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Aim. - This study explores the changes in glucose-lowering drug (GLD) use before and after cancer diagnosis among patients with diabetes. Methods. - New GLD users (1998-2011) living in the Dutch ECR-PHARMO catchment area were selected from the PHARMO Database Network (n = 52,228). Those with a primary cancer diagnosis were considered cases (n = 3281) and matched with eligible controls (n = 12,891) without cancer during follow-up. Conditional logistic regression analysis was used to assess changes in GLD use, such as treatment add-ons, treatments drops and initiation of insulin, for cases compared with controls associated with specific cancer types in four time windows (6-3 and 0-3 months before cancer diagnosis; 0-3 and 3-6 months after cancer diagnosis). Results. - In the 3 months before cancer diagnosis, patients with upper gastrointestinal (GI) cancers (oesophageal, stomach, pancreatic, liver cancers) had higher odds of initiating insulin (OR: 9.3; 95% CI: 3.6-24.1); to a lesser extent, this was also observed in the 3 months prior to that (at 6 months, OR: 3.9; 95% CI: 1.31-2.1). Diagnosis of colorectal (OR: 3.4; 95% CI: 1.4-8.4), pulmonary (OR: 2.5; 95% CI: 1.1-5.4) and upper GI (OR: 13.6; 95% CI: 5.0-36.9) cancers was associated with increased odds of initiating insulin in the 3 months after cancer diagnosis. During all study time windows, the odds of treatment drops were higher for patients with upper GI cancers whereas, for most other cancers, these odds were higher only after a diagnosis of cancer. Conclusion. - The greater odds of initiating insulin during the 6 months prior to diagnosis of upper GI cancers suggest reverse causation. After cancer diagnosis, drops in use of GLDs was commonly seen. (C) 2017 Elsevier Masson SAS. All rights reserved.

Het aantal patienten met diabetes en kanker is de afgelopen jaren sterk toegenomen. Dat merken huisartsen en praktijkondersteuners ook. Voor hen is een belangrijke rol weggelegd in het coordineren van de behandeling en de controle van twee of meer chronische ziekten. Dit artikel schetst daarvoor de wetenschappelijke achtergronden.

WHAT IS KNOWN AND OBJECTIVE: The concomitant use of multiple drugs is common among the general population of elderly. The aim of this study was to provide an overview of which drugs are dispensed to elderly in the year before colon cancer diagnosis and to compare this with cancer-free controls. METHODS: Data from the Eindhoven Cancer Registry were linked to the PHARMO Database Network. Patients with colon cancer aged ≥70 years were included and matched with controls on gender, year of birth and postal code. Proportions of cases and controls with ≥1 dispensing of each WHO ATC-2-level drug during the total year and during each quarter of the year were calculated and differences between cases and controls tested. RESULTS AND DISCUSSION: Proportion of cases with ≥1 drug dispensing was highest for drugs for constipation (cases vs. controls 58% vs. 10%), antithrombotics (42% vs. 33%), drugs for acid-related disorders (35% vs. 22%), antibacterials (34% vs. 24%), agents acting on the renin-angiotensin system (33% vs. 27%), beta-blockers (33% vs. 23%), lipid-modifying agents (29% vs. 22%), diuretics (29% vs. 21%), psycholeptics (25% vs. 18%) and antianaemics (23% vs. 6%). The proportion of cases with ≥1 drug dispensing increased from the first to the last quarter of the year for drugs for constipation (7%-53%), drugs for acid-related disorders (16%-27%), antibacterials (12%-16%), beta-blockers (26%-28%), psycholeptics (15%-19%) and antianaemics (6%-18%). Elevated proportions of cases with ≥1 drug dispensing for several drugs are mostly related to comorbidity, although increasing proportions of cases with ≥1 drug dispensing for certain drugs during the year can be attributed to the incidence of colon cancer. WHAT IS NEW AND CONCLUSION: We have provided insight into which drugs are commonly used in the year preceding colon cancer diagnosis. This may trigger general practitioners and medical specialists to further evaluate the patient.

