Prognostic value of the REBECCA prognostic score and the Tabernero classification in refractory metastatic colorectal cancer treated with regorafenib: a multicenter real-world study

Prognostic value of the REBECCA prognostic score and the Tabernero classification in refractory metastatic colorectal cancer treated with regorafenib: a multicenter real-world study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic value of the REBECCA prognostic score and the Tabernero classification in refractory metastatic colorectal cancer treated with regorafenib: a multicenter real-world study Martinez-Lago Nieves, Carnero Lopez Beatriz, de la Camara Gomez Juan, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8357626/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Feb, 2026 Read the published version in BMC Cancer → Version 1 posted 10 You are reading this latest preprint version Abstract Background: Regorafenib is a standard treatment option for patients with metastatic colorectal cancer (mCRC) refractory to conventional therapies. However, outcomes remain heterogeneous, and simple and reproducible prognostic tools applicable in routine clinical practice are needed to optimize patient selection. This study aimed to perform an external real-world validation of the REBECCA prognostic score and the Tabernero classification in a multicenter cohort of refractory mCRC patients treated with regorafenib. Methods: We conducted a retrospective multicenter study including 130 patients with refractory mCRC treated with regorafenib across five university hospitals in Galicia, Spain. Overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were analyzed according to the REBECCA prognostic score and the Tabernero classification. Kaplan–Meier estimates, log-rank tests, and chi-squared analyses were used to compare outcomes between prognostic subgroups. Results: Median age was 63 years, and 94.6% of patients had ECOG performance status 0–1. Median OS and PFS were 6.7 and 2.9 months, respectively. According to the REBECCA prognostic score, median OS was 9.2, 6.9, and 5.3 months for low-, intermediate-, and high-risk groups, respectively (p = 0.138). In contrast, the Tabernero classification identified significant OS differences, with median OS of 10.5, 6.9, and 5.2 months in patients with best, good, and poor prognostic characteristics, respectively (p = 0.022). DCR was also significantly stratified by the Tabernero classification (48.0%, 21.1%, and 24.4%; p = 0.004). Treatment was well tolerated, with a safety profile consistent with previous studies. Conclusions: In this multicenter real-world study, the Tabernero classification demonstrated robust prognostic stratification in a real-world setting in refractory mCRC patients treated with regorafenib, whereas the REBECCA prognostic score showed limited discriminatory ability in this contemporary cohort. Given its simplicity, objectivity, and reproducibility, the Tabernero model may represent a practical tool to support prognostic assessment and clinical decision-making in routine practice. Metastatic colorectal cancer regorafenib prognostic score Tabernero classification REBECCA prognostic score real-world evidence Figures Figure 1 Introduction Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and remains a leading cause of cancer-related mortality, with over 1.9 million new cases and 935,000 deaths reported in 2020 alone [ 1 ]. Despite advances in systemic therapy, the prognosis of patients with metastatic CRC (mCRC) who progress after standard treatments remains poor, with median overall survival (OS) typically ranging from 6 to 12 months [ 2 ]. Current third-line or later treatment options include regorafenib, trifluridine/tipiracil (FTD/TPI) with or without bevacizumab, fruquintinib, and targeted therapies for selected molecular subgroups [ 3 ]. Regorafenib is an oral multikinase inhibitor that targets angiogenic, stromal, and oncogenic pathways. Its clinical benefit was demonstrated in the pivotal CORRECT trial, which showed a significant overall survival (OS) improvement over placebo (6.4 vs. 5.0 months; hazard ratio [HR] 0.77) in patients with refractory mCRC [ 4 ]. Subsequent studies confirmed these findings, including the large phase IIIb CONSIGN trial with over 2,800 patients (median OS: 6.3 months) [ 5 ], and the REBECCA observational study, which supported the drug’s efficacy and safety in real-world clinical practice [ 6 ]. Additional insights into treatment patterns and tolerability were provided by the prospective CORRELATE study [ 7 ]. The ReDOS trial further demonstrated that a dose-escalation strategy could improve tolerability without compromising efficacy [ 8 ]. These data collectively confirm regorafenib as a standard third-line option in mCRC, although outcomes remain heterogeneous and reliable predictors of benefit are lacking. Given the modest efficacy of regorafenib and the heterogeneity of patient outcomes, simple, reproducible prognostic tools applicable in routine clinical practice are needed to better identify individuals most likely to derive clinical benefit. The REBECCA prognostic score, developed from a large compassionate-use cohort, incorporates four adverse clinical factors: Eastern Cooperative Oncology Group performance status (ECOG PS), number of metastatic sites, presence of liver metastases, and time from diagnosis of metastatic disease, and stratifies patients into distinct prognostic groups in real-world settings [ 6 ]. The Tabernero classification, originally developed in the context of the RECOURSE trial, is based exclusively on objective tumor-related variables—number of metastatic sites, presence of liver metastases, and time from metastatic diagnosis—thereby avoiding subjective clinical parameters [ 9 ]. This characteristic may enhance its reproducibility and applicability in daily practice. Its prognostic value has been confirmed in real-world settings in patients receiving FTD/TPI, as demonstrated in the TALLISUR trial [ 10 ]; however, its prognostic impact in patients treated with regorafenib has not been formally validated. The aim of the present study was to perform an external real-world validation of the REBECCA prognostic score and the Tabernero classification in a multicenter cohort of patients with refractory mCRC treated with regorafenib, with a specific focus on their ability to stratify survival outcomes and their clinical applicability in routine practice. Materials and Methods Study design and population This was a retrospective, multicenter study including patients with histologically confirmed metastatic colorectal cancer (mCRC) refractory to standard therapies. Eligible patients were ≥ 18 years old and had received at least one dose of regorafenib after progression or intolerance to approved treatments, including fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF agents, and anti-EGFR agents in RAS/BRAF wild-type tumors. Patients were treated between January 2016 and December 2021 at five university hospitals in Galicia (Spain), all members of the Galician Research Group on Gastrointestinal Tumors (GITuD). Patients with incomplete clinical or follow-up data were excluded. The study was approved by the Galician Research Ethics Committee (CEIm-G; reference 2022/235) and registered under the identifier GIT-ICI-2022-02. All patients provided written informed consent for the use of their anonymized clinical data for research purposes. This study was conducted in accordance with the ESMO-Guidance for Reporting Oncology real-world evidence (GROW) recommendations. The GROW checklist and patient flowchart are provided as supplementary material. Data collection Demographic, clinical, pathological, and laboratory data were retrospectively extracted from electronic medical records. Variables included age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), primary tumor location, RAS/BRAF mutation status, mismatch repair protein expression, number and location of metastatic sites, and prior systemic treatments. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Tumor response assessments were performed according to RECIST version 1.1 at regular intervals based on routine clinical practice, typically every 8–12 weeks, or earlier if clinically indicated, in accordance with institutional protocols. Prognostic stratification Patients were classified according to the REBECCA prognostic score and the Tabernero classification. The REBECCA prognostic score, developed from a large compassionate-use cohort, assigns one point for each of the following adverse clinical features: ECOG PS ≥ 1, time from diagnosis of metastatic disease < 18 months, presence of liver metastases, and ≥ 3 metastatic sites [ 6 ]. Based on the cumulative score (0–4), patients were categorized as low risk (0–1 points), intermediate risk (2 points), or high risk (≥ 3 points). The Tabernero classification was applied according to the original definition described in the RECOURSE trial exploratory analysis [ 9 ]. Patients with good prognostic characteristics (GPC) were defined as those with 1–2 metastatic sites and ≥ 18 months from diagnosis of first metastasis. Among these, patients without liver metastases were further classified as having best prognostic characteristics (BPC). Patients with poor prognostic characteristics (PPC) were defined as those with ≥ 3 metastatic sites and/or < 18 months from diagnosis of metastatic disease. For descriptive and survival analyses, patients were grouped into best, good, and poor prognostic categories, reflecting the hierarchical structure of the original classification. Endpoints and statistical analysis The primary endpoints were overall survival (OS) and progression-free survival (PFS), defined from the initiation of regorafenib to death from any cause, and to radiological or clinical disease progression or death, respectively. Disease control rate (DCR) and safety outcomes were also evaluated. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. PFS and OS were analyzed according to prognostic subgroups defined by the REBECCA and Tabernero classifications. Categorical variables were analyzed using the chi-squared or Fisher’s exact test, and continuous variables using the Mann–Whitney U test. All statistical analyses were performed using IBM SPSS Statistics, version 25. A two-sided p-value < 0.05 was considered statistically significant. Missing data were minimal and were handled by complete-case analysis; no imputation was performed. Results Patient characteristics A total of 130 patients with refractory mCRC treated with regorafenib were included. Baseline characteristics are summarized in Table 1 . The median age was 63 years (range, 38–84), and 65.4% were male. Most patients (94.6%) had an ECOG performance status (PS) of 0–1. Primary tumors were located in the right colon (22.3%), left colon (63.1%), or rectum (14.6%). RAS mutations were present in 55.4% of tumors, BRAF mutations in 1.5%, and 41.5% of patients had RAS/BRAF wild-type tumors. Liver metastases were present in 75.4%, and 32.3% had three or more metastatic sites. In 86.0% of cases, the interval between metastatic diagnosis and regorafenib initiation was > 18 months. Patients had received a median of three prior lines of therapy (range, 2–8), and 29.2% had been previously treated with trifluridine/tipiracil. Regorafenib was initiated at the full dose of 160 mg in 53.1% of patients, while 46.9% started treatment at a reduced dose or with a ReDOS dose-escalation strategy, including 120 mg in 14.6%, 80 mg in 16.9%, and a ReDOS strategy in 15.4% of patients. Table 1 Baseline characteristics of patients with metastatic colorectal cancer treated with regorafenib (n = 130). Characteristic n (%) Age, median (range) 63 (38–84) Sex Male 85 (65.4) Female 45 (34.6) ECOG PS 0 53 (40.8) 1 70 (53.8) 2 7 (5.4) Tumor location Right-sided 29 (22.3) Left-sided 82 (63.1) Rectum 19 (14.6) Molecular status RAS/BRAF wild-type 54 (41.6) RAS mutated 72 (55.4) BRAF mutated 2 (1.5) Unknown 2 (1.5) Liver metastases Yes 98 (75.4) No 32 (24.6) Number of metastatic sites 18 months 112 (86.0) ≤18 months 18 (14.0) Number of prior treatment lines Median (range) 3 (2–8) Previous FTD/TPI 38 (29.2) Initial REG dose 160 mg 69 (53.1) 120 mg 19 (14.6) 80 mg 22 (16.9) ReDOS strategy 20 (15.4) Table footnote: Baseline demographic, clinical, molecular, metastatic, and treatment characteristics of the study population, structured by subcategories. ECOG PS: Eastern Cooperative Oncology Group Performance Status; FTD/TPI: trifluridine/tipiracil; REG: regorafenib. Treatment exposure and efficacy Patients received a median of 3 cycles of regorafenib (range, 1–18). Among 118 evaluable patients, no complete responses were observed. Partial response was achieved in 5 patients (4.2%), and stable disease in 25 patients (21.2%), resulting in a disease control rate (DCR) of 25.4%. Progressive disease was documented in 88 patients (74.6%). After a median follow-up of 23.4 months, the median overall survival (OS) was 6.7 months (95% CI, 6.1–7.3), and median progression-free survival (PFS) was 2.9 months (95% CI, 2.7–3.0). The 12-month OS rate was 20.8% (Table 2 ). Survival outcomes were subsequently analyzed according to prognostic subgroups defined by the REBECCA prognostic score and the Tabernero classification. Table 2 Treatment efficacy outcomes in evaluable patients treated with regorafenib (n = 118) Outcome Value Complete Response (CR), n (%) 0 (0.0) Partial Response (PR), n (%) 5 (4.2) Stable Disease (SD), n (%) 25 (21.2) Progressive Disease (PD), n (%) 88 (74.6) Objective response rate (ORR), n (%) 5 (4.2) Disease control rate (DCR), n (%) 30 (25.4) Median progression-free survival (PFS), months (95% CI) 2.9 (2.7–3.0) Median overall survival (OS), months (95% CI) 6.7 (6.1–7.3) 12-month OS rate (%) 24 (20.8) Table footnote: Updated efficacy outcomes including response rates, survival metrics and long-term OS rate at 12 months. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; DCR: disease control rate; PFS: progression-free survival; OS: overall survival. Safety Treatment-related adverse events (AEs) were reported in 52.3% of patients, with grade 3–4 events in 19.2%. The most frequent all-grade AEs included asthenia (80.8%), hand–foot skin reaction (37.7%), hyperbilirubinemia (31.5%), anemia (21.5%), hypertension (20.8%), diarrhea (19.2%), and stomatitis (20.0%). Grade 3–4 toxicities were less common, with asthenia (12.3%), hyperbilirubinemia (6.4%), hand–foot skin reaction (3.9%), and hypertension (3.9%) being the most frequent. Rash occurred in 6.9% of patients, with 1.5% experiencing grade 3–4 severity. Dose reductions were required in 39.2% of patients. The incidence and severity of adverse events were comparable across prognostic subgroups, and no unexpected safety signals were observed (Table 3 ). Table 3 Adverse events by grade in patients treated with regorafenib (n = 130) Adverse Event All grades, n (%) Grade 3–4, n (%) Asthenia 105 (80.8) 16 (12.3) Hand-foot skin reaction 49 (37.7) 5 (3.9) Hyperbilirubinemia 41 (31.5) 8 (6.4) Anemia 28 (21.5) 3 (2.3) Hypertension 27 (20.8) 5 (3.9) Diarrhea 25 (19.2) 3 (2.3) Stomatitis 26 (20.0) 2 (1.5) Rash 9 (6.9) 2 (1.5) Table footnote: Adverse events reported during regorafenib treatment in 130 patients. Grade 3–4 toxicities are shown separately. AE: adverse event; Grade 3–4: CTCAE v5.0 grade 3 or 4 events. Prognostic classification according to REBECCA and Tabernero According to the REBECCA prognostic score, 32.6% of patients were classified as low risk (0–1 points), 35.7% as intermediate risk (2 points), and 31.8% as high risk (≥ 3 points); one patient could not be classified due to missing ECOG PS. Median OS by risk group was 9.2 months in the low-risk group, 6.9 months in the intermediate-risk group, and 5.3 months in the high-risk group (p = 0.138), showing a non-significant trend. DCR by REBECCA category was 37.5%, 28.5%, and 22.9%, respectively (p = 0.121) (Table 4 , Fig. 1 A). Progression-free survival showed a similar numerical trend across REBECCA risk groups (Table 4 ). Table 4 Prognostic stratification according to the REBECCA prognostic score and the Tabernero classification (N = 130). Prognostic Group n (%) Median OS, months Disease Control Rate, n (%) REBECCA Score Low risk (0–1 points) 42 (32.6) 9.2 18 (37.5) Intermediate risk (2 points) 46 (35.7) 6.9 20 (28.5) High risk (≥ 3 points) 41 (31.8) 5.3 13 (22.9) Tabernero Classification Best prognosis (0 points) 26 (20.0) 10.5 12 (48.0) Good prognosis (1 point) 55 (42.3) 6.9 12 (21.1) Poor prognosis (2–3 points) 49 (37.7) 5.2 10 (24.4) Table footnote: Prognostic classification of patients according to REBECCA and Tabernero scores. OS: overall survival; DCR: disease control rate; REBECCA: includes ECOG PS ≥ 1, liver metastases, ≥ 3 metastatic sites, and < 18 months from metastatic diagnosis. Tabernero score: includes liver metastases, ≥ 3 metastatic sites, and < 18 months from metastatic diagnosis. The Tabernero classification follows a hierarchical structure in which