Efficacy of First-line Therapy With Anti-EGFR Versus Anti-VEGF Therapy for WT RAS Metastatic Colorectal Cancer: Real-world Experience from a Single Institute

Efficacy of First-line Therapy With Anti-EGFR Versus Anti-VEGF Therapy for WT RAS Metastatic Colorectal Cancer: Real-world Experience from a Single Institute | 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 Efficacy of First-line Therapy With Anti-EGFR Versus Anti-VEGF Therapy for WT RAS Metastatic Colorectal Cancer: Real-world Experience from a Single Institute Shih-Wei Chiang, Yi-Lin Huang, Feng-Fan Chiang, Ming-Cheng Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3949891/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background/Aim: Top prospective clinical trials comparing anti-epidermal growth factor receptor (EGFR) therapy and anti-vascular endothelial growth factor (VEGF) therapy plus chemotherapy for wild-type Ras proto-oncogene, GTPase (WT RAS ) metastatic colorectal cancer (mCRC) have yielded different outcomes, and real-world data are lacking. This study established real-world experiences and identified challenges in treating patients with mCRC. Patients and Methods : This retrospective study identified first-line regimens for patients with mCRC on anti-EGFR or anti-VEGF therapy plus chemotherapy. The effects on overall survival (OS) were estimated; secondary endpoints were progression-free survival (PFS). OS in the two groups was compared on the basis of sex, age, primary tumor site, oxaliplatin-based chemotherapy, and number of organs with metastases through Cox multivariate regression analysis. Results : A total of 129 patients diagnosed with WT RAS mCRC from June 1, 2018, to December 31, 2021, were included. The median OS was 33.3 months for the anti-EGFR group (n = 78) and 26.1 months for the anti-VEGF group (n = 51; 95% confidence interval = 1.008–2.550; p = 0.044). PFS was 17.6 and 12 months, respectively (95% confidence interval = 0.9-1.963; p = 0.15). Multivariate Cox regression models revealed good OS for patients with WT RAS and left-sided primary tumor. The liver-only metastasis conversion rate after systemic chemotherapy was higher in the anti-EGFR group. Conclusion : High survival rates can be achieved when anti-EGFR is used in patients with WT RAS mCRC. Surgery still plays an important role in patients with mCRC and on systemic treatments. Metastatic colorectal cancer RAS cetuximab panitumumab bevacizumab Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction In Taiwan, more than 17,000 new colorectal cancer (CRC) cases were recorded in 2019, with an incidence rate of 42.9 per 100,000 and mortality rate of 14.6 per 100,000 (1). The incidence of CRC is increasing, and it has become the most common cancer type in Taiwan. Hence, managing patients with CRC through multiple modalities, including surgery, systemic chemotherapy, target therapy, immunotherapy, and regional radiotherapy, to improve outcomes and survival is crucial. 5-Fluorouracil has been used for inoperable CRC after chemotherapy since 1962 (2), and options for metastatic CRC (mCRC) treatment have become increasingly complex and varied with combinations of 5-fluorouracil, oxaliplatin, irinotecan, and targeted therapies. According to the National Comprehensive Cancer Network guidelines (3), the first-line chemotherapy regimens for mCRC are doublet regimens with 5-fluorouracil plus oxaliplatin or irinotecan and triplet regimens with 5-fluorouracil plus oxaliplatin and irinotecan. Targeted agents used as first-line treatments for mCRC are anti-epidermal growth factor receptor (EGFR) (cetuximab and panitumumab) and anti-vascular endothelial growth factor (VEGF) (bevazicumab). The most common Ras proto-oncogene, GTPase ( RAS ) gene mutation in mCRC is of the KRAS proto-oncogene, GTPase (KRAS) (4). Somatic single-nucleotide points in mutation codons 12 and 13 in exon 2 of the KRAS gene activate the mitogen-activated protein kinase pathway and confer resistance to EGFR inhibitors. This finding is well established by randomized control trials (RCTs). A retrospective analysis from the PRIME trial (5) showed other mutations in the genes of the RAS family ( KRAS exon 3 and 4 and NRAS 2, 3, and 4) are associated with poor response to EGFR inhibitors. The ‘all RAS wild-type’ (WT RAS ) subgroup, i.e. , those with no mutations in exons 2, 4, and 4 for either KRAS or NRAS , is expected to show excellent response to EGFR inhibitors. A meta-analysis showed that EGFR inhibitor therapy is effective against tumors harboring one of the RAS mutations (except KRAS exon 2) (6). In a study of the ‘super’ WT, i.e. , those patients whose genetic findings show all WT RAS adding WT for B-Raf proto-oncogene serine/threonine kinase ( BRAF ) exon 15, the retrospective analysis revealed liver metastases of CRC are more likely to exhibit a super WT (7). Phase III trials, including FIRE-3 (8) and CALGB/SWOG 80405 (9), have established which targeted agent (bevacizumab/cetuximab) is effective for WT RAS mCRC. The final FIRE-3 results (10) revealed that patients who received cetuximab had better overall survival (OS) than those who received bevacizumab; however, the CALGB/SWOG 80405 trial showed no difference in OS between the two. The phase II PEAK trial (11) compared first-line chemotherapy plus panitumumab with bevacizumab in patients with WT KRAS exon 2 mCRC and found that the panitumumab group had superior OS compared with the bevacizumab group. In the trial, the EGFR inhibitor significantly prolonged OS compared with inhibition of VEGF (12), but no difference in progression-free survival (PFS) was found between the groups. No decisive results have indicated which first-line treatment is superior, and this is still being debated. With regard to primary tumor location, post-hoc analyses have revealed that patients with left-sided WT RAS mCRC on first-line chemotherapy plus anti-EGFR have better survival outcomes than those with right-sided tumors (6, 9-10). The PEAK and PRIME (13) trials indicated that right-sided primary tumors are associated with poor prognosis (14). Moreover, benefits to the overall response rate (ORR) and PFS have been observed for patients with left-sided tumors on chemotherapy plus anti-EGFR compared with those with right-sided tumors (15). The National Comprehensive Cancer Network has recommended EGFR inhibitor as a first-line treatment for left-sided mCRC, and our national consensus supports this recommendation after experts’ discussion (16). Given the lack of prospective or real-world retrospective studies, whether this treatment strategy can achieve ideal effectiveness remains to be proven. Thus, in this retrospective study, we evaluated the effectiveness of bevacizumab and cetuximab/panitumumab in patients with WT RAS mCRC using real-world data. Patients and Methods This study retrospectively analyzed medical charts and recruited patients with mCRC who satisfied the following inclusion criteria: Age ≥ 18 years, unresectable or metastatic colorectal adenocarcinoma, at least two courses of the same regimen of cetuximab/panitumumab or bevacizumab plus fluoropyrimidine-based doublet or triplet chemotherapy of oxaliplatin and irinotecan as first-line chemotherapy, a lesion that can be evaluated by Response Evaluation Criteria in Solid Tumors (version 1.1) ( 17 ), WT RAS status (for KRAS/NRAS exons 2, 3, and 4), and enrollment between June 2018 and December 2021. The exclusion criteria were as follows: Two or more active malignancies, no RAS reports, no first-line treatments (receiving at other institutes), and incomplete medical charts. Written consent was obtained from the patients for the use of their data. Evaluation and endpoints. The primary endpoint was OS. We compared patients who received cetuximab/panitumumab and those who received bevacizumab in the full cohort. OS was defined as the time from the start of first-time chemotherapy to death from any cause or censoring at the last follow-up event. The secondary endpoints were ORR and PFS. ORR was defined as the proportion of patients with a partial or complete response to therapy per RECIST 1.1, and PFS was estimated as the time from start of treatment to the date of disease progression or death from any cause. The covariates included age, sex, first-line regimen (oxaliplatin/irinotecan), primary tumor location (right/left), and number of metastases. We defined right-sided mCRC as primary tumor originating from the cecum, ascending colon or transverse colon, and left-sided mCRC was defined as the primary tumor originating from the descending colon, sigmoid colon or rectum. Computed tomographic scan (chest, abdomen, and pelvis) supplemented by magnetic resonance imaging and 18 F-fluorodeoxyglucose positron-emission tomography were conducted for imaging. The conversion rate was defined as the proportion of metastasectomy after systemic treatments in the cohort (patients undergoing synchronous/staged operation were not included), and decision-making was made through medical team or multidisciplinary team (MDT) assessments in the combined conference. Statistical analysis . Patient baseline characteristics were summarized using descriptive statistics. OS and PFS rates for the full cohort were calculated using the Kaplan–Meier method. OS rate was compared between patients who received Cet/x panitumumab and those who received bevacizumab by performing multivariate Cox regression analysis on the following covariates: Age (< 65/≥65 years), sex (male/female), first-line regimen (oxaliplatin-based/irinotecan-based chemotherapy), primary tumor location (right-sided/left-sided), and number of metastases (< 2/≥2). Hazard ratios (HRs) were calculated using multivariate Cox regression models. All statistical analyses were performed with SPSS version 26.0. (IBM Corp., Armonk, NY, USA). Results Patient characteristics . Figure 1 shows the screening process of patients with mCRC in accordance with the selection criteria. A total of 129 patients were enrolled in the study, and their characteristics are shown in Table I . Seventy-eight patients received EGFR inhibitors, and 51 received VEGF inhibitors as the first regimens. Lacking a routine BRAF mutation profile, most patients in both groups had unknown BRAF status. On the basis of the known BRAF results, mutation accounted for a large proportion in both groups possibly because of response considerations by individual clinical physicians. Genetic typing details showed that most patients had WT KRAS/NRAS exons 2 and 3 in both groups. Primary left-sided tumors were predominant in both groups. The patients who