Jg Kuiper

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.

A cohort study on the risk of lymphoma and skin cancer in users of topical tacrolimus, pimecrolimus, and corticosteroids (Joint European Longitudinal Lymphoma and Skin Cancer Evaluation – JOELLE study)

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.

Pre- and post-diagnostic beta-blocker use and prognosis after colorectal cancer: Results from a population-based study

Recent experimental and epidemiological studies have suggested that beta‐blocker use might be associated with better cancer prognosis, but results were inconclusive and only few studies have investigated the association specifically for colorectal cancer (CRC) patients. We investigated this hypothesis using a linked dataset of the Eindhoven area of the Netherlands Cancer Registry and the PHARMO record linkage, including patients diagnosed with CRC between 1998 and 2011. Eligible patients were matched on propensity scores to control for potential confounders such as socio‐demographic factors, comorbidity, cancer treatment and use of other medications. Controls were subsequently restricted to active comparators. The association between pre‐diagnostic and time‐dependent post‐diagnostic beta‐blocker use and overall survival was estimated using Cox proportional hazard regression models. Subgroup analyses by cancer site and stage and by beta‐blocker type were conducted. Of 8,100 CRC patients with a median follow‐up of 6.6 years, 1,813 (22%) used beta‐blockers prior to diagnosis. In multivariate analysis, we observed no significant association in overall mortality for pre‐diagnostic [hazard ratio 1.07, 95% confidence interval (0.96‐1.19)] and post‐diagnostic [1.10 (0.98‐1.23)] beta‐blocker use, respectively. Analyses by beta‐blocker type, by cancer site, cancer stage and by cumulative dose showed no significant survival improvements for beta‐blocker users. However, there was a significant association between cumulative duration of use of 1‐12 months and increased overall mortality [1.20 (1.03‐1.39)]. Thus, our results do not support the hypothesis of a beneficial effect of pre‐ or post‐diagnostic beta‐blocker intake on CRC prognosis, neither for specific patient subgroups nor for specific types of beta‐blockers.

Patterns Of Metachronous Metastases After Curative Treatment Of Breast Cancer.

Background: This study aimed to provide information on timing, anatomical location, and predictors for metachronous metastases of colorectal cancer based on a large consecutive series of non-selected patients. Methods: All patients operated on with curative intent for colorectal cancer (TanyNanyM0) between 2003 and 2008 in the Dutch Eindhoven Cancer Registry were included (N = 5671). By means of active followup by the Cancer Registry staff within ten hospitals, data on development of metastatic disease were collected. Median follow-up was 5.0 years. Results: Of the 5671 colorectal cancer patients, 1042 (18%) were diagnosed with metachronous metastases. Most common affected sites were the liver (60%), lungs (39%), extra-regional lymph nodes (22%), and peritoneum (19%). 86% of all metastases was diagnosed within three years and the median time to diagnosis was 17 months (interquartile range 10–29 months). Male gender (HR = 1.2, 95%CI 1.03–1.32), an advanced primary T-stage (T4 vs. T3 HR = 1.6, 95%CI 1.32–1.90) and N-stage (N1 vs. N0 HR = 2.8, 95%CI 2.42–3.30 and N2 vs. N0 HR = 4.5, 95%CI 3.72–5.42), high-grade tumour differentiation (HR = 1.4, 95%CI 1.17–1.62), and a positive (HR = 2.1, 95%CI 1.68–2.71) and unknown (HR = 1.7, 95%CI 1.34–2.22) resection margin were predictors for metachronous metastases. Conclusions: Different patterns of metastatic spread were observed for colon and rectal cancer patients and differences in time to diagnosis were found. Knowledge on these patterns and predictors for metachronous metastases may enhance tailor-made follow-up schemes leading to earlier detection of metastasized disease and increased curative treatment options. 2014 Elsevier Ltd. All rights reserved.

Drug dispensings among elderly in the year before colon cancer diagnosis versus matched cancer-free controls.

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.