patients with best prognostic characteristics are a subset of those with good prognostic characteristics. According to the hierarchical structure of the Tabernero classification, patients with best prognostic characteristics represent a subset of those with good prognostic characteristics. Using the Tabernero classification, 20.0% of patients were classified as best prognostic characteristics, 42.3% as good prognostic characteristics, and 37.7% as poor prognostic characteristics. Median OS was significantly different across these groups: 10.5 months in the best prognostic group, 6.9 months in the good prognostic group, and 5.2 months in the poor prognostic group (p = 0.022). DCR was also significantly stratified: 48.0% in the best group, 21.1% in the good group, and 24.4% in the poor group (p = 0.004) (Table 4 , Fig. 1 B). Progression-free survival was also numerically longer in patients with best and good prognostic characteristics compared with those in the poor prognostic group (Table 4 ). Discussion This multicenter real-world study provides updated evidence on the effectiveness and safety of regorafenib in patients with refractory metastatic colorectal cancer (mCRC), and represents the first external real-world validation of the Tabernero prognostic classification in patients treated with regorafenib. The observed median overall survival (OS) of 6.7 months and median progression-free survival (PFS) of 2.9 months are consistent with the pivotal CORRECT trial [ 4 ] and with large European series such as CONSIGN [ 5 ], REBECCA [ 6 ], and CORRELATE [ 7 ], supporting the external validity of regorafenib across diverse clinical settings. The safety profile was manageable and comparable to previous studies, with fatigue, hand–foot skin reaction, and hyperbilirubinemia being the most frequently reported adverse events. Grade 3–4 toxicities occurred in fewer than 20% of patients, and no treatment-related deaths were reported. As in the ReDOS trial [ 8 ], the use of dose-escalation strategies in a subset of patients may have contributed to improved tolerability. These findings reinforce the role of regorafenib as a therapeutic option in later lines, even in unselected real-world populations and in the absence of validated predictive biomarkers. The key focus of our study was the external clinical validation of two prognostic models—the REBECCA prognostic score and the Tabernero classification—with the aim of assessing their ability to stratify outcomes in routine clinical practice rather than to compare their methodological construction. The REBECCA model, developed from a large compassionate-use cohort, combines clinical and disease-related parameters, including ECOG performance status (PS), time from metastatic diagnosis, number of metastatic sites, and presence of liver metastases [ 6 ]. In our cohort, this score showed a numerical trend toward survival stratification; however, differences in OS and disease control rate (DCR) did not reach statistical significance. Notably, survival outcomes in the high-risk REBECCA group were better than those originally reported, which may partly explain the lack of discriminatory power observed in this cohort. In contrast, the Tabernero classification, based exclusively on objective tumor-related variables—time from metastatic diagnosis, number of metastatic sites, and liver metastases—demonstrated significant prognostic discrimination for both OS and DCR [ 9 ]. This finding is particularly relevant in clinical practice, where the subjective nature of ECOG PS may limit reproducibility due to interobserver variability [ 11 – 13 ]. By relying solely on objective and routinely available tumor-related factors, the Tabernero model offers a pragmatic and reproducible approach to prognostic stratification in daily practice. Although initially developed in the context of the RECOURSE trial, the Tabernero classification has shown consistent prognostic value in subsequent studies involving trifluridine/tipiracil, including TALLISUR [ 10 ] and BeTAS [ 14 ], and most recently in the SUNLIGHT trial evaluating FTD/TPI plus bevacizumab [ 15 ]. Our findings extend the applicability of this classification to patients treated with regorafenib, a drug with a distinct mechanism of action, and support its robustness across different later-line treatment strategies in mCRC. Several limitations of this study should be acknowledged. Its retrospective design may introduce selection bias, and the lack of central radiologic review may have influenced response assessment. In addition, no multivariate analysis was performed. Given that both prognostic models evaluated in this study are composite scores derived from predefined and overlapping clinical variables, performing multivariate analyses including these factors would introduce collinearity and would be unlikely to provide additional clinically meaningful information. Accordingly, the present analysis focused on descriptive survival stratification and real-world clinical applicability. Another limitation is the heterogeneity in regorafenib dosing strategies across the cohort, with patients receiving full-dose, reduced-dose, or dose-escalation regimens. Furthermore, some patients received subsequent active therapies after regorafenib, which may have influenced overall survival outcomes. Although these aspects reflect real-world clinical practice, they limit the ability to attribute prognostic differences solely to baseline patient or tumor characteristics. In summary, our study confirms the efficacy and tolerability of regorafenib in routine clinical practice and supports the use of the Tabernero classification as a simple, objective, and reproducible prognostic tool to guide clinical decision-making in refractory mCRC. In contrast, the REBECCA prognostic score showed limited discriminatory ability in this contemporary real-world cohort. Future prospective studies integrating validated clinical scores with molecular biomarkers and inflammatory indices may further refine patient stratification in this challenging setting. Conclusions This multicenter real-world study confirms the efficacy and tolerability of regorafenib in refractory mCRC and demonstrates the prognostic value of the Tabernero classification in this setting. Compared with the REBECCA prognostic score, the Tabernero model provided clearer stratification of survival and disease control using only objective and easily assessable tumor-related variables. These findings support its implementation as a practical tool to inform treatment decisions in patients receiving regorafenib. Prospective studies combining clinical scores with molecular and inflammatory markers are warranted to further optimize patient selection in later-line mCRC. Abbreviations AE, adverse event; AEs, adverse events; BPC, best prognostic characteristics; BRAF, B-Raf proto-oncogene, serine/threonine kinase; CEIm-G, Galician Research Ethics Committee; CI, confidence interval; CRC, colorectal cancer; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; FTD/TPI, trifluridine/tipiracil; GITuD, Galician Research Group on Gastrointestinal Tumors; GPC, good prognostic characteristics; GROW, Guidance for Reporting Oncology real-world evidence; HR, hazard ratio; IBM SPSS, IBM Statistical Package for the Social Sciences; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; PPC, poor prognostic characteristics; RECIST, Response Evaluation Criteria in Solid Tumors; RAS, rat sarcoma viral oncogene homolog; VEGF, vascular endothelial growth factor. Declarations Funding This research received no specific funding from any funding agency in the public, commercial, or not-for-profit sectors. Consent for publication Not applicable. Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and approved by the Galician Research Ethics Committee (CEIm-G; reference 2022/235). All patients provided written informed consent for the use of their anonymized clinical data for research purposes. Competing interests The authors declare the following financial relationships which may be considered as potential competing interests: N.M.L., B.C.L., J.C.C.G., A.F.M., A.C.C., M.C.R., A.C.M., and M.S.F. report advisory roles, speaker fees, or travel support from pharmaceutical companies outside the submitted work. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Authors’ contributions All authors contributed substantially to the conception or design of the work, or the acquisition, analysis, or interpretation of data; were involved in drafting the manuscript or revising it critically for important intellectual content; and approved the final version to be published. Availability of data and materials The datasets supporting the conclusions of this article are available from the corresponding author upon reasonable request. Acknowledgements The authors are deeply grateful to the patients and their families for their participation and trust. We also thank all the investigators of the Galician Research Group on Gastrointestinal Tumors (GITuD) for their collaboration and commitment to improving the care of patients with gastrointestinal cancers. Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this manuscript, the authors used ChatGPT (OpenAI) to support language editing and formatting. 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Supplementary Files ESMOGROWChecklistCOREStudy.docx COREFlowchartESMOGROW.docx Cite Share Download PDF Status: Published Journal Publication published 15 Feb, 2026 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 23 Jan, 2026 Reviews received at journal 14 Jan, 2026 Reviews received at journal 18 Dec, 2025 Reviewers agreed at journal 18 Dec, 2025 Reviewers agreed at journal 16 Dec, 2025 Reviewers invited by journal 16 Dec, 2025 Editor invited by journal 16 Dec, 2025 Editor assigned by journal 14 Dec, 2025 Submission checks completed at journal 14 Dec, 2025 First submitted to journal 14 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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09:53:01","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":85986,"visible":true,"origin":"","legend":"","description":"","filename":"5ddcaad21d4d4820a96c38f65d42df051structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8357626/v1/f3f90c95c16f800bdb07de35.xml"},{"id":98760309,"identity":"796301a7-481a-4058-88f4-cff4cbabf09e","added_by":"auto","created_at":"2025-12-22 09:53:00","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":98412,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8357626/v1/117eef82481090049923b386.html"},{"id":98780261,"identity":"2dbbd981-2fe5-4424-884f-7016748e443d","added_by":"auto","created_at":"2025-12-22 12:31:11","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":297443,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier overall survival curves according to prognostic classification in patients treated with regorafenib. (A) Overall survival stratified by the REBECCA prognostic score (low, intermediate, and high risk). (B) Overall survival according to the Tabernero classification (best, good, and poor prognostic characteristics).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8357626/v1/9b8fd68b7cc53373d928a9c1.jpeg"},{"id":102785492,"identity":"e8e9db15-6438-4278-9a45-e7205052cab4","added_by":"auto","created_at":"2026-02-16 16:07:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1178408,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8357626/v1/fdd93e2c-d9b5-40a5-a8e7-01f811587cf3.pdf"},{"id":98760305,"identity":"14449d87-b820-40b4-b9c2-18d92d5e5553","added_by":"auto","created_at":"2025-12-22 09:53:00","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":27783,"visible":true,"origin":"","legend":"","description":"","filename":"ESMOGROWChecklistCOREStudy.docx","url":"https://assets-eu.researchsquare.com/files/rs-8357626/v1/75d23b6a0786369158a6c5e3.docx"},{"id":98760314,"identity":"d9fc164d-1652-4f67-8e7f-77753fc975f0","added_by":"auto","created_at":"2025-12-22 09:53:01","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":27229,"visible":true,"origin":"","legend":"","description":"","filename":"COREFlowchartESMOGROW.docx","url":"https://assets-eu.researchsquare.com/files/rs-8357626/v1/071f9b21889455b07ef7411d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003ePrognostic value of the REBECCA prognostic score and the Tabernero classification in refractory metastatic colorectal cancer treated with regorafenib: a multicenter real-world study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is one of the most prevalent malignancies worldwide and remains a leading cause of cancer-related mortality, with over 1.9\u0026nbsp;million new cases and 935,000 deaths reported in 2020 alone [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite advances in systemic therapy, the prognosis of patients with metastatic CRC (mCRC) who progress after standard treatments remains poor, with median overall survival (OS) typically ranging from 6 to 12 months [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent third-line or later treatment options include regorafenib, trifluridine/tipiracil (FTD/TPI) with or without bevacizumab, fruquintinib, and targeted therapies for selected molecular subgroups [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Regorafenib is an oral multikinase inhibitor that targets angiogenic, stromal, and oncogenic pathways. Its clinical benefit was demonstrated in the pivotal CORRECT trial, which showed a significant overall survival (OS) improvement over placebo (6.4 vs. 5.0 months; hazard ratio [HR] 0.77) in patients with refractory mCRC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Subsequent studies confirmed these findings, including the large phase IIIb CONSIGN trial with over 2,800 patients (median OS: 6.3 months) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and the REBECCA observational study, which supported the drug\u0026rsquo;s efficacy and safety in real-world clinical practice [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Additional insights into treatment patterns and tolerability were provided by the prospective CORRELATE study [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The ReDOS trial further demonstrated that a dose-escalation strategy could improve tolerability without compromising efficacy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These data collectively confirm regorafenib as a standard third-line option in mCRC, although outcomes remain heterogeneous and reliable predictors of benefit are lacking.\u003c/p\u003e \u003cp\u003eGiven the modest efficacy of regorafenib and the heterogeneity of patient outcomes, simple, reproducible prognostic tools applicable in routine clinical practice are needed to better identify individuals most likely to derive clinical benefit. The REBECCA prognostic score, developed from a large compassionate-use cohort, incorporates four adverse clinical factors: Eastern Cooperative Oncology Group performance status (ECOG PS), number of metastatic sites, presence of liver metastases, and time from diagnosis of metastatic disease, and stratifies patients into distinct prognostic groups in real-world settings [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The Tabernero classification, originally developed in the context of the RECOURSE trial, is based exclusively on objective tumor-related variables\u0026mdash;number of metastatic sites, presence of liver metastases, and time from metastatic diagnosis\u0026mdash;thereby avoiding subjective clinical parameters [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This characteristic may enhance its reproducibility and applicability in daily practice. Its prognostic value has been confirmed in real-world settings in patients receiving FTD/TPI, as demonstrated in the TALLISUR trial [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]; however, its prognostic impact in patients treated with regorafenib has not been formally validated.\u003c/p\u003e \u003cp\u003eThe aim of the present study was to perform an external real-world validation of the REBECCA prognostic score and the Tabernero classification in a multicenter cohort of patients with refractory mCRC treated with regorafenib, with a specific focus on their ability to stratify survival outcomes and their clinical applicability in routine practice.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eThis was a retrospective, multicenter study including patients with histologically confirmed metastatic colorectal cancer (mCRC) refractory to standard therapies. Eligible patients were \u0026ge;\u0026thinsp;18 years old and had received at least one dose of regorafenib after progression or intolerance to approved treatments, including fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF agents, and anti-EGFR agents in RAS/BRAF wild-type tumors. Patients were treated between January 2016 and December 2021 at five university hospitals in Galicia (Spain), all members of the Galician Research Group on Gastrointestinal Tumors (GITuD). Patients with incomplete clinical or follow-up data were excluded.