Preoperative Prognostic Nutritional Index Predicts Long-Term Surgical Outcomes in Patients with Esophageal Squamous Cell Carcinoma

Preoperative Prognostic Nutritional Index Predicts Long-Term Surgical Outcomes in Patients with... Background The purpose of the present study is to investigate the utility of prognostic nutritional index (PNI) as a simple and readily available marker in esophageal squamous cell carcinoma (ESCC). Methods We retrospectively analyzed 169 patients who underwent potentially curative esophagectomy, for histo- logically verified ESCC. We decided to set the optimal cutoff value for preoperative PNI levels at 49.2, based on the cancer-specific survival (CSS) and the overall survival (OS) by receiver operating characteristic curve analysis. Results Multivariate logistic regression analysis identified that TNM pStage III [hazard ratio (HR) 3.261, p \ 0.0001] and PNI \ 49.2 (HR 3.887, p\ 0.0001) were confirmed as independent poor predictive factors for CSS, and age [70 (HR 2.024, p\ 0.0042), TNM pStage III (HR 2.510, p = 0.0002), and PNI \ 49.2 (HR 2.248, p = 0.0013) were confirmed as independent poor predictive factors for OS. In non-elderly patients, TNM pStage III (CSS; HR 3.488, p \ 0.0001, OS; HR 2.615, p = 0.0007) and PNI \ 49.2 (CSS; HR 3.849, p \ 0.0001, OS; HR 2.275, p = 0.001) were confirmed as independent poor predictive factors for CSS, and OS when multivariate logistic regression analysis was applied. But in elderly patients, univariate analyses demonstrated that the TNM pStage III was the only significant risk factor for CSS (HR 3.701, p = 0.0057) and OS (HR 1.974, p = 0.0224). Conclusions The PNI was a significant and independent predictor of CSS and OS of ESCC patients after curative esophagectomy. The PNI was cost-effective and readily available, and it could act as a marker of survival. Introduction treatments, despite improvements in surgical techniques and perioperative care with reduced perioperative mortality Esophageal cancer is a disease of the elderly, with peak after esophagectomy. Therefore, there is a continuing incidence occurring in patients in their 70 s, and the elderly interest in prognostic factors to identify patients who are at population is rapidly increasing in worldwide. Early greater risks of recurrence in order to better tailor indi- detection and treatment confers the greatest chance of long- vidual treatments to those who are more likely to benefit term survival in patients with esophageal cancer. However, from them. Progression and prognosis of cancer has been a common problem among esophageal cancer patients shown to be impacted by both the tumor features as well as (especially the elderly) is low tolerance to the available the patient’s nutritional and immunologic status [1, 2]. Several screening tools are now available for assessing the preoperative nutritional status of patients with cancer, & Noriyuki Hirahara including the subjective global assessment, nutritional risk norinorihirahara@yahoo.co.jp scoring 2002, body mass index, Glasgow Prognostic Score, and prognostic nutritional index (PNI) [3–6]. Many studies Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, have addressed the association between preoperative Shimane 693-8501, Japan 123 2200 World J Surg (2018) 42:2199–2208 nutritional status and postoperative outcomes. However, surgery with an elevation of the gastric conduit to the neck there is little data to show the impact of nutritional status via the posterior mediastinal approach or retrosternal on long-term outcomes in patients undergoing radical approach with an end-to-end anastomosis of the cervical thoracoscopic esophagectomy for esophageal squamous esophagus and gastric conduit. The patients’ clinical cell carcinoma (ESCC) [7, 8]. characteristics, laboratory data, treatment regimen, and The PNI was originally developed to predict the risk of pathological data were obtained from their medical postoperative morbidity and mortality after gastrointestinal records. None of the patients had clinical signs of infection surgery [9]. However, the method for calculating PNI is or other systemic inflammatory conditions preoperatively. complicated and difficult to use routinely in clinical prac- In this study, we excluded patients who had received pre- tice. In contrast, the simplified PNI proposed by Onodera or postoperative adjuvant chemotherapy and/or et al. [6] can be easily measured because it is based on only radiotherapy. two laboratory parameters, namely the serum albumin level We introduced a perioperative multidisciplinary man- and the peripheral blood lymphocyte count. Albumin is a agement team, including surgeon, anesthesiologist, dental widely used parameter of nutrition, and its levels have been hygienist doctor, pharmacist, nutritionist, and rehabilitation shown to correlate well with postoperative complications technician, and certified expert surgical nurse, which aimed and long-term outcomes in several malignancies [10]. to decrease the incidence rate of postoperative complica- Similarly, reduced lymphocyte count and function also tions. This team mainly managed dental cleaning, medi- correlate with poor prognosis, by enabling cancer cells to cation assistance, physical exercise and rehabilitation, escape immune surveillance [11]. PNI, therefore, is a respiratory training, and nutritional support. We provided favorable indicator and is more reflective of the overall preoperative enteral nutrition to optimize preoperative status of cancer patients. condition as possible. In the management of cancer patients, there has been a The severity of postoperative complications was evalu- continuing interest in preoperative prognostic indicators ated according to the Clavien–Dindo classification, and that can allow more accurate patient stratification, precise grade II or higher was recorded as a postoperative com- clinical decision-making, and improvement of short- and plication [13]. long-term outcomes. The TNM classification is widely We evaluated cancer-specific survival (CSS) and overall used as a good standard prognostic indicator of patients survival (OS) as the endpoints of the study. The observa- with cancer [12]. However, since it includes pathological tion period started from the day of the operation and lasted findings of the tumor, a conclusive classification can only for up to 5 years, loss to follow-up, withdrawal of consent, be made postoperatively. In contrast, the PNI is based on or until death. CSS was defined as the interval from the the preoperative laboratory data alone and could be a date of operation to the date of cancer-specific death or the comprehensive indicator of postoperative morbidity, mor- last follow-up. Two patients who died of myocardial tality, and prognosis of cancer patients prior to surgery. infarction within 60 days after esophagectomy were Therefore, we have demonstrated the prognostic sig- excluded from the analysis. We defined ‘elderly’ patients nificance of the simplified PNI in overall and age-stratified as those aged 70 years or older and ‘non-elderly’ as those ESCC patients with a low versus high PNI, and evaluated aged less than 70 years of age [14]. its potential as a useful surrogate marker for predicting Permission to perform this retrospective study was postoperative patient survival. obtained from the ethical board of our institution and the study was conducted in accordance with the Declaration of Helsinki. Methods Preoperative calculation of the PNI and its cutoff Patients value We retrospectively reviewed a database containing data The preoperative PNI was calculated using the following from 169 patients who underwent potentially curative formula: 10 9 serum albumin (g/dl) ? 