Skip to main content
Free access
ORIGINAL REPORTS
August 04, 2014

Statin Use After Colorectal Cancer Diagnosis and Survival: A Population-Based Cohort Study

Publication: Journal of Clinical Oncology
PDF

Abstract

Purpose

To investigate whether statins used after colorectal cancer diagnosis reduce the risk of colorectal cancer-specific mortality in a cohort of patients with colorectal cancer.

Patients and Methods

A cohort of 7,657 patients with newly diagnosed stage I to III colorectal cancer were identified from 1998 to 2009 from the National Cancer Data Repository (comprising English cancer registry data). This cohort was linked to the United Kingdom Clinical Practice Research Datalink, which provided prescription records, and to mortality data from the Office of National Statistics (up to 2012) to identify 1,647 colorectal cancer–specific deaths. Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% CIs by postdiagnostic statin use and to adjust these HRs for potential confounders.

Results

Overall, statin use after a diagnosis of colorectal cancer was associated with reduced colorectal cancer–specific mortality (fully adjusted HR, 0.71; 95% CI, 0.61 to 0.84). A dose-response association was apparent; for example, a more marked reduction was apparent in colorectal cancer patients using statins for more than 1 year (adjusted HR, 0.64; 95% CI, 0.53 to 0.79). A reduction in all-cause mortality was also apparent in statin users after colorectal cancer diagnosis (fully adjusted HR, 0.75; 95% CI, 0.66 to 0.84).

Conclusion

In this large population-based cohort, statin use after diagnosis of colorectal cancer was associated with longer rates of survival.

Introduction

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce serum cholesterol and are widely used to manage and prevent coronary heart disease.1 Accumulating preclinical evidence suggests statins could have anticancer properties by inhibiting cell proliferation, inducing apoptosis, or inhibiting angiogenesis.2,3 In humans, recent epidemiologic studies have shown reductions in cancer recurrence or cancer-specific mortality in statin users with breast4 and prostate5 cancer. Furthermore, there have been calls for randomized controlled trials of statins as adjuvant cancer therapy, for instance for breast cancer.6
Despite these studies and other preclinical evidence specific to colorectal cancer,7,8 few epidemiologic studies have investigated statin use after diagnosis and cancer progression in patients with colorectal cancer. A Scottish study9 of 308 patients with colorectal cancer observed a marked but nonsignificant reduction in colorectal cancer-specific mortality in statin users after diagnosis. An American study of 407 patients with rectal cancer who were undergoing chemoradiotherapy also observed a marked, nonsignificant reduction in cancer-specific mortality in statin users before and after surgery.10 Finally, another American study in 842 patients with stage III colon cancer did not detect any association between patient-reported statin use after diagnosis and cancer recurrence.11 Because some of these studies investigated specific colorectal cancer subgroups10,11 or had limitations such as relatively small size,911 measurement of medication use at one time-point,11 and potential for immortal time bias,9 a need for further study of the effect of statins on survival after colorectal cancer diagnosis remains to inform the decision to conduct randomized trials of statins as adjuvant cancer therapy in colorectal cancer patients.
Therefore, we investigated the effect of statin use after colorectal cancer diagnosis on cancer-specific mortality in a large cancer registry–defined population-based cohort of patients with colorectal cancer.

Patients and Methods

Data Source

Our study used recent links between death-registration data from the United Kingdom Clinical Practice Research Datalink (CPRD), the National Cancer Data Repository (NCDR), and the Office of National Statistics (ONS). The CPRD is the world's largest computerized database of longitudinal patient records, comprising approximately 7% of the United Kingdom population and including demographic information, clinical diagnoses, and prescription data of documented high quality.12 The NCDR provided data on all patients with cancer identified in English cancer registries, including patients' date and site of primary cancer diagnosis, stage, grade, and treatment data. ONS death-registration data provide date and cause of death. Links between data sources were conducted using a deterministic algorithm based on National Health Service number, sex, date of birth, and postcode. Ethical approval for all observational research using CPRD data has been obtained from a multicenter research ethics committee.

Study Design

We identified a cohort of patients with newly diagnosed colorectal cancer, based on a primary diagnosis of colorectal cancer recorded by the NCDR between 1998 and 2009 (comprising ICD codes of the colon [C18] or rectum [C20], including the recto-sigmoid junction [C19]). Cohort members with previous NCDR cancer diagnoses, apart from in situ neoplasms and nonmelanoma skin cancers, were excluded. Only colorectal cancer patients with stage I to III disease were included (as recorded by the NCDR), because postdiagnostic medication usage is unlikely to influence stage IV disease. This cohort was linked to CPRD and ONS death-registration data. Deaths were identified from ONS, with coverage up to January 2012, with colorectal cancer-specific deaths defined as those with underlying cause of death (ICD codes C18, C19, C20, C21 [anus], or C26 [other and ill-defined digestive organs]). Patients who died in the first year after their colorectal cancer diagnoses were removed from study, because it seemed unlikely that postdiagnostic medication use could influence such deaths, therefore the follow-up period started 1 year after diagnosis. The patients received follow-up from 1 year after colorectal cancer diagnosis to death, end of registration with the general practice, last date of data collection from general practice, or end of ONS follow-up.

Exposure Data

Statin use (available in the United Kingdom since 198913) were determined from general practitioners' (GP) prescribing records in the CPRD, based on the statins section of the British National Formulary14 (section 2.12). A quantity of 28 tablets was assumed for approximately 1% of prescriptions for which quantity was missing or assumed incorrect. The daily defined doses (DDD) in each prescription were calculated by multiplying the quantity by the strength (in mg) and dividing by the mg in a DDD from the World Health Organization.15 Statin use was investigated as a time-varying covariate16 (patients were initially considered nonusers and then users after a lag of 6 months after their first statin prescription). The use of a lag is recommended17 and in this study removed prescriptions in the 6 months before death because they could reflect end-of-life treatment (in sensitivity analyses the lag duration varied). We conducted dose-response analyses in which an individual was considered a nonuser prior to 6 months after first use, a short-term user between 6 months after first use and 6 months after the 12th prescription (or 365 DDDs), and a longer-term user after this time.

Covariates

Data available from NCDR included data about patients' cancer stage; histologic grade; and surgery, chemotherapy, and radiotherapy received in the 6 months after diagnosis. Patients' smoking, alcohol, and body mass index (BMI) data were determined from the closest GP records before colorectal cancer diagnosis (values more than 10 years before diagnoses were ignored). Comorbidities from before patients' cancer diagnoses were determined from GP diagnosis codes, using comorbidities comprising a recent adaptation of the Charlson index.18 CPRD provided a deprivation based on residential postcodes, using the 2004 index of multiple deprivations for England.19 Angiotensin-converting enzyme (ACE) inhibitor, low-dose aspirin, and metformin use were determined from GP prescription records.

