Originally published as JCO Early Release 10.1200/JCO.2006.08.1935 on September 17 2007

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Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy

Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

From the Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Canada; and the Departments of Human Oncology and Medical Physics, University of Wisconsin Comprehensive Cancer Center, Madison, WI

Address reprint requests to Lillian L. Siu, MD, FRCPC, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, Suite 5-718, Toronto, Canada M5G 2M9; e-mail: lillian.siu{at}uhn.on.ca

	ABSTRACT

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Purpose Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS.

Methods Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points.

Results Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (r_s) between differences () in surrogate end points (PFS, TTP, and RR) and OS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The r_s for PFS was not significantly different from the r_s TTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 ± 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% ± 1% risk reduction for OS.

Conclusion In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.

	INTRODUCTION

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The most commonly used end point for phase III trials and for regulatory approval of new anticancer drugs is overall survival (OS), defined as the time from random assignment or first treatment to death. OS is clinically meaningful and objectively measured, but can be influenced by effective sequential therapies. Furthermore, OS requires long follow-up periods after disease progression, resulting in long and expensive phase III studies. For example, the median length of follow-up in published phase III studies of first-line chemotherapy in metastatic colorectal cancer (MCRC) from 2004 to 2006 ranged from 20.4 to 43.9 months.^1-7 The estimated average cost of a pharmaceutical industry–sponsored phase III study was more than US $10 million (in 2000 dollars), whereas that of a public-funded phase III study was more than US $1 million.⁸ A validated shorter term surrogate end point would reduce drug development costs, and allow for more rapid completion of randomized controlled trials. There is no general consensus regarding the definition of a valid surrogate end point for OS, but intuitively a useful surrogate end point would produce a reliable quantitative estimate of the expected treatment effect in OS based on the observed treatment effect in the surrogate. Potential surrogate end points for OS include progression-free survival (PFS), time to progression (TTP), and response rate (RR). PFS differs from TTP in that PFS includes death as a result of any cause in its definition in addition to progression; however, both end points are unaffected by subsequent therapies.

Despite recent advances in systemic cytotoxic and targeted therapies,^5,9-12 MCRC remains largely incurable. However, more effective therapies in the first-line setting can be expected to improve PFS, TTP, and RR. Therefore, disease progression is a logical surrogate for OS in MCRC, given that it is a common reason for stopping first-line treatment, and subsequent therapies are not curative and often much less effective. Objective response is another surrogate end point that is easily assessed during the course of treatment using standardized criteria.^13,14 RR is a good measure of efficacy and is often associated with subjective improvement in symptoms. Other end points such as toxicity and quality of life are clinically important but may be less directly related to survival.

Our aim was to perform a comprehensive literature-based analysis to determine whether PFS, TTP, or RR were correlated with OS, and whether improvements in PFS, TTP, and RR with first-line therapies were associated with improvements in OS in MCRC. The latter analysis was performed to reduce bias, given that variations in prognostic factors between trial populations among different studies could contribute to the association between a disease-related end point and OS.

	METHODS

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Literature Search and Data Extraction
Randomized controlled trials of first-line chemotherapy in MCRC published between 1990 and 2005 were identified through a systematic search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials using the keywords "colorectal neoplasm" and "neoplasm metastasis." Results were limited to "clinical trial," "clinical trial, phase III," "controlled clinical trial," or "randomized controlled trial." A manual search was performed for abstracts presented at the annual meetings of the American Society of Clinical Oncology, European Cancer Conference, and European Society for Medical Oncology between 1995 and 2005. Bibliographies of published overviews^15-18 were checked for additional citations.

Reports of trials with a sample size of at least 100 patients per arm were included if they contained mature data on OS, RR, and either TTP or PFS. Exclusion criteria were locally advanced, unresectable disease; intermittent as opposed to continuous chemotherapy; and hepatic chemotherapy infusion. For each trial, data on sample size, RR, and chemotherapy regimens were collected. In addition, TTP or PFS and OS were determined for all treatment arms using published data or survival curves. The standard chemotherapy arm in each trial was determined by consensus of three investigators (P.A.T., E.X.C., and L.L.S.); all other arms were considered experimental. Two investigators (P.A.T. and L.L.S.) labeled an end point as TTP or PFS according to established (ie, per protocol) definitions, regardless of the terminology used by the original authors, and classified the results of each trial for TTP or PFS and OS as significant (P .05) or nonsignificant for the per-protocol analysis. The analysis was performed using the original authors' and per-protocol end point definitions. When available, hazard ratios (HRs) for PFS and OS were recorded.

