Tailoring treatment strategy for stage IV colorectal cancer: assessing the impact of lung metastasis on multi-organ management

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However, surgical strategy for multiple organ metastases (MOM) is complicated and chemotherapy is often prioritized over surgical resection. This study analyzed the clinicopathological features of stage IV CRC with MOM to identify strategies for improving prognosis. Methods Among 281 stage IV CRC patients who were treated at our hospital from 2008 to 2022, 89 patients with MOM were included. Results The number of metastatic organs was 2 in 60 (67%) patients and 3 or more in 29 (33%). The most common metastatic site was liver (n=76, 85%), followed by lung (n=54, 61%), peritoneum (n=37, 42%), distant lymph node (n=31, 35%). Thirteen (15%) patients underwent curative-intended resection during the median follow-up of 52.8 months. Overall survival for patients with lung metastasis had significantly better than that for patients without (median 2.23 vs. 1.37 years, P = 0.007). In 49 patients with both liver and lung metastases, the overall survival rates at 3 years were 100% in 8 patients who underwent resections of the both and 64.8% in 9 patients who underwent resection of liver alone, which was significantly higher than 5.1% in 32 patients who received chemotherapy alone (P < 0.001 and P = 0.001, respectively). Conclusion In patients with MOM, lung metastasis was associated with a favorable survival probability even when being left in situ. This finding suggests that survival benefit of aggressive resection would depend on the metastatic site. Colorectal cancer Stage IV Multiple organ metastases Lung metastasis Surgical indications Figures Figure 1 Figure 2 Figure 3 Introduction Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide [ 1 ]. Approximately 17–23% of CRC patients are diagnosed with stage IV disease at initial presentation [ 2 , 3 ]. Previously, patients with stage IV CRC had a median survival of only 10 months around 1990s [ 4 ]. However, subsequent advances in surgical techniques and chemotherapy have significantly prolonged this poor outcome in stage IV disease [ 5 – 7 ]. In particular, never-quit surgical resection plays a vital role in improving the prognosis, and complete resection of both primary tumor and distant metastases has carried a reported overall survival (OS) rate of 38–58% at 5 years even in stage IV disease [ 8 – 11 ]. Nonetheless, the long-term survival remains unsatisfactory, provided stage IV patients have multiple organ metastases (MOM) [ 12 , 13 ]. Luo et al. analyzed and reported that prognosis deteriorated with an increasing number of metastatic organs [ 13 ]. MOM is a common clinical condition that accounts for 32–50% of stage IV CRC [ 14 , 15 ], therefore, advance in treatment for MOM presents a significant challenge in improving prognosis for CRC. Regarding the impact of surgical resection on stage IV CRC with MOM, Leung et al. reported the OS rates 28% at 5 years for complete resection and concluded that complete resection increased survival probability in selected patients [ 16 ]. Following several studies also documented the benefits of surgical resection [ 17 – 19 ], which now serves a key strategy even in stage IV, MOM disease. In clinical practice, however, chemotherapy is often prioritized over surgical resection due to the disease or therapeutic complexity of stage IV CRC with MOM. Additionally, postoperative immune suppression could promote cancer metastasis and recurrence, which could result in the reluctance among surgeons to proceed with surgery[ 20 ]. Recently, several studies have explored integrating treatment strategies of resection and chemotherapy in the setting of MOM. Mise et al. reported that liver resection without resection of lung metastases resulted in significantly better prognosis compared to chemotherapy alone in patients with stage IV CRC with simultaneous technically resectable liver and unresectable lung metastases (3-year OS: 42.9% vs. 14.1%, P < 0.01). This suggests a potential benefit of selective surgical resection [ 21 ]. Therefore, flexible treatment strategies, which include tumor clearance of a specific metastatic foci, need further exploration. However, the clinicopathogenesis of stage IV CRC with MOM remains poorly understood. In this study, we hypothesized that lung metastasis would have an amenable nature to chemotherapy among the whole metastatic sites, and analyzed the clinicopathological features of stage IV CRC with MOM, focusing on lung metastasis. Patients and Methods Design This is a single-center retrospective clinical cohort study and has been approved by Nagoya University Hospital Institutional Review Board (approval number: #2021 − 0519). Patients This study included patients with stage IV CRC with synchronous MOM who were treated at Nagoya University Hospital between January 2008 and December 2022. All patients had histologically confirmed colorectal adenocarcinoma, diagnosed with endoscopic or surgical biopsy. Metastatic lesions were identified using computed tomography, magnetic resonance imaging, or positron emission tomography-computed tomography. Patients who underwent only palliative surgery, who received initial treatment at another hospital, or who continued treatment elsewhere after undergoing only palliative surgery at our hospital were excluded. Data Collection Collected data included age, gender, performance status, primary tumor location (right-sided colon from the cecum to the transvers colon, and left-sided colon from the descending colon to the rectum), histological type, RAS and BRAF status, preoperative carcinoembryonic antigen (CEA), location and number of metastatic sites, liver metastatic classification[ 22 ] resection of each metastatic site, achievement of curative-intended resection, and OS. Histological grades were categorized as differentiated histological grade (well or moderately differentiated adenocarcinoma) and undifferentiated histological grade (poorly differentiated or mucinous adenocarcinoma, or signet ring cell carcinoma). Metastatic sites included liver, lung, peritoneum, distant lymph node, and others (e.g., brain, bone, ovary, spleen, pancreas, and adrenal gland). Curative-intended resection was defined as R0 or R1 resection of both primary and metastatic tumor. Statistical Analysis Categorical variables were analyzed using a chi-squared test. Continuous variables were presented as medians with ranges and analyzed using the Mann-Whitney U test. Univariate and multivariate analyses were conducted using logistic regression, with hazard ratio (HR) and 95% confidence intervals (CI) reported for prognostic factors. OS was calculated from the date of the first treatment initiation. Survival curves were generated using the Kaplan-Meier method and compared by the log-rank test. Covariates with a P value < 0.2 in the univariate analysis were included in the subsequent multivariate analysis. P values < 0.05 were considered statistically significant. All analyses were performed using SPSS version 29.0 (IBM. NY, US). Results Characteristics of patients Among 281 patients who were treated for stage IV CRC between January 2008 and December 2022, 100 patients had multiple metastatic sites. Excluding patients who underwent only palliative surgery, or who started or continued treatment at another hospital, the remaining 89 patients were analyzed (Fig. 1 ). Characteristics are summarized in Table 1 . Two-organ metastases were observed in 60 patients (67.4%), and three or more organ metastases in 29 patients (32.6%). Metastatic sites included the liver (n = 76, 85.4%), lung (n = 54, 60.7%), peritoneum (n = 37, 41.6%), distant lymph node (n = 31, 34.8%), and others (n = 22, 24.7%) with overlaps, details of which were listed in Table 2 . Curative-intended resection was performed in 13 patients (14.6%). Table 1 Characteristics of patients with two or more metastatic sites (n = 89). Age, years 65 (33–87) Gender, Male 43 (48.3%) Performance status 0 62 (69.7%) 1 22 (24.7%) 2–3 5 (5.6%) Primary tumor location Right-sided 28 (31.5%) Left-sided 61 (68.5%) Histological grade Differentiated 75 (84.3%) Undifferentiated 14 (15.7%) RAS mutation type Wild* 39 (43.8%) Mutated 42 (47.2%) Unknown 8 (9.0%) BRAF mutation type Wild 53 (59.6%) Mutated 5 (5.6%) Unknown 31 (34.8%) Serum level of CEA, ng/ml 64.3 (0.8-11063) Observation period, months 52.8 (0.7-134.8) Number of metastatic sites 2 60 (67.4%) ≥ 3 29 (32.6%) Metastatic sites (including overlap) Liver 76 (85.4%) Lung 54 (60.7%) Peritoneum 37 (41.6%) Distant lymph node 31 (34.8%) Others 22 (24.7%) Curative-intended