Colorectal Cancer-specific Deaths Research Articles

Long-Term Usage of Proton Pump Inhibitors Associated with Prognosis in Patients with Colorectal Cancer.

The dose-response effect of proton pump inhibitors on colorectal cancer prognosis is still under exploration. This population-based study in Taiwan was designed to examine the effect of proton pump inhibitors on overall death, colorectal cancer-specific death, and recurrence in colorectal cancer patients with different cumulative proton pump inhibitor dose levels. This cohort study was based on the Taiwan Cancer Registry and Taiwan National Health Insurance Research Database from 2005 to 2020. After frequency matching with a 1:1 ratio, a total of 20,889 users with proton pump inhibitors and 20,889 without proton pump inhibitors were analyzed. The cumulative defined daily dose level of proton pump inhibitor was stratified to explore the dose-response relationship. A proton pump inhibitor exposure cumulative defined daily dose > 60 after colorectal cancer diagnosis had higher risk of all-cause death than non-proton pump inhibitor users with adjusted hazard ratios of 1.10 (95% CIs: 1.04-1.18). For recurrence, a proton pump inhibitor exposure cumulative defined daily dose > 60 had reduced recurrence risk with an adjusted hazard ratio of 0.84 (95% CIs: 0.76-0.93). This study demonstrated that the long-term use of proton pump inhibitors in patients with colorectal cancer was associated with an increased risk of death that related to the proton pump inhibitor exposure cumulative defined daily dose > 60 and had different dose-response effect in various dose level.

Adherence to the World Cancer Research Fund/American Institute for Cancer Research Cancer Prevention Recommendations and Colorectal Cancer Survival.

Patients with cancer are recommended to follow cancer prevention guidelines due to inadequate evidence for specific recommendations for cancer survivors. We examined whether diet and lifestyle scores measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines were associated with colorectal cancer-specific and overall mortality among 1,491 patients with colorectal cancer in two prospective cohorts. Cox proportional hazards regression models were used to calculate the multivariable-adjusted HRs and 95% confidence intervals (CI). During a median follow-up of 7.92 years, there were 641 deaths (179 colorectal cancer-specific deaths). Patients in the highest quartile of the post-diagnostic WCRF/AICR lifestyle score including diet, body mass index (BMI), and physical activity had a 24% lower risk (HR = 0.76, 95% CI: 0.49-1.18) of colorectal cancer-specific mortality and a 37% lower risk (HR = 0.63, 95% CI: 0.50-0.78) of overall mortality compared with the lowest quartile. When BMI was not included in the lifestyle score due to potential disease-related weight loss, stronger inverse associations were observed for both colorectal cancer-specific and overall mortality for the same comparison (colorectal cancer-specific: HR = 0.50, 95% CI: 0.32-0.79; overall: HR = 0.59, 95% CI: 0.47-0.75). The post-diagnostic WCRF/AICR diet score was not statistically significantly associated with either colorectal cancer-specific or overall mortality. Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with improved survival in patients with colorectal cancer. This study provides support for patients with colorectal cancer to follow cancer prevention recommendations after diagnosis. Future studies on cancer survivors will continue to contribute to evidence-based diet and lifestyle recommendations for patients with cancer.

Estimating Population-Based Recurrence Rates of Colorectal Cancer over Time in the United States.

