Prognostic divergence of hematogenous and lymphatic metastases in patients with stage IV colorectal cancer

Prognostic divergence of hematogenous and lymphatic metastases in patients with stage IV colorectal cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic divergence of hematogenous and lymphatic metastases in patients with stage IV colorectal cancer Haoyue Ma, Liming Wang, Yinggang Chen, Yasumitsu Hirano This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8690733/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background: In patients with stage IV colorectal cancer (CRC), the prognostic impact of lymph node metastasis (LNM) remains controversial. A qualifying cohort served to explore its importance. Methods: We selected 493 eligible patients with stage IV CRC for retrospective study. All were surgically treated between April 2007 and December 2020 at a high-volume cancer center in Japan. Subjects were stratified by presence/absence of LNM (N+M1 vs N0M1), and propensity score matching (PSM) was done at 1:1 ratio. We then compared cancer-specific (CSS) and overall (OS) survival rates before and after PSM, using Cox regression to identify pertinent independent risk factors. Results: Patients assigned to N+M1 and N0M1 groups totaled 384 (77.9%) and 109 (22.1%), respectively. Five-year OS proved superior for the N0M1 (vs N+M1) group, both before (41.7% vs 30.8%; p =0.020) and after (43.7% vs 26.5%; p =0.042) PSM. LNM also emerged as an independent prognosticator of OS in multivariate analyses conducted before (hazard ratio [HR]=1.5, 95% confidence interval [CI]: 1.09-2.08; p =0.014) and after (HR=1.72, 95% CI: 1.121-2.64; p =0.013) matching. The same was true of 5-year CSS, both before (N0M1, 46.1%; N+M1, 32.4%; p =0.009) and after (N0M1, 48.8%; N+M1, 28.0%; p =0.027) matching, again verifying LNM as an independent prognostic factor before (HR=1.6, 95% CI: 1.13-2.25; p =0.007) and after (HR=1.86, 95% CI: 1.185-2.90; p =0.007) PSM. Conclusions: In the setting of stage IV CRC, distant hematogenous metastasis (N0M1) confers a better prognosis than does regional LNM (N+M1). This apparent prognostic divergence must be reflected in refined tumor classification subsets. stage IV colorectal cancer lymph node metastasis propensity score matching Figures Figure 1 Figure 2 Figure 3 Introduction Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide [ 1 ]. Although early detection is achievable through screening, distant metastases are seen in a number of patients (~ 20–25%) at time of discovery [ 2 ]. Historically, such patients have done poorly, but recent gains through surgical advances and novel chemotherapeutic agents [ 3 ] have fueled efforts to subdivide stage IV CRC on the basis of patient survival. The 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging manual now stipulates three subsets of stage IV CRC (IVA, IVB, and IVC [M1a/M1b/M1C]), a move requiring commensurate survival stratification. However, spread to distant organs is chiefly addressed at present [ 4 ], largely ignoring lymph node metastasis (LNM) in the staging hierarchy. For stage III CRC, LNM status is the most important prognostic factor [ 5 ], yet it is unclear whether LNM is truly prognostic of stage IV CRC. There is controversy surrounding this issue, some sources confirming [ 6 – 8 ] and others denying [ 9 ] the ramifications thereof. No doubt, the reason for such controversy is the paucity of related research [ 8 , 10 , 11 ]. To further improve outcomes of stage IV CRC, it is imperative that survival factors be established through patient stratification, identifying those individuals amenable to cure. Our intent during this study was to explore the impact of LNM on patient survival in the setting of stage IV CRC. Patients and methods This study was retrospective in nature, drawn from a 13-year body of data (April 2007 to December 2020) collected at Saitama Medical University International Medical Center in Japan. During this period, 626 patients were surgically treated for stage IV CRC, and cases with simultaneous or metachronous resection of distant metastases were included in the study. Our protocol received approval of the institutional Ethics Committee, with written informed consent granted by all subjects preoperatively. All tumor (T) and lymph node (N) classifications adhered to guidelines of the Japanese Society for Cancer of the Colon and Rectum (JSCCR, 7th Edition). Mesenteric lymph nodes were thus separable into pericolic, intermediate, and apical nodes. Because degrees of peritoneal metastasis were not well evaluated and locations of distant LNM were diverse, those patients with peritoneal metastases (n = 78) or distant LNM (n = 55) only were excluded, leaving 493 eligible study subjects. No patients with recurrences of stage IV CRC or histories of preoperative chemotherapy were allowed to participate (Fig. 1 ). We grouped subjects as N + M1 (n = 384) or N0M1 (n = 109). Initially, we compared clinicopathologic characteristics and survival rates by group (ie, extent of LNM). Perioperative outcomes were then reviewed, to include additional data on stage III CRC. Propensity score matching (PSM) served to offset differences in baseline variables, and multivariate regression models were used to identify potential independent risk factors. The