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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

Authors Weberpals J, Jansen L, Silversmit G, Verbeeck J, van der Geest LG, Vissers PAJ, Zadnik V, Brenner H

Received 28 December 2017

Accepted for publication 2 May 2018

Published 30 August 2018 Volume 2018:10 Pages 1109—1125


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 5

Editor who approved publication: Professor Vera Ehrenstein

Janick Weberpals,1 Lina Jansen,1 Geert Silversmit,2 Julie Verbeeck,2 Lydia van der Geest,3 Pauline AJ Vissers,3 Vesna Zadnik,4 Hermann Brenner1,5,6

1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Belgian Cancer Registry (BCR), Brussels, Belgium; 3Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands; 4Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia; 5Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; 6German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

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.

Keywords: immortal time bias, landmark analysis, pancreatic cancer, chemotherapy, population-based

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