Abstract
Background/Aim: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC. Patients and Methods: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29). Results: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan–Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999). Conclusion: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event.
Trifluridine/tipiracil (FTD/TPI), an oral combination anticancer drug comprising FTD and TPI, exerts dual cytotoxic effects against fluoropyrimidine-resistant tumors (1). Both the National Comprehensive Cancer Network (NCCN) guidelines (2, 3) and the Japanese Society for Cancer of the Colon and Rectum guidelines (4) recommend FTD/TPI therapy in patients with metastatic colorectal cancer (mCRC) after the 3rd line of treatment. The international phase III RECOURSE trial demonstrated that FTD/TPI, when compared with placebo, significantly improved overall survival (OS) with acceptable toxicity in patients with refractory mCRC (5). The Asian phase III TERRA trial also confirmed survival benefits and safety of FTD/TPI in Asian populations (6). Therefore, the cumulative number of patients treated with FTD/TPI has gradually increased.
The major common adverse events associated with FTD/TPI are hematological toxicities (neutropenia and anemia), gastrointestinal disorders (nausea and anorexia), and fatigue (7, 8). Notably, approximately 50% of patients receiving FTD/TPI treatment experience neutropenia, which often restricts the continuation of FTD/TPI therapy (9). Thus, preventing the development of neutropenia and maintaining a higher dose of FTD/TPI could prove beneficial for patients.
In general, FTD/TPI is orally administered on days 1-5 and 8-12 every 28 days (8). However, this standard regimen features a complex dosing schedule and frequently results in severe hematological toxicities. Recently, a simplified off-label regimen has emerged, in which 35 mg/m2 FTD/TPI is orally administered biweekly (twice a day on days 1-5 and 15-19 of a 28-day cycle) (10). A case report demonstrated that the development of neutropenia could be avoided by switching from the standard regimen to the biweekly regimen of FTD/TPI (11). In addition, a retrospective study reported that biweekly administration of FTD/TPI significantly improved progression-free survival (PFS) and lowered the incidence of neutropenia in 14 patients with mCRC (12). However, OS and other adverse events, excluding neutropenia, were not comprehensively evaluated in previous studies because of their small sample sizes.
In the present study, we retrospectively investigated the differences in efficacy and safety of the standard and biweekly FTD/TPI regimens in patients with mCRC.
Patients and Methods
Patients. Data of 90 hospitalized patients who received FTD/TPI (Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) to treat mCRC between April 2014 and September 2022 at the Osaka University Hospital were extracted. We excluded clinical trial participants and those who received FTD/TPI treatment at other hospitals. Eligible patients received either the standard regimen (35 mg/m2 oral FTD/TPI twice daily on days 1-5 and 8-12 every 28 days) or the biweekly regimen (35 mg/m2 oral FTD/TPI twice daily on days 1-5 and 15-19 every 28 days), based on physician judgement considering the adverse effects of FTD/TPI. Patients who initially received the standard regimen before transitioning to the biweekly regimen (n=10) were included in the biweekly regimen group. Both regimens were administered with or without bevacizumab (5.0 mg/kg) on days 1 and 15. Treatment was continued until there was evidence of progressive disease (PD), unacceptable toxicity, consent withdrawal, or in accordance with clinical indications for discontinuation. This study was conducted in accordance with the Declaration of Helsinki and approved by the ethical review board of Osaka University Hospital (No. 21017). Informed consent was obtained from patients via opt-out option on the website.
Assessment. The following patient characteristics were collected from their electronic medical records: age, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), FTD/TPI initial dose per body surface area, relative dose intensity, number of treatment courses, combination therapy with bevacizumab, prior chemotherapeutic agents, primary tumor location, number of metastatic sites, rat sarcoma viral oncogene (RAS) status, and baseline biological parameters. The primary endpoint was OS following FTD/TPI administration, and was defined as the time period from the initiation of FTD/TPI therapy to death from any cause. Secondary endpoints included PFS and the incidence of adverse events subsequent to FTD/TPI administration. PFS was defined as the time from the initiation of FTD/TPI therapy to disease progression or death from any cause. Patients who died or did not show disease progression were censored on the last follow-up date, i.e., August 7, 2023. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. We investigated the incidence of adverse events (grade ≥1) and evaluated OS, PFS, and adverse events during the biweekly FTD/TPI administration in the biweekly group.