resection 13 (14.6%) Values are presented as the median (range). *Only KRAS mutation test was done in 11 patients. CEA: carcinoembryonic antigen Table 2 Details of metastatic sites. Metastatic sites n Two metastatic sites 60 Liver + Lung 26 (43.3%) Liver + Peritoneum 12 (20.0%) Liver + Distant lymph node 8 (13.3%) Peritoneum + Others 4 (6.7%) Lung + Distant lymph node 3 (5.0%) Peritoneum + Distant lymph node 3 (5.0%) Liver + Others 2 (3.3%) Lung + Peritoneum 1 (1.7%) Distant lymph node + Others 1 (1.7%) Three or more metastatic sites 29 Liver + Lung + Distant lymph node 5 (17.2%) Liver + Lung + Others 5 (17.2%) Liver + Lung + Peritoneum 4 (13.8%) Liver + Peritoneum + Distant lymph node 2 (6.9%) Liver + Peritoneum + Others 1 (3.4%) Liver + Lung + Peritoneum + Distant lymph node 3 (10.3%) Liver + Lung + Peritoneum + Others 3 (10.3%) Liver + Lung + Distant lymph node + Others 2 (6.9%) Liver + Peritoneum + Distant lymph node + Others 1 (3.4%) Lung + Peritoneum + Distant lymph node + Others 1 (3.4%) Liver + Lung + Peritoneum + Distant lymph node + Others 2 (6.9%) Survival outcomes and prognostic factors in the total cohort During the median follow-up duration of 52.8 months (range 0.7–134.8 months), the OS rates for the whole sample were 73.9% at 1 year, 28.5% at 3 years, and 16.4% at 5 years with a median survival time of 22.5 months. Comparing OS of patients with and without each organ metastasis, no significant difference was found among patients with each metastatic sites other than lung (P = 0.668 for Liver, 0.090 for peritoneum, 0.388 for distant lymph node, and 0.057 for Others) (Supplementary Figure). However, patients with lung metastasis had significantly better OS than those without (median OS [95% CI] = 2.23 years [1.86–2.59] vs. 1.37 years [1.09–1.65]; P = 0.007) (Fig. 2 ). In the univariate analysis (Table 3 ), right-sided colon cancer and undifferentiated histological grade were significantly associated with worse OS (P = 0.019 and 0.035, respectively), while presence of lung metastasis was associated with more favorable OS (P = 0.009). Patients with three or more metastatic sites also have worse OS, although not significant (P = 0.079). In the multivariate analysis, right-sided colon cancer (HR 1.669 [95% CI: 1.020–2.732]; P = 0.041) and three or more metastatic sites (HR 2.093 [95% CI: 1.116–3.924]; P = 0.021) were significantly associated with poorer OS, whereas the presence of lung metastasis was significantly associated with more favorable OS (HR 0.432 [95% CI: 0.224–0.832]; P = 0.012). Table 3 Univariate and multivariate analysis of prognostic pre-treatment factors for overall survival in patients with two or more metastatic sites. Variables n 5y-OS (%) Univariate Multivariate HR (95% CI) P HR (95% CI) P Age, years < 70 60 17.7 1 0.901 ≥ 70 29 13.1 1.032 (0.628–1.696) Gender Male 43 10.5 1 0.289 Female 46 20.9 1.290 (0.806–2.066) Performance status 0–1 84 17.5 1 0.486 2–3 5 0 1.384 (0.554–3.456) Primary tumor location Left-sided 61 24.2 1 0.019 1 0.041 Right-sided 28 3.6 1.763 (1.096–2.841) 1.669 (1.020–2.732) Histological grade Differentiated 75 19.9 1 0.035 1 0.485 Undifferentiated 14 0 1.898 (1.046–3.445) 1.291 (0.630–2.645) Serum level of CEA, ng/ml > 50 45 17.7 1 0.899 < 50 44 15.1 1.112 (0.610–1.543) Number of metastatic sites 2 60 19.9 1 0.079 1 0.021 ≥ 3 29 10.7 1.567 (0.950–2.585) 2.093 (1.116–3.924) Liver metastasis Absence 13 15.4 1 0.668 Presence 76 17.0 1.152 (0.604–2.196) Lung metastasis Absence 35 8.6 1 0.009 1 0.012 Presence 54 21.9 0.527 (0.327–0.849) 0.432 (0.224–0.832) Peritoneal metastasis Absence 52 21.8 1 0.093 1 0.424 Presence 37 9.5 1.492 (0.936–2.379) 0.781 (0.425–1.433) Distant lymph node metastasis Absence 58 16.9 1 0.390 Presence 31 16.1 1.241 (0.759–2.027) Other organ metastases Absence 67 20.9 1 0.060 1 0.633 Presence 22 4.5 1.639 (0.980–2.742) 0.850 (0.437–1.655) CEA: carcinoembryonic antigen, 0S: overall survival Comparison of the characteristics between patients with and without lung metastasis Characteristics of patients are shown according to presence and absence of lung metastasis (Table 4 ). Patients with lung metastasis more frequently had RAS mutation (64.0% vs. 32.3%; P = 0.005) and three or more metastatic sites (44.4% vs. 14.3%; P = 0.003) but less frequently had differentiated histological grade (7.4% vs. 28.6%; P = 0.007) and peritoneal metastasis (24.1% vs. 68.6%; P < 0.001). Table 4 Characteristics of patients with or without lung metastasis. Without lung metastasis (n = 35) With lung metastasis (n = 54) P Age ≥ 70, years 9 (25.7%) 20 (37.0%) 0.266 Gender, Male 20 (57.1%) 26 (48.1%) 0.407 Performance status 2–3 1 (2.9%) 4 (7.4%) 0.362 Primary tumor location 0.353 Right-sided 13 (37.1%) 15 (27.8%) Left-sided 22 (62.9%) 39 (72.2%) RAS mutation* 10 (32.3%) 32 (64.0%) 0.005 Undifferentiated 10 (28.6%) 4 (7.4%) 0.007 CEA ≥ 50, ng/ml 14 (40.0%) 31 (57.4%) 0.109 Number of metastatic sites ≥ 3 5 (14.3%) 24 (44.4%) 0.003 Liver metastasis 27 (77.1%) 49 (90.7%) 0.076 H classification 2–3 20 (57.1%) 32 (59.3%) 0.843 Peritoneal metastasis 24 (68.6%) 13 (24.1%) < 0.001 Distant lymph node metastasis 16 (45.7%) 15 (27.8%) 0.083 Other organ metastases 10 (28.6%) 12 (22.2%) 0.498 Primary tumor resection 19 (54.3%) 32 (59.3%) 0.643 Curative-intended resection 3 (8.6%) 10 (18.5%) 0.194 CEA: carcinoembryonic antigen *Excluding patients without all RAS status in each 4 patients with and without lung metastasis. Survival outcomes for patients with both liver and lung metastases Long-term survival in patients with both liver and lung metastases, including three or more organ metastases, was shown according to treatment type (Fig. 3 ). The OS rates at 3 years were 100% for patients who underwent resection of both liver and lung metastases, and 64.8% for those who underwent liver resection alone. Both outcomes were significantly better than for patients who received chemotherapy alone (5.1%; P < 0.001 and P = 0.001, respectively). There was no significant difference in the long-term OS between patients who underwent liver and lung resection and those who underwent liver resection alone (P = 0.194). Discussion This study demonstrated that presence of lung metastasis hardly contributed to the dismal prognostic nature of stage IV CRC with MOM. Furthermore, in patients with dual metastatic site of liver and lung, liver resection even without lung resection improved prognosis compared to those with received systemic chemotherapy alone. The results of this study suggested the possibility of treatment options other than chemotherapy alone or curative-intended resection for stage IV CRC with MOM. One of the major findings of this study is that the presence of lung metastasis serves as a favorable prognostic factor in stage IV CRC with MOM, which is similar to the results from the Surveillance, Epidemiology, and End Results (SEER) database that patients with isolated lung metastasis had better OS and cancer-specific survival compared to those with any other sites [ 13 ]. Additionally, Treasure et al. reported that patients with lung metastasis who receive chemotherapy alone, without metastasectomy, had a favorable prognosis, with the OS rate of 22% at 5 years in a study based on data from the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). They concluded that lung metastasis contributes minimally to its lethality associated with prognosis of CRC and that local control in the chest is largely irrelevant to survival or palliative outcomes; rather, survival is primarily determined by extrathoracic disease [ 11 , 23 ]. In the present study, patients with lung metastasis have “mixed” oncological nature with less undifferentiated histological grade and peritoneal metastasis, and more RAS mutation and three or more metastatic sites, speculating that the pathogenetical association between lung metastasis and favorable prognosis may not be simple. Regarding RAS status, Bando et al. reported that the proportion of RAS mutation identified from circulating-tumor DNA in patients with lung metastasis was lower than that of RAS mutation identified histologically [ 24 ], and the pathogenesis of the metastatic process may explain the results of this study. Liver metastasis represents the most common metastatic site and a leading cause of mortality in patients with CRC [ 25 ]. Conversely, several large case series have reported long-term survival following surgical resection of colorectal liver metastasis, with the OS rate between 21% and 58% at 5 years, and between 22% and 26% at 10 years [ 8 , 26 , 27 ]. Given the significant prognostic impact of resection of liver metastasis, a liver-first approach