Research ArticleClinical Studies

The Efficacy and Safety of Trifluridine/Tipiracil Treatment for Elderly Patients With Metastatic Colorectal Cancer in a Real-world Setting

MASATSUNE SHIBUTANI, WANG EN, YUKI OKAZAKI, SHINICHIRO KASHIWAGI, TATSUNARI FUKUOKA, YASUHITO ISEKI, KOSEI HIRAKAWA and MASAICHI OHIRA
Anticancer Research December 2021, 41 (12) 6211-6216; DOI: https://doi.org/10.21873/anticanres.15440

Abstract

Background/Aim: Recently, trifluridine/tipiracil (FTD/TPI) treatment was established as a later-line treatment for metastatic colorectal cancer (mCRC). However, FTD/TPI treatment is frequently associated with hematological toxicity. The aim of this study was to evaluate the efficacy and safety of FTD/TPI in elderly patients with mCRC in a real-world setting. Patients and Methods: We retrospectively reviewed the medical records of 74 patients with mCRC who were treated with FTD/TPI. Results: The treatment effect of the elderly patient group was not inferior to that of the younger patient group. Although the incidence of hematological toxicity in the elderly patient group was higher than that in the younger patient group, there were no significant differences in the rate of treatment discontinuation due to adverse events between the two groups. Conclusion: In elderly patients with mCRC, FTD/TPI treatment was effective for prolonging survival. However, it should be noted that elderly patients showed a higher rate of hematological toxicity than younger patients.

Key Words:

Phase III trials have demonstrated a survival benefit of later-line chemotherapy in patients with metastatic colorectal cancer (mCRC) who are refractory to standard regimens, including fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor receptor monoclonal antibody, and anti-epidermal growth factor receptor monoclonal antibody (1, 2). Recently, later-line treatment for mCRC was established and recommended in the National Comprehensive Cancer Network (NCCN), Pan-Asian European Society for Medical Oncology (ESMO) and Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines (3-5). Trifluridine/tipiracil (FTD/TPI) is an oral anticancer drug, which has cytotoxic effects on tumors that are resistant to fluoropyrimidine (6). Furthermore, the survival benefit of bevacizumab in combination with FTD/TPI has been demonstrated in some studies (7-9). However, hematological toxicity, especially neutropenia, is frequently observed in patients undergoing FTD/TPI treatment (1, 10, 11).

Most elderly patients enrolled in clinical trials were in relatively good condition and there have been only a few reports regarding FTD/TPI treatment in elderly patients who often have impaired organ functions (12, 13). Therefore, it is unclear whether or not FTD/TPI treatment is well-tolerated and suitable as a later-line treatment for elderly patients in the clinical setting. The aim of this study was to evaluate the efficacy and safety of FTD/TPI in elderly patients with mCRC in a real-world setting.

Patients and Methods

Patients. We retrospectively reviewed the medical records of 74 patients with mCRC who were treated with FTD/TPI at Osaka City University Hospital between June 2014 and August 2021. Patients who failed to complete one course due to causes other than adverse events or disease progression were excluded from this study. All patients had received at least two previous chemotherapeutic regimens. This retrospective study was approved by the ethics committee of Osaka City University (approval number: 4182) and conducted in accordance with the Declaration of Helsinki. All patients provided their written informed consent.

Methods. In this study, we defined patients of <65 years of age as younger patients and those of ≥65 years of age as elderly patients. Patients were classified into the younger patient group and the elderly patient group, and efficacy and safety were compared between the two groups.

The response was evaluated by computed tomography every eight weeks. Variation of approximately two weeks was regarded as allowable error. We adopted the response evaluation criteria in solid tumors to classify the treatment response as follows (14): complete response, partial response, stable disease, and progressive disease. If treatment was discontinued due to adverse events before the first response evaluation, the response was judged as not evaluable. If the treatment was discontinued due to a deterioration in the patient’s general condition caused by the tumor burden, then the response was judged to be clinical progressive disease. An objective response was defined as a complete or partial response. Disease control was defined as either a complete or partial response or stable disease. Progression-free survival was defined as the time from the initiation of FTD/TPI treatment to disease progression, death due to any cause or last follow-up. Overall survival was defined as the time from initiation of FTD/TPI treatment to death due to any cause or last follow-up. Adverse events were graded using the Common Terminology Criteria for Adverse Events (Version 4.0) (15).

Statistical analyses. All statistical analyses were performed using the SPSS software program for Windows (SPSS, Chicago, IL, USA). χ2 and Fisher’s exact tests were used to analyze the significance of correlations between age and clinicopathological characteristics/chemotherapeutic response/adverse events. Survival curves were estimated using the Kaplan–Meier method, and the differences in the survival curves were assessed with the log-rank test. p-Values of <0.05 were considered to indicate statistical significance.

