MCO Molecular and Clinical Oncology 2049-9450 2049-9469 D.A. Spandidos MCO-24-1-02915 10.3892/mco.2025.2915 Articles Impact of TAS-102 dose reduction on severe neutropenia and survival outcomes in patients with metastatic colorectal cancer and prior chemotherapy-induced neutropenia SuzukiChihiro 1 KimuraMichio 2 GoMakiko 2 IkedaYoshiaki 1 UsamiEiseki 2 Faculty of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya, Aichi 463-8521, Japan Department of Pharmacy, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan Correspondence to: Mr. Michio Kimura, Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8502, Japan kimkim0305nao@yahoo.co.jp 012026 07112025 24 1 6 27 06 2025 03 10 2025 Copyright © 2025, Spandidos Publications 2025

The present study aimed to evaluate the impact of initial dose reduction of trifluridine/tipiracil (TAS-102) monotherapy on the incidence of severe neutropenia and overall survival (OS) in individuals with metastatic colorectal cancer, considering prior chemotherapy-induced severe neutropenia. Participants were classified into the following three groups: A group, individuals who did not experience severe neutropenia during previous chemotherapy and did not undergo dose reduction (n=61); B1 group, those who experienced severe neutropenia during previous chemotherapy and received an initial dose reduction of TAS-102 (n=28); and B2 group, those who experienced severe neutropenia but did not receive a dose reduction (n=88). Neutropenia severity, progression-free survival (PFS) and OS were compared among the groups. Notably, there was no significant difference in the incidence of grade 3 or higher neutropenia among the three groups during TAS-102 administration (P=0.958). The median OS times in the A group (n=61), B1 group (n=28) and B2 group (n=88) were 273 days (95% CI, 199-299), 285 days (95% CI, 202-NA) and 233 days (95% CI, 182-272), respectively (log-rank test, P=0.165). The median PFS times among the three groups were 133.0 days (95% CI, 98-153), 94.5 days (95% CI, 77-133) and 93.5 days (95% CI, 83-100), respectively (log-rank test, P=0.053). In conclusion, a proactive dose reduction at TAS-102 treatment initiation based on pre-existing severe neutropenia should be carefully considered, as it may not be necessary.

 severe neutropenia trifluridine/tipiracil overall survival dose reduction pre-chemotherapy metastatic colorectal cancer Funding: No funding was received. Introduction

Trifluridine/tipiracil (TAS-102) is an oral antitumour agent comprising a thymidine-based nucleic acid analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, at a molar ratio of 1:0.5. In a phase 3 clinical trial, TAS-102 demonstrated a significant survival benefit over placebo in terms of overall survival (OS) in individuals with metastatic colorectal cancer (mCRC) who were unresponsive to standard therapies, including fluoropyrimidines, irinotecan, and oxaliplatin (1,2). Additionally, a randomised phase 2 trial revealed that TAS-102 in combination with bevacizumab (Bmab) extended progression-free survival (PFS) compared to that of TAS-102 monotherapy (3).

Neutropenia is the most frequently observed adverse event (AE) associated with TAS-102 monotherapy. In the RECOURSE trial, 37.9% of individuals receiving TAS-102 monotherapy developed grade 3 or higher neutropenia (1). Furthermore, the incidence of grade 3 or higher neutropenia was higher in individuals receiving TAS-102 plus Bmab than in those receiving TAS-102 monotherapy (67% vs. 38%) (3). Several retrospective cohort studies have suggested that the development of neutropenia during TAS-102 monotherapy or TAS-102 plus Bmab therapy is associated with improved long-term survival (4-7).

In cases where TAS-102 cannot be combined with Bmab, TAS-102 monotherapy is administered, often as a late-line treatment following regimens known to cause bone marrow suppression such as FOLFOX (fluorouracil/leucovorin and oxaliplatin) therapy. To mitigate severe neutropenia, dose reduction of TAS-102 may be considered from the initial administration, particularly in individuals with a history of severe neutropenia from prior chemotherapy. However, given that severe neutropenia is a prognostic factor, there is concern that reducing the dose could not only lower the risk of neutropenia but also potentially compromise OS.

