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Jordi Castellsague,1 Josephina G Kuiper,2 Anton Pottegård,3 Ingegärd Anveden Berglind,4 Daniel Dedman,5 Lia Gutierrez,1 Brian Calingaert,6 Myrthe PP van Herk-Sukel,2 Jesper Hallas,3 Anders Sundström,4 Arlene M Gallagher,5 James A Kaye,7 Carolina Pardo,8 Kenneth J Rothman,7 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, Spain; 2Department Research, PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 3Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; 4Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, London, UK; 6Department Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 7Department of Epidemiology, RTI Health Solutions, Waltham, MA, USA; 8Pharmacovigilance Department, Astellas Pharma Europe B.V., Leiden, the Netherlands Background: There is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children.Objective: The aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects.Methods: This is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel–Haenszel methods for stratified analysis.Results: We included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00–14.06) in children and 1.27 (0.94–1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58–17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81–3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33–5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60–43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer.Conclusion: Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results. Keywords: topical calcineurin inhibitors, cutaneous T-cell lymphoma, malignant melanoma skin cancer, database study

Objective: Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives.Research Design and Methods: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant.Results: Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88-0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives.Conclusions: In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated. [ABSTRACT FROM AUTHOR]

Previous studies on metformin use and gastrointestinal (GI) cancer risk have yielded inconclusive results on metformin's chemoprotective effects. We aimed to evaluate GI cancer risk in users of metformin in The Netherlands using a time-varying approach in a large population-based database. A cohort study was performed using the NCR-PHARMO database. Patients using ≥1 non-insulin antidiabetic drug (NIAD) during 1998 to 2011 were included ( N = 57,621). Exposure to NIADs was modeled time-varyingly. Cox regression analysis estimated HRs of GI cancers in current metformin users versus current users of other NIADs. Covariables included age, sex, drugs known to impact cancer risk, history of hospitalization, and starting year of follow-up. A sensitivity analysis was performed, applying a new-user design. Current use of metformin was not associated with a decreased risk of GI cancer [HR, 0.97; 95% confidence interval (CI), 0.82-1.15] or specific GI cancer sites. The sensitivity analysis yielded comparable results. No decreasing trends were observed with increasing cumulative dose of metformin [HR 1.05, 95% CI, 0.85-1.28; HR 0.89, 95% CI, 0.73-1.10; HR 0.96, 95% CI, 0.77-1.19 for dose tertiles low (<405 g), medium (405-999 g), and high (≥999 g)]. In contrast, an increased risk of pancreatic cancer was found in current users of metformin plus insulin (HR, 4.90; 95% CI, 2.64-9.10). In conclusion, no decreased risk of GI cancer was found in current metformin users compared with current users of other NIADs. Variations in the exposure definition of metformin use may be one of the explanations of previously found reduced cancer risks in metformin users. Cancer Prev Res; 10(5); 290-7. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Use of aspirin after diagnosis of colon cancer has been associated with improved survival. Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens. The aim of this study was to investigate the influence of BRAF and KRAS mutation status on the association between aspirin use and overall survival after colon cancer diagnosis., Methods: A random selection of 599 patients with colon cancer were analyzed, selected from the Eindhoven Cancer Registry, and BRAF and KRAS mutation status was determined. Data on aspirin use (80 mg) were obtained from the PHARMO Database Network. Parametric survival models with exponential (Poisson) distribution were used., Results: Aspirin use after colon cancer diagnosis was associated with improved overall survival in wild-type BRAF tumors, adjusted rate ratio (RR) of 0.60 (95% CI 0.44-0.83). In contrast, aspirin use in BRAF mutated tumors was not associated with an improved survival (RR 1.11, 95% CI 0.57-2.16). P-value for interaction was non-significant. KRAS mutational status did not differentiate in the association between aspirin use and survival., Conclusion: Low-dose aspirin use after colon cancer diagnosis was associated with improved survival in BRAF wild-type tumors only. However, the large confidence interval of the rate ratio for the use of aspirin in patients with BRAF mutation does not rule out a possible benefit. These results preclude BRAF and KRAS mutation status to be used as a marker for individualized treatment with aspirin, if aspirin becomes regular adjuvant treatment for colon cancer patients in the future., Competing Interests: Myrthe P.P. van Herk-Sukel is an employee of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. However, this study was not financially supported by a pharmaceutical company. The remaining authors declare no competing (financial) interests.

