Pretreatment nutritional risk scores and performance status are prognostic factors in esophageal cancer patients treated with definitive chemoradiotherapy

This study evaluated the prognostic effects of nutritional risk scores and performance status (PS) on unresectable locally advanced esophageal cancer (LAEC) patients who were treated with definitive concurrent chemoradiotherapy (dCRT). A total of 202 LAEC patients from four different cancer centers were retrospectively reviewed. Nutritional risk and PS were measured using the Nutritional Risk Screening 2002 (NRS-2002) scores and Eastern Cooperative Oncology Group (ECOG) scales. Outcomes were clinical response rate, overall survival (OS) and progression-free survival (PFS). Multivariate analysis of predictive factors of response to dCRT and survival were performed using a logistic regression and a Cox model, respectively. The majority of patients (71.8%) had an ECOG PS score of 0-1, and 52.5% (n=106) of patients were identified as having nutritional risk (NRS-2002 ≥3) upon treatment initiation. There was no correlation between NRS-2002 scores and ECOG PS (Spearman's ρ=0.046; P=0.516). In multivariate analysis, NRS-2002 scores (P=0.002, HR 2.805, 95%CI: 1.445-5.446) and ECOG PS (P=0.015, HR 2.719, 95%CI: 1.218-6.067) were independent prognostic factors for the response to dCRT. NRS-2002 scores (OS: HR 1.530, 95%CI 1.059-2.209; P=0.023; PFS: HR 1.517, 95%CI 1.105-2.082; P=0.010) and ECOG PS (OS: HR 1.729, 95%CI 1.185-2.522; P=0.005; PFS: HR 1.678, 95%CI 1.179-2.387; P=0.004) were both independent prognostic factors for OS and PFS. In conclusions, NRS-2002 scores and ECOG PS scales both have prognostic effects on clinical response and survival in LAEC, but a significant association of NRS-2002 scores and ECOG PS were not observed.


INTRODUCTION
Esophageal carcinoma is an aggressive disease and is often diagnosed at an advanced stage. Dysphagia has been found to be the primary symptom in more than 90% patients, [1] and 40%-80% patients experienced malnutrition at initial diagnosis. [2] Moreover, along with the depletion of nutrition, it increases the individual's risk of having poor performance status (PS). [3] As such, patients with esophageal cancer are potentially at high risk of poor treatment outcomes because of preexisting malnutrition and physical deconditioning. [4] Treatments for esophageal cancer are commonly multimodal, incorporating surgery, chemotherapy (CT) and radiation therapy (RT). Definitive concurrent chemoradiotherapy (dCRT) is recommended as a preferred curative treatment option for unresectable locally advanced esophageal cancer (LAEC) based on the landmark results of the Radiation Therapy Oncology Group (RTOG) 85-01 trial, in which the long-term follow-up result showed a 5-year overall survival (OS) rate of 26% in the dCRT group compared with 0% in the RT alone group. [5] In LAEC, there is a paucity of studies clarifying the combined effect of nutritional risk screening 2002 (NRS-2002) scores and Eastern Cooperative Oncology Group (ECOG) PS (also called the WHO or Zubrod score) in predicting treatment response and survival outcomes. A better understanding of these specific indicators is necessary to improve the patient's compliance, increase the therapeutic ratio, reduce the toxic reactions, and compare the results across different studies. Therefore, the purposes of this study were: (1) to evaluate the correlation of baseline NRS-2002 scores and ECOG PS; (2) to determine the impact of NRS-2002 scores and ECOG PS on clinical response; (3) to assess the prognostic effects of NRS-2002 scores and ECOG PS on overall survival (OS) and progression-free survival (PFS) and further provide information for making decisions about dCRT in patients with unresectable LAEC.