Population-based metastatic recurrence rates for patients diagnosed with nonmetastatic colorectal cancer cannot be estimated directly from population-based cancer registries because recurrence information is not reported. We derived population-based colorectal cancer recurrence rates using disease-specific survival data based on our understanding of the colorectal cancer recurrence-death process. We used a statistical continuous-time multistate survival model to derive population-based annual colorectal cancer recurrence rates from 6 months to 10 years after colorectal cancer diagnosis using relative survival data from the Surveillance, Epidemiology, and End Results Program. The model was based on the assumption that, after 6 months of diagnosis, all colorectal cancer-related deaths occur only in patients who experience a metastatic recurrence first, and that the annual colorectal cancer-specific death rate among patients with recurrence was the same as in those diagnosed with de novo metastatic disease. We allowed recurrence rates to vary by post-diagnosis time, age, stage, and location for two diagnostic time periods. In patients diagnosed in 1975-1984, annual recurrence rates 6 months to 5 years after diagnosis ranged from 0.054 to 0.060 in stage II colon cancer, 0.094 to 0.105 in stage II rectal cancer, and 0.146 to 0.177 in stage III colorectal cancer, depending on age. We found a statistically significant decrease in colorectal cancer recurrence among patients diagnosed in 1994-2003 compared with those diagnosed in 1975-1984 for 6 months to 5 years after diagnosis (hazard ratios between 0.43 and 0.70). We derived population-based annual recurrence rates for up to 10 years after diagnosis using relative survival data. Our estimates can be used in decision-analytic models to facilitate analyses of colorectal cancer interventions that are more generalizable.

Post-diagnosis dietary insulinemic potential and survival outcomes among colorectal cancer patients

BackgroundThe empirical dietary index for hyperinsulinemia (EDIH) score is a validated food-based dietary score that assesses the ability of whole-food diets to predict plasma c-peptide concentrations. Although the EDIH has been extensively applied and found to be predictive of risk of developing major chronic diseases, its influence on cancer survival has not been evaluated. We applied the EDIH score in a large cohort of colorectal cancer patients to assess the insulinemic potential of their dietary patterns after diagnosis and determine its influence on survival outcomes.MethodsWe calculated EDIH scores to assess the insulinemic potential of post-diagnosis dietary patterns and examined survival outcomes in a sample of 1718 stage I-III colorectal cancer patients in the Nurses’ Health Study and Health Professionals Follow-up Study cohorts. Multivariable-adjusted Cox regression was applied to compute hazard ratios (HR) and 95% confidence intervals (CI) for colorectal cancer-specific mortality and all-cause mortality. We also examined the influence of change in diet from pre- to post-diagnosis period, on mortality.ResultsDuring a median follow-up of 9.9 years, there were 1008 deaths, which included 272 colorectal cancer-specific deaths (27%). In the multivariable-adjusted analyses, colorectal cancer patients in the highest compared to lowest EDIH quintile, had a 66% greater risk of dying from colorectal cancer: HR, 1.66; 95% CI, 1.03, 2.69; and a 24% greater risk of all-cause death: HR, 1.24; 95%CI, 0.97, 1.58. Compared to patients who consumed low insulinemic diets from pre- to post-diagnosis period, patients who persistently consumed hyperinsulinemic diets were at higher risk of colorectal cancer death (HR,1.51; 95%CI, 0.98, 2.32) and all-cause death (HR, 1.31; 95%CI, 1.04, 2.64).ConclusionOur findings suggest that a hyperinsulinemic dietary pattern after diagnosis of colorectal cancer is associated with poorer survival. Interventions with dietary patterns to reduce insulinemic activity and impact survivorship are warranted.

Risk factors and predictors of lymph nodes metastasis and distant metastasis in newly diagnosed T1 colorectal cancer.

