The Prognostic Value of Log Odds of Positive Lymph Nodes in Early-Stage Esophageal Cancer Patients: A Study Based on the SEER Database and a Chinese Cohort

Xi, Kexing; Chen, Wenyou; Yu, Hui

doi:https://doi.org/10.1155/2021/8834912

Journal of Oncology

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Abstract Introduction Materials and Methods Results Discussion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2021 | Article ID 8834912 | https://doi.org/10.1155/2021/8834912

The Prognostic Value of Log Odds of Positive Lymph Nodes in Early-Stage Esophageal Cancer Patients: A Study Based on the SEER Database and a Chinese Cohort

Kexing Xi,¹Wenyou Chen,²and Hui Yu^3,4

Academic Editor: Amir Radfar

Received18 Aug 2020

Revised19 Dec 2020

Accepted02 Feb 2021

Published05 Mar 2021

Abstract

Objective. Early detection and timely treatment are important for improving the prognosis of esophageal cancer (EC). Identification of the prognostic risk factors could help us to discern the high-risk population. This study was aimed at exploring the prognostic significance of log odds of positive lymph nodes (LODDS) in early-stage EC patients. Methods. Patients who underwent esophagectomy and diagnosed as pathologic T1-2 N0 EC were reviewed between January 2005 and December 2015 from the Surveillance, Epidemiology, and End Results (SEER) database (the development cohort, n = 1004). The X-tile software was used to determine the optimal cutoff values of LODDS. A separate Chinese cohort including 245 patients (the validation cohort) was used to externally validate the results of the SEER database. Result. Patients were divided into two groups based on the cutoff points of LODDS: <−1.40 (LODDS1) and ≥−1.40 (LODDS2). In the development cohort, the 5-year overall survival (OS) rate was 75.3% for patients in the LODDS1 group, compared with 67.5% for those in the LODDS2 group (). In multivariate Cox analysis, LODDS was associated with OS significantly (hazard ratio (HR), 1.48; 95% confidence intervals (CI), 1.19–1.85). In the validation cohort, the 5-year OS rate was 76.6% for patients in the LODDS1 group, compared with 64.4% for those in the LODDS2 group (). The HR value in multivariate Cox analysis for OS was 2.00 (95% CI, 1.26–3.18). Conclusion. LODDS was an important independent factor for survival in early-stage EC patients.

1. Introduction

Esophageal cancer (EC) is one of the most common cancers and the fifth common cause of cancer-related death worldwide [1, 2]. The prognosis of EC is poor and the 5-year overall survival rate is approximately 17% for all patients [3]. Up to now, surgery is still the main treatment for early-stage and localized EC. However, surgical treatment remains unsatisfactory and the 5-year overall survival is less than 25% for patients who received surgery alone [4, 5]. The main cause of treatment failure for EC is local recurrence and distant metastasis.

Early detection and timely treatment are important for improving the prognosis of EC [6]. Identification of the prognostic risk factors is the first step which can help us to discern the high-risk population and take appropriate precautions. Moreover, for high-risk population, the postoperative follow-up should be more intensive so that there could be early detection of the recurrence and metastasis. TNM staging is significantly associated with the survival outcome for EC patients [6, 7]. Previous studies have reported that age, heavy drinking, smoking, etc. are also strong independent factors for EC [8–11]. Although many prognostic factors have been found, we still could not adequately stratify risk in EC patients. Therefore, we need to find additional new factors to provide more precise prognostic prediction for EC patients.

Recently, several studies have demonstrated that the logarithmic odds of positive lymph nodes (LODDS) plays an important role in some cancers for prognostic prediction, including colorectal cancer, gastric cancer, pancreatic cancer, and lung cancer [12–16]. LODDS is defined as the log of the ratio between the number of positive lymph nodes (PLNs) and the number of negative lymph nodes (NLNs). As a new prognostic factor, LODDS is considered better than the lymph node ratio (LNR, the number of PLNs divided by the number of examined LNs) and pN for predicting survival in some cancers [12]. LODDS takes into consideration the number of positive and negative lymph nodes (LNs), which may make it more precise than other factors for prognostic prediction for certain patients [15].