following parameters were incorporated into a multivariate model for PSM: sex; age; family history of cancer; carcinoembryonic antigen (CEA) level; tumor location, size, histotype, and differentiation; pathologic T/N classification; lymphatic invasion; perineural infiltration; venous invasion; distribution of distant organ metastases; hospital stay; postoperative complications; and adjuvant chemotherapy. Logistic regression analysis was also undertaken to assess group differences (N0M1 vs N1M1) in overall (OS) and cancer-specific (CSS) survival. To compare categorical variables, chi-square and Fisher’s exact tests were applied, and Kaplan-Meier plots were generated for CSS estimates. All statistical computations relied on standard software (SPSS v22; IBM Corp, Tokyo, Japan), setting significance at p < 0.05. Results CRC survival rates (stage III vs stage IV) with and without LNM As a related exercise, we grouped 1060 patients with stage III CRC according to LNM locations and counts, using pericolic, intermediate, and apical compartments as measures of remoteness from primary tumors. The resultant 5-year OS rates were 83.3%, 77.7%, and 63.2%, respectively (Figure 2A). We then analyzed our cohort (n=493) with stage IV CRC. Five-year OS in the N0M1 group was 41.7%, whereas N1M1 and N2M1 subsets of the N+M1 group showed 5-year OS rates of 35.0% and 26.8%, respectively (Figure 2A). Five-year CSS rates across these six subsets similarly reflected worsening prognosis as the scope of primary CRC and nodal involvement advanced, recorded as 86.1%, 80.3%, 63.8%, 46.1%, 37.1%, and 27.6%, respectively (Figure 2B). Clinicopathologic features of stage IV CRC cohort Once all qualifying patients (n=493) with stage IV CRC had been grouped by LNM status (N0M1: 109/493, 22.1%; N+M1: 384/493, 77.9%) (Table1), our analysis indicated greater propensity for lymphatic (60.9% vs 33.0%; p <0.001) and venous (89.8% vs 78.0%; p =0.008) invasion in the presence (N+M1) vs absence (N0M1) of LNM. The N0M1 (vs N+M1) group registered a lengthier mean hospital stay (15.1±9.0 vs 10.3±8.0; p =0.03), but the two groups did not differ significantly in terms of family history of cancer, carcinoembryonic antigen (CEA) level, tumor characteristics (location, size, histotype, differentiation), pathologic T/N classifications, postoperative complications, or adjuvant chemotherapy (Table 1). Outcomes of LNM analysis before matching In analyzing long-term outcomes of LNM subsets, the N0M1 (vs N+M1) group demonstrated significantly better 5-year OS (41.7% vs 30.8%; p =0.020) (Figure 3A1) and CSS (46.1% vs 32.4%; p =0.009) (Figure 3A2). Cox regression analysis was done before PSM to assess effects of various parameters on patient prognosis. LNM subsequently emerged as a significant independent predictor of OS (hazard ratio [HR]=1.5, 95% CI: 1.09-2.08; p =0.014), as did CEA level (HR=1.37, 95% CI: 1.03-1.84; p =0.033), tumor histotype (HR=0.54, 95% CI: 0.32-0.94; p =0.03), tumor differentiation (HR=0.45, 95% CI: 0.30-0.67; p <0.001), liver metastasis (HR=1.54, 95% CI: 1.02-2.32; p =0.041), lung metastasis (HR=1.63, 95% CI: 1.16-2.29; p =0.005), and chemotherapy (HR=0.53, 95% CI: 0.40-0.71; p <0.001) (Table 2). Findings were similar for 5-year CSS, LNM again constituting a significant independent predictor (HR =1.6, 95% CI: 1.13-2.25; p =0.007), along with CEA level (HR=1.40, 95% CI: 1.04-1.90; p =0.028), tumor histotype (HR=0.54, 95% CI: 0.31-0.94; p =0.029), tumor differentiation (HR=0.43, 95% CI: 0.29-0.64; p <0.001), liver metastasis (HR=1.62, 95% CI: 1.06-2.46; p =0.024), lung metastasis (HR=1.78, 95% CI: 1.26-2.52; p =0.001), and chemotherapy (HR=0.57, 95% CI: 0.43-0.77; p <0.001) (Table 3). Outcomes of LNM analysis after matching After 1:1 PSM (N0M1, 87; N+M1, 87), we compared clinical characteristics and pathologic variables of LNM subsets. Univariate analysis confirmed that the two groups were comparable (Table 1), and OS was still significantly better in the N0M1 (vs N+M1) group (43.7% vs 26.5%; p =0.042) (Figure 3B1). LNM (HR=1.72, 95% CI: 1.121-2.64; p =0.013) also proved to be independently predictive of OS, in addition to tumor histotype (HR=0.31, 95% CI: 0.099-0.95; p =0.04), tumor differentiation (HR=0.19, 95% CI: 0.076-0.47; p <0.001), and chemotherapy (HR=0.49, 95% CI: 0.306-0.79; p =0.004) (Table 2). Likewise, the N0M1 group surpassed the N+M1 group in CSS (48.8% vs 28.0%; p =0.027) (Figure 3B2), and LNM was identified as a significant independent predictor of CSS (HR =1.86, 95% CI: 1.185-2.90; p =0.007). Other factors predictive of CSS included tumor histotype (HR=0.24, 95% CI: 0.074-0.79 p =0.018), tumor differentiation (HR=0.16, 95% CI: 0.063-0.40; p <0.001), and chemotherapy (HR=0.53, 95% CI: 0.327-0.87; p =0.013) (Table 3). Discussion Above findings clearly demonstrate that in patients with stage IV CRC, hematogenous organ metastasis carries a significantly better prognosis than does regional LNM. Our analysis also confirmed regional LNM as an independent risk factor for long-term prognosis. This is not surprising, given the presumption by Dukes long ago that depth of tumor invasion (through colorectal wall) and LNM are strongly implicated in CRC prognosis [ 12 ]. LNM status has since become a critical factor in the treatment of CRC [ 13 , 14 ]. The Japanese