Nomograms enable visualize the prognostic strength of various relevant factors in a single model which allow them to have more accurate survival prediction than conventional TNM staging system or an individual molecular biomarker. Nomograms have been widespread used in the prognosis prediction in clinical oncology. Compared with the other cancers, nomograms have been sparingly studied for head and neck tumors. For OSCC, several studies have reported on the development of nomograms to predict the survival22-25. However, to our knowledge, there was no study specifically for the locally advanced OSCC patients. The present study was the first attempt to investigate the usage of nomograms for survival prediction of locally advanced OSCC.
Our nomograms were constructed based on the COX proportional hazards regression analyses in the training set of 201 locally advanced OSCC patients after curative surgery. In the multivariate analyses, we found that advanced age, KFI, pT, the number of positive nodes and SII were significant prognosticators for OS and CSS. Based on these significant prognosticators, we developed the nomograms for OS and CSS. The nomograms showed good discrimination abilities with C-index values of 0.712 for OS and 0.709 for CSS. Calibration curves demonstrated satisfactory agreement between the nomograms and actual survival. Moreover, the nomograms exhibited the net clinical benefit using DCA. We also externally validated the nomograms performance in a validation set of 68 patients. External validation also supported the satisfactory accuracy and calibration of our nomograms. Besides, the performance of nomograms was, in turn, validated by Kaplan-Meier curves which showed distinct prognosis in three subgroups sorting by the total points of the nomograms.
The significant prognosticators incorporated in our nomograms were clinically feasible and economical, especially including the novel preoperative systemic inflammation-immune biomarker SII. Notably, accumulating evidence demonstrated that inflammatory cells including neutrophils, platelets, monocytes and lymphocytes carry out a robust role in contributing to proliferation and survival of malignant cells, angiogenesis and metastasis26. Many reports also have revealed the significant prognostic values of preoperative systemic inflammation-immune biomarkers, for example, NLR, PLR and LMR, in various types of cancers9-12. Recently, SII based on neutrophils, lymphocytes and platelets, has been demonstrated as a novel integrated biomarker and exhibited prognostic value in several tumors including advanced pancreatic cancer27, cervical cancer28, gastric cancer29 and colorectal cancer30. The study published in 201813 reported for the first time that high preoperative SII was associated with poor outcome and could be served as an independent prognostic predictor in patients with OSCC. Elevated SII probably resulted from neutrophilia, thrombocythemia and lymphopenia. Solid tumor-related neutrophilia, after excluding obvious reasons such as infections, bone marrow metastasis and the usage of corticosteroid, may arise from hematopoietic colony-stimulating factors and inflammatory cytokines triggered by tumors including granulocyte colony-stimulating factor and others31 32. Neutrophils could facilitate tumor growth by the secretion of various chemokines and cytokines, as well as actively recruiting other tumor-supporting cells to the tumor microenvironment33. What’s more, tumor associated neutrophils play the critical role in the metastasis process by inhibiting the activity of natural killer cells and enhancing the extravasation of tumor cells, mainly through secreting various matrix metalloproteinases to degrade and modify the extracellular matrix34. Thrombocythemia usually promote tumor progression and metastasis. Several studies showed that cancer incidence could increase in patients with abnormally elevated platelet count and those with over 3.5 × 1011/L count probably have more than a 3% risk of cancer in one year of observation35 36. A meta-analysis suggested platelet quantity as a potential prognostic marker in pancreatic cancer37. Tumors firstly activate platelets through tissue factors -containing microparticles (MPs). The platelet MPs can express signals and communicate with a variety of cells to induce angiogenesis38 39. Also platelets or platelet activation can directly interact with cancer cells, synergistically promotes TGF-β and NF-kB pathways in cancer which in turn triggers the epithelial mesenchymal transition of cancer cells to facilitate tumor metastasis36. Lymphopenia has been frequently observed in patients with advanced cancers and shown as a powerful prognostic factor in advanced solid tumors including renal cell carcinoma, colorectal, lung cancer and breast cancer40-43. Lymphocytes as major immune cells play a fundamental role in cell-mediated immunologic destruction of cancer cells, although different subtypes of lymphocytes vary in their functional roles against cancer 44 45. Thus, lymphopenia could be considered as indicative of impaired immune surveillance and contribute to the favorable tumor microenvironment for tumor metastasis. In our study, multivariate analyses revealed that SII was a powerful prognosticator of OS and CSS in advanced OSCC.