Statistical Analysis

In the main analysis, time-dependent Cox regression models were used to calculate hazard ratios (HRs) for colorectal cancer–specific death and 95% CIs for statin users compared with nonusers, using a time-varying covariate as described in the Exposure Data section. We conducted adjusted analyses, including the following potential confounders, which were available for the entire analysis cohort: year of diagnosis, age at diagnosis, sex, cancer stage, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site (colon or rectum), comorbidities from before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), and other medication use (including low-dose aspirin, ACE inhibitors, and metformin as time-varying covariates, with a 6-month lag). A separate analysis also adjusted for grade, deprivation (in fifths), and smoking before diagnosis. We conducted analyses by number of prescriptions, number of DDDs, and type of statin, and this was repeated for all-cause mortality. Subgroup analyses were conducted by site (colon or rectal), sex, age (excluding patients younger than 50 years), stage, surgical treatment, diabetes, BMI, and prediagnostic statin use. Interaction tests were conducted using terms within Cox regression models.
We conducted sensitivity analyses, increasing the lag to 1 and 2 years, investigating longer durations of use, and adjusting for aspirin use in categories, as well as adjusting for BMI before diagnosis and not restricting the cohort to individuals with recorded stage I to III disease. A simplified analysis was conducted using Cox regression to compare statin users with nonusers in the first year after colorectal cancer diagnosis in individuals alive more than 1 year after diagnosis; this controls immortal time bias20 without requiring time-varying covariates. We then used logistic regression to create a propensity score for statin use in the first year after diagnosis, using all potential confounders mentioned earlier in this section. Matching, implemented by PSMATCH2,21 was conducted on the logit of the propensity score, using single nearest neighbor matching with a caliper width of 0.33 (based on 0.2 standard deviations of the logit, as recommended22). Cox regression compared cancer-specific mortality in the statin user and propensity score–matched control group, using a robust variance estimator to account for the lack of independence within matched pairs, as recommended.23 We also conducted a nested case-control analysis (Appendix Table A5 [online-only]). We analyzed statin prescriptions in the year before diagnosis, not excluding patient deaths in the first year after diagnosis, and not adjusting for stage (or restricting to stage I to III disease) or for grade to avoid overadjustment,24,25 because stage and grade could be on the causal pathway for the association between prediagnosis statin use and colorectal cancer–specific mortality. This analysis was repeated, adjusting for BMI before diagnosis, and was restricted to patients diagnosed before 2006 (when national bowel cancer screening began26).

Results

Patient Cohort

A total of 7,657 patients newly diagnosed with stage I to III colorectal cancer met the inclusion criteria (see Fig 1); these patients received on average 5 years of follow-up after diagnosis (minimum, 1 year; maximum, 14 years). Patient characteristics by statin use are listed in Table 1. Statin users were more likely to have been diagnosed more recently, be older, be men, to have smoked, and to have higher BMI. Stage and grade were generally similar by statin use, but a slightly smaller proportion of statin users versus nonusers had stage III disease (36% v 43%, respectively). Statin users were more likely to have comorbidities (particularly for cerebrovascular disease, diabetes, and myocardial infarction) and use other medications (such as aspirin, ACE-inhibitors, and metformin).
Fig 1. Patient selection for analysis. (*) No history of other cancers in the National Cancer Data Repository (NCDR), excluding in situ neoplasms and nonmelanoma skin cancers. (†) Excluding patients diagnosed at a United Kingdom Clinical Practice Research Datalink (CPRD) practice prior to the data recording at the practice reaching a quality standard specified by the CPRD.
Table 1. Characteristics of Patients With Colorectal Cancer by Postdiagnosis Statin Use
Characteristic Statin Use After Diagnosis
Ever Used No. of Patients/% Never Used No. of Patients/%
Year of diagnosis        
    1998-2000 317 12 961 19
    2001-2003 665 25 1,294 26
    2004-2006 816 31 1,341 27
    2007-2009 864 32 1,399 28
Age at diagnosis, years        
    < 50 37 1 364 7
    50-59 233 9 848 17
    60-69 850 32 1,216 24
    70-79 1,077 40 1,584 32
    80-89 452 17 911 18
    ≥ 90 13 0 72 1
Men 1,650 62 2,586 52
Stage        
    1 550 21 772 15
    2 1,154 43 2,090 42
    3 958 36 2,133 43
Grade        
    Well 175 7 274 5
    Moderate 2,000 75 3,639 73
    Poor 319 12 760 15
    Missing 168 6 322 6
Treatment within 6 months of cancer diagnosis 2,548 96 4,791 96
    Surgery        
    Chemotherapy 660 25 1,619 32
    Radiotherapy 297 11 610 12
Smoking status before cancer diagnosis        
    Nonsmoker 1,157 43 2,332 47
    Former smoker 966 36 1,208 24
    Current smoker 289 11 644 13
    Missing 250 9 811 16
Alcohol consumption before diagnosis        
    Never 316 12 588 12
    Ever 1,787 67 2,943 59
    Missing 559 21 1,464 29
BMI before diagnosis, kg/m2 27.6 4.7 26.1 4.6
    Mean        
    SD        
    Underweight (< 18.5) 22 1 85 2
    Normal (18.5 to 25) 662 25 1,485 30
    Overweight (25-30) 999 38 1,480 30
    Obese (> 30) 589 22 616 12
    Missing 390 15 1,329 27
Deprivation quintile        
    First (least deprived) 635 24 1,358 27
    Second 619 23 1,266 25
    Third 575 22 999 20
    Fourth 490 18 840 17
    Fifth (most deprived) 339 13 523 10
    Missing 4 0 9 0
Comorbidity before cancer diagnosis        
    Cerebrovascular disease 251 9 172 3
    Chronic pulmonary disease 453 17 764 15
    Congestive heart disease 120 5 137 3
    Diabetes 607 23 213 4
    Myocardial infarction 320 12 82 2
    Peptic ulcer disease 178 7 239 5
    Peripheral vascular disease 172 6 102 2
    Renal disease 218 8 146 3
Medication after diagnosis        
    Low-dose aspirin use (in exposure period) 1,646 62 898 18
    ACE use (in exposure period) 1,445 54 977 20
    Metformin use (in exposure period) 550 21 148 3
Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index; SD, standard deviation.

