In earlier studies of the influence of hydroxymethylglutaryl-coenzyme A reductase inhibitors (also known as statins) on colorectal cancer prognosis, investigators reported a reduced rate of cancer-specific mortality. Studies of recurrence are few and small. Using data from Danish registries, we followed 21,152 patients diagnosed with stage I–III colorectal cancer from 2001 to 2011. We estimated the association between statin use in the preceding year and cancer recurrence, cancer-specific mortality, and all-cause mortality rates. We identified 5,036 recurrences, 7,084 deaths from any cause, and 4,066 deaths from colorectal cancer. After adjustment for potential confounders, statin use was not associated with recurrence (adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.93, 1.09), but it was associated with death from colorectal cancer (aHR = 0.72, 95% CI: 0.65, 0.79) and death from any cause (aHR = 0.72, 95% CI: 0.67, 0.76). Statin use in the year preceding recurrence was associated with a reduced risk of cancer-specific mortality (aHR = 0.83, 95% CI: 0.74, 0.92) but also a reduced risk of death from any other cause (aHR = 0.78, 95% CI: 0.61, 1.00). Statin use was not associated with a reduced rate of colorectal cancer recurrence, but it was associated with a reduced rate of cancer-specific mortality, which suggests that there is no cancer-directed benefit; therefore, there is no basis to prescribe statins to colorectal cancer patients who do not have cardiovascular indications.
The DCCG identified 34,801 colorectal cancer patients. Of these, we excluded 4,649 who had metastatic disease at diagnosis, 4,189 who had an unknown cancer stage at diagnosis, and 94 who had no evidence of a primary tumor (T0). Of the remaining 25,963 patients with stage I, II, or III colorectal cancer, we excluded 2,312 because they previously had a cancer other than nonmelanoma skin cancer, 143 because they had metastases more than 180 days before the colorectal cancer diagnosis, 20 because they had an earlier colorectal cancer diagnosis more than 180 days before the present date of colorectal cancer diagnosis, 73 who were not found in the Central Personal Registry, and 10 who had a colorectal cancer diagnosis date more than 60 days after date of surgery. We also excluded patients with events within 180 days of their colorectal cancer diagnosis that would complicate identification of a recurrence, including 779 with a new primary cancer, 1 with a potential colorectal cancer recurrence that may have been residual primary disease, and 2,220 who died. Some patients were excluded for more than 1 reason. Eighty percent of patients had surgery with 39 days of diagnosis (median, 18 days), and statin use in the year preceding diagnosis was not associated with mortality rates in the 90 days after surgery (adjusted hazard ratio (aHR) = 0.80, 95% CI: 0.29, 2.23). After exclusions, there were 21,152 eligible cohort members.
In what is to our knowledge the largest study to date of this association, we found a near null association between time-varying use of statins—with prescriptions lagged by 1 year—and the risk of colorectal cancer recurrence. We found a protective association between use of statins and the hazards of colorectal cancer–specific mortality or death from any cause. Finally, the inconsistent association between recurrence and colorectal cancer–specific mortality rates led us to estimate the association of use of statins in the year before a recurrence with death from colorectal cancer and death from any cause except colorectal cancer. Both of these associations suggested that use of statins before cancer recurrence reduced the mortality risk.
The null association between statin use and colorectal cancer recurrence rate contrasts with results from a study of the association between prediagnostic use of statins and cancer-specific mortality rates among 43,487 Danish colon cancer patients diagnosed from 1995 to 2007, which overlapped our study population for 6 years. In that study, colon cancer patients who were prescribed a statin before diagnosis had a reduced risk of death with colon cancer as the underlying cause (HR = 0.81, 95% CI: 0.75, 0.87). This interval does not overlap the interval of our estimate of the association between statin use and recurrence rate (aHR = 1.01, 95% confidence interval: 0.93, 1.09), but it does overlap the interval of our estimate of the association between statin use and cancer-specific mortality rate (aHR = 0.72, 95% CI: 0.65, 0.79).
