Open Access

ARTICLE

On-Treatment Grade 3–4 Neutropenia and Clinical Outcomes with Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer: ReTrITA Real-World Evidence

Carlo Signorelli^1,*, Michele Basso², Annunziato Anghelone², Maria Alessandra Calegari², Alessandro Passardi³, Chiara Gallio³, Alessandro Bittoni³, Jessica Lucchetti⁴, Lorenzo Angotti⁴, Emanuela Di Giacomo⁴, Ina Valeria Zurlo⁵, Cristina Morelli⁶, Emanuela Dell’Aquila⁷, Adele Artemi⁷, Donatello Gemma⁸, Domenico Cristiano Corsi⁹, Alessandra Emiliani⁹, Marta Ribelli⁹, Federica Mazzuca¹⁰, Giulia Arrivi¹⁰, Federica Zoratto¹¹, Maria Grazia Morandi¹², Fiorenza Santamaria^13,14, Manuela Dettori¹⁵, Antonella Cosimati¹⁶, Rosa Saltarelli¹⁷, Alessandro Minelli¹⁸, Emanuela Lucci-Cordisco¹⁹, Mario Giovanni Chilelli¹
1 Medical Oncology Unit, S. Rosa Hospital, ASL Viterbo, Viterbo, Italy
2 Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli-IRCCS, Rome, Italy
3 Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
4 Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, Rome, Italy
5 Medical Oncology, “Vito Fazzi” Hospital, Lecce, Italy
6 Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Rome, Italy
7 IRCCS Regina Elena National Cancer Institute, Rome, Italy
8 Medical Oncology Unit, ASL Frosinone, Sora, Italy
9 Medical Oncology, Isola Tiberina Hospital, Gemelli Isola, Rome, Italy
10 Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy
11 UOC Oncologia, Ospedale Santa Maria Goretti, ASL Latina, Latina, Italy
12 Medical Oncology Unit, San Camillo de Lellis Hospital, ASL Rieti, Rieti, Italy
13 UOC Oncology A, Policlinico Umberto I, Rome, Italy
14 Experimental Medicine, Network Oncology and Precision Medicine, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
15 Medical Oncology Department, Ospedale Oncologico Armando Businco, Cagliari, Italy
16 Medical Oncology Department, UO Oncologia Universitaria della Casa della Salute di Aprilia, Aprilia, Italy
17 UOC Oncology, San Giovanni Evangelista Hospital, ASL RM5, Tivoli, Italy
18 Medical Oncology Dept., UO Oncologia, Ospedale San Paolo, ASL RM4, Civitavecchia, Italy
19 UOC Genetica Medica, Dipartimento di Scienze della Vita e Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
* Corresponding Author: Carlo Signorelli. Email:
(This article belongs to the Special Issue: Precision Beyond Progression: Real-World Evidence and Dynamic Prognostic Markers in Refractory Metastatic Colorectal Cancer)

Oncology Research https://doi.org/10.32604/or.2026.080964

Received 19 February 2026; Accepted 24 April 2026; Published online 01 June 2026

Abstract

Background: Trifluridine/tipiracil (T) is a standard treatment for refractory metastatic colorectal cancer (mCRC). In randomized trials, treatment-emergent neutropenia has been associated with improved outcomes, suggesting a potential link with drug activity. However, evidence from routine clinical practice remains limited. This sub-analysis of the multicenter ReTrITA study evaluated the association between severe neutropenia and clinical outcomes in a real-world setting. Methods: Patients with refractory mCRC treated with T within the ReTrITA cohort were included. Patients were stratified according to the occurrence of grade 3–4 neutropenia. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method and compared with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox models. Results: Among 843 patients, 271 (32.1%) developed grade 3–4 neutropenia. The occurrence of severe neutropenia was significantly associated with improved survival outcomes. Median OS was 10.9 months versus 7.6 months, HR 0.64; 95% CI, 0.55–0.75; p < 0.0001), and median PFS was 4.3 months versus 3.3 months (HR 0.63; 95% CI, 0.55–0.73; p < 0.0001) in patients with versus without neutropenia, respectively. Conclusions: In this large real-world cohort, grade 3–4 neutropenia during T treatment was associated with significantly improved OS and PFS, supporting its role as a potential on-treatment prognostic marker. Prospective studies are warranted to confirm these findings.

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Keywords

Trifluridine/tipiracil; metastatic colorectal cancer; neutropenia; real-world evidence; survival outcomes; prognostic biomarkers

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