Association Between Statin Use and Survival

Overall, statin users had a 28% reduction in rate of colorectal cancer–specific mortality compared with nonusers (HR, 0.72; 95% CI, 0.64 to 0.81; Table 2). Compared with nonusers, individuals using 1 to 365 DDDs of statins (equivalent to less than 1 year's use) had a 21% reduction in their rate of colorectal cancer–specific mortality (HR, 0.79; 95% CI, 0.68 to 0.93). And individuals using more than 365 DDDs had a 35% reduction in colorectal cancer–specific mortality (HR, 0.65; 95% CI, 0.56 to 0.77). The observed associations seemed similar by type of statin (Appendix Table A1) and after adjustment for potential confounders.
Table 2. Association Between Statin Use After Cancer Diagnosis and Cancer-Specific Death in Patients With Colorectal Cancer
Medication Use After Diagnosis Cancer-Specific Mortality All Patients Person Years Unadjusted HR (n = 7,657) 95% CI P Adjusted HR* (n = 7,657) 95% CI P Fully Adjusted HR (n = 6,178) 95% CI P
Statin nonuser 1,337 4,995 21,770 1.00   1.00   1.00  
Statin user 346 2,662 9,047 0.72 0.64 to 0.81 < .001 0.68 0.59 to 0.79 < .001 0.71 0.61 to 0.84 < .001
Statin user, 1 to 11 prescriptions§ 158 745 3,373 0.70 0.59 to 0.83 < .001 0.69 0.57 to 0.82 < .001 0.73 0.60 to 0.88 < .001
Statin user ≥ 12 prescriptions§ 188 1,917 5,672 0.73 0.63 to 0.86 < .001 0.71 0.60 to 0.85 < .001 0.70 0.57 to 0.85 < .001
Statin user 1 to 365 DDD§ 170 687 3,257 0.79 0.68 to 0.93 .005 0.76 0.64 to 0.90 .002 0.79 0.65 to 0.95 .01
Statin user ≥ 365 DDD§ 176 1,975 5,789 0.65 0.56 to 0.77 < .001 0.65 0.54 to 0.78 < .001 0.64 0.53 to 0.79 < .001
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; DDD, daily defined doses; HR, hazard ratio.
*
Adjusted for year of diagnosis, age at diagnosis, sex, stage, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site (colon or rectum), comorbidities (before diagnosis, including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), and other medication use after diagnosis as time-varying covariates (including low-dose aspirin, ACEIs, and metformin).
Adjusted for all variables in (*) footnote, and also adjusted for grade, deprivation (in fifths), and smoking before diagnosis in individuals without missing values.
Medication use modeled as a time varying covariate. An individual was considered a nonuser prior to 6 months after first medication usage and a user after this time, excludes deaths in the year after cancer diagnosis.
§
Medication use modeled as a time varying covariate. An individual was considered a nonuser prior to 6 months after first medication usage, a short-term user from 6 months after first prescription to 6 months after the 12th prescription (or 365 DDDs), and a longer-term user after this time, excludes deaths in the year after cancer diagnosis.
There was a 12% reduction in the rate of all-cause mortality in statin users before adjustment (HR, 0.88; 95% CI, 0.81 to 0.96), but after adjustment for confounders this association was more marked and more similar to the colorectal cancer–specific mortality analysis (fully adjusted HR, 0.75; 95% CI, 0.66 to 0.84; Table 3). A similar pattern (of attenuated associations in unadjusted analyses) was observed for analyses by number of prescriptions, DDDs, and type of statin (Appendix Table A2).
Table 3. Association Between Statin Use After Cancer Diagnosis and Death From Any Cause in Patients With Colorectal Cancer
Medication Use After Diagnosis All-Cause Mortality All Patients Person Years Unadjusted HR (n = 7,657) 95% CI P Adjusted HR* (n = 7,657) 95% CI P Fully Adjusted HR (n = 6,178) 95% CI P
Statin nonuser 1,963 4,995 21,770 1.00     1.00     1.00    
Statin user 678 2,662 9,046 0.88 0.81 to 0.96 .006 0.72 0.65 to 0.80 < .001 0.75 0.66 to 0.84 < .001
Statin user, 1 to 11 prescriptions§ 269 745 3,373 0.85 0.74 to 0.96 .01 0.73 0.63 to 0.84 < .001 0.74 0.64 to 0.87 < .001
Statin user, ≥ 12 prescriptions§ 409 1,917 5,672 0.91 0.82 to 1.02 .10 0.74 0.65 to 0.84 < .001 0.75 0.65 to 0.86 < .001
Statin user, 1 to 365 DDD§ 281 687 3,257 0.92 0.82 to 1.05 .22 0.77 0.67 to 0.88 < .001 0.78 0.68 to 0.91 .001
Statin user, ≥ 365 DDD§ 397 1,975 5,789 0.86 0.76 to 0.96 .01 0.71 0.62 to 0.81 < .001 0.72 0.62 to 0.83 < .001
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; DDD, daily defined doses; HR, hazard ratio.
*
Adjusted for year of diagnosis, age at diagnosis, sex, stage, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site (colon or rectum), comorbidities before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), and other medication use after diagnosis as time-varying covariates (including low-dose aspirin, ACEIs, and metformin).
Adjusted for all variables in (*) footnote, and also adjusted for grade, deprivation (in fifths), and smoking before diagnosis in individuals without missing values.
Medication use modeled as a time varying covariate. An individual was considered a nonuser prior to 6 months after first medication usage and a user after this time, excludes deaths in the year after cancer diagnosis.
§
Medication use modeled as a time varying covariate. An individual was considered a nonuser prior to 6 months after first medication usage, a short-term user from 6 months after first prescription to 6 months after the 12th prescription (or 365 DDDs), and a longer-term user after this time, excludes deaths in the year after cancer diagnosis.