received cetuximab/panitumumab had a higher degree of liver metastasis but less peritoneal involvement than the bevacizumab group. The proportion of patients who had metastasis in more than two organs was higher in the cetuximab/panitumumab group than in the bevacizumab group (25.6% vs. 19.6%). With regard to chemotherapy, most patients received irinotecan-based chemotherapy as the backbone in both groups. The patients who received cetuximab/panitumumab were more likely to have undergone primary tumor resection than the patients in the bevacizumab group (75.6% vs. 58.8%), it showed significant difference (Table I; p = 0.011). The median follow-up period was 22.2 months. OS and PFS. Patients who received cetuximab/panitumumab had better OS and PFS than those who received bevacizumab. The median OS (Fig. 2 ) was significantly better at 33.3 months for patients who received cetuximab/panitumumab compared with 26.1 months for those who received bevacizumab [HR = 1.604, 95% confidence interval (CI) = 1.008–2.550; p = 0.044]. The median PFS (Fig. 3 ) was 17.6 months for the cetuximab/panitumumab group and 12 months for the bevacizumab group (HR = 1.329, 95% CI = 0.9-1.963; p = 0.15). Figure 4 and Fig. 5 show OS and PFS subclassified by primary tumor sidedness in both groups. In the patients with left-sided tumor (n = 93), the cetuximab/panitumumab group had higher OS than the bevacizumab group but the difference did not achieve significance (OS: 36.6 vs. 28.9 months, p = 0.061; PFS: 17.2 vs. 12.1 months, p = 0.371). In the patients with right-sided tumor (n = 32), no benefits to survival were observed in both groups (OS: 18 vs. 14 months, p = 0.262; PFS: 14.9 vs. 10 months, p = 0.148). Liver-limited metastasis mCRC conversion rates and resection margin assessment. Subgroup analysis for those with liver-only metastasis mCRC was evaluated. A nonsignificant difference in metastatic conversion rate was found between the cetuximab/panitumumab and bevacizumab groups (Fig. 6A) ( p = 0.403). The likelihood of conversion for those with liver-only metastasis was lower for the bevacizumab group (n = 5/21, 23.8%) than for the cetuximab/panitumumab group (n = 14/41, 34.1%). The R0 resection rate after conversion surgery (Fig. 6B) was higher in the cetuximab/panitumumab group (n = 10/14, 71.4%) than in the bevacizumab group (n = 3/5, 60%). Cox proportional hazard models for patients with WT RAS. The prognostic factors for OS from univariate analyses are presented in Table II . The HRs for OS were age ≥ 65 years (HR = 2.0), right-sided primary tumor (HR = 2.93), metastases ≥ 2 organs (HR = 1.78), and anti-VEGF for first-line regimen (HR = 1.60). In the multivariate analysis of prognostic factors for OS ( Table III ), right-sided primary tumor was the strongest factor associated with poor prognosis (HR = 2.08, 95% CI = 1.17–3.69). metastases ≥ 2 organs (HR = 1.80), and anti-VEGF for first-line regimen (HR = 1.66) were associated with impaired OS, and significant difference was noted. Discussion Unlike multicenter studies, this single-center study performed retrospective comparisons of the efficacy of chemo-targeted agents in WT RAS mCRC. KRAS mutations predict poor prognosis and response from cetuxamab and panitumumab therapies in CRC, hence we ruled out this as a prognostic factor and selected patients with WT RAS CRC as our candidates ( 18 ). In preliminary pathological gene profiles, only 38 patients (29.5%) had all WT RAS status, and the majority of patients (69, 53.5%) had WT KRAS / NRAS exons 2 and 3. Low prevalence of KRAS or NRAS exon 4 mutation was found in a retrospective cohort study in North Africa ( 19 ), however, potential KRAS or NRAS exon 4 mutations were not assessed comprehensively in our database. In our real-world data, therapy with cetuximab/panitumumab led to better OS and PFS than therapy with bevacizumab, and the difference in OS even reached significance. Notably, OS and PFS were better in patients with left-sided primary tumors and on cetuximab/panitumumab than those receiving bevacizumab, but no significant difference was found. In the patients with right-sided primary tumors, our data showed better survival outcomes in those receiving cetuximab/panitumumab as the first-line agent, but no statistical difference was found. Primary tumor sidedness is a prognostic factor in patients with WT RAS mCRC, and right-sided primary tumors was associated with poor prognosis. A cohort study with 178 patients with mCRC showed similar results in that superior OS and PFS were observed when anti-EGFR was added to therapy for patients with for left-sided primary tumors ( 20 ). A meta-analysis of RCTs with large sample sizes ( 21 ) showed that the ORR and OS (overall response) after anti-EGFR therapy were superior to those after anti-VEGF therapy in patients with WT RA S mCRC (odds ratio = 0.79, 95% CI = 0.68–0.92, p = 0.002) but not in patients with WT KRAS mCRC (odds ratio = 0.81, 95% CI = 0.64–1.01, p = 0.06). However, the exact mechanism has not been clarified yet. Early tumor shrinkage may be beneficial when anti-EGFR is added as first-line chemotherapy for WT RAS mCRC ( 22 ). Our study’s results are compatible with the abovementioned results. The reasons for the difference in PFS may be as follows: there was a relatively small number of patients in each group; there was a high rate of peritoneal metastasis in the bevacizumab group, which implied poor treatment response and prognosis ( 23 ); and a higher number of patients in the bevacizumab group (n = 9) compared with the cetuximab/panitumumab group (n = 5) regardless of the incomplete mutation data ( 24 ). The poor prognoses of patients with mCRC are due to right-sided primary tumor. Wu et al. ( 25 ) recently performed a network meta-analysis of large RCTs and found that in patients with WT RAS disease, anti-EGFR is the most effective treatment for left-sided, and bevacizumab is effective for right-sided tumors. Our real-world data showed a similar effect, that is, using cetuximab/panitumumab provided nearly 4 months of survival benefit compared with using bevacizumab for patients with left-sided tumors, but no benefits to survival were observed when bevacizumab was used for patients with right-sided tumors. A few patients with right-sided tumors (n = 32) were present in the cohort, and the prevalence of RAS and BRAF mutations may have a prognostic impact. Our study ruled out RAS mutation possibility at initial enrollment. However, a previous review ( 26 ) revealed patients with right-sided tumors had significantly higher prevalence of BRAF mutations than patients with left-sided tumors (16.3% vs. 4.3%). Hence, we applied the current consensus of using anti-EGFR for patients with WT RAS/BRAF and left-sided tumor. With regard to patients with right-sided tumors, further discussions through MDT conference should be performed case by case. In the early 2000s, only 10–25% of patients with CRC liver metastasis underwent liver metastasectomy according to the extent of their disease. Owing to inadequate liver remnant, hepatic surgery is unsuitable for many patients ( 27 ). Surgical intervention, including primary resection, secondary resection, and even third resection after systemic treatment, plays an important role in patients with mCRC. In the FIRE-3 central review analysis, patients with resectable disease and the best response who underwent resection had OS superior to those who did not undergo resection (51.3 vs. 30.8 months) ( 28 ). Another study reported that 22% of patients underwent surgery after treatment, which is higher than the percentage for other clinical trials ( 9 , 11 , 29 ). Meanwhile, a small trial with liver-limited mCRC ( 30 ) showed similar rates of resectability or conversion. The liver-limited mCRC conversion rate in our study was 34.1% in the cetuximab/panitumumab group and 23.8% in the bevacizumab group, and these values are similar to those of the above-mentioned trials. In a total of 82 patients with non-resectable liver metastases from CRC, no significant benefits on disease-free survival were shown for bevacizumab when added to chemotherapy ( 31 ). No comparison of conversion rate with additional anti-EGFR or anti-VEGF after first-line systemic treatment is available for WT RAS mCRC ( 31 – 33 ). Further studies or trials should be performed. Study limitations. Firstly, a single-center population with a certain number of patients was used, but this limitation is unlikely to have influenced the results. Panitumumab was officially included in the Taiwanese national health payment guideline in June 2018 because of the US National Institutes of Health policy. Secondly, survival benefits that can be obtained from different targeted agents for WT RAS mCRC cannot be statistically compared because of the small number of patients involved. Further research is necessary to elucidate the association. Thirdly, perfectly matching cases for propensity score-matching analysis were not obtained. Thus, the results should be managed and interpreted with caution. Fourthly, our Pathological Department has started to use complete KRAS/NRAS panels for tissue genetic typing in recent years, and thus some patients had only KRAS exon 2 and 3 data or the deficiency mutation profile of the KRAS/NRAS exon 4. Conclusion In this ever-changing world, researchers have devoted considerable effort to creating enhanced chemotherapeutic regimens, improving patient selection, and performing MDT discussions to achieve the best outcomes possible. Treatment guidelines have been established through rigorous RCTs and clinical trials. By using real-world data, we present the advantages of using first-line chemotherapy with anti-EGFR over using anti-VEGF plus chemotherapy with respect to OS and PFS in patients with WT RAS mCRC. Our results showed that adopting anti-EGFR treatment for patients with left-sided tumors enhances their survival. Surgery still plays an important role in patients with mCRC and on systemic treatments. This work emphasizes treatment effects on patients using anti-EGFR as their first-line regimen. In view of the limited number of patients, methods for overcoming limitations are needed, and the results of this study should be interpreted with caution. Declarations Conflicts of Interest All Authors declare they have no competing interests in regard to this work. Authors’ Contributions Shih-Wei Chiang , Yi-Lin Huang , and Feng-Fan Chiang were responsible for the study design. Shih-Wei Chiang collected and analyzed the data. Feng-Fan Chiang and Ming-Cheng Chen interpreted the data. Shih-Wei Chiang wrote the article. References Health Promotion Administration, Ministry of Health and Welfare. (2020, June19) 2019 Health Promotion Administration Annual Report. Retrieved March, 1, 2023 from https://www.hpa.gov.tw/EngPages/Detail.aspx?nodeid=1070&pid=12811. Gs S, Ww B: 5-fluorouracil in the treatment of inoperable carcinoma of the colon and rectum. Cancer chemotherapy reports 20(97-101, 1962. Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA: Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 19(3): 329-359, 2021. DOI: 10.6004/jnccn.2021.0012 Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA: Systematic review: Anti-epidermal growth factor receptor treatment effect modification by kras mutations in advanced colorectal cancer. Ann Intern Med 154(1): 37-49, 2011. DOI: 10.7326/0003-4819-154-1-201101040-00006 Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD: Panitumumab-folfox4 treatment and ras mutations in colorectal cancer. N Engl J Med 369(11): 1023-1034, 2013. DOI: 10.1056/NEJMoa1305275 Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS: Extended ras mutations and anti-egfr monoclonal antibody survival benefit in metastatic colorectal cancer: A meta-analysis of randomized, controlled trials. Ann Oncol 26(1): 13-21, 2015. DOI: 10.1093/annonc/mdu378 Allard MA, Saffroy R, de la Maisonneuve PB, Ricca L, Bosselut N, Hamelin J, Lecorche E, Bejarano MA, Innominato P, Sebagh M, Adam R, Morère JF, Lemoine A: Colorectal liver metastases are more often super wild type. Toward treatment based on metastatic site genotyping? Target Oncol 10(3): 415-421, 2015. DOI: 10.1007/s11523-014-0346-5 Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S: Folfiri plus cetuximab versus folfiri plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (fire-3): A randomised, open-label, phase 3 trial. Lancet Oncol 15(10): 1065-1075, 2014. DOI: 10.1016/s1470-2045(14)70330-4 Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB, 3rd, Mulkerin DL, Mayer RJ, Blanke C: Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with kras wild-type advanced or metastatic colorectal cancer: A randomized clinical trial. Jama 317(23): 2392-2401, 2017. DOI: 10.1001/jama.2017.7105 Heinemann V, von Weikersthal LF, Decker T, Kiani A, Kaiser F, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Moehler M, Scheithauer W, Held S, Miller-Phillips L, Modest DP, Jung A, Kirchner T, Stintzing S: Folfiri plus cetuximab or bevacizumab for advanced colorectal cancer: Final survival and per-protocol analysis of fire-3, a randomised clinical trial. Br J Cancer 124(3): 587-594, 2021. DOI: 10.1038/s41416-020-01140-9 Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY: Peak: A randomized, multicenter phase ii study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mfolfox6) or bevacizumab plus mfolfox6 in patients with previously untreated, unresectable, wild-type kras exon 2 metastatic colorectal cancer. J Clin Oncol 32(21): 2240-2247, 2014. DOI: 10.1200/jco.2013.53.2473 Zhang C, Liu L, Lv Y, Li J, Cao C, Lu J, Wang S, Du B, Yang X: Chemotherapy plus panitumumab/cetuximab versus chemotherapy plus bevacizumab in wild-type kras/ras metastatic colorectal cancer: A meta-analysis. Expert Rev Anticancer Ther 22(12): 1333-1347, 2022. DOI: 10.1080/14737140.2022.2147512 Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R: Final results from prime: Randomized phase iii study of panitumumab with folfox4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25(7): 1346-1355, 2014. DOI: 10.1093/annonc/mdu141 Boeckx N, Koukakis R, Op de Beeck K, Rolfo C, Van Camp G, Siena S, Tabernero J, Douillard JY, André T, Peeters M: Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: Results from two randomized first-line panitumumab studies. Ann Oncol 28(8): 1862-1868, 2017. DOI: 10.1093/annonc/mdx119 Arnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, Heinemann V, Van Cutsem E, Pignon JP, Tabernero J, Cervantes A, Ciardiello F: Prognostic and predictive value of primary tumour side in patients with ras wild-type metastatic colorectal cancer treated with chemotherapy and egfr directed antibodies in six randomized trials. Ann Oncol 28(8): 1713-1729, 2017. DOI: 10.1093/annonc/mdx175 Chen HH, Ke TW, Huang CW, Jiang JK, Chen CC, Hsieh YY, Teng HW, Lin BW, Liang YH, Su YL, Hsu HC, Kuan FC, Chou YH, Lin J, Lin BR, Chang YY, Wang JY: Taiwan society of colon and rectal surgeons consensus on mcrc treatment. Front Oncol 11(764912, 2021. DOI: 10.3389/fonc.2021.764912 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: Revised recist guideline (version 1.1). Eur J Cancer 45(2): 228-247, 2009. DOI: 10.1016/j.ejca.2008.10.026 Dempke WC, Heinemann V: Ras mutational status is a biomarker for resistance to egfr inhibitors in colorectal carcinoma. Anticancer Res 30(11): 4673-4677, 2010. Jafari M, Laraqui A, Baba W, Benmokhtar S, Zaitouni SE, Ali AA, Bounaim A, Moujahid M, Tanz R, Mahfoud T, Sbitti Y, Annaz HE, Abi R, Tagajdid MR, Kochri SE, Lahlou IA, Hsaini HE, Belayachi L, Benjouad A, Ichou M, En-Nya A, Ennibi K: Prevalence and patterns of mutations in ras/raf/mek/erk/mapk signaling pathway in colorectal cancer in north africa. BMC Cancer 22(1): 1142, 2022. DOI: 10.1186/s12885-022-10235-w Fiala O, Ostasov P, Hosek P, Sorejs O, Liska V, Buchler T, Poprach A, Kucera R, Topolcan O, Sustr J, Sedivcova M, Finek J: The predictive role of primary tumour sidedness in metastatic colorectal cancer treated with targeted agents. Anticancer Res 39(10): 5645-5652, 2019. DOI: 10.21873/anticanres.13761 Wang JX, Wu HL, Zhu M, Zhou R: Role of anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy for metastatic colorectal cancer: An update meta-analysis of randomized clinical trials. Pathol Oncol Res 26(1): 159-166, 2020. DOI: 10.1007/s12253-017-0365-5 Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, Tejpar S: Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 31(30): 3764-3775, 2013. DOI: 10.1200/jco.2012.42.8532 Sánchez-Hidalgo JM, Rodríguez-Ortiz L, Arjona-Sánchez Á, Rufián-Peña S, Casado-Adam Á, Cosano-Álvarez A, Briceño-Delgado J: Colorectal peritoneal metastases: Optimal management review. World J Gastroenterol 25(27): 3484-3502, 2019. DOI: 10.3748/wjg.v25.i27.3484 Grothey A, Fakih M, Tabernero J: Management of braf-mutant metastatic colorectal cancer: A review of treatment options and evidence-based guidelines. Ann Oncol 32(8): 959-967, 2021. DOI: 10.1016/j.annonc.2021.03.206 Wu CC, Wang JH, Lin PC, Liang CA, Huang CY, Lien HC, Chen CY, Chou KJ, Su YC: Tumor sidedness and efficacy of first-line therapy in patients with ras/braf wild-type metastatic colorectal cancer: A network meta-analysis. Crit Rev Oncol Hematol 145(102823, 2020. DOI: 10.1016/j.critrevonc.2019.102823 Bylsma LC, Gillezeau C, Garawin TA, Kelsh MA, Fryzek JP, Sangaré L, Lowe KA: Prevalence of ras and braf mutations in metastatic colorectal cancer patients by tumor sidedness: A systematic review and meta-analysis. Cancer Med 9(3): 1044-1057, 2020. DOI: 10.1002/cam4.2747 Kemeny N: Presurgical chemotherapy in patients being considered for liver resection. Oncologist 12(7): 825-839, 2007. DOI: 10.1634/theoncologist.12-7-825 Modest DP, Denecke T, Pratschke J, Ricard I, Lang H, Bemelmans M, Becker T, Rentsch M, Seehofer D, Bruns CJ, Gebauer B, Modest HI, Held S, Folprecht G, Heinemann V, Neumann UP: Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer-central evaluation of fire-3. Eur J Cancer 88(77-86, 2018. DOI: 10.1016/j.ejca.2017.10.028 Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A: Initial therapy with folfoxiri and bevacizumab for metastatic colorectal cancer. N Engl J Med 371(17): 1609-1618, 2014. DOI: 10.1056/NEJMoa1403108 Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, Köhne CH: Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: The celim randomised phase 2 trial. Lancet Oncol 11(1): 38-47, 2010. DOI: 10.1016/s1470-2045(09)70330-4 Alt M, Truant S, Renaud-Vantroys T, Séquier C, Duhamel A, El Amrany M, Turpin A, Makhloufi S, Pruvot FR, Hebbar M: Bevacizumab associated with chemotherapy for initially non-resectable liver metastases from colorectal cancer: A case-control study. Anticancer Res 36(10): 5551-5555, 2016. DOI: 10.21873/anticanres.11139 Huiskens J, van Gulik TM, van Lienden KP, Engelbrecht MR, Meijer GA, van Grieken NC, Schriek J, Keijser A, Mol L, Molenaar IQ, Verhoef C, de Jong KP, Dejong KH, Kazemier G, Ruers TM, de Wilt JH, van Tinteren H, Punt CJ: Treatment strategies in colorectal cancer patients with initially unresectable liver-only metastases, a study protocol of the randomised phase 3 cairo5 study of the dutch colorectal cancer group (dccg). BMC Cancer 15(365, 2015. DOI: 10.1186/s12885-015-1323-9 Hatano E, Okuno M, Nakamura K, Ishii T, Seo S, Taura K, Yasuchika K, Yazawa T, Zaima M, Kanazawa A, Terajima H, Kaihara S, Adachi Y, Inoue N, Furumoto K, Manaka D, Tokka A, Furuyama H, Doi K, Hirose T, Horimatsu T, Hasegawa S, Matsumoto S, Sakai Y, Uemoto S: Conversion to complete resection with mfolfox6 with bevacizumab or cetuximab based on k-ras status for unresectable colorectal liver metastasis (beck study). J Hepatobiliary Pancreat Sci 22(8): 634-645, 2015. DOI: 10.1002/jhbp.254 Tables Table I. Patient characteristics. Anti-EGFR Anti-VEGF Characteristic (Cet/Pan, n=78) (Bev, n=51) Age, years Median (range) 60 (24-83) 58.6 (29-87) 0.510 Sex, n (%) Male 45 (57.7) 35 (68.6) 0.211 Female 33 (42.3) 16 (31.4) BRAF status, n (%) Wild-type 14 (17.9) 13 (25.5) 0.049 Mutation 5 (6.4) 9 (17.6) Unknown 59 (75.7) 29 (56.9) Wild-type RAS details, n (%) KRAS exon 2, 3 4 (5.1) 2 (3.9) 0.389 KRAS/NRAS exon 2, 3 41 (52.6) 28 (54.9) KRAS/NRAS exon 2, 3, 4 26 (33.3) 12 (23.5) ECOG score, n (%) 0 29 (37.2) 15 (29.4) 0.273 1 42 (53.8) 29 (56.9) 2 7 (9) 7 (13.7) Primary tumor sidedness, n (%) Left 60 (76.5) 33 (70.2) 0.409 Right 18 (23.5) 14 (29.8) Metastatic sites, n (%) Liver 45 (57.7) 21 (41.2) 0.580 Lung 1 (1.3) 7 (13.7) Peritoneum 10 (12.8) 10 (19.6) Distal lymph nodes 2 (2.6) 3 (8.2) ≥2 20 (25.6) 10 (19.6) First-line regimen (chemotherapy backbone), n (%) Oxaliplatin 15 (19.2) 12 (23.5) 0.324 Irinotecan 52 (66.7) 33 (64.7) Oxaliplatin/irinotecan 7 (9) 6 (11.8) 5-FU 4 (5.1) 0 (0) Primary tumor resection, n (%) Yes 59 (75.6) 30 (58.8) 0.011 5-FU: 5-Fluorouracil; Bev: bevacizumab; Cet/Pan: cetuximab or panitumumab; Eastern Cooperative Oncology Group; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor. Table II . Univariate Cox proportional hazard model for patients with wild-type RAS metastatic colorectal cancer. 