Efficacy and safety of TAS-102 followed by regorafenib or reverse sequence in later-line treatment of metastatic colorectal cancer: a systematic review and meta-analysis

Introduction

Background

Colorectal cancer is the third leading cause of cancer death in the United States in 2022, and for those with metastatic colorectal cancer (mCRC), the 5-year survival rate is approximately 15% (1). Currently, the National Comprehensive Cancer Network 2025 (NCCN 2025) treatment guidelines (2) recommend a fluorouracil-based chemotherapy regimen for the treatment of mCRC, and the addition of oxaliplatin or irinotecan to the chemotherapy regimen can improve progression-free survival (PFS) and overall survival (OS) (3-5). In addition, there is evidence that the addition of biological agents to chemotherapy can improve clinical outcomes, such as anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) in patients with RAS/RAF wild-type (6-8). Therefore, the currently recommended chemotherapy regimens for mCRC patients as first-line and second-line treatments consist of fluorouracil, oxaliplatin, irinotecan, and biologic agents (2). After the failure of first-line and second-line therapy, oral chemotherapy is recommended as the later-line of treatment. The recommended and widely used agents include trifluridine/tipiracil (TAS-102) (9) and regorafenib (10).

TAS-102 is a combination of trifluridine and tipiracil. Trifluridine interferes with DNA replication in cancer cells. However, it is eliminated by the enzyme thymidine phosphorylase; thus, it has a short elimination half-life. Tipiracil is a thymidine phosphorylase inhibitor that prolongs the action of trifluridine (9,11). Regorafenib is an oral multi-kinase inhibitor that blocks several enzymes involved in the growth of cancer cells, including the vascular endothelial growth factor receptor (VEGFR), v-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), REarranged during Transfection (RET), platelet-derived growth factor receptor (PDGFR), and rapidly accelerated fibrosarcoma (RAF). As a result, regorafenib can effectively inhibit cancer cell growth (10,12). Currently, treatment guidelines do not specify which drug should be administered first. If either TAS-102 or regorafenib is ineffective, one of these two drugs can still be pursued sequentially.

Rationale and knowledge gap

The survival and safety profile of starting TAS-102 followed by regorafenib (TR) compared to starting regorafenib followed by TAS-102 (RT) in patients with mCRC who have failed first-line and second-line chemotherapy is uncertain. An observational study by Ottaiano et al. [2023] (13) found that the TR group had a statistically significantly longer OS than the RT group. In contrast, a study by Signorelli et al. [2024] (14) reported that the RT group experienced a statistically significantly longer OS than the TR group. Additionally, studies by Nakashima et al. [2020] (15) and Nevala-Plagemann et al. [2023] (16) found no statistically significant difference in OS between the TR and RT groups.

Objective

Consequently, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of TR versus RT (reverse sequence) in patients with mCRC who had previously failed chemotherapy. We present this article in accordance with the PRISMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0018/rc) (17).

Methods

Search strategy

The protocol was registered in PROSPERO (CRD42024622437). We searched for relevant studies across six databases: PubMed, Scopus, CINAHL, ScienceDirect, medRXiv, and Opengrey.eu from inception to June 1, 2025. The search concept was “regorafenib” AND (“trifluridine tipiracil drug combination” OR “TAS 102”). The entire search term is in Table S1. Language and time restrictions were not applied in this study.

Study eligibility criteria

A systematic review was conducted based on the following eligibility criteria: (I) randomized controlled trials (RCTs) or cohort studies; (II) studies included patients with mCRC who had failed first-line or second-line chemotherapy; (III) studies included patients who received TAS-102 followed by regorafenib or vice versa; (IV) studies reported efficacy outcomes as OS, PFS, and disease control rate (DCR), or reported safety outcomes as adverse events (AEs). OS is defined as the duration from initiating treatment with TAS-102, followed by regorafenib or the reverse sequence, until death from any cause. PFS refers to the time from the initiation of TAS-102, or the initiation of regorafenib in the reverse sequence, until disease progression or death occurs. The DCR is the proportion of patients achieving either complete response (CR), partial response (PR), or stable disease (SD) by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. (18). AEs were categorized using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. (19). We excluded studies that did not stratify patients into participants who received TAS-102 followed by regorafenib or regorafenib followed by TAS-102.