Sensitivity/Secondary Analyses

Sensitivity/secondary analyses are listed in Table 4. There were no marked differences in associations by cancer site, cancer stage, patient age (excluding patients younger than 50 years), surgery status, or diabetes status. Associations were slightly more marked in men compared with women (men: adjusted HR, 0.64; 95% CI, 0.52 to 0.78; women: adjusted HR, 0.85; 95% CI, 0.66 to 1.09) and in patients with higher BMI (BMI > 25 kg/m2: adjusted HR, 0.68; 95% CI, 0.55 to 0.84; BMI < 25 kg/m2: adjusted HR, 0.85; 95% CI, 0.64 to 1.13), but these differences were not significant (P for interaction = .50 and .13, respectively). Notably, in patients who had not used statins before diagnosis, the association between statin use after diagnosis (ie, de novo use) and cancer-specific mortality remained (adjusted HR, 0.66; 95% CI, 0.50 to 0.85). The observed protective statin association was slightly attenuated when the lag was increased to 1 year (reducing reverse causality by removing prescriptions in the year before death; adjusted HR, 0.77; 95% CI, 0.66 to 0.90) and was further attenuated when the lag was increased to 2 years (adjusted HR, 0.84; 95% CI, 0.69 to 1.02) but was still apparent with a 2-year lag in individuals using more than 365 DDDs (adjusted HR, 0.75; 95% CI, 0.56 to 0.99). The observed associations were similar in longer-term users, after adjusting for BMI, adjusting for aspirin use in categories, stratifying by aspirin use (Appendix Table A3), and when not restricting to recorded disease stages I to III. Repeating the analysis using a simplified 1-year analysis and using a nested case-control approach produced similar findings (Appendix Table A5). Propensity score matched estimates (Table 4) were also similar to the main analysis (characteristics of statin users and matched controls are listed in Appendix Table A4).
Table 4. Sensitivity Analyses for Association Between Statin Use and Cancer-Specific Mortality in Patients With Colorectal Cancer
Analysis Users Nonusers Unadjusted Fully Adjusteda
Cancer-Specific Mortality All Patients Person Years Cancer-Specific Mortality All Patients Person Years HR 95% CI P HR 95% CI P
Statin users v nonusers, after diagnosis                        
    Main analysis 346 2,662 9,047 1,337 4,995 21,770 0.72 0.64 to 0.81 < .001 0.71 0.61 to 0.84 < .001
    Subgroup analyses                        
        Colon cancer patients 219 1,726 5,824 834 3,228 13,738 0.72 0.62 to 0.83 < .001 0.76 0.62 to 0.92 .006
        Rectal cancer patients (including rectosigmoid junction) 127 936 3,222 503 1,767 8,032 0.71 0.59 to 0.86 .001 0.63 0.48 to 0.82 .001
    Excluding patients ≤ 50 years 343 2,616 8,866 1,226 4,577 20,003 0.73 0.64 to 0.82 < .001 0.74 0.63 to 0.86 < .001
    Sex                        
        Men 228 1,650 5,611 746 2,586 11,311 0.71 0.61 to 0.82 < .001 0.64 0.52 to 0.78 <0.001
        Women 118 1,012 3,435 591 2,409 10,459 0.71 0.58 to 0.86 .001 0.85 0.66 to 1.09 .19
    Stage                        
        1 23 550 1,980 72 772 4,160 0.69 0.43 to 1.11 .13 0.79 0.39 to 1.60 .52
        2 108 1,154 4155 386 2,090 10,038 0.76 0.61 to 0.93 .01 0.81 0.61 to 1.07 .14
        3 215 958 2,912 879 2,133 7,572 0.73 0.63 to 0.85 < .001 0.69 0.57 to 0.84 < .001
    Surgically treated 332 2,548 8,604 1,265 4791 20,976 0.73 0.65 to 0.83 < .001 0.75 0.64 to 0.88 <0.001
    Diabetes before diagnosis                        
        Yes 86 2,055 2,040 79 4,782 928 0.57 0.42 to 0.77 < .001 0.76 0.64 to 0.90 .002
        No 260 607 7,006 1,258 213 20,842 0.73 0.64 to 0.83 < .001 0.52 0.34 to 0.78 .002
    BMI before diagnosis, kg/m2                        
        ≤ 25 98 684 2,300 399 1,570 6,889 0.86 0.69 to 1.08 .19 0.85 0.64 to 1.13 .26
        > 25 199 1,588 5,437 547 2,096 9,207 0.69 0.59 to 0.81 < .001 0.68 0.55 to 0.84 < .001
    Prediagnosis statin use                        
        Nonusersb 96 1,032 3,585 1,182 4,518 19,536 0.69 0.56 to 0.85 .001 0.66 0.50 to 0.85 .002
        Usersb 226 1,469 4,817 27 86 274 0.55 0.37 to 0.82 .003 0.59 0.37 to 0.94 .03
Sensitivity analyses: statin users v nonusers, after diagnosis                        
    Adjusting for aspirin in categoriesc 346 2,662 9,047 1,337 4,995 21,770 0.72 0.64 to 0.81 < .001 0.71 0.61 to 0.84 .001
    Increasing lag to 1 year 323 2,548 8,347 1,360 5,109 22,470 0.75 0.67 to 0.85 < .001 0.77 0.66 to 0.90 .001
    Increasing lag to 2 yearsd 204 2,139 5,987 860 4,470 17,704 0.83 0.71 to 0.97 .02 0.84 0.69 to 1.02 .09
    Increasing lag to 2 years, user status based on ≥ 365 DDDsd 77 1,361 3,281 987 5,248 20,411 0.72 0.56 to 0.91 .01 0.75 0.56 to 0.99 .04
    Statin user status based on ≥ 36 prescriptions 44 868 2,053 1,639 6,789 28,764 0.74 0.54 to 1.01 .06 0.72 0.50 to 1.03 .08
    Available BMI before diagnosis (adjusted for diagnosis)e 297 2,272 7,738 946 3,666 16,096 0.74 0.65 to 0.85 < .001 0.74 0.62 to 0.87 < .001
    Not restricted to stage 1 to 3 (or known stage)f 562 3,478 11,392 2,162 6,879 27,563 0.75 0.69 to 0.83 < .001 0.71 0.63 to 0.79 < .001
    Based on first year after diagnosisg 275 1,698 5,742 1,408 5,959 25,074 0.76 0.66 to 0.86 < .001 0.78 0.66 to 0.92 .004
    Propensity score matched analysish 165 1,020 3,671 214 1,020 3,330       0.72 0.58 to 0.88 .001
Prediagnostic statin use                        
    Statin users v nonusers before diagnosisi 1,018 2,990 8,899 4,473 11,036 37,553 0.85 0.79 to 0.90 < .001 0.86 0.79 to 0.93 <.001
    Year of diagnosis before 2006 416 1,128 4,514 3,172 7,266 28,615 0.80 0.73 to 0.89 < .001 0.81 0.72 to 0.92 .001
    Available BMI before diagnosis (and adjusted for diagnosis)j 927 2,674 7,934 3,086 7,957 28,045 0.92 0.86 to 0.99 .03 0.91 0.83 to 0.99 .03
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; BMI, body-mass index; DDD, daily defined doses; HR, hazard ratio; NCDR, National Cancer Data Repository.
a
Except where otherwise stated, all analyses were adjusted for year of diagnosis, age at diagnosis, sex, stage, grade, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site (colon or rectum), deprivation (in fifths), comorbidities before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), other medication use after diagnosis as time-varying covariates (including low-dose aspirin, ACEIs, and metformin), and smoking before diagnosis.
b
Based on use in the year before diagnosis; restricted to individuals with 1 year of recorded date of colorectal cancer diagnosis.
c
Model contains all variables in (a) footnote, but aspirin was adjusted after diagnosis as a time-varying covariate (in categories 0-365 tablets and ≥ 365 tablets).
d
Excluding deaths in the 2 years after diagnosis.
e
Unadjusted only for individuals with available BMIs; adjusted model contains all variables in (a) footnote, along with BMI before diagnosis.
f
Not restricted to NCDR-recorded stages 1 to 3, not adjusting for stage, grade, deprivation, or smoking.
g
Simplified analysis, not requiring time-varying covariate use, comparing statin users to statin nonusers in the first year after diagnosis for individuals living more than 1 year after cancer diagnosis, adjusted for all confounders in (a) footnote, but other medication use was also restricted to first year after diagnosis.
h
Propensity score was calculated using logistic regression with statin use as the outcome and the following exposure variables: aspirin, ACE, metformin (in first year after diagnosis), age, year, sex, stage, grade, surgery, radiotherapy, chemotherapy, cancer site (colon or rectum), deprivation score (in fifths), comorbidities before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), and smoking before diagnosis.
i
Based on one or more prescriptions in the year before diagnosis, restricted to individuals with 1 year of records before colorectal cancer diagnosis, does not exclude deaths in the first year after diagnosis and is not restricted to individuals with a recorded NCDR stage of 1 to 3. Adjusted analysis includes all variables used in (a) footnote, apart from stage and grade (as these could be on the causal pathway) and other medication use (including low-dose aspirin, ACEIs, and metformin), which are adjusted in the year before diagnosis.
j
Analysis is the same as (i) footnote, but only in individuals with available BMIs; adjusted models also include BMIs before diagnosis.
Table 4 also contains an analysis of prediagnostic statin use, showing a reduction of 14% (adjusted HR, 0.86; 95% CI, 0.79 to 0.93) in rate of cancer-specific mortality in prediagnostic statin users compared with nonusers. Restriction to patients diagnosed before 2006 little altered this estimate. This association was attenuated after the analysis was restricted to individuals with high BMIs (HR, 0.92; 95% CI, 0.86 to 0.99), but additional adjustment for BMI seemed to make little difference (adjusted HR, 0.91; 95% CI, 0.83 to 0.99).