95% CI Factor HR Lower Upper p -Value Female 1.07 0.66 1.72 0.78 Age ≥65 years 2.0 1.25 3.20 0.004 Oxaliplatin-based regimen 1.3 0.79 2.14 0.29 Right-sided primary tumors 2.93 1.75 4.89 <0.0001 Metastases in ≥2 organs 1.78 1.05 3.00 0.031 VEGF inhibitor as first-line regimen 1.60 1.01 2.55 0.046 CI: Confidence interval; HR: hazard ratio; VEGF: vascular endothelial growth factor. Significant p -values are shown in bold. Table III . Multivariate Cox proportional hazard model for patients with wild-type RAS . Variable HR 95% CI p- Value Lower Upper Female 1.06 0.64 1.77 0.83 Age ≥65 years 1.60 0.96 2.65 0.07 Oxaliplatin-based regimen 1.19 0.70 2.03 0.51 Right-sided primary tumor 2.08 1.17 3.69 0.012 Metastases in ≥2 organs 1.80 1.00 3.25 0.048 VEGF inhibitor as first-line regimen 1.66 1.01 2.73 0.047 CI: Confidence interval; HR: hazard ratio; VEGF: vascular endothelial growth factor. Significant p -values are shown in bold. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3949891","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":281779045,"identity":"e9c5507b-c515-4fc4-8f3c-cc71ba19a94d","order_by":0,"name":"Shih-Wei Chiang","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shih-Wei","middleName":"","lastName":"Chiang","suffix":""},{"id":281779046,"identity":"0fdcdad8-4d7f-4dc6-9cc2-7111fb746271","order_by":1,"name":"Yi-Lin Huang","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi-Lin","middleName":"","lastName":"Huang","suffix":""},{"id":281779047,"identity":"1016f724-66b2-4cbc-acba-2b7ad60e6ae5","order_by":2,"name":"Feng-Fan Chiang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYDACCcYGIGkDZJCoJQ3IYIaKsBHUAiYPk6CFf3Zz4+eCX+cT50f3H/zA8MsmsUG+xwC/JXcONkvP7LuduPHOYWYJxr60xAY2HvxaDCQSG6R5e24bG85IZmNg7DlszMDGu4GQlubfvD3nSNPSJs3z44CcvARQC8OPw3IEtUjcSGyz5m1IljOQSDYGOjJNjo0t/wNeLfwz0h/f5vljxyM/I/Hhhw9/bHj4mY8l4NUCBoxtQBceADIS24iISQj4w8Ag3wBljIJRMApGwShABwDCUEICH5vPFAAAAABJRU5ErkJggg==","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Feng-Fan","middleName":"","lastName":"Chiang","suffix":""},{"id":281779048,"identity":"04c4f81c-58e0-4912-8686-93c9ac2a8083","order_by":3,"name":"Ming-Cheng Chen","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming-Cheng","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-02-12 02:00:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3949891/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3949891/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53255653,"identity":"6704d426-1adf-43b6-a6c1-7b62d470edc6","added_by":"auto","created_at":"2024-03-22 13:29:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54906,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3949891/v1/af2c40df71fc59f28121cd9c.png"},{"id":53255654,"identity":"78f79769-87ac-4213-a39f-a281eb64b658","added_by":"auto","created_at":"2024-03-22 13:29:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":237574,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival curve according to targeted therapy. Bev: Bevacizumab; Cet/Pan: cetuximab or panitumumab; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3949891/v1/fa72b0cc6e91fb95b3f3c57e.png"},{"id":53255652,"identity":"0ebd97ba-ad85-480e-b2b3-69ed67ab8489","added_by":"auto","created_at":"2024-03-22 13:29:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":224879,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival (PFS) curve according to targeted therapy. Bev: Bevacizumab; Cet/Pan: cetuximab or panitumumab; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3949891/v1/4910d09b8258b49d8d3936e6.png"},{"id":53255655,"identity":"f6f4c2c0-9032-401f-a364-6bf10f8fd1d4","added_by":"auto","created_at":"2024-03-22 13:29:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":434147,"visible":true,"origin":"","legend":"\u003cp\u003eOverall (OS) (A) and progression-free (PFS) (B) survival curves in patients with left-sided primary tumor according to targeted therapy. Bev: Bevacizumab; Cet/Pan: cetuximab or panitumumab; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3949891/v1/e33c5c6fc2a78592f6b7faa7.png"},{"id":53255657,"identity":"99ac7851-6d36-46ef-bc4e-f537069c4ea8","added_by":"auto","created_at":"2024-03-22 13:29:18","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":359827,"visible":true,"origin":"","legend":"\u003cp\u003eOverall (OS) (A) and progression-free (PFS) (B) survival curves in patients with right-sided primary tumor according to targeted therapy. Bev: Bevacizumab; Cet/Pan: cetuximab or panitumumab; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3949891/v1/d75f6a00f23329aeb1131619.png"},{"id":53255656,"identity":"f466c364-62ae-4826-a513-95daf323fcb6","added_by":"auto","created_at":"2024-03-22 13:29:18","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1343297,"visible":true,"origin":"","legend":"\u003cp\u003eRates of conversion (A) and resection margins after conversion surgery (B) in patients with liver-limited metastatic colorectal cancer. Bev: Bevacizumab; Cet/Pan: cetuximab or panitumumab; EGFR: epidermal growth factor receptor and VEGF: vascular endothelial growth factor.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-3949891/v1/4dfb501f37611a47548b6982.png"},{"id":57757843,"identity":"f65043c4-39d9-49e8-88a4-a06d897f31b7","added_by":"auto","created_at":"2024-06-05 08:50:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2908957,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3949891/v1/b0eb19f2-ad38-488d-859c-a460ac2b5a41.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of First-line Therapy With Anti-EGFR Versus Anti-VEGF Therapy for WT RAS Metastatic Colorectal Cancer: Real-world Experience from a Single Institute","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn Taiwan, more than 17,000 new colorectal cancer (CRC) cases were recorded in 2019, with an incidence rate of 42.9 per 100,000 and mortality rate of 14.6 per 100,000 (1). The incidence of CRC is increasing, and it has become the most common cancer type in Taiwan. Hence, managing patients with CRC through multiple modalities, including surgery, systemic chemotherapy, target therapy, immunotherapy, and regional radiotherapy, to improve outcomes and survival is crucial. 5-Fluorouracil has been used for inoperable CRC after chemotherapy since 1962 (2), and options for metastatic CRC (mCRC) treatment have become increasingly complex and varied with combinations of 5-fluorouracil, oxaliplatin, irinotecan, and targeted therapies. According to the National Comprehensive Cancer Network guidelines (3), the first-line chemotherapy regimens for mCRC are doublet regimens with 5-fluorouracil plus oxaliplatin or irinotecan and triplet regimens with 5-fluorouracil plus oxaliplatin and irinotecan. Targeted agents used as first-line treatments for mCRC are anti-epidermal growth factor receptor (EGFR) (cetuximab and panitumumab) and anti-vascular endothelial growth factor (VEGF) (bevazicumab).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;The most common Ras proto-oncogene, GTPase (\u003cem\u003eRAS\u003c/em\u003e) gene mutation in mCRC is of the\u0026nbsp;KRAS proto-oncogene, GTPase\u003cem\u003e\u0026nbsp;(KRAS)\u003c/em\u003e (4). Somatic single-nucleotide points in mutation codons 12 and 13 in exon 2 of the \u003cem\u003eKRAS\u003c/em\u003e gene activate the mitogen-activated protein kinase pathway and confer resistance to EGFR inhibitors. This finding is well established by randomized control trials (RCTs). A retrospective analysis from the PRIME trial (5) showed other mutations in the genes of the \u003cem\u003eRAS\u003c/em\u003e family (\u003cem\u003eKRAS\u003c/em\u003e exon 3 and 4 and \u003cem\u003eNRAS\u0026nbsp;\u003c/em\u003e2, 3, and 4) are associated with poor response to EGFR inhibitors. The \u0026lsquo;all \u003cem\u003eRAS\u003c/em\u003e wild-type\u0026rsquo; (WT \u003cem\u003eRAS\u003c/em\u003e) subgroup, \u003cem\u003ei.e.\u003c/em\u003e, those with no mutations in exons 2, 4, and 4 for either \u003cem\u003eKRAS\u003c/em\u003e or \u003cem\u003eNRAS\u003c/em\u003e, is expected to show excellent response to EGFR inhibitors. A meta-analysis showed that EGFR inhibitor therapy is effective against tumors harboring one of the \u003cem\u003eRAS\u0026nbsp;\u003c/em\u003emutations\u0026nbsp;(except \u003cem\u003eKRAS\u003c/em\u003e exon 2) (6). In a study of the \u0026lsquo;super\u0026rsquo; WT, \u003cem\u003ei.e.\u003c/em\u003e, those patients whose genetic findings show all WT \u003cem\u003eRAS\u003c/em\u003e adding WT for B-Raf proto-oncogene serine/threonine kinase (\u003cem\u003eBRAF\u003c/em\u003e) exon 15, the retrospective analysis revealed liver metastases of CRC are more likely to exhibit a super WT (7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Phase III trials, including FIRE-3 (8) and CALGB/SWOG 80405 (9), have established which targeted agent (bevacizumab/cetuximab) is effective for WT \u003cem\u003eRAS\u003c/em\u003e mCRC. The final FIRE-3 results (10) revealed that patients who received cetuximab had better overall survival (OS) than those who received bevacizumab; however, the CALGB/SWOG 80405 trial showed no difference in OS between the two. The phase II PEAK trial (11) compared first-line chemotherapy plus panitumumab with bevacizumab in patients with WT \u003cem\u003eKRAS\u003c/em\u003e exon 2 mCRC and found that the panitumumab group had superior OS compared with the bevacizumab group. In the trial, the EGFR inhibitor significantly prolonged OS compared with inhibition of VEGF (12), but no difference in progression-free survival (PFS) was found between the groups. No decisive results have indicated which first-line treatment is superior, and this is still being debated.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;With regard to primary tumor location, \u003cem\u003epost-hoc\u003c/em\u003e analyses have revealed that patients with left-sided WT \u003cem\u003eRAS\u003c/em\u003e mCRC on first-line chemotherapy plus anti-EGFR have better survival outcomes than those with right-sided tumors (6, 9-10). The PEAK and PRIME (13) trials indicated that right-sided primary tumors are associated with poor prognosis (14). Moreover, benefits to the overall response rate (ORR) and PFS have been observed for patients with left-sided tumors on chemotherapy plus anti-EGFR compared with those with right-sided tumors (15). The National Comprehensive Cancer Network has recommended EGFR inhibitor as a first-line treatment for left-sided mCRC, and our national consensus supports this recommendation after experts\u0026rsquo; discussion (16).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Given the lack of prospective or real-world retrospective studies, whether this treatment strategy can achieve ideal effectiveness remains to be proven. Thus, in this retrospective study, we evaluated the effectiveness of bevacizumab and cetuximab/panitumumab in patients with WT \u003cem\u003eRAS\u003c/em\u003e mCRC using real-world data.