Impact of renal impairment on chemotherapy-induced neutropenia in patients who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab for metastatic colorectal cancer: A retrospective study

doi:10.21203/rs.3.rs-4360382/v1

Download PDF

Research Article

Impact of renal impairment on chemotherapy-induced neutropenia in patients who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab for metastatic colorectal cancer: A retrospective study

https://doi.org/10.21203/rs.3.rs-4360382/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Although the phase III SUNLIGHT trial has demonstrated the survival benefit of the addition of bevacizumab (Bmab) to trifluridine/thymidine phosphorylase inhibitor (FTD/TPI), neutropenia, which frequently occurs during FDT/TPI + Bmab therapy, is a concern for clinicians. As TPI is excreted by the kidneys, the risk of adverse events is likely to be high in patients with an impaired renal function. This study aimed to investigate the relationship between renal impairment and the incidence of chemotherapy-induced neutropenia during FTD/TPI + Bmab therapy using real-world data.

Methods: We retrospectively reviewed the medical records of 69 patients with metastatic colorectal cancer (mCRC) who were treated with FTD/TPI + Bmab for more than 28 days. Patients with renal impairment with an eGFR of 30-44 mL/min/1.73 m² were defined as the G3b group.

Results: Seven patients (10.1%) were classified into the G3b group. Among the 69 patients enrolled in this study, grade ≥3 neutropenia was observed in 34 patients (49.3%), and grade 4 neutropenia was observed in 9 patients (13.0%). Patients in the G3b group had an approximately 24% higher incidence of grade ≥3 neutropenia in comparison to others (71.4% vs. 46.8%), and the incidence of grade 4 neutropenia in the G3b group was significantly higher than that in others (42.9% vs. 9.7%, p=0.042). In an analysis limited to the G3b group, of the 5 patients who developed grade ≥3 neutropenia, four patients (80%) developed grade ≥3 neutropenia, and 2 (40%) developed grade 4 neutropenia within 30 days after initiation of FTD/TPI + Bmab therapy. However, the duration required for neutrophil count to recover to ≥1500 /mm³ and the treatment effects of the G3b group were comparable to those observed in other patients.

Conclusion: FTD/TPI + Bmab therapy is associated with a high risk of severe neutropenia within 30 days of initiation, especially in patients with a decreased renal function.

Colorectal cancer

trifluridine/thymidine phosphorylase inhibitor

bevacizumab

neutropenia

renal function

The phase III SUNLIGHT trial has demonstrated the survival benefit of the addition of bevacizumab (Bmab) to trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) [1], and FTD/TPI + Bmab therapy has established its position as a later-line treatment for metastatic colorectal cancer (mCRC). Relatively good treatment outcomes have been obtained even in patients who are refractory to standard regimens containing oxaliplatin or irinotecan. However, neutropenia, which frequently occurs during FTD/TPI + Bmab therapy, is a concern for clinicians [2, 3]. FTD exerts its antitumor effect by causing DNA dysfunction, and TPI increases the bioavailability of FTD by specifically inhibiting thymidine phosphorylase, an enzyme that degrades FTD [4–7]. As TPI is excreted by the kidneys, its plasma concentration is likely to be high in patients with an impaired renal function, resulting in an increased risk of chemotherapy-induced neutropenia [8–11]. However, there is no need to reduce the initial dose if the creatinine clearance is ≥ 30 mL/min [12]. This study aimed to investigate the relationship between renal impairment and the incidence of chemotherapy-induced neutropenia during FTD/TPI + Bmab therapy using real-world data.

Patients

We retrospectively reviewed the medical records of 69 patients with mCRC who were treated with FTD/TPI + Bmab for > 28 days at Osaka City University Hospital between January 2016 and December 2023. Patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² were excluded from this study. Patients were treated with FTD/TPI 35 mg/m² orally twice a day on days 1–5 and 8–12 in a 28-day cycle, with Bmab 5 mg/kg administered by intravenous infusion every 2 weeks. Blood examinations were scheduled on days 1, 15, and 22, and added as needed.

This retrospective study was approved by the Ethics Committee of Osaka City University (approval number: 2020-026) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.