Understanding the impact of dose reduction at the initiation of TAS-102 monotherapy in mCRC management is crucial for optimising treatment strategies. Therefore, this study aimed to investigate the effect of dose reduction during the initial administration of TAS-102 monotherapy on the occurrence of severe neutropenia and OS.

 Patients and methods <sec> <title>Patients and evaluations

A total of 203 patients treated with TAS-102 among patients with advanced or recurrent colorectal cancer (CRC) at Ogaki Municipal Hospital (Ogaki, Japan) between January 2015 and December 2024 were retrospectively evaluated. Patients who were unable to complete one course of TAS-102 and who received TAS-102 in combination with Bmab were excluded from the study, as this regimen had not yet been routinely adopted at our institution during the study period. Furthermore, patients who underwent an initial dose reduction of TAS-102 for reasons other than neutropenia were excluded from the study. Thus, 177 patients were considered eligible for this study. Participants were categorised into those who did not experience severe neutropenia during previous chemotherapy and did not undergo dose reduction (A group, n=61), those who experienced severe neutropenia during previous chemotherapy and received an initial dose reduction of TAS-102 (B1 group, n=28), and those who had severe neutropenia but did not receive a dose reduction (B2 group, n=88). The flow diagram is presented in Fig. 1. We analysed the patients' characteristics, OS, PFS, and neutropenia grade with TAS-102 treatment in patients with CRC using data collected from electronic charts and pharmacy service records. AEs were evaluated according to the Common Terminology Criteria for Adverse Events, version 5.0(8), and the most severe grades during chemotherapy were reported. Personal information was protected in aggregated data. The study protocol was approved by the Institutional Review Board of Ogaki Municipal Hospital, Ogaki, Japan (approval no. 202520227-22). The requirement for informed consent was waived owing to the retrospective study design. Consent to participate was waived by the Institutional Review Board of Ogaki Municipal Hospital owing to the retrospective study design. Consent to publish was also waived by the Institutional Review Board for the same reason.

 Treatment protocol

Trifluridine/tipiracil combination tablet: TAS-102 (at a dose of 35 mg per square metre) was administered twice daily after morning and evening meals for 5 days, followed by a 2-day rest period. This regimen was repeated for 2 weeks, followed by a 14-day rest period, constituting one treatment cycle. The cycle was repeated every 4 weeks.

The dose of TAS-102 was generally reduced by one level in individuals with severe neutropenia due to prior chemotherapy.

 Statistical analysis

Kruskal-Wallis tests or Fisher's exact probability tests were used for comparisons of patient characteristics, AEs, and reasons for treatment discontinuation. Steel-Dwass test was used for multiple comparisons of creatinine clearance among the 3 groups. The Kaplan-Meier method and log-rank tests were used to compare treatment duration. P<0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed using EZR software (v1.30; Saitama Medical Centre, Jichi Medical University, Saitama, Japan) (9).

 Results <sec> <title>Patient characteristics

The patient characteristics are summarised in Table I. Differences in creatinine clearance were observed among the 3 groups. Moreover, differences were observed in certain metastatic sites. No significant differences were observed in other variables.

A significant difference in creatinine clearance was observed between groups A and B2 (P=0.006). No difference was observed between groups A and B1 or between groups B1 and B2 (P=0.059, 0.892, respectively).

No significant differences were observed in prior treatment regimens among the three groups (Table I).

 Overall survival according to the highest neutropenia grade

Kaplan-Meier survival curves stratified by neutropenia severity are presented in Fig. 2. The median OS in the absent (n=40), mild (n=49), and severe (n=88) neutropenia groups was 147 days (95% CI, 126-176), 234 days (95% CI, 183-281), and 300 days (95% CI, 269-393), respectively (log-rank test, P<0.001).