Background: Previous studies suggested a relationship between aspirin use and mortality reduction. The mechanism for the effect of aspirin on cancer outcomes remains unclear. The aim of this study was to evaluate aspirin use and survival in patients with gastrointestinal tract cancer., Methods: Patients with gastrointestinal tract cancer diagnosed between 1998 and 2011 were included. The population-based Eindhoven Cancer Registry was linked to drug-dispensing data from the PHARMO Database Network. The association between aspirin use after diagnosis and overall survival was analysed using Cox regression models., Results: In total, 13 715 patients were diagnosed with gastrointestinal cancer. A total of 1008 patients were identified as aspirin users, and 8278 patients were identified as nonusers. The adjusted hazard ratio for aspirin users vs nonusers was 0.52 (95% CI 0.44-0.63). A significant association between aspirin use and survival was observed for patients with oesophageal, hepatobiliary and colorectal cancer., Conclusions: Post-diagnosis use of aspirin in patients with gastrointestinal tract malignancies is associated with increased survival in cancers with different sites of origin and biology. This adds weight to the hypothesis that the anti-cancer effects of aspirin are not tumour-site specific and may be modulated through the tumour micro-environment.

Background: Preclinical studies have demonstrated that propranolol inhibits several pathways involved in breast cancer progression and metastasis. We investigated whether breast cancer patients who used propranolol, or other non-selective beta-blockers, had reduced breast cancer-specific or all-cause mortality in eight European cohorts., Methods: Incident breast cancer patients were identified from eight cancer registries and compiled through the European Cancer Pharmacoepidemiology Network. Propranolol and non-selective beta-blocker use was ascertained for each patient. Breast cancer-specific and all-cause mortality were available for five and eight cohorts, respectively. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality by propranolol and non-selective beta-blocker use. HRs were pooled across cohorts using meta-analysis techniques. Dose-response analyses by number of prescriptions were also performed. Analyses were repeated investigating propranolol use before cancer diagnosis., Results: The combined study population included 55,252 and 133,251 breast cancer patients in the analysis of breast cancer-specific and all-cause mortality respectively. Overall, there was no association between propranolol use after diagnosis of breast cancer and breast cancer-specific or all-cause mortality (fully adjusted HR = 0.94, 95% CI, 0.77, 1.16 and HR = 1.09, 95% CI, 0.93, 1.28, respectively). There was little evidence of a dose-response relationship. There was also no association between propranolol use before breast cancer diagnosis and breast cancer-specific or all-cause mortality (fully adjusted HR = 1.03, 95% CI, 0.86, 1.22 and HR = 1.02, 95% CI, 0.94, 1.10, respectively). Similar null associations were observed for non-selective beta-blockers., Conclusions: In this large pooled analysis of breast cancer patients, use of propranolol or non-selective beta-blockers was not associated with improved survival.

Safety concerns of the concomitant use of clopidogrel and proton pump inhibitors (PPIs) were published in 2009 and 2010 by the medicines regulatory agencies, including a direct healthcare professional communication. We examined the association between various safety statements and prescription behavior for gastroprotective drugs in naïve patients in the Netherlands during the years 2008-2011. Data from the PHARMO Database Network were analyzed with interrupted time series analyses to estimate the impact of each communication on drug prescriptions. Dispensings were used as a proxy variable for prescription behavior. After the early communication in January 2009, 15.5% (95% CI 7.8, 23.4) more patients started concomitantly with (es)omeprazole and 13.8% (95% CI 6.5, 21.2) less with other PPIs. Directly after the first statement in June 2009, we found a steep increase in histamine 2-receptor antagonists (H2RA) peaking at 25%, placing those patients at risk for gastrointestinal events. This effect for H2RA faded away after a few months. In February 2010, when the official advice via an adjusted statement was to avoid (es)omeprazole, we found a decrease of 11.9% (95% CI 5.7, 18.2) for (es)omeprazole and an increase of +16.0% (95% CI 10.3, 21.7) for other PPIs. Still 22.6% (95% CI 19.5, 25.7) of patients started on (es)omeprazole in February 2010, placing them at risk for cardiovascular events. Advices of regulatory authorities were followed, however, reluctantly and not fully, probably partly because of the existing scientific doubt about the interaction.

