A population-based linked cohort of cancer and primary care data: A new source to study the management of cancer in primary care.

OBJECTIVE: Insight into the management of cancer in the primary care setting is pivotal to improve early recognition and survival of cancer patients. Therefore, the Netherlands Cancer Registry (NCR) was linked to the General Practitioner (GP) Database of the PHARMO Database Network to make this research possible. METHODS: The NCR collects tumour data on all newly diagnosed cancer patients, whereas the GP Database comprises data from electronic patient records registered by GPs. Databases were linked using a probabilistic record linkage technology. RESULTS: Through record linkage of the NCR and the GP Database, we have established a large population-based cohort (NCR-PHARMO GP cohort) of 135,868 cancer patients. Data are available on demographics, tumour characteristics, primary health care use before and after cancer diagnosis including medication use, medical conditions, laboratory tests, and referrals. Data can be used for a number of different studies, for example, to study the diagnostic pathway in the primary care setting in order to identify possibilities for early recognition. CONCLUSION: The NCR-PHARMO GP cohort provides rich data on the primary care management of cancer facilitating large-scale observational cancer research in the primary care setting. The patient-level linkage allows for long-term follow-up of cancer patients, with ongoing annual updates.

A steep increase in healthcare seeking behaviour in the last months before colorectal cancer diagnosis.

BACKGROUND: Timely recognition of colorectal cancer related symptoms is essential to reduce time to diagnosis. This study aims to investigate the primary healthcare use preceding a colorectal cancer diagnosis. METHODS: From a cohort of linked cancer and primary care data, patients diagnosed with primary colorectal cancer in the period 2007-2014 were selected and matched to cancer-free controls on gender, birth year, GP practice and follow-up period. Primary healthcare use among colorectal cancer cases before diagnosis was compared with matched cancer-free controls. Mean monthly number of GP consultations and newly prescribed medication was assessed in the year before index date (diagnosis date for cases). Results were stratified by colorectal cancer site: proximal colon cancer, distal colon cancer and rectal cancer. RESULTS: A total of 6,087 colorectal cancer cases could be matched to four cancer-free controls (N = 24,348). While mean monthly number of GP consultation were stable through the year among cancer-free controls, a statistical significant increase was seen among colorectal cancer cases in the last 4-8 months before diagnosis. Proximal colon cancer cases showed the longest time interval of increased mean monthly number of GP consultations. This increase was largely driven by a consultation for malignant neoplasm colon/rectum. The number patients receiving a newly prescribed medication was stable around 120 per 1,000 persons per month until 8 months before index date for proximal colon cancer cases, 4 months before index date for distal colon cancer cases and 3 months for rectal cancer cases. This increase was mainly driven by the prescription of laxatives drugs. CONCLUSION: An increase in the healthcare seeking behaviour of colorectal cancer patients prior to diagnosis was seen. The longest period of increased GP consultations and newly prescribed medication was seen among patients diagnosed with proximal colon cancer. This can be explained by the difficultly to diagnose proximal colon cancer given the more subtle signs compared to distal colon cancer and rectal cancer. Therefore, faster diagnosis for this specific tumour subtype may only be possible when clear clinical signs and symptoms are present.

Statin Use After Diagnosis of Colon Cancer and Patient 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.

Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: A systematic review and meta-analysis.

The long-term impact of dipeptidyl peptidase-4 (DPP-4) inhibition is unknown, and there are concerns about the influence of DPP-4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP-4 is a rather unselective enzyme present in many tissues, we focused on all specific cancer types. PubMed and EMBASE were searched between January 2005 and April 2017 to identify studies comparing DPP-4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow-up of at least 1 year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaboration's tool and the Newcastle-Ottawa Scale. Twenty-five studies met the inclusion criteria (12 randomized controlled trials and 13 observational studies). Sample sizes of the DPP-4 inhibitor groups ranged from 29 to 8212 patients for randomized controlled trials and from 2422 to 71 137 patients for observational studies. Mean age ranged from 51 to 76 years, and mean follow-up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (hazard ratio [95% CI]: 0.76 [0.60-0.96]), showed evidence for an association between DPP-4 inhibitors and site-specific cancer. Also for pancreatic and thyroid cancer, no statistically significant risk was found. Based on the current literature, it is not possible to conclude whether DPP-4 inhibitors were associated with an increased risk of site-specific cancer. Future studies should address the methodological limitations and follow patients for a longer period to determine the long-term cancer risk of DPP-4 inhibitors.