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eThis study retrospectively analyzed medical charts and recruited patients with mCRC who satisfied the following inclusion criteria: Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, unresectable or metastatic colorectal adenocarcinoma, at least two courses of the same regimen of cetuximab/panitumumab or bevacizumab plus fluoropyrimidine-based doublet or triplet chemotherapy of oxaliplatin and irinotecan as first-line chemotherapy, a lesion that can be evaluated by Response Evaluation Criteria in Solid Tumors (version 1.1) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), WT \u003cem\u003eRAS\u003c/em\u003e status (for \u003cem\u003eKRAS/NRAS\u003c/em\u003e exons 2, 3, and 4), and enrollment between June 2018 and December 2021. The exclusion criteria were as follows: Two or more active malignancies, no \u003cem\u003eRAS\u003c/em\u003e reports, no first-line treatments (receiving at other institutes), and incomplete medical charts. Written consent was obtained from the patients for the use of their data.\u003c/p\u003e \u003cp\u003e \u003cem\u003eEvaluation and endpoints.\u003c/em\u003e The primary endpoint was OS. We compared patients who received cetuximab/panitumumab and those who received bevacizumab in the full cohort. OS was defined as the time from the start of first-time chemotherapy to death from any cause or censoring at the last follow-up event. The secondary endpoints were ORR and PFS. ORR was defined as the proportion of patients with a partial or complete response to therapy per RECIST 1.1, and PFS was estimated as the time from start of treatment to the date of disease progression or death from any cause. The covariates included age, sex, first-line regimen (oxaliplatin/irinotecan), primary tumor location (right/left), and number of metastases.\u003c/p\u003e \u003cp\u003eWe defined right-sided mCRC as primary tumor originating from the cecum, ascending colon or transverse colon, and left-sided mCRC was defined as the primary tumor originating from the descending colon, sigmoid colon or rectum. Computed tomographic scan (chest, abdomen, and pelvis) supplemented by magnetic resonance imaging and \u003csup\u003e18\u003c/sup\u003eF-fluorodeoxyglucose positron-emission tomography were conducted for imaging. The conversion rate was defined as the proportion of metastasectomy after systemic treatments in the cohort (patients undergoing synchronous/staged operation were not included), and decision-making was made through medical team or multidisciplinary team (MDT) assessments in the combined conference.\u003c/p\u003e \u003cp\u003e \u003cem\u003eStatistical analysis\u003c/em\u003e. Patient baseline characteristics were summarized using descriptive statistics. OS and PFS rates for the full cohort were calculated using the Kaplan\u0026ndash;Meier method. OS rate was compared between patients who received Cet/x panitumumab and those who received bevacizumab by performing multivariate Cox regression analysis on the following covariates: Age (\u0026lt;\u0026thinsp;65/\u0026ge;65 years), sex (male/female), first-line regimen (oxaliplatin-based/irinotecan-based chemotherapy), primary tumor location (right-sided/left-sided), and number of metastases (\u0026lt;\u0026thinsp;2/\u0026ge;2). Hazard ratios (HRs) were calculated using multivariate Cox regression models. All statistical analyses were performed with SPSS version 26.0. (IBM Corp., Armonk, NY, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cem\u003ePatient characteristics\u003c/em\u003e. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the screening process of patients with mCRC in accordance with the selection criteria. A total of 129 patients were enrolled in the study, and their characteristics are shown in \u003cb\u003eTable I\u003c/b\u003e. Seventy-eight patients received EGFR inhibitors, and 51 received VEGF inhibitors as the first regimens. Lacking a routine \u003cem\u003eBRAF\u003c/em\u003e mutation profile, most patients in both groups had unknown \u003cem\u003eBRAF\u003c/em\u003e status. On the basis of the known BRAF results, mutation accounted for a large proportion in both groups possibly because of response considerations by individual clinical physicians. Genetic typing details showed that most patients had WT \u003cem\u003eKRAS/NRAS\u003c/em\u003e exons 2 and 3 in both groups. Primary left-sided tumors were predominant in both groups. The patients who received cetuximab/panitumumab had a higher degree of liver metastasis but less peritoneal involvement than the bevacizumab group. The proportion of patients who had metastasis in more than two organs was higher in the cetuximab/panitumumab group than in the bevacizumab group (25.6% \u003cem\u003evs.\u003c/em\u003e 19.6%). With regard to chemotherapy, most patients received irinotecan-based chemotherapy as the backbone in both groups. The patients who received cetuximab/panitumumab were more likely to have undergone primary tumor resection than the patients in the bevacizumab group (75.6% \u003cem\u003evs.\u003c/em\u003e 58.8%), it showed significant difference (Table I; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011). The median follow-up period was 22.2 months.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eOS and PFS.\u003c/em\u003e Patients who received cetuximab/panitumumab had better OS and PFS than those who received bevacizumab. The median OS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) was significantly better at 33.3 months for patients who received cetuximab/panitumumab compared with 26.1 months for those who received bevacizumab [HR\u0026thinsp;=\u0026thinsp;1.604, 95% confidence interval (CI)\u0026thinsp;=\u0026thinsp;1.008\u0026ndash;2.550; \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.044]. The median PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) was 17.6 months for the cetuximab/panitumumab group and 12 months for the bevacizumab group (HR\u0026thinsp;=\u0026thinsp;1.329, 95% CI\u0026thinsp;=\u0026thinsp;0.9-1.963; \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.15). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e show OS and PFS subclassified by primary tumor sidedness in both groups. In the patients with left-sided tumor (n\u0026thinsp;=\u0026thinsp;93), the cetuximab/panitumumab group had higher OS than the bevacizumab group but the difference did not achieve significance (OS: 36.6 \u003cem\u003evs.\u003c/em\u003e 28.9 months, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.061; PFS: 17.2 \u003cem\u003evs.\u003c/em\u003e 12.1 months, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.371). In the patients with right-sided tumor (n\u0026thinsp;=\u0026thinsp;32), no benefits to survival were observed in both groups (OS: 18 \u003cem\u003evs.\u003c/em\u003e 14 months, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.262; PFS: 14.9 \u003cem\u003evs.\u003c/em\u003e 10 months, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.148).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eLiver-limited metastasis mCRC conversion rates and resection margin assessment.\u003c/em\u003e Subgroup analysis for those with liver-only metastasis mCRC was evaluated. A nonsignificant difference in metastatic conversion rate was found between the cetuximab/panitumumab and bevacizumab groups (Fig.\u0026nbsp;6A) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.403). The likelihood of conversion for those with liver-only metastasis was lower for the bevacizumab group (n\u0026thinsp;=\u0026thinsp;5/21, 23.8%) than for the cetuximab/panitumumab group (n\u0026thinsp;=\u0026thinsp;14/41, 34.1%). The R0 resection rate after conversion surgery (Fig.\u0026nbsp;6B) was higher in the cetuximab/panitumumab group (n\u0026thinsp;=\u0026thinsp;10/14, 71.4%) than in the bevacizumab group (n\u0026thinsp;=\u0026thinsp;3/5, 60%).\u003c/p\u003e \u003cp\u003e \u003cem\u003eCox proportional hazard models for patients with WT RAS.\u003c/em\u003e The prognostic factors for OS from univariate analyses are presented in \u003cb\u003eTable II\u003c/b\u003e. The HRs for OS were age\u0026thinsp;\u0026ge;\u0026thinsp;65 years (HR\u0026thinsp;=\u0026thinsp;2.0), right-sided primary tumor (HR\u0026thinsp;=\u0026thinsp;2.93), metastases\u0026thinsp;\u0026ge;\u0026thinsp;2 organs (HR\u0026thinsp;=\u0026thinsp;1.78), and anti-VEGF for first-line regimen (HR\u0026thinsp;=\u0026thinsp;1.60). In the multivariate analysis of prognostic factors for OS (\u003cb\u003eTable III\u003c/b\u003e), right-sided primary tumor was the strongest factor associated with poor prognosis (HR\u0026thinsp;=\u0026thinsp;2.08, 95% CI\u0026thinsp;=\u0026thinsp;1.17\u0026ndash;3.69). metastases\u0026thinsp;\u0026ge;\u0026thinsp;2 organs (HR\u0026thinsp;=\u0026thinsp;1.80), and anti-VEGF for first-line regimen (HR\u0026thinsp;=\u0026thinsp;1.66) were associated with impaired OS, and significant difference was noted.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eUnlike multicenter studies, this single-center study performed retrospective comparisons of the efficacy of chemo-targeted agents in WT \u003cem\u003eRAS\u003c/em\u003e mCRC. \u003cem\u003eKRAS\u003c/em\u003e mutations predict poor prognosis and response from cetuxamab and panitumumab therapies in CRC, hence we ruled out this as a prognostic factor and selected patients with WT \u003cem\u003eRAS\u003c/em\u003e CRC as our candidates (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In preliminary pathological gene profiles, only 38 patients (29.5%) had all WT \u003cem\u003eRAS\u003c/em\u003e status, and the majority of patients (69, 53.5%) had WT \u003cem\u003eKRAS\u003c/em\u003e/\u003cem\u003eNRAS\u003c/em\u003e exons 2 and 3. Low prevalence of \u003cem\u003eKRAS\u003c/em\u003e or \u003cem\u003eNRAS\u003c/em\u003e exon 4 mutation was found in a retrospective cohort study in North Africa (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), however, potential \u003cem\u003eKRAS\u003c/em\u003e or \u003cem\u003eNRAS\u003c/em\u003e exon 4 mutations were not assessed comprehensively in our database.