BackgroundLymph nodes metastasis (LNM) and distant metastasis (DM) are important prognostic factors in colorectal cancer (CRC) and determine the following treatment approaches. We aimed to find clinicopathological factors associated with LNM and DM, and analyze the prognosis of CRC patients with T1 stage.MethodsA total of 17 516 eligible patients with T1 CRC were retrospectively enrolled in the study based on the Surveillance, Epidemiology, and End Results (SEER) database during 2004‐2016. Logistic regression analysis was performed to identify risk factors for LNM and DM. Unadjusted and adjusted Cox proportional hazard models were used to identify prognostic factors for overall survival. We performed the cumulative incidence function (CIF) to further determine the prognostic role of LNM and DM in colorectal cancer‐specific death (CCSD). LNM, DM, and OS nomogram were constructed based on these models and evaluated by the C‐index and calibration plots for discrimination and accuracy, respectively. The clinical utility of the nomograms was measured by decision curve analyses (DCAs) and subgroups with different risk scores.ResultsTumor grade, mucinous adenocarcinoma, and age accounted for the first three largest proportion among the LNM nomogram scores (all, P < .001), whereas N stage, carcinoembryonic antigen (CEA), and tumor size occupied the largest percentage in DM nomogram (all, P < .001). OS nomogram was formulated to visually to predict 3‐, 5‐, and 10‐ year overall survivals for patients with T1 CRC. The calibration curves showed an effectively predictive accuracy of prediction nomograms, of which the C‐index were 0.666, 0.874, and 0.760 for good discrimination, respectively. DCAs and risk subgroups revealed the clinical effectiveness of these nomograms.ConclusionsNovel population‐based nomograms for T1 CRC patients could objectively and accurately predict the risk of LNM and DM, as well as OS for different stages. These predictive tools may help clinicians to make individual clinical decisions, before clinical management.

The effect of using fecal testing after a negative sigmoidoscopy on the risk of death from colorectal cancer.

ObjectiveTo examine whether receiving a fecal occult blood test after a negative sigmoidoscopy reduced mortality from colorectal cancer.MethodsWe used a nested case–control design with incidence-density matching in historical cohorts of 1,877,740 50–90-year-old persons during 2006–2012, in an integrated health-system setting. We selected 1758 average risk patients who died from colorectal cancer and 3503 matched colorectal cancer-free persons. Colorectal cancer-specific death was ascertained from cancer and mortality registries. Screening histories were determined from electronic and chart–audit clinical data in the 5- to 10-year period prior to the reference date. We evaluated receipt of subsequent fecal occult blood test within five years of the reference date among patients with negative sigmoidoscopy two to six years before the reference date.ResultsOf the 5261 patients, 831 patients (204 colorectal cancer deaths/627 controls) had either negative sigmoidoscopy only (n = 592) or negative sigmoidoscopy with subsequent screening fecal occult blood test (n = 239). Fifty-six (27.5%) of the 204 patients dying of colorectal cancer and 183 (29.2%) of the 627 colorectal cancer-free patients received fecal occult blood test following a negative sigmoidoscopy. Conditional regressions found no significant association between fecal occult blood test receipt and colorectal cancer death risk, overall (adjusted odds ratio = 0.93, confidence interval: 0.65–1.33), or for right (odds ratio = 1.02, confidence interval: 0.65–1.60) or left-colon/rectum (odds ratio = 0.77, confidence interval: 0.39–1.52) cancers. Similar results were obtained in sensitivity analyses with alternative exposure ascertainment windows or timing of fecal occult blood test.ConclusionsOur results suggest that receipt of at least one fecal occult blood test during the several years after a negative sigmoidoscopy did not substantially reduce mortality from colorectal cancer.

Abnormal Stool Blood Tests and Colorectal Cancer Mortality in a Large United States Cohort

