Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan

Ya-Wen Chang; Chun-Nan Kuo; Chia-Lun Chang; Jason C. Hsu; Yu Ko

doi:10.4143/crt.2024.376

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Original Article Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan: Ya-Wen Chang¹, Chun-Nan Kuo^1,2, Chia-Lun Chang^3,4, Jason C. Hsu^5,6, Yu Ko^1,7,; DOI: https://doi.org/10.4143/crt.2024.376
Published online: November 18, 2024

¹Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

²Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

³Department of Hemato-Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

⁴Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

⁵International Ph.D. Program in Biotech and Healthcare Management, College of Management, Taipei Medical University, Taipei, Taiwan

⁶Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

⁷Research Center for Pharmacoeconomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

Correspondence: Yu Ko, Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, No.250, Wuxing St., Taipei 11031, Taiwan
Tel: 886-2-2736-1661 (ext. 6174) E-mail: nancykotw@gmail.com

• Received: April 16, 2024 • Accepted: November 16, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
This study aimed to examine the real-world effectiveness and safety of regorafenib and trifluridine/tipiracil (TAS-102) in metastatic colorectal cancer (mCRC) patients in Taiwan.
Materials and Methods
Data were extracted from Taiwan’s National Health Insurance Research Database to evaluate the clinical outcomes of mCRC patients treated with either regorafenib or TAS-102 between 2016 and 2019. Overall survival (OS) was compared using Kaplan-Meier curves and Cox’s proportional hazard models, adjusting for age, sex, Quan-CCI score, liver metastases, number of metastatic sites, and the use of anti–epidermal growth factor receptor medications. Additionally, OS was compared between regorafenib monotherapy and TAS-102 monotherapy, excluding patients who had received both regorafenib and TAS-102.
Results
A total of 2,608 patients in the regorafenib group and 521 patients in the TAS-102 group were identified. The median OS was 6.5 months for regorafenib and 7.5 months for TAS-102, with a significant difference observed (p=0.001). The mean duration of treatment was similar for regorafenib and TAS-102 (108 days vs. 101 days) with no significant difference. The safety profiles of the two drugs were distinct; a higher proportion of patients in the regorafenib group had hypertension and hand-foot skin reaction while nausea and vomiting were more common in the TAS-102 group. In the subgroup analysis, patients receiving TAS-102 monotherapy showed significantly longer OS than those receiving regorafenib monotherapy.
Conclusion
The findings of this study indicated that TAS-102 had superior survival outcomes compared to regorafenib in mCRC patients. This study provides insights into the effectiveness and safety profiles of regorafenib and TAS-102 in Taiwan.
Key words: Metastatic colorectal cancer, Regorafenib, Trifluridine/tipiracil, Cohort studies

Introduction

Colorectal cancer (CRC) ranks as the third most common type of cancer, representing 10% of all cancers and causing 9.4% of cancer-related deaths worldwide in 2020 [1]. In Taiwan, CRC is the second most commonly diagnosed cancer with an estimated 16,829 new cases and 6,489 deaths attributed to CRC every year [2]. Among patients diagnosed with CRC, the 5-year survival rate for localized CRC is approximately 90%, but that declines significantly to 16% when the cancer has spread to distant parts of the body, which occurs in around 20% of the patients [3].

Patients with metastatic CRC (mCRC) are primarily treated with systematic chemotherapies. The first- and second-line treatments for mCRC usually include oxaliplatin and irinotecan-based regimens [4]. The combination of chemotherapies with anti–vascular endothelial growth factor (anti-VEGF) monoclonal antibodies (e.g., bevacizumab) or epidermal growth factor receptor (EGFR) inhibitors if the cancer is RAS wild-type (e.g., cetuximab and panitumumab) have improved clinical outcomes [4-7]. Despite undergoing the aforementioned treatments, patients with mCRC may still experience disease progression, which is known as refractory disease. In such circumstances, regorafenib or trifluridine/tipiracil (TAS-102), both oral medications, have been approved as alternative treatment options [8,9].

