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Reimers M.S.,Leiden University | Bastiaannet E.,Leiden University | Langley R.E.,University College London | Van Eijk R.,Leiden University | And 9 more authors.
JAMA Internal Medicine | Year: 2014

IMPORTANCE Use of aspirin (which inhibits platelet function) after a colon cancer diagnosis is associated with improved overall survival. Identifying predictive biomarkers of this effect could individualize therapy and decrease toxic effects. OBJECTIVE To demonstrate that survival benefit associated with low-dose aspirin use after a diagnosis of colorectal cancer might depend on HLA class I antigen expression. DESIGN, SETTING, AND PARTICIPANTS A cohort study with tumor blocks from 999 patients with colon cancer (surgically resected between 2002 and 2008), analyzed for HLA class I antigen and prostaglandin endoperoxide synthase 2 (PTGS2) expression using a tissue microarray. Mutation analysis of PIK3CA was also performed. Data on aspirin use after diagnosis were obtained from a prescription database. Parametric survival models with exponential (Poisson) distribution were used to model the survival. MAIN OUTCOMES AND MEASURES Overall survival. RESULTS The overall survival benefit associated with aspirin use after a diagnosis of colon cancer had an adjusted rate ratio (RR) of 0.53 (95%CI, 0.38-0.74; P < .001) when tumors expressed HLA class I antigen compared with an RR of 1.03 (0.66-1.61; P = .91) when HLA antigen expression was lost. The benefit of aspirin was similar for tumors with strong PTGS2 expression (0.68; 0.48-0.97; P = .03), weak PTGS2 expression (0.59; 0.38-0.97; P = .02), and wild-type PIK3CA tumors (0.55; 0.40-0.75; P < .001). No association was observed with mutated PIK3CA tumors (0.73; 0.33-1.63; P = .44). CONCLUSIONS AND RELEVANCE Contrary to the original hypothesis, aspirin use after colon cancer diagnosis was associated with improved survival if tumors expressed HLA class I antigen. Increased PTGS2 expression or the presence of mutated PIK3CA did not predict benefit from aspirin. HLA class I antigen might serve as a predictive biomarker for adjuvant aspirin therapy in colon cancer. © 2014 American Medical Association. All rights reserved. Source

Zanders M.M.J.,Netherlands Comprehensive Cancer Organisation | Haak H.R.,Maxima Medical Center | Haak H.R.,Maastricht University | van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 3 more authors.
Diabetologia | Year: 2015

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. © 2015, Springer-Verlag Berlin Heidelberg. Source

Reimers M.S.,Leiden University | Bastiaannet E.,Leiden University | Van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | Lemmens V.E.P.,Comprehensive Cancer Center South | And 4 more authors.
Journal of the American Geriatrics Society | Year: 2012

Objectives To assess survival in relation to aspirin use after diagnosis in older adults with colon cancer. Design Subgroup analysis of a previously published cohort and retrospective study. Setting Individuals registered in the Eindhoven Cancer Registry (ECR) between 1998 and 2007, linked to prescriptions of low-dose aspirin (80 mg) registered in a community pharmacy database. Participants Five hundred thirty-six individuals aged 70 and older diagnosed with colon cancer with or without aspirin use after diagnosis. Measurements Survival was analyzed with user status as a time-dependent covariate. Multivariate Poisson regression survival models were used to study the effect of aspirin on overall survival. Results One hundred seven participants (20.0%) started aspirin after being diagnosed with colon cancer; 429 (80.0%) were not prescribed aspirin. Three hundred thirty-nine participants (63.2%) had died by the end of follow-up. Aspirin use after diagnosis was associated with longer overall survival (rate ratio (RR) = 0.51, 95% confidence interval (CI) = 0.38-0.70, P < .001). Multivariate proportional hazards regression analysis revealed that aspirin use was associated with longer overall survival (adjusted RR = 0.59, 95% CI = 0.44-0.81, P = .001). Conclusion Aspirin use after the diagnosis of colon cancer in older adults was associated with longer survival. Low-dose aspirin could be used as an effective adjuvant therapy in older adults with colon cancer. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society. Source

