Elsevier

The Lancet Oncology

Volume 7, Issue 9, September 2006, Pages 741-746
The Lancet Oncology

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Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis

https://doi.org/10.1016/S1470-2045(06)70800-2Get rights and content

Summary

Background

The duration and cost of cancer clinical trials could be reduced if a surrogate endpoint were used in place of survival. We did a meta-analysis to assess the extent to which two surrogates, tumour response and time to progression, are predictive of mortality in metastatic colorectal cancer and non-small-cell lung cancer.

Methods

Summary data (median time to progression, proportion of patients responding to treatment, and median overall survival) from randomised trials of first-line treatment in colorectal cancer (146 trials) and lung cancer (191 trials) were identified. Data were extracted and analysed by linear regression. We used prediction bands for trials with 250, 500, and 750 patients to identify the surrogate threshold effect that would predict a significant difference in survival.

Findings

Response to treatment and time to progression correlated with improvement in survival for both lung cancer (p<0·0001 and p=0·0003, respectively) and colorectal cancer (p<0·0001 for both). To predict a significant survival gain in colorectal cancer trials, an improvement of 20% in the number of patients responding to treatment was required in trials with 750 patients, increasing to 26% in trials with 500 patients and 38% in trials with 250 patients. In lung cancer trials, the same prediction required differences in response of 18% for 750 patients, 21% for 500 patients, and 30% for 250 patients. For time to progression for both cancer types, the incremental gain needed to predict a survival improvement was a median of 1·8 months for trials with 750 patients, 2·2 months for 500 patients, and 3·3 months for 250 patients.

Interpretation

Irrespective of trial size, large differences in tumour response rate are needed to predict a significant survival benefit. If surrogates are chosen as the primary endpoint in a clinical trial, time to progression is the preferred measure because more modest and achievable differences are needed for a significant survival benefit. Trials in metastatic lung cancer and colorectal cancer should measure survival as their primary outcome unless the surrogate outcome difference is anticipated to exceed the threshold effect size.

Introduction

Adverse cardiovascular events can be prevented by drugs that lower blood pressure and cholesterol concentration. By using these drugs, clinicians have accepted that changing a surrogate (blood pressure or cholesterol) will predictably change the clinical outcome of interest (cardiovascular events).1 Furthermore, it is generally accepted that drugs with a large effect on the surrogate will have a proportionally greater effect on the clinically relevant endpoint of cardiovascular events. Thus, surrogate or intermediate endpoints are very attractive targets to measure, because they can hasten access to new effective drugs, by reducing the size and duration of randomised controlled trials.

With this potential advantage of surrogates in the investigation of cancer drugs, the lack of attention given to this approach so far is surprising. The first prerequisite for use of a surrogate is the existence of a standard measurement procedure. Since 1977, WHO2 has standardised the reporting of tumour response to cancer treatments, and these guidelines have been further refined by the Southwest Oncology Group3 and the Response Evaluation Criteria in Solid Tumors (RECIST) group.4 These guidelines all present explicit criteria for the assessment of tumour response, and have produced similar findings, irrespective of measurement strategy.4, 5 This consistency helps to compare results between clinical trials. Accordingly, tumour response and time to progression are good candidates for surrogate measures of survival.6 However, their usefulness as surrogates ultimately depends on how accurately the changes in their values can predict a change in subsequent survival.7

Sargent and colleagues8 have rekindled enthusiasm for the use of surrogates in oncology by showing a correlation between 3-year disease-free survival and 5-year overall survival in adjuvant colorectal cancer. Although this study analysed fluorouracil-based regimens, the results were used subsequently to support the registration of oxaliplatin for adjuvant treatment of colon cancer.6, 9 Notably, registration occurred on the basis of a significant improvement in disease-free survival, despite the fact that an overall survival advantage of oxaliplatin, fluorouracil, and folinic acid had not yet been realised.

We aimed to investigate the relation between tumour response, time to progression, and survival in patients with metastatic colorectal cancer and non-small-cell lung cancer. Furthermore, we aimed to determine the minimum change in response or in time to progression that would predict a significant difference in survival for trials of various sizes.

Section snippets

Search strategy and selection criteria

We searched electronic databases (MEDLINE [1966, to June, 2005], Embase [1980–2005], the Cochrane Library Issue 2 [2004], PubMed [June 14, 2005], Current Contents [1993, to June, 2005], CINAHL [1982, to June, 2005], and OldMedline [1950–65]) to identify all randomised controlled trials of metastatic colorectal cancer and non-small-cell lung cancer that assessed a first-line pharmacological treatment in two or more groups, and that reported response or time to progression, as well as median

Results

146 trials of colorectal cancer (n=35 337 patients) and 191 trials of non-small-cell lung cancer (n=44 125 patients; Table 1, Table 2, webappendix) were identified. 18 (12%) of 146 studies assessed oxaliplatin or irinotecan in first-line treatment of metastatic colorectal cancer. Many studies of non-small-cell lung cancer included the use of new chemotherapy agents such as taxanes, gemcitabine, and vinorelbine. Schulz scores did not differ between full trial reports and abstracts, or with time (

Discussion

Improved response and delayed time to progression are valuable as clinical endpoints in the treatment of metastatic colorectal cancer and non-small-cell lung cancer. Nevertheless, long-term survival is clearly the ultimate goal of treatment. In this study, we showed that a difference in response and time to progression strongly correlates with an improvement in survival, for both lung cancer and colorectal cancer. However, since correlation between two variables does not imply prediction of one

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