title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, 55905, MN, USA. kasi.pashtoon@mayo.edu.
authors.forename: Pashtoon M
authors.initials: PM
authors.lastname: Kasi
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kotani
authors.affiliation: Division of Medical Oncology, Yale Cancer Center, New Haven, CT, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cecchini
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Scottsdale, Arizona, USA.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.affiliation: Division of Medical Oncology, Yale Cancer Center, New Haven, CT, USA.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Hochster
authors.affiliation: Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, 55905, MN, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
mesh_terms: D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000209:etiology*; D017326:Clinical Trials, Phase III as Topic; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011759:Pyrrolidines; D013941:Thymine; D014271:Trifluridine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014481:United States; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine
keywords: Biomarker; Chemotherapy induced neutropenia; Colorectal Cancer; Hematological toxicity; Pharmacogenomics; Predictive biomarker; Prognostic marker; TAS-102