Abstract
Background: To investigate whether malnutrition is associated with poor prognosis of patients who undergo salvage esophagectomy. We examined the association between the preoperative prognostic nutritional index (PNI) and prognosis of patients who undergo salvage esophagectomy. Patients and Methods: We conducted a single-center retrospective study and reviewed hospital patient records for tumor characteristics and patient outcomes. Univariate and multivariate survival analyses were carried out using the Cox proportional hazards regression model. Results: Thirty-two patients with esophageal squamous cell carcinoma (ESCC) who underwent salvage esophagectomy between 1998 and 2015 at our Institute were included in this study. Univariate analysis revealed that clinical response (p=0.045), preoperative PNI (p<0.001), pT (p=0.024), pN (p=0.004), and residual tumors (p<0.001) were significant prognostic factor for overall survival. Multivariate analysis using age and these five variables found no independent prognostic factors. Multivariate analysis using three preoperative variables (age, clinical response, and preoperative PNI) revealed that PNI was an independent prognostic preoperative factor for overall survival (p=0.005). Conclusion: Preoperative nutritional status is associated with the prognosis of patients undergoing salvage esophagectomy.
Salvage esophagectomy is now thought to be the only established therapeutic strategy that provides any chance of long-term survival after local failure for patients with esophageal squamous cell carcinoma (ESCC) receiving definitive chemoradiotherapy (CRT) (1, 2). However, previous studies demonstrated that salvage esophagectomy was associated with high morbidity and mortality rates (1, 3). Long-term outcome of salvage esophagectomy also remains poor, with 5-year survival rate after salvage esophagectomy of 0-33% as described by Watanabe et al. (4) and references therein. When conducting and performing this type of high-risk operation, the patient's nutritional status must not be ignored. Malnutrition has been reported in 60-85% of patient with esophageal cancer. Immunosuppression and malnourished state have been suggested to occur in patients following definitive CRT (5, 6). To date, several studies have reported prognostic factors for patients undergoing salvage esophagectomy, such as pretreatment tumor depth and lymph node metastasis, response to initial CRT, pathological tumor depth and lymph node metastasis, and R0 resection (1, 7-9). However, the actual impact of preoperative nutritional status on the prognosis of patients who undergo salvage esophagectomy remains unclear. Thus, we hypothesized that malnutrition is associated with the poor prognosis of patients who undergo salvage esophagectomy. To investigate this hypothesis, we examined the association between the preoperative prognostic nutritional index (PNI), a simple and efficient parameter for evaluating nutritional condition, and prognosis of patients who undergo salvage esophagectomy by univariate and multivariate analysis.
Patients and Methods
Patients. This retrospective study was approved by the Ethics Committee of the Graduate School of Medicine, Gunma University (approval number 1457). Written informed consent was obtained from all patients before treatment. The criteria for inclusion were patients with ESCC who underwent salvage esophagectomy between 1998 and 2015 at our Institute. Patients were excluded from this study if they had no data on serum albumin and lymphocyte count in peripheral blood within 1 month before surgery and if the follow-up period was less than 1 year for survivors. Hospital patient records were reviewed for tumor characteristics and patient outcomes. Tumor stage and disease grade were classified according to the seventh edition of the TNM classification of the International Union Against Cancer (UICC) (10). The tumor stage was determined conventionally using computed tomography (CT) of the neck, chest, and abdomen, endoscopic ultrasonography (EUS), endoscopy, and esophagography. The preoperative prognostic nutritional index (PNI) was calculated as: 10× serum albumin level (g/dl) + 0.005× lymphocyte count in peripheral blood (11) within 1 month before surgery.
Flow chart showing patient recruitment.
Chemoradiation and salvage surgery. Patients received concurrent radiotherapy and chemotherapy for 6 weeks after the diagnostic procedures. External radiotherapy was delivered using a two-field technique with a 10-to 15-MV photon beam at 1.8-2 Gy per fraction per day, five fractions per week, to a total of 50.4-60 Gy. Three concurrent chemotherapy protocols were performed. Concurrent chemotherapy from 1999 to 2004 consisted of 80 mg/m2 nedaplatin on days 1 and 29, followed by 350 mg/m2 5-flurouracil administered as a continuous intravenous infusion on days 1 to 5 and days 29 to 33. Concurrent chemotherapy from 2005 to 2007 consisted of 10 mg/m2 docetaxel on days 1, 8, 15, 22, 29, and 36. Concurrent chemotherapy from 2008 consisted of 50 mg/m2 docetaxel on days 1 and 29, 60 mg/m2 cisplatin on days 1 and 29, followed by 600 mg/m2 5-flurouracil administered as a continuous intravenous infusion on days 1 to 4 and days 29 to 32. Salvage esophagectomy was defined as esophagectomy for either residual or recurrent disease following definitive CRT (radiation 50-60 Gy).
Statistical analysis. Subject characteristics were compared using Chi-squared tests for categorical variables and Student's t-test for continuous variables. Univariate and multivariate survival analyses were carried out using the Cox proportional hazards regression model. Kaplan–Meier curves were generated for overall survival and significance was determined using the log-rank test. A probability value of less than 0.05 was considered significant. All analyses were performed using R version 2.13.0 (The R Foundation for Statistical Computing, Vienna, Austria) statistical software.
Patient characteristics.
Results
Patient characteristics. The flowchart presented in Figure 1 outlines this study. A total of 40 patients were assessed for eligibility for inclusion in the study. Subsequently, eight patients were excluded. Six patients were excluded for having no data on serum albumin and lymphocyte count in peripheral blood within 1 month before surgery, and two surviving patients for follow-up period less than 1 year. The remaining 32 patients were included in this study. Table I summarizes the baseline characteristics, and Table II summarizes the perioperative data of patients.
