome of randomized clinical trials are noted. In contrast, even a small amount of systematic errors can severely bias the estimated treatment effects. Therefore, resources devoted to randomized clinical trials should be spent primarily on minimizing sources of systematic errors which can bias the analyses, rather than on random errors which result only in a small loss in power.

scholarly journals Blinded Independent Central Review of Progression-Free Survival in Phase III Clinical Trials: Important Design Element or Unnecessary Expense?

2008 ◽  
Vol 26 (22) ◽  
pp. 3791-3796 ◽  
Author(s):  
Lori E. Dodd ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
C. Carl Jaffe ◽  
Lawrence V. Rubinstein ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Treatment Effectiveness ◽  
Progression Free Survival ◽  
Informative Censoring ◽  
Phase Iii ◽  
General Strategy ◽  
Design Element ◽  
Free Survival ◽  
Using Data

Progression-free survival is an important end point in advanced disease settings. Blinded independent central review (BICR) of progression in randomized clinical trials has been advocated to control bias that might result from errors in progression assessments. However, although BICR lessens some potential biases, it does not remove all biases from evaluations of treatment effectiveness. In fact, as typically conducted, BICRs may introduce bias because of informative censoring, which results from having to censor unconfirmed locally determined progressions. In this article, we discuss the rationale for BICR and different ways of implementing independent review. We discuss the limitations of these approaches and review published trials that report implementing BICR. We demonstrate the existence of informative censoring using data from a randomized phase II trial. We conclude that double-blinded trials with consistent application of measurement criteria are the best means of ensuring unbiased trial results. When such designs are not practical, BICR is not recommended as a general strategy for reducing bias. However, BICR may be useful as an auditing tool to assess the reliability of marginally positive results.

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