Prediction of survival in patients with advanced, refractory colorectal cancer in treatment with trifluridine/tipiracil: real-world vs clinical trial data

Carmen Carriles Fernández,Paula Gonzalez Villarroel,Teresa Garcia García,Juan De la Cámara Gómez,Alberto Carmona-Bayonas,Ana Fernández Montes,José Carlos Méndez Méndez,Manuel Sanchez Cánovas,Nieves Martinez Lago,Antía Cousillas Castiñeiras,Marta Covela Rúa,Francisca Vázquez Rivera,Paula Jimenez-Fonseca

doi:10.1038/s41598-021-93732-5

Abstract

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer (mCRC). A post hoc exploratory analysis of the RECOURSE randomized clinical trial (RCT) established two categories, a good prognosis corresponding to subjects having a low tumor burden and indolent disease. Other models in refractory mCRC are the FAS-CORRECT and Colon Life nomogram. The main objective was to externally validate the prognostic factors of the RECOURSE and FAS-CORRECT trials, and the Colon Life nomogram in a multicenter, real-world series of mCRC treated in 3rd and successive lines with trifluridine/tipiracil. The secondary aim was to develop an OS predictive model, TAS-RECOSMO. Between 2016 and 2019, 244 patients were recruited. Median OS was 8.15 vs 8.12 months for the poor (85% of the subjects) and good (15%) prognosis groups from the RESOURCE trial, respectively, log-rank p = 0.9. The most common grade 3–4 toxicities were neutropenia (17%), asthenia (6%), and anemia (5%). The AFT lognormal model TAS-RECOSMO included six variables: ECOG-PS, KRAS/NRAS/BRAF mutation status, time between diagnosis of metastasis and beginning of trifluridine/tipiracil, NLR, CEA, and alkaline phosphatase. The model’s bootstrapped bias-corrected c-index was 0.682 (95% CI, 0.636–0.722). The factors from the Colon Life model, FAS-CORRECT, and RECOURSE displayed a c-index of 0.690, 0.630, and 0.507, respectively. TAS-RECOSMO, FAS-CORRECT, and the Colon Life nomogram appear to predict OS in patients with refractory mCCR who begin trifluridine/tipiracil treatment in the real world. The prognostic groups of the RECOURCE RCT were unable to capture the situation of real-world subjects treated with trifluridine/tipiracil in this series.

Highlights

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer
External validity is the dimension that is overlooked in ranking evidence, since some randomized clinical trial (RCT) may not be representative of the target population or exclude types of patients who do receive the therapy in the real w orld[17,18]
This pertains to average effects and safety concerns, but is key, inasmuch as it impacts the capacity to generalize the analyses of prognostic factors to specific populations

Summary

Introduction

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer (mCRC). The OS benefit does not project to all groups, casting doubt on the use of aggressive therapies in subjects with an expectation of limited survival or at the end of life when the foreseeable benefit is d iminished[4] Following this line of reasoning, Tabernero et al evaluated the prognostic factors in the RECOURSE trial, concluding that OS was independent of age, Eastern Cooperative Oncology Group Performance Status (ECOGPS), KRAS mutational status, and site of metastases at r andomization[5]. These models might help to enhance patient classification In this sense, we have sought to externally validate the RECOURSE RCT prognostic factors, as well as the Colon Life nomogram and FAS-CORRECT, in a multicenter, real-world series. We have elaborated the TAS-RECOSMO (TAS-102- trifluridine-tipiracil- in REfractory COlorectal cancer Spanish MOdel) model that makes individualized prediction possible in this population

Methods

Results

Conclusion