is sometimes proposed for patients with liver metastasis and asymptomatic primary CRC. The purpose of this approach is to optimize a potentially curative hepatic resection and prolong survival by initially controlling liver metastasis, which has a greater prognostic impact [ 28 ]. In CRC, where the prognostic benefits of metastasectomy have been proven, this concept of prioritizing surgical resection based on the biological nature and progression level of each organ metastasis is also crucial for patients with MOM. In a detailed study of synchronous and metachronous CRC metastases involving 99 cases of simultaneous MOM, the most common organ combination was found to be liver and lung (52.5%, n = 52) [ 3 ]. In our study, 55.1% (n = 49) of cases also involved both liver and lung, identifying these patients as key candidates for tailored treatment strategies in stage IV CRC with MOM. For about 50% of stage IV CRC patients with synchronous liver and lung metastases, the prognostic benefit of liver resection was confirmed in the present study even if concomitant lung metastasis cannot be resected, which is consistent with the results by Mise et al. [ 21 ] and Albertsmeier et al. [ 29 ]. To our knowledge, this is the first study to demonstrate such findings in an Asian cohort. Additionally, the damage of chemotherapy on organ health must be considered; the liver is particularly vulnerable to chemotherapy-related damage, such as sinusoidal injury and steatohepatitis, which can lead to loss of surgical chance due to injury-related morbidity [ 30 , 31 ]. From these results, tailoring surgical treatment would be beneficial and feasible particularly for patients with liver metastasis, which has a greater prognostic impact, and lung metastasis, which has a lesser prognostic impact. This study has several limitations that should be acknowledged. First, retrospective nature of the study may introduce variability in treatment strategies depending on the treatment period. However, as this is a single-center study where treatment decisions are made at multidisciplinary team meetings, there are no significant differences in treatment strategies among physicians. Secondly, the number of patients analyzed is relatively small (n = 89). As a result, the characteristics and prognoses examined in this study may represent only a subset of stage IV CRC patients with MOM. However, synchronous liver and lung metastases, which are analyzed in detail in this study, represent the most common combination of MOM, and the findings are likely to be broadly applicable in clinical practice. In conclusion, lung metastasis was an independent favorable prognostic factor among stage IV CRC with MOM. Furthermore, among patients with both liver and lung metastases, liver resection without lung resection had a better prognosis than chemotherapy alone. We need to tailor surgical indications considering the prognostic impact of each metastatic sites and the influence of chemotherapy on each organ to improve prognosis of stage IV CRC with MOM. Declarations Author Contributions Shingo Maeda and Atsushi Ogura contributed to the study conception and design. Material preparation, data collection and analysis were performed by Shingo Maeda, Atsushi Ogura, Yuki Murata and Motonobu Nishimura. The first draft of the manuscript was written by Shingo Maeda and Atsushi Ogura and Tomoki Ebata commented on previous versions of the manuscript. All authors read and approved of the final manuscript. Acknowledgments We are grateful to Konosuke Yogo, Hiroaki Isaji, and Kenji Okuda for data collection. ・Funding and Competing Interests No funding was received for conducting this study. The authors declare they have no financial interest. ・Ethics Approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Nagoya University Hospital Institutional Review Board (approval number: #2021 − 0519). ・Consent to Participate Informed consent was obtained from all individual participants included in the study. References Bray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74:229-263 van der Geest LG, Lam-Boer J, Koopman M, Verhoef C, Elferink MA, de Wilt JH (2015) Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 32:457-465 Väyrynen V, Wirta EV, Seppälä T et al (2020) Incidence and management of patients with colorectal cancer and synchronous and metachronous colorectal metastases: a population-based study. BJS Open 4:685-692 Piedbois P, Rougier P, Buyse M et al (1998) Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308 Loupakis F, Cremolini C, Masi G et al (2014) Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371:1609-1618 Yamazaki K, Nagase M, Tamagawa H et al (2016) Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol 27:1539-1546 Oweira H, Mehrabi A, Reissfelder C, Abdel-Rahman O (2020) A Real-World, Population-Based Analysis of the Outcomes of Colorectal Cancer Patients with Isolated Synchronous Liver or Lung Metastases Treated with Metastasectomy. World J Surg 44:1604-1611 Choti MA, Sitzmann JV, Tiburi MF et al (2002) Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235:759-766 de Santibañes E, Lassalle FB, McCormack L et al (2002) Simultaneous colorectal and hepatic resections for colorectal cancer: postoperative and longterm outcomes. J Am Coll Surg 195:196-202 Tanaka K, Shimada H, Matsuo K et al (2004) Outcome after simultaneous colorectal and hepatic resection for colorectal cancer with synchronous metastases. Surgery 136:650-659 Treasure T, Farewell V, Macbeth F et al (2021) The Pulmonary Metastasectomy in Colorectal Cancer cohort study: Analysis of case selection, risk factors and survival in a prospective observational study of 512 patients. Colorectal Dis 23:1793-1803 Rumpold H, Kirchweger P, Niedersüß-Beke D et al (2021) Prognostic value of metastatic pattern in colorectal cancer: a multicenter retrospective analysis in a real-life cohort. Acta Oncol 60:180-186 Luo D, Liu Q, Yu W et al (2018) Prognostic value of distant metastasis sites and surgery in stage IV colorectal cancer: a population-based study. Int J Colorectal Dis 33:1241-1249 Mekenkamp LJ, Koopman M, Teerenstra S et al (2010) Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases. Br J Cancer 103:159-164 Brouwer NPM, van der Kruijssen DEW, Hugen N et al (2020) The Impact of Primary Tumor Location in Synchronous Metastatic Colorectal Cancer: Differences in Metastatic Sites and Survival. Ann Surg Oncol 27:1580-1588 Leung U, Gönen M, Allen PJ et al (2017) Colorectal Cancer Liver Metastases and Concurrent Extrahepatic Disease Treated With Resection. Ann Surg 265:158-165 Matsumura M, Yamashita S, Ishizawa T et al (2020) Oncological benefit of complete metastasectomy for simultaneous colorectal liver and lung metastases. Am J Surg 219:80-87 Andres A, Mentha G, Adam R et al (2015) Surgical management of patients with colorectal cancer and simultaneous liver and lung metastases. Br J Surg 102:691-699 Elias D, Ouellet JF, Bellon N, Pignon JP, Pocard M, Lasser P (2003) Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases. Br J Surg 90:567-574 Market M, Tennakoon G, Auer RC (2021) Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery. Int J Mol Sci 22 Mise Y, Kopetz S, Mehran RJ et al (2015) Is complete liver resection without resection of synchronous lung metastases justified? Ann Surg Oncol 22:1585-1592 Yamaguchi T, Mori T, Takahashi K, Matsumoto H, Miyamoto H, Kato T (2008) A new classification system for liver metastases from colorectal cancer in Japanese multicenter analysis. Hepatogastroenterology 55:173-178 Treasure T, Farewell V, Macbeth F et al (2019) Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial. Trials 20:718 Bando H, Kagawa Y, Kato T et al (2019) A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer. Br J Cancer 120:982-986 Stewart CL, Warner S, Ito K et al (2018) Cytoreduction for colorectal metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When does it palliate, prolong survival, and potentially cure? Curr Probl Surg 55:330-379 Chua TC, Saxena A, Chu F, Zhao J, Morris DL (2011) Predictors of cure after hepatic resection of colorectal liver metastases: an analysis of actual 5- and 10-year survivors. J Surg Oncol 103:796-800 Abdalla EK, Vauthey JN, Ellis LM et al (2004) Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-825; discussion 825-817 Mentha G, Majno PE, Andres A, Rubbia-Brandt L, Morel P, Roth AD (2006) Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary. Br J Surg 93:872-878 Albertsmeier M, Riedl K, Stephan AJ et al (2020) Improved survival after resection of colorectal liver metastases in patients with unresectable lung metastases. HPB (Oxford) 22:368-375 Kishi Y, Zorzi D, Contreras CM et al (2010) Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol 17:2870-2876 Reissfelder C, Brand K, Sobiegalla J et al (2014) Chemotherapy-associated liver injury and its influence on outcome after resection of colorectal liver metastases. