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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

Item does not contain fulltext As the value of palliative primary tumor resection in stage IV colorectal cancer (CRC) is still under debate, the purpose of this population-based study was to investigate if palliative primary tumor resection as the initial treatment after diagnosis was associated with improved overall survival. All patients with stage IV colorectal adenocarcinoma (2008-2011) were selected from the Netherlands Cancer Registry, and patients undergoing treatment with curative intent (i.e., metastasectomy, radiofrequency ablation and/or hyperthermic intraperitoneal chemotherapy), or best supportive care were excluded. After propensity score matching, a multivariable Cox proportional hazard model was performed to determine the association between treatment strategy and mortality. From a total group of 10,371 patients with stage IV CRC, 2,746 patients (26%) underwent an elective palliative resection of the primary tumor, whether or not followed by systemic therapy, and 3,345 patients (32%) were initially treated with palliative systemic therapy. After propensity score matching, median overall survival in these groups was 17.2 months (95% CI 16.3-18.1) and 11.5 months (95% CI 11.0-12.0), respectively. In Cox regression analysis, primary tumor resection was significantly associated with improved overall survival (hazard ratio of death = 0.44 [95% CI 0.35-0.55], p < 0.001). This large population-based study shows an overall survival benefit for patients with incurable stage IV CRC who underwent primary tumor resection as the initial treatment after diagnosis, compared to patients who started systemic therapy with the primary tumor in situ. This result is an argument in favor of resection of the primary tumor, even when patients have little to no symptoms.