\u003c/p\u003e \u003cp\u003eIn our real-world data, therapy with cetuximab/panitumumab led to better OS and PFS than therapy with bevacizumab, and the difference in OS even reached significance. Notably, OS and PFS were better in patients with left-sided primary tumors and on cetuximab/panitumumab than those receiving bevacizumab, but no significant difference was found. In the patients with right-sided primary tumors, our data showed better survival outcomes in those receiving cetuximab/panitumumab as the first-line agent, but no statistical difference was found. Primary tumor sidedness is a prognostic factor in patients with WT \u003cem\u003eRAS\u003c/em\u003e mCRC, and right-sided primary tumors was associated with poor prognosis. A cohort study with 178 patients with mCRC showed similar results in that superior OS and PFS were observed when anti-EGFR was added to therapy for patients with for left-sided primary tumors (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA meta-analysis of RCTs with large sample sizes (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) showed that the ORR and OS (overall response) after anti-EGFR therapy were superior to those after anti-VEGF therapy in patients with WT \u003cem\u003eRA\u003c/em\u003eS mCRC (odds ratio\u0026thinsp;=\u0026thinsp;0.79, 95% CI\u0026thinsp;=\u0026thinsp;0.68\u0026ndash;0.92, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.002) but not in patients with WT \u003cem\u003eKRAS\u003c/em\u003e mCRC (odds ratio\u0026thinsp;=\u0026thinsp;0.81, 95% CI\u0026thinsp;=\u0026thinsp;0.64\u0026ndash;1.01, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.06). However, the exact mechanism has not been clarified yet. Early tumor shrinkage may be beneficial when anti-EGFR is added as first-line chemotherapy for WT \u003cem\u003eRAS\u003c/em\u003e mCRC (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Our study\u0026rsquo;s results are compatible with the abovementioned results. The reasons for the difference in PFS may be as follows: there was a relatively small number of patients in each group; there was a high rate of peritoneal metastasis in the bevacizumab group, which implied poor treatment response and prognosis (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e); and a higher number of patients in the bevacizumab group (n\u0026thinsp;=\u0026thinsp;9) compared with the cetuximab/panitumumab group (n\u0026thinsp;=\u0026thinsp;5) regardless of the incomplete mutation data (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe poor prognoses of patients with mCRC are due to right-sided primary tumor. Wu \u003cem\u003eet al.\u003c/em\u003e (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) recently performed a network meta-analysis of large RCTs and found that in patients with WT \u003cem\u003eRAS\u003c/em\u003e disease, anti-EGFR is the most effective treatment for left-sided, and bevacizumab is effective for right-sided tumors. Our real-world data showed a similar effect, that is, using cetuximab/panitumumab provided nearly 4 months of survival benefit compared with using bevacizumab for patients with left-sided tumors, but no benefits to survival were observed when bevacizumab was used for patients with right-sided tumors. A few patients with right-sided tumors (n\u0026thinsp;=\u0026thinsp;32) were present in the cohort, and the prevalence of \u003cem\u003eRAS\u003c/em\u003e and \u003cem\u003eBRAF\u003c/em\u003e mutations may have a prognostic impact. Our study ruled out \u003cem\u003eRAS\u003c/em\u003e mutation possibility at initial enrollment. However, a previous review (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) revealed patients with right-sided tumors had significantly higher prevalence of \u003cem\u003eBRAF\u003c/em\u003e mutations than patients with left-sided tumors (16.3% \u003cem\u003evs.\u003c/em\u003e 4.3%). Hence, we applied the current consensus of using anti-EGFR for patients with WT \u003cem\u003eRAS/BRAF\u003c/em\u003e and left-sided tumor. With regard to patients with right-sided tumors, further discussions through MDT conference should be performed case by case.\u003c/p\u003e \u003cp\u003eIn the early 2000s, only 10\u0026ndash;25% of patients with CRC liver metastasis underwent liver metastasectomy according to the extent of their disease. Owing to inadequate liver remnant, hepatic surgery is unsuitable for many patients (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Surgical intervention, including primary resection, secondary resection, and even third resection after systemic treatment, plays an important role in patients with mCRC. In the FIRE-3 central review analysis, patients with resectable disease and the best response who underwent resection had OS superior to those who did not undergo resection (51.3 \u003cem\u003evs.\u003c/em\u003e 30.8 months) (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Another study reported that 22% of patients underwent surgery after treatment, which is higher than the percentage for other clinical trials (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Meanwhile, a small trial with liver-limited mCRC (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) showed similar rates of resectability or conversion. The liver-limited mCRC conversion rate in our study was 34.1% in the cetuximab/panitumumab group and 23.8% in the bevacizumab group, and these values are similar to those of the above-mentioned trials. In a total of 82 patients with non-resectable liver metastases from CRC, no significant benefits on disease-free survival were shown for bevacizumab when added to chemotherapy (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). No comparison of conversion rate with additional anti-EGFR or anti-VEGF after first-line systemic treatment is available for WT \u003cem\u003eRAS\u003c/em\u003e mCRC (\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Further studies or trials should be performed.\u003c/p\u003e \u003cp\u003e\u003cem\u003eStudy limitations.\u003c/em\u003e Firstly, a single-center population with a certain number of patients was used, but this limitation is unlikely to have influenced the results. Panitumumab was officially included in the Taiwanese national health payment guideline in June 2018 because of the US National Institutes of Health policy. Secondly, survival benefits that can be obtained from different targeted agents for WT \u003cem\u003eRAS\u003c/em\u003e mCRC cannot be statistically compared because of the small number of patients involved. Further research is necessary to elucidate the association. Thirdly, perfectly matching cases for propensity score-matching analysis were not obtained. Thus, the results should be managed and interpreted with caution. Fourthly, our Pathological Department has started to use complete \u003cem\u003eKRAS/NRAS\u003c/em\u003e panels for tissue genetic typing in recent years, and thus some patients had only \u003cem\u003eKRAS\u003c/em\u003e exon 2 and 3 data or the deficiency mutation profile of the \u003cem\u003eKRAS/NRAS\u003c/em\u003e exon 4.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this ever-changing world, researchers have devoted considerable effort to creating enhanced chemotherapeutic regimens, improving patient selection, and performing MDT discussions to achieve the best outcomes possible. Treatment guidelines have been established through rigorous RCTs and clinical trials. By using real-world data, we present the advantages of using first-line chemotherapy with anti-EGFR over using anti-VEGF plus chemotherapy with respect to OS and PFS in patients with WT \u003cem\u003eRAS\u003c/em\u003e mCRC. Our results showed that adopting anti-EGFR treatment for patients with left-sided tumors enhances their survival. Surgery still plays an important role in patients with mCRC and on systemic treatments. This work emphasizes treatment effects on patients using anti-EGFR as their first-line regimen. In view of the limited number of patients, methods for overcoming limitations are needed, and the results of this study should be interpreted with caution.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll Authors declare they have no competing interests in regard to this work.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShih-Wei Chiang\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eYi-Lin Huang\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eand\u0026nbsp;Feng-Fan Chiang\u0026nbsp;were responsible for the study design.\u0026nbsp;Shih-Wei Chiang\u0026nbsp;collected and analyzed the data.\u0026nbsp;Feng-Fan Chiang and\u0026nbsp;Ming-Cheng Chen interpreted the data. Shih-Wei Chiang\u0026nbsp;wrote the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHealth Promotion Administration, Ministry of Health and Welfare. (2020, June19) 2019 Health Promotion Administration Annual Report. Retrieved March, 1, 2023 from https://www.hpa.gov.tw/EngPages/Detail.aspx?nodeid=1070\u0026amp;pid=12811.\u003c/li\u003e\n\u003cli\u003eGs S, Ww B: 5-fluorouracil in the treatment of inoperable carcinoma of the colon and rectum. Cancer chemotherapy reports 20(97-101, 1962. \u003c/li\u003e\n\u003cli\u003eBenson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA: Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 19(3): 329-359, 2021. DOI: 10.6004/jnccn.2021.0012\u003c/li\u003e\n\u003cli\u003eDahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA: Systematic review: Anti-epidermal growth factor receptor treatment effect modification by kras mutations in advanced colorectal cancer. Ann Intern Med 154(1): 37-49, 2011. DOI: 10.7326/0003-4819-154-1-201101040-00006\u003c/li\u003e\n\u003cli\u003eDouillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Koc\u0026aacute;kova I, Ruff P, Błasińska-Morawiec M, \u0026Scaron;makal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD: Panitumumab-folfox4 treatment and ras mutations in colorectal cancer. N Engl J Med 369(11): 1023-1034, 2013. DOI: 10.1056/NEJMoa1305275\u003c/li\u003e\n\u003cli\u003eSorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS: Extended ras mutations and anti-egfr monoclonal antibody survival benefit in metastatic colorectal cancer: A meta-analysis of randomized, controlled trials. Ann Oncol 26(1): 13-21, 2015. DOI: 10.1093/annonc/mdu378\u003c/li\u003e\n\u003cli\u003eAllard MA, Saffroy R, de la Maisonneuve PB, Ricca L, Bosselut N, Hamelin J, Lecorche E, Bejarano MA, Innominato P, Sebagh M, Adam R, Mor\u0026egrave;re JF, Lemoine A: Colorectal liver metastases are more often super wild type. Toward treatment based on metastatic site genotyping? Target Oncol 10(3): 415-421, 2015. DOI: 10.1007/s11523-014-0346-5 \u003c/li\u003e\n\u003cli\u003eHeinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenm\u0026uuml;ller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, M\u0026uuml;ller S, Link H, Niederle N, Rost A, H\u0026ouml;ffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S: Folfiri plus cetuximab versus folfiri plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (fire-3): A randomised, open-label, phase 3 trial. Lancet Oncol 15(10): 1065-1075, 2014. DOI: 10.1016/s1470-2045(14)70330-4\u003c/li\u003e\n\u003cli\u003eVenook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O\u0026apos;Neil BH, Atkins JN, Berry S, Polite BN, O\u0026apos;Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB, 3rd, Mulkerin DL, Mayer RJ, Blanke C: Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with kras wild-type advanced or metastatic colorectal cancer: A randomized clinical trial. Jama 317(23): 2392-2401, 2017. DOI: 10.1001/jama.2017.7105\u003c/li\u003e\n\u003cli\u003eHeinemann V, von Weikersthal LF, Decker T, Kiani A, Kaiser F, Al-Batran SE, Heintges T, Lerchenm\u0026uuml;ller C, Kahl C, Seipelt G, Kullmann F, Moehler M, Scheithauer W, Held S, Miller-Phillips L, Modest DP, Jung A, Kirchner T, Stintzing S: Folfiri plus cetuximab or bevacizumab for advanced colorectal cancer: Final survival and per-protocol analysis of fire-3, a randomised clinical trial. Br J Cancer 124(3): 587-594, 2021. DOI: 10.1038/s41416-020-01140-9\u003c/li\u003e\n\u003cli\u003eSchwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY: Peak: A randomized, multicenter phase ii study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mfolfox6) or bevacizumab plus mfolfox6 in patients with previously untreated, unresectable, wild-type kras exon 2 metastatic colorectal cancer. J Clin Oncol 32(21): 2240-2247, 2014. DOI: 10.1200/jco.2013.53.2473\u003c/li\u003e\n\u003cli\u003eZhang C, Liu L, Lv Y, Li J, Cao C, Lu J, Wang S, Du B, Yang X: Chemotherapy plus panitumumab/cetuximab versus chemotherapy plus bevacizumab in wild-type kras/ras metastatic colorectal cancer: A meta-analysis. Expert Rev Anticancer Ther 22(12): 1333-1347, 2022. DOI: 10.1080/14737140.2022.2147512\u003c/li\u003e\n\u003cli\u003eDouillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Koc\u0026aacute;kova I, Ruff P, Błasińska-Morawiec M, \u0026Scaron;makal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R: Final results from prime: Randomized phase iii study of panitumumab with folfox4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25(7): 1346-1355, 2014. DOI: 10.1093/annonc/mdu141\u003c/li\u003e\n\u003cli\u003eBoeckx N, Koukakis R, Op de Beeck K, Rolfo C, Van Camp G, Siena S, Tabernero J, Douillard JY, Andr\u0026eacute; T, Peeters M: Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: Results from two randomized first-line panitumumab studies. Ann Oncol 28(8): 1862-1868, 2017. DOI: 10.1093/annonc/mdx119\u003c/li\u003e\n\u003cli\u003eArnold D, Lueza B, Douillard JY, Peeters M, Lenz HJ, Venook A, Heinemann V, Van Cutsem E, Pignon JP, Tabernero J, Cervantes A, Ciardiello F: Prognostic and predictive value of primary tumour side in patients with ras wild-type metastatic colorectal cancer treated with chemotherapy and egfr directed antibodies in six randomized trials. Ann Oncol 28(8): 1713-1729, 2017. DOI: 10.1093/annonc/mdx175\u003c/li\u003e\n\u003cli\u003eChen HH, Ke TW, Huang CW, Jiang JK, Chen CC, Hsieh YY, Teng HW, Lin BW, Liang YH, Su YL, Hsu HC, Kuan FC, Chou YH, Lin J, Lin BR, Chang YY, Wang JY: Taiwan society of colon and rectal surgeons consensus on mcrc treatment. Front Oncol 11(764912, 2021. DOI: 10.3389/fonc.2021.764912\u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: Revised recist guideline (version 1.1). Eur J Cancer 45(2): 228-247, 2009. DOI: 10.1016/j.ejca.2008.10.026\u003c/li\u003e\n\u003cli\u003eDempke WC, Heinemann V: Ras mutational status is a biomarker for resistance to egfr inhibitors in colorectal carcinoma. Anticancer Res 30(11): 4673-4677, 2010. \u003c/li\u003e\n\u003cli\u003eJafari M, Laraqui A, Baba W, Benmokhtar S, Zaitouni SE, Ali AA, Bounaim A, Moujahid M, Tanz R, Mahfoud T, Sbitti Y, Annaz HE, Abi R, Tagajdid MR, Kochri SE, Lahlou IA, Hsaini HE, Belayachi L, Benjouad A, Ichou M, En-Nya A, Ennibi K: Prevalence and patterns of mutations in ras/raf/mek/erk/mapk signaling pathway in colorectal cancer in north africa. BMC Cancer 22(1): 1142, 2022. DOI: 10.1186/s12885-022-10235-w\u003c/li\u003e\n\u003cli\u003eFiala O, Ostasov P, Hosek P, Sorejs O, Liska V, Buchler T, Poprach A, Kucera R, Topolcan O, Sustr J, Sedivcova M, Finek J: The predictive role of primary tumour sidedness in metastatic colorectal cancer treated with targeted agents. Anticancer Res 39(10): 5645-5652, 2019. DOI: 10.21873/anticanres.13761\u003c/li\u003e\n\u003cli\u003eWang JX, Wu HL, Zhu M, Zhou R: Role of anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy for metastatic colorectal cancer: An update meta-analysis of randomized clinical trials. Pathol Oncol Res 26(1): 159-166, 2020. DOI: 10.1007/s12253-017-0365-5\u003c/li\u003e\n\u003cli\u003ePiessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, Tejpar S: Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 31(30): 3764-3775, 2013. DOI: 10.1200/jco.2012.42.8532\u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez-Hidalgo JM, Rodr\u0026iacute;guez-Ortiz L, Arjona-S\u0026aacute;nchez \u0026Aacute;, Rufi\u0026aacute;n-Pe\u0026ntilde;a S, Casado-Adam \u0026Aacute;, Cosano-\u0026Aacute;lvarez A, Brice\u0026ntilde;o-Delgado J: Colorectal peritoneal metastases: Optimal management review. World J Gastroenterol 25(27): 3484-3502, 2019. DOI: 10.3748/wjg.v25.i27.3484\u003c/li\u003e\n\u003cli\u003eGrothey A, Fakih M, Tabernero J: Management of braf-mutant metastatic colorectal cancer: A review of treatment options and evidence-based guidelines. Ann Oncol 32(8): 959-967, 2021. DOI: 10.1016/j.annonc.2021.03.206\u003c/li\u003e\n\u003cli\u003eWu CC, Wang JH, Lin PC, Liang CA, Huang CY, Lien HC, Chen CY, Chou KJ, Su YC: Tumor sidedness and efficacy of first-line therapy in patients with ras/braf wild-type metastatic colorectal cancer: A network meta-analysis. Crit Rev Oncol Hematol 145(102823, 2020. DOI: 10.1016/j.critrevonc.2019.102823\u003c/li\u003e\n\u003cli\u003eBylsma LC, Gillezeau C, Garawin TA, Kelsh MA, Fryzek JP, Sangar\u0026eacute; L, Lowe KA: Prevalence of ras and braf mutations in metastatic colorectal cancer patients by tumor sidedness: A systematic review and meta-analysis. Cancer Med 9(3): 1044-1057, 2020. DOI: 10.1002/cam4.2747\u003c/li\u003e\n\u003cli\u003eKemeny N: Presurgical chemotherapy in patients being considered for liver resection. Oncologist 12(7): 825-839, 2007. DOI: 10.1634/theoncologist.12-7-825\u003c/li\u003e\n\u003cli\u003eModest DP, Denecke T, Pratschke J, Ricard I, Lang H, Bemelmans M, Becker T, Rentsch M, Seehofer D, Bruns CJ, Gebauer B, Modest HI, Held S, Folprecht G, Heinemann V, Neumann UP: Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer-central evaluation of fire-3. Eur J Cancer 88(77-86, 2018. DOI: 10.1016/j.ejca.2017.10.028\u003c/li\u003e\n\u003cli\u003eLoupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A: Initial therapy with folfoxiri and bevacizumab for metastatic colorectal cancer. N Engl J Med 371(17): 1609-1618, 2014. DOI: 10.1056/NEJMoa1403108\u003c/li\u003e\n\u003cli\u003eFolprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, K\u0026ouml;hne CH: Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: The celim randomised phase 2 trial. Lancet Oncol 11(1): 38-47, 2010. DOI: 10.1016/s1470-2045(09)70330-4\u003c/li\u003e\n\u003cli\u003eAlt M, Truant S, Renaud-Vantroys T, S\u0026eacute;quier C, Duhamel A, El Amrany M, Turpin A, Makhloufi S, Pruvot FR, Hebbar M: Bevacizumab associated with chemotherapy for initially non-resectable liver metastases from colorectal cancer: A case-control study. Anticancer Res 36(10): 5551-5555, 2016. DOI: 10.21873/anticanres.11139\u003c/li\u003e\n\u003cli\u003eHuiskens J, van Gulik TM, van Lienden KP, Engelbrecht MR, Meijer GA, van Grieken NC, Schriek J, Keijser A, Mol L, Molenaar IQ, Verhoef C, de Jong KP, Dejong KH, Kazemier G, Ruers TM, de Wilt JH, van Tinteren H, Punt CJ: Treatment strategies in colorectal cancer patients with initially unresectable liver-only metastases, a study protocol of the randomised phase 3 cairo5 study of the dutch colorectal cancer group (dccg). BMC Cancer 15(365, 2015. DOI: 10.1186/s12885-015-1323-9\u003c/li\u003e\n\u003cli\u003eHatano E, Okuno M, Nakamura K, Ishii T, Seo S, Taura K, Yasuchika K, Yazawa T, Zaima M, Kanazawa A, Terajima H, Kaihara S, Adachi Y, Inoue N, Furumoto K, Manaka D, Tokka A, Furuyama H, Doi K, Hirose T, Horimatsu T, Hasegawa S, Matsumoto S, Sakai Y, Uemoto S: Conversion to complete resection with mfolfox6 with bevacizumab or cetuximab based on k-ras status for unresectable colorectal liver metastasis (beck study). J Hepatobiliary Pancreat Sci 22(8): 634-645, 2015. DOI: 10.1002/jhbp.254\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable I.\u0026nbsp;\u003c/strong\u003ePatient characteristics.\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003eAnti-EGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003eAnti-VEGF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e(Cet/Pan, n=78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e(Bev, n=51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e60 (24-83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e58.6 (29-87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.510\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e45 (57.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e35 (68.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.211\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e33 (42.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e16 (31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eWild-type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e14 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e13 (25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eMutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e5 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e9 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e59 (75.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e29 (56.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003eWild-type \u003cem\u003eRAS\u003c/em\u003e details, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eKRAS exon 2, 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e4 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e2 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.389\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eKRAS/NRAS exon 2, 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e41 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e28 (54.