0.005 9 total esophagectomy with R0 resection, for histologically veri- lymphocyte count (per mm ) in peripheral blood [6]. fied ESCC in our institute, between January 2006 and The receiver operating characteristics (ROC) curve of December 2015. R0 resection was defined as complete preoperative PNI levels was generated for multiple logistic tumor removal without the involvement of any microscopic regression analysis using CSS and OS. The area under the resection margin. Video-assisted or thoracoscopic subtotal curve (AUC) estimation was used to assess the predictive esophagectomy with three-field lymph node dissection was ability of the PNI. performed for all patients, followed by laparoscopic gastric 123 World J Surg (2018) 42:2199–2208 2201 We decided to set the optimal cutoff value for preop- All statistical analyses were performed using the sta- erative PNI levels at 49.2 in this study, based on the CSS tistical software JMP (version 11 for Windows; SAS (sensitivity: 52.99%; specificity: 80.77%; AUC of the ROC Institute, Cary, NC), and p values \0.05 were considered curve: 0.653) and the OS (sensitivity: 52.63%; specificity: statistically significant. 70.27%; AUC of the ROC curve: 0.6132) at 5 years after surgery (Fig. 1). Based on their PNI values, patients were categorized as having a high PNI (49.2 or greater) or as Results having a low PNI (less than 49.2). Relationship between PNI and clinicopathological TNM pathological Stage (pStage) features The pathological classification of the primary tumor, the The correlation between the PNI and clinicopathological degree of lymph node involvement, and the presence of parameters in the 169 patients enrolled in this study is organ metastasis were determined according to the TNM summarized in Table 1. The preoperative mean value of classification system (7th edition of the cancer staging the PNI in this study was 47.3 ± 6.2, ranging from 26.8 to manual of the American Joint Committee on Cancer) [15]. 65.7. Based on the cutoff value of 49.2, 98 patients (58%) were in the low PNI category and 71 patients (42%) were Statistical analysis in the high PNI category. The results of our analysis showed that the PNI value correlated significantly with The mean and standard deviation were calculated, and the lymphocyte count (p \ 0.0001), tumor size (p = 0.0327), differences were analyzed using Student’s t test. Differ- depth of tumor (p\ 0.0001), TNM pStage (p = 0.0005), ences between the various clinicopathological features SCC antigen level (p = 0.0072), albumin level were analyzed using the Chi-square test. The CSS was (p\ 0.0001), and CRP level (p = 0.0012). analyzed using Kaplan–Meier statistics, and inter-group differences were assessed using the log-rank test. Prognostic factors for postoperative survival Univariate analyses were performed to determine vari- in patients with ESCC ables associated with CSS. Variables with p values \ 0.05 in the univariate analyses were included in a multivariate Univariate analyses identified advanced TNM pStage logistic regression analysis. The potential prognostic fac- [hazard ratio (HR), 4.170; 95% confidence interval (CI), tors assessed were as follows: age (\70 vs. C70 years), sex 2.377–7.525; p\ 0.0001], large tumor size (HR 1.854; (female vs. male), TNM pStage (I/II vs. III), tumor size (\3 95% CI 1.093–3.678; p = 0.0233), prolonged operation vs. C3 cm), operation time (\600 vs. C600 min), intra- time (HR 1.756; 95% CI 1.012–3.035; p = 0.0452), and operative blood loss (\500 vs. C500 mL), serum squamous low PNI (HR 4.566; 95% CI 2.375–9.674; p \ 0.0001) as cell carcinoma antigen (SCC) value (\1.5 vs. C1.5), and significant risk factors for shorter CSS. The TNM pStage PNI (\49.2 vs. C49.2). (HR 3.261; 95% CI 1.808–6.043; p\ 0.0001) and PNI (HR 3.887; 95% CI 1.999–8.309; p\ 0.0001) were Fig. 1 Receiver operating (a) 1.0 (b) 1.0 curves for postoperative survival were plotted to verify the optimum cutoff value for 0.8 0.8 PNI. a cancer-specific survival, b overall survival 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity 1-Specificity Sensitivity Sensitivity 2202 World J Surg (2018) 42:2199–2208 Table 1 Relationships between PNI and clinicopathological features in 169 patients with esophageal cancer Characteristics Total patients PNI \49.2 C49.2 p value (n = 98) (n = 71) Age (years) 67.1 ± 8.2 65.4 ± 8.0 0.1804 Sex 0.628 Male 150 86 64 Female 19 12 7 WBC 5830.0 ± 2404.6 6233.9 ± 1616.6 0.2209 Neutrophil 3773.6 ± 2197.3 3669.2 ± 1264.6 0.7199 Lymphocyte 1396.4 ± 562.7 1931.8 ± 599.2 \0.0001 Platelet 232.8 ± 75.5 225.5 ± 50.2 0.4796 Location of tumor 0.0696 Ce 13 12 1 Ut 10 6 4 Mt 73 39 34 Lt 59 31 28 Ae 14 10 4 Tumor size (mm) 5.27 ± 4.98 3.88 ± 2.53 0.0327 Depth of tumor \0.0001 T1a–1b 72 27 45 213 8 5 367 48 19 4a–4b 17 15 2 Lymph node metastasis 0.1573 N089 49 40 N148 28 20 N218 9 9 N314 12 2 Pathological stage 0.0005 1a–1b 62 24 38 2a–2b 39 28 11 3a–3c 68 46 22 Operation time (min) 656.1 ± 196.1 646.7 ± 158.6 0.7391 Intraoperative blood loss (ml) 665.5 ± 601.2 580.0 ± 612.3 0.3666 SCC antigen 1.67 ± 2.04 0.97 ± 0.85 0.0072 Albumin 3.64 ± 0.43 4.32 ± 0.30 \0.0001 CRP 0.658 ± 1.098 0.217 ± 0.314 0.0012 confirmed as independent prognostic factors for CSS when 2.248; 95% CI 1.362–3.832; p = 0.0013) were confirmed multivariate logistic regression analysis was applied as independent prognostic factors for OS in multivariate (Table 2). logistic regression analysis (Table 3). Univariate analyses identified advanced age (HR 1.930; 95% CI 1.205–3.061; p = 0.0066), advanced TNM pStage Prognostic factors for postoperative survival in non- (HR 2.725; 95% CI 1.714–4.349; p \ 0.0001), large tumor elderly patients with ESCC size (HR 1.868; 95% CI 1.149–3.141; p = 0.0112), and low PNI (HR 2.612; 95% CI 1.600–4.405; p \ 0.0001) as Among 110 non-elderly patients, univariate analyses significant risk factors for shorter OS. The age (HR 2.024; identified advanced TNM pStage (HR 4.646; 95% CI 95% CI 1.255–3.236; p = 0.0042), TNM pStage (HR 2.281–10.027; p \ 0.0001), large tumor size (HR 2.872; 2.510; 95% CI 1.555–4.064; p = 0.0002), and PNI (HR 95% CI 1.349–6.825; p = 0.0054), and low PNI (HR 123 World J Surg (2018) 42:2199–2208 2203 Table 2 Prognostic factors for cancer-specific survival in patients with esophageal cancer Variables Patients (n = 169) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 19/150 (Female/male) 1.14 0.499–3.290 0.7765 Age 59/110 (\70/C70) 1.42 0.790–2.480 0.2344 TNM pStage 101/68 (1,2/3) 4.17 2.377–7.525 \0.0001 3.261 1.808–6.043 \0.0001 Tumor size 64/105 (\3/C3) 1.854 1.093–3.678 0.0233 1.076 0.583–2.079 0.8203 Operation time 111/58 (\600/C600) 1.756 1.012–3.035 0.0452 1.595 0.910–2.786 0.1024 Intraoperative blood loss 87/82 (\500/C500) 0.973 0.562–1.685 0.9226 PNI 98/71 (C49.2/\49.2) 4.566 2.375–9.674 \0.0001 3.887 1.999–8.309 \0.0001 SCC 126/43 (\1.5/C1.5) 1.169 0.584–2.171 0.6425 Table 3 Prognostic factors for overall survival in patients with esophageal cancer Variables Patients(n = 169) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 19/150 (Female/male) 1.12 0.550–2.687 0.773 Age 59/110 (\70/C70) 1.93 1.205–3.061 0.0066 2.024 1.255–3.236 0.0042 TNM pStage 101/68 (1,2/3) 2.725 1.714–4.349 \0.0001 2.51 1.555–4.065 0.0002 Tumor size 64/105 (\3/C3) 1.868 1.149–3.141 0.0112 1.219 0.7364–2.083 0.5582 Operation time 111/58 (\600/C600) 1.481 0.9288–2.344 0.0981 Intraoperative blood loss 87/82 (\500/C500) 1.308 0.825–2.098 0.2541 PNI 98/71 (C49.2/\49.2) 2.612 1.600–4.405 \0.0001 2.248 1.362–3.832 0.0013 SCC 126/43 (\1.5/C1.5) 1.589 0.934–2.609 0.0859 11.370; 95% CI 4.040–47.500; p \ 0.0001) as significant PNI (HR 3.671; 95% CI 1.864–7.897; p = 0.0001) as risk factors for shorter CSS. The TNM pStage (HR 3.488; significant risk factors for shorter OS. The TNM pStage 95% CI 1.948–6.424; p \ 0.0001) and PNI (HR 3.849; (HR 2.615; 95% CI 1.430–3.768; p = 0.0007) and PNI 95% CI 1.987–8.205; p\ 0.0001) were confirmed as (HR 2.275; 95% CI 1.384–3.863; p = 0.001) were con- independent prognostic factors for CSS when multivariate firmed as independent prognostic factors for OS in multi- logistic regression analysis was applied (Table 4). variate logistic regression analysis (Table 5). Univariate analyses identified advanced TNM pStage (HR 3.772; 95% CI 2.027–7.234; p \ 0.0001), large tumor size (HR 2.539; 95% CI 1.315-5.298; p = 0.0050), and low Table 4 Univariate and multivariate analysis of cancer-specific survival in 110 non-elderly patients with esophageal cancer Variables Patients Category or Univariate Multivariate (n = 110) characteristics HR 95% CI p value HR 95% CI p value Gender 11/99 (Female/male) 0.865 0.307–3.612 0.8142 TNM pStage 64/46 (1,2/3) 4.646 2.281–10.027 \0.0001 3.488 1.948–6.424 \0.0001 Tumor size 44/66 (\3/C3) 2.872 1.349–6.825 0.0054 1.115 0.607–2.149 0.7313 Operation time 74/36 (\600/C600) 1.636 0.307–1.234 0.1664 Intraoperative blood 55/55 (\500/C500) 1.176 0.591–2.371 0.6437 loss PNI 61/49 (C49.2/\49.2) 11.37 4.040–47.500 \0.0001 3.849 1.987–8.205 \0.0001 SCC 83/27 (\1.5/C1.5) 1.307 0.516–2.914 0.5471 123 2204 World J Surg (2018) 42:2199–2208 Table 5 Univariate and multivariate analysis of overall survival in 110 non-elderly patients with esophageal cancer Variables Patients (n = 110) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 11/99 (Female/male) 1.08 0.390–4.478 0.8968 TNM Stage 64/46 (1,2/3) 3.772 2.027–7.234 \0.0001 2.615 1.430–3.768 0.0007 Tumor size 44/66 (\3/C3) 2.539 1.315–5.298 0.005 1.281 0.769–2.202 0.3477 Operation time 74/36 (\600/C600) 1.254 0.661–2.320 0.4803 Intraoperative blood loss 55/55 (\500/C500) 1.524 0.822–2.911 0.1821 PNI 61/49 (C49.2/\49.2) 3.671 1.864–7.897 0.0001 2.275 1.384–3.863 0.001 SCC 83/27 (\1.5/C1.5) 1.515 0.697–3.028 0.2787 Prognostic factors for postoperative survival PNI and postoperative survival in all patients in elderly patients with ESCC with ESCC In 59 elderly patients, univariate analyses demonstrated Kaplan–Meier analysis and the log-rank test demonstrated that the TNM pStage was the only significant risk factor for that patients with a low PNI had a significantly worse shorter CSS and OS (HR 3.701; 95% CI 1.470–9.743; prognosis in terms of CSS and OS than those with a high p = 0.0057, HR 1.974; 95% CI 0.938–4.038; p = 0.0224, PNI (p\ 0.0001, and p = 0.0003, respectively). The respectively) (Table 6). 5-year CSS rates were 46.5 and 84.2%, and the 5-year OS rates were 38.3 and 74.1% for patients with a low PNI and a high PNI, respectively (Fig. 2). Table 6 Univariate and multivariate analysis of cancer-specific survival and overall survival in 59 elderly patients with esophageal cancer Variables Patients (n = 59) Category or characteristics Cancer-specific survival Overall survival Univariate Univariate HR 95% CI p value HR 95% CI p value Gender 8/51 (Female/male) 1.85 0.526–11.717 0.3755 1.577 0.615–5.349 0.37 TNM pStage 37/22 (1,2/3) 3.701 1.470–9.743 0.0057 1.974 0.938–4.038 0.0224 Tumor size 20/39 (\3/C3) 0.973 0.390–2.623 0.9542 1.073 0.526–2.313 0.8507 Operation time 37/22 (\600/C600) 1.909 0.768–4.815 0.1614 1.731 0.859–3.491 0.1235 Intraoperative blood loss 32/27 (\500/C500) 0.689 0.265–1.714 0.4235 1.023 0.506–2.088 0.9493 PNI 37/22 (C49.2/\49.2) 1.68 0.655–4.679 0.2838 1.748 0.845–3.784 0.1333 SCC 43/16 (\1.5/C1.5) 1.218 0.387–3.287 0.715 2.003 0.909–4.214 0.0828 Fig. 2 Kaplan–Meier curves of (a) (b) 1.0 1.0 postoperative survival based on PNI in 169 patients with ESCC. 0.8 0.8 a cancer-specific survival, b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=71) 0.2 PNI 49.2 (n=71) 0.2 PNI <49.2 (n=98) PNI <49.2 (n=98) P<0.0001 P=0.0003 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Cumulative survival Cumulative survival World J Surg (2018) 42:2199–2208 2205 PNI and postoperative survival in non-elderly low versus high PNI. Similarly, there were no significant patients with ESCC differences in postoperative hospital stay (data not shown). Kaplan–Meier analysis and the log-rank test demonstrated that patients with a low PNI had a significantly worse Discussion prognosis in terms of CSS and OS than those with a high PNI (p\ 0.0001, and p = 0.0003, respectively). The Treatment strategies for ESCC include surgery, radiation, 5-year CSS rates were 44.1, and 92.8% and the 5-year OS chemotherapy, or a combination thereof. Although a rates were 41.5 and 84.8% for patients with a low PNI and complete surgical resection of the tumor offers a chance for a high PNI, respectively (Fig. 3). cure, the rate of disease recurrence is very high in ESCC even after an aggressive surgery. Histopathology of surgi- PNI and postoperative survival in elderly patients cal specimens is widely used to estimate the prognosis after with ESCC surgery [12]; however, its predictive value is still limited. The precise evaluation of the risk of postoperative recur- Kaplan–Meier analysis and the log-rank test showed no rence is important in planning a customized risk-adapted significant relationship between PNI and CSS (p = 0.1398) therapeutic strategy for individual patients. In particular, or OS (p = 0.1907) in elderly patients with ESCC (Fig. 4). identifying prognostic factors prior to surgery is important to determine the optimal preoperative therapy, and to PNI and postoperative complications improve postoperative short- and long-term outcomes [16]. The original PNI consists of tests measuring