Therefore, in the present study, we specifically studied patients with T1-2 N0 M0 ESCC and determined the prognostic role of LODDS in patients with early-stage esophageal cancer.

2. Materials and Methods

2.1. Patient Selection and Data Collection

We reviewed consecutive esophageal cancer patients who underwent esophagectomy between January 2005 and December 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were included based on the following criteria: (1) patients who underwent esophagectomy, confirmed R0 resection; (2) diagnosed as pT1-2 N0 M0 esophageal cancer. The excluding criteria were as follows: (1) patients who received preoperative radiotherapy; (2) with a second cancer; (3) not adenocarcinoma or squamous cell carcinoma; (4) incomplete clinicopathologic information; (5) patients who were less than 18 years of age; and (6) patients who died within 30 days of surgery. Finally, 1004 patients in SEER database were included in this retrospective study (Figure 1).

To validate the results of the SEER databases, EC patients who underwent esophagectomy at Sun Yat-sen University Cancer Center in Guangzhou (Guangdong, China) between January 2005 and June 2010 were selected under the same criteria of exclusions and inclusions which were used in the SEER database. Moreover, patients who had received preoperative chemotherapy or chemoradiotherapy were also excluded. Finally, 245 patients were included for further analysis. This study was approved by the Institute Research Medical Ethics Committee of Sun Yat-sen University Cancer Center. Informed consent was obtained from all patients before the study. Patients of the Chinese cohort had follow-up after surgery every 3 months for the first year, every 6 months for the second to third year, and once a year thereafter. Evaluations included tumor markers, endoscopy with or without biopsy, thoracoabdominal CT, and esophageal barium swallow generally. The follow-up data was reviewed by July 1, 2015.

2.2. Statistical Analysis

The optimal cutoff values of LODDS were identified using the X-tile software (Version 3.6.1, Copyright Yale University 2003). We used χ² or Fisher’s exact tests to compare the baseline characteristics between different LODDS groups. We compared the differences of survival using Kaplan–Meier method and log-rank test. Univariate Cox regression was applied to calculate hazard ratio (HR) for continuous variables. The variables which were significant in the univariate analysis were tested by using multivariate analysis. In the development cohort, age, tumor size, tumor location, pathologic T (pT) status, histology, adjuvant radiotherapy, number of resected LNs, and LODDS were included for multivariate analysis. And Cox regression multivariate analysis was used to test the variables: pT status, number of resected LNs, and LODDS in the validation cohort. Statistical analyses were completed using SPSS 25.0 software (SPSS Inc., Chicago, IL, USA). value less than 0.05 was considered statistically significant. LODDS was calculated as log ((the number of PLNs + 0.5)/(the number of NLNs + 0.5)); 0.5 is added to both the numerator and the denominator to avoid an infinite number [14, 17, 18].

3. Results

3.1. Patient Characteristics

Patients with T1-2 N0 M0 esophageal cancer (EC) were enrolled in the present study, including 1004 patients from the SEER database (development cohort) and 245 patients from a Chinese cohort (validation cohort). The demographics and tumor characteristics of all patients are summarized in Table 1. The distribution of the number of resected LNs in patients is shown in Figure 2. The mean and median numbers of resected LNs in the SEER database were 14.5 and 13.0, respectively (range, 1–71). In the Chinese cohort, the mean and median numbers of resected LNs were 20.6 and 18.0, respectively (range, 1–79).

(a)

(b)

3.2. The Optimal Cutoff Points of LODDS

According to the results of the X-tile, the optimal cutoff points of LODDS were identified as < −1.40 (LODDS1) and ≥−1.40 (LODDS2) based on the patients of the SEER database (development cohort) (Figure 3). Then, patients in the Chinese cohort (validation cohort) were also divided into two groups according to the above cutoff points of LODDS. The correlations between baseline characteristics and LODDS groups are shown in Table 1. Only surgical approach was significantly associated with LODDS in the validation cohort ().