Data extraction

Three authors independently screened the titles, abstracts, and full texts of retrieved articles. Full texts that were not accessible were addressed by contacting their corresponding authors via email. Those studies were excluded if the authors did not respond within a reasonable time. Three authors extracted the author’s name, year of publication, study design, location, duration of study, sample size, sex, mean age, Eastern Cooperative Oncology Group (ECOG) score, number of metastatic sites, primary site of the tumor, RAS/RAF status, number of prior chemotherapy regimens, survival outcomes, AEs, and information necessary for evaluating the risk of bias. The median age and interquartile range were converted to mean and standard deviation using a formula proposed by Wan et al. (20). Three authors independently assessed the risk of bias in the included studies. The risk of bias in RCTs and non-randomized trials was evaluated using the Cochrane Risk-of-Bias tool 2.0 (RoB 2.0) (21) and the Risk Of Bias In Non-randomized Studies (ROBINS-I) (22), respectively. All disagreements were resolved by consulting the senior author on the team.

Statistical analysis

We extracted the adjusted hazard ratios (HRs) related to OS and PFS, adjusted odds ratios (ORs), or adjusted relative risks (RRs) from DCR and AEs. The duration of survival (in months) and the number of patients were converted to unadjusted HRs, RRs, and ORs with 95% confidence intervals (CI) using OpenMeta(Analyst) (23). In cases where HRs were not reported, we approximated HRs using the observed survival ratio (OSR), defined as the ratio of median survival times between the TR and RT groups (24). Zero values were addressed by imputing with 0.5 (25). We utilized a random-effects model with inverse variance weighting to evaluate the outcomes (OpenMetaAnalyst for Windows 8) (26). Heterogeneity was assessed using Cochrane’s Q statistic and I² values. I² values greater than 75% indicated high heterogeneity, while I² values less than 25% suggested low heterogeneity. A P value for Cochrane’s Q of less than 0.10 indicated significant heterogeneity (27). We used a funnel plot to assess publication bias. Additionally, we planned a sensitivity analysis by analyzing only studies that reported adjusted HRs to minimize potential confounding effects from unadjusted or crude effect estimates.

Results

Study characteristics

From a search of six databases, we retrieved 1,627 records. After removing records marked as ineligible and duplicates, 612 studies were screened. Following title and abstract screening and full-text assessment of potentially relevant studies, a total of 13 studies were included for further analysis (13-16,28-36), as shown in Figure 1. However, some studies that met the inclusion criteria, specifically those that classified participants into TR/RT groups and reported survival or safety outcomes, were excluded due to insufficient data for pooling in this meta-analysis. Further details of these excluded studies are provided in Table S2. Of the 13 included studies, the total sample size was 17,527 participants. However, only 4,178 participants were included in the final analysis. Among them, 3,654 were male, with a mean age of approximately 63.80±2.86 years. Most participants had an ECOG performance status of 0–1, ≤2 metastatic sites, and the primary tumor location was mainly in the left-sided colon and rectum. The RAS status was predominantly mutant-type, the BRAF status was wild-type, and the majority of participants had received fewer than three prior chemotherapy regimens. Detailed study characteristics are presented in Table S3, and additional information on metastatic sites is provided in Table S4.

Figure 1 The PRISMA flow chart of the study selection. RT, regorafenib followed by TAS-102; TAS-102, trifluridine/tipiracil; TR, TAS-102 followed by regorafenib.

Risk of bias assessment

Risk of bias was assessed in all 13 observational studies using the ROBINS-I, as shown in Figure 2. Five studies (15,16,28,30,31) were at moderate risk of bias, while eight studies (13,14,29,32-36) were at critical risk of bias. The primary reason for the critical rating was that these studies reported survival outcomes comparing TR and RT groups using unadjusted HRs.

