Janick Weberpals

Beta blockers and cancer prognosis - The role of immortal time bias: A systematic review and meta-analysis.

BACKGROUND Findings from experimental and observational studies have suggested beneficial effects of beta blocker (BB) use on cancer survival. Nevertheless, results have been inconclusive and there have been concerns that the observed associations might have resulted from immortal time bias (ITB). We conducted a systematic review and meta-analysis to summarize existing evidence, paying particular attention to this potential source of bias. METHODS A systematic literature search was performed in PubMed and Web of Science. Studies investigating the association between BB use and overall or cancer-specific survival were included. Summary estimates were derived from meta-analyses using random effects models. The potential influence of ITB was investigated. RESULTS We identified 30 eligible studies including 88,026 cancer patients in total. We deemed 11 studies to be at high or unclear risk of ITB. Including all studies in the meta-analysis, BB users had a significantly better overall (hazard ratio (HR) 0.88, 95% CI 0.79-0.97) and cancer-specific (HR 0.75, 95% CI 0.64-0.88) survival. Excluding the studies deemed to be prone to ITB resulted in HRs (95% CIs) of 1.00 (0.93-1.07) and 0.90 (0.83-0.98), respectively. Analyses on cancer site and BB type did not show beneficial associations besides overall survival among melanoma patients. However, melanoma-specific survival was not improved. CONCLUSION We found no clinically meaningful evidence for an association between BB use and survival after excluding studies with a possible ITB. Our results support suggestions that the proposed beneficial effect of BBs on cancer survival might be based on ITB.

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.

Survival of patients with lymphoplasmacytic lymphoma and solitary plasmacytoma in Germany and the United States of America in the early 21st century

Population-level survival has increased for a number of hematologic malignancies.[1][1]–[3][2] Multiple myeloma, in particular, has seen improved survival both in clinical trials[4][3]–[8][4] and on the population level.[3][2],[9][5]–[11][6] However, it is not known whether the changes in

Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses

Introduction The association of lifestyle factors with molecular pathological subtypes of colorectal cancer (CRC), such as microsatellite instability (MSI), could provide further knowledge about the colorectal carcinogenic process. The aim of this review was to evaluate possible associations between lifestyle factors and risk of sporadic CRC by MSI status. Methods PubMed and Web of Science were searched for studies investigating the association between alcohol, body mass index, dietary fiber, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs, physical activity, red meat, smoking, or statin use, with MSI-high (MSI-H) and microsatellite stable (MSS) CRC. Meta-analyses were carried out to calculate summary relative risks (sRR). Results Overall, 31 studies reporting on the association between lifestyle factors and CRC according to MSI status were included in this review. Ever smoking was associated with MSI-H (sRR = 1.62; 95% CI: 1.40-1.88) and MSS/MSI-low CRC (sRR = 1.10; 95% CI: 1.01-1.20), but the association was significantly stronger for MSI-H CRC. The use of HRT was associated with a 20% decrease (sRR = 0.80; 95% CI: 0.73-0.89) in the risk of MSS CRC, but was not associated with MSI-H CRC. An increase in body mass index per 5 kg/m2 was equally associated with MSS and MSI-H CRC (sRR = 1.22, in both cases), but was statistically significant for MSS CRC only (95% CI: 1.11-1.34 and 0.94-1.58, respectively). Limited evidence for associations between other lifestyle factors and CRC by MSI status exists. Conclusions Lifestyle factors, such as HRT and smoking are differentially associated with the risk of MSI-H and MSS CRC. Further research on associations of lifestyle factors and CRC subtypes is necessary to provide a better understanding of the CRC disease pathway.

Pre- and post-diagnostic β-blocker use and lung cancer survival: A population-based cohort study

Beta-blockers have been associated with decreased cancer mortality. However, evidence for lung cancer is sparse and reported beneficial effects might be based on biased analyses. In this so far largest study we investigated the association between β-blocker use and lung cancer survival. Therefore, patients with a lung cancer diagnosis between April 1998 and December 2011 were selected from a database linkage of the Netherlands Cancer Registry and the PHARMO Database Network. After matching eligible patients on the propensity score, adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were calculated using Cox proportional hazards regression to investigate the association between pre-diagnostic and time-dependent β-blocker use and overall survival. Duration and dose-response analyses and stratified analyses by β-blocker type, histological subgroups and stage were conducted. Of 3,340 eligible lung cancer patients, 1437 (43%) took β-blockers four months prior to diagnosis. Pre-diagnostic β-blocker use was not associated with overall survival (HR 1.00 (0.92–1.08)) in the adjusted model. Time-dependent post-diagnostic analysis showed similar results with a HR of 1.03 (0.94–1.11). Trend analyses showed no association for cumulative dose (HR 0.99 (0.97–1.02)) and cumulative duration (HR 1.00 (0.96–1.05)). In conclusion, β-blocker use is not associated with reduced mortality among lung cancer patients.

