Optimal endpoints in the studies of colorectal cancer (CRC) have not yet been definitively decided. The aim of a study endpoint should convey a clinically meaningful outcome; currently, progression-free survival (PFS) is the most widely used alternative endpoint in addition to the response rate (RR).1 Unfortunately, RR does not predict eventual success in phase II trials; this may be partly because the two-level approach of RR (using responder vs non-responder) does not provide for those patients with stable disease (SD).1 Therefore, additional endpoints have been desired to more specifically predict survival in patients with advanced CRC. Previous discussions regarding the use of actual tumor size appear intriguing. Therefore, Heun and colleagues1 explored the prognostic value of using actual tumor measurements (TM) versus World Health Organization (WHO) criteria as a three-level (responder, stable and progression) and two level (responder and non-responder) measurement variables at 12 and 24 weeks as predictors of survival in Intergroup Trial N9741, a phase III trial of patients with metastatic CRC. Tumor measurements for the N9741 study were reviewed for data quality beyond the normal study data validation.
- The prognostic value of actual change in tumor size versus WHO disease status were compared at 12 and 24 months using Cox models for OS, adjusting for baseline tumor size, performance status and treatment arm
- The prognostic value for each model was assessed using the concordance index C. The concordance index is a useful supplement to a P value in a Cox regression. P values may be statistically significant but the result not clinically meaningful.1
- WHO status at 12 weeks was strongly associated with survival when used as either a three-level (P < .01) or two-level variable (P < .01)
- Actual TM was strongly associated with OS at 12 weeks (P < .01) but did not provide additional meaningful predictive value (C = 0.64) in comparison to the WHO three level assessment (C = 0.66)
- Similar results were found at the 24 week analysis period with WHO status as a two-level variable and actual TM remaining strongly associated with survival
- The 24 week analysis provided no meaningful additional predictive value (C = 0.68)
The study authors noted that patients in the N9741 study without a tumor response still obtained clinical benefit from treatment; this study further demonstrates further separation among “non-responders” by separating survival curves for SD patients and those with progressive disease. They concluded that tumor status as a three-level variable at 12 weeks was an important predictor of survival (incorporating SD) and could be considered for an appropriate endpoint in future phase II clinical trials. Using RR alone as an endpoint in phase II trials will miss potentially helpful agents that could provide tumor control. The use of actual tumor measurements versus a three-level WHO criteria at 12 weeks demonstrated a small improvement in survival prediction and was seen only in those patients who had a tumor response.
Traditionally, OS is the gold standard end point, but this requires long patient follow-up and can be muddled with the different therapies used to treat CRC.2 When patients are allowed to cross over to an investigative agent in a clinical study, OS is difficult to achieve. Therefore there are other endpoints that are considered useful when determining clinical benefit in CRC treatments. These include PFS, which has mostly supplanted the previous standard of OS. PFS is the statistic reached when patients develop progression of disease or death and can be used in adjuvant and metastatic therapy trials but it is not without problems 2,3 The use of drug holidays can confound PFS measurements. It is commendable that the authors of the Heun et al study are examining the feasibility of additional endpoints in CRC. The study results add to the body of literature in the search for the optimal endpoint in colorectal cancer research. More research is needed to determine the ideal measurement for prediction of survival in CRC.
- Heun, JM, Grothey, A, Branda, ME et al. Tumor status at 12 weeks predicts survival in advanced colorectal cancer: Findings from NCCTG N9741. Oncologist 2011; 16: 859-867. doi:10.1634/theoncologist.2011-0064 Link to abstract: http://theoncologist.alphamedpress.org/content/16/6/859
- Allegra, C, Blanke, C, Buyse, M et al. End points in advanced colon cancer clinical trials: a review and proposal. J Clin Oncol 2007; 25: 3572-3575. doi:10.1200/JCO2007.12.1368 Free full text at: http://jco.ascopubs.org/content/25/24/3572.full
- Saad, ED, Katz, A, Hoff, M et al. Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature. Ann Oncol 2010; 21: 7-12. doi: 10.1093/annonc/mdp523 Free full text at: http://annonc.oxfordjournals.org/content/21/1/7.full.pdf+html