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eKRAS/NRAS exon 2, 3, 4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e26 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e12 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003eECOG score, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e29 (37.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e15 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.273\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e42 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e29 (56.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e7 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e7 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003ePrimary tumor sidedness, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e60 (76.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e33 (70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.409\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e18 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e14 (29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003eMetastatic sites, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e45 (57.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e21 (41.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.580\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e7 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003ePeritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e10 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e10 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eDistal lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e2 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e3 (8.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e20 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e10 (19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003eFirst-line regimen (chemotherapy backbone), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e15 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e12 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.324\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eIrinotecan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e52 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e33 (64.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eOxaliplatin/irinotecan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e7 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e6 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003e5-FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e4 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.2020202020202%\" valign=\"top\"\u003e\n \u003cp\u003ePrimary tumor resection, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.282828282828284%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e59 (75.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e30 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.171717171717173%\" valign=\"top\"\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e5-FU: 5-Fluorouracil; Bev: bevacizumab; Cet/Pan: cetuximab or panitumumab; Eastern Cooperative Oncology Group; EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable II\u003c/strong\u003e. Univariate Cox proportional hazard model for patients with wild-type \u003cem\u003eRAS\u003c/em\u003e metastatic colorectal cancer.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"63.91752577319588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.49484536082474%\" colspan=\"2\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"63.91752577319588%\"\u003e\n \u003cp\u003eFactor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003eLower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003eUpper\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"63.91752577319588%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"63.91752577319588%\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u0026ge;65 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e3.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.91752577319588%\" colspan=\"2\"\u003e\n \u003cp\u003eOxaliplatin-based regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e2.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.91752577319588%\" colspan=\"2\"\u003e\n \u003cp\u003eRight-sided primary tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e2.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e4.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.91752577319588%\" colspan=\"2\"\u003e\n \u003cp\u003eMetastases in\u0026nbsp;\u0026ge;2 organs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.031\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"63.91752577319588%\" colspan=\"2\"\u003e\n \u003cp\u003eVEGF inhibitor as first-line regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\"\u003e\n \u003cp\u003e2.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.046\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.14124293785310735%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"62.570621468926554%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.474576271186441%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.474576271186441%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.474576271186441%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.864406779661017%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI: Confidence interval; HR: hazard ratio; VEGF: vascular endothelial growth factor. Significant \u003cem\u003ep\u003c/em\u003e-values are shown in bold.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable III\u003c/strong\u003e. Multivariate Cox proportional hazard model for patients with\u0026nbsp;wild-type \u003cem\u003eRAS\u003c/em\u003e.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"648\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.617283950617285%\" rowspan=\"2\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.691358024691358%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cem\u003ep-\u003c/em\u003eValue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"bottom\"\u003e\n \u003cp\u003eLower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"bottom\"\u003e\n \u003cp\u003eUpper\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.617283950617285%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.617283950617285%\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u0026ge;65 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e2.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.617283950617285%\"\u003e\n \u003cp\u003eOxaliplatin-based regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e2.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.617283950617285%\"\u003e\n \u003cp\u003eRight-sided primary tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e2.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e3.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.617283950617285%\"\u003e\n \u003cp\u003eMetastases in\u0026nbsp;\u0026ge;2 organs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e3.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.048\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.617283950617285%\"\u003e\n \u003cp\u003eVEGF inhibitor as first-line regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e2.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.345679012345679%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.047\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI: Confidence interval; HR: hazard ratio; VEGF: vascular endothelial growth factor. Significant \u003cem\u003ep\u003c/em\u003e-values are shown in bold.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Metastatic colorectal cancer, RAS, cetuximab, panitumumab, bevacizumab","lastPublishedDoi":"10.21203/rs.3.rs-3949891/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3949891/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground/Aim:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTop prospective clinical trials comparing anti-epidermal growth factor receptor (EGFR) therapy and anti-vascular endothelial growth factor (VEGF) therapy plus chemotherapy for wild-type Ras proto-oncogene, GTPase (WT \u003cem\u003eRAS\u003c/em\u003e) metastatic colorectal cancer (mCRC) have yielded different outcomes, and real-world data are lacking. This study established real-world experiences and identified challenges in treating patients with mCRC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and Methods\u003c/strong\u003e: This retrospective study identified first-line regimens for patients with mCRC on anti-EGFR or anti-VEGF therapy plus chemotherapy. The effects on overall survival (OS) were estimated; secondary endpoints were progression-free survival (PFS). OS in the two groups was compared on the basis of sex, age, primary tumor site, oxaliplatin-based chemotherapy, and number of organs with metastases through Cox multivariate regression analysis. \u003cstrong\u003eResults\u003c/strong\u003e: A total of 129 patients diagnosed with WT \u003cem\u003eRAS\u003c/em\u003e mCRC from June 1, 2018, to December 31, 2021, were included. The median OS was 33.3 months for the anti-EGFR group (n = 78) and 26.1 months for the anti-VEGF group (n = 51; 95% confidence interval = 1.008–2.550; \u003cem\u003ep =\u003c/em\u003e 0.044). PFS was 17.6 and 12 months, respectively (95% confidence interval = 0.9-1.963; \u003cem\u003ep =\u003c/em\u003e 0.15). Multivariate Cox regression models revealed good OS for patients with WT \u003cem\u003eRAS\u003c/em\u003e and left-sided primary tumor. The liver-only metastasis conversion rate after systemic chemotherapy was higher in the anti-EGFR group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: High survival rates can be achieved when anti-EGFR is used in patients with WT \u003cem\u003eRAS\u003c/em\u003e mCRC. Surgery still plays an important role in patients with mCRC and on systemic treatments.\u003c/p\u003e","manuscriptTitle":"Efficacy of First-line Therapy With Anti-EGFR Versus Anti-VEGF Therapy for WT RAS Metastatic Colorectal Cancer: Real-world Experience from a Single Institute","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-22 13:29:13","doi":"10.21203/rs.3.rs-3949891/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d728d9e-f6fa-4c5f-a3b6-fa8d6ccbb65f","owner":[],"postedDate":"March 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-05T08:42:38+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-22 13:29:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3949891","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3949891","identity":"rs-3949891","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}