Combination of Modest Dosage of Bevacizumab with TAS-102 Provided the Comparable Efficacy in Treating Refractory Metastatic Colorectal Cancer

Combination of Modest Dosage of Bevacizumab with TAS-102 Provided the Comparable Efficacy in Treating Refractory Metastatic Colorectal Cancer | 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 Combination of Modest Dosage of Bevacizumab with TAS-102 Provided the Comparable Efficacy in Treating Refractory Metastatic Colorectal Cancer Kuan-Yu Tseng, Mu-Ying Yang, Wei-Shone Chen, Jeng-Kai Jiang, Huann-Sheng Wang, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4501755/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Dec, 2024 Read the published version in International Journal of Colorectal Disease → Version 1 posted 9 You are reading this latest preprint version Abstract Background Given that the combination of bevacizumab and TAS-102 is used to treat refractory metastatic colorectal cancer (mCRC), we aimed to evaluate the efficacy of modest doses of bevacizumab in combination with TAS-102 for the treatment of refractory mCRC. Methods In total, 261 patients with refractory mCRC were enrolled and categorized into two groups: TAS-102 combined with bevacizumab and TAS-102 alone. In the bevacizumab combination group, patients were further divided into two subgroups based on a median dose of 3.3 mg/kg. Categorical variables were compared using the chi-squared or Fisher’s exact tests, and continuous variables were assessed using the t-test. The Cox proportional hazards model was used to adjust for covariates. Survival analysis was performed using the log-rank test and Kaplan–Meier curves. Specific survival was evaluated using Restricted Mean Survival Time (RMST) and landmark analysis. Result The median progression-free survival (PFS) was 3.7 months in the TAS-102combined with bevacizumab group, and 2.2 months in the group without bevacizumab, showing statistical significance in favor of bevacizumab combination group (P = 0.004). The median overall survival (OS) was 9.4 months in the bevacizumab combination group and 10.3 months in the group that did not receive combination therapy. A survival benefit was observed within 9.5 months in both the RMST and landmark analyses. However, no long-term OS benefit was evident, regardless of bevacizumab combination (P = 0.248). Conclusion The modest doses of bevacizumab and TAS-102 provided comparable efficacy to the standard dose schedule, especially within a limited timeframe of 9.5 months. Bevacizumab TAS-102 Colorectal cancer Figures Figure 1 Figure 2 INTRODUCTION Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and is among the most prevalent types of cancer.[ 3 ] Unfortunately, approximately half of all patients eventually develop metastatic CRC (mCRC). At this stage, salvage chemotherapy options include 5-fluorouracil (5-FU), oxaliplatin, irinotecan, anti-VEGF agents (such as bevacizumab), anti-EGFR agents, regorafenib, and TAS-102, either alone or in combination. However, patients undergoing salvage chemotherapy may experience adverse effects such as neutropenia following TAS-102 treatment, necessitating dosage adjustments to maintain a balance between quality of life and efficacy. Effectiveness, sustained treatment response, and maintaining quality of life are crucial considerations in managing refractory mCRC. TAS-102 demonstrated an improvement in overall survival (OS) in refractory mCRC compared to a placebo in the phase III RECOURSE trial.[ 4 ] Additionally, Van Cutsem et al. investigated 800 patients from the RECOURSE study, demonstrating the effectiveness of TAS-102 across various subgroups, regardless of age, geographical region, or KRAS status. However, among the 38% of patients who received TAS-102, 4% experienced grade 3 or higher neutropenia, and an additional 4% developed febrile neutropenia despite treatment with granulocyte colony-stimulating factor. Consequently, patients may encounter risks that could profoundly impact their quality of life.[ 5 ] In the SUNLIGHT study, combining bevacizumab with TAS-102, demonstrated considerable OS benefits compared to TAS-102 monotherapy.[ 1 ] However, severe adverse events (grade ≥ 3) were more frequently reported in the combination group, with neutropenia being the most dominant. Severe (grade ≥ 3) neutropenia was noted in 43.1% of the combination group, and 29.3% of the patients in the combination group received concomitant treatment with granulocyte colony-stimulating factors. Moreover, in a retrospective analysis (n = 24), Cann et al. demonstrated that alternative biweekly dosing of TAS-102 could reduce toxicity while maintaining efficacy, with a median PFS of 2.3 months.[ 6 ] However, survival data for patients with mCRC remain unsatisfactory. In the RECOURSE trial, the OS was 7.1 months in the TAS-102 group and 5.3 months in the placebo group. The OS was 10.8 months in the combination group and 7.5 months in the TAS-102 group. In this study, we assessed the efficacy of a modest dose of bevacizumab in combination with TAS-102. We hypothesized that patients receiving modest doses of bevacizumab have poorer survival outcomes. METHOD Patient characteristics and assessment The study enrolled patients with mCRC refractory to 5-FU, oxaliplatin, irinotecan, anti-VEGF agents, or anti-EGFR agents (if RAS wild-type). Included patients underwent more than one cycle of TAS-102. We defined a patient as having concomitant use of bevacizumab if they received at least three infusions, irrespective of the bevacizumab doses or timing of administration during TAS-102 treatment. We collected patient information, including age, sex, body surface area (BSA), primary tumor location, historical pathology, TAS-102 dose (mg/m 2 /d), and molecular data such as RAS, BRAF, and microsatellite stability status. Additionally, we reviewed the time from TAS-102 administration to the diagnosis of metastatic disease, previous treatment lines before TAS-102 administration, and metastatic sites, including the liver, lymph nodes, peritoneum, lung, and brain. Institutional Review Board (IRB) approval for this study was obtained from the Taipei Veteran General Hospital. The requirement for informed consent was waived by the IRB. Modest bevacizumab combination stratification In our cohort, most patients received modest doses of bevacizumab. The combination group was categorized based on the median bevacizumab dose (3.3 mg/kg). The patients were divided into two groups: those receiving doses > 3.3 mg/kg and those receiving doses ≤ 3.3 mg/kg. Treatment response and survival The treatment response was assessed using computed tomography and magnetic resonance imaging according to the RECIST criteria. PFS signifies the duration from the initiation of TAS-102 administration to imaging-defined progression. OS was defined as the duration from the initiation of TAS-102 treatment to the patient's death from cancer. Statistical analyses Patient characteristics were summarized using means for continuous variables and medians with first and third quartiles for continuous variables. Categorical variables are presented as numbers and percentages. Categorical variables were compared using the chi-squared or Fisher’s exact tests, whereas continuous variables were assessed using the appropriate statistical test, such as the independent t-test. Survival analysis was conducted using the Kaplan–Meier method, and the log-rank test was used to compare survival curves. Univariate and multivariate Cox proportional hazards models were used to evaluate characteristics that may affect OS in patients with mCRC. Clinical factors with P < 0.1 in the univariate analysis were included in the multivariate analysis. Additionally, we used Restricted Mean Survival Time (RMST) and a landmark method for survival analysis, measuring the average survival time up to a specific time point. All statistical tests were two-sided, and statistical significance was set at P < 0.05. RESULTS Patient characteristics We retrospectively reviewed 261 patients with histologically confirmed mCRC between January 1, 2010, and February 19, 2023. Among them, 175 received TAS-102 treatment without bevacizumab, and 86 received combination therapy. The baseline characteristics did not significantly differ between the two groups (Table 1 ). Table 1 Patient characteristics (n = 261) without bevacizumab n = 175(%) bevacizumab n = 86(%) P value Age 0.22 ≤ 60-year-old 56 (32.0) 34 (39.5) > 60-year-old 119 (68.0) 52 (60.5) Sex 0.27 Male 100 (57.1) 43 (50.0) Female 75 (42.9) 43 (50.0) BSA, median, m 2 (IQR) 1.59 (1.45–1.75) 1.63 (1.45–1.79) 0.45 Primary tumor location 0.08 f Right side 50 (28.6) 17 (19.8) Life side 72 (41.1) 33 (38.4) Rectum 52 (29.7) 34 (39.5) Synchronous 1 (0.6) 0 (0.0) Site unknown 0 (0.0) 2 (2.3) Pathology 0.11 f Adenocarcinoma 164 (93.7) 85 (98.8) Mucinous adenocarcinoma 11 (6.3) 1 (1.2) TAS-102 dose(mg/m 2 /d)(IQR) 53.3 (45.7–62.1) 57.3 (45.8–66.3) 0.46 RAS # wild type 82 (46.8) 39 (45.3) 0.34 mutation 89 (50.8) 47 (54.6) BRAF + wild type mutation 5 (2.8) 2 (2.3) 0.93 Microsatellite stability status $ MSS 143 (81.7) 71 (82.5) 0.60 MSI-H 2 (1.1) 0 (0.0) Time from metastatic disease(%) 0.70 < 18 months 53 (30.2) 28 (32.5) ≥ 18 months 122 (69.8) 58 (67.5) Previous treatment before TAS-102 0.88 ≤ 3 51 (29.1) 24 (27.9) ≥ 4 124 (70.9) 62 (72.1) Metastatic site Liver 112 (64.0) 62 (72.0) 0.19 Lymph node 83 (47.4) 34 (39.5) 0.22 Peritoneum 65 (37.1) 26 (30.2) 0.27 Lung 129 (73.7) 69 (80.2) 0.24 Brain 5 (2.8) 5 (5.8) 0.30 f Chi-Square test. f Fisher’s Exact test. *P < 0.05, **P < 0.01. # 4 patients RAS mutation data miss + 37 patients BRAF data miss $ 45 patients MSS data miss # RAS including KRAS and NRAS Abbreviations: MSS, Microsatellite Stable; MSI-H, microsatellite instability-high Survival outcomes In our cohort, the Kaplan–Meier plot demonstrated a PFS of 3.7 months in the TAS-102 combined with bevacizumab group and 2.2 months in the group