Regorafenib is an oral small molecule multi-kinase inhibitor that can suppress several receptors associated with tumor angiogenesis, such as VEGF receptors 1-3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2, platelet-derived growth factor receptor, and fibroblast growth factor receptor. Furthermore, regorafenib can also block multiple oncogenic pathways including KIT, RET, and RAF1 kinases, inhibiting the proliferation of tumor cells [10]. TAS-102 is an oral chemotherapy agent that consists of a combination of trifluridine and tipiracil. Trifluridine exerts its antitumor effect by inhibiting thymidylate synthase and incorporating it into DNA to induce cell death while tipiracil can prevent the breakdown of trifluridine, therefore enhancing its bioavailability [11].

Despite regorafenib and TAS-102 having similar indications, no head-to-head randomized controlled trial has directly compared the two treatments in patients with refractory mCRC. As such, the decision of which drug to administer to an individual patient is at the discretion of treating physicians, as there is no clear preference outlined in the European Society for Medical Oncology (ESMO) or the National Comprehensive Cancer Network (NCCN) guidelines for colon cancer [4,12].

Several retrospective studies have compared regorafenib and TAS-102, with four conducted in Japan [13-16] and one conducted in the United States [17]. Most of the studies have small sample sizes and the findings have suggested that these two drugs had similar effectiveness but different safety profiles [13-15,17]. Whether the study results can be generalized to the Taiwanese population is unknown. Therefore, the present study aimed to examine the effectiveness and safety of regorafenib and TAS-102 in patients with refractory mCRC using data from a nationwide population-based database in Taiwan.

Materials and Methods

1. Data sources

This study used claims data obtained from the National Health Insurance Research Database (NHIRD), administered by the Taiwan National Health Research Institute. The national health insurance was initiated in 1995 and encompasses more than 99% of the population of 23 million beneficiaries in Taiwan. All data in the NHIRD is encrypted and includes the beneficiaries’ records of sex, age, residency area, drug prescriptions, medical procedures, and diagnoses coded in the International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM) or 10th revision, clinical modification (ICD-10-CM) [18]. Kao et al. [19] reported that the NHIRD had a 94% positive predictive value for CRC diagnoses, indicating good validity.

2. Study design and patient selection

Patients with a diagnosis of CRC between 1 January 2016 and 31 December 2019 were identified through the ICD-10-CM codes and were followed up until 31 December 2021. All CRC cases were required to have at least one inpatient or two outpatient diagnoses codes to be included. In addition, patients needed to receive either regorafenib (drug code: BC26168100) or TAS-102 (drug codes: BC27281100, BC27282100) for the first time after 2016. As a result of the National Health Insurance reimbursement requirements, these patients had previously undergone treatment with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy if RAS was wild-type. The index date was designated as the first day when regorafenib or TAS-102 was prescribed to the patient. The baseline period was defined as 6 months before the index date, and the follow-up period started with the index date continued to either the date of the patient’s death or the last date when data was available (i.e., 31 December 2021), whichever occurred first.

In this study, patients were excluded if they were under 20 years old on the index date or had a history of other cancers documented in the 6 months before the index date. Furthermore, we excluded those who received other chemotherapies, such as oxaliplatin, irinotecan, and fluorouracil (5-FU), concomitantly with regorafenib or TAS-102.

3. Procedures

We collected information about patients’ demographic and clinical characteristics, including age, sex, and primary cancer site. Data regarding primary cancer site was obtained from the cancer registration database, which records all newly diagnosed cancer cases in the Taiwan Cancer Registry [19]. The number of metastases and sites were assessed using the ICD-9-CM or ICD-10-CM codes, and previous studies have validated the use of ICD codes to define CRC and metastatic sites [20,21]. To ascertain the presence of comorbidities, we identified conditions with at least one inpatient or two outpatient diagnoses within the preceding 6 months. Furthermore, the Quan adaptation of the Charlson Comorbidity Index (Quan-CCI) was used to quantify patients’ comorbidity profiles [22].