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6788853","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":468966059,"identity":"bd927f2a-5462-4032-a671-2a8aa6c27262","order_by":0,"name":"Shingo Maeda","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Maeda","suffix":""},{"id":468966060,"identity":"6e49354f-bc17-4c3b-ae32-f7f28434ab84","order_by":1,"name":"Atsushi 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Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Murata","suffix":""},{"id":468966062,"identity":"2cbfbca4-38ae-4eab-9c90-f2ccd3e85b26","order_by":3,"name":"Motonobu Nishimura","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Motonobu","middleName":"","lastName":"Nishimura","suffix":""},{"id":468966063,"identity":"4c344113-0c28-45c3-a715-87c386a6958a","order_by":4,"name":"Shoji Kawakatsu","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Shoji","middleName":"","lastName":"Kawakatsu","suffix":""},{"id":468966064,"identity":"57bce01d-8824-4dff-91fe-1e5b41c8575d","order_by":5,"name":"Shizuki Sugita","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Shizuki","middleName":"","lastName":"Sugita","suffix":""},{"id":468966065,"identity":"c26e4c09-beb3-460a-9587-b1c016d7bb23","order_by":6,"name":"Onoe Shunsuke","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Onoe","middleName":"","lastName":"Shunsuke","suffix":""},{"id":468966066,"identity":"34537991-3a2d-4518-95cb-c7df7272d63e","order_by":7,"name":"Kazushi Miyata","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Kazushi","middleName":"","lastName":"Miyata","suffix":""},{"id":468966067,"identity":"648f2407-ac30-45d7-a319-d8b4660232a8","order_by":8,"name":"Jumpei Yamaguchi","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Jumpei","middleName":"","lastName":"Yamaguchi","suffix":""},{"id":468966068,"identity":"f983d1ee-8fac-4494-aa40-dbf7fd558f31","order_by":9,"name":"Takashi Mizuno","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Mizuno","suffix":""},{"id":468966069,"identity":"b6983c7d-19e0-41b8-83a8-d34ca03a7e09","order_by":10,"name":"Tomoki Ebata","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine Faculty of Medicine: Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Tomoki","middleName":"","lastName":"Ebata","suffix":""}],"badges":[],"createdAt":"2025-05-31 05:41:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6788853/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6788853/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84662328,"identity":"bcf2480f-1371-4650-9be2-2910a76653a1","added_by":"auto","created_at":"2025-06-16 04:57:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":340344,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of stage IV colorectal cancer patients treated from 2008 to 2022.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6788853/v1/43b1846da9d2b0386167bb85.jpg"},{"id":84662331,"identity":"1492185b-c828-4906-a7d8-e2d6bd68bfb1","added_by":"auto","created_at":"2025-06-16 04:57:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":145139,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of OS based on the presence of lung metastasis. Patients with lung metastasis had a significantly better prognosis than those without.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6788853/v1/ecdf7f4fe19ed00709779f6a.jpg"},{"id":84662541,"identity":"27824063-bfc1-481a-b58c-ec05eb416e62","added_by":"auto","created_at":"2025-06-16 05:05:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":160800,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of OS based on presence of liver or lung resection in patients with both liver and lung metastases. Liver and lung resection and liver resection without lung resection had better prognosis than chemotherapy alone in patients with both liver and lung metastases.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6788853/v1/08654ab4d81a0e4e68ec6673.jpg"},{"id":86455202,"identity":"c7ba6c87-27e4-4f2f-8139-5f902bc7dddc","added_by":"auto","created_at":"2025-07-10 21:27:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1710650,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6788853/v1/c7bfe9e1-7815-4de0-8e53-5fa83ff9f14c.pdf"}],"financialInterests":"","formattedTitle":"Tailoring treatment strategy for stage IV colorectal cancer: assessing the impact of lung metastasis on multi-organ management","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately 17\u0026ndash;23% of CRC patients are diagnosed with stage IV disease at initial presentation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Previously, patients with stage IV CRC had a median survival of only 10 months around 1990s [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, subsequent advances in surgical techniques and chemotherapy have significantly prolonged this poor outcome in stage IV disease [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In particular, never-quit surgical resection plays a vital role in improving the prognosis, and complete resection of both primary tumor and distant metastases has carried a reported overall survival (OS) rate of 38\u0026ndash;58% at 5 years even in stage IV disease [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNonetheless, the long-term survival remains unsatisfactory, provided stage IV patients have multiple organ metastases (MOM) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Luo et al. analyzed and reported that prognosis deteriorated with an increasing number of metastatic organs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. MOM is a common clinical condition that accounts for 32\u0026ndash;50% of stage IV CRC [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], therefore, advance in treatment for MOM presents a significant challenge in improving prognosis for CRC. Regarding the impact of surgical resection on stage IV CRC with MOM, Leung et al. reported the OS rates 28% at 5 years for complete resection and concluded that complete resection increased survival probability in selected patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Following several studies also documented the benefits of surgical resection [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], which now serves a key strategy even in stage IV, MOM disease. In clinical practice, however, chemotherapy is often prioritized over surgical resection due to the disease or therapeutic complexity of stage IV CRC with MOM. Additionally, postoperative immune suppression could promote cancer metastasis and recurrence, which could result in the reluctance among surgeons to proceed with surgery[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, several studies have explored integrating treatment strategies of resection and chemotherapy in the setting of MOM. Mise et al. reported that liver resection without resection of lung metastases resulted in significantly better prognosis compared to chemotherapy alone in patients with stage IV CRC with simultaneous technically resectable liver and unresectable lung metastases (3-year OS: 42.9% vs. 14.1%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). This suggests a potential benefit of selective surgical resection [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, flexible treatment strategies, which include tumor clearance of a specific metastatic foci, need further exploration. However, the clinicopathogenesis of stage IV CRC with MOM remains poorly understood. In this study, we hypothesized that lung metastasis would have an amenable nature to chemotherapy among the whole metastatic sites, and analyzed the clinicopathological features of stage IV CRC with MOM, focusing on lung metastasis.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign\u003c/h2\u003e \u003cp\u003e This is a single-center retrospective clinical cohort study and has been approved by Nagoya University Hospital Institutional Review Board (approval number: #2021\u0026thinsp;\u0026minus;\u0026thinsp;0519).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003eThis study included patients with stage IV CRC with synchronous MOM who were treated at Nagoya University Hospital between January 2008 and December 2022. All patients had histologically confirmed colorectal adenocarcinoma, diagnosed with endoscopic or surgical biopsy. Metastatic lesions were identified using computed tomography, magnetic resonance imaging, or positron emission tomography-computed tomography. Patients who underwent only palliative surgery, who received initial treatment at another hospital, or who continued treatment elsewhere after undergoing only palliative surgery at our hospital were excluded.