without bevacizumab [hazard ratio (HR) 0.69; 95% confidence interval (CI) 0.48–0.99], showing statistical significance in favor of bevacizumab combination (P = 0.004) (Fig. 1a). The OS was 10.3 months in the bevacizumab combination group and 9.4 months in the group without combination therapy. No statistically significant difference was observed in OS regardless of bevacizumab combination (P = 0.248) (Fig. 1b). In landmark analysis, survival showed statistical significance before 9.5 months and not after 9.5 months (P = 0.027) (Fig. 1c). RMST at 10 months demonstrated a change in the estimated survival probabilities for both groups (Fig. 1d). In the bevacizumab combination group, patients experienced more benefits within 9.5 months (Fig. 1e). We summarized both univariate and multivariate analyses of OS. Univariate analysis revealed statistical significance for patients with BSA ≥ 1.61 m 2 , time from metastatic disease diagnosis to TAS-102 administration > 18 months, and those with liver, lymph node, or brain metastasis. In multivariate analysis, these factors remained statistically significant (Table 2 ). Table 2 Summary of univariate and multivariate analyses of overall survival Patient Characteristics Univariate Multivariate HR (95% CI) P value HR (95% CI) P value Bevacizumab combination Without bevacizumab Reference With bevacizumab 0.82(0.59–1.15) 0.24 Bevacizumab dose lower than 3.3mg/kg Reference higher than 3.3mg/kg 1.30(0.76–2.25) 0.34 Age, years ≤ 60-year-old Reference > 60-year-old 1.11(0.78–1.56) 0.56 Sex Female Reference Male 0.85 (0.62–1.17) 0.30 BSA, median, m 2 < 1.61 Reference Reference ≥ 1.61 0.50 (0.28–0.87) < 0.01 ** 0.45(0.25–0.81) < 0.01 ** Primary tumor location Right side Reference Left side 0.80(0.53–1.20) 0.27 Rectum 0.80(0.53–1.20) 0.27 Synchronous 1.63(0.22–11.88) 0.63 Pathology Adenocarcinoma Reference Mucinous adenocarcinoma 0.94(0.42–2.14) 0.89 TAS-102 dose (mg/m 2 /d) <56 mg/m 2 /d Reference ≥ 56 mg/m 2 /d 0.87(0.64–1.20) 0.40 RAS # wild type Reference mutation 0.86(0.62–1.18) 0.34 BRAF + wild type Reference mutation 1.22(0.50-3.00) 0.66 Microsatellite stability status $ MSS Reference MSI-H 0.69(0.10–4.96) 0.90 Time from metastatic disease < 18 months Reference Reference ≥ 18 months 0.60(0.42–0.84) 0.003 ** 0.64(0.45–0.91) 0.013 ** Previous treatment before TAS-102 ≤ 3 Reference ≥ 4 1.44(0.97–2.12) 0.06 1.43(0.94–2.16) 0.08 Metastatic site Liver 1.58(1.10–2.26) 0.01 * 1.58(1.10–2.27) 0.01 * Lymph node 1.43(1.03–1.97) 0.02 * 1.83(1.30–2.57) 0.001 ** Peritoneum 1.08(0.77–1.52) 0.64 Lung 1.01(0.70–1.46) 0.94 Brain 2.12(1.08–4.18) 0.02 * 6.51(2.97–14.27) < 0.001 ** *P < 0.05, **P < 0.01. # 4 patients RAS mutation data miss + 37 patients BRAF data miss $ 45 patients MSS data miss # RAS including KRAS and NRAS Impact of bevacizumab dose We also investigated the effect of bevacizumab dose on survival. A statistically significant improvement in PFS was noted via the log-rank test, indicating that patients experienced a survival benefit with combination therapy compared to TAS-102 monotherapy (P = 0.007) (Fig. 2a). No significant difference was observed in OS between patients without bevacizumab combination and those with varying doses, whether above or below 3.3 mg/kg (P = 0.472) (Fig. 2b). Among patients receiving bevacizumab combination therapy (n = 86), PFS rates did not significantly differ between the two groups, regardless of dosage (Fig. 2c). The median PFS was 4.2 months in the bevacizumab group with doses lower than 3.3 mg/kg and 4.4 months in the comparison group (P = 0.509). These results suggest that bevacizumab treatment is associated with improved PFS, and that a combination of modest doses of bevacizumab and TAS-102 provided comparable efficacy. No significant difference was observed in OS between different bevacizumab doses. This implies that patients receiving doses either slightly lower than the standard (between 3.3 mg/kg and 5 mg/kg) or significantly lower (below 3.3 mg/kg) do not show significant effects (P = 0.338). In our cohort, the median dose of bevacizumab was 3.3 mg/kg. Consequently, we summarized the characteristics of patients in the bevacizumab combination group using this dosage. Sex exhibited statistically significant differences, with a higher prevalence of females in the bevacizumab group at a dosage exceeding 3.3 mg/kg, whereas males were more predominant. Other characteristics were not statistically significant (Table 3 ). Table 3 Patient characteristics, combination with bevacizumab bevacizumab lower than 3.3mg/kg n = 43(%) bevacizumab higher than 3.3mg/kg n = 43(%) P value Age, median, years(IQR) 64 (55–72) 63 (54–71) 0.34 ≤ 60-year-old 18 (41.8) 16 (37.2) >60-year-old 25 (58.2) 27 (62.8) Sex 0.01 * Male 27 (62.8) 16 (37.2) Female 16 (37.2) 27 (62.8) BSA, median, m 2 1.75 (1.56–1.94) 1.55 (1.42–1.65) 0.09 Primary tumor location 0.12 Right side 6 (14.0) 11 (25.6) Life side 20 (46.5) 13 (30.2) Rectum 17 (39.5) 17 (39.5) Site unknown 0 (0.0) 2 (4.7) Pathology 0.31 Adenocarcinoma 43 (100.0) 42 (97.6) Mucinous adenocarcinoma 0 (0.0) 1 (2.4) TAS-102 dose (mg/m 2 /) (IQR) 54.8 (47.9–63.6) 59.9 (52.6–69.4) 0.59 RAS 0.12 wild type 23 (53.4) 16 (37.2) mutation 20 (46.5) 27 (62.8) BRAF 0.95 wild type 42 (97.6) 42 (97.6) mutation 1 (2.4) 1 (2.4) Microsatellite stability status 0.77 MSS 36 (83.7) 35 (81.4) MSI-H 0 (1.1) 0 (0.0) Time from metastatic disease 0.64 < 18 months 13 (30.2) 15 (34.8) ≥ 18 months 30 (69.8) 28 (65.2) Previous treatment before TAS-102 0.27 ≤ 3 10 (23.2) 14 (32.5) ≥ 4 33 (76.8) 29 (67.5) Metastatic site Liver 29 (67.4) 33 (76.8) 0.33 Lymph node 21 (48.8) 13 (30.2) 0.07 Peritoneum 16 (37.2) 33 (76.8) 0.27 Lung 35 (81.4) 34 (79.0) 0.78 Brain f 4 (9.3) 1 (2.4) 0.16 Mann-Whitney U test. Chi-Square test. f Fisher's Exact test. *P < 0.05, **P < 0.01. Subgroup analysis of PFS in bevacizumab combination Our findings demonstrate the potential PFS benefits of combining TAS-102 with bevacizumab, particularly in specific subgroups (Table 4 ). These subgroups included patients > 60 years old, men, individuals with a BSA 56 mg/m 2 /d, individuals with RAS mutation, wild-type BRAF, microsatellite stable status, those with a duration of < 18 months from metastatic disease diagnosis to starting TAS-102, heavily pretreated patients, and those with liver, lymph node, or lung metastasis. Patients with BRAF mutations were also observed to have PFS benefits; however, the data are limited. PFS in patients with microsatellite instability status was not analyzed because no patients in the bevacizumab combination group had microsatellite instability status. These findings suggest that TAS-102 in combination with bevacizumab may result in improved PFS in patients with mCRC with the abovementioned characteristics. Table 4 Subgroup analysis of progression-free survival in combination with bevacizumab Subgroup Hazard ratio 95% CI P value Age, median, years ≤ 60-year-old 0.66 0.41–1.08 0.10 >60-year-old 0.63 0.44–0.91 0.01 * Sex Male 0.62 0.42–0.93 0.02 * Female 0.69 0.45–1.05 0.08 BSA, median, m 2 <1.61 0.57 0.38–0.87 0.01 * ≥ 1.61 0.73 0.49–1.10 0.14 Primary tumor location Right side 0.61 0.32–1.13 0.12 Life side 0.68 0.43–1.08 0.10 Rectum 0.68 0.42–1.12 0.13 Pathology Adenocarcinoma 0.63 0.47–0.85 0.003 ** Mucinous adenocarcinoma 0.74 0.08–6.54 0.79 TAS-102 dose (mg/m 2 /d) <56 mg/m 2 /d 0.70 0.45–1.08 0.11 ≥ 56 mg/m 2 /d 0.60 0.41–0.90 0.01 ** RAS wild type 0.70 0.45–1.08 0.11 mutation 0.56 0.38–0.85 0.006 ** BRAF wild type 0.65 0.47–0.89 0.008 ** mutation ¶f 6.30 1.42–27.93 0.01 * Microsatellite stability status § MSS 0.67 0.49–0.93 0.01 * Time from metastatic disease <18 months 0.40 0.22–0.71 0.002 ** ≥ 18 months 0.72 0.51–1.02 0.06 Previous treatment before TAS-102 ≤ 3 0.73 0.42–1.28 0.28 ≥ 4 0.62 0.44–0.87 0.006 ** Metastatic site Liver 0.63 0.45–0.89 0.009 ** Lymph node 0.60 0.39–0.94 0.02 * Peritoneum 0.86 0.51–1.45 0.58 Lung 0.60 0.43–0.84 0.003 ** Brain f 0.52 0.07–3.94 0.53 Chi-Square test. f Fisher's Exact test. *P < 0.05, **P < 0.01. § There were no patients with MSI-H in the bevacizumab combination group. ¶ There were 2 patients with BRAF mutation in the bevacizumab combination group. DISCUSSION Our report is the first to demonstrate that a modest dose of bevacizumab in combination with TAS-102 provides comparable survival benefits that have not been directly compared in clinical studies. This survival benefit was limited to 9.5 months. In the RECOURSE study, TAS-102 demonstrated proven efficacy compared to the placebo, with acceptable toxicities. Patients were administered TAS-102 at a dose of 35 mg/m 2 /d twice daily, following a 5-day-on and 2-day-off schedule each week for 2 weeks, followed by a 14-day rest period.[ 4 ] However, 53% experienced a delay of ≥ 4 d in commencing their next cycle owing to toxicity, with approximately half of this subgroup experiencing an extended delay of ≥ 8 d. In addition, 3.6% of patients discontinued treatment owing to adverse reactions, and 14% of patients required a dose reduction.[ 5 ] In clinical practice, patients often experience gastrointestinal symptoms, leading to the postponement of treatment owing to grade 3 or 4 neutropenia. As we retrospectively reviewed patients diagnosed with CRC, the rationale for using this combination was based on preliminary studies.[ 2 , 8 , 9 ] In comparison with the SUNLIGHT study, the overall survival (OS) was 10.8 months in the bevacizumab combination group, whereas in our cohort, it was 10.3 months with a modest-dose of bevacizumab. The survival was similar to that observed with relatively low doses of bevacizumab. Furthermore, OS was confined to within 10 months via RMST analysis. Patients who underwent TAS-102 treatment, however, experienced greater survival benefits with early bevacizumab combination therapy.