Prognostic significance of lymph node-related indices and a novel nomogram for rectal cancer patients with synchronous liver metastases after the preoperative chemoradiotherapy: a population-based study

Introduction

Colorectal cancer (CRC) is the fourth common cancer worldwide (1). Approximately 30% of CRC patients have metastatic disease at diagnosis (2). Of these, 15–25% of CRC cases are accompanied by synchronous liver metastases (3). Multimodal therapy, including preoperative chemoradiotherapy followed by surgical resection, has been established as a standard approach for locally advanced rectal cancer. In the context of synchronous liver metastases, this strategy aims to achieve local control and enable curative-intent resection of both primary and metastatic lesions. However, patient outcomes remain heterogeneous, underscoring the need for reliable prognostic factors to guide individualized treatment strategies. The prognosis for colorectal cancer with synchronous liver metastases (CRLM) without treatment is poor, with a 5-year survival rate of less than 5% (4). For patients with rectal cancer and synchronous liver metastases, the clinical management is particularly challenging due to the dual complexity of local pelvic disease and systemic metastatic burden.

It is estimated that over 700,000 new cases of rectal cancer occur worldwide each year (1). Preoperative chemoradiotherapy is the standard of care for advanced rectal cancer due to its improved disease control (5,6). However, several studies have found that preoperative chemoradiotherapy reduces the total number of lymph nodes (TLN) examined and number of positive lymph nodes (PLN) in rectal cancer surgery (7-10). The current guidelines recommend that a minimum of 12 lymph nodes (LNs) should be examined in rectal cancer surgery, without distinguishing the use of preoperative chemoradiotherapy (11,12). There is no consensus on the optimal number of examined LNs for rectal cancer patients with preoperative chemoradiotherapy, especially for those with synchronous liver metastases.

Previous studies have shown that TLN, NLN, and PLN are prognostic factors for survival in CRC (13-15). However, the prognostic significance of these LN-related indices in rectal cancer patients with synchronous liver metastases remains unclear. Furthermore, few studies have investigated the prognostic role of these LN-related indices in rectal cancer patients with synchronous liver metastases after preoperative chemoradiotherapy.

Therefore, the aim of this study was to examine the influence of LN-related indices on the survival of rectal cancer patients with synchronous liver metastases following preoperative chemoradiotherapy. We present this article in accordance with the TRIPOD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2043/rc).

Methods

Study population

Data of rectal cancer patients with synchronous liver metastases who underwent preoperative chemoradiotherapy between January 2010 and December 2019 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. The inclusion criteria were as follows: (I) patients received preoperative chemoradiotherapy; and (II) patients underwent surgical resection of the primary tumor and were pathologically diagnosed as having rectal cancer with liver metastases. The exclusion criteria were as follows: (I) presence of non-liver metastases or combined extrahepatic metastases; (II) tumor not being adenocarcinoma; (III) presence of a second tumor; (IV) patients with incomplete tumor-node-metastasis (TNM) information; (V) primary tumor not undergoing surgical resection; (VI) survival time of not more than 1 month; (VII) failure to undergo preoperative chemoradiotherapy; and (VIII) patients being less than 18 years old or more than 85 years old; (IX) patients with stage N1c. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Statistical analysis

The statistical analyses were performed using the SPSS 25.0 statistical package (SPSS, Chicago, IL, USA) and R (version 4.2.2). The cutoff values for TLN, PLN, and NLN were established with the X-tile software (version 3.6.1, © Yale University 2003). We employed the Kaplan-Meier method to evaluate 5-year survival rates and used the log-rank test to compare survival disparities between different groups. The Kaplan-Meier curve was produced with the R software (version 4.1.2). Both univariate and multivariate analysis were conducted with Cox’s proportional hazards model. A P value of less than 0.05 was considered significant. A novel nomogram was established based on the independent prognostic factors indicated in the multivariate Cox analysis. The concordance index (C-index) and calibration curve were used to determine the predictive accuracy and discriminative ability of the nomogram. P<0.05 was considered significantly.

Results

Clinicopathological characteristics

In this study, a total of 547 patients were enrolled, including 370 men and 177 women with a median age of 55 years (range, 21–84 years). Eighty point six percent (441/547) of patients were White, and more than half of patients were married. More than 50% of patients had a positive pretreatment carcinoembryonic antigen (CEA) level, but only 23.9% (131/547) had perineural invasion. Seventy-two point two percent of patients had moderate tumor grades, and most patients had ≥12 LNs examined. The clinicopathological characteristics are shown in Table 1.