albumin, The postoperative complications in the high and low PNI transferrin, triceps skin fold, and skin sensitivity reaction to groups are shown in Table 7. No significant differences in common antigens [17], and it was developed to assess the incidence rates of postoperative complication were perioperative complications, including anastomotic leak- observed between overall and age-stratified patients with a age, delayed tissue repair, and length of hospital stay in patients undergoing gastrointestinal surgery [11, 18]. The Fig. 3 Kaplan–Meier curves of (a) (b) 1.0 1.0 survival based on PNI in 110 non-elderly patients with ESCC. 0.8 0.8 a Cancer-specific survival, b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=49) PNI 49.2 (n=49) 0.2 0.2 PNI <49.2 (n=61) PNI <49.2 (n=61) P<0.0001 P=0.0003 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Fig. 4 Kaplan–Meier curves of (a) (b) survival based on PNI in 59 1.0 1.0 elderly patients with ESCC. a Cancer-specific survival, 0.8 0.8 b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=22) PNI 49.2 (n=22) 0.2 0.2 PNI <49.2 (n=37) PNI <49.2 (n=37) P=0.1398 P=0.1907 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Cumulative survival Cumulative survival Cumulative survival Cumulative survival 2206 World J Surg (2018) 42:2199–2208 simplified PNI, on the other hand, consists of only two laboratory parameters, namely serum albumin concentra- tion and total lymphocyte count in the peripheral blood [6], both of which are measured routinely in clinical practice. Recently, several studies have reported that albumin is produced by hepatocytes and is regulated by pro-inflam- matory cytokines, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-a (TNF-a) that adversely affect catabolic metabolism [19–21]. These cytokines produced by either the tumor itself or the host are crucial for car- cinogenesis, cancer progression, and neo-angiogenesis. In addition, albumin has been shown to help stabilize cell growth and DNA replication, buffer a variety of bio- chemical changes and maintain sex hormone homeostasis to protect against tumorigenesis [10]. Albumin, therefore, is reflective of the inflammation and immune status of cancer, although it alone is not sufficient to predict the final outcome in cancer patients. Another element of the sim- plified PNI is the lymphocyte count. Lymphocytes are one of the fundamental components of cell-mediated immunity with inhibitory effects on the proliferation and invasion of tumor cells via cytokine-mediated cytotoxicity [11, 22]. Most patients with ESCC are malnourished, either due to poor dietary intake, protein loss from the primary lesion or due to catabolic metabolism [23]. Impaired nutritional and immunologic status accelerates tumor progression due to a decline in tumor immunity [16, 22]. The PNI is, therefore, a comprehensive indicator of the nutritional and immuno- logic status in cancer patients [24]. In this study, we evaluated the potential of simplified PNI as a prognostic marker of CSS and OS in ESCC patients who underwent radical thoracoscopic esophagec- tomy. Patients with a low PNI (less than 49.2) showed a significantly shorter CSS and decreased OS in comparison with patients who had a high PNI (49.2 or greater). This is consistent with our finding that PNI is inversely related to the stage of cancer, the value being lower in patients with a larger, deeper and more aggressive tumor at an advanced TNM pStage [25]. Recent studies have also demonstrated an association between the occurrences of postoperative complications with deteriorated CSS in patients with gas- trointestinal cancer [26, 27]. Patients with a low PNI are, therefore, more likely to develop postoperative complica- tions [11, 17, 18], including a systemic inflammatory response, which can also contribute to the decreased CSS and OS. However, this correlation between PNI and CSS/ OS was found only in non-elderly patients and not in the elderly patients. This difference could be due to the fact that irrespective of being a cancer patient or not, hypoal- buminemia and leukocytopenia are often associated with aging, leading to malnutrition and immune suppression [28]. Previous studies have reported that cancer patients experiencing postoperative complications generally have a Table 7 Comparison between postoperative complications and PNI Overall patients PNI Non-elderly patients PNI Elderly patients PNI \49.2 C49.2 p value \49.2 C49.2 p value \49.2 C49.2 p value (n = 169) (n = 98) (n = 71) (n = 110) (n = 61) (n = 49) (n = 59) (n = 37) (n = 22) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Anastomotic leakage 17 (10.1) 9 (9.2) 8 (11.3) 0.657 8 (7.3) 4 (6.6) 4 (8.2) 0.747 9 (15.2) 5 (13.5) 4 (18.2) 0.63 Vocal code paresis 11 (6.5) 6 (6.1) 5 (7.0) 0.811 4 (3.6) 2 (3.3) 2 (4.1) 0.823 7 (11.9) 4 (10.8) 3 (13.6) 0.746 Pulmonary complication 48 (28.4) 30 (30.6) 18 (25.4) 0.454 20 (18.2) 12 (19.7) 8 (16.3) 0.651 28 (47.5) 18 (48.6) 10 (45.5) 0.812 Chylothorax 1 (0.6) 0 (0) 1 (1.4) 0.239 1 (0.9) 1 (1.6) 0 (0) 0.368 0 (0) 0 (0) 0 (0) NaN Surgical site infection 10 (5.9) 4 (4.1) 6 (8.5) 0.235 5 (4.5) 2 (3.3) 3 (6.1) 0.477 5 (8.5) 2 (5.4) 3 (13.6) 0.272 NaN Not a number World J Surg (2018) 42:2199–2208 2207 the institutional and national research committee and with the 1964 poorer prognosis [29–31]. Because patients with a low Helsinki declaration and its later amendments or comparable ethical preoperative PNI value are at a high risk of postoperative standards. complications, the preoperative PNI value may affect both postoperative short- and long-term outcomes. However, in Informed consent Informed consent was obtained from all individ- ual participants included in the study. this study, no significant differences were observed between the PNI value and the rate of postoperative com- Open Access This article is distributed under the terms of the plications. Therefore, further studies are thus needed to Creative Commons Attribution 4.0 International License (http://crea address this issue. tivecommons.org/licenses/by/4.0/), which permits unrestricted use, The optimal cutoff points for PNI in predicting post- distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a operative survival in patients with malignant tumors is still link to the Creative Commons license, and indicate if changes were controversial. Thus, one of the aims of this study was to made. evaluate the prognostic value of the PNI and propose an optimal cutoff, which can predict CSS and OS with better accuracy, in patients with ESCC. Based on our study of References 169 patients who underwent curative esophagectomy, and using a ROC curve, we have arrived at 49.2 as the cutoff 1. Mainous MR, Deitch EA (1994) Nutrition and infection. Surg Clin N Am 74(3):659–676 value for PNI. 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Preoperative Prognostic Nutritional Index Predicts Long-Term Surgical Outcomes in Patients with Esophageal Squamous Cell Carcinoma