Abstract Our aim was to examine the association between fatal colorectal cancer (CRC) and time to colonoscopy among individuals who underwent diagnostic colonoscopy after abnormal stool blood test (SBT) in a cohort of United States Veterans. Methods: We performed a cohort study of Veterans aged 50–75 years, with an abnormal SBT using the Veterans Health Administration's (VA) national electronic health record data during the years 1999 and 2010. Colonoscopy receipt was ascertained using current procedural terminology codes after abnormal SBT. The study outcome, CRC death, was defined through National Death Index cause-specific mortality data. We followed patients through CRC-related death, other death, or until December 31, 2015. Multivariable Cox proportional hazards modeling was used to generate CRC-specific mortality hazard ratios (HRs) and 95% confidence intervals (CI) for 3-month colonoscopy intervals, with 3–6 months as the reference. Models were adjusted for age, sex, race/ethnicity, smoking, diabetes, body mass index, and Charlson Comorbidity Index. Results: We included 222,004 patients with abnormal SBTs; the average age was 63 with a standard deviation of 7.2 years, 97% were male, 72% were Non-Hispanic White and 20% were Black. Of the 222,004 patients, 69% completed diagnostic colonoscopy within 12 months of abnormal SBT, 4% were diagnosed with CRC, and 1% died of CRC specific death. Compared to patients with a colonoscopy at 3–6 months (standard of care), CRC-related mortality risk was significantly higher for patients with colonoscopies at 0–3 months (HR = 1.29; 95% CI, 1.14–1.47), 18–21 months (HR = 1.57; 95% CI, 1.19–2.06), and 21–24 months (HR = 1.46; 95% CI, 1.07–1.97). No significant increase in mortality risk was shown for 6–9 month, 9–12 month, 12–15 month, 15–18 months, and 24+ month intervals. Conclusion: Time to colonoscopy plays a significant role in CRC death after abnormal SBT. Compared to a colonoscopy performed during a 3–6-month window, a colonoscopy performed outside of the 15-month window had a higher risk for mortality. Given the impact of timely diagnostic colonoscopy on CRC mortality, development of interventions to increase timely diagnostic follow-up after abnormal SBT are essential to CRC outcome improvement.

Competing risks analysis of the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer.

Despite numerous reports over three decades, the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer remains controversial. This cohort study used competing risks statistical methods to examine the association between transfusion and recurrence and colorectal cancer-specific death after potentially curative and noncurative resection. A hospital database provided prospectively recorded clinical, operative and follow-up information. All surviving patients were followed for at least 5years. Data were analysed by multivariable competing risks regression. From 2575 patients in the period 1995-2010 inclusive, after exclusions, 2334 remained for analysis. Among 1941 who had a potentially curative resection and 393 who had a noncurative resection the transfusion rates were 24.9% and 33.6%, respectively. After potentially curative resection there was no significant bivariate association between transfusion and recurrence (HR 0.93, CI 0.74-1.16, P=0.499) or between transfusion and colorectal cancer-specific death (HR 1.04, CI 0.82-1.33, P=0.753). After noncurative resection there was no significant association between transfusion and cancer-specific death (HR 0.93, CI 0.73-1.19, P=0.560). Multivariable models showed no material effect of potential confounder variables on these results. The competing risks findings in this study showed no significant association between perioperative transfusion and recurrence or colorectal cancer-specific death.

Follow-up strategies for patients treated for non-metastatic colorectal cancer

Follow-up strategies for patients treated for non-metastatic colorectal cancer

Impact of old age on resectable colorectal cancer outcomes.

ObjectiveThis study was performed to identify a reasonable cutoff age for defining older patients with colorectal cancer (CRC) and to examine whether old age was related with increased colorectal cancer-specific death (CSD) and poor colorectal cancer-specific survival (CSS).MethodsA total of 76,858 eligible patients from the surveillance, epidemiology, and end results (SEER) database were included in this study. The Cox proportional hazard regression model and the Chow test were used to determine a suitable cutoff age for defining the older group. Furthermore, a propensity score matching analysis was performed to adjust for heterogeneity between groups. A competing risk regression model was used to explore the impact of age on CSD and non-colorectal cancer-specific death (non-CSD). Kaplan–Meier survival curves were plotted to compare CSS between groups. Also, a Cox regression model was used to validate the results. External validation was performed on data from 1998 to 2003 retrieved from the SEER database.ResultsBased on a cutoff age of 70 years, the examined cohort of patients was classified into a younger group (n = 51,915, <70 years of old) and an older group (n = 24,943, ≥70 years of old). Compared with younger patients, older patients were more likely to have fewer lymph nodes sampled and were less likely to receive chemotherapy and radiotherapy. When adjusted for other covariates, age-dependent differences of 5-year CSD and 5-year non-CSD were significant in the younger and older groups (15.84% and 22.42%, P < 0.001; 5.21% and 14.21%, P < 0.001). Also an age of ≥70 years remained associated with worse CSS comparing with younger group (subdistribution hazard ratio, 1.51 95% confidence interval (CI) [1.45–1.57], P < 0.001). The Cox regression model as a sensitivity analysis had a similar result. External validation also supported an age of 70 years as a suitable cutoff, and this older group was associated with having reduced CSS and increased CSD.ConclusionsA total of 70 is a suitable cutoff age to define those considered as having elderly CRC. Elderly CRC was associated with not only increased non-CSD but also with increased CSD. Further research is needed to provide evidence of whether cases of elderly CRC should receive stronger treatment if possible.

Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses' health study and health professionals follow-up study.

Although experimental evidence suggests calcium-sensing receptor (CASR) as a tumor-suppressor, the prognostic role of tumor CASR expression in colorectal carcinoma remains unclear. We hypothesized that higher tumor CASR expression might be associated with improved survival among colorectal cancer patients. We evaluated tumor expression levels of CASR by immunohistochemistry in 809 incident colorectal cancer patients within the Nurses' Health Study and the Health Professionals Follow-up Study. We used Cox proportional hazards regression models to estimate multivariable hazard ratio (HR) for the association of tumor CASR expression with colorectal cancer-specific and all-cause mortality. We adjusted for potential confounders including tumor biomarkers such as microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, expressions of PTGS2, VDR and CTNNB1 and mutations of KRAS, BRAF and PIK3CA. There were 240 colorectal cancer-specific deaths and 427 all-cause deaths. The median follow-up of censored patients was 10.8 years (interquartile range: 7.2, 15.1). Compared with patients with no or weak expression of CASR, the multivariable HRs for colorectal cancer-specific mortality were 0.80 [95% confidence interval (CI): 0.55-1.16] in patients with moderate CASR expression and 0.50 (95% CI: 0.32-0.79) in patients with intense CASR expression (p-trend = 0.003). The corresponding HRs for overall mortality were 0.85 (0.64-1.13) and 0.81 (0.58-1.12), respectively. Higher tumor CASR expression was associated with a lower risk of colorectal cancer-specific mortality. This finding needs further confirmation and if confirmed, may lead to better understanding of the role of CASR in colorectal cancer progression.

End-of-life prescribing of aspirin in patients with breast or colorectal cancer

ObjectivesThe aim of this study was to evaluate the influence of an approaching cancer death on end-of-life aspirin use, a frequently prescribed medication for cardiovascular disease prevention.MethodsThis study was conducted...

Abstract 3270: Association of low-carbohydrate diet and macronutrient intake with colorectal cancer survival

