Prognostic Impact of Severe Neutropenia in Colorectal Cancer Patients Treated with TAS-102 and Bevacizumab, Addressing Immortal-Time Bias

Background Several studies have reported an association between severe neutropenia and long-term survival in patients treated with trifluridine-tipiracil (TAS-102). Because some of these studies failed to address immortality time bias, however, their findings should be interpreted with caution. Additionally, the association between severe neutropenia and survival in patients receiving TAS-102 in combination with bevacizumab (Bmab) remains unclear. Patients and methods We conducted a single-center retrospective cohort study in patients with colorectal cancer who received Bmab + TAS-102. We compared overall survival (OS) between patients who developed grade ≥ 3 neutropenia during the treatment period and those who did not. To account for immortal time bias, we used two approaches, time-varying Cox regression and landmark analysis. Results Median OS was 15.3 months [95% CI: 14.1–NA] in patients with grade ≥ 3 neutropenia and 10.0 months [95% CI: 8.1–NA] in those without. In time-varying Cox regression, onset grade ≥ 3 neutropenia was significantly related to longer survival after adjustment for age and modified Glasgow Prognostic Score. Additionally, 30-, 60-, 90-, and 120-day landmark analysis showed that grade ≥ 3 neutropenia was associated with longer survival after adjustment for age and modified Glasgow Prognostic Score, with respective HRs of 0.30 [0.10–0.90], 0.65 [0.30–1.42], 0.39 [0.17–0.90], and 0.41 [0.18–0.95]. Conclusion We identified an association between long-term survival and the development of severe neutropenia during the early cycle of Bmab + TAS-102 using an approach that addressed immortality time bias.