Figure 2 The evaluation of the risk of bias in non-randomized studies using The Risk Of Bias In Non-randomized Studies (ROBINS-I).

Survival outcomes

A pooled analysis demonstrated no difference in OS between the TR and RT groups (HR =1.04; 95% CI: 0.86–1.25, N=9). The heterogeneity across studies was high, with an I² of 72%, as shown in Figure 3. We did a sensitivity analysis by analyzing only studies that reported HRs. The result still showed no difference in OS between the TR and RT groups (HR =1.04, 95% CI: 0.84-1.28, I² = 79%, N=7) (Figure S1). A pooled analysis of two studies revealed no statistically significant difference in PFS between the TR and RT groups (HR =1.34; 95% CI: 0.77–2.34, I²=92%, N=2, Figure 4). The DCR in the TR group was 28.0% (95% CI: 14.4%-41.7%; I²=76.45%, N=5), while the RT group reported a DCR of 33.1% (95% CI: 18.8%-47.4%; I²=77.76%, N=5, Figures 5,6). In addition, a direct comparative analysis of DCR between the TR and RT groups was performed. The pooled analysis showed no statistically significant difference between the two sequences (RR = 1.11, 95% CI: 0.98–1.26; I²=0%, Figure 7).

Figure 3 Forest plot of overall survival comparing sequential treatment with TR versus RT in patients with metastatic colorectal cancer who failed prior chemotherapy. CI, confidence interval; IV, inverse variance; RT, regorafenib followed by TAS-102; SE, standard deviation; TAS-102, trifluridine/tipiracil; TR, TAS-102 followed by regorafenib.

Figure 4 Forest plot of progression-free survival comparing sequential treatment with TR versus RT in patients with metastatic colorectal cancer who failed prior chemotherapy. CI, confidence interval; IV, inverse variance; RT, regorafenib followed by TAS-102; SE, standard deviation; TAS-102, trifluridine/tipiracil; TR, TAS-102 followed by regorafenib.

Figure 5 Forest plot of disease control rate in patients with metastatic colorectal cancer who received TR after failure of prior chemotherapy. TAS-102, trifluridine/tipiracil; TR, TAS-102 followed by regorafenib.

Figure 6 Forest plot of disease control rate in patients with metastatic colorectal cancer who received RT after failure of prior chemotherapy. TAS-102, trifluridine/tipiracil; RT, regorafenib followed by TAS-102.

Figure 7 Forest plot of disease control rate comparing TR versus RT in patients with metastatic colorectal cancer who failed prior chemotherapy. CI, confidence interval; IV, inverse variance; RT, regorafenib followed by TAS-102; SE, standard deviation; TAS-102, trifluridine/tipiracil; TR, TAS-102 followed by regorafenib.

Safety outcomes

Details of AEs are summarized in Table S5 and Figures S2-S12. The incidence of AEs in the TR and RT groups was not different (P>0.05). The AEs tended to be higher in the RT group than the TR group, including both hematologic AEs (anemia, neutropenia, and thrombocytopenia) and non-hematologic AEs (alopecia, hepatotoxicity, hand-foot skin reaction, and nausea/vomiting).

Publication bias

The funnel plot (Figure S13) was used to analyze potential publication bias. Upon visual inspection, most studies showed a symmetric distribution around the central line of RRs. This plot suggests no apparent publication bias among the nine included studies.

Discussion

Key findings

Since the approval of TAS-102 and regorafenib for use as later-line treatments in mCRC patients who have failed prior chemotherapy, it has been widely recognized that both agents offer comparable survival benefits, but each drug has its own distinct toxicity profile (37-40). Although previous studies have shown that the sequential use of both agents may improve survival compared to using either agent alone (15,41), the question of which drug should be initiated first remains unclear. This systematic review and meta-analysis found that patients receiving TR and those receiving the reverse sequence (RT) achieved similar outcomes in OS (HR 1.04, 95% CI: 0.86–1.25) and PFS (HR 1.34, 95% CI: 0.77–2.34), as previously shown. The RT group demonstrated a numerically higher DCR than the TR group (33.1% vs. 28.0%) and also exhibited a trend toward a higher incidence of AEs. Nevertheless, when directly compared using a pooled relative risk, the difference in DCR between the RT and TR groups was not statistically significant. This finding suggests that the apparent difference observed in pooled proportions may be influenced by between-study variability rather than reflecting a true difference between the treatment sequences.