Discussion

In this large, population-based cohort of newly diagnosed colorectal cancer patients, we observed a 29% reduction in the rate of cancer-specific mortality in colorectal cancer patients who used statins after diagnosis. This association followed a dose-response with a more marked 36% reduction with statin use for more than 1 year. We also observed reductions in all-cause mortality in individuals using statins after diagnosis.
Few epidemiologic studies have investigated the effect of statin use after diagnosis on cancer-specific mortality in patients with colorectal cancer. Although our main finding (fully adjusted HR, 0.71; 95% CI, 0.61 to 0.84) is consistent with a Scottish study of 308 patients with colorectal cancer, which observed a nonsignificant 58% reduction in colorectal cancer-specific mortality in statin users after diagnosis (HR, 0.42; 95% CI, 0.17 to 1.05),9 their findings may be subject to immortal time bias.16 This bias occurs because individuals who survive longer are more likely to receive a medication and, consequently, the medication erroneously seems protective.16 Lakha et al9 used Cox regression models and therefore, to account for immortal time bias, medication use should be investigated with time-varying covariates,16 but this is not mentioned. Our main finding is consistent with a recent American study by Mace et al10 of 407 patients with rectal cancer who were undergoing chemoradiotherapy, which observed a marked but nonsignificant reduction in cancer-specific mortality in patients using statins both before and after surgery (HR, 0.62; 95% CI, 0.32 to 1.18). Finally, another American study by Ng et al11 used observational data from a trial investigating chemotherapy regimens (statin use was not randomly assigned) and found no association between statin use and cancer recurrence (adjusted HR, 1.14; 95% CI, 0.77 to 1.69). Although there is some overlap in the CIs from our study and in the study by Ng et al,11 inconsistency in the estimates could reflect the different methodologies used. Their study used a different outcome (cancer recurrence), different method of statin ascertainment (based upon patient recall at one time point 14 months after surgery) and investigated a specific population (trial participants with stage III colon cancer undergoing surgery and chemotherapy).
The analysis of statins before cancer diagnosis was a secondary objective (because it is more difficult to intervene before diagnosis). However, our findings for statins before colorectal cancer diagnosis (fully adjusted HR, 0.86; 95% CI, 0.79 to 0.93) are consistent with the colorectal cancer subgroup of a Danish study by Nielsen et al27 that showed a weak protective effect of prediagnostic statins on cancer-specific mortality (adjusted HR, 0.81; 95% CI, 0.75 to 0.87). An American study by Siddiqui et al28 observed a protective effect of statin use before diagnosis on all-cause mortality (adjusted odds ratio; 0.7; 95% CI, 0.6 to 0.9), but this estimate could partly reflect the protective effect of statins on death from noncancer causes.
The cause of the reduction in colorectal cancer-specific mortality in colorectal cancer patients using statins is unknown. However, this reduction is consistent with accumulating preclinical evidence suggesting that statins have anticancer properties.2,3 Specifically, studies of colorectal cancer cells have shown that statins induce apoptosis8 and in animal models can inhibit colon carcinogenesis.7 The association we observed requires confirmation in large, well-conducted observational studies before randomized controlled trials of statins as an adjuvant cancer therapy can be recommended. An ongoing trial29 that is randomly allocating patients with stage II and III colon cancer to receive statins to investigate their effect on polyp prevention, is due to report in 2020 and may provide further evidence on the potential of statins as cancer therapy.
Our study has several strengths and limitations. This is the largest study yet to investigate statin use after diagnosis and its effect on colorectal cancer-specific mortality (it included 7,500 patients with colorectal cancer more than the previous largest study by Ng et al,11 which enrolled fewer than 850 patients). Our patients had a long follow-up period after diagnosis of up to 14 years. NCDR and ONS data allowed robust verification of cancer diagnosis and death, although some misclassification of cause is possible.27 GP-prescribed drug data gave us detailed timing of statin use and eliminated the recall bias possible in questionnaire-based studies. Statins are not available over the counter in the United Kingdom (apart from low-dose 10 mg simvastatin, which became available in 2004),30 limiting misclassification by over-the-counter use. A previous methodologic study has shown that valid treatment effects can be obtained when over-the-counter use occurs.31 Misclassification of statin use is also possible because of noncompliance, but associations were also apparent in patients using multiple prescriptions, for whom noncompliance is of less concern. Furthermore, any misclassification of statin use (owing to noncompliance or over-the-counter use) is likely to drag associations to the null rather than create spurious associations. Potential differences in the association between statins and cancer-specific mortality by BMI and sex (consistent with sex-specific associations seen for colorectal cancer risk32) merit further investigation. Although we used adjusted models and propensity-score methods to account for confounding, as with all observational studies, we cannot rule out residual confounding by unrecorded or incomplete variables such as passive smoking or BMI.
Confounding by indication33 is often a problem in pharmacoepidemiology, but it is not obvious how such confounding could create a protective association of statins on cancer-specific and all-cause mortality. It is plausible though that the healthy-user effect34 could explain some of the observed protective effect of statin use. The adjusted analyses are likely to have corrected for some of this healthy-user effect, particularly by accounting for the small differences in stage between statin users and nonusers. Moreover, there was little evidence within our group of colorectal cancer patients, or in a recent cohort of prostate cancer patients,5 that cancer patients receiving statins were markedly healthier than cancer patients not receiving statins (for instance, in our cohort, statin users had higher BMI and more comorbidities).
In conclusion, in this large, population-based colorectal cancer cohort, statin use after diagnosis of colorectal cancer was associated with increased time to cancer-specific death.

