Tumor Status at 12 Weeks Predicts Survival in Advanced Colorectal Cancer: Findings from NCCTG N9741

Heun, James M.; Grothey, Axel; Branda, Megan E.; Goldberg, Richard M.; Sargent, Daniel J.

doi:10.1634/theoncologist.2011-0064

Cited by 15 publications

(11 citation statements)

References 34 publications

(46 reference statements)

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“…30, 31 Although these results might seem to contradict ours given the overlap in the source data, the methodology differed in that they used landmark analyses to measure associations with OS. The resampling approach used in our study does not test how well end points associate with OS, but rather how powerful they are for making the correct go/no-go decision at the end of phase II.…”

Section: 27mentioning

confidence: 80%

Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

Sharma

Gray

Goldberg

et al. 2015

JCO

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A B S T R A C T PurposeThe optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]). MethodsTumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with ␣ ϭ 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS. ResultsFor FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited Ͼ 80% power with 60 to 80 patients per arm. ConclusionTTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.

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Section: 27mentioning

confidence: 80%

Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

Sharma

Gray

Goldberg

et al. 2015

JCO

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“…There was a statistically significant difference between CR/PR and SD status for patients with colorectal cancer based on the 12-and 24-week landmark analyses, thus lending support to the use of the TriTR metric as reported previously. 7,11 The RECIST definition for SD does not distinguish patients with true SD from those with a minor increase or minor decrease. The TriTR metric puts SD patients into their own category unlike the DiTR or the DCR metrics.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][10][11] For example, nonprogression rate or the disease control rate (DCR) classifies patients who achieve SD for an extended period of time as a success, in addition to those who achieve complete response (CR) or PR. DCR was shown to be superior to response rate in predicting survival in the setting of non-small-cell lung cancer (NSCLC).…”

Section: Introductionmentioning

confidence: 99%

“…8,9 A trichotomous tumor response (TriTR) has also been considered, in which response is categorized into CR/PR versus SD versus PD. 7,11 With the advent of targeted therapies that prolong disease stabilization, patients may experience SD rather than tumor shrinkage (CR/PR). Ignoring SD when assessing treatment efficacy, as is the case with the RECIST dichotomous tumor response (DiTR) metric, is therefore not appropriate.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Alternate Categorical Tumor Metrics and Cut Points for Response Categorization Using the RECIST 1.1 Data Warehouse

Mandrekar

Meyers

et al. 2014

JCO

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Purpose We sought to test and validate the predictive utility of trichotomous tumor response (TriTR; complete response [CR] or partial response [PR] v stable disease [SD] v progressive disease [PD]), disease control rate (DCR; CR/PR/SD v PD), and dichotomous tumor response (DiTR; CR/PR v others) metrics using alternate cut points for PR and PD. The data warehouse assembled to guide the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used. Methods Data from 13 trials (5,480 patients with metastatic breast cancer, non–small-cell lung cancer, or colorectal cancer) were randomly split (60:40) into training and validation data sets. In all, 27 pairs of cut points for PR and PD were considered: PR (10% to 50% decrease by 5% increments) and PD (10% to 20% increase by 5% increments), for which 30% and 20% correspond to the RECIST categorization. Cox proportional hazards models with landmark analyses at 12 and 24 weeks stratified by study and number of lesions (fewer than three v three or more) and adjusted for average baseline tumor size were used to assess the impact of each metric on overall survival (OS). Model discrimination was assessed by using the concordance index (c-index). Results Standard RECIST cut points demonstrated predictive ability similar to the alternate PR and PD cut points. Regardless of tumor type, the TriTR, DiTR, and DCR metrics had similar predictive performance. The 24-week metrics (albeit with higher c-index point estimate) were not meaningfully better than the 12-week metrics. None of the metrics did particularly well for breast cancer. Conclusion Alternative cut points to RECIST standards provided no meaningful improvement in OS prediction. Metrics assessed at 12 weeks have good predictive performance.

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“…4 Recently, early tumour shrinkage (ETS), usually defined by a relative (per cent) reduction in tumour size at a certain time point, has garnered attention as an important clinical marker associated with long survival in the treatment of mCRC. [5][6][7] Several studies [8][9][10][11][12][13][14][15][16][17][18] showed that achieving ETS during first-line treatments can predict improved OS, suggesting its potential use as a surrogate endpoint. 5 6 However, the definition of ETS is inconsistent in various studies with respect to time points and cut-off values.…”

Section: How Might This Impact On Clinical Practice?mentioning

confidence: 99%

Exploration of time points and cut-off values for early tumour shrinkage to predict survival outcomes of patients with metastatic colorectal cancer treated with first-line chemotherapy using a biexponential model for change in tumour size

Sakamaki

Kito²,

Yamazaki³

et al. 2017

ESMO Open

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BackgroundSeveral studies reported that early tumour shrinkage (ETS) was associated with overall survival in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy. However, appropriate time point and cut-off value for ETS remain unclear because these varied in previous studies.Patients and methodsWe investigated patients with mCRC who received FOLFOX or FOLFIRI with/without molecular-targeted agents as first-line treatment between 2005 and 2014. Using a biexponential model for change in tumour size, a relative change in the sum of the longest diameters of target lesions from baseline was estimated at a certain time point in each individual patient. Associations of survival outcomes with ETS at various time points based on various cut-off values were evaluated by Cox regression analysis with a landmark approach.ResultsAmong the 67 patients reviewed, the objective response rate was 73.1% (95% CI 62.5% to 83.7%), the median progression-free survival was 10.9 months (95% CI 8.7 to 13.0 months) and the median overall survival was 25.6 months (95% CI 20.1 to 27.3 months). The model for change in tumour size agreed with the actual measured sizes well. Multivariate Cox regression analysis, including performance status, number of metastatic sites and use of targeted agents, showed that ETS at 8 weeks based on a cut-off value of 20% was most significantly associated with overall survival (HR: 0.404, 95% CI 0.231 to 0.707, P=0.0015).ConclusionIt is suggested that a time point of 8 weeks and a cut-off value of 20% may be optimal criteria for defining ETS.

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Tumor Status at 12 Weeks Predicts Survival in Advanced Colorectal Cancer: Findings from NCCTG N9741

Cited by 15 publications

References 34 publications

Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

Evaluation of Alternate Categorical Tumor Metrics and Cut Points for Response Categorization Using the RECIST 1.1 Data Warehouse

Exploration of time points and cut-off values for early tumour shrinkage to predict survival outcomes of patients with metastatic colorectal cancer treated with first-line chemotherapy using a biexponential model for change in tumour size

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