classification of CRC takes into account distant reaches of positive lymph nodes, using pericolic, intermediate, and apical regions to gauge their relative remoteness from primary tumors [ 5 ]. In our examination of patients with stage III CRC, it was apparent that the further positive nodes were situated from sites of primary lesions, the worse the prognosis seemed to be. LNM status thus proved highly prognostic of stage III CRC. In an analogous manner, distant organ metastasis (N0M1) should carry a worse prognosis than that of regional LNM. However, distant implants of CRC likely result from hematogenous spread, becoming more ominous when coupled with LNM (N + M1). Indeed, the prognosis worsens as lymph node positivity climbs, lending support to a link between outcomes of stage IV CRC and LNM. The natural process of CRC metastasis is generally one in which tumor first breaks through intestinal wall, then invades nearby lymph nodes, and finally arrives at distant organs. In our cohort with stage IV CRC, regional LNM was lacking for ~ 22.1%, with the progression of nodal spread (N0M1→N1M1→N2M1) met by a worsening of prognosis. Such events raise the question of whether LNM and hematogenous metastasis occur together or independently. In some of our patients, hematogenous metastases actually preceded nodal metastases. Common sites of metastasis from CRC are liver, lung, peritoneum, and systemic lymph nodes, each variably ascribed to hematogenous, lymphatic, or peritoneal routes of spread [ 15 ]. Because venous drainage of the intestine is through the portal system, hematogenous metastases to liver are the first to occur, followed by tumor dissemination to lungs, bone, brain, and other sites. Cancers of distal rectum may instead first metastasize directly to the lungs, traveling from inferior rectal vein to inferior vena cava (IVC). Prior to PSM, our patient groups showed no significant differences in tumor locations or in metastases to liver or lung, but the mechanisms for metastasis of stage IV CRC must be researched more extensively. Since 1977, the AJCC has assumed publication of the TNM classification system originally devised by Pierre Denoix [ 16 ], relegating stage IV CRC to a consistently poor prognosis throughout the years. Although little attention has been paid to its risk factors, recent advances in preoperative imaging, improved survival rates after hepatectomy, and the availability of new adjuvant chemotherapeutic agents [ 17 ] have now provided the impetus for refinement of outcome projections. During the present investigation, we found no significant difference between groups (N0M1 vs N + M1) with respect to postoperative adjuvant chemotherapy, whereas survival proved significantly better for members of the N0M1 (vs N + M1) group. This discovery underscores the potential curability of otherwise systemic metastatic disease, in the absence of LNM. Unfortunately, a consensus is lacking on the order of needed tumor resection (primary vs metastasis). In Europe and in the United States, "liver first" is the rule, removing metastatic and primary tumors sequentially. Primary lesions are generally resected first in Japan, owing to lower rates of postsurgical complications [ 18 , 19 ]. A primary lesion left intact at time of hepatectomy may continue to seed the liver or lungs, risking recurrence or metastatic spread [ 14 ]. Despite observed preferences in treating stage IV CRC, the shared objective is still radical removal of both primary and secondary tumors, hoping to prolong patient survival [ 17 , 20 ]. At present, stage IV CRC is defined by the status of organ metastasis, designating solitary organ involvement as IVA, dual involvement as IVB, and combined peritoneal spread as IVC. Alternatively, our data have implicated LNM as an independent prognostic factor for stage IV disease. As with stage III CRC, it is quite feasible that precise counts of positive nodes may more accurately reflect the true prognosis of stage IV CRC, helping to ensure proper clinical treatment. There are some study limitations that are worthy of mention. Our single-center, retrospective design and the relatively small population examined may have influenced these results. Various treatments methods for distant metastases, such as resection (in any order) or chemoradiotherapy alone, are inclined to impact patient prognosis as well. A broader patient study, mandating synchronous removal of distant tumors, is warranted to corroborate the findings herein. Conclusion In the setting of stage IV CRC, distant hematogenous metastasis (N0M1) confers a better prognosis than does regional LNM (N + M1). This apparent prognostic divergence must be reflected in refined tumor classification subsets. Declarations Author contributions Liming Wang and Haoyue Ma provided original pictures and drafted the manuscript, which was reviewed by Bolun Song, Yinggang Chen and Yasumitsu Hirano. All authors have approved the final submission. Funding This study was supported by the Shenzhen High-level Hospital Construction Fund. Availability of data and materials Not applicable Ethics approval and consent to participate All study subjects granted informed consent. Our investigatory protocol was approved by the Ethics Committee of Saitama Medical University International Medical Center. Consent