Abstract Background: Metabolic reprogramming is a hallmark of cancer characterized by the switch from oxidative phosphorylation to aerobic glycolysis. Accumulating evidence suggests that reducing dietary carbohydrate intake may ameliorate metabolic reprogramming and suppress proliferation of tumor cells. However, the clinical benefit of carbohydrate restriction remains unknown. Objective: To examine the low-carbohydrate diet and macronutrient intake after colorectal cancer diagnosis in relation to mortality among stage I-III patients. Methods: We evaluated data on 1,303 colorectal cancer patients in the Nurses’ Health Study (1980-2012) and Health Professionals Follow-up Study (1986-2012) who completed a validated food frequency questionnaire at least one year after diagnosis. An overall low-carbohydrate-diet score was created based on the percentage of energy as carbohydrate, fat, and protein (a higher score reflects a higher intake of fat and protein and a lower intake of carbohydrate). We also created an animal- and vegetable-based low-carbohydrate-diet score on the basis of the intake from animal and vegetable food sources, respectively. We prospectively assessed the association of the low-carbohydrate-diet score and macronutrient intake with CRC-specific and overall mortality using Cox proportional hazards regression. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated after adjusting for a variety of potential confounding factors, including age, sex, cancer stage, grade of differentiation, subsite, alcohol use, smoking status, physical activity, body mass index, regular use of aspirin, total calorie, and intake of folate, calcium, fiber, processed red meat, and vitamin D. Results: We observed 584 deaths, of which 132 were classified as colorectal cancer-specific deaths over a median of 10 years of follow-up. No association was found for overall and animal-based low-carbohydrate-diet score with colorectal cancer-specific mortality, with the HR comparing the highest to the lowest quartiles of 0.92 (95% CI, 0.77-1.09, P for trend=0.33) for the overall score and 0.99 (95% CI, 0.84-1.17, P for trend=0.94) for the animal-based score. In contrast, vegetable-based low-carbohydrate-diet score was associated with lower colorectal cancer-specific mortality (HR, 0.67, 95% CI, 0.53-0.85, P for trend&amp;lt;0.001). Replacement of carbohydrate with fat, particularly vegetable fat, was associated with lower mortality of colorectal cancer (HR per 10%-energy substitution, 0.49, 95% CI, 0.29-0.85, P for trend=0.01). Similar results were found for all-cause mortality. Conclusion: Among patients with colorectal cancer, replacing carbohydrates with vegetable fat may reduce the risk of all-cause and colorectal cancer-specific mortality. Citation Format: Mingyang Song, Kana Wu, Jeffrey Meyerhardt, Omer Yilmaz, Shuji Ogino, Charles Fuchs, Edward Giovannucci, Andrew T. Chan. Association of low-carbohydrate diet and macronutrient intake with colorectal cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3270. doi:10.1158/1538-7445.AM2017-3270

Competing risks analysis of microsatellite instability as a prognostic factor in colorectal cancer

Despite an extensive literature suggesting that high microsatellite instability (MSI-H) enhances survival and protects against recurrence after colorectal cancer resection, such effects remain controversial as many studies show only a weak bivariate association or no multivariable association with outcome. This study examined the relationship between MSI status and colorectal cancer outcomes with adjustment for death from other causes as a competing risk. A hospital database of patients following colorectal cancer resection was interrogated for clinical, operative, pathology, adjuvant therapy and follow-up information. MSI-H status was determined by immunohistochemistry for mismatch repair protein deficiency. The cumulative incidence of recurrence and colorectal cancer-specific death was evaluated by competing risks methods. Among 1009 patients who had a resection between August 2002 and December 2008, and were followed to at least December 2013, there were 114 (11·3 per cent) with MSI-H (72·8 per cent aged at least 70 years; 63·2 per cent women). After potentially curative resection, with adjustment for non-colorectal cancer death as a competing risk and adjustment for 22 clinical, operative and pathological variables, there was no association between MSI-H and recurrence (hazard ratio (HR) 0·81, 95 per cent c.i. 0·42 to 1·57) or colorectal cancer-specific death (HR 0·73, 0·39 to 1·35) in this patient population. For palliative resections, there was no association between MSI-H and colorectal cancer-specific death (HR 0·65, 0·21 to 2·04). MSI-H was associated with non-colorectal cancer death after both curative (HR 1·55, 1·04 to 2·30) and palliative (HR 3·80, 1·32 to 11·00) resections. Microsatellite instability status was not an independent prognostic variable in these patients.

Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women.

Background: Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study.Methods: Using paraffin-embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer-specific death associated with each composite score.Results: CTL and GZMB composite scores were positively correlated (r = 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, or BRAF mutation status. HRs (95% CI) were 0.53 (0.38-0.75; Ptrend = 0.0004) and 0.66 (0.51-0.86; Ptrend = 0.002) for all-cause death, respectively, and 0.30 (0.18-0.51; Ptrend < 0.0001) and 0.41 (0.27-0.63; Ptrend < 0.0001) for colorectal cancer-related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer-related death.Conclusions: Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients.Impact: Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage. Cancer Epidemiol Biomarkers Prev; 26(4); 622-31. ©2016 AACR.