Methods

The eGFR was calculated using serum creatinine values, sex and age [13]. Patients with renal impairment with an eGFR of 30–44 mL/min/1.73 m² were defined as the G3b group according to the GFR categories [14]. The incidence of grade ≥ 3 adverse events, including neutropenia, and treatment efficacy was compared between patients in the G3b group and others. Furthermore, we verified the timing of grade ≥ 3 neutropenia and the duration required for the neutrophil count to recover to ≥ 1500/mm³.

Response evaluations using computed tomography were performed every 8–10 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [15]. If the treatment was discontinued due to deterioration of the general condition caused by the tumor burden, the response was considered progressive disease.

Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Statistical analyses

All statistical analyses were performed using the SPSS software package for Windows (SPSS, Chicago, IL, USA). The significance of differences in the renal function and clinicopathological factors, adverse events, and treatment outcomes were analyzed using the chi-squared test, Fisher’s exact test, and Mann-Whitney U-test. The overall survival was defined as the interval between the date of initiation of FTD/TPI + Bmab and the date of death from any cause or the last follow-up examination. Progression-free survival was defined as the interval between the date of initiation of FTD/TPI + Bmab and the date of disease progression, death from any cause, or the last follow-up examination. An objective response was defined as complete or partial response. Disease control was defined as a complete or partial response or stable disease. Survival curves were estimated using the Kaplan–Meier method, and differences in survival curves were assessed using a log-rank test. P values of < 0.05 were considered to indicate statistical significance.

Patient characteristics according to renal function are listed in Table 1, and adverse events according to renal function are listed in Table 2. Patients in the G3b group were significantly older than other patients. Seven patients (10.1%) were classified into the G3b group. Among the 69 patients enrolled in this study, grade ≥ 3 neutropenia was observed in 34 patients (49.3%), and grade 4 neutropenia was observed in 9 patients (13.0%). The incidence of grade ≥ 3 neutropenia in the G3b group was approximately 24% higher than in other patients (71.4% vs. 46.8%), although no statistically significant difference was observed. Furthermore, the incidence of grade 4 neutropenia was significantly higher in the G3b group than that in other patients (42.9% vs. 9.7%, p = 0.042). In addition, the incidence of grade ≥ 3 thrombocytopenia was significantly higher in the G3b group than in other patients (42.9% vs. 4.8%, p = 0.012). Furthermore, although no statistically significant difference was observed in the incidence of grade 3 proteinuria, the incidence of proteinuria (3+) was higher in the G3b group than in the other patients (42.9% vs. 14.5%, p = 0.095).

Table 1

Association between the renal function and clinicopathological factors
Factors	Overall patient population (n = 69)	G3b group (n = 7)	Others (n = 62)	p-Value
Age (years)
Median (range)	69 (36–88)	77 (58–77)	68.5 (36–88)	0.012
Sex, n
Male	35	4	31
Female	34	3	31	0.517
Performance status, n
0, 1	65	7	58
≥ 2	4	0	4	0.645
Location of primary tumor, n
Right side	20	2	18
Left side	49	5	44	0.675
RAS status, n
Wild type	35	2	33
Mutant type	32	5	27	0.178
Unknown	2	0	2
Number of metastatic organs, n
1	29	3	26
≥ 2	40	4	36	0.632
Serum CEA levels (ng/mL), n
≤ 5.0	13	0	13
> 5.0	56	7	49	0.215
CEA: Carcinoembryonic antigen.