Analysis of Trials
For each trial, the differences in overall survival (OS) and in surrogate end points (PFS, TTP, RR) were calculated as the estimate in the experimental arm(s) minus the estimate in the standard arm. For trials with multiple arms, we compared the control arm to a randomly chosen experimental arm, to avoid the analysis of correlated data in multiarm trials and to better parallel the two-arm trials. The nonparametric Spearman rank correlation coefficient (r_s) was used as a measure of correlation between the difference in each surrogate end point and the difference in OS. Correlation coefficients were compared using the normal approximation to the z-transformation of r_S and its standard deviation. Linear regression analysis through the origin of the plot evaluating OS as a function of PFS was used to obtain a conversion factor between PFS and OS, and to determine the proportion of variability explained (R²). Linear regression analysis was also performed through the origin of the plot evaluating percent risk reduction of OS as a function of percent risk reduction of PFS, calculated based on the HR of PFS and HR of OS.

Statistical analyses were performed using SPSS software release 14.0.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Trials Included in Analysis
A total of 45 trials were identified with at least 100 patients per arm. One trial only reported TTP for one study arm,¹⁹ four included patients with locally advanced disease,^20-23 and one had a secondary randomization to continuous chemotherapy until progression compared with intermittent chemotherapy.²⁴ These six trials were excluded from the analysis. Therefore, 39 trials with 87 treatment arms and 18,668 patients were included.^{2,4-7,9-12,25-54} Seven trials had multiple arms^{5,11,31,42,48,49,51}: six of these had three arms and one had five arms. Median follow-up duration ranged from 12 to 57.6 months. Trial characteristics are outlined in Table 1. Four trials included death in the definition of TTP^5,39,41,43 and were labeled as PFS in the per-protocol analysis. The results were similar for the per-protocol and the original authors' analyses; hence, only per-protocol data are included. All trials that reported a significant difference in OS also reported a significant difference in TTP or PFS.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Correlation between median progression-free survival and median overall survival. FU, fluorouracil; LV, leucovorin.

Correlation Between Differences in Surrogate End Points and OS Within Trials

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Correlation between differences in progression-free survival (PFS) and differences in overall survival (OS). The middle line is the regression line; the 95% CIs are indicated by the outside lines.

Correlation Between HR for Surrogate End Points and OS
A total of 18 pairs of HRs for PFS and OS between treatment arms were reported in 15 trials. There is a highly significant relationship between risk reductions for PFS and OS on linear regression analysis (P = 6 x 10^–5; Fig 3). Because of the potential correlation of data in trials with multiple arms, the linear regression analysis was performed by including only one randomly chosen pair comparison in each multiarm trial, resulting in 15 pairs of HRs for OS and PFS. Pairs of HRs between trial arms were analyzed by linear regression through the origin (ie, assuming that trials comparing fully equivalent treatment options would give rise to the same risk reduction estimates between trial arms for both PFS and OS). The slope of this regression line was 0.54 ± 0.10. This means that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% ± 1% risk reduction for OS. A similar analysis for TTP was not performed because only three trials reported HR for this end point.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Correlation between percent risk reductions for progression-free survival and overall survival. The linear regression line is shown.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Lead-time resulting from using progression-free survival (PFS) rather than overall survival (OS) as the primary end point. The difference between the median OS and the median PFS is plotted against the median OS.

	DISCUSSION

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There is no consensus on the definition of a valid surrogate end point.^55,56 Ideally, a surrogate would correlate with the true end point, and would fully capture the net effect of treatment on the true end point.⁵⁷ Others have proposed that for a surrogate to be valid, the effect of treatment on the surrogate end point must predict the effect of treatment on the true end point, or that a test of a statistical hypothesis based on the surrogate end point should come to the same conclusion as a statistical hypothesis based on the true end point.^58-60

In our analysis, the percent risk reduction calculated from HR for OS showed a highly significant association with the percent risk reduction calculated from HR for PFS, indicating that the effect of treatment on PFS predicts the effect of treatment on OS. HRs take into account the entire pattern of events for each treatment arm, and may be more meaningful than a single time point estimate such as median PFS. Given that the present analysis focuses on surrogate end point at the level of a trial rather than at the level of an individual patient, the strongest result presented here is the demonstration of a highly significant relationship between the HRs for the two end points.

Table 1 demonstrates some discordance between PFS and OS based on historical trials. Twenty-one trials did not show a significant difference in TTP/PFS or OS. For the remaining trials, there were six in which there was a significant difference in OS and a corresponding significant difference in TTP or PFS.^{5,10-12,28,38} There were two trials in which there was a significant difference in TTP, but no significant difference in OS.^31,46 There were 10 trials that demonstrated a significant difference in PFS, but no significant difference in OS.^{4,9,33,39,40,47,49-51,54} However, only four of these studies were powered to show a difference in OS.^33,50,51,54 The observed percent risk reduction for PFS was nearly twice that of the percent risk reduction for OS, indicating that this is a more sensitive end point for treatment effect. Given that we have also demonstrated a significant lead time using PFS rather than OS as the end point, there typically will be more events at the time of analysis for PFS compared with OS. This will result in a higher statistical power when using the surrogate end point.