Impact of TLN on survival

Using the X-tile software, patients were divided into two groups based on their TLN: those with TLN less than 7 and those with TLN equal to or greater than 7 (Figure 1). Notably, the survival outcomes for patients with TLN less than 7 were significantly worse compared to those with TLN equal to or greater than 7. Specifically, the 5-year overall survival (OS) rates were 22.9% and 43.8% for the respective groups (P=0.001) (Figure 2).

Figure 1 The optimal cutoff point of TLN was determined by the X-tile software (the cyan line/bar represents patients with TLN <7, while the gray line/bar represents patients with TLN ≥7). TLN, total number of lymph nodes.

Figure 2 Kaplan-Meier curve for OS according to TLN. LNs, lymph nodes; OS, overall survival; TLN, total number of lymph nodes.

To identify the clinicopathological factors that influenced OS, Cox regression analysis was performed. The results of the univariate analysis showed that age, pretreatment CEA levels, tumor grade, perineural invasion, N status, and TLN were all significantly associated with OS (the P value was <0.001, 0.02, 0.001, <0.001, <0.001, 0.001, respectively) (Table 1). Multivariate analysis further demonstrated that TLN was an independent prognostic factor for OS [hazard ratio (HR) =0.571, 95% confidence interval (CI): 0.408–0.799, P=0.001] (Table 1).

Impact of PLN and NLN on survival

We divided patients into two groups based on PLN (group PLN <7 and group PLN ≥7) using the X-tile software (Figure 3). Survival analysis revealed that patients with PLN <7 had significantly better OS compared to those with PLN ≥7 (3-year OS rate: 63.5% vs. 36.0%; 5-year OS rate: 44.1% vs. 12.6%, P<0.001) (Figure 4). Similarly, patients were divided into two groups based on NLN (group NLN <11 and group NLN ≥11) (Figure 5). The 3-year OS rate was 49.7% for patients with NLN <11 compared with 68.6% for patients with NLN ≥11; and the 5-year OS rate was 23.9% and 53.6% for patients with NLN <11 and patients with NLN ≥11, respectively (P<0.001) (Figure 6).

Figure 3 Using the X-tile software to determine the optimal cutoff point of PLN (the cyan line/bar represents patients with PLN <7, while the gray line/bar represents patients with PLN ≥7). PLN, number of positive lymph nodes.

Figure 4 Kaplan-Meier curve for OS based on PLN. LNs, lymph nodes; OS, overall survival; PLN, number of positive lymph nodes.

Figure 5 Using the X-tile software to determine the optimal cutoff point of NLN (the cyan line/bar represents patients with NLN <11, while the gray line/bar represents patients with NLN ≥11). NLN, number of negative lymph nodes.

Figure 6 Kaplan-Meier curve for OS based on NLN. LNs, lymph nodes; NLN, number of negative lymph nodes; OS, overall survival.

In Cox univariate analysis, we found that age, pretreatment CEA, grade, perineural invasion, N status, NLN, and PLN were significantly associated with OS (the P value was <0.001, 0.02, 0.001, <0.001, <0.001, <0.001, <0.001, respectively) (Table 2). Furthermore, multivariate analysis revealed that NLN and PLN were independent prognostic factors for OS (NLN: HR =0.593, 95% CI: 0.456–0.770, P<0.001; PLN: HR =1.736, 95% CI: 1.201–2.509, P=0.003) (Table 2).

Impact of other factors on survival

The 3-year OS was 66.3% for patients with N0 compared with 56.6% for patients with N+; the 5-year OS rate was 55.4% and 30.7% for N0 and N+ patients, respectively (P<0.001). In Cox univariate analysis, N status was significantly associated with OS (HR =1.828, 95% CI: 1.394–2.397) (Tables 1,2). The result of Cox multivariate analysis showed that N status was an independent prognostic factor for OS (Tables 1,2). Additionally, age and tumor grade were also found to be significantly associated with OS in both Cox univariate and multivariate analysis.

A novel prognostic nomogram construction and validation

We developed a novel nomogram to estimate 3-year OS according to the independent prognostic factors indicated in the multivariate Cox analysis. The nomogram that integrated all significant independent factors for OS was shown in Figure 7. The nomogram-derived individual scores allowed for the computation of comprehensive patient-specific total scores. These cumulative scores demonstrated an inverse relationship with clinical outcomes, where elevated values correlated with diminished prognostic indicators. Internal validation of the nomogram’s predictive accuracy was conducted through bootstrap resampling analysis utilizing the original cohort of 547 cases. The C-index for prognostic nomogram was 0.67 (95% CI: 0.63–0.71). The calibration plot for the probability of 3-year survival demonstrated an optimal agreement between the predicted and actual survival (Figure 8).