for publication Each participant agreed to the use of relevant personal medical data for research and publication. Conflicts of interest The authors have no competing interests to declare with respect to this study. References Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, Vignat J, Ferlay J, Murphy N, Bray F (2023) Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut 72:338–344 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 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Ann Surg 250:440–448 Rees M, Tekkis PP, Welsh FK, O'Rourke T, John TG (2008) Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 247:125–135 Han EC, Kwon YH, Park KJ, Jeong SY, Kang SB, Oh JH, Heo SC, Seoul Colorectal G (2018) Significance of lymph node metastasis in the survival of stage IV colorectal cancer by hematogenous metastasis. Ann Surg Treat Res 95:201–212 Elias D, Liberale G, Vernerey D, Pocard M, Ducreux M, Boige V, Malka D, Pignon JP, Lasser P (2005) Hepatic and extrahepatic colorectal metastases: when resectable, their localization does not matter, but their total number has a prognostic effect. Ann Surg Oncol 12:900–909 Hotta T, Takifuji K, Arii K, Yokoyama S, Matsuda K, Higashiguchi T, Tominaga T, Oku Y, Yamaue H (2006) Potential predictors of long-term survival after surgery for patients with stage IV colorectal cancer. 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Med (Baltim) 94:e1215 Hashiguchi Y, Muro K, Saito Y, Ito Y, Ajioka Y, Hamaguchi T, Hasegawa K, Hotta K, Ishida H, Ishiguro M et al (2020) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 25:1–42 O'Sullivan B, Brierley J, Byrd D, Bosman F, Kehoe S, Kossary C, Pineros M, Van Eycken E, Weir HK, Gospodarowicz M (2017) The TNM classification of malignant tumours-towards common understanding and reasonable expectations. Lancet Oncol 18:849–851 Hernandez Dominguez O, Yilmaz S, Steele SR (2023) Stage IV Colorectal Cancer Management and Treatment. J Clin Med 12 Matsubara N, Miyata H, Gotoh M, Tomita N, Baba H, Kimura W, Nakagoe T, Simada M, Kitagawa Y, Sugihara K, Mori M (2014) Mortality after common rectal surgery in Japan: a study on low anterior resection from a newly established nationwide large-scale clinical database. Dis Colon Rectum 57:1075–1081 Kobayashi H, Miyata H, Gotoh M, Baba H, Kimura W, Kitagawa Y, Nakagoe T, Shimada M, Tomita N, Sugihara K, Mori M (2014) Risk model for right hemicolectomy based on 19,070 Japanese patients in the National Clinical Database. J Gastroenterol 49:1047–1055 Kuo YT, Tsai WS, Hung HY, Hsieh PS, Chiang SF, Lai CC, Chern YJ, Hsu YJ, You JF (2021) Prognostic value of regional lymph node involvement in patients with metastatic colorectal cancer: palliative versus curative resection. World J Surg Oncol 19:150 Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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01:12:52","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":49115,"visible":true,"origin":"","legend":"","description":"","filename":"StageIVtable260125.docx","url":"https://assets-eu.researchsquare.com/files/rs-8690733/v1/36c706c0623f230ec91a2bef.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic divergence of hematogenous and lymphatic metastases in patients with stage IV colorectal cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although early detection is achievable through screening, distant metastases are seen in a number of patients (~\u0026thinsp;20\u0026ndash;25%) at time of discovery [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Historically, such patients have done poorly, but recent gains through surgical advances and novel chemotherapeutic agents [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] have fueled efforts to subdivide stage IV CRC on the basis of patient survival. The 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging manual now stipulates three subsets of stage IV CRC (IVA, IVB, and IVC [M1a/M1b/M1C]), a move requiring commensurate survival stratification. However, spread to distant organs is chiefly addressed at present [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], largely ignoring lymph node metastasis (LNM) in the staging hierarchy.\u003c/p\u003e \u003cp\u003eFor stage III CRC, LNM status is the most important prognostic factor [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], yet it is unclear whether LNM is truly prognostic of stage IV CRC. There is controversy surrounding this issue, some sources confirming [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and others denying [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] the ramifications thereof. No doubt, the reason for such controversy is the paucity of related research [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo further improve outcomes of stage IV CRC, it is imperative that survival factors be established through patient stratification, identifying those individuals amenable to cure. Our intent during this study was to explore the impact of LNM on patient survival in the setting of stage IV CRC.