Elsevier

Cancer Treatment Reviews

Volume 37, Issue 7, November 2011, Pages 495-504
Cancer Treatment Reviews

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Evolving options for the treatment of metastatic breast cancer: Progression-free survival as an endpoint

https://doi.org/10.1016/j.ctrv.2011.01.002Get rights and content

Abstract

Because of its direct clinical relevance, overall survival is the gold standard endpoint for measuring clinical efficacy. However, achieving improvements in overall survival can be confounded by factors such as crossover to active treatment arms and subsequent treatment with non-experimental active therapies. Powering studies to detect significant overall survival increases requires prohibitively large patient numbers and long follow-up and may not always be practical. Trials incorporating progression free survival (PFS) or time to progression (TTP) as primary outcome measures are likely to be shorter, require fewer patients and are usually more affordable, which may ultimately translate into a more rapid evaluation of potentially effective experimental therapies. In heavily pretreated metastatic breast cancer, significant improvements in progression-free survival may indicate a clinically meaningful benefit for patients with otherwise limited salvage therapy options available. Approval for several newer agents in the advanced resistant or refractory metastatic breast cancer setting has been based on prolonged progression-free survival or time to progression as primary trial endpoints. In this paper, clinical trial data relating to OS, PFS and TTP endpoints are reviewed and the use of surrogate markers of survival for the evaluation of new drugs is considered.

Introduction

Overall survival (OS) remains the gold standard measure of clinical efficacy when evaluating experimental chemotherapy regimens for cancer.1 The advantage of OS is that it is of direct clinical relevance to the patient. Furthermore, OS is an objective endpoint, whereas other endpoints such as response rate and progression free survival may be influenced by methods of evaluation and the drug schedules used, and may be biased by the knowledge of therapy.2

This review discusses the use of OS as a primary endpoint, particularly in the metastatic setting, and considers PFS as an alternative endpoint. PFS, TTP and OS data from recent, large, randomized trials of novel single agent or combination regimens for the treatment of patients with MBC are compared.

Section snippets

Obstacles to the interpretation of OS

A number of challenges exist in achieving an accurate assessment of survival in the randomized clinical trial setting. As the median survival for metastatic breast cancer is relatively long, patients who do not respond to one therapy are often well enough to go onto another regimen. Thus, at the time of disease progression, study participants with advanced breast cancer are able to switch to another active non-experimental treatment after coming off study. These subsequent treatments, which are

Surrogate endpoints for survival: PFS and TTP

Given these challenges, investigators in oncology have begun to evaluate alternative clinical trial endpoints that better reflect the small gains that contribute positively to the quality of life of patients with previously treated MBC. PFS and TTP have become common primary endpoints in clinical trials, and the US Food and Drug Administration (FDA) has accepted both as surrogate endpoints for accelerated approval in cancer trials. PFS is defined as the time from randomization until objective

Chemotherapy trials showing TTP and OS benefit

A small number of randomized phase III clinical trials were able to demonstrate significant improvements in both TTP and OS in MBC (Table 1A).[8], [9], [10], [11], [12], [13] These have included trials of taxanes as single agents or in combination with anthracyclines, gemcitabine, or capecitabine.

A head-to-head comparison of q3 weekly single agent docetaxel (100 mg/m2) vs. paclitaxel (175 mg/m2) in patients with MBC whose disease had progressed after anthracycline therapy (N = 449) showed that

Survival outcomes in MBC – progression free vs. overall

A recent analysis of phase III treatment trials in patients with advanced breast cancer (75 trials; 159 trial arms; N = 28,973) indicated that OS increased in trials of first-line hormone-based therapy and decreased with subsequent lines of any type of treatment. For trials of first-line chemotherapy (with or without targeted agents) and hormone therapy (with or without chemotherapy), the median OS was 20.7 and 31.1 months, respectively. With trials of second-line chemotherapy and hormone therapy,

Conclusions

Although OS remains the gold standard for assessing efficacy, there is a need for more practical outcome measures. PFS and TTP are commonly used primary endpoints in MBC, but are not yet validated surrogates for overall survival in this setting. In heavily pretreated MBC in particular, significant PFS improvements may indicate a clinically meaningful benefit for patients with otherwise limited salvage therapy options available. Powering studies to detect significant OS increases may not be

Conflict of interest

The author receives research funding from Genentech/Roche and is on the Speakers Bureau for BMS.

Acknowledgements

The author takes full responsibility for the content of this publication and confirms that it reflects her viewpoint and medical expertise. The author also wishes to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editing support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the author receive financial compensation for authoring the manuscript.

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