Timmers L.,VU University Amsterdam | Beckeringh J.J.,Health Care Insurance Board CVZ | van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | Boven E.,VU University Amsterdam | Hugtenburg J.G.,VU University Amsterdam
Pharmacoepidemiology and Drug Safety | Year: 2012

Purpose: In recent years, the number of oral anticancer agents has increased substantially. Although these agents have quickly been incorporated in the treatment of a variety of malignancies, data on their incidence, prevalence and costs are lacking. The objective of the present study was to obtain insight into the use and the costs of oral anticancer agents (with Anatomical Therapeutic Chemical classification system (World Health Organisation) code L01) in the Netherlands between 2000 and 2008. Methods: Incidence and prevalence were determined using community pharmacy dispensing records obtained from the PHARMO Record Linkage System database. The data of costs were provided by the Genees- en hulpmiddelen Informatie Project of the Dutch Health Care Insurance Board (CVZ, Diemen, The Netherlands). Results: In the years 2000-2008, the use of oral anticancer agents has more than doubled from 64 to 140 users per 100000 inhabitants. The increase is mainly caused by the prescription of capecitabine for various indications. There was a 50-fold rise in costs on oral anticancer agents from €2m in 2000 to approximately €100m in 2008. The share in the costs of tyrosine kinase inhibitors (TKIs) in 2008 was 67% (€70m) with the oldest TKI, imatinib, having a share of more than 50% within the group of TKIs. Conclusions: The increased use of oral anticancer agents is mainly due to the frequent prescription of capecitabine. The increased costs are caused by the registration of a variety of TKIs, in particular imatinib. The costs of new agents with an orphan drug status are very high as compared with those of capecitabine, a newer agent for which there are alternative treatment options. © 2011 John Wiley & Sons, Ltd. Source

Binkhorst L.,Erasmus Medical Center | Binkhorst L.,Erasmus University Rotterdam | Mathijssen R.H.J.,Erasmus Medical Center | Van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 5 more authors.
Breast Cancer Research and Treatment | Year: 2013

Tamoxifen is a largely inactive pro-drug, requiring metabolism into its most important metabolite endoxifen. Since the cytochrome P450 (CYP) 2D6 enzyme is primarily involved in this metabolism, genetic polymorphisms of this enzyme, but also drug-induced CYP2D6 inhibition can result in considerably reduced endoxifen formation and as a consequence may affect the efficacy of tamoxifen treatment. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have been effectively used for the treatment of depression and hot flashes, both of which occur frequently in tamoxifen-treated women. Due to the drug-drug interaction considerably reduced endoxifen concentrations by inhibition of CYP2D6 will be the result. Evidence of a significant influence of strong CYP2D6-inhibiting drugs on the pharmacokinetics of tamoxifen has resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants (e.g., paroxetine, fluoxetine) in patients treated with tamoxifen for breast cancer. Nevertheless, dispensing data for tamoxifen and seven regularly used SSRIs/SNRIs in the period between 2005 and 2010, obtained from a large community pharmacy database in the Netherlands (3,000,000 people), show that the potent CYP2D6-inhibiting drug paroxetine remains one of the most frequently used antidepressants in tamoxifen-treated patients. Moreover, trends in the use of SSRIs/SNRIs in the population of all women were similar with trends in women using tamoxifen. Apparently, the recommendations to avoid paroxetine in tamoxifen-treated women have not been implemented into clinical practice. Several reasons may underlie continued use of this drug-drug combination. Contrary to CYP2D6 polymorphisms, drug-induced CYP2D6 inhibition can easily be avoided, since alternative drugs are available. In clinical practice, one should strive to avoid potent CYP2D6 inhibitors as much as possible in tamoxifen-treated patients to reduce the risk of compromising the efficacy of the hormonal therapy. Co-medication should be reviewed by both physicians and pharmacists and potent CYP2D6 inhibitors ought to be switched to weaker alternatives. © 2013 Springer Science+Business Media New York. Source

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