Evaluation of Tumor Response, Disease Control, Progression-Free Survival, and Time to Progression As Potential Surrogate End Points in Metastatic Breast Cancer

Burzykowski, Tomasz; Buyse, Marc; Piccart‐Gebhart, Martine; Sledge, George W.; Carmichael, James; Lück, Hans-Joachim; Mackey, John R.; Nabholtz, Jean‐Marc; Paridaens, Robert; Biganzoli, Laura; Jassem, Jacek; Bontenbal, M.; Bonneterre, Jacques; Chan, Stephen Y.; Başaran, Gül; Therasse, Patrick

doi:10.1200/jco.2007.10.8407

Cited by 317 publications

(217 citation statements)

References 22 publications

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“…However, that meta-analysis appears to be unweighted. Our weighted analysis of anthracycline studies produced an R 2 value almost double that reported by Burzykowski et al (2008). Using sample sizes as weights, we show a moderately strong linear correlation between progression-free survival and survival, in a large group of studies covering many treatment types.…”

Section: Discussionmentioning

confidence: 57%

“…Interestingly, they found a stronger relationship between the end points in studies performed prior to 1990 when second-line therapies for metastatic cancer were not commonly used. More recently, a meta-analysis of 11 studies in (Burzykowski et al, 2008). The researchers found tumour response to be more highly associated with overall survival than was progression-free survival.…”

Section: Discussionmentioning

confidence: 99%

“…The authors questioned whether the relationship was strong enough to support objective response rate as a valid surrogate of survival when comparing treatments. Articles by two groups (Hackshaw et al, 2005;Burzykowski et al, 2008) examined the association with survival of several potential surrogate end points, specifically in studies of anthracyclines for advanced or metastatic breast cancer.We performed a broad-based structured review and metaanalysis of randomised controlled trials in metastatic breast cancer. The objective of this research was to document and model the relationship between time-to-disease progression and OS in metastatic breast cancer studies across the literature.…”

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Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer

Sherrill

Amonkar

et al. 2008

Br J Cancer

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The relationship between overall survival (OS) and disease progression end points has been demonstrated in colorectal, colon, and non-small cell lung cancers. We assessed the association between OS and time-to-progression (TTP) or progression-free survival (PFS) in metastatic breast cancer (MBC) studies. A literature search retrieved all randomised controlled trials since 1994 in patients with MBC in which OS and either TTP or PFS were reported. Summary data on trial and patient characteristics were abstracted. Study effect sizes were derived as the ratio of median progression (or survival) times, which approximates the hazard ratio. Effects were centred at zero for regression analyses weighted by sample size. Numerous treatments were represented in 67 studies (17 081 patients). Modeling showed a positive association between outcomes for progression and survival (R 2 ¼ 0.30) with a slope of 0.32 (Po0.001) and a non-significant intercept. Thus, a treatment effect on TTP/PFS translated into a concordant effect on OS, but with attenuated effect size. Similar results were found in models of subsets and sensitivity analyses. These results demonstrate that treatment effects on progression end points in MBC trials are expected to result in treatment differences on OS that are smaller yet consistently in the same direction. British Journal of Cancer (2008) Most studies of anticancer agents are designed and powered to show differences between groups on disease progression end points such as response rates, time-to-progression, time-torecurrence or disease-free survival. Although increased survival time is clearly an implicit goal, it is difficult to establish in randomised studies when standard clinical practise is to change treatments at the onset of new progressive events. Especially in the metastatic setting, where expected survival time may be very short, the use of drug combinations or sequential use of multiple drug classes is commonplace. Increasingly, patients in clinical trials are offered alternate treatment upon progression. Consequently, few studies actually demonstrate an unequivocal survival benefit using intent-to-treat analysis approaches.In several tumour types, efforts have been made to justify the use of alternate, more easily established end points by showing how well they are correlated with survival. Several meta-analyses have been published (Table 1) that show a link between time-toprogression (TTP) or progression-free survival (PFS) with overall survival (OS) in metastatic colorectal or non-small cell lung cancer (Johnson et al, 2006) and colon cancer in the adjuvant setting (Sargent et al, 2005). For breast cancer, a moderately strong correlation between 2-year disease-free survival and 5-year overall survival was observed in the adjuvant setting (Ng et al, 2008). A meta-analysis of metastatic breast cancer studies found a positive relationship between objective response and overall survival on an individual patient basis, but the relationship was less clear when treatment regimens were compared...