[ 1 ] In our retrospective review, the median dose of TAS-102 was 56 mg/m 2 /d. TAS-102 was reduced at our institution owing to intolerance. In other words, most patients initially received the standard dose in their prescription, and experienced dose reduction after the first cycle of administration. Once patients received a reduced dose, they were not titrated back to the standard dose. We observed a trend of an elevated TAS-102 dose in the bevacizumab combination group compared to the others; however, the difference was not statistically significant. No significant difference was observed in the OS between the bevacizumab combination groups. This was attributed to the absence of TAS-102 and bevacizumab underdosing in our cohort, possibly owing to complications. Furthermore, the majority of patients had refractory disease, with 71.2% (n = 186) receiving TAS-102 as their 4th line of treatment or beyond.[ 10 ] The lack of OS benefits in in the higher standard dose of the bevacizumab group (> 3.3 mg/kg) may be attributed to several factors. First, men dominated the lower bevacizumab dose group. Second, the relatively small sample size may have influenced the results. Finally, the higher proportion of left-side-origin tumors in the lower bevacizumab group (46.5%) than their counterparts (30.2%) in our cohort may have had an impact. In the Monitoring of Cancer Incidence in Japan (MCIJ) project, which reviewed 62,350 participants with colon cancer from 2006 to 2008, the authors found that five-year net survival for left- and right-sided colon cancer were 74.0% (95% CI, 73.4–74.7%) and 70.4% (95% CI, 69.7–71.0%), respectively.[ 11 ] This suggests that patients with left-sided colon cancer have better survival rates than those with other cancers. No precise explanation exists for the better OS trend in the lower-dose group. We observed a significant PFS difference with TAS-102 combined with bevacizumab, regardless of bevacizumab dose. Specifically, patients receiving TAS-102 treatment experienced extended PFS after receiving more than three infusions of bevacizumab. Additionally, we observed that certain individuals, including those > 60, men with a BSA under 1.61, adenocarcinoma (versus mucinous adenocarcinoma), receiving a TAS-102 dose over 56 mg/m 2 /d, having RAS mutations, diagnosed with metastatic disease < 18 months before starting TAS-102, heavily pre-treated, or with liver, lymph nodes, or lung metastases, may experience prolonged PFS. Some subgroups of patients with factors indicative of a good prognosis have been described previously. In a combined analysis of two phase III studies, mucinous adenocarcinomas exhibited worse OS, PFS, and overall response rates than adenocarcinomas.[ 12 ] This suggests that mucinous adenocarcinoma may be an independent factor for a poor prognosis. Although RAS mutations conferred a PFS benefit in our cohort, the role of KRAS mutations as a prognostic factor independent of treatment seems unlikely; however, this remains controversial.[ 13 ] BRAF mutation present distinct clinical characteristics and prognoses;[ 13 – 15 ] however, limited data exists on this aspect. Our study had several limitations. First, it was retrospective in nature. Further prospective randomized clinical trials are required to validate the role of different doses in combination therapy. Second, our cohort received various TAS-102 doses, complicating exact efficacy determination for TAS-102 or bevacizumab. We could not determine the most beneficial dose combination. Factors such as limited BRAF and microsatellite stable data, and a small population with mucinous adenocarcinoma, made statistical significance questionable. Different salvage chemotherapy regimens were used before or after bevacizumab combination therapy. CONCLUSION In conclusion, this retrospective study highlights the survival benefits of TAS-102 combined with a modest dose of bevacizumab in patients with refractory mCRC. Further prospective investigations are essential to determine the optimal combination of modest doses of bevacizumab and TAS-102 among heavily treated patients with CRC in real-world practice. ADDITIONAL INFORMATION Declarations Acknowledgements A portion of data for this study was obtained from the Cancer Registry Database of Taipei Veterans General Hospital. Authors’ contributions Kuan-Yu Tseng collected and analyzed the data, wrote, and submitted the manuscript. Mu-Ying Yang, Wei-Shone Chen, Jeng-Kai Jiang, Huann-Sheng Wang, Shih-Ching Chang, Yuan-Tzu Lan, Chun-Chi Lin, Hung-Hsin Lin, Sheng-Chieh Huang, Hou-Hsuan Cheng, Yu-Zu Lin, Che-Yuan Chang, and Yi-Wen Yang provided data. Hao-Wei Teng designed the study and approved the manuscript and bioinformatics. Ethics approval and consent to participate This retrospective study was conducted using population-based data from Taipei Veterans General Hospital, Taiwan, following the guidelines of the Declaration of Helsinki. Approved was obtained from the Ethics Committee and Institutional Review Board of Taipei Veterans General Hospital, Taiwan. The requirement for written informed consent was waived owing to the retrospective nature of the study. Consent for publication Not applicable. Data availability The datasets generated and/or analyzed in the current study are available from the corresponding author upon request. Competing interests The authors declare that they have no conflicts of interest. Funding information No. Supplementary information Supplementary information is available for this paper at the website. References Prager GW et al (2023) Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. 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Sci Rep 12(1):14612 Nakagawa-Senda H et al (2019) Prognostic impact of tumor location in colon cancer: the Monitoring of Cancer Incidence in Japan (MCIJ) project. BMC Cancer 19(1):431 Mekenkamp LJ et al (2012) Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 48(4):501–509 Roth AD et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60 – 00 trial. J Clin Oncol 28(3):466–474 Di Nicolantonio F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705–5712 Karagkounis G et al (2013) Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer 119(23):4137–4144 Prager GW et al (2023) Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med 388(18):1657–1667 Kuboki Y et al (2017) TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol 18(9):1172–1181 Hossain MS et al (2022) Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies. Cancers (Basel), 14(7) Mayer RJ et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909–1919 Van Cutsem E et al (2017) Proxies of quality of life in metastatic colorectal cancer: analyses in the RECOURSE trial. ESMO open 2(5):e000261 Cann CG et al (2022) Alternative biweekly dosing schedule of trifluridine-tipiracil (TAS-102) reduces rates of myelosuppression while maintaining therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC). American Society of Clinical Oncology Pfeiffer P et al (2020) TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol 21(3):412–420 Kotani D et al (2019) Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC Cancer 19(1):1253 Satake H et al (2020) Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study). Oncologist 25(12):e1855–e1863 Martinez-Lago N et al (2022) Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting. Sci Rep 12(1):14612 Nakagawa-Senda H et al (2019) Prognostic impact of tumor location in colon cancer: the Monitoring of Cancer Incidence in Japan (MCIJ) project. BMC Cancer 19(1):431 Mekenkamp LJ et al (2012) Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 48(4):501–509 Roth AD et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60 – 00 trial. J Clin Oncol 28(3):466–474 Di Nicolantonio F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705–5712 Karagkounis G et al (2013) Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer 119(23):4137–4144 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Dec, 2024 Read the published version in International Journal of Colorectal Disease → Version 1 posted Editorial decision: Revision requested 02 Oct, 2024 Reviews received at journal 02 Oct, 2024 Reviewers agreed at journal 05 Sep, 2024 Reviews received at journal 12 Jun, 2024 Reviewers agreed at journal 06 Jun, 2024 Reviewers invited by journal 06 Jun, 2024 Submission checks completed at journal 02 Jun, 2024 Editor assigned by journal 02 Jun, 2024 First submitted to journal 30 May, 2024 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4501755","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":313407028,"identity":"83f11aed-cda3-4549-99f2-28a28f1c941b","order_by":0,"name":"Kuan-Yu Tseng","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kuan-Yu","middleName":"","lastName":"Tseng","suffix":""},{"id":313407029,"identity":"31e1e96d-50fd-4045-89a4-92cb4d7954bd","order_by":1,"name":"Mu-Ying Yang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mu-Ying","middleName":"","lastName":"Yang","suffix":""},{"id":313407030,"identity":"75caa8ff-893f-4408-b8aa-3bb479fb8bee","order_by":2,"name":"Wei-Shone Chen","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei-Shone","middleName":"","lastName":"Chen","suffix":""},{"id":313407031,"identity":"4cdd0404-9376-4a09-a65a-c0ad93ceb5d2","order_by":3,"name":"Jeng-Kai Jiang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jeng-Kai","middleName":"","lastName":"Jiang","suffix":""},{"id":313407032,"identity":"477deaf5-08eb-4885-97ab-11e4ee47adbf","order_by":4,"name":"Huann-Sheng Wang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huann-Sheng","middleName":"","lastName":"Wang","suffix":""},{"id":313407033,"identity":"b613792a-5a8b-427a-b65e-ded809487311","order_by":5,"name":"Shih-Ching Chang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shih-Ching","middleName":"","lastName":"Chang","suffix":""},{"id":313407034,"identity":"42b51832-0c2c-4ecb-8919-456f9152eeae","order_by":6,"name":"Yuan-Tzu Lan","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuan-Tzu","middleName":"","lastName":"Lan","suffix":""},{"id":313407035,"identity":"08cf0cfd-f3a7-4a09-a17d-3648da62c557","order_by":7,"name":"Chun-Chi