Figure 7 Nomogram to evaluate the survival outcome of rectal cancer patients with liver metastases. N, node; NLN, number of negative lymph nodes; PLN, number of positive lymph nodes.

Figure 8 The calibration curve of the nomogram.

Discussion

Previous study has reported that approximately 25% of patients with CRC have liver metastases at diagnosis (16). However, the standard treatment for patients with metastatic rectal cancer, especially those with liver metastases, has not been consistent (17,18). The treatment options for rectal cancer with liver metastases include radiotherapy, chemotherapy, and resection of the primary tumor. Unfortunately, the prognosis for these patients remains poor (19). Therefore, identifying the risk factors that impact survival is crucial to improving outcomes.

It is widely recognized that an adequate number of TLN can contribute to accurate tumor staging. Furthermore, numerous studies have verified that TLN is a significant prognostic factor in CRC (20,21). In this study, we observed that patients with TLN ≥7 had a significantly better OS compared to patients with TLN <7. Surprisingly, survival analysis revealed no significant difference in survival between patients with TLN <12 and patients with TLN ≥12 (5-year OS rate: 32.4% vs. 44.5%, P=0.06). This finding suggests that the current criterion (examination of ≥12 LNs) may not be appropriate for rectal cancer patients with liver metastases who have received preoperative chemoradiotherapy. Moreover, based on the results of this study, examining 7 or more LNs may be more appropriate for these patients.

LN status is a crucial prognostic factor in rectal cancer patients (22). Compared to patients with node-negative tumors, patients with node-positive tumors experienced significantly worse survival rates. In our study, the 5-year OS rate of patients with ypN0 was 55.4%, while it was only 30.7% for patients with ypN+ (P<0.001). Our findings suggest that LN status remains a risk prognostic factor for rectal cancer patients with liver metastases, aligning with previous studies (23,24).

Previous studies have shown that PLN has a significant impact on the survival of patients with CRC, with a negative correlation between the number of PLN and survival rates (15,25). In this current study, we used the X-tile software to determine the optimal cutoff value for PLN. We found that patients with PLN ≥7 had a lower 5-year survival rate compared to those with PLN <7. PLN is the basis for current guidelines for pN staging, and its prognostic role in CRC patients has been demonstrated. Our study found that PLN remained an important risk factor for rectal cancer patients with liver metastases. For patients with more PLN, the systematic therapy might need to be enhanced.

The prognostic impact of NLN in CRC has been well established in recent years. Ogino et al. reported that the survival rate of CRC patients with NLN ≥13 was significantly higher than that of patients with NLN ≤3 (P<0.001) (26). In this study, we also observed that for rectal cancer patients with liver metastases, those with more NLN had a better prognosis. The survival of patients with NLN ≥11 was better than that of patients with NLN <11 (5-year OS rate: 53.6% vs. 23.9%, P<0.001). Therefore, NLN can provide additional prognostic detail for rectal cancer patients with liver metastases. Furthermore, we developed a novel nomogram based on the variables of age, grade, N status, PLN and NLN and it resulted in more-accurate prognostic prediction for rectal cancer patients with liver metastases.

Therefore, LN-related indices are significant prognostic factors in rectal cancer patients with liver metastases, providing valuable prognostic information for treatment. In this present study, we specifically analyzed rectal cancer patients with liver metastases who had received preoperative chemoradiotherapy, helping to eliminate potential interference factors. Previous studies have not focused on this aspect. Therefore, our study can offer useful information for future similar investigations.

There are some limitations in this study. Firstly, data were extracted from the SEER database. Due to missing information for some variables, potential bias may arise. This includes the lack of details on chemotherapy regimens and dosages, absence of information regarding regional therapy for liver metastases and characteristics of liver metastases (solitary or multiple, size, etc.), as well as missing data on the resectability status of liver disease, its molecular features (RAS, BRAF, MSI, etc.), and pharmacotherapy. Secondly, this was a retrospective study with a small sample size. More research need be done to verify our results in the future. Thirdly, the model primarily targets the specific population of rectal cancer patients with synchronous liver metastases, which limits its generalizability to some extent. At the same time, it has not yet been validated using an independent dataset from other centers.