Table 2

Comparison of adverse events between the G3b group and others.
	Overall cohort (n = 69)		G3b group (n = 7)		Others (n = 62)
Adverse events	Grade ≥ 3	Grade 4	Grade ≥ 3	Grade 4	Grade ≥ 3	Grade 4	p-value
Hematological
Neutropenia, n (%)	34 (49.3)	9 (13.0)	5 (71.4)	3 (42.9)	29 (46.8)	6 (9.7)	0.259/0.042
Anemia, n (%)	7 (10.1)	2 (2.9)	2 (28.6)	1 (14.3)	5 (8.1)	1 (1.6)	0.145/0.194
Thrombocytopenia, n (%)	6 (8.7)	1 (1.4)	3 (42.9)	1 (14.3)	3 (4.8)	0 (0)	0.012/0.101
Non-hematological
Nausea, n (%)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	NA/NA
Anorexia, n (%)	1 (1.4)	0 (0)	0 (0)	0 (0)	1 (1.6)	0 (0)	> 0.999/NA
Diarrhea, n (%)	1 (1.4)	0 (0)	0 (0)	0 (0)	1 (1.6)	0 (0)	> 0.999/NA
Fatigue, n (%)	2 (2.9)	0 (0)	1 (14.3)	0 (0)	1 (1.6)	0 (0)	0.194/NA
Hypertension, n (%)	1 (1.4)	0 (0)	0 (0)	0 (0)	1 (1.6)	0 (0)	> 0.999/NA
Proteinuria, n (%)	3 (4.3)		1 (14.3)		2 (3.2)		0.278
Edema, n (%)	2 (2.9)	0 (0)	0 (0)	0 (0)	2 (3.2)	0 (0)	> 0.999/NA
NA: not applicable.

Regarding the onset of neutropenia, of the 34 patients who developed grade ≥ 3 neutropenia, 17 (50%) developed neutropenia within 30 days after the initiation of FTD/TPI + Bmab therapy, and 23 (67.6%) developed neutropenia within 60 days after the initiation of FTD/TPI + Bmab therapy (Fig. 1a). In an analysis limited to the G3b group, of the 5 patients who developed grade ≥ 3 neutropenia, 4 patients (80%) developed grade ≥ 3 neutropenia, and 2 patients (40%) developed grade 4 neutropenia within 30 days after initiation of FTD/TPI + Bmab therapy (Fig. 1b). Among the 34 patients with grade ≥ 3 neutropenia, there were no differences in the duration required for neutrophil count to recover to ≥ 1500/mm³ or higher between the G3b group and the other patients (Table 3).

Table 3

The duration required for neutrophil count to recover to ≥ 1500 /mm³ according to the renal function among 34 cases with grade ≥ 3 neutropenia.
	G3b group (n = 5)	Others (n = 29)	p-Value
The duration required for the neutrophil count to recover to ≥ 1500 /mm³ (days)
Median (range)	13 (6–14)	14 (2-112)	0.232

Treatment effects, such as response rate, disease control rate, progression-free survival, and overall survival, of the G3b group were comparable to those of other patients (Table 4, Fig. 2).

Table 4

Comparison of the objective response rate/disease control rate according to the renal function.
Response	G3b group (n = 7)	Others (n = 62)	p-Value
Complete response, n	0	0
Partial response, n	0	3
Stable disease, n	3	18
Progressive disease, n	4	14
Response rate	0%	9.70%	0.513
Disease control rate	42.9%	51.6%	0.483

This study revealed that the risk of neutropenia increases as the renal function declines during FTD/TPI + Bev therapy for mCRC. To our knowledge, this is the first study to examine the relationship between renal impairment and chemotherapy-induced neutropenia, specifically for FTD/TPI + Bmab therapy. Unlike clinical trials, in which enrolled patients were in relatively good condition, this study used real-world data, which included patients with renal impairment. Therefore, the results of this study provide useful information for daily clinical practice.

Previous clinical trials have demonstrated that the incidence of chemotherapy-induced neutropenia is as high as 33–38%, even with FTD/TPI monotherapy [16, 17]. Furthermore, the addition of Bmab to FTD/TPI therapy further increases the incidence of chemotherapy-induced neutropenia [18–20]. No statistically significant difference in the incidence of chemotherapy-induced neutropenia was observed between the impaired renal function group and others because the incidence of chemotherapy-induced neutropenia was high regardless of the renal function. However, the incidence of grade ≥ 3 neutropenia was approximately 24% higher in patients with renal impairment than in other cases. Furthermore, the incidence of grade 4 neutropenia was significantly higher in patients with an impaired renal function than in other cases. Based on these findings, it is necessary to pay more attention to the occurrence of neutropenia in patients with renal impairment.