\u003c/p\u003e \u003cp\u003e The study was approved by the Galician Research Ethics Committee (CEIm-G; reference 2022/235) and registered under the identifier GIT-ICI-2022-02. All patients provided written informed consent for the use of their anonymized clinical data for research purposes. This study was conducted in accordance with the ESMO-Guidance for Reporting Oncology real-world evidence (GROW) recommendations. The GROW checklist and patient flowchart are provided as supplementary material.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eDemographic, clinical, pathological, and laboratory data were retrospectively extracted from electronic medical records. Variables included age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), primary tumor location, RAS/BRAF mutation status, mismatch repair protein expression, number and location of metastatic sites, and prior systemic treatments. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.\u003c/p\u003e \u003cp\u003eTumor response assessments were performed according to RECIST version 1.1 at regular intervals based on routine clinical practice, typically every 8\u0026ndash;12 weeks, or earlier if clinically indicated, in accordance with institutional protocols.\u003c/p\u003e\n\u003ch3\u003ePrognostic stratification\u003c/h3\u003e\n\u003cp\u003ePatients were classified according to the REBECCA prognostic score and the Tabernero classification.\u003c/p\u003e \u003cp\u003eThe REBECCA prognostic score, developed from a large compassionate-use cohort, assigns one point for each of the following adverse clinical features: ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;1, time from diagnosis of metastatic disease\u0026thinsp;\u0026lt;\u0026thinsp;18 months, presence of liver metastases, and \u0026ge;\u0026thinsp;3 metastatic sites [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Based on the cumulative score (0\u0026ndash;4), patients were categorized as low risk (0\u0026ndash;1 points), intermediate risk (2 points), or high risk (\u0026ge;\u0026thinsp;3 points).\u003c/p\u003e \u003cp\u003eThe Tabernero classification was applied according to the original definition described in the RECOURSE trial exploratory analysis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Patients with good prognostic characteristics (GPC) were defined as those with 1\u0026ndash;2 metastatic sites and \u0026ge;\u0026thinsp;18 months from diagnosis of first metastasis. Among these, patients without liver metastases were further classified as having best prognostic characteristics (BPC). Patients with poor prognostic characteristics (PPC) were defined as those with \u0026ge;\u0026thinsp;3 metastatic sites and/or \u0026lt;\u0026thinsp;18 months from diagnosis of metastatic disease. For descriptive and survival analyses, patients were grouped into best, good, and poor prognostic categories, reflecting the hierarchical structure of the original classification.\u003c/p\u003e\n\u003ch3\u003eEndpoints and statistical analysis\u003c/h3\u003e\n\u003cp\u003eThe primary endpoints were overall survival (OS) and progression-free survival (PFS), defined from the initiation of regorafenib to death from any cause, and to radiological or clinical disease progression or death, respectively. Disease control rate (DCR) and safety outcomes were also evaluated.\u003c/p\u003e \u003cp\u003eSurvival curves were estimated using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. PFS and OS were analyzed according to prognostic subgroups defined by the REBECCA and Tabernero classifications. Categorical variables were analyzed using the chi-squared or Fisher\u0026rsquo;s exact test, and continuous variables using the Mann\u0026ndash;Whitney U test. All statistical analyses were performed using IBM SPSS Statistics, version 25. A two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Missing data were minimal and were handled by complete-case analysis; no imputation was performed.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eA total of 130 patients with refractory mCRC treated with regorafenib were included. Baseline characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 63 years (range, 38\u0026ndash;84), and 65.4% were male. Most patients (94.6%) had an ECOG performance status (PS) of 0\u0026ndash;1. Primary tumors were located in the right colon (22.3%), left colon (63.1%), or rectum (14.6%). RAS mutations were present in 55.4% of tumors, BRAF mutations in 1.5%, and 41.5% of patients had RAS/BRAF wild-type tumors. Liver metastases were present in 75.4%, and 32.3% had three or more metastatic sites. In 86.0% of cases, the interval between metastatic diagnosis and regorafenib initiation was \u0026gt;\u0026thinsp;18 months. Patients had received a median of three prior lines of therapy (range, 2\u0026ndash;8), and 29.2% had been previously treated with trifluridine/tipiracil. Regorafenib was initiated at the full dose of 160 mg in 53.1% of patients, while 46.9% started treatment at a reduced dose or with a ReDOS dose-escalation strategy, including 120 mg in 14.6%, 80 mg in 16.9%, and a ReDOS strategy in 15.4% of patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of patients with metastatic colorectal cancer treated with regorafenib (n\u0026thinsp;=\u0026thinsp;130).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (38\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (65.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (34.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (40.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 (53.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (22.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (63.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRectum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (14.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS/BRAF wild-type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (41.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS mutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (55.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF mutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98 (75.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (24.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of metastatic sites\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88 (67.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (32.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from diagnosis of metastatic disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112 (86.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (14.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of prior treatment lines\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (2\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious FTD/TPI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (29.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial REG dose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e160 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (53.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e120 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (14.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e80 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (16.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReDOS strategy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (15.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eTable footnote: Baseline demographic, clinical, molecular, metastatic, and treatment characteristics of the study population, structured by subcategories. ECOG PS: Eastern Cooperative Oncology Group Performance Status; FTD/TPI: trifluridine/tipiracil; REG: regorafenib.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment exposure and efficacy\u003c/h3\u003e\n\u003cp\u003ePatients received a median of 3 cycles of regorafenib (range, 1\u0026ndash;18). Among 118 evaluable patients, no complete responses were observed. Partial response was achieved in 5 patients (4.2%), and stable disease in 25 patients (21.2%), resulting in a disease control rate (DCR) of 25.4%. Progressive disease was documented in 88 patients (74.6%). After a median follow-up of 23.4 months, the median overall survival (OS) was 6.7 months (95% CI, 6.1\u0026ndash;7.3), and median progression-free survival (PFS) was 2.9 months (95% CI, 2.7\u0026ndash;3.0). The 12-month OS rate was 20.8% (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Survival outcomes were subsequently analyzed according to prognostic subgroups defined by the REBECCA prognostic score and the Tabernero classification.