Survival analysis. Univariate analysis revealed that clinical response, preoperative PNI, pT, pN, and residual tumors were a significant prognostic factor for overall survival (Table III). Multivariate analysis using age and these five variables found no independent prognostic factors (Table IV). Multivariate analysis using three preoperative variables (age, clinical response, and preoperative PNI) revealed PNI was an independent prognostic preoperative factor for overall survival (Table V). We divided patients into two groups based on PNI value according to previous reports (12): low PNI (PNI <45) and high PNI (PNI ≥45). The overall survival rate was significantly higher in patients with high PNI than in those with low PNI (p=0.037; Figure 2). However, disease-specific survival rate had no significant difference according to PNI value (p=0.424; Figure 3).
Perioperative data.
Comparison of background of esophageal cancer survivors after salvage esophagectomy. Table VI summarizes the baseline characteristics of survivors from primary esophageal cancer, living patients and patients who died from non-cancer -related causes. Preoperative PNI of living patients was significantly higher than those of patients dying from non-cancer causes (p=0.044).
Univariate analysis for overall survival.
Discussion
The most significant finding of the present study was that PNI was an independent prognostic preoperative factor for overall survival of patients with ESCC undergoing salvage esophagectomy. Additionally, the preoperative PNI of patients who remained alive was significantly higher than that of patients dying from non-cancer-related causes among survivors from primary cancer. These results support our hypothesis that preoperative nutritional status is associated with the prognosis of patients who undergo salvage esophagectomy.
Overall survival of patients who underwent salvage esophagectomy for esophageal squamous cell carcinoma according to their prognostic nutritional index (PNI). The overall survival rate was significantly higher in patients with high PNI than in those with low PNI (p=0.037).
Multivariate analysis for overall survival.
Disease-specific survival of patients who underwent salvage esophagectomy for esophageal squamous cell carcinoma according to their prognostic nutritional index (PNI). The disease-specific survival rate did not significantly differ according to PNI value (p=0.424).
Multivariate analysis of preoperative variables for overall survival.
The PNI is one of the tools and is calculated using the serum albumin level and the total lymphocyte count. PNI was previously proposed as a marker to predict the prognosis of patients with gastrointestinal malignancies (12). Although Nozoe et al. had already reported PNI was correlated with the incidence of postoperative complications and prognosis in patients with ESCC (13), to our best knowledge, this is the first study to report a relationship between PNI and prognosis of patients with ESCC who underwent salvage esophagectomy.
Malnutrition has been reported to be associated with poor outcomes and is characterized by a decreased quality of life, weaker response to chemotherapy, and lower survival rates in esophageal cancer (14). Focused on salvage esophagectomy, several preoperative factors (T and N status at initial treatment, time to relapse, and complete response to initial treatment) and postoperative factors (tumor pathological stage, R0 resection and total number of dissected mediastinal lymph nodes) have been reported as prognostic factors as described by Watanabe et al. (4) and references therein. However, the actual impact of preoperative nutritional status on the prognosis of patients underwent salvage esophagectomy was unclear. In our study, clinical response, preoperative PNI, pT, pN, and residual tumors were a significant prognostic factor for overall survival based on univariate analysis. Although multivariate analysis using age and those five variables found no independent prognostic factors, multivariate analysis using three preoperative variables (age, clinical response, and preoperative PNI) revealed PNI was an independent favorable prognostic preoperative factor for overall survival. Our results showed that preoperative nutritional status had a unignorable effect on the long-term outcome after salvage esophagectomy.
Characteristics of survivors from primary cancer at study end.
In our study, the overall survival rate was significantly higher in patients with high PNI than in those with low PNI. However, the disease-specific survival rate did not significantly differ according to PNI value. Therefore, we next hypothesized that preoperative nutritional status is also associated with death from other illness of survivors after salvage esophagectomy for esophageal cancer. Comparing baseline characteristics of survivors from primary esophageal cancer, preoperative PNI of patients who were alive was significantly higher than those of patients dying of other causes (p=0.044). In general, cancer survivors have been recognized to have significantly elevated risk of morbidity due to chronic health conditions (15). Nutrition has a major role in the etiology of chronic health conditions, and poor nutritional status may worsen these morbidities in cancer survivors (16). After receiving definitive CRT, patients are considered to be immune-suppressed, and salvage esophagectomy exacerbates immune suppression even in cancer survivors because of its high invasiveness. Thus, the preoperative nutritional status may predict the postoperative healthy condition even of cancer-free patients after salvage esophagectomy. Perioperative immunonutrition was recently reported to improve both the nutritional and immunological status of surgical patients and reduce the risk of postoperative complications (17-18). Regarding the clinical application of our findings, to improve the outcome of salvage esophagectomy, we speculate that patients with ESCC with poor nutritional status may require more intensive perioperative nutritional support, stricter criteria for salvage surgery and long-term chronic health condition management.
Our study has several potential limitations. Firstly, this was a retrospective study and was performed without randomization of patient selection. Secondly, since we assessed nutritional status as PNI, it remains unclear whether analysis using other nutritional indicators, such as the neutrophil-to-lymphocyte ratio and sarcopenia, would lead to the same results.
In conclusion, our study demonstrated that PNI was an independent prognostic preoperative factor for overall survival of patients who underwent salvage esophagectomy for ESCC. Additionally, preoperative PNI of patients remaining alive was significantly higher than that of patients dying from non-cancer-related causes among survivors from primary cancer. Preoperative nutritional status is associated with the poor prognosis of patients who undergo salvage esophagectomy.
- Received October 24, 2017.
- Revision received November 16, 2017.
- Accepted November 23, 2017.
- Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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