Lin","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chun-Chi","middleName":"","lastName":"Lin","suffix":""},{"id":313407037,"identity":"5d9989e5-2506-4c8e-bf56-225a953c93e6","order_by":8,"name":"Hung-Hsin Lin","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hung-Hsin","middleName":"","lastName":"Lin","suffix":""},{"id":313407038,"identity":"30d290fd-20a0-408d-96a9-6fe1e993e15b","order_by":9,"name":"Sheng-Chieh Huang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sheng-Chieh","middleName":"","lastName":"Huang","suffix":""},{"id":313407040,"identity":"f4c9e5d4-a00a-40a6-a30f-44a488c0879f","order_by":10,"name":"Hou-Hsuan Cheng","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hou-Hsuan","middleName":"","lastName":"Cheng","suffix":""},{"id":313407042,"identity":"003997ef-8881-4556-8780-cdd0bc98a09a","order_by":11,"name":"Yu-Zu Lin","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu-Zu","middleName":"","lastName":"Lin","suffix":""},{"id":313407044,"identity":"eb956b24-b48e-4ddb-a60a-f09d1f6f3f21","order_by":12,"name":"Che-Yuan Chang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Che-Yuan","middleName":"","lastName":"Chang","suffix":""},{"id":313407046,"identity":"958380af-2393-4def-adb8-49859a37d09d","order_by":13,"name":"Yi-Wen Yang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi-Wen","middleName":"","lastName":"Yang","suffix":""},{"id":313407048,"identity":"7bcc4df5-4ba6-465e-b7d0-a7f3a099e274","order_by":14,"name":"Hao-Wei Teng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYBACAwglIWd/mPkAiCFDhBZmEGVhzHCcLQGkhYdYLRWJDed5wDYS1mIukX/wccEvicTGZp7Pr27UWPAwsB8+ugGfFssZyczGM/skjJuZebdZ5xwDOownLe0GXofdTmaT5u2RkG0DajHOYQNqkeAxI6SF/TdQC2MPM88z45x/xGlhY+b5IaE4g5mH+XFuGzFa7j82luZtkDA2YGYzY87tk+BhI+iXMwcffub5UydnwH/48eecb3Vy/OyHj+HVAgaMbWCKTQJMElQOBn/AJPMH4lSPglEwCkbBSAMAEoJCoH5m/pcAAAAASUVORK5CYII=","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hao-Wei","middleName":"","lastName":"Teng","suffix":""}],"badges":[],"createdAt":"2024-05-30 09:06:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4501755/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4501755/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00384-024-04767-9","type":"published","date":"2024-12-04T15:57:49+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58746578,"identity":"d895058f-49b3-42e4-ba5b-e0100d0ea921","added_by":"auto","created_at":"2024-06-20 15:10:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27331,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Onlinefig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4501755/v1/9ffc5c5be58122382f3aeb93.png"},{"id":58746579,"identity":"b23146d7-dcb6-4655-828a-1f4865b815cd","added_by":"auto","created_at":"2024-06-20 15:10:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":17912,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Onlinefig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4501755/v1/6aa4852edb3fc7d2c4db3bd8.png"},{"id":70964793,"identity":"041627f2-05e5-4750-acb2-9397f4305427","added_by":"auto","created_at":"2024-12-09 16:15:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1124053,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4501755/v1/132bc118-09f8-4b91-86cb-579c2b5a1ad0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Combination of Modest Dosage of Bevacizumab with TAS-102 Provided the Comparable Efficacy in Treating Refractory Metastatic Colorectal Cancer","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eColorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and is among the most prevalent types of cancer.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Unfortunately, approximately half of all patients eventually develop metastatic CRC (mCRC). At this stage, salvage chemotherapy options include 5-fluorouracil (5-FU), oxaliplatin, irinotecan, anti-VEGF agents (such as bevacizumab), anti-EGFR agents, regorafenib, and TAS-102, either alone or in combination. However, patients undergoing salvage chemotherapy may experience adverse effects such as neutropenia following TAS-102 treatment, necessitating dosage adjustments to maintain a balance between quality of life and efficacy.\u003c/p\u003e \u003cp\u003eEffectiveness, sustained treatment response, and maintaining quality of life are crucial considerations in managing refractory mCRC. TAS-102 demonstrated an improvement in overall survival (OS) in refractory mCRC compared to a placebo in the phase III RECOURSE trial.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Additionally, Van Cutsem et al. investigated 800 patients from the RECOURSE study, demonstrating the effectiveness of TAS-102 across various subgroups, regardless of age, geographical region, or KRAS status. However, among the 38% of patients who received TAS-102, 4% experienced grade 3 or higher neutropenia, and an additional 4% developed febrile neutropenia despite treatment with granulocyte colony-stimulating factor. Consequently, patients may encounter risks that could profoundly impact their quality of life.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn the SUNLIGHT study, combining bevacizumab with TAS-102, demonstrated considerable OS benefits compared to TAS-102 monotherapy.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] However, severe adverse events (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) were more frequently reported in the combination group, with neutropenia being the most dominant. Severe (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) neutropenia was noted in 43.1% of the combination group, and 29.3% of the patients in the combination group received concomitant treatment with granulocyte colony-stimulating factors. Moreover, in a retrospective analysis (n\u0026thinsp;=\u0026thinsp;24), Cann et al. demonstrated that alternative biweekly dosing of TAS-102 could reduce toxicity while maintaining efficacy, with a median PFS of 2.3 months.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] However, survival data for patients with mCRC remain unsatisfactory. In the RECOURSE trial, the OS was 7.1 months in the TAS-102 group and 5.3 months in the placebo group. The OS was 10.8 months in the combination group and 7.5 months in the TAS-102 group.\u003c/p\u003e \u003cp\u003eIn this study, we assessed the efficacy of a modest dose of bevacizumab in combination with TAS-102. We hypothesized that patients receiving modest doses of bevacizumab have poorer survival outcomes.\u003c/p\u003e"},{"header":"METHOD","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics and assessment\u003c/h2\u003e \u003cp\u003eThe study enrolled patients with mCRC refractory to 5-FU, oxaliplatin, irinotecan, anti-VEGF agents, or anti-EGFR agents (if RAS wild-type). Included patients underwent more than one cycle of TAS-102. We defined a patient as having concomitant use of bevacizumab if they received at least three infusions, irrespective of the bevacizumab doses or timing of administration during TAS-102 treatment.\u003c/p\u003e \u003cp\u003eWe collected patient information, including age, sex, body surface area (BSA), primary tumor location, historical pathology, TAS-102 dose (mg/m\u003csup\u003e2\u003c/sup\u003e/d), and molecular data such as RAS, BRAF, and microsatellite stability status. Additionally, we reviewed the time from TAS-102 administration to the diagnosis of metastatic disease, previous treatment lines before TAS-102 administration, and metastatic sites, including the liver, lymph nodes, peritoneum, lung, and brain. Institutional Review Board (IRB) approval for this study was obtained from the Taipei Veteran General Hospital. The requirement for informed consent was waived by the IRB.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eModest bevacizumab combination stratification\u003c/h2\u003e \u003cp\u003eIn our cohort, most patients received modest doses of bevacizumab. The combination group was categorized based on the median bevacizumab dose (3.3 mg/kg). The patients were divided into two groups: those receiving doses\u0026thinsp;\u0026gt;\u0026thinsp;3.3 mg/kg and those receiving doses\u0026thinsp;\u0026le;\u0026thinsp;3.3 mg/kg.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eTreatment response and survival\u003c/h2\u003e \u003cp\u003eThe treatment response was assessed using computed tomography and magnetic resonance imaging according to the RECIST criteria. PFS signifies the duration from the initiation of TAS-102 administration to imaging-defined progression. OS was defined as the duration from the initiation of TAS-102 treatment to the patient's death from cancer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003ePatient characteristics were summarized using means for continuous variables and medians with first and third quartiles for continuous variables. Categorical variables are presented as numbers and percentages. Categorical variables were compared using the chi-squared or Fisher\u0026rsquo;s exact tests, whereas continuous variables were assessed using the appropriate statistical test, such as the independent t-test. Survival analysis was conducted using the Kaplan\u0026ndash;Meier method, and the log-rank test was used to compare survival curves. Univariate and multivariate Cox proportional hazards models were used to evaluate characteristics that may affect OS in patients with mCRC. Clinical factors with P\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in the univariate analysis were included in the multivariate analysis. Additionally, we used Restricted Mean Survival Time (RMST) and a landmark method for survival analysis, measuring the average survival time up to a specific time point. All statistical tests were two-sided, and statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003e We retrospectively reviewed 261 patients with histologically confirmed mCRC between January 1, 2010, and February 19, 2023. Among them, 175 received TAS-102 treatment without bevacizumab, and 86 received combination therapy. The baseline characteristics did not significantly differ between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003ePatient characteristics (n\u0026thinsp;=\u0026thinsp;261)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ewithout bevacizumab\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;175(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ebevacizumab\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;86(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(32.