4. Outcome measures

The primary outcome was overall survival (OS), measured from the index date to the date of death from any cause or censoring at the last follow-up. Patients who were still alive on 31 December 2021 were censored. Secondary outcomes included the duration of treatment and treatment-related adverse events (AEs), including anemia, diarrhea, febrile neutropenia, hand-foot skin reaction (HFSR), hypertension, liver injury, nausea and vomiting, neutropenia, and thrombocytopenia. Treatment duration was defined as the period from the index date to the last prescription date plus the days of medication supplied. The AEs were identified using ICD codes and/or medications that treat the AEs [23-25] (S1 Table). For example, the occurrence of HFSR was identified by the use of topical corticosteroids and salicylic acid [26]. The observation period of AEs started from the first prescription of the drug of interest (i.e., either regorafenib or TAS-102) and continued to its final prescription, adding 28 days to account for the duration of a treatment cycle. Any AE of interest first reported while the patient was receiving regorafenib or TAS-102 that had not occurred within 6 months before the index date was classified as an occurrence of AE.

5. Statistical analysis

In this retrospective study, continuous variables were presented by mean, standard deviation, and median with interquartile range, while categorical variables were presented by numbers with percentages. The baseline characteristics of the two treatment groups were compared using the student’s t test and the chi-squared test, where appropriate. The OS for each treatment cohort was measured using the Kaplan-Meier method, with the differences evaluated by the log-rank test. Cox’s proportional hazard models were employed to estimate the unadjusted and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), and the adjusted variables included age, sex, Quan-CCI score, metastases of the liver (yes or no), metastatic sites (≥ 3 or < 3), and the use of anti-EGFR medications (yes or no). Moreover, two subgroup analyses and one sensitivity analysis were conducted to ensure the robustness of the results. The first subgroup analysis stratified patients based on age (≥ 65 years) and the second divided patients by the type of monotherapy they received, either regorafenib or TAS-102 (i.e., those who received both regorafenib and TAS-102, regardless of sequence, were excluded). For the sensitivity analysis, only those patients who received the standard initial dose of regorafenib (i.e., 160 mg once daily for 21 days with 7 days of rest) were selected to compare with the TAS-102 group. The data analyses utilized the SAS statistical software ver. 9.3 (SAS Institute Inc.). All tests were two-sided, and a p-value of < 0.05 was considered statistically significant.

Results

1. Patients

The flowchart for this study shows the patient selection process (Fig. 1). A total of 4,991 patients received either regorafenib or TAS-102 for the first time between 2016 and 2019. After applying exclusion criteria, 3,129 patients were included in this study, with 2,608 in the regorafenib group and 521 in the TAS-102 group. The baseline characteristics of the study patients are summarized in Table 1. The sex distribution was similar between the two groups (p=0.500) while the mean ages were 62.5 and 61.3 years in the regorafenib and TAS-102 groups, respectively (p=0.039). The liver was the most common site for metastasis, and the proportion of patients with three or more metastatic sites was higher in the TAS-102 group than in the regorafenib group (9.6% vs. 6.9%, p=0.028). Additionally, the proportion of patients with each comorbidity included in the study was similar between the two groups, except that there was a higher proportion of patients with diabetes mellitus with complications in the TAS-102 group than in the regorafenib group (5.0% vs. 2.7%, p=0.006).

2. Effectiveness

By the censoring date, a total of 2,503 patients (96%) in the regorafenib group and 470 patients (90%) in the TAS-102 group had died. The median OS was 6.5 months (95% CI, 6.1 to 6.8) for regorafenib and 7.5 months (95% CI, 6.7 to 8.5) for TAS-102 (HR, 0.87; 95% CI, 0.79 to 0.96; p=0.006) (Fig. 2). The treatment benefit of TAS-102 was maintained in the multivariate model (adjusted HR, 0.85; 95% CI, 0.77 to 0.93; p=0.001).