Strengths and limitations

This study has several limitations. First, the meta-analysis included 1 prospective study and 12 retrospective cohort studies, with no RCTs, which may have introduced selection bias and confounding by indication. Second, quality assessment using the ROBINS-I tool revealed that 8 of the 13 studies had a critical risk of bias, primarily due to the use of unadjusted HRs, which could lead to over- or underestimation of the pooled effects. Third, I² values for both OS and PFS were high (72–92%), indicating substantial heterogeneity. Although a random-effects model was applied, the certainty of the pooled estimates remains limited. This heterogeneity may be attributable to the observational nature of the included studies and differences in baseline characteristics (e.g., ethnicity, prior lines of therapy, metastatic sites, and RAS status), as well as variability in effect estimation methods, including the use of adjusted and unadjusted HRs or approximations derived from median survival times. Due to the limited number of studies, particularly for PFS, subgroup analyses or meta-regression were not feasible; therefore, the results should be interpreted with caution. Fourth, several studies reported relevant survival outcomes but lacked sufficient data for HR calculation. This results in fewer studies being included in the quantitative synthesis than were initially available. Especially for PFS, only two studies were pooled, thus reducing confidence in the results. Fifth, although HRs are the preferred effect measure for time-to-event analyses, some studies did not report them. In such cases, OSRs derived from median survival times were used, as previously described. While OSRs are not a perfect substitute for HRs, sensitivity analyses excluding studies using OSRs were conducted to assess the robustness of the findings (Figure S1). The analysis showed that including OSRs did not affect the pooled results. Finally, most observational studies lacked detailed reporting on treatment-related variables, such as dose modification, which may have influenced survival outcomes.

Comparison with similar research

The sequence of administration may not significantly affect survival outcomes, as the primary mechanisms of action of TAS-102 and regorafenib are distinct and non-overlapping. TAS-102 exerts its anticancer effect primarily through trifluridine, which is activated by thymidine kinase 1 into a monophosphate form that inhibits thymidylate synthase, leading to deoxythymidine triphosphate (dTTP) reduction and deoxyuridine monophosphate (dUMP) accumulation, thereby disrupting DNA synthesis. Additionally, trifluridine is incorporated into DNA in its triphosphate form, leading to strand breaks and subsequent cell death in cancer cells. Tipiracil, a thymidine phosphorylase inhibitor, enhances trifluridine’s bioavailability by preventing its degradation, sustaining its antitumor activity even in 5-fluorouracil (5-FU)-resistant tumors (11). In contrast, regorafenib is a multi-kinase inhibitor that targets key signaling pathways involved in cancer progression, including VEGFR, KIT, RET, PDGFR, and RAF, thereby inhibiting tumor proliferation, angiogenesis, and metastasis (12). Considering these mechanistically distinct pathways, it is reasonable to hypothesize that the order of administration does not influence overall therapeutic efficacy. Alternatively, from the patient’s perspective, another possible explanation is that individuals enrolled in these studies had already undergone multiple prior lines of chemotherapy, potentially resulting in chemoresistance and reduced tumor responsiveness to subsequent treatments. Additionally, many patients may have experienced cumulative toxicities from previous regimens and presented with a declining performance status, limiting their ability to tolerate optimal drug dosages or maintain treatment for the recommended duration. These factors may collectively explain why the sequencing of TAS-102 and regorafenib did not result in a meaningful difference in survival outcomes. A numerically higher DCR was observed in the RT group than in the TR group. Although the absolute difference in DCR in our analysis was modest (RT showing approximately 5.1% greater benefit), in patients with metastatic disease, this may still represent a clinically meaningful outcome that could inform treatment decisions aimed at disease stabilization.