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment efficacy outcomes in evaluable patients treated with regorafenib (n\u0026thinsp;=\u0026thinsp;118)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete Response (CR), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial Response (PR), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable Disease (SD), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25 (21.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive Disease (PD), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e88 (74.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response rate (ORR), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (4.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease control rate (DCR), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30 (25.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian progression-free survival (PFS), months (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.9 (2.7\u0026ndash;3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian overall survival (OS), months (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.7 (6.1\u0026ndash;7.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12-month OS rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24 (20.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eTable footnote: Updated efficacy outcomes including response rates, survival metrics and long-term OS rate at 12 months. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; DCR: disease control rate; PFS: progression-free survival; OS: overall survival.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSafety\u003c/h3\u003e\n\u003cp\u003eTreatment-related adverse events (AEs) were reported in 52.3% of patients, with grade 3\u0026ndash;4 events in 19.2%. The most frequent all-grade AEs included asthenia (80.8%), hand\u0026ndash;foot skin reaction (37.7%), hyperbilirubinemia (31.5%), anemia (21.5%), hypertension (20.8%), diarrhea (19.2%), and stomatitis (20.0%). Grade 3\u0026ndash;4 toxicities were less common, with asthenia (12.3%), hyperbilirubinemia (6.4%), hand\u0026ndash;foot skin reaction (3.9%), and hypertension (3.9%) being the most frequent. Rash occurred in 6.9% of patients, with 1.5% experiencing grade 3\u0026ndash;4 severity. Dose reductions were required in 39.2% of patients. The incidence and severity of adverse events were comparable across prognostic subgroups, and no unexpected safety signals were observed (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events by grade in patients treated with regorafenib (n\u0026thinsp;=\u0026thinsp;130)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse Event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll grades, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 3\u0026ndash;4, n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e105 (80.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16 (12.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand-foot skin reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49 (37.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (3.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperbilirubinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41 (31.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (6.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (21.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27 (20.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (3.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25 (19.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStomatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eTable footnote: Adverse events reported during regorafenib treatment in 130 patients. Grade 3\u0026ndash;4 toxicities are shown separately. AE: adverse event; Grade 3\u0026ndash;4: CTCAE v5.0 grade 3 or 4 events.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic classification according to REBECCA and Tabernero\u003c/h2\u003e \u003cp\u003eAccording to the REBECCA prognostic score, 32.6% of patients were classified as low risk (0\u0026ndash;1 points), 35.7% as intermediate risk (2 points), and 31.8% as high risk (\u0026ge;\u0026thinsp;3 points); one patient could not be classified due to missing ECOG PS. Median OS by risk group was 9.2 months in the low-risk group, 6.9 months in the intermediate-risk group, and 5.3 months in the high-risk group (p\u0026thinsp;=\u0026thinsp;0.138), showing a non-significant trend. DCR by REBECCA category was 37.5%, 28.5%, and 22.9%, respectively (p\u0026thinsp;=\u0026thinsp;0.121) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Progression-free survival showed a similar numerical trend across REBECCA risk groups (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic stratification according to the REBECCA prognostic score and the Tabernero classification (N\u0026thinsp;=\u0026thinsp;130).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrognostic Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian OS, months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDisease Control Rate, n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREBECCA Score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow risk (0\u0026ndash;1 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42 (32.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18 (37.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate risk (2 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46 (35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20 (28.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh risk (\u0026ge;\u0026thinsp;3 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41 (31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13 (22.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTabernero Classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBest prognosis (0 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12 (48.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGood prognosis (1 point)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55 (42.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12 (21.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor prognosis (2\u0026ndash;3 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49 (37.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10 (24.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eTable footnote: Prognostic classification of patients according to REBECCA and Tabernero scores. OS: overall survival; DCR: disease control rate; REBECCA: includes ECOG PS\u0026thinsp;\u0026ge;\u0026thinsp;1, liver metastases, \u0026ge;\u0026thinsp;3 metastatic sites, and \u0026lt;\u0026thinsp;18 months from metastatic diagnosis. Tabernero score: includes liver metastases, \u0026ge;\u0026thinsp;3 metastatic sites, and \u0026lt;\u0026thinsp;18 months from metastatic diagnosis. The Tabernero classification follows a hierarchical structure in which patients with best prognostic characteristics are a subset of those with good prognostic characteristics.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAccording to the hierarchical structure of the Tabernero classification, patients with best prognostic characteristics represent a subset of those with good prognostic characteristics. Using the Tabernero classification, 20.0% of patients were classified as best prognostic characteristics, 42.3% as good prognostic characteristics, and 37.7% as poor prognostic characteristics. Median OS was significantly different across these groups: 10.5 months in the best prognostic group, 6.9 months in the good prognostic group, and 5.2 months in the poor prognostic group (p\u0026thinsp;=\u0026thinsp;0.022). DCR was also significantly stratified: 48.0% in the best group, 21.1% in the good group, and 24.4% in the poor group (p\u0026thinsp;=\u0026thinsp;0.004) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Progression-free survival was also numerically longer in patients with best and good prognostic characteristics compared with those in the poor prognostic group (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter real-world study provides updated evidence on the effectiveness and safety of regorafenib in patients with refractory metastatic colorectal cancer (mCRC), and represents the first external real-world validation of the Tabernero prognostic classification in patients treated with regorafenib. The observed median overall survival (OS) of 6.7 months and median progression-free survival (PFS) of 2.9 months are consistent with the pivotal CORRECT trial [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and with large European series such as CONSIGN [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], REBECCA [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and CORRELATE [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], supporting the external validity of regorafenib across diverse clinical settings.