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(60.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\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 \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \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\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\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\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBSA, median, m\u003csup\u003e2\u003c/sup\u003e(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.45\u0026ndash;1.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.45\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary tumor location\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.08\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(41.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(38.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\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\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSynchronous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathology\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.11\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(93.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(98.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAS-102 dose(mg/m\u003csup\u003e2\u003c/sup\u003e/d)(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(45.7\u0026ndash;62.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(45.8\u0026ndash;66.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS\u003csup\u003e#\u003c/sup\u003e\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(46.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(45.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(50.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(54.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF\u003csup\u003e+\u003c/sup\u003e\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewild type\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrosatellite stability status\u003csup\u003e$\u003c/sup\u003e\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(81.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(82.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSI-H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from metastatic disease(%)\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(67.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious treatment before\u003c/p\u003e \u003cp\u003eTAS-102\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(29.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(27.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(70.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic site\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(64.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(73.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(80.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(5.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.30\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eChi-Square test. \u003csup\u003ef\u003c/sup\u003eFisher\u0026rsquo;s Exact test. *P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **P\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/p\u003e \u003cp\u003e\u003csup\u003e#\u003c/sup\u003e 4 patients RAS mutation data miss\u003c/p\u003e \u003cp\u003e\u003csup\u003e+\u003c/sup\u003e37 patients BRAF data miss\u003c/p\u003e \u003cp\u003e\u003csup\u003e$\u003c/sup\u003e 45 patients MSS data miss\u003c/p\u003e \u003cp\u003e\u003csup\u003e#\u003c/sup\u003e RAS including KRAS and NRAS\u003c/p\u003e \u003cp\u003eAbbreviations: MSS, Microsatellite Stable; MSI-H, microsatellite instability-high\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSurvival outcomes\u003c/h2\u003e \u003cp\u003eIn our cohort, the Kaplan\u0026ndash;Meier plot demonstrated a PFS of 3.7 months in the TAS-102 combined with bevacizumab group and 2.2 months in the group without bevacizumab [hazard ratio (HR) 0.69; 95% confidence interval (CI) 0.48\u0026ndash;0.99], showing statistical significance in favor of bevacizumab combination (P\u0026thinsp;=\u0026thinsp;0.004) (Fig.\u0026nbsp;1a). The OS was 10.3 months in the bevacizumab combination group and 9.4 months in the group without combination therapy. No statistically significant difference was observed in OS regardless of bevacizumab combination (P\u0026thinsp;=\u0026thinsp;0.248) (Fig.\u0026nbsp;1b). In landmark analysis, survival showed statistical significance before 9.5 months and not after 9.5 months (P\u0026thinsp;=\u0026thinsp;0.027) (Fig.\u0026nbsp;1c). RMST at 10 months demonstrated a change in the estimated survival probabilities for both groups (Fig.\u0026nbsp;1d). In the bevacizumab combination group, patients experienced more benefits within 9.5 months (Fig.\u0026nbsp;1e).\u003c/p\u003e \u003cp\u003eWe summarized both univariate and multivariate analyses of OS. Univariate analysis revealed statistical significance for patients with BSA\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;1.61 m\u003csup\u003e2\u003c/sup\u003e, time from metastatic disease diagnosis to TAS-102 administration\u0026thinsp;\u0026gt;\u0026thinsp;18 months, and those with liver, lymph node, or brain metastasis. In multivariate analysis, these factors remained statistically significant (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\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\u003eSummary of univariate and multivariate analyses of overall survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient Characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab combination\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout bevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith bevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.82(0.59\u0026ndash;1.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab dose\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elower than 3.3mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehigher than 3.3mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.30(0.76\u0026ndash;2.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.11(0.78\u0026ndash;1.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\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 \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\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\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\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\u003e0.85 (0.62\u0026ndash;1.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBSA, median, m\u003csup\u003e2\u003c/sup\u003e\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.50 (0.28\u0026ndash;0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45(0.25\u0026ndash;0.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary tumor location\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.80(0.53\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\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\u003e0.80(0.53\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSynchronous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.63(0.22\u0026ndash;11.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathology\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.94(0.42\u0026ndash;2.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAS-102 dose (mg/m\u003csup\u003e2\u003c/sup\u003e/d)\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;56 mg/m\u003csup\u003e2\u003c/sup\u003e/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e56 mg/m\u003csup\u003e2\u003c/sup\u003e/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.87(0.64\u0026ndash;1.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS\u003csup\u003e#\u003c/sup\u003e\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.86(0.62\u0026ndash;1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF\u003csup\u003e+\u003c/sup\u003e\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.22(0.50-3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrosatellite stability status\u003csup\u003e$\u003c/sup\u003e\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSI-H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.69(0.10\u0026ndash;4.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from metastatic disease\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.60(0.42\u0026ndash;0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.64(0.45\u0026ndash;0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.013\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious treatment before TAS-102\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.44(0.97\u0026ndash;2.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.43(0.94\u0026ndash;2.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic site\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.58(1.10\u0026ndash;2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.58(1.10\u0026ndash;2.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.43(1.03\u0026ndash;1.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.83(1.30\u0026ndash;2.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08(0.77\u0026ndash;1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01(0.70\u0026ndash;1.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.12(1.08\u0026ndash;4.