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eCollected data included age, gender, performance status, primary tumor location (right-sided colon from the cecum to the transvers colon, and left-sided colon from the descending colon to the rectum), histological type, RAS and BRAF status, preoperative carcinoembryonic antigen (CEA), location and number of metastatic sites, liver metastatic classification[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] resection of each metastatic site, achievement of curative-intended resection, and OS. Histological grades were categorized as differentiated histological grade (well or moderately differentiated adenocarcinoma) and undifferentiated histological grade (poorly differentiated or mucinous adenocarcinoma, or signet ring cell carcinoma). Metastatic sites included liver, lung, peritoneum, distant lymph node, and others (e.g., brain, bone, ovary, spleen, pancreas, and adrenal gland). Curative-intended resection was defined as R0 or R1 resection of both primary and metastatic tumor.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were analyzed using a chi-squared test. Continuous variables were presented as medians with ranges and analyzed using the Mann-Whitney U test. Univariate and multivariate analyses were conducted using logistic regression, with hazard ratio (HR) and 95% confidence intervals (CI) reported for prognostic factors. OS was calculated from the date of the first treatment initiation. Survival curves were generated using the Kaplan-Meier method and compared by the log-rank test. Covariates with a P value\u0026thinsp;\u0026lt;\u0026thinsp;0.2 in the univariate analysis were included in the subsequent multivariate analysis. P values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. All analyses were performed using SPSS version 29.0 (IBM. NY, US).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of patients\u003c/h2\u003e \u003cp\u003eAmong 281 patients who were treated for stage IV CRC between January 2008 and December 2022, 100 patients had multiple metastatic sites. Excluding patients who underwent only palliative surgery, or who started or continued treatment at another hospital, the remaining 89 patients were analyzed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Two-organ metastases were observed in 60 patients (67.4%), and three or more organ metastases in 29 patients (32.6%). Metastatic sites included the liver (n\u0026thinsp;=\u0026thinsp;76, 85.4%), lung (n\u0026thinsp;=\u0026thinsp;54, 60.7%), peritoneum (n\u0026thinsp;=\u0026thinsp;37, 41.6%), distant lymph node (n\u0026thinsp;=\u0026thinsp;31, 34.8%), and others (n\u0026thinsp;=\u0026thinsp;22, 24.7%) with overlaps, details of which were listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Curative-intended resection was performed in 13 patients (14.6%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients with two or more metastatic sites (n\u0026thinsp;=\u0026thinsp;89).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(33\u0026ndash;87)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eGender, Male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(48.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePerformance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(69.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(24.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(5.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrimary tumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(31.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(68.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHistological grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDifferentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(84.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUndifferentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(15.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRAS mutation type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWild*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(43.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(47.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(9.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBRAF mutation type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(59.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(5.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(34.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSerum level of CEA, ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0.8-11063)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eObservation period, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0.7-134.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNumber of metastatic sites\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(67.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(32.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMetastatic sites (including overlap)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(85.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(60.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(41.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDistant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(34.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(24.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCurative-intended resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(14.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eValues are presented as the median (range).\u003c/p\u003e \u003cp\u003e*Only KRAS mutation test was done in 11 patients.\u003c/p\u003e \u003cp\u003eCEA: carcinoembryonic antigen\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetails of metastatic sites.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMetastatic sites\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTwo metastatic sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(43.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Peritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(20.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Distant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(13.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeritoneum\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung\u0026thinsp;+\u0026thinsp;Distant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(5.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeritoneum\u0026thinsp;+\u0026thinsp;Distant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(5.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung\u0026thinsp;+\u0026thinsp;Peritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(1.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDistant lymph node\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(1.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThree or more metastatic sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e29\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u0026thinsp;+\u0026thinsp;Distant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(17.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(17.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u0026thinsp;+\u0026thinsp;Peritoneum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(13.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Peritoneum\u0026thinsp;+\u0026thinsp;Distant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Peritoneum\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(3.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u0026thinsp;+\u0026thinsp;Peritoneum\u0026thinsp;+\u0026thinsp;Distant lymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u0026thinsp;+\u0026thinsp;Peritoneum\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u0026thinsp;+\u0026thinsp;Distant lymph node\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Peritoneum\u0026thinsp;+\u0026thinsp;Distant lymph node\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(3.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung\u0026thinsp;+\u0026thinsp;Peritoneum\u0026thinsp;+\u0026thinsp;Distant lymph node\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(3.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver\u0026thinsp;+\u0026thinsp;Lung\u0026thinsp;+\u0026thinsp;Peritoneum\u0026thinsp;+\u0026thinsp;Distant lymph node\u0026thinsp;+\u0026thinsp;Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(6.