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eThis study was retrospective in nature, drawn from a 13-year body of data (April 2007 to December 2020) collected at Saitama Medical University International Medical Center in Japan. During this period, 626 patients were surgically treated for stage IV CRC, and cases with simultaneous or metachronous resection of distant metastases were included in the study. Our protocol received approval of the institutional Ethics Committee, with written informed consent granted by all subjects preoperatively.\u003c/p\u003e \u003cp\u003e All tumor (T) and lymph node (N) classifications adhered to guidelines of the Japanese Society for Cancer of the Colon and Rectum (JSCCR, 7th Edition). Mesenteric lymph nodes were thus separable into pericolic, intermediate, and apical nodes. Because degrees of peritoneal metastasis were not well evaluated and locations of distant LNM were diverse, those patients with peritoneal metastases (n\u0026thinsp;=\u0026thinsp;78) or distant LNM (n\u0026thinsp;=\u0026thinsp;55) only were excluded, leaving 493 eligible study subjects. No patients with recurrences of stage IV CRC or histories of preoperative chemotherapy were allowed to participate (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). We grouped subjects as N\u0026thinsp;+\u0026thinsp;M1 (n\u0026thinsp;=\u0026thinsp;384) or N0M1 (n\u0026thinsp;=\u0026thinsp;109).\u003c/p\u003e \u003cp\u003eInitially, we compared clinicopathologic characteristics and survival rates by group (ie, extent of LNM). Perioperative outcomes were then reviewed, to include additional data on stage III CRC. Propensity score matching (PSM) served to offset differences in baseline variables, and multivariate regression models were used to identify potential independent risk factors. The following parameters were incorporated into a multivariate model for PSM: sex; age; family history of cancer; carcinoembryonic antigen (CEA) level; tumor location, size, histotype, and differentiation; pathologic T/N classification; lymphatic invasion; perineural infiltration; venous invasion; distribution of distant organ metastases; hospital stay; postoperative complications; and adjuvant chemotherapy.\u003c/p\u003e \u003cp\u003eLogistic regression analysis was also undertaken to assess group differences (N0M1 vs N1M1) in overall (OS) and cancer-specific (CSS) survival. To compare categorical variables, chi-square and Fisher\u0026rsquo;s exact tests were applied, and Kaplan-Meier plots were generated for CSS estimates. All statistical computations relied on standard software (SPSS v22; IBM Corp, Tokyo, Japan), setting significance at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCRC survival rates (stage III vs stage IV) with and without LNM\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs a related exercise, we grouped 1060 patients with stage III CRC according to LNM locations and counts, using pericolic, intermediate, and apical compartments as measures of remoteness from primary tumors. The resultant 5-year OS rates were 83.3%, 77.7%, and 63.2%, respectively (Figure 2A). We then analyzed our cohort (n=493) with stage IV CRC. Five-year OS in the N0M1 group was 41.7%, whereas N1M1 and N2M1 subsets of the N+M1 group showed 5-year OS rates of 35.0% and 26.8%, respectively (Figure 2A).\u0026nbsp;Five-year CSS rates across these six subsets similarly reflected worsening prognosis as the scope of primary CRC and nodal involvement advanced, recorded as 86.1%, 80.3%, 63.8%, 46.1%, 37.1%, and 27.6%, respectively (Figure 2B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinicopathologic features of stage IV CRC cohort\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnce all qualifying patients (n=493) with stage IV CRC had been grouped by LNM status (N0M1: 109/493,\u0026nbsp;22.1%;\u0026nbsp;N+M1: 384/493,\u0026nbsp;77.9%) (Table1), our analysis indicated greater propensity for\u0026nbsp;lymphatic\u0026nbsp;(60.9% vs 33.0%; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001) and venous (89.8% vs 78.0%; \u003cem\u003ep\u003c/em\u003e=0.008) invasion in the presence (N+M1) vs absence (N0M1) of LNM. The N0M1 (vs N+M1) group registered a lengthier mean hospital stay (15.1\u0026plusmn;9.0 vs 10.3\u0026plusmn;8.0; \u003cem\u003ep\u003c/em\u003e=0.03), but the two groups did not differ significantly in terms of family history of cancer, carcinoembryonic antigen (CEA) level, tumor characteristics (location, size, histotype, differentiation), pathologic T/N classifications, postoperative complications, or adjuvant chemotherapy (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOutcomes of LNM analysis before matching\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn analyzing long-term outcomes of LNM subsets, the N0M1 (vs N+M1) group demonstrated significantly better 5-year OS (41.7% vs 30.8%; \u003cem\u003ep\u003c/em\u003e=0.020) (Figure 3A1) and CSS (46.1% vs 32.4%; \u003cem\u003ep\u003c/em\u003e=0.009) (Figure 3A2).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCox regression analysis was done before PSM to assess effects of various parameters on patient prognosis. LNM subsequently emerged as a significant independent predictor of OS (hazard ratio [HR]=1.5, 95% CI: 1.09-2.08; \u003cem\u003ep\u003c/em\u003e=0.014), as did CEA level (HR=1.37, 95% CI: 1.03-1.84; \u003cem\u003ep\u003c/em\u003e=0.033), tumor histotype (HR=0.54, 95% CI: 0.32-0.94; \u003cem\u003ep\u003c/em\u003e=0.03), tumor differentiation (HR=0.45, 95% CI: 0.30-0.67; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001), liver metastasis (HR=1.54, 95% CI: 1.02-2.32; \u003cem\u003ep\u003c/em\u003e=0.041), lung metastasis (HR=1.63, 95% CI: 1.16-2.29; \u003cem\u003ep\u003c/em\u003e=0.005), and chemotherapy (HR=0.53, 95% CI: 0.40-0.71; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001) (Table 2).