In a study reported in JAMA Network Open, Shen et al found that data from both phase III trials and the Surveillance, Epidemiology, and End Results (SEER) database indicate significant improvements in overall survival for patients with metastatic colorectal cancer over a 30-year period. Increases in the clinical trial setting, however, have been incremental, with a minority showing improvements in survival of 2 months or longer; additionally, testing of novel agents and targets has decreased over time.
The study included data from 150 phase III trials of systemic therapy including a total of 77,494 patients reported between 1986 and 2016, and from 67,126 patients in the SEER database from 1986 to 2015. Comparisons of overall survival in phase III trials were made for the 10-year periods of 1986 to 1996 (36 trials), 1997 to 2006 (62 trials), and 2007 to 2016 (52 trials).
Key Findings
In phase III trials, significant increases in overall survival and progression-free survival were observed over time. Improvements were most marked in the experimental groups of first-line therapy trials, in which median overall survival increased by 5.7 months (95% confidence interval [CI] = 4.7–6.6 months) per 10 years and median progression-free survival increased by 1.4 months (95% CI = 0.7–2.1 months) per 10 years.
A total of 69 (46.6%) of 148 trials met the predefined primary endpoint, including 20 (45.5%) of 44 trials with overall survival as the primary endpoint. However, only 35 (26.5%) of 132 trials showed an improvement in overall survival by 2 or more months, including 13 (31.0%) of 42 trials with overall survival as the primary endpoint. On multivariate analysis, third-line or later therapies were associated with a reduced likelihood of showing ≥ 2-month improvement (odds ratio = 0.57, 95% CI = 0.51–0.63).
A decrease in the novelty of targets and agents over time was observed, with trials that evaluated regimens completely composed of previously approved drugs in the metastatic setting increasing from 28% to 50%.
In the SEER analysis, median overall survival increased from 12 months (95% CI = 12–13 months) in the 1986 to 1996 time period, to 21 months (95% CI = 21–22 months) in the 2007 to 2015 time period (P < .001). One-year survival rates improved from < 40% to approximately 70%, and 2-year survival rates improved from < 20% to > 40% over time. Five-year survival rates also improved, although 5-year survival remained at 12.2% in 2011.
The investigators concluded, “In this systematic review, overall survival for patients with metastatic colorectal cancer appeared to improve significantly in trials, translating into meaningful benefits outside the clinical trial setting; however, these advances, although significant cumulatively, are largely incremental individually. These data should be a call to aim for larger gains from future trials with novel drugs, building on the increasing understanding of the biology of metastatic colorectal cancer and sophisticated translational research tools.”
Arvind Dasari, MD, MS, of the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for the JAMA Network Open article.
Disclosure: The study was supported by the National Institutes of Health. For full disclosures of the study authors, visit jamanetwork.com.