The proportion of variability in OS explained by PFS was moderate (R² = 0.65), but some of the unexplained variation simply reflects random sampling error associated with the final sample size of each trial. The inadequacy of R² as a measure of surrogacy can be illustrated by the fact that even for a perfect surrogate end point, R² is likely to be smaller in a set of trials with smaller sample sizes.

PFS is appealing as a surrogate end point for several reasons. From a patient's point of view, prolongation of PFS is clearly desirable regardless whether OS is improved or not. Using PFS instead of OS would accelerate the drug development process by allowing for earlier reporting of results, thereby bringing new treatments to patients more rapidly. However, there are a few important considerations if PFS is used as a primary end point. A standard definition of progression (eg, WHO, Response Evaluation Criteria in Solid Tumors Group) should be used.^13,14 The time interval between clinical and radiologic assessments should be the same across study arms, and at sufficiently frequent intervals to maximize the lead time gained. The magnitude of improvements in PFS will always have to be balanced by toxicity, both acute and chronic, and quality of life.

Our literature-based analysis encompassed the largest number of randomized controlled trials of first-line chemotherapy for MCRC to date, and included recent trials that evaluated combination regimens containing irinotecan, oxaliplatin, or bevacizumab. Other groups have also examined the relationship between surrogate end points and OS in MCRC. Louvet et al⁶¹ performed a literature-based analysis of 29 phase III trials of first-line chemotherapy published between 1990 and 2000. There was a moderate correlation between RR and OS, with an r_s of 0.408 (P = .0009). PFS and TTP were used as a combined end point, and the correlation between PFS/TTP and OS was moderate (0.481; P < .0001). Buyse et al⁶² examined the relationship between RR and OS in an individual patient data meta-analysis of 25 randomized trials of first-line treatment comparing standard bolus fluoropyrimidines versus experimental treatments (fluorouracil and leucovorin, fluorouracil plus methotrexate, fluorouracil continuous infusion, or hepatic-arterial infusion of floxuridine). The coefficient of determination of the regression line between the treatment effects on RR and OS was 0.38, indicating that less than half of the variability of the survival benefits in the trials could be explained by the variability of the response benefits.

In another study, Buyse et al⁶³ performed an individual patient data meta-analysis of 11 historical randomized trials of first-line therapy comparing fluorouracil and leucovorin versus either fluorouracil alone or raltitrexed, and found strong correlations between PFS and OS, and their HRs, using bivariate distribution over the entire time range ( = 0.82 and = 0.986, respectively). The historical trials were used to create a model that accurately predicted the treatment effect of OS, based on the effect on PFS, for two recent trials^10,11 in which there was no effective second-line therapy. The model was not as accurate for trials in which there were effective second-line therapies.^5,9 Thus, sequential lines of treatment disconnect early effects on tumor control from OS, making PFS an ideal surrogate. The different composition of trials and statistical methods may account for the varying strengths of association between PFS and OS reported in the literature. However, all of the analyses have shown a consistent relationship between PFS and OS, similar to our results.

There are a few limitations to our analysis because it was based on literature, rather than based on individual patient data. PFS andthe associated HRs were only reported in 55 of 87 treatment arms and in 15 of 39 trials, respectively. The definitions of progression varied among the trials we analyzed, and it was impossible to ascertain whether disease progression was assessed at comparable time points between treatment arms within the same trial. Most trials did not report on the details of subsequent treatments after progression on first-line regimens; therefore, the potential confounding effects of subsequent treatments on OS could not be evaluated.

In summary, we found a strong association between improvements in PFS and improvements in OS. The usage of PFS as a surrogate end point in randomized controlled trials in first-line chemotherapy for MCRC may be appropriate.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Patricia A. Tang, Søren M. Bentzen, Lillian L. Siu

Collection and assembly of data: Patricia A. Tang

Data analysis and interpretation: Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

Manuscript writing: Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

Final approval of manuscript: Patricia A. Tang, Søren M. Bentzen, Eric X. Chen, Lillian L. Siu

	NOTES

 
published online ahead of print at www.jco.org on September 17, 2007.

Presented in part at the 2006 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 26-28, 2006, San Francisco, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted July 6, 2006; accepted April 17, 2007.

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