3. Treatment exposure and subsequent treatment

Table 2 summarizes the treatment exposure and subsequent anticancer agents in the two groups. The mean duration of treatment was similar for regorafenib and TAS-102 (108 days vs. 101 days) with no significant difference. Overall, treatment patterns were comparable between the two groups during the study period. The most common subsequent systematic chemotherapy was 5-FU (22.8%) in the regorafenib group and irinotecan (25.0%) in the TAS-102 group. There was a difference between the proportions of patients subsequently treated with tegafur/uracil (12.2% and 8.5% in the regorafenib and TAS-102 groups, respectively; p=0.013).

4. Treatment-related adverse events

The treatment-related AEs in the two treatment groups are summarized in Table 3. Diarrhea was the most common AE in both groups, which occurred in 851 (32.6%) and 178 (34.2%) patients in the regorafenib and TAS-102 groups, respectively. Other AEs that occurred in > 10% of the patients included hypertension, HFSR, anemia, and nausea and vomiting. Among these AEs, a higher proportion of patients in the regorafenib group had hypertension and HFSR (p < 0.001) while nausea and vomiting were more common in the TAS-102 group.

5. Subgroup and sensitivity analyses

Two subgroup analyses and one sensitivity analysis were performed in this study as shown in Fig. 3. The analysis results suggested a longer OS in the TAS-102 group compared to regorafenib in both patients under 65 years (6.5 months vs. 7.4 months; adjusted HR, 0.84; 95% CI, 0.74 to 0.96; p=0.008) and those aged ≥ 65 years (6.5 months vs. 7.6 months; adjusted HR, 0.85; 95% CI, 0.72 to 0.99; p=0.045). Moreover, in the subgroup analysis where patients were divided by the type of monotherapy (i.e., regorafenib only and TAS-102 only), a consistent survival benefit with TAS-102 was observed. The median OS was 5.2 months (95% CI, 5.0 to 5.6) in the regorafenib only group and 6.9 months (95% CI, 5.6 to 7.8) in the TAS-102 only group (adjusted HR, 0.76; 95% CI, 0.68 to 0.85; p < 0.001) (Fig. 4). In the sensitivity analysis, 1,557 patients who did not receive the standard initial dose of regorafenib were excluded, and the remaining patients were compared with the TAS-102 group. The median OS was slightly increased to 7.1 months (95% CI, 6.7 to 7.7) in the regorafenib group and it was not significantly different from that of TAS-102 (adjusted HR, 0.91; 95% CI, 0.81 to 1.02; p=0.091) (Fig. 5).

Discussion

This is the first population-based study to compare the effectiveness and safety of regorafenib and TAS-102 in patients with mCRC refractory to standard therapies in Taiwan. This nationwide study provides real-world evidence on the clinical outcomes of these two drugs. Our findings demonstrated that patients taking TAS-102 experienced increased survival benefits compared to regorafenib users. Several small-scale studies have compared the effectiveness of regorafenib and TAS-102 but reported no difference between the two drugs [13-17]. However, another study, one with a large sample taken from a medical claims database in Japan, found a 0.8-month longer OS in patients receiving TAS-102 [16], which result was in line with our findings. An explanation for the findings could be the difference in time of reimbursement where regorafenib was approved in 2015 and TAS-102 was in 2018 in Taiwan. Patients in the regorafenib group who were enrolled between 2015 and 2017 did not have the opportunity to be treated with TAS-102 while patients in the TAS-102 group were more likely to be managed with more advanced treatments. Moreover, due to National Health Insurance restrictions in Taiwan, patients receiving regorafenib or TAS-102 were required to have prior regimens of standard therapy such as 5-FU, oxaliplatin, and irinotecan-based chemotherapies, an anti-VEGF agent, and if RAS wild-type, an EGFR inhibitor. This requirement may have made our study sample differ to a certain extent from those in published clinical trials and retrospective studies. In our study sample, there was a higher proportion of patients who had used bevacizumab in the regorafenib group compared to that in the TAS-102 group (70.3% vs. 63.7%, p=0.002). A previous study has found a correlation between early tumor shrinkage and progression-free survival among patients receiving bevacizumab [27]. In our study, the duration of treatment was used as a surrogate for progression-free survival since information about disease progression and the reasons for discontinuing treatment were unavailable [28]. Despite the shorter OS in the regorafenib group, the duration of treatment was similar between the two drugs, which might have resulted from the impact of previous use of bevacizumab and similar tolerability of side effects.