Statin use and survival in colorectal cancer: Results from a population-based cohort study and an updated systematic review and meta-analysis

BackgroundThe aim of this study was to investigate the association between statin use and survival in a population-based colorectal cancer (CRC) cohort and perform an updated meta-analysis to quantify the magnitude of any association. MethodsA cohort of 8391 patients with newly diagnosed Dukes’ A-C CRC (2009–2012) was identified from the Scottish Cancer Registry. This cohort was linked to the Prescribing Information System and the National Records of Scotland Death Records (until January 2015) to identify 1064 colorectal cancer-specific deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by statin use were calculated using time dependent Cox regression models. The systematic review included relevant studies published before January 2016. Meta-analysis techniques were used to derive combined HRs for associations between statin use and cancer-specific and overall mortality. ResultsIn the Scottish cohort, statin use before diagnosis (HR=0.84, 95% CI 0.75–0.94), but not after (HR=0.90, 95% CI 0.77–1.05), was associated with significantly improved cancer-specific mortality. The systematic review identified 15 relevant studies. In the meta-analysis, there was consistent (I2=0%,heterogeneity P=0.57) evidence of a reduction in cancer-specific mortality with statin use before diagnosis in 6 studies (n=86,622, pooled HR=0.82, 95% CI 0.79–0.86) but this association was less apparent and more heterogeneous (I2=67%,heterogeneity P=0.03) with statin use after diagnosis in 4 studies (n=19,152, pooled HR=0.84, 95% CI 0.68–1.04). ConclusionIn a Scottish CRC cohort and updated meta-analysis there was some evidence that statin use was associated with improved survival. However, these associations were weak in magnitude and, particularly for post-diagnosis use, varied markedly between studies.

Digoxin use after diagnosis of colorectal cancer and survival: a population-based cohort study.

Digoxin has been shown to affect a number of pathways that are of relevance to cancer, and its use has been associated with increased risks of breast and uterus cancer and, more recently, a 40% increase in colorectal cancer risk. These findings raise questions about the safety of digoxin use in colorectal cancer patients, and, therefore, we investigated whether digoxin use after colorectal cancer diagnosis increased the risk of colorectal cancer-specific mortality. A cohort of 10,357 colorectal cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2,724 colorectal cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted HRs and 95% confidence intervals (CI) were calculated for the association between postdiagnostic exposure to digoxin and colorectal cancer-specific mortality. Overall, 682 (6%) colorectal cancer patients used digoxin after diagnosis. Digoxin use was associated with a small increase in colorectal cancer-specific mortality before adjustment (HR, 1.25; 95% CI, 1.07-1.46), but after adjustment for confounders, the association was attenuated (adjusted HR, 1.10; 95% CI, 0.91-1.34) and there was no evidence of a dose response. In this large population-based colorectal cancer cohort, there was little evidence of an increase in colorectal cancer-specific mortality with digoxin use after diagnosis. These results provide some reassurance that digoxin use is safe in colorectal cancer patients.

Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival

Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas. In contrast, results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia. We tested the hypothesis that higher total folate intake (including food folate and folic acid from fortified foods and supplements) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer. We used rectal and colon cancer cases within the following 2 US prospective cohort studies: the Nurses' Health Study and the Health Professionals Follow-Up Study. Biennial questionnaires were used to gather information on medical history and lifestyle factors, including smoking and alcohol consumption. B-vitamin and methionine intakes were derived from food-frequency questionnaires. Data on tumor molecular characteristics (including microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long interspersed nucleotide element 1 methylation level) were available for a subset of cases. We assessed colorectal cancer-specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models. In 1550 stage I-III colorectal cancer cases with a median follow-up of 14.9 y, we documented 641 deaths including 176 colorectal cancer-specific deaths. No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer-specific mortality (multivariate P-trend ≥ 0.21). In an exploratory molecular pathologic epidemiology survival analysis, there was no significant interaction between one-carbon nutrients or alcohol and any of the tumor molecular biomarkers examined. Higher postdiagnostic intakes of one-carbon nutrients are not associated with the prognosis in stage I-III colorectal cancer. Our findings do not support the hypothesis that higher folate intake after colorectal cancer diagnosis might increase risk of cancer-related death.