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer

Sherrill

Amonkar

et al. 2008

Br J Cancer

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“…Correlations between PFS or other endpoints and OS have been analyzed in an effort to identify surrogate endpoints of OS [10][11][12][13][14][15]. A validated shorter-term surrogate endpoint would likely both reduce drug development costs and facilitate the assessment of efficacy [16].…”

Section: Introductionmentioning

confidence: 99%

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer

et al. 2013

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Background The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. No corresponding analysis has been done in patients who have undergone second-line chemotherapy. Methods We evaluated the correlation between PFS, TTP, objective response rate (ORR), disease control rate (DCR), and OS in patients with AGC who underwent second-line chemotherapy. Correlations were evaluated by Spearman rank correlation coefficient (q). Results Sixty-four trials, including 10 randomized studies, were selected for analysis. Median PFS/TTP moderately correlated with OS (q = 0.56). The correlation tended to be stronger in non-Asian trials (q = 0.74) than in Asian trials (q = 0.37). ORR and DCR did not strongly correlate with OS (q = 0.38 for ORR; q = 0.54 for DCR). The hazard ratio of PFS and OS in each of the arms of the 10 randomized studies also showed a low correlation (q = 0.36). Conclusions PFS/TTP, ORR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who have undergone second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.

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The Strength of Association Between Surrogate End Points and Survival in Oncology

et al. 2015

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The strength of association between surrogate end points and survival in oncology is important to understand because surrogate end points are frequently used in oncology clinical trials, supporting US Food and Drug Administration approvals and National Comprehensive Cancer Network guideline recommendations. OBJECTIVE To identify and evaluate trial-level meta-analyses of randomized clinical trials quantifying the association between a surrogate end point and overall survival in medical oncology. Trial-level correlations test whether treatments that improve the surrogate end point also improve the final end point and are widely considered the strongest evidence to validate a surrogate end point. EVIDENCE REVIEW Our literature search was built on earlier reported data sets and updated with Google Scholar and MEDLINE searches conducted on December 26, 2014. For MEDLINE, search terms included ("regression" or "correlation") and "surrogate" and "end point [or endpoint]" and ("oncology" or "cancer"). For Google scholar, search terms included ("regression" or "correlation") and "surrogate end point [or endpoint]" and "overall survival" and "trial level." A total of 108 abstracts were retrieved, and 62 articles were read in full in addition to articles identified through prior reviews. FINDINGS We found 36 articles in which 65 specific correlations between a surrogate end point and survival were identified. Surrogate end points were studied in the neoadjuvant, adjuvant, locally advanced, and metastatic settings. The most common sources for trials included in the 36 articles were systematic reviews of the published literature (10 of 36; 28%), and published literature and meeting abstracts (14 of 36; 39%). Four meta-analyses (11%) used a convenience sample, and only 5 studies (14%) attempted to include unpublished trials by surveying clinical trial registries. Among these 5 studies, only 352 of 684 eligible trials (51.1%) were included in the analyses. More than half of reported correlations (34 of 65; 52%) were of low strength (r Յ 0.7). Approximately a quarter (16 of 65; 25%) were of medium strength (r > 0.7 to r < 0.85), and 15 of 65 (23%) were highly correlated (r Ն 0.85) with survival. CONCLUSIONS AND RELEVANCE Most trial-level validation studies of surrogate end points in oncology find low correlations with survival. All validation studies use only a subset of available trials. The evidence supporting the use of surrogate end points in oncology is limited.

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Evaluation of Tumor Response, Disease Control, Progression-Free Survival, and Time to Progression As Potential Surrogate End Points in Metastatic Breast Cancer

Cited by 317 publications

References 22 publications

Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer

Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer

The Strength of Association Between Surrogate End Points and Survival in Oncology

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