Exploring and validating surrogate endpoints in colorectal cancer.

Center for Statistics, Hasselt University, Agoralaan D, 3590 Diepenbeek, Belgium.
Lifetime Data Analysis (Impact Factor: 0.54). 04/2008; 14(1):54-64. DOI: 10.1007/s10985-007-9079-4
Source: PubMed

ABSTRACT Sargent et al (J Clin Oncol 23: 8664-8670, 2005) concluded that 3-year disease-free survival (DFS) can be considered a valid surrogate (replacement) endpoint for 5-year overall survival (OS) in clinical trials of adjuvant chemotherapy for colorectal cancer. We address the question whether the conclusion holds for trials involving other classes of treatments than those considered by Sargent et al. Additionally, we assess if the 3-year cutpoint is an optimal one. To this aim, we investigate whether the results reported by Sargent et al. could have been used to predict treatment effects in three centrally randomized adjuvant colorectal cancer trials performed by the Japanese Foundation for Multidisciplinary Treatment for Cancer (JFMTC) (Sakamoto et al. J Clin Oncol 22:484-492, 2004). Our analysis supports the conclusion of Sargent et al. and shows that using DFS at 2 or 3 years would be the best option for the prediction of OS at 5 years.

  • [Show abstract] [Hide abstract]
    ABSTRACT: AimThe influence of the level of rectal cancer from the anal verge on the oncological outcome is controversial. The study aimed to determine the influence of the height of the tumour on survival of patients treated in a specialised rectal cancer unit.Method Patients undergoing surgery for primary rectal cancer from 2006 to 2013 were identified from a prospectively maintained rectal cancer database. Those requiring total or multi-compartmental pelvic exenteration were excluded. Low cancer was defined as tumour below 5cm from the anal verge, assessed by endoscopy and/or digital rectal examination. The primary outcome was 3-year disease-free survival (DFS).ResultsFrom 340 patients, 203 (59.7%) had low cancer. There were 302 (89%) restorative and 38 (11%) non-restorative procedures. The positive CRM rate was similar for low compared with high cancer (3.4% vs 2.9%, [p=1.0]), and for restorative compared with non-restorative procedures in low cancer only (3.0% and 5.3%, [p=0.619]). Low compared with high anterior resection was associated with increased anastomotic leakage (8.5% vs 2.2%, p=0.023). Three-year disease free survival (DFS) was similar for low and high resection (82% vs 86% [p=0.305]), and between restorative versus non-restorative procedures in low cancer only (88% versus 77%, p=0.215). In an adjusted model, low height did not lead to worse survival outcome (3-DFS hazard ratio 0.54, 95% confidence interval 0.24-1.24, p=0.147).Conclusion With careful planning and a multidisciplinary approach, equivalent oncologic outcome can be achieved for patients with rectal cancer who undergo curative surgery regardless of differences in tumour characteristics, location and operation performed.This article is protected by copyright. All rights reserved.
    Colorectal Disease 07/2014; 16(10). DOI:10.1111/codi.12703 · 2.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antibodies are proteins secreted by vertebrates, which bind to specific molecular moieties [1]. Millions of different antibodies are made by organisms, and early in development most self-recognising antibodies are removed from the repertoire. The remaining antibodies, accordingly, recognise non-self molecules, and are used by the host to eliminate microorganisms, foreign objects, and malignant cells. Manufacturing these highly specific molecules and using them for cancer treatment represents a major breakthrough. Nonetheless, the challenges required to bring this technology to the clinic are significant and costly. Drug discovery, manufacturing, and clinical development are all expensive and have high risk [2], and optimising these processes are crucial. This chapter will summarise the science behind this technology, the current use of antibodies in anti-cancer treatment, the methodology of antibody anti-cancer drug development, and the ways in which these components may be improved to facilitate the transition from the laboratory to the clinic.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Evaluation of surrogate endpoints using patient-level data from multiple trials is the gold standard, where multi-trial copula models are used to quantify both patient-level and trial-level surrogacy. While limited consideration has been given in the literature to copula choice (e.g., Clayton), no prior consideration has been given to direction of implementation (via survival versus distribution functions). We demonstrate that even with the "correct" copula family, directional misspecification leads to biased estimates of patient-level and trial-level surrogacy. We illustrate with a simulation study and a re-analysis of disease-free survival as a surrogate for overall survival in early stage colon cancer.
    Journal of Biopharmaceutical Statistics 06/2014; DOI:10.1080/10543406.2014.920870 · 0.72 Impact Factor

Full-text (2 Sources)

Available from
May 20, 2014