Acknowledgment

This study is based partly on data from the Clinical Practice Research Datalink, obtained under license from the United Kingdom Medicines and Healthcare products Regulatory Agency. However, the interpretation and conclusions contained in this study are those of the authors alone.

The JCO Exclusive series features interviews with authors of recent JCO and JOP Original Reports
JCO Exclusive Coverage is a new series of articles on ASCO.org that are designed to provide quick insight and additional author perspectives on select studies recently published in Journal of Clinical Oncology and Journal of Oncology Practice. Based on interviews conducted with the lead or corresponding researchers behind JCO and JOP Original Reports, Exclusive Coverage articles convey the authors’ thoughts on their study's key points and significance for clinical practice. The articles are written in an accessible style designed for quick reading.

To read story: Statins May Reduce Death Among Patients With Colorectal Cancer

The JCO Exclusive Coverage series features interviews with authors
of recent
JCO and JOP Original Reports

JCO Exclusive Coverage is a new series of articles on ASCO.org that are designed to provide quick insight and additional author perspectives on select studies recently published in Journal of Clinical Oncology and Journal of Oncology Practice. Based on interviews conducted with the lead or corresponding researchers behind JCO and JOP Original Reports, Exclusive Coverage articles convey the authors' thoughts on their study's key points and significance for clinical practice. The articles are written in an accessible style designed for quick reading.

Read the story: Statins May Reduce Death Among Patients With Colorectal Cancer

Authors' Disclosures of Potential Conflicts of Interest

The author(s) indicated no potential conflicts of interest.

References

1.
DM Boudreau, O Yu, J Johnson: Statin use and cancer risk: A comprehensive review Expert Opin Drug Saf 9: 603– 621,2010
2.
K Gauthaman, CY Fong, A Bongso: Statins, stem cells, and cancer J Cell Biochem 106: 975– 983,2009
3.
KK Chan, AM Oza, LL Siu: The statins as anticancer agents Clin Cancer Res 9: 10– 19,2003
4.
TP Ahern, L Pedersen, M Tarp, etal: Statin prescriptions and breast cancer recurrence risk: A Danish nationwide prospective cohort study J Natl Cancer Inst 103: 1461– 1468,2011
5.
O Yu, M Eberg, S Benayoun, etal: Use of statins and the risk of death in patients with prostate cancer J Clin Oncol 32: 5– 11,2014
6.
AS Kumar, M Campbell, CC Benz, etal: A call for clinical trials: Lipophilic statins may prove effective in treatment and prevention of particular breast cancer subtypes J Clin Oncol 24: 2127– 2128,2006
7.
T Narisawa, M Morotomi, Y Fukaura, etal: Chemoprevention by pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, of N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats Jpn J Cancer Res 87: 798– 804,1996
8.
LL Kodach, SA Bleuming, MP Peppelenbosch, etal: The effect of statins in colorectal cancer is mediated through the bone morphogenetic protein pathway Gastroenterology 133: 1272– 1281,2007
9.
F Lakha, E Theodoratou, SM Farrington, etal: Statin use and association with colorectal cancer survival and risk: Case control study with prescription data linkage BMC Cancer 12: 487,2012
10.
AG Mace, GA Gantt, M Skacel, etal: Statin therapy is associated with improved pathologic response to neoadjuvant chemoradiation in rectal cancer Dis Colon Rectum 56: 1217– 1227,2013
11.
K Ng, S Ogino, JA Meyerhardt, etal: Relationship between statin use and colon cancer recurrence and survival: Results from CALGB 89803 J Natl Cancer Inst 103: 1540– 1551,2011
12.
H Jick, SS Jick, LE Derby: Validation of information recorded on general practitioner based computerised data resource in the United Kingdom BMJ 302: 766– 768,1991
13.
N Booth-Clibborn, C Packer, A Stevens: Health technology diffusion rates: Statins, coronary stents, and MRI in England Int J Technol Assess Health Care 16: 781– 786,2000
14.
British National Formulary British Medical Association and the Royal Pharmaceutical Society of Great Britain http://www.bnf.org/bnf/index.htm
15.
World Health Organization Collaborating Centre for Drug Statistics Methodology World Health Organization http://www.whocc.no/
16.
LE Levesque, JA Hanley, A Kezouh, etal: Problem of immortal time bias in cohort studies: Example using statins for preventing progression of diabetes BMJ 340: b5087,2010
17.
J Chubak, DM Boudreau, HS Wirtz, etal: Threats to validity of nonrandomized studies of postdiagnosis exposures on cancer recurrence and survival J Natl Cancer Inst 105: 1456– 1462,2013
18.
NF Khan, R Perera, S Harper, etal: Adaptation and validation of the Charlson Index for Read/OXMIS coded databases BMC Fam Pract 11: 1,2010
19.
M Noble, G Wright, C Dibben, etal: Indices of deprivation 2004: Report to the office of the deputy prime minister 2004 London, UK Neighbourhood Renewal Unit
20.
Z Zhou, E Rahme, M Abrahamowicz, etal: Survival bias associated with time-to-treatment initiation in drug effectiveness evaluation: A comparison of methods Am J Epidemiol 162: 1016– 1023,2005
21.
E Leuven, B Sianesi: PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing: Version 4.0.5 http://ideas.repec.org/c/boc/bocode/s432001.html
22.
PC Austin: Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies Pharm Stat 10: 150– 161,2011
23.
PC Austin: The performance of different propensity score methods for estimating marginal hazard ratios Stat Med 32: 2837– 2849,2013
24.
CR Weinberg: Toward a clearer definition of confounding Am J Epidemiol 137: 1– 8,1993
25.
EF Schisterman, SR Cole, RW Platt: Overadjustment bias and unnecessary adjustment in epidemiologic studies Epidemiology 20: 488– 495,2009
26.
RF Logan, J Patnick, C Nickerson, etal: Outcomes of the Bowel Cancer Screening Programme (BCSP) in England after the first 1 million tests Gut 61: 1439– 1446,2012
27.
SF Nielsen, BG Nordestgaard, SE Bojesen: Statin use and reduced cancer-related mortality N Engl J Med 367: 1792– 1802,2012
28.
AA Siddiqui, H Nazario, A Mahgoub, etal: For patients with colorectal cancer, the long-term use of statins is associated with better clinical outcomes Dig Dis Sci 54: 1307– 1311,2009
29.
Study record detail: Statin polyp prevention trial in patients with resected colon cancer United States National Institutes of Health http://clinicaltrials.gov/show/NCT01011478
30.
D Stewart, IT Cunningham, D Hansford, etal: General practitioners' views and experiences of over-the-counter simvastatin in Scotland Br J Clin Pharmacol 70: 356– 359,2010
31.
MU Yood, UB Campbell, KJ Rothman, etal: Using prescription claims data for drugs available over-the-counter (OTC) Pharmacoepidemiol Drug Saf 16: 961– 968,2007
32.
Z Clancy, SW Keith, C Rabinowitz, etal: Statins and colorectal cancer risk: A longitudinal study Cancer Causes Control 24: 777– 782,2013
33.
JL Bosco, RA Silliman, SS Thwin, etal: A most stubborn bias: No adjustment method fully resolves confounding by indication in observational studies J Clin Epidemiol 63: 64– 74,2010
34.
WH Shrank, AR Patrick, MA Brookhart: Healthy user and related biases in observational studies of preventive interventions: A primer for physicians J Gen Intern Med 26: 546– 550,2011