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.51(2.97\u0026ndash;14.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **P\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/p\u003e \u003cp\u003e\u003csup\u003e#\u003c/sup\u003e 4 patients RAS mutation data miss\u003c/p\u003e \u003cp\u003e\u003csup\u003e+\u003c/sup\u003e37 patients BRAF data miss\u003c/p\u003e \u003cp\u003e\u003csup\u003e$\u003c/sup\u003e 45 patients MSS data miss\u003c/p\u003e \u003cp\u003e\u003csup\u003e#\u003c/sup\u003e RAS including KRAS and NRAS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eImpact of bevacizumab dose\u003c/h2\u003e \u003cp\u003eWe also investigated the effect of bevacizumab dose on survival. A statistically significant improvement in PFS was noted via the log-rank test, indicating that patients experienced a survival benefit with combination therapy compared to TAS-102 monotherapy (P\u0026thinsp;=\u0026thinsp;0.007) (Fig.\u0026nbsp;2a). No significant difference was observed in OS between patients without bevacizumab combination and those with varying doses, whether above or below 3.3 mg/kg (P\u0026thinsp;=\u0026thinsp;0.472) (Fig.\u0026nbsp;2b). Among patients receiving bevacizumab combination therapy (n\u0026thinsp;=\u0026thinsp;86), PFS rates did not significantly differ between the two groups, regardless of dosage (Fig.\u0026nbsp;2c). The median PFS was 4.2 months in the bevacizumab group with doses lower than 3.3 mg/kg and 4.4 months in the comparison group (P\u0026thinsp;=\u0026thinsp;0.509). These results suggest that bevacizumab treatment is associated with improved PFS, and that a combination of modest doses of bevacizumab and TAS-102 provided comparable efficacy. No significant difference was observed in OS between different bevacizumab doses. This implies that patients receiving doses either slightly lower than the standard (between 3.3 mg/kg and 5 mg/kg) or significantly lower (below 3.3 mg/kg) do not show significant effects (P\u0026thinsp;=\u0026thinsp;0.338).\u003c/p\u003e \u003cp\u003eIn our cohort, the median dose of bevacizumab was 3.3 mg/kg. Consequently, we summarized the characteristics of patients in the bevacizumab combination group using this dosage. Sex exhibited statistically significant differences, with a higher prevalence of females in the bevacizumab group at a dosage exceeding 3.3 mg/kg, whereas males were more predominant. Other characteristics were not statistically significant (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\u003ePatient characteristics, combination with bevacizumab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ebevacizumab lower than 3.3mg/kg\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;43(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ebevacizumab higher than 3.3mg/kg\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;43(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\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, years(IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(55\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(54\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(41.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(37.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(58.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\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 \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \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\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(37.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\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\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(37.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBSA, median, m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.56\u0026ndash;1.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.42\u0026ndash;1.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary tumor location\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\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\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathology\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(97.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAS-102 dose (mg/m\u003csup\u003e2\u003c/sup\u003e/) (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(47.9\u0026ndash;63.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(52.6\u0026ndash;69.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(53.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(37.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ewild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(97.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(97.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrosatellite stability status\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(83.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(81.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSI-H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from metastatic disease\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(69.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(65.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious treatment before\u003c/p\u003e \u003cp\u003eTAS-102\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(23.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(76.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(67.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic site\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 \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(67.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(76.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(48.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(37.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(76.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(81.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(79.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003eMann-Whitney U test. Chi-Square test. \u003csup\u003ef\u003c/sup\u003eFisher's Exact test. *P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **P\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis of PFS in bevacizumab combination\u003c/h2\u003e \u003cp\u003eOur findings demonstrate the potential PFS benefits of combining TAS-102 with bevacizumab, particularly in specific subgroups (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These subgroups included patients\u0026thinsp;\u0026gt;\u0026thinsp;60 years old, men, individuals with a BSA\u0026thinsp;\u0026lt;\u0026thinsp;1.61 m\u003csup\u003e2\u003c/sup\u003e, patients with adenocarcinoma, those receiving a TAS-102 dose\u0026thinsp;\u0026gt;\u0026thinsp;56 mg/m\u003csup\u003e2\u003c/sup\u003e/d, individuals with RAS mutation, wild-type BRAF, microsatellite stable status, those with a duration of \u0026lt;\u0026thinsp;18 months from metastatic disease diagnosis to starting TAS-102, heavily pretreated patients, and those with liver, lymph node, or lung metastasis. Patients with BRAF mutations were also observed to have PFS benefits; however, the data are limited. PFS in patients with microsatellite instability status was not analyzed because no patients in the bevacizumab combination group had microsatellite instability status. These findings suggest that TAS-102 in combination with bevacizumab may result in improved PFS in patients with mCRC with the abovementioned characteristics.\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\u003eSubgroup analysis of progression-free survival in combination with bevacizumab\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=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubgroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\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, years\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\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41\u0026ndash;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;60-year-old\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.44\u0026ndash;0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\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 \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\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.42\u0026ndash;0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\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\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.45\u0026ndash;1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBSA, median, m\u003csup\u003e2\u003c/sup\u003e\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\u003e\u0026lt;1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38\u0026ndash;0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.49\u0026ndash;1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary tumor location\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\u003eRight side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.32\u0026ndash;1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife side\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43\u0026ndash;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\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\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.42\u0026ndash;1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathology\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\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.47\u0026ndash;0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.08\u0026ndash;6.