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival outcomes and prognostic factors in the total cohort\u003c/h3\u003e\n\u003cp\u003eDuring the median follow-up duration of 52.8 months (range 0.7\u0026ndash;134.8 months), the OS rates for the whole sample were 73.9% at 1 year, 28.5% at 3 years, and 16.4% at 5 years with a median survival time of 22.5 months. Comparing OS of patients with and without each organ metastasis, no significant difference was found among patients with each metastatic sites other than lung (P\u0026thinsp;=\u0026thinsp;0.668 for Liver, 0.090 for peritoneum, 0.388 for distant lymph node, and 0.057 for Others) (Supplementary Figure). However, patients with lung metastasis had significantly better OS than those without (median OS [95% CI]\u0026thinsp;=\u0026thinsp;2.23 years [1.86\u0026ndash;2.59] vs. 1.37 years [1.09\u0026ndash;1.65]; P\u0026thinsp;=\u0026thinsp;0.007) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the univariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), right-sided colon cancer and undifferentiated histological grade were significantly associated with worse OS (P\u0026thinsp;=\u0026thinsp;0.019 and 0.035, respectively), while presence of lung metastasis was associated with more favorable OS (P\u0026thinsp;=\u0026thinsp;0.009). Patients with three or more metastatic sites also have worse OS, although not significant (P\u0026thinsp;=\u0026thinsp;0.079). In the multivariate analysis, right-sided colon cancer (HR 1.669 [95% CI: 1.020\u0026ndash;2.732]; P\u0026thinsp;=\u0026thinsp;0.041) and three or more metastatic sites (HR 2.093 [95% CI: 1.116\u0026ndash;3.924]; P\u0026thinsp;=\u0026thinsp;0.021) were significantly associated with poorer OS, whereas the presence of lung metastasis was significantly associated with more favorable OS (HR 0.432 [95% CI: 0.224\u0026ndash;0.832]; P\u0026thinsp;=\u0026thinsp;0.012).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analysis of prognostic pre-treatment factors for overall survival in patients with two or more metastatic sites.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5y-OS (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.032 (0.628\u0026ndash;1.696)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.290 (0.806\u0026ndash;2.066)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePerformance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.384 (0.554\u0026ndash;3.456)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrimary tumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.041\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.763 (1.096\u0026ndash;2.841)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.669 (1.020\u0026ndash;2.732)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHistological grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDifferentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.035\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.485\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUndifferentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.898 (1.046\u0026ndash;3.445)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.291 (0.630\u0026ndash;2.645)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSerum level of CEA, ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.899\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.112 (0.610\u0026ndash;1.543)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNumber of metastatic sites\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.567 (0.950\u0026ndash;2.585)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.093 (1.116\u0026ndash;3.924)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLiver metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.668\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.152 (0.604\u0026ndash;2.196)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLung metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.527 (0.327\u0026ndash;0.849)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.432 (0.224\u0026ndash;0.832)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePeritoneal metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.424\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.492 (0.936\u0026ndash;2.379)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.781 (0.425\u0026ndash;1.433)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDistant lymph node metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.390\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.241 (0.759\u0026ndash;2.027)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eOther organ metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.639 (0.980\u0026ndash;2.742)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.850 (0.437\u0026ndash;1.655)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eCEA: carcinoembryonic antigen, 0S: overall survival\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eComparison of the characteristics between patients with and without lung metastasis\u003c/h3\u003e\n\u003cp\u003eCharacteristics of patients are shown according to presence and absence of lung metastasis (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Patients with lung metastasis more frequently had RAS mutation (64.0% vs. 32.3%; P\u0026thinsp;=\u0026thinsp;0.005) and three or more metastatic sites (44.4% vs. 14.3%; P\u0026thinsp;=\u0026thinsp;0.003) but less frequently had differentiated histological grade (7.4% vs. 28.6%; P\u0026thinsp;=\u0026thinsp;0.007) and peritoneal metastasis (24.1% vs. 68.6%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients with or without lung metastasis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eWithout lung metastasis (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eWith lung metastasis (n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;70, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(25.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(37.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eGender, Male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(57.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(48.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.407\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePerformance status 2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(2.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.362\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrimary tumor location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.353\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRight-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(37.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(27.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(62.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(72.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eRAS mutation*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(64.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eUndifferentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(28.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCEA\u0026thinsp;\u0026ge;\u0026thinsp;50, ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(40.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(57.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNumber of metastatic sites\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLiver metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(77.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(90.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eH classification 2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(57.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(59.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.843\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePeritoneal metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(24.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDistant lymph node metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(45.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(27.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eOther organ metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(28.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(22.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.498\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePrimary tumor resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(54.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(59.