Appendix

Table A1. Association Between Statin Usage (by type) After Cancer Diagnosis and Cancer-Specific Death in Patients With Colorectal Cancer
Medication Use After Diagnosis Cancer-Specific Mortality All Patients Person Years Unadjusted HR (n = 7,657) 95% CI P Adjusted HR* (n = 7,657) 95% CI P Fully Adjusted HR (n = 6,178) 95% CI P
Simvastatin use                        
    No 1,445 5,544 24,145 1.00     1.00     1.00    
    Yes 238 2,113 6,670 0.71 0.62 to 0.81 < .001 0.71 0.61 to 0.83 < .001 0.72 0.61 to 0.85 < .001
Atorvastatin use                        
    No 1,575 6,907 27,914 1.00     1.00     1.00    
    Yes 108 750 2,903 0.77 0.64 to 0.94 .01 0.81 0.66 to 0.99 .04 0.91 0.73 to 1.13 .38
Pravastatin                        
    No 1,661 7,474 30,165 1.00     1.00     1.00    
    Yes 22 183 652 0.76 0.50 to 1.16 .20 0.80 0.52 to 1.22 .29 0.79 0.50 to 1.23 .29
Rosuvastatin                        
    No 1,674 7,549 30,445 1.00     1.00     1.00    
    Yes 9 108 372 0.57 0.29 to 1.09 .09 0.57 0.30 to 1.11 .10 0.49 0.22 to 1.10 .08
Fluvastatin                        
    No 1,675 7,622 30,630 1.00     1.00     1.00    
    Yes 8 35 186 1.01 0.50 to 2.01 .99 1.00 0.50 to 2.01 .99 1.23 0.58 to 2.61 .59
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; DDD, daily defined doses; HR, hazard ratio.
*
Adjusted for year of diagnosis, age at diagnosis, sex, stage, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site (colon or rectum), comorbidities before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), and other medication use after diagnosis as time-varying covariates (including low-dose aspirin, ACEIs, and metformin).
Adjusted for all variables in (*) footnote; also adjusted for grade, deprivation (in fifths), and smoking before diagnosis in individuals without missing values.
Medication use modeled as a time-varying covariate with an individual considered to be a nonuser in the first 6 months after first medication use (12th prescription or 365th DDD) and a user after this time; excludes deaths in the year after cancer diagnosis.
Table A2. Association Between Statin Usage (by type) After Cancer Diagnosis and Death From Any Cause in Patients With Colorectal Cancer
Medication Use After Diagnosis All-Cause Mortality All Patients Person Years Unadjusted HR (n = 7,657) 95% CI P Adjusted HR* (n = 7,657) 95% CI P Fully Adjusted HR (n = 6,178) 95% CI P
Simvastatin                        
    No 2,149 5,544 24,146 1.00     1.00     1.00    
    Yes 492 2,113 6,670 0.89 0.81 to 0.98 .02 0.77 0.69 to 0.86 < .001 0.79 0.70 to 0.90 < .001
Atorvastatin                        
    No 2,438 6,907 27,914 1.00     1.00     1.00    
    Yes 203 750 2902 0.86 0.74 to 0.99 .04 0.80 0.69 to 0.93 .004 0.84 0.72 to 099 .04
Pravastatin                        
    No 2,601 7,474 30,165 1.00     1.00     1.00    
    Yes 40 183 652 0.78 0.57 to 1.06 .11 0.71 0.52 to 0.97 .03 0.65 0.46 to 0.91 .01
Rosuvastatin                        
    No 2,621 7,549 30,445 1.00     1.00     1.00    
    Yes 20 108 372 0.69 0.45 to 1.08 .10 0.65 0.42 to 1.00 .05 0.61 0.36 to 1.01 .06
Fluvastatin                        
    No 2,628 7,622 30,630 1.00     1.00     1.00    
    Yes 13 35 186 0.90 0.52 to 1.55 .70 0.82 0.47 to 1.42 .48 1.00 0.57 to 1.78 .99
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; DDD, daily defined doses; HR, hazard ratio.
*
Adjusted for year of diagnosis, age at diagnosis, sex, stage, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site (colon or rectum), comorbidities before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), and other medication use after diagnosis as time-varying covariates (including low-dose aspirin, ACEIs, and metformin).
Adjusted for all variables in (*) footnote; also adjusted for grade, deprivation (in fifths), and smoking before diagnosis in individuals without missing values.
Medication use modeled as a time varying covariate. An individual was considered a nonuser prior to 6 months after first medication usage and a user after this time, excludes deaths in the year after cancer diagnosis.
Table A3. Association Between Statin Use (after diagnosis) and Cancer-Specific Mortality in Patients With Colorectal Cancer, Stratifying by Low-Dose Aspirin Use (after diagnosis)
Medication Usage After Diagnosis Cancer-Specific Mortality All Patients Person Years Unadjusted HR 95% CI P Fully Adjusted HR* 95% CI P
No aspirin and no statin use 1,122 4,097 18,310 1.00   1.00  
Aspirin use, but no statin use 215 898 3,460 1.11 0.95 to 1.28 .18 1.06 0.90 to 1.27 .49
No aspirin use, but statin use 131 1,016 3,632 0.67 0.56 to 0.80 < .001 0.70 0.57 to 0.86 .001
Aspirin and statin use 215 1,646 5,414 0.77 0.66 to 0.89 < .001 0.78 0.65 to 0.94 .009
Test for interaction between statin and aspirin use           .79     .74
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; HR, hazard ratio.
*
Adjusted model contains all variables in main analysis: year of diagnosis, age at diagnosis, sex, stage, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, site (colon or rectum), comorbidities before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), and other medication use after diagnosis as time-varying covariates (including ACEIs and metformin), grade, deprivation (in fifths), and smoking before diagnosis in individuals without missing values.
Table A4. Characteristics of Statin-User Group and Propensity Score–Matched Control Group
Characteristic Statin-User Group Propensity-Matched Control Group
No. of Patients % No. of Patients %
Year of diagnosis        
    1998-2000 46 5 83 8
    2001-2003 189 19 190 19
    2004-2006 370 36 280 27
    2007-2009 415 41 467 46
Age at diagnosis, years        
    < 50 11 1 34 3
    50-59 81 8 99 10
    60-69 318 31 238 23
    70-79 429 42 371 36
    80-89 175 17 257 25
    ≥ 90 6 1 21 2
Male sex 602 59 589 58
Stage        
    1 180 18 173 17
    2 431 42 421 41
    3 409 40 426 42
Grade        
    Well 58 6 50 5
    Moderate 818 80 820 80
    Poor 144 14 150 15
Treatment within 6 months of cancer diagnosis        
    Surgery 978 96 966 95
    Chemotherapy 271 27 269 26
    Radiotherapy 106 10 129 13
Smoking status before cancer diagnosis        
    Nonsmoker 505 49 486 48
    Former smoker 401 39 430 42
    Current smoker 114 11 104 10
Alcohol consumption before diagnosis        
    Never 115 11 157 15
    Ever 737 72 674 66
    Missing 168 16 189 19
BMI before diagnosis, kg/m2        
    Mean 27.3 26.9    
    SD 4.7 4.8    
    Underweight, < 18.5 13 1 20 2
    Normal, 18.5 to 25 274 27 295 29
    Overweight, 25-30 387 38 371 37
    Obese, > 30 227 22 205 20
    Missing 119 12 129 13
Deprivation fifth        
    First (least deprived) 252 25 254 25
    Second 228 22 227 22
    Third 214 21 225 22
    Fourth 196 19 185 18
    Fifth (most deprived) 130 13 129 13
Comorbidities before cancer diagnosis        
    Cerebrovascular disease 98 10 96 9
    Chronic pulmonary disease 174 17 178 17
    Congestive heart disease 46 5 46 5
    Diabetes 192 19 200 20
    Myocardial infarction 77 8 88 9
    Peptic ulcer disease 70 7 75 7
    Peripheral vascular disease 62 6 65 6
    Renal disease 85 8 89 9
Medication after diagnosis in exposure period        
    Low-dose aspirin use 422 41 448 44
    ACE use 308 30 340 33
    Metformin use 90 9 86 8
Abbreviations: ACE, angiotensin-converting enzyme; BMI, body-mass index; SD, standard deviation.
Table A5. Nested Case-Control Analysis of the Association Between Statin Use and Cancer-Specific Mortality in Patients With Colorectal Cancer
Statins After Diagnosis (No. of prescriptions) Colorectal Cancer–Specific Deaths Unadjusted OR 95% CI P Adjusted OR* 95% CI P
No. of Cases % No. of Patients %
0 1,323 79.3 5,993 73.6 1.00 Ref cat   1.00 Ref cat  
≥ 1 345 20.7 2,145 26.4 0.72 0.63 to 0.82 < .001 0.73 0.60 to 0.88 < .001
1-11 158 9.5 1,007 12.4 0.70 0.59 to 0.85 < .001 0.76 0.61 to 0.95 .02
≥ 12 187 11.2 1,138 14.0 0.73 0.61 to 0.87 < .001 0.69 0.54 to 0.87 .002
NOTE. The nested case-control analysis was conducted in cases who died as a result of colorectal cancer and were matched by age (in 5-year intervals), year of cancer diagnosis (in 2-year intervals), sex, and site (colon or rectum and rectosigmoid junction) to up to five colorectal cancer risk-set controls who lived at least as long after their cancer diagnosis. The exposure period was from colorectal cancer diagnosis to 6 months before cancer-specific death in cases and for a period of identical duration from diagnosis in matched controls. Conditional logistic regression was then used to calculate corresponding odds ratios and 95% CIs for statin use.
Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; OR, odds ratios; Ref cat, reference category.
*
Matched by age at diagnosis, year of diagnosis, sex, and type (colon or rectum) and adjusted for stage, grade, surgery within 6 months, radiotherapy within 6 months, chemotherapy within 6 months, deprivation (in fifths), comorbidities before diagnosis (including cerebrovascular disease, chronic pulmonary disease, congestive heart disease, diabetes, myocardial infarction, peptic ulcer disease, peripheral vascular disease, and renal disease), other medication use in the exposure period (including low-dose aspirin, ACEIs, and metformin), and smoking before diagnosis.

