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.