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAS-102 dose (mg/m\u003csup\u003e2\u003c/sup\u003e/d)\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\u003e\u0026lt;56 mg/m\u003csup\u003e2\u003c/sup\u003e/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.45\u0026ndash;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e56 mg/m\u003csup\u003e2\u003c/sup\u003e/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41\u0026ndash;0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRAS\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\u003ewild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.45\u0026ndash;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38\u0026ndash;0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF\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\u003ewild type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.47\u0026ndash;0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emutation\u003csup\u003e\u0026para;f\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.42\u0026ndash;27.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrosatellite stability status\u003csup\u003e\u0026sect;\u003c/sup\u003e\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\u003eMSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.49\u0026ndash;0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from metastatic disease\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\u003e\u0026lt;18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.22\u0026ndash;0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51\u0026ndash;1.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious treatment before TAS-102\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\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.42\u0026ndash;1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.44\u0026ndash;0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic site\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\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.45\u0026ndash;0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.009\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.39\u0026ndash;0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51\u0026ndash;1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43\u0026ndash;0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.07\u0026ndash;3.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eChi-Square test. \u003csup\u003ef\u003c/sup\u003eFisher's Exact test. *P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **P\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/p\u003e \u003cp\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003eThere were no patients with MSI-H in the bevacizumab combination group.\u003c/p\u003e \u003cp\u003e\u003csup\u003e\u0026para;\u003c/sup\u003eThere were 2 patients with BRAF mutation in the bevacizumab combination group.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur report is the first to demonstrate that a modest dose of bevacizumab in combination with TAS-102 provides comparable survival benefits that have not been directly compared in clinical studies. This survival benefit was limited to 9.5 months.\u003c/p\u003e \u003cp\u003eIn the RECOURSE study, TAS-102 demonstrated proven efficacy compared to the placebo, with acceptable toxicities. Patients were administered TAS-102 at a dose of 35 mg/m\u003csup\u003e2\u003c/sup\u003e/d twice daily, following a 5-day-on and 2-day-off schedule each week for 2 weeks, followed by a 14-day rest period.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e4\u003c/span\u003e] However, 53% experienced a delay of \u0026ge;\u0026thinsp;4 d in commencing their next cycle owing to toxicity, with approximately half of this subgroup experiencing an extended delay of \u0026ge;\u0026thinsp;8 d. In addition, 3.6% of patients discontinued treatment owing to adverse reactions, and 14% of patients required a dose reduction.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] In clinical practice, patients often experience gastrointestinal symptoms, leading to the postponement of treatment owing to grade 3 or 4 neutropenia.\u003c/p\u003e \u003cp\u003eAs we retrospectively reviewed patients diagnosed with CRC, the rationale for using this combination was based on preliminary studies.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] In comparison with the SUNLIGHT study, the overall survival (OS) was 10.8 months in the bevacizumab combination group, whereas in our cohort, it was 10.3 months with a modest-dose of bevacizumab. The survival was similar to that observed with relatively low doses of bevacizumab. Furthermore, OS was confined to within 10 months via RMST analysis. Patients who underwent TAS-102 treatment, however, experienced greater survival benefits with early bevacizumab combination therapy.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn our retrospective review, the median dose of TAS-102 was 56 mg/m\u003csup\u003e2\u003c/sup\u003e/d. TAS-102 was reduced at our institution owing to intolerance. In other words, most patients initially received the standard dose in their prescription, and experienced dose reduction after the first cycle of administration. Once patients received a reduced dose, they were not titrated back to the standard dose. We observed a trend of an elevated TAS-102 dose in the bevacizumab combination group compared to the others; however, the difference was not statistically significant.\u003c/p\u003e \u003cp\u003eNo significant difference was observed in the OS between the bevacizumab combination groups. This was attributed to the absence of TAS-102 and bevacizumab underdosing in our cohort, possibly owing to complications. Furthermore, the majority of patients had refractory disease, with 71.2% (n\u0026thinsp;=\u0026thinsp;186) receiving TAS-102 as their 4th line of treatment or beyond.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe lack of OS benefits in in the higher standard dose of the bevacizumab group (\u0026gt;\u0026thinsp;3.3 mg/kg) may be attributed to several factors. First, men dominated the lower bevacizumab dose group. Second, the relatively small sample size may have influenced the results. Finally, the higher proportion of left-side-origin tumors in the lower bevacizumab group (46.5%) than their counterparts (30.2%) in our cohort may have had an impact. In the Monitoring of Cancer Incidence in Japan (MCIJ) project, which reviewed 62,350 participants with colon cancer from 2006 to 2008, the authors found that five-year net survival for left- and right-sided colon cancer were 74.0% (95% CI, 73.4\u0026ndash;74.7%) and 70.4% (95% CI, 69.7\u0026ndash;71.0%), respectively.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] This suggests that patients with left-sided colon cancer have better survival rates than those with other cancers. No precise explanation exists for the better OS trend in the lower-dose group. We observed a significant PFS difference with TAS-102 combined with bevacizumab, regardless of bevacizumab dose. Specifically, patients receiving TAS-102 treatment experienced extended PFS after receiving more than three infusions of bevacizumab.\u003c/p\u003e \u003cp\u003eAdditionally, we observed that certain individuals, including those\u0026thinsp;\u0026gt;\u0026thinsp;60, men with a BSA under 1.61, adenocarcinoma (versus mucinous adenocarcinoma), receiving a TAS-102 dose over 56 mg/m\u003csup\u003e2\u003c/sup\u003e/d, having RAS mutations, diagnosed with metastatic disease\u0026thinsp;\u0026lt;\u0026thinsp;18 months before starting TAS-102, heavily pre-treated, or with liver, lymph nodes, or lung metastases, may experience prolonged PFS.\u003c/p\u003e \u003cp\u003eSome subgroups of patients with factors indicative of a good prognosis have been described previously. In a combined analysis of two phase III studies, mucinous adenocarcinomas exhibited worse OS, PFS, and overall response rates than adenocarcinomas.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] This suggests that mucinous adenocarcinoma may be an independent factor for a poor prognosis. Although RAS mutations conferred a PFS benefit in our cohort, the role of KRAS mutations as a prognostic factor independent of treatment seems unlikely; however, this remains controversial.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] BRAF mutation present distinct clinical characteristics and prognoses;[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] however, limited data exists on this aspect.\u003c/p\u003e \u003cp\u003eOur study had several limitations. First, it was retrospective in nature. Further prospective randomized clinical trials are required to validate the role of different doses in combination therapy. Second, our cohort received various TAS-102 doses, complicating exact efficacy determination for TAS-102 or bevacizumab. We could not determine the most beneficial dose combination. Factors such as limited BRAF and microsatellite stable data, and a small population with mucinous adenocarcinoma, made statistical significance questionable. Different salvage chemotherapy regimens were used before or after bevacizumab combination therapy.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, this retrospective study highlights the survival benefits of TAS-102 combined with a modest dose of bevacizumab in patients with refractory mCRC. Further prospective investigations are essential to determine the optimal combination of modest doses of bevacizumab and TAS-102 among heavily treated patients with CRC in real-world practice.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eADDITIONAL INFORMATION\u003c/h2\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA portion of data for this study was obtained from the Cancer Registry Database of Taipei Veterans General Hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKuan-Yu Tseng collected and analyzed the data, wrote, and submitted the manuscript. Mu-Ying Yang, Wei-Shone Chen, Jeng-Kai Jiang, Huann-Sheng Wang, Shih-Ching Chang, Yuan-Tzu Lan, Chun-Chi Lin, Hung-Hsin Lin, Sheng-Chieh Huang, Hou-Hsuan Cheng, Yu-Zu Lin, Che-Yuan Chang, and Yi-Wen Yang provided data. Hao-Wei Teng designed the study and approved the manuscript and bioinformatics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was conducted using population-based data from Taipei Veterans General Hospital, Taiwan, following the guidelines of the Declaration of Helsinki. Approved was obtained from the Ethics Committee and Institutional Review Board of Taipei Veterans General Hospital, Taiwan. The requirement for written informed consent was waived owing to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed in the current study are available from the corresponding author\u0026nbsp;upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding information\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSupplementary information\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary information is available for this paper at the website.