The safety profiles of regorafenib and TAS-102 were distinct. Our study observed that regorafenib caused more symptomatic AEs, such as HFSR and hypertension, while TAS-102 was attributed to asymptomatic AEs, particularly neutropenia. While the AEs reported in this analysis were consistent with the known toxicity of regorafenib and TAS-102 reported in previous randomized controlled trials [8,9], the proportion of patients with AEs in this study was relatively low, which could have resulted from the omission of ICD coding for low-grade side effects for which treatment was deemed unnecessary. As such, the actual occurrence of AEs may have been underestimated.

The REGOTAS study showed a trend that regorafenib was preferred for patients < 65 years while TAS-102 was favorable among those aged ≥ 65 years [14]. However, in both subgroup analyses of the present study, patients in the TAS-102 group tended to live longer than those in the regorafenib group. Moreover, we found that OS was longer in patients receiving TAS-102 monotherapy than those receiving regorafenib monotherapy (HR, 0.76; p < 0.001). The nuanced insights from these subgroup analyses contribute to a better understanding of differential treatment effects and add valuable evidence for clinical practice for mCRC. Furthermore, the sensitivity analysis allows for an explicit comparison of OS between TAS-102 and the standard initial dose of regorafenib. The increase in median OS to 7.1 months in the standard dose group suggests that receiving the standard initial dose of regorafenib may lead to better effectiveness. This observation aligns with the findings of the REBECCA study, which reported that an initial dose of regorafenib < 160 mg/day was associated with poorer survival [29]. Moreover, the strategy of using TAS-102 with bevacizumab for treating patients with mCRC has shown promising results in the recent SUNLIGHT trial, which led to the U.S. Food and Drug Administration’s approval of this combination in the United States in 2023. However, this combination therapy has yet to be approved for reimbursement or used in practice in Taiwan. Therefore, further research is necessary to provide real-world evidence for this drug combination in patients with mCRC in Taiwan.

There are several limitations to the present study. First, the retrospective nature of this study may have potentially introduced selection bias, making it difficult to draw rigid conclusions from the observed results. Second, information about several key factors were unavailable in the claim database, e.g., performance status, RAS gene mutation, laboratory examinations, and the time since initiation of first-line chemotherapy. This lack of data prevented estimation of progression-free survival and examination of other prognostic factors. Lastly, some patients may have used self-pay treatments, including the competing drug, for refractory mCRC and the information would not have been captured in the study database. As a result, these patients may have been misclassified and the study results could have been influenced.

In patients with mCRC, our study found that those treated with TAS-102 exhibited prolonged survival compared to those receiving regorafenib. Consistent survival benefits in favor of TAS-102 were observed across different age groups and in patients receiving monotherapy of the study drugs. The findings offer valuable guidance for therapeutic decision-making.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2024-376_S1_Table.pdf

NOTES

Ethical Statement

The study was approved by the Institutional Review Board of Taipei Medical University (approval No. N202310007) and informed consent was waived.

Author Contributions

Conceived and designed the analysis: Chang YW, Ko Y, Kuo CN.

Collected the data: Chang YW.