Results

Patient characteristics. The patient characteristics are shown in Table I. Approximately 60% of the patients enrolled in this study were elderly patients. There were no significant differences in oncological factors between the younger patient group and the elderly patient group. In addition, there was no significant difference between the two groups in the rate of combined use of bevacizumab, which has been reported to enhance the therapeutic effect of FTD/TPI. Regarding the renal function, elderly patients tended to have a higher rate of decreased renal function (estimated glomerular filtration rate <60 ml/min/1.73 m2) in comparison to younger patients (p=0.065).

View this table:
Table I.

Patient characteristics.

Comparison of the therapeutic effect of FTD/TPI between the younger patient group and elderly patient group. The elderly patient group tended to have longer progression-free survival in comparison to the younger patient group (Figure 1A), whereas no significant difference was observed in overall survival between the two groups (Figure 1B). There was no difference in the objective response rate or disease control rate between the two groups (Table II).

Figure 1.
Figure 1.

Kaplan–Meier survival curves for progression-free survival (A) and overall survival (B).

View this table:
Table II.

Comparison of chemotherapeutic response between the younger patient group and the elderly patient group.

Comparison of safety and feasibility of FTD/TPI treatment between the younger patient group and the elderly patient group. The incidence of hematological toxicities (e.g., neutropenia, anemia and thrombocytopenia) in the elderly patient group was higher than that in the younger patient group (Table III). There was no significant difference in the rate of treatment discontinuation due to adverse events between the two groups (Table IV).

View this table:
Table III.

Comparison of the incidence of adverse events between the younger patient group and the elderly patient group.

View this table:
Table IV.

Comparison of treatment discontinuation due to adverse events between the younger patient group and the elderly patient group.

Discussion

With the increase in the elderly population, the number of elderly patients with colorectal cancer has increased all over the world (16-18). As elderly patients often have decreased basic physical strength and organ function, it is unclear whether or not the treatment strategy that has been established based on the results of randomized controlled trials can be applied to elderly patients. It is therefore meaningful to re-examine the treatment outcomes in elderly patients.

This study demonstrated no significant difference in the efficacy of FTD/TPI treatment between the younger patient group and the elderly patient group. This finding was in accordance with the results of the RECOURSE and REGOTAS trials (1, 19), subgroup analyses of which reported that elderly patients could expect the same survival benefit as young patients. However, the incidence of adverse events, especially hematological toxicities, was found to be higher in the elderly patient group than in the younger patient group, whereas there was no significant difference in the survival benefit of the two groups. FTD/TPI is a combination of a nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride (20, 21). Trifluridine exerts an antitumor effect via DNA dysfunction, whereas tipiracil hydrochloride maintains an adequate plasma concentration of trifluridine by inhibiting thymidine phosphorylase, which degrades trifluridine (20-23). Tipiracil is excreted from the kidneys. Therefore, the plasma concentration of trifluridine is likely to be high in patients with renal impairment (10, 11), leading to an increased risk of adverse events. As confirmed in this study, the renal function is often decreased in elderly patients; thus, the frequency of adverse events may have been increased in elderly patients. However, similarly to previous studies (12), there was no significant difference in the rate of discontinuation of treatment due to adverse events between the younger patients and the elderly patients, and treatment could be continued with appropriate interruptions, delays and/or dose reduction in many cases. Thus, FTD/TPI treatment was considered to be a useful treatment for elderly patients.

It was of great significance that this study demonstrated the efficacy of FTD/TPI treatment for elderly patients and identified the risk factors for adverse events using real-world data. However, this was a retrospective study of a small cohort of patients who were treated in a single center. A large prospective study of FTD/TPI treatment for elderly patients, which also includes the evaluation of the relationship between renal function and adverse events, is therefore needed.

Conclusion

In elderly patients with mCRC, as with younger patients with mCRC, FTD/TPI treatment was effective for prolonging survival. However, it should be noted that the incidence of hematological toxicity in elderly patients was higher than that in younger patients.

Footnotes

  • Authors’ Contributions

    MS designed the study, performed the statistical analysis and drafted the manuscript. WE, YO, SK, TF, YI, KH and MO designed the study and critically reviewed the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in association with the present study.

  • Received October 19, 2021.
  • Revision received November 3, 2021.
  • Accepted November 4, 2021.

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The Efficacy and Safety of Trifluridine/Tipiracil Treatment for Elderly Patients With Metastatic Colorectal Cancer in a Real-world Setting
MASATSUNE SHIBUTANI, WANG EN, YUKI OKAZAKI, SHINICHIRO KASHIWAGI, TATSUNARI FUKUOKA, YASUHITO ISEKI, KOSEI HIRAKAWA, MASAICHI OHIRA
Anticancer Research Dec 2021, 41 (12) 6211-6216; DOI: 10.21873/anticanres.15440
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