No Evidence for an Association Between Renal Function and Serious Bleeding Events in Patients Treated With Coumarins: A Population-Based Study.

BACKGROUND: Although anticoagulation therapy is closely monitored in the Netherlands, coumarin-induced serious bleeding events are still observed. Current literature suggests that renal impairment may contribute to this. OBJECTIVE: To explore the association between renal function and bleeding events during coumarin treatment. METHODS: A nested case-control study was conducted using data from the PHARMO Database Network. Patients hospitalized for a bleeding event during coumarin treatment were selected as cases and matched on sex, birth year, and geographic region to up to 2 controls using coumarins without hospitalization for bleeding. All values of estimated glomerular filtration rates (eGFRs) were selected in the year before index date (case hospitalization date) and compared between cases and controls using logistic regression analyses. RESULTS: In total, 2224 cases were matched to 4398 controls (61% male; mean ± SD age 75 ± 11 and 78 ± 11 years among cases and controls, respectively). Availability of eGFR values was higher among cases compared with controls (mean ± SD eGFR values 4.5 ± 7.1 vs 3.2 ± 5.5), reflected in the significantly shorter time since last eGFR value (at index date, mean ± SD = 2.7 ± 3.0 vs 3.8 ± 3.1 months; odds ratio [OR] = 0.91, 95%CI = 0.89-0.92). No statistically significant difference was found for the mean eGFR value in the year before index date (mean ± SD 65.7 ± 22.8 vs 64.6 ± 20.9 mL/min/1.73 m2; OR per 10 units [95%CI] = 0.99 [0.96-1.02]). CONCLUSIONS: No association between renal function and serious bleeding events during coumarin treatment was observed.

Pharmaceutically treated anxiety but not depression prior to cancer diagnosis predicts the onset of cardiovascular disease among breast cancer survivors.

PURPOSE: To examine the associations between pharmaceutically treated anxiety and depression present in the year prior to breast cancer diagnosis and the risk of incident cardiovascular disease (CVD), while controlling for traditional cardiovascular risk factors and clinical characteristics in a population-based observational study. METHODS: Adult 1-year breast cancer survivors (n = 7227), diagnosed between 01-01-1999 and 12-31-2010, with no history of CVD, were selected from the Netherlands Cancer Registry. Drug dispensing data were derived from the PHARMO Database Network and used as proxy for CVD, anxiety, and depression. By multivariable Cox regression analysis, we examined the risk associated with pharmaceutically treated anxiety and depression for developing CVD after cancer diagnosis, adjusting for age, pharmaceutically treated hypertension, hypercholesterolemia, and diabetes mellitus in the year prior to cancer diagnosis, tumor stage, and cancer treatment. RESULTS: During the 13-year follow-up period, 193 (3%) breast cancer survivors developed CVD. Women pharmaceutically treated for anxiety in the year prior to their cancer diagnosis had a 48% increased hazard for CVD [HR = 1.48; 95% CI 1.05-1.08] after full adjustment. This association was restricted to breast cancer survivors who were 65 years or younger. Depression was not associated with CVD risk [HR = 0.89; 95% CI 0.52-1.53]. Older age [HR = 1.06; 95% CI 1.05-1.08], hypertension [HR = 1.80; 95% CI 1.32-2.46], and hypercholesterolemia [HR = 1.63; 95% CI 1.15-2.33] were associated with an increased hazard for incident CVD, whereas hormone therapy [HR = 0.59; 95% CI 0.42-0.83] was protective. CONCLUSIONS: Anxiety present in the year prior to breast cancer diagnosis increases the risk of incident CVD in 1-year breast cancer survivors, after adjustment for depression, traditional cardiovascular risk factors, and clinical characteristics.