Contributed data or analysis tools: Ko Y, Hsu JC.

Performed the analysis: Chang YW.

Wrote the paper: Chang YW.

Writing-review and editing: Ko Y, Kuo CN, Hsu JC, Chang CL.

Conflict of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgments

This study’s data source is the National Health Insurance Research Database (NHIRD), which is regulated by the Health and Welfare Data Center (HWDC) of the Department of Statistics under Taiwan’s Ministry of Health and Welfare (MOHW). All the interpretations and conclusions in this study do not represent those of the Health Data Science Center.

Fig. 1.

Flowchart of patient selection. CRC, colorectal cancer.

Fig. 2.

Kaplan-Meier curves for overall survival. CI, confidence interval; HR, hazard ratio.

Fig. 3.

Overall survival in patients aged under 65 years (A) and patients aged 65 years or older (B). CI, confidence interval; HR, hazard ratio.

Fig. 4.

Overall survival in patients who received monotherapy of regorafenib or TAS-102. CI, confidence interval; HR, hazard ratio.

Fig. 5.

Overall survival in patients who received the standard dose of regorafenib vs. TAS-102 patients. CI, confidence interval; HR, hazard ratio.

Table 1.

Baseline characteristics of study patients

Characteristic	Regorafenib (n=2,608)	TAS-102 (n=521)	p-value
Age at index date (yr)	62.5±11.5	61.3±11.4	0.039
Sex
Male	1,500 (57.5)	289 (55.5)	0.500
Female	1,108 (42.5)	232 (44.5)
Primary cancer site
Colon	1,472 (56.4)	281 (55.5)	0.306
Rectosigmoid junction	207 (8.0)	50 (9.6)
Rectum	875 (33.6)	185 (35.5)
No. of metastatic sites
< 3	2,429 (93.1)	471 (90.4)	0.028
≥ 3	179 (6.9)	50 (9.6)
Metastatic sites
Bone	154 (5.9)	41 (7.9)	0.090
Brain	48 (1.8)	10 (1.9)	0.903
Liver	864 (33.1)	171 (32.8)	0.892
Lung	571 (21.9)	128 (24.6)	0.181
Lymph node	109 (4.2)	28 (5.4)	0.223
Peritoneum	279 (10.7)	59 (11.3)	0.674
Other	284 (10.9)	62 (11.9)	0.501
Quan-CCI	7.1±2.8	7.3±2.7	0.102
Selected comorbidities
Diabetes mellitus without complications	401 (15.4)	75 (14.4)	0.569
Diabetes mellitus with complications	71 (2.7)	26 (5.0)	0.006
Hepatitis B virus	203 (7.8)	45 (8.6)	0.510
Hepatitis C virus	35 (1.3)	12 (2.3)	0.099
Hypertension	748 (28.7)	141 (27.1)	0.454
Hyperlipidemia	225 (8.6)	44 (8.5)	0.892
Mild liver disease	259 (9.9)	56 (10.8)	0.571
Metastatic solid tumor	2,552 (97.9)	514 (98.7)	0.233
Peptic ulcer disease	150 (5.8)	28 (5.4)	0.734
Renal disease	95 (3.6)	18 (3.5)	0.833
Previous systemic anticancer agent
Bevacizumab	1,834 (70.3)	332 (63.7)	0.002
Capecitabine	1,432 (54.9)	295 (56.6)	0.472
Cetuximab	1,013 (38.8)	195 (37.4)	0.545
Fluorouracil	2,434 (93.3)	484 (92.9)	0.720
Irinotecan	2,439 (93.5)	490 (94.1)	0.651
Oxaliplatin	2,146 (82.3)	419 (80.4)	0.312
Panitumumab	16 (0.6)	4 (0.8)	0.686
Tegafur/Uracil	809 (31.0)	150 (28.8)	0.313

Values are presented as mean±SD or number (%). CCI, Charlson Comorbidity Index; SD, standard deviation.