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Medicine & Public Health; Surgery; Abdominal Surgery; Cardiac Surgery; General Surgery; Thoracic Surgery; Vascular Surgery
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Abstract

Background The purpose of the present study is to investigate the utility of prognostic nutritional index (PNI) as a simple and readily available marker in esophageal squamous cell carcinoma (ESCC). Methods We retrospectively analyzed 169 patients who underwent potentially curative esophagectomy, for histo- logically verified ESCC. We decided to set the optimal cutoff value for preoperative PNI levels at 49.2, based on the cancer-specific survival (CSS) and the overall survival (OS) by receiver operating characteristic curve analysis. Results Multivariate logistic regression analysis identified that TNM pStage III [hazard ratio (HR) 3.261, p \ 0.0001] and PNI \ 49.2 (HR 3.887, p\ 0.0001) were confirmed as independent poor predictive factors for CSS, and age [70 (HR 2.024, p\ 0.0042), TNM pStage III (HR 2.510, p = 0.0002), and PNI \ 49.2 (HR 2.248, p = 0.0013) were confirmed as independent poor predictive factors for OS. In non-elderly patients, TNM pStage III (CSS; HR 3.488, p \ 0.0001, OS; HR 2.615, p = 0.0007) and PNI \ 49.2 (CSS; HR 3.849, p \ 0.0001, OS; HR 2.275, p = 0.001) were confirmed as independent poor predictive factors for CSS, and OS when multivariate logistic regression analysis was applied. But in elderly patients, univariate analyses demonstrated that the TNM pStage III was the only significant risk factor for CSS (HR 3.701, p = 0.0057) and OS (HR 1.974, p = 0.0224). Conclusions The PNI was a significant and independent predictor of CSS and OS of ESCC patients after curative esophagectomy. The PNI was cost-effective and readily available, and it could act as a marker of survival. Introduction treatments, despite improvements in surgical techniques and perioperative care with reduced perioperative mortality Esophageal cancer is a disease of the elderly, with peak after esophagectomy. Therefore, there is a continuing incidence occurring in patients in their 70 s, and the elderly interest in prognostic factors to identify patients who are at population is rapidly increasing in worldwide. Early greater risks of recurrence in order to better tailor indi- detection and treatment confers the greatest chance of long- vidual treatments to those who are more likely to benefit term survival in patients with esophageal cancer. However, from them. Progression and prognosis of cancer has been a common problem among esophageal cancer patients shown to be impacted by both the tumor features as well as (especially the elderly) is low tolerance to the available the patient’s nutritional and immunologic status [1, 2]. Several screening tools are now available for assessing the preoperative nutritional status of patients with cancer, & Noriyuki Hirahara including the subjective global assessment, nutritional risk norinorihirahara@yahoo.co.jp scoring 2002, body mass index, Glasgow Prognostic Score, and prognostic nutritional index (PNI) [3–6]. Many studies Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, have addressed the association between preoperative Shimane 693-8501, Japan 123 2200 World J Surg (2018) 42:2199–2208 nutritional status and postoperative outcomes. However, surgery with an elevation of the gastric conduit to the neck there is little data to show the impact of nutritional status via the posterior mediastinal approach or retrosternal on long-term outcomes in patients undergoing radical approach with an end-to-end anastomosis of the cervical thoracoscopic esophagectomy for esophageal squamous esophagus and gastric conduit. The patients’ clinical cell carcinoma (ESCC) [7, 8]. characteristics, laboratory data, treatment regimen, and The PNI was originally developed to predict the risk of pathological data were obtained from their medical postoperative morbidity and mortality after gastrointestinal records. None of the patients had clinical signs of infection surgery [9]. However, the method for calculating PNI is or other systemic inflammatory conditions preoperatively. complicated and difficult to use routinely in clinical prac- In this study, we excluded patients who had received pre- tice. In contrast, the simplified PNI proposed by Onodera or postoperative adjuvant chemotherapy and/or et al. [6] can be easily measured because it is based on only radiotherapy. two laboratory parameters, namely the serum albumin level We introduced a perioperative multidisciplinary man- and the peripheral blood lymphocyte count. Albumin is a agement team, including surgeon, anesthesiologist, dental widely used parameter of nutrition, and its levels have been hygienist doctor, pharmacist, nutritionist, and rehabilitation shown to correlate well with postoperative complications technician, and certified expert surgical nurse, which aimed and long-term outcomes in several malignancies [10]. to decrease the incidence rate of postoperative complica- Similarly, reduced lymphocyte count and function also tions. This team mainly managed dental cleaning, medi- correlate with poor prognosis, by enabling cancer cells to cation assistance, physical exercise and rehabilitation, escape immune surveillance [11]. PNI, therefore, is a respiratory training, and nutritional support. We provided favorable indicator and is more reflective of the overall preoperative enteral nutrition to optimize preoperative status of cancer patients. condition as possible. In the management of cancer patients, there has been a The severity of postoperative complications was evalu- continuing interest in preoperative prognostic indicators ated according to the Clavien–Dindo classification, and that can allow more accurate patient stratification, precise grade II or higher was recorded as a postoperative com- clinical decision-making, and improvement of short- and plication [13]. long-term outcomes. The TNM classification is widely We evaluated cancer-specific survival (CSS) and overall used as a good standard prognostic indicator of patients survival (OS) as the endpoints of the study. The observa- with cancer [12]. However, since it includes pathological tion period started from the day of the operation and lasted findings of the tumor, a conclusive classification can only for up to 5 years, loss to follow-up, withdrawal of consent, be made postoperatively. In contrast, the PNI is based on or until death. CSS was defined as the interval from the the preoperative laboratory data alone and could be a date of operation to the date of cancer-specific death or the comprehensive indicator of postoperative morbidity, mor- last follow-up. Two patients who died of myocardial tality, and prognosis of cancer patients prior to surgery. infarction within 60 days after esophagectomy were Therefore, we have demonstrated the prognostic sig- excluded from the analysis. We defined ‘elderly’ patients nificance of the simplified PNI in overall and age-stratified as those aged 70 years or older and ‘non-elderly’ as those ESCC patients with a low versus high PNI, and evaluated aged less than 70 years of age [14]. its potential as a useful surrogate marker for predicting Permission to perform this retrospective study was postoperative patient survival. obtained from the ethical board of our institution and the study was conducted in accordance with the Declaration of Helsinki. Methods Preoperative calculation of the PNI and its cutoff Patients value We retrospectively reviewed a database containing data The preoperative PNI was calculated using the following from 169 patients who underwent potentially curative formula: 10 9 serum albumin (g/dl) ? 