Journal Article

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

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

2016

Overview

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/mm 3 ). 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Age Factors / Aged / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - adverse effects / Antineoplastic Agents - therapeutic use / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer therapies / Care and treatment / Chemotherapy / Chemotherapy-Induced Febrile Neutropenia - etiology / Clinical Trials, Phase III as Topic / Cohort analysis / Cohort Studies / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - mortality / Colorectal Neoplasms - pathology / Disease-Free Survival / Dose-Response Relationship, Drug / Drug Combinations / Drug dosages / Drug Resistance, Neoplasm / FDA approval / Female / Health Promotion and Disease Prevention / Hematology / Humans / Hypotheses / Japan / Kaplan-Meier Estimate / Male / Medical and radiation oncology / Medicine/Public Health / Metastasis / Middle Aged / Neutropenia / Neutrophils / Oncology / Prognosis / Research Article / Risk factors / Surgical Oncology / Toxicity / Trifluridine - administration & dosage / Trifluridine - adverse effects / Trifluridine - therapeutic use / United States / Uracil - administration & dosage / Uracil - adverse effects / Uracil - analogs & derivatives / Uracil - therapeutic use