 Neutropenia grade during TAS-102 administration

Neutropenia grades among the 3 groups during TAS-102 administration are presented in Table II. There was no significant difference in the incidence of grade 3 or higher neutropenia among the 3 groups during TAS-102 administration (P=0.958). Differences in the incidence of grade 0 neutropenia were observed among the 3 groups (P=0.033). The dose reductions of TAS-102 based on severe neutropenia due to prior chemotherapy were as follows: 10 cases of a one-step dose reduction; 16 cases of a two-step dose reduction; 2 cases of a three-step dose reduction.

 OS and PFS

OS and PFS among the 3 groups are presented in Fig. 3. The median OS in the A group (n=61), B1 group (n=28), and B2 group (n=88) were 273 days (95% CI, 199-299), 285 days (95% CI, 202-NA), and 233 days (95% CI, 182-272), respectively (log-rank test, P=0.165). The median PFS among the 3 groups were 133.0 days (95% CI, 98-153), 94.5 days (95% CI, 77-133) and 93.5 days (95% CI, 83-100), respectively (log-rank test, P=0.053).

 Renal function and treatment outcomes

OS and PFS between the high and low Ccr groups are presented in Fig. 4. To evaluate whether renal function affected the incidence of severe neutropenia or survival outcomes, a subgroup analysis was performed by stratifying patients according to creatinine clearance (Ccr), using the median value of 70.6 ml/min as the cutoff. Of the 177 patients, 89 were in the high Ccr group (≥70.6 ml/min), and 88 were in the low Ccr group (<70.6 ml/min).

The incidence of grade ≥3 neutropenia was similar between the two groups: 49/89 (55.1%) in the high Ccr group and 49/88 (55.7%) in the low Ccr group. There was no statistically significant difference in the rate of neutropenia.

Median progression-free survival (PFS) was 104 days (95% CI: 92-119) in the high Ccr group and 92.5 days (95% CI: 84-112) in the low Ccr group (P=0.789). Median overall survival (OS) was 262 days (95% CI: 199-285) in the high Ccr group and 253 days (95% CI: 201-299) in the low Ccr group (P=0.411).

 Discussion

This study is the first to clarify the impact of initial dose reduction of TAS-102 monotherapy for colorectal cancer (CRC) on the incidence of severe neutropenia and overall survival (OS). Our results showed that patients who developed severe neutropenia had longer OS, consistent with previous reports linking chemotherapy-induced neutropenia to better prognosis (7,10-14). Despite a history of severe neutropenia from prior chemotherapy, initial dose reduction of TAS-102 did not reduce the incidence of severe neutropenia, nor did it improve progression-free survival (PFS) or OS compared to standard dosing.

Neutropenia may serve as a surrogate marker of adequate drug exposure and antitumor activity (15-19). However, factors such as prior treatment regimens, baseline comorbidities, renal function, and actual dose intensity may also influence outcomes. We considered performing multivariate analysis including creatinine clearance (Ccr); however, due to the small sample size and limited number of events in the B1 subgroup (n=28), it was challenging to ensure the reliability of a multivariate model. Nonetheless, we acknowledge the importance of further investigation, and future large-scale prospective studies incorporating multivariate analyses including Ccr are warranted to better elucidate its potential confounding effect. We therefore performed subgroup analyses stratified by Ccr, which showed no significant differences in neutropenia incidence or survival, suggesting renal function was unlikely to confound our main findings. In addition, prior treatment regimens were comparable across groups, as shown in Table I, indicating that this factor was unlikely to bias the results. By contrast, detailed comorbidity profiles and relative dose intensity were not systematically evaluated in this study, which should be acknowledged as limitations.