Immortal time bias in pharmacoepidemiological studies on cancer patient survival: empirical illustration for beta-blocker use in four cancers with different prognosis.

Immortal time bias (ITB) is still seen frequently in medical literature. However, not much is known about this bias in the field of cancer (pharmaco-)epidemiology. In context of a hypothetical beneficial beta-blocker use among cancer patients, we aimed to demonstrate the magnitude of ITB among 9876 prostate, colorectal, lung and pancreatic cancer patients diagnosed between 1998 and 2011, which were selected from a database linkage of the Netherlands Cancer Registry and the PHARMO Database Network. Hazard ratios (HR) and 95% confidence intervals from three ITB scenarios, defining exposure at a defined point after diagnosis (model 1), at any point after diagnosis (model 2) and as multiple exposures after diagnosis (model 3), were calculated to investigate the association between beta-blockers and cancer prognosis using Cox proportional hazards regression. Results were compared to unbiased estimates derived from the Mantel-Byar model. Ignoring ITB led to substantial smaller HRs for beta-blocker use proposing a significant protective association in all cancer types [e.g. HR 0.18 (0.07-0.43) for pancreatic cancer in model 1], whereas estimates derived from the Mantel-Byar model were mainly suggesting no association [e.g. HR 1.10 (0.84-1.44)]. The magnitude of bias was consistently larger among cancer types with worse prognosis [overall median HR differences between all scenarios in model 1 and Mantel-Byar model of 0.56 (prostate), 0.72 (colorectal), 0.77 (lung) and 0.85 (pancreas)]. In conclusion, ITB led to spurious beneficial associations of beta-blocker use among cancer patients. The magnitude of ITB depends on the duration of excluded immortal time and the prognosis of each cancer.

Propranolol and survival from breast cancer: a pooled analysis of European breast cancer cohorts.

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.

The effect of aspirin and nonsteroidal anti-inflammatory drug use after diagnosis on survival of oesophageal cancer patients.

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.

Impact of cancer on adherence to glucose-lowering drug treatment in individuals with diabetes.

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.

Incident cancer risk after the start of aspirin use: results from a Dutch population-based cohort study of low dose aspirin users.

Observational and intervention studies suggest that low dose aspirin use may prevent cancer. The objective of this study was to investigate the protective effect of long term low dose aspirin use (≤100 mg daily) on cancer in general and site-specific cancer among low dose aspirin users in the Dutch general population. We conducted a population-based cohort study with detailed information on aspirin exposure and cancer incidence. Only incident (new) low dose aspirin users, who were included in the linkage between PHARMO and the Eindhoven Cancer Registry (1998-2010) and free of cancer before the start of follow up were included. A Cox proportional hazard model with cumulative aspirin use as a time-varying determinant was used to obtain hazard ratios (HR). Duration of aspirin use amongst 109,276 incident low dose aspirin users was not associated with a decreased risk of any of the site-specific cancers or cancer in general (adjusted HR per year of aspirin use for all cancers: 1.02, 95% confidence interval [CI] 1.00-1.04, HR of >6 years aspirin use compared to <2 years: 1.17, 95% CI 1.02-1.34). After adjusting for current and past aspirin use, 2-6 years of low dose aspirin use was associated with a reduced colorectal cancer risk compared to <2 years of aspirin use (adjusted HR 0.75, 95% CI 0.59-0.96). However, a clear dose-response relationship was not observed (adjusted HR >6 years aspirin use 0.95, 95% CI 0.60-1.49). Our results do not support the primary prevention of cancer among long term aspirin users.

Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen.

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.

Pulmonary embolism, myocardial infarction, and ischemic stroke in lung cancer patients: results from a longitudinal study.