Conclusions

In summary, this study examined the prognostic impact of LN-related indices in rectal cancer patients with synchronous liver metastases who received preoperative chemoradiotherapy. Our findings demonstrate that LN-related indices are crucial prognostic factors that may aid in predicting survival and guiding personalized treatment strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2043/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2043/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-2043/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
2. Jones RP, Jackson R, Dunne DF, et al. Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases. Br J Surg 2012;99:477-86. [Crossref] [PubMed]
3. Borner MM. Neoadjuvant chemotherapy for unresectable liver metastases of colorectal cancer--too good to be true? Ann Oncol 1999;10:623-6. [Crossref] [PubMed]
4. Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006;244:254-9. [Crossref] [PubMed]
5. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-40. [Crossref] [PubMed]
6. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46. [Crossref] [PubMed]
7. Tsai CJ, Crane CH, Skibber JM, et al. Number of lymph nodes examined and prognosis among pathologically lymph node-negative patients after preoperative chemoradiation therapy for rectal adenocarcinoma. Cancer 2011;117:3713-22. [Crossref] [PubMed]
8. Miller ED, Robb BW, Cummings OW, et al. The effects of preoperative chemoradiotherapy on lymph node sampling in rectal cancer. Dis Colon Rectum 2012;55:1002-7. [Crossref] [PubMed]
9. Ha YH, Jeong SY, Lim SB, et al. Influence of preoperative chemoradiotherapy on the number of lymph nodes retrieved in rectal cancer. Ann Surg 2010;252:336-40. [Crossref] [PubMed]
10. Mechera R, Schuster T, Rosenberg R, et al. Lymph node yield after rectal resection in patients treated with neoadjuvant radiation for rectal cancer: A systematic review and meta-analysis. Eur J Cancer 2017;72:84-94. [Crossref] [PubMed]
11. Sobin LH, Greene FL. TNM classification: clarification of number of regional lymph nodes for pNo. Cancer 2001;92:452. [Crossref] [PubMed]
12. Awwad GE, Tou SI, Rieger NA. Prognostic significance of lymph node yield after long-course preoperative radiotherapy in patients with rectal cancer: a systematic review. Colorectal Dis 2013;15:394-403. [Crossref] [PubMed]
13. Swanson RS, Compton CC, Stewart AK, et al. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003;10:65-71. [Crossref] [PubMed]
14. Johnson PM, Porter GA, Ricciardi R, et al. Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol 2006;24:3570-5. [Crossref] [PubMed]
15. Gunderson LL, Jessup JM, Sargent DJ, et al. Revised tumor and node categorization for rectal cancer based on surveillance, epidemiology, and end results and rectal pooled analysis outcomes. J Clin Oncol 2010;28:256-63. [Crossref] [PubMed]
16. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg 1990;77:1241-6. [Crossref] [PubMed]
17. Shida D, Boku N, Tanabe T, et al. Primary Tumor Resection for Stage IV Colorectal Cancer in the Era of Targeted Chemotherapy. J Gastrointest Surg 2019;23:2144-50. [Crossref] [PubMed]
18. Lykke J, Jess P, Roikjaer O, et al. The prognostic value of lymph node ratio in a national cohort of rectal cancer patients. Eur J Surg Oncol 2016;42:504-12. [Crossref] [PubMed]
19. Kanas GP, Taylor A, Primrose JN, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 2012;4:283-301. [Crossref] [PubMed]
20. Bui L, Rempel E, Reeson D, et al. Lymph node counts, rates of positive lymph nodes, and patient survival for colon cancer surgery in Ontario, Canada: a population-based study. J Surg Oncol 2006;93:439-45. [Crossref] [PubMed]
21. Vather R, Sammour T, Kahokehr A, et al. Lymph node evaluation and long-term survival in Stage II and Stage III colon cancer: a national study. Ann Surg Oncol 2009;16:585-93. [Crossref] [PubMed]
22. Benson AB, Venook AP, Al-Hawary MM, et al. Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018;16:874-901. [Crossref] [PubMed]
23. Ahmed S, Leis A, Chandra-Kanthan S, et al. Regional Lymph Nodes Status and Ratio of Metastatic to Examined Lymph Nodes Correlate with Survival in Stage IV Colorectal Cancer. Ann Surg Oncol 2016;23:2287-94. [Crossref] [PubMed]
24. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309-18; discussion 318-21. [Crossref] [PubMed]
25. Gunderson LL, Jessup JM, Sargent DJ, et al. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol 2010;28:264-71. [Crossref] [PubMed]
26. Ogino S, Nosho K, Irahara N, et al. Negative lymph node count is associated with survival of colorectal cancer patients, independent of tumoral molecular alterations and lymphocytic reaction. Am J Gastroenterol 2010;105:420-33. [Crossref] [PubMed]