Abstract
The identification of new surrogate endpoints for advanced colorectal cancer is becoming crucial and, along with drug development, it represents a research field increasingly studied. Although overall survival (OS) remains the strongest trial endpoint available, it requires larger sample size and longer periods of time for an event to happen. Surrogate endpoints such as progression free survival (PFS) or response rate (RR) may overcome these issues but, as such, they need to be prospectively validated before replacing the real endpoints; moreover, they often bear many other limitations. In this narrative review we initially discuss the role of time-to-event endpoints, objective response and response rate as surrogates of OS in the advanced colorectal cancer setting, discussing also how such measures are influenced by the tumor assessment criteria currently employed. We then report recent data published about early tumor shrinkage and deepness of response, which have recently emerged as novel potential endpoint surrogates, discussing their strengths and weaknesses and providing a critical comment. Despite being very compelling, the role of such novel response measures is yet to be confirmed and their surrogacy with OS still needs to be further investigated within larger and well-designed trials.
Highlights
Despite the remarkable survival improvements achieved with modern therapies, unresectable metastatic colorectal cancer (CRC) remains an incurable disease with a 5-year survival rate of approximately 10% [1]
To verify if faster tumor shrinkage may be used as a prognostic factor, a retrospective analysis of 113 www.impactjournals.com/oncotarget irinotecan-refractory patients enrolled in four clinical trials (BOND, EVEREST, SALVAGE and BABEL) showed that the decrease in tumor size was greater in KRAS wild-type patients when compared to mutants, and that the rapid tumor shrinkage correlated with a better outcome [62]
Waterfall plots are frequently used as graphical illustrations to display the magnitude of each individual patient’s response to a particular drug based on a parameter, such as tumor burden. These graphic models have rapidly garnered optimism because they may and intuitively represent results for individual patients, they are subject to substantial variability, may be influenced by measurement errors, and should be generated by experienced radiologist before being interpreted in the context of clinical trials [86]. In this narrative review we have reported recent data on the value of early tumor shrinkage and deepness of response, and we have discussed how these response measures have recently emerged as novel potential surrogates in advanced stages of colorectal cancer
Summary
Despite the remarkable survival improvements achieved with modern therapies, unresectable metastatic colorectal cancer (CRC) remains an incurable disease with a 5-year survival rate of approximately 10% [1]. To verify if faster tumor shrinkage may be used as a prognostic factor, a retrospective analysis of 113 www.impactjournals.com/oncotarget irinotecan-refractory patients enrolled in four clinical trials (BOND, EVEREST, SALVAGE and BABEL) showed that the decrease in tumor size was greater in KRAS wild-type patients when compared to mutants (mean relative change −13.73% versus +2.27%, p < 0.001), and that the rapid tumor shrinkage correlated with a better outcome [62].
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