PURPOSE: In this cohort study, the rates of pulmonary embolism (PE), myocardial infarction (MI), and ischemic stroke (IS) before and after lung cancer (LC) diagnosis were compared to cancer-free controls. METHODS: Patients with LC during 2000-2007 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO medical record linkage system, including drug use and hospitalizations of 3 million inhabitants in the Netherlands. Included LC patients were matched 1:10 by age and gender to cancer-free controls. Hospitalizations for PE, MI, and IS were assessed in the 12 months before and after LC diagnosis. RESULTS: LC patients (N = 3,717) were six times more likely than cancer-free controls to have had a PE in the 12 months before diagnosis. After LC diagnosis, patients experienced an extremely increased risk of PE in the first 6 months (hazard ratio [HR] 16.8; 95 % confidence interval [CI] 7.6-36.8) compared with controls), which decreased to a five times increased risk (HR 5.1; 95 % CI 2.7-9.4) thereafter. However, there were less than two events per 100 person years during both time periods. LC patients receiving chemotherapy were eight times more likely to develop PE, whereas surgery increased the risk on PE three times. For MI and IS, no significant difference was observed compared with cancer-free controls before or after LC diagnosis. CONCLUSIONS: LC patients have a higher risk of developing PE compared with cancer-free controls, although the frequency of PE hospitalizations was low. Surgery and chemotherapy were associated with an increased risk of PE.

Major changes in chemotherapy regimens administered to breast cancer patients during 2000-2008 in the Netherlands.

There is little information available on the patterns of chemotherapy regimens administered in daily practice to patients with early stage and metastatic or recurrent breast cancer. To determine the trends in type of chemotherapy regimens used in breast cancer patients, newly diagnosed breast cancer patients in the period 2000-2008 who received chemotherapy were identified from the Eindhoven Cancer Registry (ECR) and linked to the PHARMO RLS, including data on, e.g., in- and outpatient drug use. Chemotherapy regimens were classified based on the received combinations and sequences. Trends in the distribution of adjuvant chemotherapy regimens (for early-stage breast cancer) and palliative chemotherapy regimens (for metastatic or recurrent breast cancer) were determined and stratified by Her2/neu status when possible. In this study, 422 patients diagnosed with early-stage breast cancer received adjuvant chemotherapy. The use of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) decreased from 90% in 2000 to almost none since 2005. Administration of regimens that included anthracyclines increased from 4% in 2000 to 96% in 2005, but decreased to 68% in 2008. The use of trastuzumab- and taxane-containing regimens (with or without anthracyclines) increased from 2005 onwards to 24% and 34%, respectively, in 2008. Among the 82 breast cancer patients who received palliative chemotherapy at diagnosis or after breast cancer recurrence, the use of CMF and anthracyclines (without taxanes) decreased, while the use of taxanes (with or without anthracyclines) increased (26% in 2008). Trastuzumab was used as palliative chemotherapy from 2003 onwards, with 22% of the metastatic breast cancer patients receiving trastuzumab-containing regimens in 2008, and bevacizumab was administered since 2007 with 19% of the patients receiving bevacizumab-containing regimens in 2008. In conclusion, major changes have taken place in the chemotherapeutic treatment of patients with early and recurrent breast cancer. These changes reflect the key findings from large clinical trials, as incorporated in the Dutch guidelines.

Use and costs of oral anticancer agents in the Netherlands in the period 2000-2008.

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 100 000 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 €2 m in 2000 to approximately €100 m in 2008. The share in the costs of tyrosine kinase inhibitors (TKIs) in 2008 was 67% (€70 m) 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.

Occurrence of Comorbidities before and after Soft Tissue Sarcoma Diagnosis.

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.

Risk of heart failure among colon and rectal cancer survivors: a population-based case-control study.

