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

doi:10.21203/rs.3.rs-4957923/v1

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

https://doi.org/10.21203/rs.3.rs-4957923/v1

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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.

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.

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.

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.

Health sciences/Gastroenterology

Health sciences/Oncology

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.

Acknowledgements

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

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.

Competing interests

The authors declare that they have no competing interests.

Data availability

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

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No competing interests reported.

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

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