Among patients who developed grade ≥ 3 neutropenia, the first neutropenia episode developed within 30 days in 50% of cases and within 60 days in 67.6% of cases. This is consistent with previous reports that FTD/TPI therapy tends to cause neutropenia soon after initiation [8]. Clinicians must keep in mind that FTD/TPI + Bmab therapy is likely to cause neutropenia relatively early after the initiation of treatment. Furthermore, it should be noted that in patients with an impaired renal function, not only grade 3 but also grade 4 neutropenia frequently occur within 30 days after administration. As stated in the guide for the appropriate use of medication and previous report [8, 21], it is important to conduct blood examinations on days 1, 15, and 22.

Although neutropenia occurred more frequently in patients with an impaired renal function, there were no significant differences in the time required for neutrophil count recovery (≥ 1500/mm³) between the impaired renal function group and other patients. Therefore, special measures against chemotherapy-induced neutropenia may not be necessary, even in patients with an impaired renal function. We were able to continue treatment even after grade 3 or higher neutropenia in patients with an impaired renal function. In addition, as in previous reports on FTD/TPI monotherapy, no difference was observed in the therapeutic effects based on renal function [11]. Therefore, FTD/TPI + Bmab therapy is a useful treatment, even for patients with impaired renal function, as long as adverse events are carefully monitored. However, if neutropenia occurs repeatedly, it may be better to reduce the dose upon restart, even with grade 3 neutropenia.

The present study was associated with several limitations. First, it was a non-randomized retrospective study with a limited sample size in a single institution. Second, this study used the eGFR, which approximates creatinine clearance and is easier to calculate than creatinine clearance, to evaluate the renal function. It is appropriate to use creatinine clearance to accurately assess renal the function because there may be a small difference between eGFR and creatinine clearance in elderly patients [22].

FTD/TPI + Bmab therapy carries a high risk of developing severe neutropenia within 30 days of initiation, especially in patients with a decreased renal function. Therefore, FTD/TPI + Bmab therapy requires careful follow-up, depending on the renal function.

Bmab

bevacizumab

FTD/TPI

trifluridine/thymidine phosphorylase inhibitor

mCRC

metastatic colorectal cancer

eGFR

estimated glomerular filtration rate

RECIST

the Response Evaluation Criteria in Solid Tumors

CTCAE

the National Cancer Institute Common Terminology Criteria for Adverse Events

CEA

Carcinoembryonic antigen

N/A

not applicable

Ethics approval and consent to participate

This research conformed to the provisions of the Declaration of Helsinki. Written informed consent was obtained from all participants. This retrospective study was approved by the Ethics Committee of Osaka City University (approval number: 2020-026).

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding was acquired for this study.

Authors’ contributions

MS designed the study, performed the statistical analysis and draft the manuscript. HT, HK, TF and SK collected the clinical data and revised the manuscript critically. KM designed the study and critically reviewed the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank Brian Quinn who provided medical writing services on behalf of JMC, Ltd.

Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Pápai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023; 388: 1657-1667.
2. Pfeiffer P, Yilmaz M, Möller S, Zitnjak D, Krogh M, Petersen LN, Poulsen LØ, Winther SB, Thomsen KG, Qvortrup C. TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol. 2020; 21: 412-420.
Kuboki Y, Nishina T, Shinozaki E, Yamazaki K, Shitara K, Okamoto W, Kajiwara T, Matsumoto T, Tsushima T, Mochizuki N, Nomura S, Doi T, Sato A, Ohtsu A, Yoshino T. TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol. 2017; 18: 1172-1181.
Emura T, Suzuki N, Fujioka A, Ohshimo H, Fukushima M. Potentiation of the antitumor activity of alpha, alpha, alpha-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo. Int J Oncol. 2005; 27: 449-455.
Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ. Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007; 98: 779-789.
Tanaka N, Sakamoto K, Okabe H, Fujioka A, Yamamura K, Nakagawa F, Nagase H, Yokogawa T, Oguchi K, Ishida K, Osada A, Kazuno H, Yamada Y and Matsuo K. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep. 2014; 32: 2319-2326.
Sakamoto K, Yokogawa T, Ueno H, Oguchi K, Kazuno H, Ishida K, Tanaka N, Osada A, Yamada Y, Okabe H, Matsuo K. Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2'-deoxy-5-fluorouridine into DNA. Int J Oncol. 2015; 46: 2327-2334.
Yoshino T, Uetake H, Funato Y, Yamaguchi Y, Koyama T, Ozawa D, Tajiri M, Muro K. Post-marketing surveillance study of trifluridine/tipiracil in patients with metastatic colorectal cancer. Jpn J Clin Oncol. 2021; 51: 700-706.
Falcone A, Ohtsu A, Van Cutsem E, Mayer RJ, Buscaglia M, Bendell JC, Kopetz S, Bebeau P, Yoshino T. Integrated safety summary for trifluridine/tipiracil (TAS-102). Anticancer Drugs. 2018; 29: 89-96.
Yoshida N, Kuriu Y, Ikeda J, Kudou M, Kirishima T, Okayama T, Miyagawa K, Takagi T, Nakanishi M, Doi T, Ishikawa T, Itoh Y, Otsuji E. Effects and risk factors of TAS-102 in real-world patients with metastatic colorectal cancer, EROTAS-R study. Int J Clin Oncol. 2023; 28: 1378-1387.
Shiroyama M, Fukuoka S, Masuishi T, Takashima A, Kumekawa Y, Kajiwara T, Yamazaki K, Shimada Y, Esaki T, Makiyama A, Moriwaki T. Renal impairment as a risk factor for trifluridine/tipiracil-induced adverse events in metastatic colorectal cancer patients from the REGOTAS study. Sci Rep. 2023; 13: 17931.
Lee JJ, Chu E. Adherence, Dosing, and Managing Toxicities With Trifluridine/Tipiracil (TAS-102). Clin Colorectal Cancer. 2017; 16:85-92.
Japanese Society of Nephrology, Guideline, Evidence-based Practice Guideline for the Treatment of CKD. [cited 2024 May 2]. Available from https://jsn.or.jp/en/guideline/guideline.php
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024; 105: S117-S314.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-247.
Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015; 372: 1909-1919.
Moriwaki T, Fukuoka S, Taniguchi H, Takashima A, Kumekawa Y, Kajiwara T, Yamazaki K, Esaki T, Makiyama C, Denda T, Satake H, Suto T, Sugimoto N, Enomoto M, Ishikawa T, Kashiwada T, Sugiyama M, Komatsu Y, Okuyama H, Baba E, Sakai D, Watanabe T, Tamura T, Yamashita K, Gosho M, Shimada Y. Propensity Score Analysis of Regorafenib Versus Trifluridine/Tipiracil in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy (REGOTAS): A Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study. Oncologist. 2018; 23: 7-15.
Chida K, Kotani D, Nakamura Y, Kawazoe A, Kuboki Y, Shitara K, Kojima T, Taniguchi H, Watanabe J, Endo I, Yoshino T. Efficacy and safety of trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil or regorafenib monotherapy for chemorefractory metastatic colorectal cancer: a retrospective study. Ther Adv Med Oncol. 2021; 13: 17588359211009143.
Fujii H, Matsuhashi N, Kitahora M, Takahashi T, Hirose C, Iihara H, Yamada Y, Watanabe D, Ishihara T, Suzuki A, Yoshida K. Bevacizumab in Combination with TAS-102 Improves Clinical Outcomes in Patients with Refractory Metastatic Colorectal Cancer: A Retrospective Study. Oncologist. 2020; 25: e469-e476.
Kotani D, Kuboki Y, Horasawa S, Kaneko A, Nakamura Y, Kawazoe A, Bando H, Taniguchi H, Shitara K, Kojima T, Tsuji A, Yoshino T. Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC Cancer. 2019; 19: 1253.
Trifluridine/tipiracil (Lonsurf) prescribing information guide. Tokyo: Taiho Pharmaceutical Co., Ltd.; 2024(in Japanese)
Kikuchi T, Akamatsu H, Mori K, Tanaka A, Kanai K, Hayata A, Tokudome N, Akamatsu K, Koh Y, Nakanishi M, Ueda H, Yamamoto N. Applicability of the Japanese equation for estimating glomerular filtration rate in patients with advanced-stage thoracic cancer. Respir Investig. 2016; 54: 479-483.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Impact of renal impairment on chemotherapy-induced neutropenia in patients who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab for metastatic colorectal cancer: A retrospective study

Status:

Version 1

Abstract

Figures

Background

Methods

Patients

Methods

Statistical analyses

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1