Background: Metformin, statin and aspirin use seem associated with decreased mortality in cancer patients, though, without adjusting for one another. Independent associations of these drugs with overall mortality after colorectal cancer (CRC) diagnosis within glucose-lowering drugs (GLDs) users were assessed.Methods: Patients starting GLDs before CRC diagnosis (1998–2011) were selected from the Eindhoven Cancer Registry linked with the PHARMO Database Network. The Cox regression model, with time since CRC diagnosis, included time-dependent variables of cumulative exposure to metformin, statins and aspirin after cancer diagnosis and time-dependent ever-never terms for drug exposure.Results: A total of 1043 patients used GLDs before CRC diagnosis; 666 (64%) used metformin, 639 (61%) used statins and 490 (47%) used aspirin after CRC diagnosis. Multivariable analyses revealed that longer cumulative exposure to metformin was not associated with overall mortality (HRCumulative exposure/6 months 1.02; 95% CI 0.97–1.07), whereas the favourable effect of statins increased with cumulative exposure (HRCumulative exposure/6 months 0.93; 95% CI 0.89–0.98). No association between aspirin use and overall mortality was seen (HRCumulative exposure/6 months 0.98; 95% CI 0.93–1.03).Conclusions: No independent association between cumulative exposure to metformin, aspirin and overall mortality was found. Cumulative exposure to statins after CRC diagnosis was associated with lower overall mortality, supporting a drug effect of statins among GLDs users.Keywords: diabetes; cancer; overall mortality; drug exposure

Aims/hypothesisAdherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabolic control and improving prognosis. Because a diagnosis of cancer might have an impact on adherence to medication, this study explored changes in adherence to GLDs following a cancer diagnosis.MethodsAll new users of GLDs between 1998 and 2011 who lived in the Eindhoven Cancer Registry–PHARMO Database Network catchment area were selected. Those with a primary cancer diagnosis during follow-up were considered cases and matched with eligible controls without cancer during follow-up. Medication possession ratio (MPR) was used as indicator for medication adherence. Segmented linear auto-regression analysis with interrupted time series was used to assess changes in MPR for cases compared with controls (i.e. overall trend) due to (any) cancer diagnosis and specific cancer types.ResultsFrom the 52,228 GLD users selected, 3,281 cases with cancer and 12,891 controls without cancer during follow-up were included in the study. In our analyses, before cancer diagnosis the MPR increased by 0.10% per month (95% CI 0.10, 0.10). Besides a significant drop in MPR at the time of cancer diagnosis of −6.3% (95% CI −6.5, −6.0), there was an ongoing, yet lower, monthly decline in MPR (−0.20%; 95% CI −0.21, −0.20) after cancer diagnosis. The largest drops in MPR at the time of cancer diagnosis, in the range of 11–15%, were seen among patients with stage IV disease and gastrointestinal or pulmonary cancers.Conclusions/interpretationOur findings indicate a clear decline in adherence to GLD treatment regimens following a cancer diagnosis. The reason for the decline in MPR needs to be further elucidated.Keywords: Adherence, Cancer, Glucose-lowering drugs

PurposeThe aim of this study was to assess the difference in explained variance of Health-Related Quality of Life (HRQoL) between comorbidity, sociodemographic characteristics and cancer characteristics. This association was assessed among thyroid cancer, colorectal cancer, and (non-)Hodgkin's lymphoma patients.MethodsData from three large population-based surveys on survivors of thyroid cancer, colorectal cancer, and (non-)Hodgkin's lymphoma were used. Cancer-specific HRQoL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) of which physical function, emotional function, fatigue, and pain were included in the analyses. Comorbidity was assessed using the Self-reported Comorbidity Questionnaire. The association between comorbidity and HRQoL was assessed with multivariate linear regression models. Semi-partial R2 was reported to assess the amount of variance in HRQoL explained by comorbidity in comparison with sociodemographic and cancer characteristics.ResultsIn total, 3,792 cancer survivors were included in this analysis. The variance in HRQoL subscales explained by comorbidity was higher compared with sociodemographic and cancer characteristics for physical function (11–17 vs. 2–4 and 1–2 %, respectively) and emotional function (7–17 vs. 1–3 and 1–3 %, respectively), regardless of cancer type. In addition, comorbidity explained 7–20 and 11–13 % of the variance in pain and fatigue, respectively, compared to 0–4 % for both sociodemographic and cancer characteristics. Osteoarthritis and back pain were strongly associated with physical function and pain, while depression was strongly associated with emotional function. Depression and back pain were strongly associated with fatigue.ConclusionsThis study showed that comorbidity explained more variance in physical and emotional function, pain, and fatigue in comparison with sociodemographic and cancer characteristics in cancer survivors, regardless of cancer type. Our findings emphasize the importance of adjusting for the presence of comorbid diseases when assessing HRQoL in cancer survivors.Implication for cancer survivorsCancer survivors suffering from comorbid diseases experience lower levels of health-related quality of life. Clinicians should become more aware of the impact of comorbidity on HRQoL and provide necessary psychological support to assist self-management of comorbid diseases.Keywords: Health-related quality of life, Cancer, Comorbidity, Elderly/ Population-based