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.643\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCurative-intended resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.194\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003eCEA: carcinoembryonic antigen\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"9\" nameend=\"c9\" namest=\"c1\"\u003e \u003cp\u003e*Excluding patients without all RAS status in each 4 patients with and without lung metastasis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSurvival outcomes for patients with both liver and lung metastases\u003c/h2\u003e \u003cp\u003eLong-term survival in patients with both liver and lung metastases, including three or more organ metastases, was shown according to treatment type (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The OS rates at 3 years were 100% for patients who underwent resection of both liver and lung metastases, and 64.8% for those who underwent liver resection alone. Both outcomes were significantly better than for patients who received chemotherapy alone (5.1%; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and P\u0026thinsp;=\u0026thinsp;0.001, respectively). There was no significant difference in the long-term OS between patients who underwent liver and lung resection and those who underwent liver resection alone (P\u0026thinsp;=\u0026thinsp;0.194).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrated that presence of lung metastasis hardly contributed to the dismal prognostic nature of stage IV CRC with MOM. Furthermore, in patients with dual metastatic site of liver and lung, liver resection even without lung resection improved prognosis compared to those with received systemic chemotherapy alone. The results of this study suggested the possibility of treatment options other than chemotherapy alone or curative-intended resection for stage IV CRC with MOM.\u003c/p\u003e \u003cp\u003eOne of the major findings of this study is that the presence of lung metastasis serves as a favorable prognostic factor in stage IV CRC with MOM, which is similar to the results from the Surveillance, Epidemiology, and End Results (SEER) database that patients with isolated lung metastasis had better OS and cancer-specific survival compared to those with any other sites [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, Treasure et al. reported that patients with lung metastasis who receive chemotherapy alone, without metastasectomy, had a favorable prognosis, with the OS rate of 22% at 5 years in a study based on data from the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). They concluded that lung metastasis contributes minimally to its lethality associated with prognosis of CRC and that local control in the chest is largely irrelevant to survival or palliative outcomes; rather, survival is primarily determined by extrathoracic disease [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the present study, patients with lung metastasis have \u0026ldquo;mixed\u0026rdquo; oncological nature with less undifferentiated histological grade and peritoneal metastasis, and more RAS mutation and three or more metastatic sites, speculating that the pathogenetical association between lung metastasis and favorable prognosis may not be simple. Regarding RAS status, Bando et al. reported that the proportion of RAS mutation identified from circulating-tumor DNA in patients with lung metastasis was lower than that of RAS mutation identified histologically [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and the pathogenesis of the metastatic process may explain the results of this study.\u003c/p\u003e \u003cp\u003eLiver metastasis represents the most common metastatic site and a leading cause of mortality in patients with CRC [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Conversely, several large case series have reported long-term survival following surgical resection of colorectal liver metastasis, with the OS rate between 21% and 58% at 5 years, and between 22% and 26% at 10 years [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Given the significant prognostic impact of resection of liver metastasis, a liver-first approach is sometimes proposed for patients with liver metastasis and asymptomatic primary CRC. The purpose of this approach is to optimize a potentially curative hepatic resection and prolong survival by initially controlling liver metastasis, which has a greater prognostic impact [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In CRC, where the prognostic benefits of metastasectomy have been proven, this concept of prioritizing surgical resection based on the biological nature and progression level of each organ metastasis is also crucial for patients with MOM.\u003c/p\u003e \u003cp\u003eIn a detailed study of synchronous and metachronous CRC metastases involving 99 cases of simultaneous MOM, the most common organ combination was found to be liver and lung (52.5%, n\u0026thinsp;=\u0026thinsp;52) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our study, 55.1% (n\u0026thinsp;=\u0026thinsp;49) of cases also involved both liver and lung, identifying these patients as key candidates for tailored treatment strategies in stage IV CRC with MOM. For about 50% of stage IV CRC patients with synchronous liver and lung metastases, the prognostic benefit of liver resection was confirmed in the present study even if concomitant lung metastasis cannot be resected, which is consistent with the results by Mise et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and Albertsmeier et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. To our knowledge, this is the first study to demonstrate such findings in an Asian cohort. Additionally, the damage of chemotherapy on organ health must be considered; the liver is particularly vulnerable to chemotherapy-related damage, such as sinusoidal injury and steatohepatitis, which can lead to loss of surgical chance due to injury-related morbidity [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. From these results, tailoring surgical treatment would be beneficial and feasible particularly for patients with liver metastasis, which has a greater prognostic impact, and lung metastasis, which has a lesser prognostic impact.\u003c/p\u003e \u003cp\u003eThis study has several limitations that should be acknowledged. First, retrospective nature of the study may introduce variability in treatment strategies depending on the treatment period. However, as this is a single-center study where treatment decisions are made at multidisciplinary team meetings, there are no significant differences in treatment strategies among physicians. Secondly, the number of patients analyzed is relatively small (n\u0026thinsp;=\u0026thinsp;89). As a result, the characteristics and prognoses examined in this study may represent only a subset of stage IV CRC patients with MOM. However, synchronous liver and lung metastases, which are analyzed in detail in this study, represent the most common combination of MOM, and the findings are likely to be broadly applicable in clinical practice.\u003c/p\u003e \u003cp\u003eIn conclusion, lung metastasis was an independent favorable prognostic factor among stage IV CRC with MOM. Furthermore, among patients with both liver and lung metastases, liver resection without lung resection had a better prognosis than chemotherapy alone. We need to tailor surgical indications considering the prognostic impact of each metastatic sites and the influence of chemotherapy on each organ to improve prognosis of stage IV CRC with MOM.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eShingo Maeda and Atsushi Ogura contributed to the study conception and design. Material preparation, data collection and analysis were performed by Shingo Maeda, Atsushi Ogura, Yuki Murata and Motonobu Nishimura. The first draft of the manuscript was written by Shingo Maeda and Atsushi Ogura and Tomoki Ebata commented on previous versions of the manuscript. All authors read and approved of the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eWe are grateful to Konosuke Yogo, Hiroaki Isaji, and Kenji Okuda for data collection.\u003c/p\u003e \u003cp\u003e・Funding and Competing Interests\u003c/p\u003e \u003cp\u003eNo funding was received for conducting this study. The authors declare they have no financial interest.\u003c/p\u003e \u003cp\u003e・Ethics Approval\u003c/p\u003e \u003cp\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Nagoya University Hospital Institutional Review Board (approval number: #2021\u0026thinsp;\u0026minus;\u0026thinsp;0519).