Regarding safety outcomes, the RT group may have had a higher incidence of both hematological and non-hematological AEs than in the TR group. However, the difference was not statistically significant, as the pooled estimates and their 95% CIs largely overlapped. This trend aligns with previous studies, which also reported a higher incidence of AEs in the RT group without statistical significance (15,28,35). We hypothesize that patients in the TR group received TAS-102 first, which is more commonly associated with hematologic AEs such as anemia, neutropenia, and thrombocytopenia (9,37). These toxicities tend to be more predictable and manageable, possibly allowing patients to tolerate the subsequent regorafenib treatment better. However, this interpretation contrasts with the findings of Signorelli et al. [2021] (42), who reported that AEs tended to reflect the toxicity profile of the agent administered first in the treatment sequence. In their analysis, patients who were first treated with TAS-102 exhibited higher rates of hematologic AEs, while those who were first treated with regorafenib more frequently experienced non-hematologic AEs such as hand-foot skin reaction and fatigue. These findings are consistent with known toxicity profiles reported in earlier studies (9,10,37).

Explanations of findings

To our knowledge, this is the first systematic review and meta-analysis that comprehensively synthesizes up-to-date real-world data and clinical practice outcomes, including a large sample of 4,178 patients across multiple countries. Although studies on later-line treatments in mCRC are emerging, such as the SUNLIGHT study (43), which showed improved OS and PFS with TAS-102 plus bevacizumab compared to TAS-102 alone, the combination was also associated with a higher incidence of neutropenia. Similarly, the FRESCO-2 study (44) demonstrated that fruquintinib significantly improved median OS compared to placebo. While these agents have shown efficacy in clinical trials, their broader implementation remains limited by a lack of long-term real-world data and accessibility challenges in many countries. Therefore, the sequential use of TAS-102 and regorafenib remains a relevant and widely used strategy in many countries. Although our analysis showed no significant difference in survival outcomes between the two sequences, the higher DCR observed in the RT group, along with a trend toward more frequent AEs, albeit not statistically significant, may offer additional guidance for treatment decisions.

Patient characteristics may also need to be considered when choosing the initial agent. For instance, the choice of initial agent may be influenced by patient age, as evidenced by Moriwaki et al. [2018] (45), who suggest that regorafenib may confer a greater survival advantage in individuals under 65 years of age, while TAS-102 tends to be more beneficial in patients aged 65 and above. Furthermore, in cases where patient compliance is a concern, sequence selection may benefit from considering adherence patterns. Supporting this, evidence from Patel et al. [2020] (46) suggests that initiating treatment with TAS-102 followed by regorafenib results in significantly better adherence and persistence compared to the reverse sequence, indicating improved tolerability or treatment acceptance in this order. In addition, assessing RAS mutation status before initiating treatment may be considered, as recent evidence from Basso et al. [2024] (47) suggests that the RT sequence may provide a survival benefit over the TR sequence, specifically in patients with KRAS codon 12 mutations. By contrast, no significant difference was observed between the two groups in other RAS subgroups, including wild-type, codon 13 mutations, rare mutations, G12C mutation, and G12D mutation. However, these predictive biomarker-based findings remain inconclusive.

Implications and actions needed

We recommend that future large, prospective, pragmatic trials should be conducted to identify potential predictors of sequencing efficacy. Furthermore, subsequent studies should evaluate other clinically meaningful endpoints in the later-line treatment setting, such as health-related quality of life, time to treatment failure, and cost-effectiveness.

