Abstract
Multidisciplinary treatment for esophageal cancer leads to nutritional and inflammatory changes. Recent studies showed that nutritional and inflammatory changes during multidisciplinary treatment affect both short and long-term oncological outcomes in esophageal cancer treatment. Therefore, evaluation of the nutritional and inflammatory status during treatment is necessary in order to optimize and utilize multidisciplinary therapy for esophageal cancer. If patients with esophageal cancer are able to determine their nutritional and inflammatory status, they will be able to select the optimal esophageal cancer, anti-inflammation, and nutritional treatments. Various types of nutrition and inflammation assessment tools have been developed and reported for esophageal cancer, with each tool having its own clinical characteristics, which must be understood before being applied in clinical practice. This review summarizes the background, current status, and future perspectives on the application of nutrition and inflammation assessment tools in esophageal cancer treatment.
Esophageal cancer is the eighth most common type of cancer and the sixth-leading cause of cancer-related death in the world (1, 2). Curative resection and perioperative adjuvant treatment is a standard treatment for resectable esophageal cancer (3-5). Although the survival rate after surgery and adjuvant treatment is gradually increasing, almost half of all patients develop recurrent disease, even after curative treatment (6, 7).
Recently, some studies have reported that the perioperative nutritional and inflammatory status affect both the short-term and long-term oncological outcomes in various malignancies (8, 9). Therefore, it is necessary to evaluate the nutritional and inflammatory status during the perioperative period in patients with esophageal cancer. If a physician can determine the nutritional and inflammatory status during treatment, they can control and manage the nutritional and inflammatory status to optimize esophageal cancer treatment. Thus far, the application of various nutritional and inflammation assessment tools, such as the Glasgow Prognostic Score (GPS), Prognostic Nutritional Index (PNI), and Controlling Nutritional Status (CONUT) have been reported in esophageal cancer (10-14). To introduce these various nutritional and inflammation assessment tools into daily clinical practice, it is necessary to understand the characteristics of each.
This review summarizes the background, current status, and future perspectives of nutrition and inflammation assessment tools in esophageal cancer treatment.
Search Strategy
The search strategy used in the current study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A literature search was performed on PubMed. The following keywords were used: “Glasgow Prognostic Score (GPS)” and “esophageal cancer (or carcinoma)”; “Prognostic Nutritional Index” and “esophageal cancer (or carcinoma)”; “Controlling Nutritional Status” and “esophageal cancer (or carcinoma)”; “neutrophil-lymphocyte ratio (NLR)” and “esophageal cancer (or carcinoma).” “CRP to albumin ratio (CAR)” and “esophageal cancer (or carcinoma)”; “platelet-to-lymphocyte ratio (PLR)” and “esophageal cancer (or carcinoma)”; “albumin-to-globulin ratio (AGR)” and “esophageal cancer (or carcinoma)”; and “lymphocyte-to-C-reactive-protein ratio (LCR)” and “esophageal cancer (or carcinoma)”. In addition, the references of the cited articles were overlooked. In total, 920 articles were identified. However, 782 were excluded
Clinical Use of the GPS and Modified GPS (mGPS) in Esophageal Cancer Treatment
The GPS is calculated using the serum C-reactive protein level (CRP) and serum albumin level (15). Both CRP and albumin are produced by the liver. The serum CRP level reflects the systemic inflammation status, and the serum albumin level reflects the nutritional status. Therefore, the GPS can assess both the inflammatory and nutritional status during treatment. The mGPS has also been investigated and reported in various malignancies. A total of 29 studies have evaluated the clinical impact of the GPS/mGPS in esophageal cancer, using a cut-off value of 1 or 2. Table I summarizes each study (16-44). Among them, 21 studies evaluated patients with esophageal cancer who underwent esophagectomy, four evaluated patients who received chemotherapy, four evaluated patients who received chemoradiation therapy, one evaluated patients who received radiation therapy, and one evaluated patients who underwent esophageal stent insertion. All studies demonstrated that a high GPS/mGPS (GPS/mGPS >1 or 2) was associated with a poor prognosis. The hazard ratio (HR) of a high GPS/mGPS for OS was 1.367-5.62 in the surgery group, 1.51-2.151 in the chemotherapy group, and 1.694-2.528 in the chemoradiation group. Accordingly, the GPS/mGPS had a clinical impact on the oncological outcomes in esophageal cancer, irrespective of the treatment method. Further studies are needed to clarify whether the GPS/mGPS has a clinical impact on short-term oncological outcomes (e.g., occurrence of postoperative surgical complications, continuation of chemotherapy/radiation therapy, and occurrence of chemotherapy/radiation therapy toxicity).