\u003c/p\u003e\n\u003cp\u003eFindings were similar for 5-year CSS, LNM again constituting a significant independent predictor (HR =1.6, 95% CI: 1.13-2.25; \u003cem\u003ep\u003c/em\u003e=0.007), along with CEA level (HR=1.40, 95% CI: 1.04-1.90; \u003cem\u003ep\u003c/em\u003e=0.028), tumor histotype (HR=0.54, 95% CI: 0.31-0.94; \u003cem\u003ep\u003c/em\u003e=0.029), tumor differentiation (HR=0.43, 95% CI: 0.29-0.64; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001), liver metastasis (HR=1.62, 95% CI: 1.06-2.46; \u003cem\u003ep\u003c/em\u003e=0.024), lung metastasis (HR=1.78, 95% CI: 1.26-2.52; \u003cem\u003ep\u003c/em\u003e=0.001), and chemotherapy (HR=0.57, 95% CI: 0.43-0.77; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001) (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOutcomes of LNM analysis after matching\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter 1:1 PSM (N0M1, 87; N+M1, 87), we compared clinical characteristics and pathologic variables of LNM subsets.\u0026nbsp;Univariate analysis confirmed that the two groups were comparable (Table 1), and\u0026nbsp;OS was still significantly better in the N0M1 (vs N+M1) group (43.7% vs 26.5%; \u003cem\u003ep\u003c/em\u003e=0.042) (Figure 3B1). LNM (HR=1.72, 95% CI: 1.121-2.64; \u003cem\u003ep\u003c/em\u003e=0.013) also proved to be independently predictive of OS, in addition to tumor histotype (HR=0.31, 95% CI: 0.099-0.95; \u003cem\u003ep\u003c/em\u003e=0.04), tumor differentiation (HR=0.19, 95% CI: 0.076-0.47; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001), and chemotherapy (HR=0.49, 95% CI: 0.306-0.79; \u003cem\u003ep\u003c/em\u003e=0.004) (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLikewise, the N0M1 group surpassed the N+M1 group in CSS (48.8% vs 28.0%; \u003cem\u003ep\u003c/em\u003e=0.027) (Figure 3B2), and LNM was identified as a significant independent predictor of CSS (HR =1.86, 95% CI: 1.185-2.90; \u003cem\u003ep\u003c/em\u003e=0.007). Other factors predictive of CSS included tumor histotype (HR=0.24, 95% CI: 0.074-0.79 \u003cem\u003ep\u003c/em\u003e=0.018), tumor differentiation (HR=0.16, 95% CI: 0.063-0.40; \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001), and chemotherapy (HR=0.53, 95% CI: 0.327-0.87; \u003cem\u003ep\u003c/em\u003e=0.013) (Table 3).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAbove findings clearly demonstrate that in patients with stage IV CRC, hematogenous organ metastasis carries a significantly better prognosis than does regional LNM. Our analysis also confirmed regional LNM as an independent risk factor for long-term prognosis. This is not surprising, given the presumption by Dukes long ago that depth of tumor invasion (through colorectal wall) and LNM are strongly implicated in CRC prognosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. LNM status has since become a critical factor in the treatment of CRC [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Japanese classification of CRC takes into account distant reaches of positive lymph nodes, using pericolic, intermediate, and apical regions to gauge their relative remoteness from primary tumors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In our examination of patients with stage III CRC, it was apparent that the further positive nodes were situated from sites of primary lesions, the worse the prognosis seemed to be. LNM status thus proved highly prognostic of stage III CRC. In an analogous manner, distant organ metastasis (N0M1) should carry a worse prognosis than that of regional LNM. However, distant implants of CRC likely result from hematogenous spread, becoming more ominous when coupled with LNM (N\u0026thinsp;+\u0026thinsp;M1). Indeed, the prognosis worsens as lymph node positivity climbs, lending support to a link between outcomes of stage IV CRC and LNM.\u003c/p\u003e \u003cp\u003eThe natural process of CRC metastasis is generally one in which tumor first breaks through intestinal wall, then invades nearby lymph nodes, and finally arrives at distant organs. In our cohort with stage IV CRC, regional LNM was lacking for ~\u0026thinsp;22.1%, with the progression of nodal spread (N0M1\u0026rarr;N1M1\u0026rarr;N2M1) met by a worsening of prognosis. Such events raise the question of whether LNM and hematogenous metastasis occur together or independently. In some of our patients, hematogenous metastases actually preceded nodal metastases.\u003c/p\u003e \u003cp\u003eCommon sites of metastasis from CRC are liver, lung, peritoneum, and systemic lymph nodes, each variably ascribed to hematogenous, lymphatic, or peritoneal routes of spread [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Because venous drainage of the intestine is through the portal system, hematogenous metastases to liver are the first to occur, followed by tumor dissemination to lungs, bone, brain, and other sites. Cancers of distal rectum may instead first metastasize directly to the lungs, traveling from inferior rectal vein to inferior vena cava (IVC). Prior to PSM, our patient groups showed no significant differences in tumor locations or in metastases to liver or lung, but the mechanisms for metastasis of stage IV CRC must be researched more extensively.