0.005 9 total esophagectomy with R0 resection, for histologically veri- lymphocyte count (per mm ) in peripheral blood [6]. fied ESCC in our institute, between January 2006 and The receiver operating characteristics (ROC) curve of December 2015. R0 resection was defined as complete preoperative PNI levels was generated for multiple logistic tumor removal without the involvement of any microscopic regression analysis using CSS and OS. The area under the resection margin. Video-assisted or thoracoscopic subtotal curve (AUC) estimation was used to assess the predictive esophagectomy with three-field lymph node dissection was ability of the PNI. performed for all patients, followed by laparoscopic gastric 123 World J Surg (2018) 42:2199–2208 2201 We decided to set the optimal cutoff value for preop- All statistical analyses were performed using the sta- erative PNI levels at 49.2 in this study, based on the CSS tistical software JMP (version 11 for Windows; SAS (sensitivity: 52.99%; specificity: 80.77%; AUC of the ROC Institute, Cary, NC), and p values \0.05 were considered curve: 0.653) and the OS (sensitivity: 52.63%; specificity: statistically significant. 70.27%; AUC of the ROC curve: 0.6132) at 5 years after surgery (Fig. 1). Based on their PNI values, patients were categorized as having a high PNI (49.2 or greater) or as Results having a low PNI (less than 49.2). Relationship between PNI and clinicopathological TNM pathological Stage (pStage) features The pathological classification of the primary tumor, the The correlation between the PNI and clinicopathological degree of lymph node involvement, and the presence of parameters in the 169 patients enrolled in this study is organ metastasis were determined according to the TNM summarized in Table 1. The preoperative mean value of classification system (7th edition of the cancer staging the PNI in this study was 47.3 ± 6.2, ranging from 26.8 to manual of the American Joint Committee on Cancer) [15]. 65.7. Based on the cutoff value of 49.2, 98 patients (58%) were in the low PNI category and 71 patients (42%) were Statistical analysis in the high PNI category. The results of our analysis showed that the PNI value correlated significantly with The mean and standard deviation were calculated, and the lymphocyte count (p \ 0.0001), tumor size (p = 0.0327), differences were analyzed using Student’s t test. Differ- depth of tumor (p\ 0.0001), TNM pStage (p = 0.0005), ences between the various clinicopathological features SCC antigen level (p = 0.0072), albumin level were analyzed using the Chi-square test. The CSS was (p\ 0.0001), and CRP level (p = 0.0012). analyzed using Kaplan–Meier statistics, and inter-group differences were assessed using the log-rank test. Prognostic factors for postoperative survival Univariate analyses were performed to determine vari- in patients with ESCC ables associated with CSS. Variables with p values \ 0.05 in the univariate analyses were included in a multivariate Univariate analyses identified advanced TNM pStage logistic regression analysis. The potential prognostic fac- [hazard ratio (HR), 4.170; 95% confidence interval (CI), tors assessed were as follows: age (\70 vs. C70 years), sex 2.377–7.525; p\ 0.0001], large tumor size (HR 1.854; (female vs. male), TNM pStage (I/II vs. III), tumor size (\3 95% CI 1.093–3.678; p = 0.0233), prolonged operation vs. C3 cm), operation time (\600 vs. C600 min), intra- time (HR 1.756; 95% CI 1.012–3.035; p = 0.0452), and operative blood loss (\500 vs. C500 mL), serum squamous low PNI (HR 4.566; 95% CI 2.375–9.674; p \ 0.0001) as cell carcinoma antigen (SCC) value (\1.5 vs. C1.5), and significant risk factors for shorter CSS. The TNM pStage PNI (\49.2 vs. C49.2). (HR 3.261; 95% CI 1.808–6.043; p\ 0.0001) and PNI (HR 3.887; 95% CI 1.999–8.309; p\ 0.0001) were Fig. 1 Receiver operating (a) 1.0 (b) 1.0 curves for postoperative survival were plotted to verify the optimum cutoff value for 0.8 0.8 PNI. a cancer-specific survival, b overall survival 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1-Specificity 1-Specificity Sensitivity Sensitivity 2202 World J Surg (2018) 42:2199–2208 Table 1 Relationships between PNI and clinicopathological features in 169 patients with esophageal cancer Characteristics Total patients PNI \49.2 C49.2 p value (n = 98) (n = 71) Age (years) 67.1 ± 8.2 65.4 ± 8.0 0.1804 Sex 0.628 Male 150 86 64 Female 19 12 7 WBC 5830.0 ± 2404.6 6233.9 ± 1616.6 0.2209 Neutrophil 3773.6 ± 2197.3 3669.2 ± 1264.6 0.7199 Lymphocyte 1396.4 ± 562.7 1931.8 ± 599.2 \0.0001 Platelet 232.8 ± 75.5 225.5 ± 50.2 0.4796 Location of tumor 0.0696 Ce 13 12 1 Ut 10 6 4 Mt 73 39 34 Lt 59 31 28 Ae 14 10 4 Tumor size (mm) 5.27 ± 4.98 3.88 ± 2.53 0.0327 Depth of tumor \0.0001 T1a–1b 72 27 45 213 8 5 367 48 19 4a–4b 17 15 2 Lymph node metastasis 0.1573 N089 49 40 N148 28 20 N218 9 9 N314 12 2 Pathological stage 0.0005 1a–1b 62 24 38 2a–2b 39 28 11 3a–3c 68 46 22 Operation time (min) 656.1 ± 196.1 646.7 ± 158.6 0.7391 Intraoperative blood loss (ml) 665.5 ± 601.2 580.0 ± 612.3 0.3666 SCC antigen 1.67 ± 2.04 0.97 ± 0.85 0.0072 Albumin 3.64 ± 0.43 4.32 ± 0.30 \0.0001 CRP 0.658 ± 1.098 0.217 ± 0.314 0.0012 confirmed as independent prognostic factors for CSS when 2.248; 95% CI 1.362–3.832; p = 0.0013) were confirmed multivariate logistic regression analysis was applied as independent prognostic factors for OS in multivariate (Table 2). logistic regression analysis (Table 3). Univariate analyses identified advanced age (HR 1.930; 95% CI 1.205–3.061; p = 0.0066), advanced TNM pStage Prognostic factors for postoperative survival in non- (HR 2.725; 95% CI 1.714–4.349; p \ 0.0001), large tumor elderly patients with ESCC size (HR 1.868; 95% CI 1.149–3.141; p = 0.0112), and low PNI (HR 2.612; 95% CI 1.600–4.405; p \ 0.0001) as Among 110 non-elderly patients, univariate analyses significant risk factors for shorter OS. The age (HR 2.024; identified advanced TNM pStage (HR 4.646; 95% CI 95% CI 1.255–3.236; p = 0.0042), TNM pStage (HR 2.281–10.027; p \ 0.0001), large tumor size (HR 2.872; 2.510; 95% CI 1.555–4.064; p = 0.0002), and PNI (HR 95% CI 1.349–6.825; p = 0.0054), and low PNI (HR 123 World J Surg (2018) 42:2199–2208 2203 Table 2 Prognostic factors for cancer-specific survival in patients with esophageal cancer Variables Patients (n = 169) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 19/150 (Female/male) 1.14 0.499–3.290 0.7765 Age 59/110 (\70/C70) 1.42 0.790–2.480 0.2344 TNM pStage 101/68 (1,2/3) 4.17 2.377–7.525 \0.0001 3.261 1.808–6.043 \0.0001 Tumor size 64/105 (\3/C3) 1.854 1.093–3.678 0.0233 1.076 0.583–2.079 0.8203 Operation time 111/58 (\600/C600) 1.756 1.012–3.035 0.0452 1.595 0.910–2.786 0.1024 Intraoperative blood loss 87/82 (\500/C500) 0.973 0.562–1.685 0.9226 PNI 98/71 (C49.2/\49.2) 4.566 2.375–9.674 \0.0001 3.887 1.999–8.309 \0.0001 SCC 126/43 (\1.5/C1.5) 1.169 0.584–2.171 0.6425 Table 3 Prognostic factors for overall survival in patients with esophageal cancer Variables Patients(n = 169) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 19/150 (Female/male) 1.12 0.550–2.687 0.773 Age 59/110 (\70/C70) 1.93 1.205–3.061 0.0066 2.024 1.255–3.236 0.0042 TNM pStage 101/68 (1,2/3) 2.725 1.714–4.349 \0.0001 2.51 1.555–4.065 0.0002 Tumor size 64/105 (\3/C3) 1.868 1.149–3.141 0.0112 1.219 0.7364–2.083 0.5582 Operation time 111/58 (\600/C600) 1.481 0.9288–2.344 0.0981 Intraoperative blood loss 87/82 (\500/C500) 1.308 0.825–2.098 0.2541 PNI 98/71 (C49.2/\49.2) 2.612 1.600–4.405 \0.0001 2.248 1.362–3.832 0.0013 SCC 126/43 (\1.5/C1.5) 1.589 0.934–2.609 0.0859 11.370; 95% CI 4.040–47.500; p \ 0.0001) as significant PNI (HR 3.671; 95% CI 1.864–7.897; p = 0.0001) as risk factors for shorter CSS. The TNM pStage (HR 3.488; significant risk factors for shorter OS. The TNM pStage 95% CI 1.948–6.424; p \ 0.0001) and PNI (HR 3.849; (HR 2.615; 95% CI 1.430–3.768; p = 0.0007) and PNI 95% CI 1.987–8.205; p\ 0.0001) were confirmed as (HR 2.275; 95% CI 1.384–3.863; p = 0.001) were con- independent prognostic factors for CSS when multivariate firmed as independent prognostic factors for OS in multi- logistic regression analysis was applied (Table 4). variate logistic regression analysis (Table 5). Univariate analyses identified advanced TNM pStage (HR 3.772; 95% CI 2.027–7.234; p \ 0.0001), large tumor size (HR 2.539; 95% CI 1.315-5.298; p = 0.0050), and low Table 4 Univariate and multivariate analysis of cancer-specific survival in 110 non-elderly patients with esophageal cancer Variables Patients Category or Univariate Multivariate (n = 110) characteristics HR 95% CI p value HR 95% CI p value Gender 11/99 (Female/male) 0.865 0.307–3.612 0.8142 TNM pStage 64/46 (1,2/3) 4.646 2.281–10.027 \0.0001 3.488 1.948–6.424 \0.0001 Tumor size 44/66 (\3/C3) 2.872 1.349–6.825 0.0054 1.115 0.607–2.149 0.7313 Operation time 74/36 (\600/C600) 1.636 0.307–1.234 0.1664 Intraoperative blood 55/55 (\500/C500) 1.176 0.591–2.371 0.6437 loss PNI 61/49 (C49.2/\49.2) 11.37 4.040–47.500 \0.0001 3.849 1.987–8.205 \0.0001 SCC 83/27 (\1.5/C1.5) 1.307 0.516–2.914 0.5471 123 2204 World J Surg (2018) 42:2199–2208 Table 5 Univariate and multivariate analysis of overall survival in 110 non-elderly patients with esophageal cancer Variables Patients (n = 110) Category or characteristics Univariate Multivariate HR 95% CI p value HR 95% CI p value Gender 11/99 (Female/male) 1.08 0.390–4.478 0.8968 TNM Stage 64/46 (1,2/3) 3.772 2.027–7.234 \0.0001 2.615 1.430–3.768 0.0007 Tumor size 44/66 (\3/C3) 2.539 1.315–5.298 0.005 1.281 0.769–2.202 0.3477 Operation time 74/36 (\600/C600) 1.254 0.661–2.320 0.4803 Intraoperative blood loss 55/55 (\500/C500) 1.524 0.822–2.911 0.1821 PNI 61/49 (C49.2/\49.2) 3.671 1.864–7.897 0.0001 2.275 1.384–3.863 0.001 SCC 83/27 (\1.5/C1.5) 1.515 0.697–3.028 0.2787 Prognostic factors for postoperative survival PNI and postoperative survival in all patients in elderly patients with ESCC with ESCC In 59 elderly patients, univariate analyses demonstrated Kaplan–Meier analysis and the log-rank test demonstrated that the TNM pStage was the only significant risk factor for that patients with a low PNI had a significantly worse shorter CSS and OS (HR 3.701; 95% CI 1.470–9.743; prognosis in terms of CSS and OS than those with a high p = 0.0057, HR 1.974; 95% CI 0.938–4.038; p = 0.0224, PNI (p\ 0.0001, and p = 0.0003, respectively). The respectively) (Table 6). 5-year CSS rates were 46.5 and 84.2%, and the 5-year OS rates were 38.3 and 74.1% for patients with a low PNI and a high PNI, respectively (Fig. 2). Table 6 Univariate and multivariate analysis of cancer-specific survival and overall survival in 59 elderly patients with esophageal cancer Variables Patients (n = 59) Category or characteristics Cancer-specific survival Overall survival Univariate Univariate HR 95% CI p value HR 95% CI p value Gender 8/51 (Female/male) 1.85 0.526–11.717 0.3755 1.577 0.615–5.349 0.37 TNM pStage 37/22 (1,2/3) 3.701 1.470–9.743 0.0057 1.974 0.938–4.038 0.0224 Tumor size 20/39 (\3/C3) 0.973 0.390–2.623 0.9542 1.073 0.526–2.313 0.8507 Operation time 37/22 (\600/C600) 1.909 0.768–4.815 0.1614 1.731 0.859–3.491 0.1235 Intraoperative blood loss 32/27 (\500/C500) 0.689 0.265–1.714 0.4235 1.023 0.506–2.088 0.9493 PNI 37/22 (C49.2/\49.2) 1.68 0.655–4.679 0.2838 1.748 0.845–3.784 0.1333 SCC 43/16 (\1.5/C1.5) 1.218 0.387–3.287 0.715 2.003 0.909–4.214 0.0828 Fig. 2 Kaplan–Meier curves of (a) (b) 1.0 1.0 postoperative survival based on PNI in 169 patients with ESCC. 0.8 0.8 a cancer-specific survival, b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=71) 0.2 PNI 49.2 (n=71) 0.2 PNI <49.2 (n=98) PNI <49.2 (n=98) P<0.0001 P=0.0003 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Cumulative survival Cumulative survival World J Surg (2018) 42:2199–2208 2205 PNI and postoperative survival in non-elderly low versus high PNI. Similarly, there were no significant patients with ESCC differences in postoperative hospital stay (data not shown). Kaplan–Meier analysis and the log-rank test demonstrated that patients with a low PNI had a significantly worse Discussion prognosis in terms of CSS and OS than those with a high PNI (p\ 0.0001, and p = 0.0003, respectively). The Treatment strategies for ESCC include surgery, radiation, 5-year CSS rates were 44.1, and 92.8% and the 5-year OS chemotherapy, or a combination thereof. Although a rates were 41.5 and 84.8% for patients with a low PNI and complete surgical resection of the tumor offers a chance for a high PNI, respectively (Fig. 3). cure, the rate of disease recurrence is very high in ESCC even after an aggressive surgery. Histopathology of surgi- PNI and postoperative survival in elderly patients cal specimens is widely used to estimate the prognosis after with ESCC surgery [12]; however, its predictive value is still limited. The precise evaluation of the risk of postoperative recur- Kaplan–Meier analysis and the log-rank test showed no rence is important in planning a customized risk-adapted significant relationship between PNI and CSS (p = 0.1398) therapeutic strategy for individual patients. In particular, or OS (p = 0.1907) in elderly patients with ESCC (Fig. 4). identifying prognostic factors prior to surgery is important to determine the optimal preoperative therapy, and to PNI and postoperative complications improve postoperative short- and long-term outcomes [16]. The original PNI consists of tests measuring albumin, The