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 3177 - 3183
PubMed: 25092779

History

Published online: August 04, 2014
Published in print: October 01, 2014

Permissions

Request permissions for this article.

Authors

Affiliations

Chris R. Cardwell [email protected]
All authors: Queen's University Belfast, Belfast, United Kingdom.
Blanaid M. Hicks
All authors: Queen's University Belfast, Belfast, United Kingdom.
Carmel Hughes
All authors: Queen's University Belfast, Belfast, United Kingdom.
Liam J. Murray
All authors: Queen's University Belfast, Belfast, United Kingdom.

Notes

Corresponding author: Chris R. Cardwell, PhD, Institute of Clinical Sciences, Block B, Queen's University Belfast, Royal Victoria Hospital, Belfast, BT12 6BA, United Kingdom; e-mail: [email protected].

Author Contributions

Conception and design: Chris R. Cardwell, Carmel Hughes, Liam J. Murray
Collection and assembly of data: Chris R. Cardwell, Carmel Hughes, Liam J. Murray
Data analysis and interpretation: Chris R. Cardwell, Blanaid M. Hicks, Carmel Hughes, Liam J. Murray
Manuscript writing: All authors
Final approval of manuscript: All authors

Disclosures

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Funding Information

Supported by a United Kingdom National Institute for Health Research Career Development Fellowship (C.R.C.) funded by the Health and Social Care Research and Development (Public Health Agency, Northern Ireland), which also funded access to the Clinical Practice Research Database dataset; also funded by a Northern Ireland Department of Education and Learning PhD studentship (B.M.H.).

Metrics & Citations

Metrics

Altmetric

Citations

Article Citation

Download Citation

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format





Download article citation data for:
Chris R. Cardwell, Blanaid M. Hicks, Carmel Hughes, Liam J. Murray
Journal of Clinical Oncology 2014 32:28, 3177-3183

View Options

View options

PDF

View PDF

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login

Purchase Options

Purchase this article to get full access to it.

Purchase this Article

Subscribe

Subscribe to this Journal
Renew Your Subscription
Become a Member

Media

Figures

Other

Tables

Share

Share

Share article link

Share