The CRP to Albumin Ratio (CAR) in Esophageal Cancer Treatment
The CAR is derived from laboratory tests and is determined by dividing the serum CRP level by the albumin level. The CAR evaluates both the inflammatory status and the nutritional status. Thirteen studies evaluated the clinical impact of CAR in esophageal cancer. Table II summarizes each study (45-56). Among them, 12 studies evaluated CAR as a prognostic factor and one study evaluated it as a predictive factor for postoperative surgical complications. All studies showed that a high CAR was associated with a poor oncological outcome. In the evaluation as a prognostic factor, 10 studies evaluated patients with esophageal cancer who underwent esophagectomy, one study evaluated patients who received chemotherapy, and one study evaluated patients who received chemoradiation therapy. The reported cut-off values of CAR as a prognostic factor in these studies ranged from 0.0139 to 0.5. Among the patients who underwent esophagectomy, the HR of a high CAR for OS was 1.393-3.02. Further studies are needed to clarify whether the CAR is an optimal tool for unresectable esophageal cancer.
The Neutrophil-to-Lymphocyte Ratio (NLR) in Esophageal Cancer Treatment
The NLR is determined by dividing the absolute neutrophil count by the absolute lymphocyte count. Recent studies demonstrated that a high NLR is associated with a poor prognosis in various malignancies. Thus far, 63 studies have evaluated the clinical impact of the NLR in esophageal cancer. Table III summarizes each study (57-93). Thirty-eight studies evaluated the NLR as a prognostic factor. Among them, 26 evaluated patients with esophageal cancer who underwent esophagectomy, five evaluated patients who received chemoradiation therapy, three evaluated patients who underwent chemotherapy, and three evaluated patients who received combined treatment. All studies demonstrated that a high NLR was associated with a poor prognosis. The reported cut-off values of the NLR as a prognostic factor ranged from 1.77 to 6.4 in these studies. The HR of the NLR for OS was 1.129-5.445 in the surgery group, 2.5-6.31 in the chemotherapy group, and 1.597-2.357 in the chemoradiation group. Accordingly, the NLR has a clinical impact on the oncological outcomes in esophageal cancer, irrespective of the treatment method.
The Platelet-to-Lymphocyte Ratio (PLR) in Esophageal Cancer Treatment
Recently, the PLR was reported as a promising prognostic factor for gastrointestinal malignancies. The PLR is calculated by dividing the platelet count by the lymphocyte count. Eleven studies evaluated the clinical impact of the PLR in esophageal cancer. Table IV summarizes each study (94-103). Among them, 10 evaluated the PLR as a prognostic factor, while one study evaluated the PLR as a predictive factor for postoperative surgical complications. The cut-off value of the PLR as a prognostic factor was reported to be 73-192 in these studies. In studies that evaluated the PLR as a prognostic factor, a high PLR was associated with a poor prognosis. The HR of the PLR for OS was 1.37-2.475. Although the PLR showed prognostic value in esophageal cancer treatment, most studies assessed patients who underwent esophagectomy. Therefore, further studies are needed to clarify the clinical impact of the PLR in patients who receive chemotherapy or chemoradiation therapy.
The PNI in Esophageal Cancer Treatment
The PNI is a novel index that is used to assess the immune and nutritional status based on the serum lymphocyte count and albumin level. Twenty-six studies evaluated the clinical impact of the PNI in esophageal cancer. Table V summarizes each study (104-126). Among the 23 studies that evaluated the PNI as a prognostic factor, 13 evaluated patients with esophageal cancer who underwent esophagectomy, three evaluated patients who underwent endoscopic submucosal dissection, one evaluated patients who received chemotherapy, and six studies evaluated patients who received combined treatment. The cut-off value of the PNI as a prognostic factor in these studies was reported to range from 35.93 to 54.15. All studies demonstrated that a low PNI was associated with a poor prognosis. The HR of the PNI for OS was 1.186-2.92 in the surgery group and 1.69-2.42 in the endoscopic submucosal dissection group. Accordingly, the PNI had a clinical impact on the oncological outcomes in esophageal cancer, irrespective of the treatment method.