Objective The purpose of this study was to investigate the influence of diabetes mellitus (DM) on cancer stage at diagnosis, cancer recurrence, and survival of endometrial cancer (EC) patients and the influence of the treatment of EC on glycaemic control, treatment, and complications of DM. Methods In this retrospective cohort study all 1644 patients with EC newly diagnosed in 2000–2008 and recorded in the population-based Eindhoven Cancer Registry (ECR) were included. In addition, from this total cohort a subcohort was selected for additional data collection and analyses, including 193 EC patients with DM and an age-matched sample of 195 EC patients without DM. Patients with FIGO stage IV as well as non-endometrioid histology were excluded. Results In the total cohort EC patients with DM had a significantly higher age (69 years vs. 64 years), higher FIGO stages and more additional comorbidities compared to EC patients without DM. The 5-year overall survival rate for EC patients with DM was significantly lower than for EC patients without DM (68% vs. 84%). After adjusting for age, stage, period of diagnosis, cardiovascular disease, and treatment, this significant effect of DM on overall mortality persisted (HR 1.4, 95% CI: 1.0–1.8). Subcohort analyses showed that EC patients with DM were diagnosed more often with a higher body mass index (BMI) (34 kg/m 2 vs. 30 kg/m 2 ) and EC was not significantly associated with changes in DM characteristics over time. Although the 5-year overall survival rate for EC patients with DM was significantly lower in the subcohort, for EC-specific mortality ( n = 388) no statistically significant effect of DM was observed after adjustment for FIGO stage (HR = 1.7, 95% CI: 0.7–3.9). Conclusions EC patients with DM compared to those without had worse patient characteristics, a higher FIGO stage, similar recurrence rates and worse overall survival.

BACKGROUND & AIMS: Statin use has been associated with a reduced incidence of colorectal cancer and might also affect survival of patients diagnosed with colon cancer. Statins are believed to inhibit Ras signaling and may also activate the bone morphogenetic protein (BMP) signaling pathway in colorectal cancer cells. We investigated the effects of statins on overall survival of patients with a diagnosis of colon cancer, and whether their effects were associated with changes in KRAS or the BMP signaling pathways.METHODS: Data were derived from the PHARMO database network (Netherlands) and linked to patients diagnosed with colon cancer from 2002 through 2007, listed in the Eindhoven Cancer Registry. We obtained information on causes of death from statistics Netherlands. We constructed a tissue microarray of 999 colon cancer specimens from patients who underwent surgical resection from 2002 through 2008. Survival was analyzed with statin user status after diagnosis as a time-dependent covariate. Multivariable Poisson regression survival models and Cox analyses were used to study the effect of statins on survival. Tumor tissues were analyzed by immunohistochemistry for levels of SMAD4, BMPR1A, BMPR1B, and BMPR2 proteins. Tumor tissues were considered to have intact BMP signaling if they contained SMAD4 plus BMPR1A, BMPR1B, or BMPR2. DNA was isolated from tumor tissues and analyzed by quantitative polymerase chain reaction to detect mutations in KRAS. The primary outcome measures were overall mortality and cancer-specific mortality.RESULTS: In this cohort, 21.0% of the patients (210/999) were defined as statin users after diagnosis of colon cancer. Statin use after diagnosis was significantly associated with reduced risk of death from any cause (adjusted relative risk [RR], 0.67; 95% confidence interval [CI], 0.51-0.87; P = .003) and death from cancer (adjusted RR, 0.66; 95% CI, 0.49-0.89; P = .007). Statin use after diagnosis was associated with reduced risk of death from any cause or from cancer for patients whose tumors had intact BMP signaling (adjusted RR, 0.39; 95% CI, 0.22-0.68; P = .001), but not for patients whose tumors did not have BMP signaling (adjusted RR, 0.81; 95% CI, 0.55-1.21; P = .106; P < .0001 for the interaction). Statin use after diagnosis was not associated with reduced risk of death from any cause or from cancer for patients whose tumors did not contain KRAS mutations (adjusted RR, 0.81; 95% CI, 0.56-1.18; P = .273) or whose tumors did have KRAS mutations (adjusted RR, 0.59; 95% CI 0.35-1.03; P = .062; P = .90 for the interaction).CONCLUSIONS: In an analysis of 999 patients with a diagnosis of colon cancer, we associated statin with reduced risk of death from any cause or from cancer. The benefit of statin use is greater for patients whose tumors have intact BMP signaling, independent of KRAS mutation status. Randomized controlled trials are required to confirm these results.