3.3. Prognostic Significance of LODDS on Survival

First, we used Kaplan–Meier curves to evaluate the association between LODDS and overall survival (OS) in the development cohort. The 5-year OS rate was 75.3% for patients in LODDS1 group, compared with 67.5% for those in LODDS2 group () (Figure 4(a)). In the validation cohort, the 5-year OS rate was 76.6% for patients in LODDS1 group, compared with 64.4% for those in LODDS2 group () (Figure 4(b)).

(a)

(b)

Cox univariate and multivariate analyses were performed to find the most significant prognostic factors of OS. In the development cohort, age, tumor size, tumor location, pT status, histology, adjuvant radiotherapy, number of resected LNs, and LODDS were significantly associated with OS in univariate analysis. Moreover, age, pT status, histology, and LODDS were found to be independent prognostic factors for OS in multivariate analysis (all values <0.001). Both in univariate and multivariate Cox analyses, LODDS was associated with OS significantly (hazard ratio (HR), 1.42; 95% confidence intervals (CI), 1.14–1.77 and HR, 1.48; 95% CI, 1.19–1.85, respectively) (Table 2).

In the validation cohort, the univariate analysis revealed that pT status, number of resected LNs, and LODDS were significantly related to OS (, 0.009, and 0.007, respectively). Then, Cox multivariate analysis demonstrated that pT status and LODDS were significant prognostic factors of OS ( and 0.003, respectively). The HR values in univariate and multivariate Cox analyses for OS were 1.89 (95% CI, 1.19–3.00) and 2.00 (95% CI, 1.26–3.18), respectively (Table 3). Therefore, LODDS was an independent prognostic factor of OS in the development cohort and validation cohort.

4. Discussion

In this present study, we used a relatively new statistical marker, LODDS, to evaluate the prognostic value for early EC patients and we found that LODDS was an important factor of survival. Several lines of evidence have demonstrated that LNs status is one of the most important risk factors of survival for esophageal cancer (EC) [19–21]. The current pN staging of the International Union Against Cancer (UICC) is based mainly on the number of metastatic LNs. Although the current guidelines play an important role in establishing the pN categories, however, there exist some problems; for example, the TNM staging system could not provide more meaningful information for node-negative patients. It also can lead to the phenomenon of stage migration [22].

Recently, researchers have tried to find other factors to predict the prognosis of EC and improve the efficacy of pN categories, such as the LNR (positive lymph node ratio). However, it could not provide more information for pN0 patients compared with TNM. For example, the LNRs of patients with T1-2 N0 M0 are all zero. LODDS, as another new prognostic factor, takes into consideration the number of PLNs and NLNs, which may become a better factor for predicting prognosis.

In the present study, we retrospectively evaluated the prognostic role of LOODS in T1-2 N0 M0 EC. We found that LODDS was significantly associated with OS in both the development and validation cohort. The survival was significantly better in the LODDS1 group than that in the LODDS2 group; the prognosis significantly decreased with the increased LODDS value. The above results were consistent with previous studies [18]. In this study, the enrolled EC patients were all node-negative, and the results showed that LODDS played an important role in predicting survival outcome for EC patients. Compared with the pN staging, it could provide additional meaningful information for node-negative patients.

Several studies had demonstrated that LODDS was more accurate to predict survival in some solid tumors, such as colon cancer and gastric cancer [23, 24]. LODDS contained information, both PLN and NLN. And previous studies had shown that the number of NLNs was related to the survival in EC patients [25]. However, few studies explored the role of LODDS in survival of early-stage EC patients. In this research, we specially studied T1-2 N0 M0 ESCC patients and the results confirmed that LODDS was a strong independent factor for early-stage EC patients. Although previous studies had shown the prognostic superiority of LODDS compared with LNR, pN staging in several solid carcinomas including EC [16, 18], it still needed further validation.

In this study, we firstly determined the cutoff values of LODDS based on the SEER database. Then, a separate Chinese cohort was used to externally validate the results of the SEER database. Few studies had done it like this. Moreover, the SEER database is based on the US population. All of this makes our results more reliable and representative.