\u003c/p\u003e \u003cp\u003eSince 1977, the AJCC has assumed publication of the TNM classification system originally devised by Pierre Denoix [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], relegating stage IV CRC to a consistently poor prognosis throughout the years. Although little attention has been paid to its risk factors, recent advances in preoperative imaging, improved survival rates after hepatectomy, and the availability of new adjuvant chemotherapeutic agents [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] have now provided the impetus for refinement of outcome projections. During the present investigation, we found no significant difference between groups (N0M1 vs N\u0026thinsp;+\u0026thinsp;M1) with respect to postoperative adjuvant chemotherapy, whereas survival proved significantly better for members of the N0M1 (vs N\u0026thinsp;+\u0026thinsp;M1) group. This discovery underscores the potential curability of otherwise systemic metastatic disease, in the absence of LNM.\u003c/p\u003e \u003cp\u003eUnfortunately, a consensus is lacking on the order of needed tumor resection (primary vs metastasis). In Europe and in the United States, \"liver first\" is the rule, removing metastatic and primary tumors sequentially. Primary lesions are generally resected first in Japan, owing to lower rates of postsurgical complications [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A primary lesion left intact at time of hepatectomy may continue to seed the liver or lungs, risking recurrence or metastatic spread [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Despite observed preferences in treating stage IV CRC, the shared objective is still radical removal of both primary and secondary tumors, hoping to prolong patient survival [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt present, stage IV CRC is defined by the status of organ metastasis, designating solitary organ involvement as IVA, dual involvement as IVB, and combined peritoneal spread as IVC. Alternatively, our data have implicated LNM as an independent prognostic factor for stage IV disease. As with stage III CRC, it is quite feasible that precise counts of positive nodes may more accurately reflect the true prognosis of stage IV CRC, helping to ensure proper clinical treatment.\u003c/p\u003e \u003cp\u003eThere are some study limitations that are worthy of mention. Our single-center, retrospective design and the relatively small population examined may have influenced these results. Various treatments methods for distant metastases, such as resection (in any order) or chemoradiotherapy alone, are inclined to impact patient prognosis as well. A broader patient study, mandating synchronous removal of distant tumors, is warranted to corroborate the findings herein.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn the setting of stage IV CRC, distant hematogenous metastasis (N0M1) confers a better prognosis than does regional LNM (N\u0026thinsp;+\u0026thinsp;M1). This apparent prognostic divergence must be reflected in refined tumor classification subsets.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLiming Wang and Haoyue Ma provided original pictures and drafted the manuscript, which was reviewed by Bolun Song, Yinggang Chen and Yasumitsu Hirano. All authors have approved the final submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Shenzhen High-level Hospital Construction Fund.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study subjects granted informed consent. Our investigatory protocol was approved by the Ethics Committee of Saitama Medical University International Medical Center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach participant agreed to the use of relevant personal medical data for research and publication. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare with respect to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMorgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, Vignat J, Ferlay J, Murphy N, Bray F (2023) Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. 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J Gastrointest Surg 25:1866\u0026ndash;1874\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu J, Jiang M, Tan Y, Yang J, Wu L, Feng L, Zheng S, Yuan Y (2015) Synchronous Resectable Metastatic Colorectal Cancer: Lymph Node Involvement Predicts Poor Outcome. Med (Baltim) 94:e1215\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHashiguchi Y, Muro K, Saito Y, Ito Y, Ajioka Y, Hamaguchi T, Hasegawa K, Hotta K, Ishida H, Ishiguro M et al (2020) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 25:1\u0026ndash;42\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Sullivan B, Brierley J, Byrd D, Bosman F, Kehoe S, Kossary C, Pineros M, Van Eycken E, Weir HK, Gospodarowicz M (2017) The TNM classification of malignant tumours-towards common understanding and reasonable expectations. Lancet Oncol 18:849\u0026ndash;851\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHernandez Dominguez O, Yilmaz S, Steele SR (2023) Stage IV Colorectal Cancer Management and Treatment. J