Abstract
Background: Lymph node ratio (LNR), log odds of positive lymph nodes (LODDS), and the number of postoperative lymph node staging (pN) are prognostic indicators of various cancers. However, comparison of the prognostic values of these indicators remains unclear in hypopharyngeal squamous cell carcinoma (HPSCC). This study aims to compare the prognostic values of LNR, LODDS and pN in stage Ⅲ-Ⅳ HPSCC.
Methods: We conducted a retrospective study on 166 patients with stage Ⅲ-Ⅳ HPSCC. LNR and LODDS were divided into two groups using X-tile version 3.6.1. Univariate and multivariate analyses of the risk of overall survival (OS) and disease-free survival (DFS) were performed using the log-rank (Mantel-Cox) test and the Cox proportional hazards model, respectively. We compared the prognostic value of LNR with that of LODDS and pN using receiver operating characteristic (ROC) curves.
Results: According to the X-tile, the cut-off values are 0.11 for LNR and -0.91 for LODDS. LNR, LODDS, and pN were significantly correlated with DFS by univariate analysis (P < 0.05). Multivariate analysis demonstrated that LNR was an independent prognostic factor for DFS (P < 0.01). Multivariate analysis also revealed that postoperative tumour staging (pT) classification, LNR, and surgical margins were independent prognostic factors for OS. Compared with pN and LODDS, LNR showed a stronger predictive power for DFS.
Conclusion: LNR may be a better predictor for DFS than pN and LODDS in stage Ⅲ-Ⅳ HPSCC patients. LNR in the highest tertile (≥ 0.11) may cause poor OS and DFS. LODDS in the highest tertile (≥-0.91) may cause poor DFS.
Keywords: hypopharyngeal squamous cell carcinoma, lymph node ratio, log odds of positive lymph nodes, prognosis.
key points:
  1. We conducted a retrospective study on 166 patients with stage Ⅲ-Ⅳ HPSCC.
  2. aims to compare the prognostic values of LNR, LODDS and pN in stage Ⅲ-Ⅳ HPSCC.
  3. LNR in the highest tertile (≥ 0.11) may cause poor OS and DFS.
  4. LODDS in the highest tertile (≥-0.91) may cause poor DFS.
  5. Compared with pN and LODDS, LNR showed a stronger predictive power for DFS.
Introduction
HPSCC is one of the foremost head and neck cancers. The overall 5-year survival rate remains approximately 40%, with the occurrence of local and distant recurrences after treatment in a few cases(1). Although the tumor-node-metastasis (TNM) classification is a widely used prognostic factor for many solid tumors, the staging system has been reported to be associated with poor prognosis of patients with HPSCC(2). Furthermore, N status in the TNM system provides only limited prognostic information. In order to clarify which patients are more suitable for aggressive treatment to reduce mortality and recurrence rates. Improvements in the staging system and patient risk stratification, particularly for post-operative patients, are required..
Lymph node metastasis is a well-known prognostic factor for HPSCC. Most recent studies on the parameters include the total number of harvested lymph nodes (HLNs) and the number of positive lymph nodes (PLNs)(3, 4). Low values of the parameters, which are affected by the cervical lymphatic dissection technique, may result in misdiagnosis and eventually lead to an inaccurate treatment. The LNR, defined as PLNs /HLNs, is a better prognostic indicator. It also shows a better predictive potential because it combines the information on regional metastatic disease burden and type of cervical lymphatic dissection; thus, it accommodates the advantages of both parameters while bypassing their disadvantages (5, 6). Another index, the LODDS, defined as log (PLNs +0.5)/((HLNs- PLNs ) +0.5), is correlated with the prognosis of head and neck tumors as well (7). SIRI has been proved to have independent prognostic value in head and neck tumors(8). Our previous study also found that SIRI had a better predictive value than neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in HPSCC patients.
Past research has found that LNR and LODDS staging may be superior to PLNs staging in patients with incomplete lymph node clearance because they are not significantly affected by the total number of LNs examined(9-14). LODDS has been used to predict the prognosis of several tumors, but there is little clinical evidence for the role of LODDS in HPSCC. For the first time, this study compared the predictive values of LNR, LODDS and PLNs for OS and DFS in stage Ⅲ-Ⅳ HPSCC patients and revealed new parameters to improve the predictive power.
Materials and methods
Study design and patient selection
A total of 304 patients with complete medical records and pathologically confirmed primary HPSCC without secondary primary and distant metastatic lesions were recruited. All these patients were diagnosed and treated at the Eye, Ear, Nose and Throat Hospital of Fudan University, China, between January 1, 2003, and December 31, 2014.They were classified according to the American Joint Committee on Cancer (AJCC)/TNM-Union for International Cancer Control (UICC) Staging Classification, 7th edition. Of these 304 patients, 176 patients with pathological stages III-IV were selected. The exclusion criteria included : (1)patients who had undergone cervical lymphatic dissection, chemotherapy, or radiation therapy before surgical treatment; (2)ECOG score >1 ;(3) a chronic inflammatory condition, such as hepatitis B virus and hepatitis C virus, gastritis or nephritis;(4) aggressive inflammatory disease or co-infection; (5) an autoimmune disease or treatment with steroids; (6) hematological disease. Ultimately, 166 patients were included in the study analysis.
Follow-up and clinical endpoints
A follow-up of disease progression and time to death was performed on all patients by telephone and outpatient records every three months for the first two years and every six months until the end. The last follow-up visit was performed on January 10, 2018, and OS was recorded from the date of surgery until death. DFS was defined as the time between the start of therapy and tumor relapse (locoregional recurrence and/or distant metastases) or non-cancer causes of death.
Statistical Analysis
The optimal cut-off points of LNR and LODDS were determined using X-tile version 3.6.1 (Yale University), according to the highest Chi-squared value and lowest P-value in DFS. LNR and LODDS were categorized into two groups based on the results attained from X-tile. The SIRI was defined as (N*M)/L, where N, M, and L were the absolute count of neutrophils, monocytes, and lymphocytes obtained from the pretreatment blood test. The median determined the cut-off value for the SIRI, MLN, and HLN. OS and DFS curves were plotted according to the Kaplan–Meier method using SPSS (version 25.0) and were built with Graphpad Prism (version 8.0). Univariate and multivariate analyses for the risk of OS and DFS were performed using the log-rank (Mantel-Cox) test and the Cox proportional hazard models, respectively. A P-value of 0.05 (two-tailed) was considered statistically significant.