Consistent with this, no differences in severe neutropenia or survival outcomes were observed between dose-reduction and non-dose-reduction groups. A borderline trend in PFS (P=0.053) may reflect the association between neutropenia and improved OS but did not translate into significant group differences.

Baseline absolute neutrophil count (ANC) has been reported as a prognostic factor, with higher ANC correlating with poorer outcomes and lower ANC predicting increased neutropenia risk and better survival (20-22). In our cohort, baseline ANC did not differ significantly between dose groups, even among patients with prior severe neutropenia, supporting the notion that initial dose reduction was not guided by baseline ANC.

While TAS-102 pharmacokinetics can be affected by renal function due to the renal excretion of tipiracil, 3 our analyses did not detect a significant impact of renal function on toxicity or efficacy, aligning with previous studies (23,24).

Traditional chemotherapy dosing based on body surface area (BSA) may not fully account for interindividual variability; lean body mass (LBM) and body composition analyses are emerging tools for dose individualization (25-27). However, these factors were not directly assessed in our study and should be explored in future research.

Limitations of this study include its single-center retrospective design, which may introduce selection bias and limit generalizability. Additionally, patients receiving TAS-102 combined with bevacizumab, a common regimen that may increase neutropenia incidence, were excluded. The relatively small sample size in certain subgroups and absence of multivariate analysis also limit definitive conclusions. Therefore, future studies with larger sample sizes are needed to confirm these findings.

Current NCCN and ESMO guidelines recommend initiating TAS-102 at full approved doses, with dose modifications guided by observed toxicities rather than preemptive reductions (28,29). Our findings support this approach, suggesting that initial dose reduction based solely on prior severe neutropenia may not be necessary. Standard dosing with close monitoring remains the preferred clinical strategy.

In conclusion, although grade ≥3 neutropenia frequently leads to treatment interruptions during TAS-102 monotherapy, preemptive initial dose reduction does not reduce neutropenia incidence or improve survival outcomes. Careful monitoring and appropriate dose adjustments during treatment are essential to optimize efficacy and safety.

 Acknowledgements

Not applicable.

 Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

 Authors' contributions

CS and MK contributed to the study design, collected and provided the data, served as the principal authors of the report, and are the guarantors of the article and all associated data. MG, YI and EU contributed to the study design, reviewed the manuscript, and supervised the drafting of the report and the submission process. CS and MK confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

 Ethics approval and consent to participate

The study protocol was approved by the Institutional Review Board of Ogaki Municipal Hospital (Ogaki, Japan; approval no. 202520227-22). Consent to participate was waived by the Institutional Review Board of Ogaki Municipal Hospital owing to the retrospective study design.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing interests.