AIMS: This population-based case-control study aims to investigate the occurrence of heart failure (HF) among colon and rectal cancer survivors compared with a cancer-free control population taking into account pre-existing cardiovascular risk factors and the influence of treatment. METHODS AND RESULTS: Colon and rectal cancer survivors diagnosed between 2007 and 2014 were selected from a linked cohort of cancer and primary care data in the Netherlands and matched based on gender, birth year, general practitioner (GP) practice, and follow-up period to cancer-free controls. The occurrence of HF was identified based on GP recorded diagnoses after index date (diagnosis date for cases). A Cox proportional hazards model was used to estimate hazard ratios (HRs), adjusted for age, sex, hypertension, diabetes, and hypercholesterolaemia. A total of 5333 colon cancer cases and 2468 rectal cancer cases could be matched to a total of 31 204 cancer-free controls. A statistically significant increased risk of HF was seen among all cases compared with cancer-free controls (HR 1.33; 95% confidence interval: 1.12-1.59). This was also seen when analysing colon cancer and rectal cancer separately. Being diagnosed with stage IV cancer, having hypertension, or having hypercholesterolaemia statistically significantly increased the risk of HF among colon cancer. Hypertension was a statistically significant risk factor for developing HF among rectal cancer cases. CONCLUSIONS: Colon and rectal cancer survivors are at increased risk for developing HF. More awareness should be created by treating physicians and GPs for this potential increased risk in order to further improve survival.

Levothyroxine use and the risk of colorectal cancer: a large population-based case-control study.

Objective: Whether an association between oral levothyroxine use, leading to supraphysiological exposure of the colon to thyroid hormones, and risk of colorectal cancer exists in humans is unclear. We therefore aimed to assess whether the use of levothyroxine is associated with a reduced risk of colorectal cancer in a linked cohort of pharmacy and cancer data. Design: Population-based matched case-control study. Methods: A total of 28,121 patients diagnosed with colorectal cancer between 1998 and 2014 were matched to 106,086 controls. Multivariable logistic regression was used to estimate the association between levothyroxine use and occurrence of colorectal cancer, adjusted for potential confounders. Results were stratified by gender, age, tumour subtype, and staging, as well as treatment duration and dosing. Results: A total of 1066 colorectal cancer patients (4%) and 4024 (4%) controls had used levothyroxine at any point before index date (adjusted odds ratio 0.95 (0.88-1.01)). Long-term use of levothyroxine was seen in 323 (30%) colorectal cancer patients and 1111 (28%) controls (adjusted odds ratio 1.00 (0.88-1.13)). Stratification by tumour subsite showed a borderline significant risk reduction of rectal cancer, while this was not seen for proximal colon cancer or distal colon cancer. There was no relationship with treatment duration or with levothyroxine dose. Conclusions: In this study, no reduced risk of colorectal cancer was seen in levothyroxine users. When stratifying by tumour subsite, a borderline significant risk reduction of rectal cancer was found and may warrant further research.

Half of breast cancer patients discontinue tamoxifen and any endocrine treatment before the end of the recommended treatment period of 5 years: a population-based analysis.

Observational studies on long-term endocrine treatment among breast cancer patients have presented discontinuation rates on tamoxifen, but lack information on the continuance of any endocrine treatment [both tamoxifen and aromatase inhibitors (AIs)] within the same cohort. In this study we determined switching rates from tamoxifen to AIs, discontinuation rates of tamoxifen only, discontinuation rates of any endocrine treatment and determinants of first treatment switch and treatment discontinuation. Patients with early stage breast cancer (stage I-IIIa) starting on tamoxifen were selected from the linked Eindhoven Cancer Registry-PHARMO RLS cohort in the period 1998-2006. Continuous use (allowing a 60 days gap between refills) of tamoxifen only and any endocrine treatment were determined after various follow-up periods: 1, 2, 3, 4, and 5 years. Time to first switch from tamoxifen to an AI was assessed. Cox regression was used to identify determinants of first treatment switch, discontinuation of tamoxifen, and discontinuation of any endocrine treatment. A total of 1,451 new early stage breast cancer patients started on tamoxifen. Of those, 380 had a treatment switch to an AI during follow-up. Of the patients followed for 5 years, 40% continuously used tamoxifen, which was 49% for any endocrine treatment. Older age (older than 70 versus 50-69 years) was independently associated with increased discontinuation of tamoxifen and any endocrine therapy. Patients with two or more concomitant diseases (versus no comorbidity) showed an increased likelihood to stop any endocrine treatment or switch treatment from tamoxifen to an AI. In conclusion, up to half of the breast cancer patients starting tamoxifen continued 5 years of endocrine treatment. Identification of patients at risk of discontinuation will assist in the development of interventions to improve treatment continuation comparable to that of patients included in clinical trials.