There were some limitations in the present study. Firstly, this was a retrospective study, which could bring the bias. Secondly, As the cutoff values varied among different researches, whether our results and the cutoff values of LODDS could be applied to other institutions remain to be further proved. Thirdly, the missing data on clinicopathologic factors, limited treatment data in the SEER database which could result in bias, such as the radiotherapy field design and dose, and chemotherapy regimen and dose could influence survival outcome.

In conclusion, our study demonstrated that LODDS was an important independent factor for survival in early-stage EC patients. The results of this study might provide additional information for survival outcome of early-stage EC patients.

Data Availability

The authors may balance the potential benefits and risks for each request and then provide the data that could be shared.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Kexing Xi and Wenyou Chen contributed relatively equally to this work.

Acknowledgments

The authors thank all staff of the SEER program for their efforts in facilitating the study.

References

W. Chen, R. Zheng, P. D. Baade et al., “Cancer statistics in China, 2015,” CA: A Cancer Journal for Clinicians, vol. 66, no. 2, pp. 115–132, 2016.
View at: Publisher Site | Google Scholar
F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA: A Cancer Journal for Clinicians, vol. 68, no. 6, pp. 394–424, 2018.
View at: Publisher Site | Google Scholar
A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA: A Cancer Journal for Clinicians, vol. 59, no. 4, pp. 225–249, 2009.
View at: Publisher Site | Google Scholar
P. C. Wu and M. C. Posner, “The role of surgery in the management of oesophageal cancer,” The Lancet Oncology, vol. 4, no. 8, pp. 481–488, 2003.
View at: Publisher Site | Google Scholar
M. Worni, J. Martin, B. Gloor et al., “Does surgery improve outcomes for esophageal squamous cell carcinoma? an analysis using the surveillance epidemiology and end results registry from 1998 to 2008,” Journal of the American College of Surgeons, vol. 215, no. 5, pp. 643–651, 2012.
View at: Publisher Site | Google Scholar
J. A. Ajani, T. A. D’Amico, D. J. Bentrem et al., “Esophageal and esophagogastric junction cancers, version 2.2019, NCCN clinical practice guidelines in oncology,” Journal of the National Comprehensive Cancer Network, vol. 17, no. 7, pp. 855–883, 2019.
View at: Publisher Site | Google Scholar
Y. Kitagawa, T. Uno, T. Oyama et al., “Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 1,” Esophagus, vol. 16, no. 1, pp. 1–24, 2019.
View at: Publisher Site | Google Scholar
Q.-Y. Gao and J.-Y. Fang, “Early esophageal cancer screening in China,” Best Practice & Research Clinical Gastroenterology, vol. 29, no. 6, pp. 885–893, 2015.
View at: Publisher Site | Google Scholar
M. Morita, H. Saeki, M. Mori, H. Kuwano, and K. Sugimachi, “Risk factors for esophageal cancer and the multiple occurrence of carcinoma in the upper aerodigestive tract,” Surgery, vol. 131, no. 1, pp. S1–S6, 2002.
View at: Publisher Site | Google Scholar
B. Secretan, K. Straif, R. Baan et al., “A review of human carcinogens-Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish,” The Lancet Oncology, vol. 10, no. 11, pp. 1033-1034, 2009.
View at: Publisher Site | Google Scholar
J. Steevens, L. J. Schouten, R. A. Goldbohm, and P. A. van den Brandt, “Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: a prospective cohort study,” Gut, vol. 59, no. 01, pp. 39–48, 2010.
View at: Publisher Site | Google Scholar
B. Huang, M. Ni, C. Chen, G. Cai, and S. Cai, “LODDS is superior to lymph node ratio for the prognosis of node-positive rectal cancer patients treated with preoperative radiotherapy,” Tumori Journal, vol. 103, no. 1, pp. 87–92, 2017.
