Progression-Free Survival as a Primary Endpoint in Clinical Trials of Metastatic Colorectal Cancer

M. Buyse,C. Butts,C. Mărginean,D. Jonker,J.A. Maroun,M. Thirlwell,B. Samson,R. Wong,S. Gill,J. Biagi,S. Berry,J. Stewart,E. Chen

doi:10.3747/co.v18is2.941

Abstract

Traditionally, overall survival (os) has been considered the "gold standard" for evaluating new systemic oncologic therapies, because death is easy to define, is easily compared across disease sites, and is not subject to investigator bias. However, as the available options for continuing therapy increase, the use of os as a clinical trial endpoint has become problematic because of the increasing crossover and contamination of trials. As a result, the approval of promising new therapies may be delayed.Many clinicians believe that progression-free survival (pfs) is a more viable option for evaluating new therapies in metastatic and advanced renal cell carcinoma. As with all endpoints, pfs has inherent biases, and those biases must be addressed to ensure that trial results are not compromised and that they will be accepted by regulatory authorities. In this paper, we examine the issues surrounding the use of pfs as a clinical trial endpoint, and we suggest solutions to ensure that data integrity is maintained.

Highlights

Colorectal cancer is the third most common malignancy worldwide and the second cause of cancer death in both sexes in the developed world 1
Meaningful advances have been achieved with the introduction of new chemotherapeutic agents and the targeted monoclonal antibodies in various therapeutic schedules 7–9
Prolonged durations of therapy and the doselimiting neurotoxicity of oxaliplatin have prompted a shift from the conventional paradigm of treatment until progression or toxicity, to chemotherapy with planned interruptions

Summary

INTRODUCTION

Colorectal cancer is the third most common malignancy worldwide and the second cause of cancer death in both sexes in the developed world 1. One quarter of patients with colorectal cancer have liver metastases at the time of diagnosis, and among those with initially localized disease, 25%–30% will present with metastases in the following 2–3 years 2,3. The life expectancy for patients with metastatic colorectal cancer (mcrc) ranges from 5 months to 9 months 2,4

CURRENT MANAGEMENT OF mCRC

OVERALL SURVIVAL AS A PRIMARY ENDPOINT IN ONCOLOGY TRIALS

CRITERIA FOR SURROGACY

PFS AS A SURROGATE ENDPOINT IN mCRC

TARGETED THERAPIES AND OBJECTIVE RESPONSE RATES

USING pfs AS AN ENDPOINT FOR HEALTH CANADA MARKETING AUTHORIZATION

CONCLUSIONS

CONFLICT OF INTEREST DISCLOSURES

Findings

10. REFERENCES