Statistical analysis. Statistical comparisons of patient characteristics and adverse events between the two groups were performed using Fisher’s exact test and Mann–Whitney U-test for categorical and continuous variables, respectively. OS, PFS and incidence of neutropenia (grade ≥3) were analyzed using the Kaplan–Meier curve method with log-rank test. Multivariate COX regression analysis was conducted to adjust the effects of patient characteristics on OS and PFS following FTD/TPI administration. Regression analysis was adjusted for the following three covariates: FTD/TPI regimen, combination with bevacizumab, and age. Statistical analyses were performed using JMP® Pro version 17.0.0 (SAS Institute, Cary, NC, USA). Statistical significance was set at a two-tailed p-value of <0.05, and the confidence interval (CI) was set to 95%.
Results
A flowchart of the patient selection process is shown in Figure 1. Ninety hospitalized patients were initially considered. After excluding clinical trial participants (n=3) and those who received FTD/TPI at other hospitals (n=2), 85 patients were ultimately enrolled in the study. Patient characteristics are summarized in Table I. Among them, 56 and 29 patients received standard and biweekly regimens of FTD/TPI, respectively. The proportion of patients receiving bevacizumab in combination was significantly higher in the biweekly group (69%) than in the standard group (27%; p<0.001). However, no significant differences were observed in the other patient characteristics between the two groups.
Flow chart of patient selection. FTD/TPI, Trifluridine/tipiracil hydrochloride.
Patient characteristics.
Using Kaplan–Meier analysis, we investigated the effects of standard and biweekly regimens on OS and PFS following FTD/TPI therapy. Figure 2 shows the OS and PFS in the standard (n=56) and biweekly (n=29) groups, respectively. As shown in Figure 2A, the median OS of patients receiving the standard and biweekly regimens was 224 days (95% CI=179-264) and 256 days (95% CI=179-610), respectively. The crude hazard ratio (HR) for OS was 0.543 (95% CI=0.336-0.878; p=0.013). The median PFS of patients receiving the standard and biweekly regimens was 84 days (95% CI=64-106) and 131 days (95% CI=86-174), respectively (Figure 2B). The crude HR for PFS was 0.626 (95% CI=0.399-0.980; p=0.041). Notably, both OS and PFS were significantly prolonged in patients receiving the biweekly regimen compared with those on the standard regimen. The primary reason for discontinuing FTD/TPI administration was PD, and the predominant subsequent treatment was regorafenib therapy post PD.
Kaplan–Meier analysis of overall survival (A) and progression-free survival (B) following FTD/TPI administration in patients treated with standard regimen (n=56) and biweekly regimen (n=29). CI, Confidence interval; FTD/TPI, trifluridine/tipiracil hydrochloride; HR, hazard ratio.
Multivariate COX regression analyses were performed to adjust for the effects of patient characteristics on OS and PFS after FTD/TPI administration (Table II). As shown in Table II, the biweekly regimen was the only significant factor affecting OS (HR=0.561, p=0.049). In PFS, combination therapy with bevacizumab was the sole significant factor (HR=0.573, p=0.024), whereas the biweekly regimen showed no significance (HR=0.783, p=0.344). In addition, we evaluated OS and PFS following FTD/TPI administration in patients treated with combination therapy with bevacizumab (n=35) and without bevacizumab (n=50). Figure 3A indicates that the median OS of patients treated with and without bevacizumab was 191 days (95% CI=160-264) and 230 days (95% CI=212-366), respectively, and HR for OS was 0.718 (95% CI=0.453-1.137, p=0.158). The median PFS of patients treated with and without bevacizumab was 75 days (95% CI=56-99) and 141 days (95% CI=93-183), respectively (Figure 3B), while HR for PFS was 0.514 (95% CI=0.329-0.804, p=0.004).
COX proportional hazards analysis for OS and PFS following FTD/TPI therapy.
Kaplan–Meier analysis of overall survival (A) and progression-free survival (B) following FTD/TPI administration in patients who received combination therapy with bevacizumab (n=35) and those who did not (n=50). CI, Confidence interval; FTD/TPI, trifluridine/tipiracil hydrochloride; HR, hazard ratio.
We analyzed the incidence of neutropenia (grade ≥3) using the Kaplan–Meier curve method (Figure 4). Moreover, we evaluated the incidence of adverse events following FTD/TPI therapy (Table III). As shown in Figure 4, the development of neutropenia (grade ≥3) in the biweekly group was significantly prolonged in comparison with the standard group (p=0.012). In contrast, no significant differences were observed in neutropenia (grade ≥3) incidence (p=0.588), all adverse events (p>0.999), or treatment discontinuation due to adverse events (p=0.603) between the standard and biweekly groups (Table III).
Kaplan–Meier analysis of neutropenia (grade ≥3) onset course following FTD/TPI administration in patients treated with standard regimen (n=56) and biweekly regimen (n=29). FTD/TPI, Trifluridine/tipiracil hydrochloride.