\u003c/p\u003e \u003cp\u003eThe safety profile was manageable and comparable to previous studies, with fatigue, hand\u0026ndash;foot skin reaction, and hyperbilirubinemia being the most frequently reported adverse events. Grade 3\u0026ndash;4 toxicities occurred in fewer than 20% of patients, and no treatment-related deaths were reported. As in the ReDOS trial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], the use of dose-escalation strategies in a subset of patients may have contributed to improved tolerability. These findings reinforce the role of regorafenib as a therapeutic option in later lines, even in unselected real-world populations and in the absence of validated predictive biomarkers.\u003c/p\u003e \u003cp\u003eThe key focus of our study was the external clinical validation of two prognostic models\u0026mdash;the REBECCA prognostic score and the Tabernero classification\u0026mdash;with the aim of assessing their ability to stratify outcomes in routine clinical practice rather than to compare their methodological construction. The REBECCA model, developed from a large compassionate-use cohort, combines clinical and disease-related parameters, including ECOG performance status (PS), time from metastatic diagnosis, number of metastatic sites, and presence of liver metastases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In our cohort, this score showed a numerical trend toward survival stratification; however, differences in OS and disease control rate (DCR) did not reach statistical significance. Notably, survival outcomes in the high-risk REBECCA group were better than those originally reported, which may partly explain the lack of discriminatory power observed in this cohort.\u003c/p\u003e \u003cp\u003eIn contrast, the Tabernero classification, based exclusively on objective tumor-related variables\u0026mdash;time from metastatic diagnosis, number of metastatic sites, and liver metastases\u0026mdash;demonstrated significant prognostic discrimination for both OS and DCR [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This finding is particularly relevant in clinical practice, where the subjective nature of ECOG PS may limit reproducibility due to interobserver variability [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. By relying solely on objective and routinely available tumor-related factors, the Tabernero model offers a pragmatic and reproducible approach to prognostic stratification in daily practice.\u003c/p\u003e \u003cp\u003eAlthough initially developed in the context of the RECOURSE trial, the Tabernero classification has shown consistent prognostic value in subsequent studies involving trifluridine/tipiracil, including TALLISUR [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and BeTAS [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and most recently in the SUNLIGHT trial evaluating FTD/TPI plus bevacizumab [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Our findings extend the applicability of this classification to patients treated with regorafenib, a drug with a distinct mechanism of action, and support its robustness across different later-line treatment strategies in mCRC.\u003c/p\u003e \u003cp\u003eSeveral limitations of this study should be acknowledged. Its retrospective design may introduce selection bias, and the lack of central radiologic review may have influenced response assessment. In addition, no multivariate analysis was performed. Given that both prognostic models evaluated in this study are composite scores derived from predefined and overlapping clinical variables, performing multivariate analyses including these factors would introduce collinearity and would be unlikely to provide additional clinically meaningful information. Accordingly, the present analysis focused on descriptive survival stratification and real-world clinical applicability. Another limitation is the heterogeneity in regorafenib dosing strategies across the cohort, with patients receiving full-dose, reduced-dose, or dose-escalation regimens. Furthermore, some patients received subsequent active therapies after regorafenib, which may have influenced overall survival outcomes. Although these aspects reflect real-world clinical practice, they limit the ability to attribute prognostic differences solely to baseline patient or tumor characteristics.\u003c/p\u003e \u003cp\u003eIn summary, our study confirms the efficacy and tolerability of regorafenib in routine clinical practice and supports the use of the Tabernero classification as a simple, objective, and reproducible prognostic tool to guide clinical decision-making in refractory mCRC. In contrast, the REBECCA prognostic score showed limited discriminatory ability in this contemporary real-world cohort. Future prospective studies integrating validated clinical scores with molecular biomarkers and inflammatory indices may further refine patient stratification in this challenging setting.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis multicenter real-world study confirms the efficacy and tolerability of regorafenib in refractory mCRC and demonstrates the prognostic value of the Tabernero classification in this setting. Compared with the REBECCA prognostic score, the Tabernero model provided clearer stratification of survival and disease control using only objective and easily assessable tumor-related variables. These findings support its implementation as a practical tool to inform treatment decisions in patients receiving regorafenib. Prospective studies combining clinical scores with molecular and inflammatory markers are warranted to further optimize patient selection in later-line mCRC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAE, adverse event; AEs, adverse events; BPC, best prognostic characteristics; BRAF, B-Raf proto-oncogene, serine/threonine kinase; CEIm-G, Galician Research Ethics Committee; CI, confidence interval; CRC, colorectal cancer; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; ESMO, European Society for Medical Oncology; FTD/TPI, trifluridine/tipiracil; GITuD, Galician Research Group on Gastrointestinal Tumors; GPC, good prognostic characteristics; GROW, Guidance for Reporting Oncology real-world evidence; HR, hazard ratio; IBM SPSS, IBM Statistical Package for the Social Sciences; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; PPC, poor prognostic characteristics; RECIST, Response Evaluation Criteria in Solid Tumors; RAS, rat sarcoma viral oncogene homolog; VEGF, vascular endothelial growth factor.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific funding from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Galician Research Ethics Committee (CEIm-G; reference 2022/235). All patients provided written informed consent for the use of their anonymized clinical data for research purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare the following financial relationships which may be considered as potential competing interests: N.M.L., B.C.L., J.C.C.G., A.F.M., A.C.C., M.C.R., A.C.M., and M.S.F. report advisory roles, speaker fees, or travel support from pharmaceutical companies outside the submitted work. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed substantially to the conception or design of the work, or the acquisition, analysis, or interpretation of data; were involved in drafting the manuscript or revising it critically for important intellectual content; and approved the final version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets supporting the conclusions of this article are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are deeply grateful to the patients and their families for their participation and trust. We also thank all the investigators of the Galician Research Group on Gastrointestinal Tumors (GITuD) for their collaboration and commitment to improving the care of patients with gastrointestinal cancers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of generative AI and AI-assisted technologies in the writing process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this manuscript, the authors used ChatGPT (OpenAI) to support language editing and formatting. The authors critically reviewed and edited all content and take full responsibility for the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7\u0026ndash;33. doi:10.3322/caac.21708.