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.

A population-based registry study on relative survival from melanoma in Germany stratified by tumor thickness for each histological subtype

Background: Differences in relative survival (RS) of melanoma between histologic subtypes were discussed to be mainly caused by tumor thickness. Objective: To investigate RS of melanoma, stratified by tumor thickness for each histologic subtype, and identify survival trends. Methods: With use of cancer registry data on melanoma cases (International Classification of Diseases, 10th Revision, codes C43.0–C43.9) diagnosed in Germany in 1997–2013, 5‐ and 10‐year age‐standardized RS stratified by histologic subtype and stratified or standardized by T stage was estimated by standard and modeled period analyses. We restricted 10‐year RS analyses to patients younger than 75 years. Results: We analyzed 82,901 cases. Overall, the 5‐ and 10‐year RS rates were 91.7% and 90.8%, respectively. Prognosis worsened with increasing T stage for all histologic subtypes, but T‐stage distribution varied substantially. Survival differences by histologic subtype were strongly alleviated after adjustment for T stage but remained significant. Overall, 5‐year RS increased significantly (by 3.8 percentage points) between the periods 2002–2005 and 2010–2013. This increase was no longer seen after adjustment for T stage. Limitations: Exclusion of cases on account of missing information on T stages, changes in the definition of T stages, and lack of information on screening and treatment limit our analyses. Conclusion: Differences in RS between histologic subtypes were strongly mediated by tumor thickness. Over time, RS of melanoma increased as a result of changes in T‐stage distribution.

Survival of patients with hepatobiliary tract and duodenal cancer sites in Germany and the United States in the early 21st century: Hepatobiliary tract cancer patient survival

Hepatobiliary tract cancers (HBTCs) are a heterogeneous group of cancers with high mortality. Because most of these cancers, with the exception of hepatocellular carcinoma (HCC), are rare, few data are available concerning the population level survival expectations of patients with HBTC. Here, we describe survival of patients with HBTC in Germany with comparison to survival in the US. Therefore, data were extracted from 12 databases in Germany and the Surveillance, Epidemiology and End Results (SEER13) database in the US. Period analysis and modeled period analysis were used to calculate 5‐year relative survival estimates for patients with HBTC diagnosed from 1997 to 2013. HCC was the most common HBTC in each database, accounting for over 1/3 of HBTC in Germany and about half of cases in the US. Overall age adjusted 5‐year relative survival for HBTC in 2006‐2013 was 19.1% in Germany and 20.6% in the US. Five‐year relative survival increased by 3.8% units in Germany and 4.5% units in the US between 2002–2005 and 2010–2013. Five‐year relative survival for individual types of HBTC ranged from 9.8% in Germany and 2.9% in the US for not otherwise specified biliary tract cancers to 44.4% and 50.1%, respectively, in Germany and the US for duodenal cancers. In conclusion, survival for HBTC remains poor in both Germany and the US, although a small increase in survival in the past decade was observed. Further work to find better treatment options for HBTC is needed to improve survival.

Comparative performance of a modified landmark approach when no time of treatment data are available within oncological databases: exemplary cohort study among resected pancreatic cancer patients

Purpose The Mantel–Byar method is the gold standard analytical approach to avoid immortal time bias, but requires information on the time between start of follow-up and exposure initiation. Alternatively, a modified landmark approach might be used to mitigate the amount of immortal time bias, which assumes exposure initiation at a predefined landmark time. In the context of an expected positive association between adjuvant chemotherapy (ACT) and overall survival among resected pancreatic cancer (PCa) patients, this study aims to empirically assess the performance of this approach relative to the Mantel–Byar method. Patients and methods Data from resected PCa patients diagnosed between 2003 and 2014 and registered in the national cancer registries of Belgium, the Netherlands, and Slovenia were used to estimate the association between ACT and overall survival using a Cox proportional hazards model by country and overall. Results derived from the immortal time bias (misclassifying the time to ACT initiation), Mantel–Byar method, and conventional and modified landmark analyses with assumed cutoff times of ACT initiation at 9, 12 and 15 weeks post-diagnosis were compared. Results In total, 5,668 patients with a total of 10,921 person-years of follow-up were eligible. All analytical approaches showed a significant survival benefit for resected PCa patients who received ACT, but immortal time bias analyses led to strong overestimation of ACT benefits compared to the Mantel–Byar method (immortal time bias: overall HR [95% CI] 0.68 [0.62–0.75] vs Mantel–Byar method: 0.82 [0.71–0.93]), whereas the conventional landmark approach generally provided rather conservative estimates (0.86 [0.75–1.00], 15 weeks landmark). HRs derived from modified landmark analyses depended on the cutoff time, but were similar compared to the Mantel–Byar method at 15 weeks (0.81 [0.70–0.94]). Conclusion A modified landmark approach might be a valid alternative to the Mantel–Byar method if no time of treatment information is available. The performance depends on the chosen cutoff time.