CONUT in Esophageal Cancer Treatment
The CONUT score was developed as an accessible nutritional screening tool for evaluating patients’ nutritional status. The CONUT score is calculated from the serum albumin level, the total cholesterol level, and the total lymphocyte count. The clinical impact of the CONUT score on the outcomes of esophageal cancer was first reported in 2016. Eight studies evaluated the clinical impact of the CONUT in esophageal cancer. Table VI summarizes each study (127-133). Among them, six studies evaluated the CONUT score as a prognostic factor and two evaluated it as a predictive factor for postoperative surgical complications. Six studies showed that a high CONUT score was associated with a poor oncological outcome. In the studies that evaluated the CONUT score as a prognostic factor, five studies evaluated esophageal cancer patients who received esophagectomy, and one study evaluated patients who received chemotherapy. The reported cut-off values of the CONUT score as a prognostic factor ranged from 1 to 5 in these studies. Among the patients who underwent esophagectomy, the HR of a high CONUT score for OS was 1.23-3.56.
The Albumin-to-Globulin Ratio (AGR) and the Lymphocyte-to-C-reactive Protein Ratio (LCR) in Esophageal Cancer Treatment
Recently, the clinical utility of albumin and globulin as tumor prognostic markers have aroused great interest, due to the close relationship with the nutritional status and the inflammatory responses of cancer patients. The AGR, which is calculated as AGR = albumin/(total protein–albumin) has been considered a possible effective combination of the two individual prognostic indicators. In addition, the lymphocyte-to-C-reactive-protein ratio (LCR) is a particularly promising marker of systemic inflammation in the perioperative period. Table VII and Table VIII showed the clinical impact of the AGR and LCR in esophageal cancer treatment (134-138). However, limited studies have shown its significance as a prognostic factor in esophageal cancer treatment. Additional studies are needed to clarify the clinical impact of the AGR and LCR in esophageal cancer treatment.
Future Prospects for Nutrition and Inflammation Assessment Tools in Esophageal Cancer Treatment
Thus far, various nutrition and inflammation assessment tools have been applied in esophageal cancer treatment. To utilize the nutrition and inflammation assessment tools in esophageal cancer treatment, the following points should be clarified. Firstly, setting the optimal cut-off value of each tool is an issue. In the previous studies, patient background factors and treatment methods were heterogeneous. In addition, the sample sizes of the previous studies were relatively small, and the studies were retrospective in nature. Therefore, these differences may have affected the cut-off values of each tool. In addition, the timing at which each tool should be applied is also unclear. It remains necessary to establish the optimal timing for assessment by these tools. Secondly, the mechanisms through which nutrition and inflammation affect the prognosis of esophageal cancer are unclear. Recently, the nutritional and inflammatory status was reported to affect postoperative surgical complications, the introduction of chemotherapy, and adverse events of chemotherapy. However, the precise mechanism through which the nutritional and inflammatory status, as assessed by these tools, influence the prognosis of esophageal cancer is unclear. Thirdly, it is unclear whether these nutrition and inflammation assessment tools will become promising indicators for treatment approaches targeting nutrition/inflammation in esophageal cancer. The clinical relationship between changes in the nutritional and inflammatory status and perioperative oral nutritional treatment need to be clarified.
Conclusion
The nutritional and inflammatory status, as assessed by nutrition and inflammation assessment tools, may have some clinical influence on both the short-term and long-term oncological outcomes of patients with esophageal cancer. However, the optimal cut-off values for each tool are unclear, as are the mechanisms through which these parameters influence prognosis. To optimize the nutrition and inflammation assessment tools for patients with esophageal cancer, it is necessary to clarify these points in further studies.
Footnotes
Authors’ Contributions
TA and KK made substantial contributions to the concept and design. TA, YM, KH, and KK made substantial contributions to the acquisition of data and the analysis and interpretation of the data. TA and KK were involved in drafting the article or revising it critically for important intellectual content. TA, YM, and KH gave their final approval of the version to be published.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received November 4, 2022.
- Revision received November 22, 2022.
- Accepted November 24, 2022.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).