Table 2.

Duration of treatment and subsequent anticancer agents

Outcome measures	Regorafenib (n=2,608)	TAS-102 (n=521)	p-value
Duration of treatment (day)
Mean±SD	108±162	101±160	0.376
Median (IQR)	60 (35-105)	45 (33-101)
Patterns of treatment duration (day)
0-90	1,808 (69.3)	379 (72.7)	0.397
91-180	442 (17.0)	75 (14.4)
181-365	221 (8.5)	39 (7.5)
≥ 366	137 (5.3)	28 (5.4)
Subsequent anticancer agents
Bevacizumab	36 (1.4)	7 (1.3)	0.947
Cetuximab	23 (0.9)	9 (1.7)	0.079
Capecitabine	426 (16.3)	93 (17.9)	0.395
Fluorouracil	595 (22.8)	125 (24.0)	0.559
Irinotecan	566 (21.7)	130 (25.0)	0.103
Oxaliplatin	345 (13.2)	74 (14.2)	0.550
Tegafur/Uracil	319 (12.2)	44 (8.5)	0.013
Regorafenib	NA	84 (16.1)
TAS-102	444 (17.0)	NA

Values are presented as number (%) unless otherwise indicated. IQR, interquartile range; NA, not available; SD, standard deviation.

Table 3.

Treatment-related adverse events

Adverse event	Regorafenib (n=2,608)	TAS-102 (n=521)	p-value
Diarrhea	851 (32.6)	178 (34.2)	0.496
Hypertension	619 (23.7)	89 (17.1)	< 0.001
HFSR	525 (20.1)	21 (4.0)	< 0.001
Anemia	438 (16.8)	98 (18.8)	0.265
Nausea and vomiting	345 (13.2)	86 (16.5)	0.047
Febrile neutropenia	189 (7.3)	37 (7.1)	0.906
Liver injury (hepatotoxicity)	156 (6.0)	15 (2.9)	0.004
Thrombocytopenia	43 (1.7)	13 (2.5)	0.183
Neutropenia	13 (0.5)	15 (2.9)	< 0.001

Values are presented as number (%). HFSR, hand-foot skin reaction.

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Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan

DOI: https://doi.org/10.4143/crt.2024.376

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan

Fig. 1. Flowchart of patient selection. CRC, colorectal cancer.

Fig. 2. Kaplan-Meier curves for overall survival. CI, confidence interval; HR, hazard ratio.

Fig. 3. Overall survival in patients aged under 65 years (A) and patients aged 65 years or older (B). CI, confidence interval; HR, hazard ratio.

Fig. 4. Overall survival in patients who received monotherapy of regorafenib or TAS-102. CI, confidence interval; HR, hazard ratio.

Fig. 5. Overall survival in patients who received the standard dose of regorafenib vs. TAS-102 patients. CI, confidence interval; HR, hazard ratio.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Effectiveness and Safety of Regorafenib and TAS-102 in Patients with Metastatic Colorectal Cancer: A Nationwide Population-Based Study in Taiwan

