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Survival gains in patients with mCRC only partially attributed to novel chemotherapies
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While overall survival of patients with metastatic colorectal cancer has steadily increased over the past 20 years, novel chemotherapies only partially account for survival gains, as improvements in supportive care and secular trends also play a role, according to results from a recent systematic review.
Investigators sought to determine what proportion of life expectancy gains in patients with metastatic colorectal cancer (mCRC) can be attributed to novel therapies vs. improvements in supportive care or secular trends. They searched for phase 3 and large phase 2 clinical trials published from 1993 to 2015 that compared chemotherapy regimens for mCRC to calculate survival gains over time with first-line and subsequent therapies. They included 96 trials (n = 26,561) in their final analysis, and examined overall response rate, stable disease, progression-free survival (PFS), overall survival (OS) and survival not directly attributable to the protocol (SNAP), in both the experimental and control arms.
Mean OS in mCRC patients increased at a rate of 0.8 (95% CI, 0.67-0.93) months per year. Mean OS in control arms increased at a rate of 0.63 (95% CI, 0.51-0.75) months per year, which “can be explained, at least in part, by the fact that once a new experimental therapy has been established as effective, that therapy becomes the control in subsequent trials,” the researchers wrote.
Chemotherapy accounted for only a portion of OS gains based on the following observations:
- mean increases in PFS were only 0.31 (95% CI, 0.22-0.39) months per year in mCRC patients and 0.23 (95% CI, 0.15-0.31) months per year in the control arms;
- SNAP gains were greater than PFS gains (0.46; 95% CI, 0.36-0.57 months per year in mCRC patients vs. 0.39; 95% CI, 0.29-0.49 months per year in the control arms); and
- second-line trials showed lower effects on OS (median IQR response rates: 8.6%; 95% CI, 0%-11% in mCRC patients vs. 7.5%; 95% CI, 3.8%-12.8% in the control arms) compared with first-line trials (39.5%; 95% CI, 24%-50.2% in mCRC patients vs. 29.4%; 95% CI, 16.4%-39.4%) in the control arms.
The modest rate of PFS gains compared with OS gains suggests “factors other than the experimental chemotherapy regimens may have contributed to the OS gains over the past 2 decades,” including lead-time bias and general improvements in patient care.
Daniel Sargent
“We reach the conclusion that novel therapies only account for a portion of survival gains in mCRC, contrary to the widespread narrative that improved therapies are primarily responsible for advances,” the researchers concluded. “However, in our opinion, the most important conclusion to be drawn from this analysis is the indisputable value of enrolling patients in clinical trials. Only with aggressive referral to and enrollment in clinical trials will we see in the next decade a continuation of the progress of the past 2 decades.”
In an accompanying editorial, Daniel Sargent, PhD, from the Mayo Clinic in Rochester, Minn., agreed with their conclusion that survival gains in mCRC are “multifactorial,” and wrote that the approach of this study “hinges on a key assumption, which is that improvements in PFS, more or less, should translate directly and predictably into improvements in OS. Their primary conclusion, that chemotherapy has only contributed partly to the overall gains in survival, is highly plausible and is consistent with other findings from observational data.”
However, he wrote that several issues that may cause bias in their findings include:
- Differences in PFS between arms do not reliably predict differences in OS.
- Literature-based analyses cannot account for subtleties in definitions of progression.
- Real-world observations conflict with the fact that the researchers “discount the possibility that a novel agent could improve OS in settings other than first-line therapies, stating that gains in second- and later-line outcomes have been unimpressive.” – by Adam Leitenberger
Disclosure: The researchers report no relevant financial disclosures. Sargent reports he has served as a paid consultant to Bayer and Genentech.
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