 References MayerRJVan CutsemEFalconeAYoshinoTGarcia-CarboneroRMizunumaNYamazakiKShimadaYTaberneroJKomatsuYRandomized trial of TAS-102 for refractory metastatic colorectal cancerN Engl J Med3721909191920152597005010.1056/NEJMoa1414325 XuJKimTWShenLSriuranpongVPanHXuRGuoWHanSWLiuTParkYSResults of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA studyJ Clin Oncol3635035820182921595510.1200/JCO.2017.74.3245 PfeifferPYilmazMMöllerSZitnjakDKroghMPetersenLNPoulsenLØWintherSBThomsenKGQvortrupCTAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: An investigator-initiated, open-label, randomised, phase 2 trialLancet Oncol2141242020203199994610.1016/S1470-2045(19)30827-7 KimuraMUsamiEIwaiMTeramachiHYoshimuraTSevere neutropenia: A prognosticator in patients with advanced/recurrent colorectal cancer under oral trifluridine-tipiracil (TAS-102) chemotherapyPharmazie72495220172944189710.1691/ph.2017.6808 NoseYKagawaYHataTMoriRKawaiKNaitoASakamotoTMurakamiKKatsuraYOhmuraYNeutropenia is an indicator of outcomes in metastatic colorectal cancer patients treated with FTD/TPI plus bevacizumab: A retrospective studyCancer Chemother Pharmacol8642743320203281615510.1007/s00280-020-04129-6 KasiPMKotaniDCecchiniMShitaraKOhtsuARamanathanRKHochsterHSGrotheyAYoshinoTChemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: A cohort studyBMC Cancer1646720162741246410.1186/s12885-016-2491-y KamiimabeppuDOsumiHShinozakiEOokiAWakatsukiTYoshinoKSatoTNakayamaIOguraMTakahariDEffect of neutropenia on survival outcomes of patients with metastatic colorectal cancer receiving trifluridine/tipiracil plus bevacizumabOncol Lett2278320213459442410.3892/ol.2021.13044 US Department Of Health And Human Services: Common terminology criteria for adverse events (CTCAE) version 5.0. United States, National Cancer Institute, 2017. (https://ctep.Cancer.Gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf). KandaYInvestigation of the freely available easy-to-use software ‘EZR’ for medical statisticsBone Marrow Transplant4845245820132320831310.1038/bmt.2012.244 IkagawaMKimuraMIwaiMUsamiEYoshimuraTYasudaKNeutropenia as a prognostic factor and safety of second-line therapy with S-1 for advanced or recurrent pancreatic cancerMol Clin Oncol528328820162758819410.3892/mco.2016.940 KimuraKUsamiEYoshimuraTAssociation between severe neutropenia and progression-free survival in patients with advanced or recurrent breast cancer treated with PalbociclibPharmazie7566266520203330306110.1691/ph.2020.0761 WatanabeDFujiiHOhataKIiharaHMakiyamaAKobayashiRHiroseCHishidaSMatsuokaSTajimaJYPrognostic impact of severe neutropenia in colorectal cancer patients treated with TAS-102 and bevacizumab, addressing immortal-time biasBMC Cancer23107820233794087810.1186/s12885-023-11618-3 Domínguez SenínLRodriguez GarcésMYAviñó TarazonaVAmor UrbanoMSantos-RubioMDBayo CaleroJAnalysis of neutropenia as a predictive factor of the efficacy of trifluridine-tipiracil treatmentInt J Clin Pharmacol Ther6134635320233728883510.5414/CP204410 GiulianiJBonettiAThe onset of grade ≥3 neutropenia is associated with longer overall survival in metastatic colorectal cancer patients treated with trifluridine/tipiracilAnticancer Res393967396920193126292910.21873/anticanres.13551 ShitaraKMatsuoKTakahariDYokotaTInabaYYamauraHSatoYNajimaMUraTMuroKNeutropaenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOXEur J Cancer451757176320091921727810.1016/j.ejca.2009.01.019 ShitaraKMatsuoKTakahariDYokotaTShibataTUraTItoSSawakiATajikaMKawaiHMuroKNeutropenia as a prognostic factor in advanced gastric cancer patients undergoing second-line chemotherapy with weekly paclitaxelAnn Oncol212403240920102049496210.1093/annonc/mdq248 GurneyHDose calculation of anticancer drugs: A review of the current practice and introduction of an alternativeJ Clin Oncol14259026111996882334010.1200/JCO.1996.14.9.2590 GamelinEDelvaRJacobJMerroucheYRaoulJLPezetDDorvalEPiotGMorelABoisdron-CelleMIndividual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial of patients with metastatic colorectal cancerJ Clin Oncol262099210520081844583910.1200/JCO.2007.13.3934 YoshinoTClearyJMVan CutsemEMayerRJOhtsuAShinozakiEFalconeAYamazakiKNishinaTGarcia-CarboneroRNeutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trialsAnn Oncol31889520203191280110.1016/j.annonc.2019.10.005 YoshinoTLenzHJReply to the letter to the editor ‘Neutropenia in metastatic colorectal cancer receiving trifluridine/tipiracil’ by Colloca et alAnn Oncol31108510872020 GrotheyAYoshinoTBodokyGCiuleanuTGarcia-CarboneroRGarcía-AlfonsoPVan CutsemEMuroKMytelkaDSLiLAssociation of baseline absolute neutrophil counts and survival in patients with metastatic colorectal cancer treated with second-line antiangiogenic therapies: Exploratory analyses of the RAISE trial and validation in an electronic medical record data setESMO Open3e00034720182971349810.1136/esmoopen-2018-000347 CarusAGurneyHGebskiVHarnettPHuiRKeffordRWilckenNLadekarlMvon der MaaseHDonskovFImpact of baseline and nadir neutrophil index in non-small cell lung cancer and ovarian cancer patients: Assessment of chemotherapy for resolution of unfavourable neutrophiliaJ Transl Med1118920132394520010.1186/1479-5876-11-189 YasueFKimuraMUsamiEIwaiMKawachiSMitsuokaMIkedaYYoshimuraTRisk factors contributing to the development of neutropenia in patients receiving oral trifluridine-tipiracil (TAS-102) chemotherapy for advanced/recurrent colorectal cancerPharmazie7317818120182954456810.1691/ph.2018.7908 SaitoYTakekumaYKomatsuYSugawaraMImpact of renal impairment on early development of severe neutropenia with trifluridine/tipiracil treatment for metastatic colorectal cancerSci Rep142699020243950602110.1038/s41598-024-78741-4 GurneyHHow to calculate the dose of chemotherapyBr J Cancer861297130220021195388810.1038/sj.bjc.6600139 NewellDRGetting the right dose in cancer chemotherapy-time to stop using surface area?Br J Cancer861207120820021195387310.1038/sj.bjc.6600226 DramiIPringETGouldLMalietzisGNaghibiMAthanasiouTGlynne-JonesRJenkinsJTBody composition and dose-limiting toxicity in colorectal cancer chemotherapy treatment; a systematic review of the literature. Could muscle mass be the new body surface area in chemotherapy dosing?Clin Oncol (R Coll Radiol)33e540e55220213414732210.1016/j.clon.2021.05.011 BensonABVenookAPAdamMChangGChenYJCiomborKKCohenSACooperHSDemingDGarrido-LagunaIColon Cancer, version 3.2024, NCCN clinical practice guidelines in oncologyJ Natl Compr Canc Netw22 (2 D)e24002920243886200810.6004/jnccn.2024.0029 KissINew ESMO guidelines for clinical practice in metastatic colorectal cancer-commentary on changes in systemic therapyKlin Onkol3647347620233815823710.48095/ccko2023473