Conclusions

No significant difference in OS or PFS was observed between the sequencing of TR and the reverse sequence (RT) in patients with mCRC who had failed prior chemotherapy. Although the RT group showed a numerically higher DCR, this difference was not statistically significant and was accompanied by a trend toward more frequent AEs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0018/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0018/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0018/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. American Cancer Society. Colorectal Cancer. 2022. Available online: http://www.cancer.org/cancer/colon-rectal-cancer.html
2. National Comprehensive Cancer Network. (2025). Colon Cancer (version 4.2025). Available online: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
3. Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 2005;23:4866-75. [Crossref] [PubMed]
4. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47. [Crossref] [PubMed]
5. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229-37. [Crossref] [PubMed]
6. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45. [Crossref] [PubMed]
7. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. [Crossref] [PubMed]
8. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658-64. [Crossref] [PubMed]
9. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015;372:1909-19. [Crossref] [PubMed]
10. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:303-12. [Crossref] [PubMed]
11. Peters GJ. Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies. Ther Adv Med Oncol 2015;7:340-56. [Crossref] [PubMed]
12. Arai H, Battaglin F, Wang J, et al. Molecular insight of regorafenib treatment for colorectal cancer. Cancer Treat Rev 2019;81:101912. [Crossref] [PubMed]
13. Ottaiano A, Santorsola M, Perri F, et al. Survival and Toxicities of Metastatic Colorectal Cancer Patients Treated with Regorafenib before TAS-102 or Vice Versa: A Mono-Institutional Real-Practice Study. J Clin Med 2023;12:596. [Crossref] [PubMed]
14. Signorelli C, Calegari MA, Anghelone A, et al. Survival Outcomes with Regorafenib and/or Trifluridine/Tipiracil Sequencing to Rechallenge with Third-Line Regimens in Metastatic Colorectal Cancer: A Multicenter Retrospective Real-World Subgroup Comparison from the ReTrITA Study. Curr Oncol 2024;31:7793-808. [Crossref] [PubMed]
15. Nakashima M, Takeuchi M, Kawakami K. Effectiveness and Safety of Regorafenib vs. Trifluridine/Tipiracil in Unresectable Colorectal Cancer: A Retrospective Cohort Study. Clin Colorectal Cancer 2020;19:e208-25. [Crossref] [PubMed]
16. Nevala-Plagemann C, Sama S, Ying J, et al. A Real-World Comparison of Regorafenib and Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer in the United States. J Natl Compr Canc Netw 2023;21:257-64. [Crossref] [PubMed]
17. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. [Crossref] [PubMed]
18. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. [Crossref] [PubMed]
19. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. National Cancer Institute (NCI); 2017. Available online: https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v5-5x7.pdf
20. Wan X, Wang W, Liu J, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14:135. [Crossref] [PubMed]
21. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. [Crossref] [PubMed]
22. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919. [Crossref] [PubMed]
23. Wallace BC, Schmid CH, Lau J, et al. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol 2009;9:80. [Crossref] [PubMed]
24. Cortés J, González JA, Campbell MJ, et al. A hazard ratio was estimated by a ratio of median survival times, but with considerable uncertainty. J Clin Epidemiol 2014;67:1172-7. [Crossref] [PubMed]
25. Deeks JJ, Higgins JP, Altman DG, et al. editors. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JP, Thomas J, Chandler J, et al. editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.5. Cochrane, 2024. Available online: cochrane.org/handbook
26. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. [Crossref] [PubMed]
27. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. [Crossref] [PubMed]
28. Chang YW, Kuo CN, Chang CL, et al. Sequential Treatment of Metastatic Colorectal Cancer in Taiwan: Real-World Evidence From Regorafenib and Trifluridine/Tipiracil Use. J Gastroenterol Hepatol 2025;40:1135-42. [Crossref] [PubMed]