Several studies have suggested an association between use of metformin and an increased overall survival in patients diagnosed with pancreatic cancer, however with several important methodological limitations. The aim of the study was to assess the association between overall survival, pancreatic cancer, and metformin use.A retrospective cohort study of 1111 patients with pancreatic cancer was conducted using data from The Netherlands Comprehensive Cancer Organization (1998-2011). Data were linked to the PHARMO Database Network containing drug-dispensing records from community pharmacies. Patients were classified as metformin user or sulfonylurea derivatives user from the moment of first dispensing until the end of follow up. The difference in overall survival between metformin users and nonusers was assessed, and additionally between metformin users and sulfonylurea derivatives users. Univariable and multivariable parametric survival models were used and use of metformin and sulfonylurea derivatives was included as time-varying covariates.Of the 1111 patients, 91 patients were excluded because of differences in morphology, 48 patients because of using merely metformin before diagnosis, and 57 metformin-users ever used contemporary sulfonylurea derivatives and were therefore excluded. Lastly, 8 patients with a survival of zero months were excluded. This resulted in 907 patients for the analysis. Overall, 77 users of metformin, 43 users of sulfonylurea derivatives, and 787 nonusers were identified. The adjusted rate ratio for overall survival for metformin users versus nonusers was 0.86 (95% CI: 0.66-1.11; P = 0.25). The difference in overall survival between metformin users and sulfonylurea derivatives users showed an adjusted rate ratio of 0.90 (95% CI: 0.59-1.40; P = 0.67).No association was found between overall survival, pancreatic cancer, and metformin use. This was in concordance with 2 recently published randomized controlled trials. Future research should focus on the use of adjuvant metformin in other cancer types and the development or repurposing of other drugs for pancreatic cancer.

The recent findings from the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial that insulin glargine has a neutral association with cancer outcomes are, as Bordeleau et al. (1) state, “reassuring,” but we suggest that they are not yet conclusive. Observational studies initially supported the hypothesis that glargine is linked with an increased cancer risk. Many of the earlier studies were justifiably criticized for methodological limitations and were arguably inconclusive. Results from the ORIGIN trial (2) seemed to bring a clearer picture. Although cancer was a post hoc end point, the findings were relevant: no differences between treatment arms for all cancer incidence or deaths, or …

TO THE EDITOR: Margel et al 1 recently reported on a populationbased retrospective cohort study that used a unique large database to investigate patients with prostate cancer diagnosed with incident diabetes. Increased cumulative duration of metformin exposure after prostate cancer diagnosis was associated with decreases in both all-cause and prostate cancer–specific mortality among men with diabetes. The study showed that prostate cancer–specific mortality even decreased by 24% for each additional 6 months of metformin use after the diagnosis of prostate cancer. Although the approach used in this study did circumvent numerous potential limitations and biases, 2 on the basis of the authors’ conclusions and study design, we have a few comments and requests for clarification. With regard to their statistical analyses, the effects of cumulative duration of exposure to metformin on mortality were assessed by using a Cox proportional hazards model in which drug exposures after prostate cancer diagnosis were modeled as time-dependent covariates. The comparison was not exclusively between users who had different durations of exposure, but also between users and nonusers of the drug. This means that in the time-dependent model, patients not using metformin were included in the analysis as 0 for cumulative use of metformin. Modeling the line for this specific hazard ratio (HR) of cumulative metformin use could be expected to be greatly influenced by events in the nonusers, given that patients using and not using metformin might differ in their previous susceptibility to dying as a result of cancer. As a consequence, these results might be affected by confounding by indication, which could not be avoided by the inclusion of cumulative drug exposure exclusively, as supposed in this analysis. It can be shown algebraically that with the inclusion of an ever-never termformetforminuseinthemodel,theHRofthecumulativeeffectterm