Flow diagram. TAS-102, trifluridine/tipiracil combination tablet; Bmab, bevacizumab.

Kaplan-Meier survival curves for overall survival based on neutropenia severity. The Kaplan-Meier survival curves illustrate overall survival following therapy with TAS-102 in 3 patient groups, including absent, mild (grade 1 or 2 neutropenia), and severe (grade 3 or 4 neutropenia). A significant difference was observed among the 3 groups (P<0.001). TAS-102, trifluridine/tipiracil combination tablet.

Kaplan-Meier survival curves for overall and progression-free survival among three groups. The Kaplan-Meier survival curves depict (A) overall survival and (B) progression-free survival following therapy with TAS-102 in the 3 patient groups: (A group) individuals who did not experience severe neutropenia during previous chemotherapy and did not undergo dose reduction (n=61); (B1 group) those who experienced severe neutropenia during previous chemotherapy and received an initial dose reduction of TAS-102 (n=28); (B2 group) those who had severe neutropenia but did not receive a dose reduction (n=88). No significant difference in survival was observed among the groups. TAS-102, trifluridine/tipiracil combination tablet.

Kaplan-Meier survival curves for overall and progression-free survival between the high and low Ccr groups. The Kaplan-Meier survival curves illustrate (A) overall survival and (B) progression-free survival following TAS-102 therapy in the high and low Ccr groups. No significant difference in survival was observed between the groups. Ccr, creatinine clearance; TAS-102, trifluridine/tipiracil combination tablet.

Patient characteristics.

Variable A group (n=61) B1 group (n=28) B2 group (n=88) P-value
Age, years 67 (41-83) 72 (49-79) 70 (36-83) 0.299
Sex, Male/Female 37/24 16/12 49/39 0.838
Height, cm 164.0 (139.0-184.0) 161.0 (145.0-178.7) 159.3 (141.0-181.7) 0.240
Body weight, kg 59.8 (35.9-95.0) 54 (36.4-85.0) 52 (30.9-85.0) 0.133
Body surface area, m2 1.62 (1.15-2.07) 1.60 (1.23-2.03) 1.54 (1.14-1.96) 0.151
Ccr, ml/mina 83.4 (19.0-142.0) 58.4 (37.6-150.1) 67.0 (32.9-171.1) 0.007b
Number of prior chemotherapy regimens 2 (1-4) 2 (1-4) 2 (1-5) 0.961
Pre-chemotherapy regimens        
     FOLFOX ± BV 37 15 58 0.546
     FOLFOX + Pan 1 3 8 0.096
     FOLFOX + Cet/AFL/Ram 7 2 7 0.785
     XELOX ± BV 13 7 9 0.122
     SOX ± BV 1 2 2 0.311
     FOLFIRI ± BV 32 20 58 0.253
     FOLFIRI + Cet/Pan/Ram/AFL 23 12 28 0.690
     CPT-11 ± Cet 4 1 2 0.467
     Xeloda ± BV 4 1 4 0.902
     S-1 6 1 5 0.621
     Others 24 5 26 0.216
Performance status 0 (0-2) 0 (0-1) 0 (0-2) 0.936
RAS mutation 32 19 56 0.282
Adjuvant chemotherapy, yes 21 6 27 0.491
Progression/recurrence 33/28 15/13 49/39 0.979
Metastatic sites        
     Liver 30 20 60 0.470
     Lung 29 13 49 0.879
     Lymph nodes 18 10 40 0.477
     Peritoneal dissemination 21 7 25 0.414
     Bone 7 0 5 0.094
     Ovaries 1 2 0 0.029b
     Brain 1 0 1 1
     Skin 1 0 0 0.479
     Others 3 5 3 0.043b
Neutrophil count, /mm3 3,580 (1,880-13,040) 2,905 (1,560-8,490) 2,910 (1,300-1,2440) 0.064
Treatment after TAS-102        
     No 50 20 64 0.368
     Regorafenib 11 7 20 0.682
     Others 0 1 4 0.239

Data are presented as n (%) or median (range).

aThe Cockcroft-Gault equation was used to estimate creatinine clearance based on serum creatinine and patient characteristics.

bP<0.05. Ccr, creatinine clearance; FOLFOX, combination of fluorouracil/leucovorin and oxaliplatin; BV, bevacizumab; Pan, panitumumab; Cet, cetuximab; AFL, aflibercept; Ram, ramucirumab; XELOX, combination of capecitabine and oxaliplatin; SOX, S-1 plus oxaliplatin; FOLFIRI, combination of fluorouracil/leucovorin and irinotecan; CPT-11, irinotecan; S-1, tegafur/gimeracil/oteracil potassium.

Neutropenia grade during TAS-102 administration.

Neutropenia grade A Group (n=61) B1 Group (n=28) B2 Group (n=88) P-value
Grade 3-4, n (%) 30 (49.2) 15 (53.6) 44 (50.0) 0.958
Grade 1-2, n (%) 12 (19.7) 11 (39.3) 26 (29.5) 0.126
Grade 0, n (%) 19 (31.1) 2 (7.1) 18 (20.5) 0.033a

aP<0.05.