Clin Med 12\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsubara N, Miyata H, Gotoh M, Tomita N, Baba H, Kimura W, Nakagoe T, Simada M, Kitagawa Y, Sugihara K, Mori M (2014) Mortality after common rectal surgery in Japan: a study on low anterior resection from a newly established nationwide large-scale clinical database. Dis Colon Rectum 57:1075\u0026ndash;1081\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobayashi H, Miyata H, Gotoh M, Baba H, Kimura W, Kitagawa Y, Nakagoe T, Shimada M, Tomita N, Sugihara K, Mori M (2014) Risk model for right hemicolectomy based on 19,070 Japanese patients in the National Clinical Database. J Gastroenterol 49:1047\u0026ndash;1055\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuo YT, Tsai WS, Hung HY, Hsieh PS, Chiang SF, Lai CC, Chern YJ, Hsu YJ, You JF (2021) Prognostic value of regional lymph node involvement in patients with metastatic colorectal cancer: palliative versus curative resection. World J Surg Oncol 19:150\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"stage IV colorectal cancer, lymph node metastasis, propensity score matching","lastPublishedDoi":"10.21203/rs.3.rs-8690733/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8690733/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e In patients with stage IV colorectal cancer (CRC), the prognostic impact of lymph node metastasis (LNM) remains controversial. A qualifying cohort served to explore its importance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe selected 493 eligible patients with stage IV CRC for retrospective study. All were surgically treated between April 2007 and December 2020 at a high-volume cancer center in Japan. Subjects were stratified by presence/absence of LNM (N+M1 vs N0M1), and propensity score matching (PSM) was done at 1:1 ratio. We then compared cancer-specific (CSS) and overall (OS) survival rates before and after PSM, using Cox regression to identify pertinent independent risk factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Patients assigned to N+M1 and N0M1 groups totaled 384 (77.9%) and 109 (22.1%), respectively. Five-year OS proved superior for the N0M1 (vs N+M1) group, both before (41.7% vs 30.8%; \u003cem\u003ep\u003c/em\u003e=0.020) and after (43.7% vs 26.5%; \u003cem\u003ep\u003c/em\u003e=0.042) PSM. LNM also emerged as an independent prognosticator of OS in multivariate analyses conducted before (hazard ratio [HR]=1.5, 95% confidence interval [CI]: 1.09-2.08; \u003cem\u003ep\u003c/em\u003e=0.014) and after (HR=1.72, 95% CI: 1.121-2.64; \u003cem\u003ep\u003c/em\u003e=0.013) matching.\u003c/p\u003e\n\u003cp\u003eThe same was true of 5-year CSS, both before (N0M1, 46.1%; N+M1, 32.4%; \u003cem\u003ep\u003c/em\u003e=0.009) and after (N0M1, 48.8%; N+M1, 28.0%; \u003cem\u003ep\u003c/em\u003e=0.027) matching, again verifying LNM as an independent prognostic factor before (HR=1.6, 95% CI: 1.13-2.25; \u003cem\u003ep\u003c/em\u003e=0.007) and after (HR=1.86, 95% CI: 1.185-2.90; \u003cem\u003ep\u003c/em\u003e=0.007) PSM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In the setting of stage IV CRC, distant hematogenous metastasis (N0M1) confers a better prognosis than does regional LNM (N+M1). This apparent prognostic divergence must be reflected in refined tumor classification subsets.\u003c/p\u003e","manuscriptTitle":"Prognostic divergence of hematogenous and lymphatic metastases in patients with stage IV colorectal cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-13 01:12:47","doi":"10.21203/rs.3.rs-8690733/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-15T09:43:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-28T15:39:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"309629181341746887145492252326652997112","date":"2026-02-15T01:26:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-13T17:17:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"137399871427491832346766270464610049782","date":"2026-02-13T17:04:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219736737602039874177987254782640608889","date":"2026-02-11T04:09:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"287681884140937169412967669966137777196","date":"2026-02-09T16:22:17+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-08T13:46:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-26T10:01:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-26T01:57:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Colorectal Disease","date":"2026-01-25T06:50:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-colorectal-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijcd","sideBox":"Learn more about [International Journal of Colorectal Disease](http://link.springer.com/journal/384)","snPcode":"384","submissionUrl":"https://submission.nature.com/new-submission/384/3","title":"International Journal of Colorectal Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"75dbed7b-53c6-4d67-872e-c18883161813","owner":[],"postedDate":"February 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-16T07:39:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-13 01:12:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8690733","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8690733","identity":"rs-8690733","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}