Metformin use and survival after colorectal cancer: A population‐based cohort study

Preclinical evidence suggests that metformin could delay cancer progression. Previous epidemiological studies however have been limited by small sample sizes and certain time-related biases. This study aimed to investigate whether colorectal cancer patients with type 2 diabetes who were exposed to metformin had reduced cancer-specific mortality. We conducted a retrospective cohort study of 1,197 colorectal cancer patients newly diagnosed from 1998 to 2009 (identified from English cancer registries) with type 2 diabetes (based upon Clinical Practice Research Datalink, CPRD, prescription and diagnosis records). In this cohort 382 colorectal cancer-specific deaths occurred up to 2012 from the Office of National Statistics (ONS) mortality data. Metformin use was identified from CPRD prescription records. Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% CIs were calculated for the association between post-diagnostic exposure to metformin and colorectal cancer-specific mortality. Overall, there was no evidence of an association between metformin use and cancer-specific death before or after adjustment for potential confounders (adjusted HR 1.06, 95% CI 0.80, 1.40). In addition, after adjustment for confounders, there was also no evidence of associations between other diabetic medications and cancer-specific mortality including sulfonylureas (HR 1.14, 95% CI 0.86, 1.51), insulin use (HR 1.35, 95% CI 0.95, 1.93) or other anti-diabetic medications including thiazolidinediones (HR 0.73, 95% CI 0.46, 1.14). Similar associations were observed by duration of use and for all-cause mortality. This population-based study, the largest to date, does not support a protective association between metformin and survival in colorectal cancer patients.

Prediagnostic intake of dairy products and dietary calcium and colorectal cancer survival--results from the EPIC cohort study.

We investigated whether prediagnostic reported intake of dairy products and dietary calcium is associated with colorectal cancer survival. Data from 3,859 subjects with colorectal cancer (42.1% male; mean age at diagnosis, 64.2 ± 8.1 years) in the European Investigation into Cancer and Nutrition cohort were analyzed. Intake of dairy products and dietary calcium was assessed at baseline (1992-2000) using validated, country-specific dietary questionnaires. Multivariable Cox regression models were used to calculate HR and corresponding 95% confidence intervals (CI) for colorectal cancer-specific death (n = 1,028) and all-cause death (n = 1,525) for different quartiles of intake. The consumption of total dairy products was not statistically significantly associated with risk of colorectal cancer-specific death (adjusted HR Q4 vs. Q1, 1.17; 95% CI, 0.97-1.43) nor that of all-cause death (Q4 vs. Q1, 1.16; 95% CI, 0.98-1.36). Multivariable-adjusted HRs for colorectal cancer-specific death (Q4 vs. Q1) were 1.21 (95% CI, 0.99-1.48) for milk, 1.09 (95% CI, 0.88-1.34) for yoghurt, and 0.93 (95% CI, 0.76-1.14) for cheese. The intake of dietary calcium was not associated with the risk of colorectal cancer-specific death (adjusted HR Q4 vs. Q1, 1.01; 95% CI, 0.81-1.26) nor that of all-cause death (Q4 vs. Q1, 1.01; 95% CI, 0.84-1.21). The prediagnostic reported intake of dairy products and dietary calcium is not associated with disease-specific or all-cause risk of death in patients diagnosed with colorectal cancer. The impact of diet on cancer survival is largely unknown. This study shows that despite its inverse association with colorectal cancer risk, the prediagnostic intake of dairy and dietary calcium does not affect colorectal cancer survival.