29. Coutzac C, Trouilloud I, Artru P, et al. Sequential Treatment With Trifluridine/Tipiracil and Regorafenib in Refractory Metastatic Colorectal Cancer Patients: An AGEO Prospective "Real-World Study". Clin Colorectal Cancer 2022;21:132-40. [Crossref] [PubMed]
30. Cremolini C, Rossini D, Martinelli E, et al. Trifluridine/Tipiracil (TAS-102) in Refractory Metastatic Colorectal Cancer: A Multicenter Register in the Frame of the Italian Compassionate Use Program. Oncologist 2018;23:1178-87. [Crossref] [PubMed]
31. Hsiao KY, Chen HP, Rau KM, et al. Association between sidedness and survival among chemotherapy refractory metastatic colorectal cancer patients treated with trifluridine/tipiracil or regorafenib. Oncologist 2024;29:e1669-79. [Crossref] [PubMed]
32. Masuishi T, Taniguchi H, Hamauchi S, et al. Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison. Clin Colorectal Cancer 2017;16:e15-22. [Crossref] [PubMed]
33. Oshima K, Hirano H, Shoji H, et al. Influence of precedent drug on the subsequent therapy in the sequence of trifluridine/tipiracil with/out bevacizumab and regorafenib for unresectable or recurrent colorectal cancer. PLoS One 2022;17:e0269115. [Crossref] [PubMed]
34. Signorelli C, Calegari MA, Basso M, et al. Treatment Settings and Outcomes with Regorafenib and Trifluridine/Tipiracil at Third-Line Treatment and beyond in Metastatic Colorectal Cancer: A Real-World Multicenter Retrospective Study. Curr Oncol 2023;30:5456-69. [Crossref] [PubMed]
35. Tanaka A, Sadahiro S, Suzuki T, et al. Retrospective study of regorafenib and trifluridine/tipiracil efficacy as a third-line or later chemotherapy regimen for refractory metastatic colorectal cancer. Oncol Lett 2018;16:6589-97. [Crossref] [PubMed]
36. Vitale P, Zanaletti N, Famiglietti V, et al. Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data. Clin Colorectal Cancer 2021;20:227-35. [Crossref] [PubMed]
37. Abrahao ABK, Ko YJ, Berry S, et al. A Comparison of Regorafenib and TAS-102 for Metastatic Colorectal Cancer: A Systematic Review and Network Meta-analysis. Clin Colorectal Cancer 2018;17:113-20. [Crossref] [PubMed]
38. Chen J, Wang J, Lin H, et al. Comparison of Regorafenib, Fruquintinib, and TAS-102 in Previously Treated Patients with Metastatic Colorectal Cancer: A Systematic Review and Network Meta-Analysis of Five Clinical Trials. Med Sci Monit 2019;25:9179-91. [Crossref] [PubMed]
39. Sonbol MB, Benkhadra R, Wang Z, et al. A Systematic Review and Network Meta-Analysis of Regorafenib and TAS-102 in Refractory Metastatic Colorectal Cancer. Oncologist 2019;24:1174-9. [Crossref] [PubMed]
40. Casadei-Gardini A, Vagheggini A, Gelsomino F, et al. Is There an Optimal Choice in Refractory Colorectal Cancer? A Network Meta-Analysis. Clin Colorectal Cancer 2020;19:82-90.e9. [Crossref] [PubMed]
41. Chida K, Kotani D, Moriwaki T, et al. Survival Benefit of Crossover Administration of Regorafenib and Trifluridine/Tipiracil Hydrochloride for Patients With Metastatic Colorectal Cancer: Exploratory Analysis of a Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study (REGOTAS). Front Oncol 2021;11:576036. [Crossref] [PubMed]
42. Signorelli C, Gemma D, Grande R, et al. Regorafenib-to-trifluridine/tipiracil Versus the Reverse Sequence for Refractory Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Real-life Experience. Anticancer Res 2021;41:2553-61. [Crossref] [PubMed]
43. Prager GW, Taieb J, Fakih M, et al. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med 2023;388:1657-67. [Crossref] [PubMed]
44. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet 2023;402:41-53. [Crossref] [PubMed]
45. Moriwaki T, Fukuoka S, Taniguchi H, et al. 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. [Crossref] [PubMed]
46. Patel AK, Barghout V, Yenikomshian MA, et al. Real-World Adherence in Patients with Metastatic Colorectal Cancer Treated with Trifluridine plus Tipiracil or Regorafenib. Oncologist 2020;25:e75-84. [Crossref] [PubMed]
47. Basso M, Signorelli C, Calegari MA, et al. Efficacy of Regorafenib and Trifluridine/Tipiracil According to Extended RAS Evaluation in Advanced Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Analysis. Target Oncol 2024;19:371-82. [Crossref] [PubMed]