Incidence of adverse events following FTD/TPI therapy.
Discussion
Little is known about the efficacy and safety of the biweekly regimen of FTD/TPI compared to the standard regimen. The present study demonstrated that the biweekly FTD/TPI regimen compared to the standard regimen improved OS and PFS in patients with mCRC without exacerbating adverse events.
In a previous study, the observed prolonged OS following biweekly administration of FTD/TPI was not significant (12), likely due to a small sample size (41 patients). In our study which involved 85 patients with FTD/TPI, OS in the biweekly group was significantly extended than the standard group (Figure 2A). In addition, our multivariate COX regression analysis demonstrated biweekly regimen as a significant factor contributing to prolonged OS (Table II). This is the first study to demonstrate that the biweekly regimen could significantly improve OS, and thus preferred over the standard regimen.
As shown in Figure 2B, our study showed a significantly prolonged PFS after the biweekly administration of FTD/TPI, which is similar to previous results (12). However, multivariate COX regression analysis demonstrated that prolonged PFS was attributed to bevacizumab, not the biweekly regimen (Table II). Based on these results, we further evaluated OS and PFS following FTD/TPI administration in patients treated with combination therapy with bevacizumab (n=35) and without bevacizumab (n=50). As depicted in Figure 3, concomitant bevacizumab administration significantly improved PFS, but no such impact was observed in OS following FTD/TPI administration. The combination therapy of FTD/TPI with bevacizumab has proven effective for patients with mCRC (13-16). On the contrary, another study showed that PFS, but not OS, was significantly increased in patients receiving combination therapy with bevacizumab than those in the monotherapy group (17). Thus, concomitant bevacizumab therapy, rather than the biweekly regimen, could have contributed to the prolongation of PFS in the present study.
To evaluate the safety of the biweekly FTD/TPI regimen, we investigated the incidence of adverse events in patients receiving the standard and biweekly regimens (Table III). Notably, there was no significant difference in the incidence of adverse events, including neutropenia, between the two groups. Although the baseline neutrophil counts were lower in the biweekly group (Table I), the development of neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012, Figure 4). These findings are consistent with those of a previous study (12). Conversely, the incidence of neutropenia grade ≥3 (17%) in biweekly group in the present study was higher than that in a previous report, where it stood at 7% (12). For this reason, the biweekly regimen might be preferred when physicians identify patients at a high risk of neutropenia. In addition, it is possible that adequate monitoring for adverse events during the treatment might not be consistently performed, because as our study included patients who transitioned to outpatient care. A previous retrospective study reported that the incidence of neutropenia (grade ≥3) was higher in the combination therapy of FTD/TPI with bevacizumab group than the monotherapy group (18), suggesting that the combination therapy with bevacizumab may have increased the incidence of neutropenia in the present study.
Study limitations. First, it was a retrospective study that included patients from a single institution, and a potential selection bias could not be excluded. Second, OS and PFS were likely underestimated because the standard regimen treatment periods in the biweekly regimen group were excluded from the monitoring period. However, OS and PFS in the present study were comparable to those in the previous studies (12, 18). Thus, the results of the present study are consistent with previous research and are considered to have a certain degree of reliability. Third, there was a possibility that incidence of adverse events was underestimated because outpatients who had transitioned to outpatient care were included in the present study. However, we assumed that critical adverse events were adequately evaluated because physicians, pharmacists, and nurses frequently monitored adverse events during the treatment. Lastly, it was difficult to examine demographic and clinical factors as potential confounders due to the retrospective nature of the study. Therefore, future large-scale and multicenter prospective studies should be undertaken to comprehensively assess the safety and efficacy of the biweekly FTD/TPI regimen. Since various therapeutic strategies for the mCRC have been established in recent clinical studies (19-21), further studies are needed to evaluate the safety and efficacy of the biweekly FTD/TPI regimen in comparison with other therapies.
Conclusion
The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event. This biweekly regimen holds promise as a new treatment option for patients with mCRC.
Acknowledgements
We would like to thank Editage (www.editage.jp) for the English language editing.
Footnotes
Authors’ Contributions
S.H. and D.S. contributed to study conception and design. S.H. and D.S. were involved in the data collection. S.H., D.S., and K.I. were involved in data analysis, interpretation, and drafting of the manuscript. K.I. and M.O. critically revised the manuscript. All the Authors have read and approved the final manuscript.
Conflicts of Interest
T.S. has received honorarium (e.g., lecture fees) and research funding to institution from Taiho Pharmaceutical Co., Ltd. Other authors declare that they have no conflicts of interests.
- Received October 24, 2023.
- Revision received December 4, 2023.
- Accepted December 8, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