Background: Aspirin use has been shown to lower incidence and mortality in cancer patients. The aim of this population-based study was to determine the effect of postdiagnosis low-dose aspirin use on survival of patients with oesophageal cancer., Methods: Patients with oesophageal cancer (1998-2010) were selected from the Eindhoven Cancer Registry and linked with outpatient pharmacy data regarding aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Users were subdivided into both prediagnosis and postdiagnosis or only postdiagnosis users. Parametric survival models with an exponential (Poisson) distribution were used with non-specific death as endpoint., Results: In this study 560 patients were included. Overall, 157 patients (28.0%) were non-users, 293 patients (52.3%) pre- and postdiagnosis (89 aspirin and 204 NSAID users) and 110 patients (19.6%) only postdiagnosis users (16 aspirin and 94 NSAID users). Postdiagnosis aspirin use was associated with overall survival (RR 0.45 (95% CI 0.34-0.60; P<0.001); adjusted rate ratio was 0.42 (95% CI: 0.30-0.57; P<0.001). Postdiagnosis use of NSAIDs was associated with overall survival (RR 0.61 (95% CI 0.49-0.76; <0.001); however, adjusted analyses did not show a significant association with a rate ratio of 0.84 (95% CI 0.66-1.07; P=0.2)., Conclusions: Our study shows that postdiagnosis aspirin use might be associated with a higher survival rate in oesophageal cancer patients. A randomised clinical trial is needed to verify our observations of possible postdiagnosis aspirin use benefit.

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.

Aims/hypothesis: Adherence 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., Methods: All 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., Results: From 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/interpretation: Our 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.

Preclinical data showed anticancer effects of statins in melanoma, but meta-analyses could not demonstrate a reduced melanoma incidence in statin users. Rather than preventing occurrence, statins might reduce growth and metastatic spread of melanomas and ultimately improve survival. In this population-based study, we investigated the relationship between statin use and survival of melanoma patients. Patients ≥18 years who were diagnosed with cutaneous melanoma (Breslow thickness >1 mm) and registered in the Eindhoven Cancer Registry and in PHARMO Database Network between 1 January 1998 and 31 December 2010 were eligible. The hazard ratio (HR) of all-cause mortality was calculated by employing adjusted time-dependent and time-fixed Cox proportional hazard models. Disease-specific survival was estimated by means of 3-year relative survival rates (RSR). A control cohort of randomly selected patients using statins from PHARMO Database Network matched on age and gender was used to compare RSR of statin users to the general population. After melanoma diagnosis, 171 of 709 patients used statins. Use of statins showed a nonsignificantly decreased hazard of death (adjusted HR 0.76, 95% confidence interval [CI] 0.50-1.61). After stratification for gender, male but not female statin users showed a favorable outcome compared to nonusers (HR 0.57, 95% CI 0.32-0.99; HR 1.22, 95% CI 0.62-2.38, respectively). Three-year RSR for male statin users tended to be higher than for nonusers (91% vs. 80.5%, P = 0.06), no differences were observed in women (87.1% vs. 92.5%, P = 0.76). Statin use was not associated with an improved survival of melanoma patients. The trend for better survival of male in contrast to female statin users warrants further research., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients., Methods: Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998-2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure., Results: In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63-0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50-0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46-0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79-1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70-2.20; P<0.001)., Conclusion: Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.

Background. Data is limited on the burden of common comorbidities, such as cardiovascular disease (CVD), respiratory disease and diabetes, or comorbidities related to cancer and its treatment, such as anemia and depression, in patients with soft tissue sarcoma (STS). Patients and Methods. From the Dutch Pathology Registry linked to the PHARMO database (including data on drug use and hospitalizations), 533 patients with STS were selected during 2000-2007 and matched 1 : 10 to cancer-free controls. The occurrences of comorbidities were assessed in the 12 months before and after STS diagnosis. Results. STS patients were 2-4 times more likely to have comorbidities at diagnosis compared with cancer-free controls. The incidence of CVD, anemia, and depression after STS diagnosis differed significantly from cancer-free controls and decreased during followup from 40-124 per 1,000 person-years (py) during the first six months to 11-38 per 1,000 py more than 12 months after diagnosis. The incidence of respiratory disease and diabetes among STS patients remained stable during followup (5-21 per 1,000 py) and did not differ significantly from cancer-free controls. Conclusions. STS patients were more likely to have comorbidities before cancer diagnosis and to develop CVD, anemia, and depression after diagnosis compared to cancer-free controls.

Aims/hypothesis: Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study., Methods: Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes., Results: Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified., Conclusion/interpretation: Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.