The principal finding of this study was that NLR emerged as the only significant inflammatory prognostic biomarker, in a cohort of UK patients with EC, supporting the primary hypothesis. No fewer than one in six patients had raised SIR markers, and some one in ten a raised NLR. Patients with mGPS of two were nearly five times more likely to have inoperable cancers when compared with patients with mGPS of zero. Moreover, elevated NLR, CRP, and mGPS, were all associated with poorer disease-free and overall survival profiles. Patients with a low NLR experienced median DFS and OS, on average 18 and 13 months respectively better than patients with a high NLR. Similarly, patients with a low NLR experienced five-year DFS and OS of 45.3%, and 49.6%, 1.6 and 1.8 fold better than patients with a high NLR.
The inflammatory markers described in this study can be broadly characterized as hepatic (mGPS and its components) or haematological (NLR, NPS, PLR, and their components), based on their predominant area of activity. NLR and mGPS have been associated with poor survival in a raft of anatomical cancer sites including breast [19, 20], colorectal [21, 22], stomach [6, 23], and prostate [24, 25]. In gastric , colorectal , and prostate  cancer patients with a mGPS of two had a five-year survival of 20%, 45%, and 33%, compared with 80%, 85%, and 75% in paients with mGPS of zero respectively. With regard to mGPS and NLR, 16.5% and 10.6% of patients respectively, had evidence of SIR on pre-operative blood analysis. This compares with previous reports citing SIR of 20% (mGPS), and 10% (NLR) of gastric cancer patients , and 41%  (mGPS) and 19% (NLR) of colorectal cancer patients . But in contrast to reports in gastric and colorectal cancer, NLR was the only prognostic inflammatory biomarker found to be associated with survival in EC. Cumulative 5-year differential survival related to NLR expression have been reported to be similar in both esophageal (17%) and colorectal cancer (20%) . Yet the absolute 5-year survival in the patient cohorts with low NLR expression was 45% in esophageal, compared with 75% in colorectal cancer ; arguably consistent with the more aggressive clinical nature of EC when compared with colorectal cancer.
The underlying basis of the relationship between the SIR and poor cancer survival in patients with EC is an enigma. But the components of the mGPS have been characterized, with cancer cachexia, compromised cellular immune response, angiogenesis, and the up-regulation of growth factors all prominent features. It is evident therefore that the mechanisms controlling the association between systemic inflammation and cancer-specific survival are compound. Immune dysfunction, growth and dissemination, nutritional and functional decline, and tumour angiogenesis, are all implicated. More explicitly, recent colorectal cancer research has indicated a strong relationship between suboptimal patient physiological stage, increased comorbidity, and elevated CRP. In patients with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) zero or one, the median CRP was 20 mg/dl, compared with 64 mg/dl in the ECOG-PS of two (p = 0.002). Arguably, a raised preoperative mGPS in EC resonates with poor cardiorespiratory fitness, more comorbidity, and higher risk profile . Most nutrition research professionals presently hold the view that in patients with cancer, nutritional status is closely related to the presence of a systemic inflammatory response as supported by the GPS, NLR, PLR, and NPS . Indeed, cachexia is now considered by a number of expert nutrition groups to constitute disease related malnutrition in addition to inflammation, and comprises an etiologic factor in the GlIM criteria . Future research should not only assess nutritional status but also the systemic inflammatory status in patients with EC cancer. The adverse prognostic power of the SIR is likely multifactorial in nature representing a more aggressive cancer phenotype on a background of a suppressed host response. However, this would be difficult to prove using association studies alone. Nevertheless, the data here confirms that survival following cancer is largely determines by the TNM stage, vascular invasion, and the presence of a SIR (Fig. 1).
Although SIR biomarkers offer valuable prognostic signals, if NLR and mGPS are to be incorporated into an upgraded TNM staging system, they should add prognostic value related to treatment response. Inclusion of biomarkers into gastric and breast cancer management algorithms was driven by the identification of adjuvant therapies for higher risk patients. Apart from Herceptin treatment for advanced esophago-gastric cancer, the principal adjuvant treatment for EC remains cytotoxic chemotherapy, despite pathological response rates of the order of one in seven . Reports regarding the treatment of colorectal cancer with neoadjuvant [31, 32] or adjuvant chemotherapy  describe poorer outcomes in patients with SIR when compared with controls. Moreover, based on histological assessment, mGPS in rectal cancer has been reported to be associated with significantly poorer response to neoadjuvant chemotherapy . Powell et al. from Cardiff, have also reported that an elevated pre-treatment NLR was associated with poorer tumour regression grade in patients undergoing neoadjuvant chemotherapy for EC . Given the associations between the SIR and relative chemo-resistance, it is unlikely that such patients will derive any discernable clinical benefit from adjuvant chemotherapy. The phase III, double blinded, placebo controlled randomized trial regarding the effect of aspirin on disease recurrence and survival after primary therapy in non-metastatic solid tumours (Add-Aspirin), commenced recruitment in 2015, and should signal whether Aspirin is beneficial in EC treatment; yet arguably only patients with a SIR will respond. In keeping with other adjuvant treatments such as Herceptin and Cetuximab, patient selection is crucial and NLR has predictive biomarker potential in this regard.
There are a number of potential inherent limitations to studies of this character, which have been described previously [6, 35]. Cohort sample size was modest and study power was built on a 15% survival difference; sub-analysis related to patient comorbid risk profile, tumour stage, and morbidity severity-score was therefore not practical, and the above are therefore clearly confounding factors. Validating the results in an appropriately powered cohort for sub-analysis stage-for-stage, may facilitate the integration of NLR into a modified TNM staging system . Though several SIR related bio-markers were used, the NLR may not predict survival independently in other patient cohorts and this matter needs international authentication. In contrast, the study has strengths. Patients were recruited from a consecutive patient cohort diagnosed with EC, from a single UK geographical region, all treated by a specialist multi-disciplinary team with standardized stage tailored treatment algorithms, operative techniques, with international peer-reviewed and published key performance indicator quality control. The survival data is particularly strong; no patients were lost to follow-up, and causes and dates of death were obtained from the office of national statistics. Moreover, the study builds on previous research by including all clinically available inflammatory and pathological factors in a multivariable regression model, and adds to the established evidence base, regarding the prognostic significance of preoperative SIR.
In summary, NLR was the sole inflammatory based prognostic biomarker associated with poor DFS and OS after potentially curative esophagectomy for cancer and was independent of histopathological stage. These findings emphasise the importance of not only staging the patient’s tumour radiologically; in essence a perceived histopathological stage; but also staging the patient’s physiological state using derivative SIR biomarkers. The results of this study consolidate the prognostic value of combined markers of the SIR, with the mGPS predicting patients at risk of inoperable disease at the time of surgery. This simple blood profile work deserves further considered reflection and should form part of routine preoperative patient work-up, and follow-up, for all such patients undergoing resection for cancer. These findings suggest that SIR presents narrative remedial goals, for patients vulnerable to cancer recurrence, and NLR may be the best biomarker to guide tailored holistic anti-inflammatory therapy, but further mechanistic studies are needed.