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePrager GW et al (2023) Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med 388(18):1657\u0026ndash;1667\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuboki Y et al (2017) TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol 18(9):1172\u0026ndash;1181\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHossain MS et al (2022) Colorectal cancer: A Review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers (Basel) 14(7):1732\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMayer RJ et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909\u0026ndash;1919\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Cutsem E et al (2017) Proxies of quality of life in metastatic colorectal cancer: analyses in the RECOURSE trial. ESMO Open 2(5):e000261\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCann CG et al (2022) Alternative biweekly dosing schedule of trifluridine-tipiracil (TAS-102) reduces rates of myelosuppression while maintaining therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC). Am Soc Clin Oncol, 40(16)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePfeiffer P et al (2020) TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol 21(3):412\u0026ndash;420\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKotani D et al (2019) Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC Cancer 19(1):1253\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSatake H et al (2020) Phase Ib/II study of biweekly TAS-102 in combination with bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (BiTS Study). Oncologist 25(12):e1855\u0026ndash;e1863\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartinez-Lago N et al (2022) Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting. Sci Rep 12(1):14612\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakagawa-Senda H et al (2019) Prognostic impact of tumor location in colon cancer: the Monitoring of Cancer Incidence in Japan (MCIJ) project. BMC Cancer 19(1):431\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMekenkamp LJ et al (2012) Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 48(4):501\u0026ndash;509\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoth AD et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60\u0026thinsp;\u0026ndash;\u0026thinsp;00 trial. J Clin Oncol 28(3):466\u0026ndash;474\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Nicolantonio F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705\u0026ndash;5712\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaragkounis G et al (2013) Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer 119(23):4137\u0026ndash;4144\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrager GW et al (2023) Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med 388(18):1657\u0026ndash;1667\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuboki Y et al (2017) TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol 18(9):1172\u0026ndash;1181\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHossain MS et al (2022) Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies. Cancers (Basel), 14(7)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMayer RJ et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909\u0026ndash;1919\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Cutsem E et al (2017) Proxies of quality of life in metastatic colorectal cancer: analyses in the RECOURSE trial. ESMO open 2(5):e000261\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCann CG et al (2022) Alternative biweekly dosing schedule of trifluridine-tipiracil (TAS-102) reduces rates of myelosuppression while maintaining therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC). American Society of Clinical Oncology\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePfeiffer P et al (2020) TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol 21(3):412\u0026ndash;420\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKotani D et al (2019) Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC Cancer 19(1):1253\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSatake H et al (2020) Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study). Oncologist 25(12):e1855\u0026ndash;e1863\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartinez-Lago N et al (2022) Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting. Sci Rep 12(1):14612\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakagawa-Senda H et al (2019) Prognostic impact of tumor location in colon cancer: the Monitoring of Cancer Incidence in Japan (MCIJ) project. BMC Cancer 19(1):431\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMekenkamp LJ et al (2012) Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 48(4):501\u0026ndash;509\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoth AD et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60\u0026thinsp;\u0026ndash;\u0026thinsp;00 trial. J Clin Oncol 28(3):466\u0026ndash;474\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDi Nicolantonio F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26(35):5705\u0026ndash;5712\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaragkounis G et al (2013) Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer 119(23):4137\u0026ndash;4144\u003c/span\u003e\u003c/li\u003e\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":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Bevacizumab, TAS-102, Colorectal cancer","lastPublishedDoi":"10.21203/rs.3.rs-4501755/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4501755/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven that the combination of bevacizumab and TAS-102 is used to treat refractory metastatic colorectal cancer (mCRC), we aimed to evaluate the efficacy of modest doses of bevacizumab in combination with TAS-102 for the treatment of refractory mCRC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 261 patients with refractory mCRC were enrolled and categorized into two groups: TAS-102 combined with bevacizumab and TAS-102 alone. In the bevacizumab combination group, patients were further divided into two subgroups based on a median dose of 3.3 mg/kg. Categorical variables were compared using the chi-squared or Fisher’s exact tests, and continuous variables were assessed using the t-test. The Cox proportional hazards model was used to adjust for covariates. Survival analysis was performed using the log-rank test and Kaplan–Meier curves. Specific survival was evaluated using Restricted Mean Survival Time (RMST) and landmark analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median progression-free survival (PFS) was 3.7 months in the TAS-102combined with bevacizumab group, and 2.2 months in the group without bevacizumab, showing statistical significance in favor of bevacizumab combination group (P = 0.004). The median overall survival (OS) was 9.4 months in the bevacizumab combination group and 10.3 months in the group that did not receive combination therapy. A survival benefit was observed within 9.5 months in both the RMST and landmark analyses. However, no long-term OS benefit was evident, regardless of bevacizumab combination (P = 0.248).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe modest doses of bevacizumab and TAS-102 provided comparable efficacy to the standard dose schedule, especially within a limited timeframe of 9.5 months.\u003c/p\u003e","manuscriptTitle":"Combination of Modest Dosage of Bevacizumab with TAS-102 Provided the Comparable Efficacy in Treating Refractory Metastatic Colorectal Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-20 15:10:00","doi":"10.21203/rs.3.rs-4501755/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-02T12:17:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-02T12:13:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"170964231173959580528542175737479304956","date":"2024-09-05T18:08:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-12T05:20:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187982095950642058994483446073661507728","date":"2024-06-07T02:29:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-06T10:24:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-03T01:26:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-03T01:26:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Colorectal Disease","date":"2024-05-30T09:02:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c1472782-8a3e-40a8-a224-526eb07e55fb","owner":[],"postedDate":"June 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T16:04:38+00:00","versionOfRecord":{"articleIdentity":"rs-4501755","link":"https://doi.org/10.1007/s00384-024-04767-9","journal":{"identity":"international-journal-of-colorectal-disease","isVorOnly":false,"title":"International Journal of Colorectal Disease"},"publishedOn":"2024-12-04 15:57:49","publishedOnDateReadable":"December 4th, 2024"},"versionCreatedAt":"2024-06-20 15:10:00","video":"","vorDoi":"10.1007/s00384-024-04767-9","vorDoiUrl":"https://doi.org/10.1007/s00384-024-04767-9","workflowStages":[]},"version":"v1","identity":"rs-4501755","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4501755","identity":"rs-4501755","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}