Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: A cohort study

Pashtoon M. Kasi, Daisuke Kotani, Michael Cecchini, Kohei Shitara, Atsushi Ohtsu, Ramesk K Ramanathan, Howard S. Hochster, Axel F Grothey, Takayuki Yoshino

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Background: TAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan. Methods: CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of≥grade 2 (absolute neutrophil count<1500/mm3). Patients had confirmed mCRC that was refractory to standard therapies. Patient demographics and clinical characteristics were compared between patients with CIN-1-month (CIN-1-month positive) versus those who did not have CIN-1-month (CIN-1-month negative); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test. Results: Our cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1-month mark. Patients who developed≥grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P-value=0.01), as well as OS (14.0 versus 5.6 months; Log-rank P-value<0.0001). Only CIN-1-month (adjusted HR: 0.21 (95 % CI: 0.11-0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95 % CI: 1.22-3.35) were noted to be independent predictors of OS. Furthermore, the CIN-1-month was noted to be a statistically significantly predictor of OS over a wide range of cutoffs. Conclusions: Our observations are novel and hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. It can be postulated that the dosage of TAS-102 potentially may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Further pharmacologic investigations should help elucidate these issues.

Original languageEnglish (US)
Article number467
JournalBMC Cancer
Issue number1
StatePublished - Jul 13 2016



  • Biomarker
  • Chemotherapy induced neutropenia
  • Colorectal Cancer
  • Hematological toxicity
  • Pharmacogenomics
  • Predictive biomarker
  • Prognostic marker
  • TAS-102

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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