View at: Publisher Site | Google Scholar
A. Scarinci, T. Di Cesare, D. Cavaniglia et al., “The impact of log odds of positive lymph nodes (LODDS) in colon and rectal cancer patient stratification: a single-center analysis of 323 patients,” Updates in Surgery, vol. 70, no. 1, pp. 23–31, 2018.
View at: Publisher Site | Google Scholar
X. Wang, D.-H. Appleby, X. Zhang, L. Gan, J.-J. Wang, and F. Wan, “Comparison of three lymph node staging schemes for predicting outcome in patients with gastric cancer,” British Journal of Surgery, vol. 100, no. 4, pp. 505–514, 2013.
View at: Publisher Site | Google Scholar
G. Ramacciato, G. Nigri, N. Petrucciani et al., “Prognostic role of nodal ratio, LODDS, pN in patients with pancreatic cancer with venous involvement,” BMC Surg, vol. 17, no. 1, p. 109, 2017.
View at: Publisher Site | Google Scholar
Y. Zhao, G. Li, D. Zheng et al., “The prognostic value of lymph node ratio and log odds of positive lymph nodes in patients with lung adenocarcinoma,” The Journal of Thoracic and Cardiovascular Surgery, vol. 153, no. 3, pp. 702–709, 2017.
View at: Publisher Site | Google Scholar
M. La Torre, G. Nigri, N. Petrucciani et al., “Prognostic assessment of different lymph node staging methods for pancreatic cancer with R0 resection: pN staging, lymph node ratio, log odds of positive lymph nodes,” Pancreatology, vol. 14, no. 4, pp. 289–294, 2014.
View at: Publisher Site | Google Scholar
J. Cao, P. Yuan, H. Ma et al., “Log odds of positive lymph nodes predicts survival in patients after resection for esophageal cancer,” The Annals of Thoracic Surgery, vol. 102, no. 2, pp. 424–432, 2016.
View at: Publisher Site | Google Scholar
H.-L. Zhang, L.-Q. Chen, R.-L. Liu et al., “The number of lymph node metastases influences survival and international union against cancer tumor-node-metastasis classification for esophageal squamous cell carcinoma,” Diseases of the Esophagus, vol. 23, no. 1, pp. 53–58, 2010.
View at: Publisher Site | Google Scholar
C.-S. Lin, S.-C. Chang, Y.-H. Wei et al., “Prognostic variables in thoracic esophageal squamous cell carcinoma,” The Annals of Thoracic Surgery, vol. 87, no. 4, pp. 1056–1065, 2009.
View at: Publisher Site | Google Scholar
Y. P. Liu, L. Ma, S. J. Wang et al., “Prognostic value of lymph node metastases and lymph node ratio in esophageal squamous cell carcinoma,” European Journal of Surgical Oncology (EJSO), vol. 36, no. 2, pp. 155–159, 2010.
View at: Publisher Site | Google Scholar
Z. Tan, G. Ma, H. Yang, L. Zhang, T. Rong, and P. Lin, “Can lymph node ratio replace pn categories in the tumor-node-metastasis classification system for esophageal cancer?” Journal of Thoracic Oncology, vol. 9, no. 8, pp. 1214–1221, 2014.
View at: Publisher Site | Google Scholar
J. Wang, J. M. Hassett, M. T. Dayton, and M. N. Kulaylat, “The prognostic superiority of log odds of positive lymph nodes in stage III colon cancer,” Journal of Gastrointestinal Surgery, vol. 12, no. 10, pp. 1790–1796, 2008.
View at: Publisher Site | Google Scholar
Z. Sun, Y. Xu, D. M. Li et al., “Log odds of positive lymph nodes: a novel prognostic indicator superior to the number-based and the ratio-based N category for gastric cancer patients with R0 resection,” Cancer, vol. 116, no. 11, pp. 2571–2580, 2010.
View at: Publisher Site | Google Scholar
Z. Zhu, H. Chen, W. Yu et al., “Number of negative lymph nodes is associated with survival in thoracic esophageal squamous cell carcinoma patients undergoing three-field lymphadenectomy,” Annals of Surgical Oncology, vol. 21, no. 9, pp. 2857–2863, 2014.
View at: Publisher Site | Google Scholar

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Copyright © 2021 Kexing Xi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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