\u003c/p\u003e \u003cp\u003e・Consent to Participate\u003c/p\u003e \u003cp\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74:229-263\u003c/li\u003e\n\u003cli\u003evan der Geest LG, Lam-Boer J, Koopman M, Verhoef C, Elferink MA, de Wilt JH (2015) Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 32:457-465\u003c/li\u003e\n\u003cli\u003eV\u0026auml;yrynen V, Wirta EV, Sepp\u0026auml;l\u0026auml; T et al (2020) Incidence and management of patients with colorectal cancer and synchronous and metachronous colorectal metastases: a population-based study. BJS Open 4:685-692\u003c/li\u003e\n\u003cli\u003ePiedbois P, Rougier P, Buyse M et al (1998) Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308\u003c/li\u003e\n\u003cli\u003eLoupakis F, Cremolini C, Masi G et al (2014) Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371:1609-1618\u003c/li\u003e\n\u003cli\u003eYamazaki K, Nagase M, Tamagawa H et al (2016) Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol 27:1539-1546\u003c/li\u003e\n\u003cli\u003eOweira H, Mehrabi A, Reissfelder C, Abdel-Rahman O (2020) A Real-World, Population-Based Analysis of the Outcomes of Colorectal Cancer Patients with Isolated Synchronous Liver or Lung Metastases Treated with Metastasectomy. World J Surg 44:1604-1611\u003c/li\u003e\n\u003cli\u003eChoti MA, Sitzmann JV, Tiburi MF et al (2002) Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235:759-766\u003c/li\u003e\n\u003cli\u003ede Santiba\u0026ntilde;es E, Lassalle FB, McCormack L et al (2002) Simultaneous colorectal and hepatic resections for colorectal cancer: postoperative and longterm outcomes. J Am Coll Surg 195:196-202\u003c/li\u003e\n\u003cli\u003eTanaka K, Shimada H, Matsuo K et al (2004) Outcome after simultaneous colorectal and hepatic resection for colorectal cancer with synchronous metastases. Surgery 136:650-659\u003c/li\u003e\n\u003cli\u003eTreasure T, Farewell V, Macbeth F et al (2021) The Pulmonary Metastasectomy in Colorectal Cancer cohort study: Analysis of case selection, risk factors and survival in a prospective observational study of 512 patients. Colorectal Dis 23:1793-1803\u003c/li\u003e\n\u003cli\u003eRumpold H, Kirchweger P, Nieders\u0026uuml;\u0026szlig;-Beke D et al (2021) Prognostic value of metastatic pattern in colorectal cancer: a multicenter retrospective analysis in a real-life cohort. Acta Oncol 60:180-186\u003c/li\u003e\n\u003cli\u003eLuo D, Liu Q, Yu W et al (2018) Prognostic value of distant metastasis sites and surgery in stage IV colorectal cancer: a population-based study. Int J Colorectal Dis 33:1241-1249\u003c/li\u003e\n\u003cli\u003eMekenkamp LJ, Koopman M, Teerenstra S et al (2010) Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases. Br J Cancer 103:159-164\u003c/li\u003e\n\u003cli\u003eBrouwer NPM, van der Kruijssen DEW, Hugen N et al (2020) The Impact of Primary Tumor Location in Synchronous Metastatic Colorectal Cancer: Differences in Metastatic Sites and Survival. Ann Surg Oncol 27:1580-1588\u003c/li\u003e\n\u003cli\u003eLeung U, G\u0026ouml;nen M, Allen PJ et al (2017) Colorectal Cancer Liver Metastases and Concurrent Extrahepatic Disease Treated With Resection. Ann Surg 265:158-165\u003c/li\u003e\n\u003cli\u003eMatsumura M, Yamashita S, Ishizawa T et al (2020) Oncological benefit of complete metastasectomy for simultaneous colorectal liver and lung metastases. Am J Surg 219:80-87\u003c/li\u003e\n\u003cli\u003eAndres A, Mentha G, Adam R et al (2015) Surgical management of patients with colorectal cancer and simultaneous liver and lung metastases. Br J Surg 102:691-699\u003c/li\u003e\n\u003cli\u003eElias D, Ouellet JF, Bellon N, Pignon JP, Pocard M, Lasser P (2003) Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases. Br J Surg 90:567-574\u003c/li\u003e\n\u003cli\u003eMarket M, Tennakoon G, Auer RC (2021) Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery. Int J Mol Sci 22\u003c/li\u003e\n\u003cli\u003eMise Y, Kopetz S, Mehran RJ et al (2015) Is complete liver resection without resection of synchronous lung metastases justified? Ann Surg Oncol 22:1585-1592\u003c/li\u003e\n\u003cli\u003eYamaguchi T, Mori T, Takahashi K, Matsumoto H, Miyamoto H, Kato T (2008) A new classification system for liver metastases from colorectal cancer in Japanese multicenter analysis. Hepatogastroenterology 55:173-178\u003c/li\u003e\n\u003cli\u003eTreasure T, Farewell V, Macbeth F et al (2019) Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial. Trials 20:718\u003c/li\u003e\n\u003cli\u003eBando H, Kagawa Y, Kato T et al (2019) A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer. Br J Cancer 120:982-986\u003c/li\u003e\n\u003cli\u003eStewart CL, Warner S, Ito K et al (2018) Cytoreduction for colorectal metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When does it palliate, prolong survival, and potentially cure? Curr Probl Surg 55:330-379\u003c/li\u003e\n\u003cli\u003eChua TC, Saxena A, Chu F, Zhao J, Morris DL (2011) Predictors of cure after hepatic resection of colorectal liver metastases: an analysis of actual 5- and 10-year survivors. J Surg Oncol 103:796-800\u003c/li\u003e\n\u003cli\u003eAbdalla EK, Vauthey JN, Ellis LM et al (2004) Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-825; discussion 825-817\u003c/li\u003e\n\u003cli\u003eMentha G, Majno PE, Andres A, Rubbia-Brandt L, Morel P, Roth AD (2006) Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary. Br J Surg 93:872-878\u003c/li\u003e\n\u003cli\u003eAlbertsmeier M, Riedl K, Stephan AJ et al (2020) Improved survival after resection of colorectal liver metastases in patients with unresectable lung metastases. HPB (Oxford) 22:368-375\u003c/li\u003e\n\u003cli\u003eKishi Y, Zorzi D, Contreras CM et al (2010) Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol 17:2870-2876\u003c/li\u003e\n\u003cli\u003eReissfelder C, Brand K, Sobiegalla J et al (2014) Chemotherapy-associated liver injury and its influence on outcome after resection of colorectal liver metastases. Surgery 155:245-254\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Supplementary Figure","content":"\u003cp\u003eSupplementary Figure not available with this version\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":"Colorectal cancer, Stage IV, Multiple organ metastases, Lung metastasis, Surgical indications","lastPublishedDoi":"10.21203/rs.3.rs-6788853/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6788853/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eResection of distant metastatic foci can improve the survival for stage IV colorectal cancer (CRC). However, surgical strategy for multiple organ metastases (MOM) is complicated and chemotherapy is often prioritized over surgical resection. This study analyzed the clinicopathological features of stage IV CRC with MOM to identify strategies for improving prognosis.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong 281 stage IV CRC patients who were treated at our hospital from 2008 to 2022, 89 patients with MOM were included.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe number of metastatic organs was 2 in 60 (67%) patients and 3 or more in 29 (33%). The most common metastatic site was liver (n=76, 85%), followed by lung (n=54, 61%), peritoneum (n=37, 42%), distant lymph node (n=31, 35%). Thirteen (15%) patients underwent curative-intended resection during the median follow-up of 52.8 months. Overall survival for patients with lung metastasis had significantly better than that for patients without (median 2.23 vs. 1.37 years, P = 0.007). In 49 patients with \u0026nbsp;both liver and lung metastases, the overall survival rates at 3 years were 100% in 8 patients who underwent resections of the both and 64.8% in 9 patients who underwent resection of liver alone, which was significantly higher than 5.1% in 32 patients who received chemotherapy alone (P \u0026lt; 0.001 and P = 0.001, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn patients with MOM, lung metastasis was associated with a favorable survival probability even when being left in situ. This finding suggests that survival benefit of aggressive resection would depend on the metastatic site.\u003c/p\u003e","manuscriptTitle":"Tailoring treatment strategy for stage IV colorectal cancer: assessing the impact of lung metastasis on multi-organ management","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-16 04:56:56","doi":"10.21203/rs.3.rs-6788853/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":"8004bf9d-780f-4dcc-9e90-9ceeecbf0b19","owner":[],"postedDate":"June 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-10T21:19:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-16 04:56:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6788853","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6788853","identity":"rs-6788853","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}