\u003c/li\u003e\n\u003cli\u003eCervantes A, Adam R, Rosell\u0026oacute; S, Arnold D, Normanno N, Ta\u0026iuml;eb J, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10\u0026ndash;32. doi:10.1016/j.annonc.2022.10.003.\u003c/li\u003e\n\u003cli\u003eCervantes A, Martinelli E; ESMO Guidelines Committee. Updated treatment recommendation for third-line treatment in advanced colorectal cancer from the ESMO Metastatic Colorectal Cancer Living Guideline. Ann Oncol. 2024;35(2):241\u0026ndash;243. doi:10.1016/j.annonc.2023.10.129.\u003c/li\u003e\n\u003cli\u003eGrothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303\u0026ndash;312. doi:10.1016/S0140-6736(12)61900-X.\u003c/li\u003e\n\u003cli\u003eVan Cutsem E, Martinelli E, Cascinu S, Sobrero A, Banzi M, Seitz JF, et al. Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study. Oncologist. 2019;24(2):185\u0026ndash;192. doi:10.1634/theoncologist.2018-0072. \u003c/li\u003e\n\u003cli\u003eAdenis A, de la Fouchardiere C, Paule B, Burtin P, Tougeron D, Wallet J, et al. Survival, safety, and prognostic factors for outcome with regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program. BMC Cancer. 2016;16:412. doi:10.1186/s12885-016-2440-9\u003c/li\u003e\n\u003cli\u003eDucreux M, Petersen LN, \u0026Ouml;hler L, Bergamo F, Metges JP, de Groot JW, et al. Safety and effectiveness of regorafenib in patients with metastatic colorectal cancer in routine clinical practice in the prospective, observational CORRELATE study. Eur J Cancer. 2019;123:146\u0026ndash;154. doi: 10.1016/j.ejca.2019.09.015.\u003c/li\u003e\n\u003cli\u003eBekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070\u0026ndash;1082. doi:10.1016/S1470-2045(19)30272-4\u003c/li\u003e\n\u003cli\u003eTabernero J, Argil\u0026eacute;s G, Sobrero AF, Borg C, Ohtsu A, Mayer RJ, et al. Effect of trifluridine/tipiracil in patients treated in RECOURSE by prognostic factors at baseline: an exploratory analysis. ESMO Open. 2020;5(4):e000752. doi:10.1136/esmoopen-2020-000752\u003c/li\u003e\n\u003cli\u003eKarthaus M, Heinemann V, Riera-Knorrenschild J, Kretzschmar A, Welslau M, Kaiser U, et al. Subgroup analyses of patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial. BMC Cancer. 2024;24(1):887. doi:10.1186/s12885-024-12599-7\u003c/li\u003e\n\u003cli\u003eAndo M, Ando Y, Hasegawa Y, Takahashi T, Tsuboi M, Sakamoto H, et al. Prognostic value of performance status assessed by Karnofsky Performance Status (KPS) and ECOG Performance Status (ECOG PS) in patients with non-small cell lung cancer. Jpn J Clin Oncol. 2001;31(8):435-442. doi:10.1093/jjco/hye081.\u003c/li\u003e\n\u003cli\u003eBlagden SP, Charman SC, Sharples LD, Magee LR, Gilligan D. Performance status score: do patients and their oncologists agree? Br J Cancer. 2003;89(6):1022-1027. doi:10.1038/sj.bjc.6601248.\u003c/li\u003e\n\u003cli\u003eS\u0026oslash;rensen JB, Klee M, Palshof T, Hansen HH. Performance status assessment in cancer patients: an inter-observer variability study. Br J Cancer. 1993;67(4):773-775. doi:10.1038/bjc.1993.140.\u003c/li\u003e\n\u003cli\u003eMart\u0026iacute;nez Lago N, Riesco Martinez MC, Lopez AM, Gonzalez Gomez B, Antonilli PC, Fernandez Montes A, et al. Real-world efficacy of trifluridine/tipiracil and bevacizumab combination according to baseline prognostic factors: The BeTAS study. J Clin Oncol. 2025;43(16_suppl):3578.\u003c/li\u003e\n\u003cli\u003eBachet JB, Taieb J, Zaanan A, Andr\u0026eacute; T, Aparicio T, Lledo G, et al. Prognostic impact of Tabernero classification in metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab: results from a multicenter study. J Clin Oncol. 2025;43(16_suppl):4000. (Abstract).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Metastatic colorectal cancer, regorafenib, prognostic score, Tabernero classification, REBECCA prognostic score, real-world evidence","lastPublishedDoi":"10.21203/rs.3.rs-8357626/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8357626/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eRegorafenib is a standard treatment option for patients with metastatic colorectal cancer (mCRC) refractory to conventional therapies. However, outcomes remain heterogeneous, and simple and reproducible prognostic tools applicable in routine clinical practice are needed to optimize patient selection. This study aimed to perform an external real-world validation of the REBECCA prognostic score and the Tabernero classification in a multicenter cohort of refractory mCRC patients treated with regorafenib.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective multicenter study including 130 patients with refractory mCRC treated with regorafenib across five university hospitals in Galicia, Spain. Overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) were analyzed according to the REBECCA prognostic score and the Tabernero classification. Kaplan\u0026ndash;Meier estimates, log-rank tests, and chi-squared analyses were used to compare outcomes between prognostic subgroups.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eMedian age was 63 years, and 94.6% of patients had ECOG performance status 0\u0026ndash;1. Median OS and PFS were 6.7 and 2.9 months, respectively. According to the REBECCA prognostic score, median OS was 9.2, 6.9, and 5.3 months for low-, intermediate-, and high-risk groups, respectively (p\u0026thinsp;=\u0026thinsp;0.138). In contrast, the Tabernero classification identified significant OS differences, with median OS of 10.5, 6.9, and 5.2 months in patients with best, good, and poor prognostic characteristics, respectively (p\u0026thinsp;=\u0026thinsp;0.022). DCR was also significantly stratified by the Tabernero classification (48.0%, 21.1%, and 24.4%; p\u0026thinsp;=\u0026thinsp;0.004). Treatment was well tolerated, with a safety profile consistent with previous studies.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eIn this multicenter real-world study, the Tabernero classification demonstrated robust prognostic stratification in a real-world setting in refractory mCRC patients treated with regorafenib, whereas the REBECCA prognostic score showed limited discriminatory ability in this contemporary cohort. Given its simplicity, objectivity, and reproducibility, the Tabernero model may represent a practical tool to support prognostic assessment and clinical decision-making in routine practice.\u003c/p\u003e","manuscriptTitle":"Prognostic value of the REBECCA prognostic score and the Tabernero classification in refractory metastatic colorectal cancer treated with regorafenib: a multicenter real-world study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:52:53","doi":"10.21203/rs.3.rs-8357626/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-23T17:21:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-14T12:16:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-18T21:06:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333433216670310373564173735607992247363","date":"2025-12-18T19:13:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"109917319434183013823521287454943388382","date":"2025-12-17T04:40:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-16T17:40:26+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-16T13:05:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-15T03:42:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-15T03:42:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-12-14T11:21:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3de430bb-4a74-4319-b4ea-cd8cc7218de1","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:04:19+00:00","versionOfRecord":{"articleIdentity":"rs-8357626","link":"https://doi.org/10.1186/s12885-026-15745-5","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2026-02-15 15:59:24","publishedOnDateReadable":"February 15th, 2026"},"versionCreatedAt":"2025-12-22 09:52:53","video":"","vorDoi":"10.1186/s12885-026-15745-5","vorDoiUrl":"https://doi.org/10.1186/s12885-026-15745-5","workflowStages":[]},"version":"v1","identity":"rs-8357626","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8357626","identity":"rs-8357626","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}