The results of Nielsen et al. were similar to those from a study of 7,657 patients diagnosed with stage I–III colorectal cancer from 1998 to 2009 in the United Kingdom. In that study, Cardwell et al. reported a hazard ratio of 0.72 (95% CI: 0.64, 0.81) for the association of postdiagnosis statin use—lagged by 6 months—with cancer-specific mortality. Between them, the Danish and United Kingdom studies contributed 83% of the weight to a recent meta-analysis that included 6 studies in all and that reported protective summary estimates of association provided in the introduction. Most recently, Shao et al. used data from the Taiwan cancer registry and administrative data to estimate the association between prediagnosis statin use and cancer-specific survival rates (HR = 0.77, 95% CI: 0.68, 0.88) in 17,115 patients with stage I–III colorectal cancer.
Earlier studies of the association between statin use and colorectal cancer recurrence are rare and small. Two studies of the association of statin use with recurrence or progression were nested in a trial of 842 patients with stage III colon cancer (HR = 1.14, 95% CI: 0.77, 1.69) and in a registry of 407 patients with rectal cancer (HR = 0.44, 95% CI: 0.26, 0.75). In a study of 891 rectal cancer patients at 5 Canadian centers, investigators reported that statin use at initial consultation was favorably associated with pathologic complete response (odds ratio = 1.72, 95% CI: 1.02, 2.92). Finally, in a study of 2,697 German patients with colorectal cancer, Hoffmeister et al.reported that the associations of statin use with recurrence-free survival (HR = 0.90, 95% CI: 0.63, 1.27) and mortality rate were near null.
Ours is the first study in which the association between statin use and colorectal cancer outcomes has been evaluated at all critical time points: before diagnosis, before recurrence, and after recurrence. We found the same protective associations of statin use with colorectal cancer–specific mortality rate and all-cause mortality rate that were reported in earlier, large studies. Our null association between statin use and colorectal cancer recurrence argues against a cancer-directed effect of statin use and calls into question the mechanism by which the protection against mortality rate arises. We did observe a protective association between statin use in the year before recurrence and colorectal cancer–specific mortality rate, but statin use in the year before recurrence was also protective against death from other causes. The distributions of sites of recurrence were similar between statin users and non-users, further arguing against a cancer-directed effect. In a recent randomized trial of patients with stage IV colorectal cancer who had adequate function of major organs, researchers found that adding 40 mg per day of simvastatin to guideline chemotherapy did not benefit progression-free survival or overall survival.
Healthy-user bias and lead-time bias provide 2 reasonable explanations for the observed protective associations of statins in the year before recurrence with death from colorectal cancer and death from another cause. Although Danish statin users do not generally have better health or health behaviors than do non-users, colorectal cancer patients who continue to take statins after their diagnosis may have healthier lifestyles or a better cancer prognosis. It is also possible that the colorectal cancer patients who continue to take statins after their diagnoses more often contact the health-care system, so their recurrences may be diagnosed earlier than those in non-users. This would result in more elapsed time between recurrence and death among statin users and downwardly bias mortality rates. Weighing against this explanation is that all Danes have unfettered access to health care and that all Danish colorectal cancer patients are invited to undergo standardized follow-up visits. These visits include computed tomography scans 1 and 3 years after diagnosis and colonoscopy every 5 years after diagnosis until age 75 years. This guideline surveillance program has been in place since 2006, before which similar but not standardized programs were used at different hospitals.
A limitation of the present study and the other earlier studies is the inability to implement an active comparator design. This design would compare colorectal cancer outcomes in users of statins with outcomes in users of another cholesterol-lowering agent, such as a bile acid sequesterant or ezetimibe. These agents are most often prescribed in combination with statins when statins alone fail to adequately control cholesterol or are prescribed alone when statins are poorly tolerated. They are seldom prescribed alone as first-line therapy to manage cholesterol levels. Thus, an active comparator design with users of these medications as the reference group would not compare persons with equivalent indications.