Characteristic	Regorafenib (n=2,608)	TAS-102 (n=521)	p-value
Age at index date (yr)	62.5±11.5	61.3±11.4	0.039
Sex
Male	1,500 (57.5)	289 (55.5)	0.500
Female	1,108 (42.5)	232 (44.5)
Primary cancer site
Colon	1,472 (56.4)	281 (55.5)	0.306
Rectosigmoid junction	207 (8.0)	50 (9.6)
Rectum	875 (33.6)	185 (35.5)
No. of metastatic sites
< 3	2,429 (93.1)	471 (90.4)	0.028
≥ 3	179 (6.9)	50 (9.6)
Metastatic sites
Bone	154 (5.9)	41 (7.9)	0.090
Brain	48 (1.8)	10 (1.9)	0.903
Liver	864 (33.1)	171 (32.8)	0.892
Lung	571 (21.9)	128 (24.6)	0.181
Lymph node	109 (4.2)	28 (5.4)	0.223
Peritoneum	279 (10.7)	59 (11.3)	0.674
Other	284 (10.9)	62 (11.9)	0.501
Quan-CCI	7.1±2.8	7.3±2.7	0.102
Selected comorbidities
Diabetes mellitus without complications	401 (15.4)	75 (14.4)	0.569
Diabetes mellitus with complications	71 (2.7)	26 (5.0)	0.006
Hepatitis B virus	203 (7.8)	45 (8.6)	0.510
Hepatitis C virus	35 (1.3)	12 (2.3)	0.099
Hypertension	748 (28.7)	141 (27.1)	0.454
Hyperlipidemia	225 (8.6)	44 (8.5)	0.892
Mild liver disease	259 (9.9)	56 (10.8)	0.571
Metastatic solid tumor	2,552 (97.9)	514 (98.7)	0.233
Peptic ulcer disease	150 (5.8)	28 (5.4)	0.734
Renal disease	95 (3.6)	18 (3.5)	0.833
Previous systemic anticancer agent
Bevacizumab	1,834 (70.3)	332 (63.7)	0.002
Capecitabine	1,432 (54.9)	295 (56.6)	0.472
Cetuximab	1,013 (38.8)	195 (37.4)	0.545
Fluorouracil	2,434 (93.3)	484 (92.9)	0.720
Irinotecan	2,439 (93.5)	490 (94.1)	0.651
Oxaliplatin	2,146 (82.3)	419 (80.4)	0.312
Panitumumab	16 (0.6)	4 (0.8)	0.686
Tegafur/Uracil	809 (31.0)	150 (28.8)	0.313

Outcome measures	Regorafenib (n=2,608)	TAS-102 (n=521)	p-value
Duration of treatment (day)
Mean±SD	108±162	101±160	0.376
Median (IQR)	60 (35-105)	45 (33-101)
Patterns of treatment duration (day)
0-90	1,808 (69.3)	379 (72.7)	0.397
91-180	442 (17.0)	75 (14.4)
181-365	221 (8.5)	39 (7.5)
≥ 366	137 (5.3)	28 (5.4)
Subsequent anticancer agents
Bevacizumab	36 (1.4)	7 (1.3)	0.947
Cetuximab	23 (0.9)	9 (1.7)	0.079
Capecitabine	426 (16.3)	93 (17.9)	0.395
Fluorouracil	595 (22.8)	125 (24.0)	0.559
Irinotecan	566 (21.7)	130 (25.0)	0.103
Oxaliplatin	345 (13.2)	74 (14.2)	0.550
Tegafur/Uracil	319 (12.2)	44 (8.5)	0.013
Regorafenib	NA	84 (16.1)
TAS-102	444 (17.0)	NA

Adverse event	Regorafenib (n=2,608)	TAS-102 (n=521)	p-value
Diarrhea	851 (32.6)	178 (34.2)	0.496
Hypertension	619 (23.7)	89 (17.1)	< 0.001
HFSR	525 (20.1)	21 (4.0)	< 0.001
Anemia	438 (16.8)	98 (18.8)	0.265
Nausea and vomiting	345 (13.2)	86 (16.5)	0.047
Febrile neutropenia	189 (7.3)	37 (7.1)	0.906
Liver injury (hepatotoxicity)	156 (6.0)	15 (2.9)	0.004
Thrombocytopenia	43 (1.7)	13 (2.5)	0.183
Neutropenia	13 (0.5)	15 (2.9)	< 0.001

Table 1. Baseline characteristics of study patients

Values are presented as mean±SD or number (%). CCI, Charlson Comorbidity Index; SD, standard deviation.

Table 2. Duration of treatment and subsequent anticancer agents

Values are presented as number (%) unless otherwise indicated. IQR, interquartile range; NA, not available; SD, standard deviation.