postoperative complications in the high and low PNI transferrin, triceps skin fold, and skin sensitivity reaction to groups are shown in Table 7. No significant differences in common antigens [17], and it was developed to assess the incidence rates of postoperative complication were perioperative complications, including anastomotic leak- observed between overall and age-stratified patients with a age, delayed tissue repair, and length of hospital stay in patients undergoing gastrointestinal surgery [11, 18]. The Fig. 3 Kaplan–Meier curves of (a) (b) 1.0 1.0 survival based on PNI in 110 non-elderly patients with ESCC. 0.8 0.8 a Cancer-specific survival, b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=49) PNI 49.2 (n=49) 0.2 0.2 PNI <49.2 (n=61) PNI <49.2 (n=61) P<0.0001 P=0.0003 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Fig. 4 Kaplan–Meier curves of (a) (b) survival based on PNI in 59 1.0 1.0 elderly patients with ESCC. a Cancer-specific survival, 0.8 0.8 b overall survival 0.6 0.6 0.4 0.4 PNI 49.2 (n=22) PNI 49.2 (n=22) 0.2 0.2 PNI <49.2 (n=37) PNI <49.2 (n=37) P=0.1398 P=0.1907 0.0 0.0 0 12 24 36 48 60 72 84 96 108 0 12 24 36 48 60 72 84 96 108 Time after esophagectomy (months) Time after esophagectomy (months) Cumulative survival Cumulative survival Cumulative survival Cumulative survival 2206 World J Surg (2018) 42:2199–2208 simplified PNI, on the other hand, consists of only two laboratory parameters, namely serum albumin concentra- tion and total lymphocyte count in the peripheral blood [6], both of which are measured routinely in clinical practice. Recently, several studies have reported that albumin is produced by hepatocytes and is regulated by pro-inflam- matory cytokines, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-a (TNF-a) that adversely affect catabolic metabolism [19–21]. These cytokines produced by either the tumor itself or the host are crucial for car- cinogenesis, cancer progression, and neo-angiogenesis. In addition, albumin has been shown to help stabilize cell growth and DNA replication, buffer a variety of bio- chemical changes and maintain sex hormone homeostasis to protect against tumorigenesis [10]. Albumin, therefore, is reflective of the inflammation and immune status of cancer, although it alone is not sufficient to predict the final outcome in cancer patients. Another element of the sim- plified PNI is the lymphocyte count. Lymphocytes are one of the fundamental components of cell-mediated immunity with inhibitory effects on the proliferation and invasion of tumor cells via cytokine-mediated cytotoxicity [11, 22]. Most patients with ESCC are malnourished, either due to poor dietary intake, protein loss from the primary lesion or due to catabolic metabolism [23]. Impaired nutritional and immunologic status accelerates tumor progression due to a decline in tumor immunity [16, 22]. The PNI is, therefore, a comprehensive indicator of the nutritional and immuno- logic status in cancer patients [24]. In this study, we evaluated the potential of simplified PNI as a prognostic marker of CSS and OS in ESCC patients who underwent radical thoracoscopic esophagec- tomy. Patients with a low PNI (less than 49.2) showed a significantly shorter CSS and decreased OS in comparison with patients who had a high PNI (49.2 or greater). This is consistent with our finding that PNI is inversely related to the stage of cancer, the value being lower in patients with a larger, deeper and more aggressive tumor at an advanced TNM pStage [25]. Recent studies have also demonstrated an association between the occurrences of postoperative complications with deteriorated CSS in patients with gas- trointestinal cancer [26, 27]. Patients with a low PNI are, therefore, more likely to develop postoperative complica- tions [11, 17, 18], including a systemic inflammatory response, which can also contribute to the decreased CSS and OS. However, this correlation between PNI and CSS/ OS was found only in non-elderly patients and not in the elderly patients. This difference could be due to the fact that irrespective of being a cancer patient or not, hypoal- buminemia and leukocytopenia are often associated with aging, leading to malnutrition and immune suppression [28]. Previous studies have reported that cancer patients experiencing postoperative complications generally have a Table 7 Comparison between postoperative complications and PNI Overall patients PNI Non-elderly patients PNI Elderly patients PNI \49.2 C49.2 p value \49.2 C49.2 p value \49.2 C49.2 p value (n = 169) (n = 98) (n = 71) (n = 110) (n = 61) (n = 49) (n = 59) (n = 37) (n = 22) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Anastomotic leakage 17 (10.1) 9 (9.2) 8 (11.3) 0.657 8 (7.3) 4 (6.6) 4 (8.2) 0.747 9 (15.2) 5 (13.5) 4 (18.2) 0.63 Vocal code paresis 11 (6.5) 6 (6.1) 5 (7.0) 0.811 4 (3.6) 2 (3.3) 2 (4.1) 0.823 7 (11.9) 4 (10.8) 3 (13.6) 0.746 Pulmonary complication 48 (28.4) 30 (30.6) 18 (25.4) 0.454 20 (18.2) 12 (19.7) 8 (16.3) 0.651 28 (47.5) 18 (48.6) 10 (45.5) 0.812 Chylothorax 1 (0.6) 0 (0) 1 (1.4) 0.239 1 (0.9) 1 (1.6) 0 (0) 0.368 0 (0) 0 (0) 0 (0) NaN Surgical site infection 10 (5.9) 4 (4.1) 6 (8.5) 0.235 5 (4.5) 2 (3.3) 3 (6.1) 0.477 5 (8.5) 2 (5.4) 3 (13.6) 0.272 NaN Not a number World J Surg (2018) 42:2199–2208 2207 the institutional and national research committee and with the 1964 poorer prognosis [29–31]. Because patients with a low Helsinki declaration and its later amendments or comparable ethical preoperative PNI value are at a high risk of postoperative standards. complications, the preoperative PNI value may affect both postoperative short- and long-term outcomes. However, in Informed consent Informed consent was obtained from all individ- ual participants included in the study. this study, no significant differences were observed between the PNI value and the rate of postoperative com- Open Access This article is distributed under the terms of the plications. Therefore, further studies are thus needed to Creative Commons Attribution 4.0 International License (http://crea address this issue. tivecommons.org/licenses/by/4.0/), which permits unrestricted use, The optimal cutoff points for PNI in predicting post- distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a operative survival in patients with malignant tumors is still link to the Creative Commons license, and indicate if changes were controversial. Thus, one of the aims of this study was to made. evaluate the prognostic value of the PNI and propose an optimal cutoff, which can predict CSS and OS with better accuracy, in patients with ESCC. Based on our study of References 169 patients who underwent curative esophagectomy, and using a ROC curve, we have arrived at 49.2 as the cutoff 1. Mainous MR, Deitch EA (1994) Nutrition and infection. Surg Clin N Am 74(3):659–676 value for PNI. 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World Journal of SurgerySpringer Journals

Published: Dec 31, 2017

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