Concerning clinical-pathologic factors, the most important prognosticators were age, comorbidity, depth of invasion (DOI), extranodal extension (ENE), number of positive nodes, perineural invasion (PNI) and tumor grade. Advanced age and greater comorbidity have been reported by various studies on the upper aerodigestive tract tumors, as elderly patients or patients in poor general health are more vulnerable to disease progression and not eligible for invasive therapies. Consistent with previous findings, our data also confirmed advanced age and greater comorbidity as the independently clinical prognostic factors in advanced OSCC patients. Tumor grade wasn’t identified as a prognostic factor in our data, which probably can be explained by the homogeneity of the study population in terms of patients and tumor profiles.
DOI has been advocated to be associated with tumor metastasis and worse survival outcomes, and included in the AJCC 8th T staging classification. In our study, pT classification was independently associated with worse prognosis. Lymph nodal involvement has been a well-established prognostic factor in head and neck cancers. The AJCC 8th staging has included lymph nodal site (ipsilateral and contralateral), size, presence of ENE in the nodal staging category. The negative impact of ENE has been fully incorporated in the AJCC 8th N staging system, where it leads to upstaging nodal positive OSCC, whatever size, number, or laterality of the positive node(s)7. However, the number of lymph node is probably overestimated in the system, as just greater than one lymph node is staging as N2, without considering the increasing number of positive lymph nodes as further stratification. Several clinical studies have observed the prognostic significance of number of positive lymph nodes in OSCC, albeit with different cut-off values46. Roberts et al. 47 reported that the number of positive lymph nodes model (0, 1, 2-4 and ≥5) performed better than AJCC 7th edition N staging model in head and neck cancers. Moreover, a recent publication by Rajappa et al.48 revealed that the number of positive lymph nodes (0, 1, 2, >2) could outperform AJCC 8th nodal staging system in the prediction of OS and DFS in oral cancer. Subramaniam et al.49 categorized the number of positive lymph nodes as 0, 1-2, 3-4 and ≥5 and exhibited it was superior to LNR and LODSS in the prediction of OS and DFS in 643 OSCC patients. In our study, we adopted the categorization system proposed by Subramaniam et al49. We also observed the inverse relationship between the number of positive lymph nodes and patients’ survival, and confirmed its prognostic significance for OS and CSS in advanced OSCC patients.
Based on the independent prognosticators discussed above, we built the first nomograms predicting OS and CSS in locally advanced OSCC patients and internal and external validations showed our models with relatively high c-indices and well-fitted calibration curves. AJCC 8th staging system is currently used system for assessment of prognosis in locally advanced OSCC patients. We performed comparative analysis between our developed nomograms and AJCC staging system. Our nomograms outperformed the AJCC 8th staging system for OS and CSS prediction in locally advanced OSCC patients, with statistically higher c-indices. Additionally, in the DCA analyses, the nomograms exhibited to be more beneficial over AJCC 8th staging system in the prognosis prediction of OS and CSS. These data demonstrated that our nomograms had better performance with clinical utility in prognosis prediction.
The present study had two main limitations. Firstly, our study was a retrospective study so that the selection bias was inevitable. Secondly, the patients enrolled were from a single institution, which may not represent the entire locally advanced OSCC patients. Notwithstanding these limitations, our study built the first nomograms predicting OS and CSS in locally advanced OSCC patients. More importantly, robust internal and external validation demonstrated sufficient discriminatory power and accurate calibration in our proposed nomograms. Additionally, the main advantages of the present study were that all the included prognosticators were feasible and accessible in daily clinical practice.