Predictive factors for the response to dCRT
The clinical response was documented according to RECIST. Complete response (CR) was observed in 47 (23.3%) patients, partial response (PR) in 66 (32.6%) patients, stable disease (SD) and progressive disease (PD) in 89 (44.1%) patients, which yielded a clinical response rate (RR) of 55.9% (Table 3)

DISCUSSION
In this study, our results suggest that increased nutritional risk scores based on NRS-2002 and impaired ECOG PS at baseline are associated with a significant poor clinical response and decreased survivals (both OS and PFS) in unresectable LAEC patients who received dCRT. Furthermore, our study shows that NRS-2002 scores and ECOG PS scales were not correlated with one another.
A series of studies in the literature have underlined that nutritional parameters can have independent prognostic effects on treatment outcomes of esophageal cancer. In a recently published post hoc analysis of the SCOPE1 trial, [6] 258 patients were randomly assigned to receive dCRT based on cisplatin and capecitabine ± cetuximab. Nutritional Risk Index (NRI) scores were collected based on the following formula: NRI=(1.519×albumin g/dl)+41.7(present weight/ideal weight). An NRI score <100 was identified as patients at nutritional risk. Nutritional interventions included dietary advice, oral supplementation and/or major intervention (enteral feeding/tube placement). With a median follow-up time of 25.0 months, their results showed that baseline NRI <100 was strongly predicted for reduced OS (HR 12.45, 95%CI 5.24-29.57; P<0.001) and positive nutritional intervention at baseline improved OS (dietary advice (HR 0.12, P=0.004), oral supplementation (HR 0.13, P<0.001) or major intervention (HR 0.13, P=0.003)). In our study, increased NRS-2002 scores (≥3) were also associated with impaired survival outcomes (OS (HR 1.530, P=0.023); PFS (HR 1.517, P=0.010)), which was consistent with their findings. In addition, this study further showed that patients with increased NRS-2002 scores had significantly decreased clinical response (32.1% vs. 23.8%; P=0.001). Other tools for nutritional screening in cancer patients at present included the subjective global assessment (SGA), [7] the malnutrition universal screening tool (MUST), [8] and the mini nutritional assessment (MNA). [9] With different nutritional screening tools and parameters utilized in the clinic, it raises the question of which should be used as the preferred screening tool to detect malnutrition in cancer patients. NRS-2002 is a recommended instrument by the www.impactjournals.com/oncotarget European Society for Clinical Nutrition and Metabolism (ESPEN) for hospitalized patients [10] and has also been validated in China. [11] Compared to other tools, a previous study has demonstrated that NRS-2002 appeared to be an ideal screening instrument relative to MUST and MNA with a sensitivity and specificity of 77.8% and 80.8%, respectively, for internal medicine, and it was less time consuming and required less examiner training than other tools. [12] Unlike a number of nutritional screening and assessment tools applied clinically, limited measures of PS are widely used, among them the ECOG PS and the Karnofsky's Scale of Performance Status (KPS). Compared with KPS, a previous study showed that KPS showed a lower ability than ECOG PS to discriminate patients with different prognoses in lung cancer. Considering the necessity of comparing results from different studies based on the "unbiased" foundation, the authors suggested that ECOG PS should be preferred to KPS. [13]  .020; P<0.001) was also an independent prognostic factor in multivariate analysis of OS. [15] Our study further identified the ECOG PS less than 1 as the other independent indicator for favorable clinical response in LAEC patients (HR 2.719, 95%CI: 1.218-6.067; P=0.015) and better ECOG PS scales evaluated at baseline were also correlated with better clinical response (46.5% vs. 9.4%; P<0.001). These results could be explained in part by the poor ECOG PS that may capture disease-related features, such as aggressive tumor biology and inadequate organ reserve, which along with the burden of preexisting malunutrition, might decrease the anti-cancer effects and increase the resistance to dCRT.
The limitations of the present study should be mentioned. First is the nature of its retrospective design and it is associated with potential and unmeasured factors that might exert an influence on the final results. In addition, the assessment of PS is subjective; several studies had indicated that the presence of a systemic inflammatory response criterion, as evidenced by the Glasgow Prognostic Score, appeared to be superior to ECOG PS in predicting the response and survival in thoracic cancer patients. [16,17] In conclusion, the current study suggests that both the NRS-2002 scores and ECOG PS provide important, distinct information in predicting clinical response and survival in unresectable LAEC patients treated with dCRT. As such, nutritional assessment and ECOG PS data should both be included in LAEC outcome studies. We expect prospective nutritional intervention studies to improve the therapeutic ratio and survival outcomes in the near future. Patients' records were anonymized and de-identified prior to analysis.

Eligibility
The inclusion criteria in the present study were as follows: I) cytopathologically confirmed as esophageal malignancy; II) unable or refusing to undergo surgical resection; III) ECOG PS of ≤2; and IV) no uncontrolled serious diseases and adequate organ function. The exclusion criteria were as follows: early-stage esophageal cancer or evidence of distant metastasis at diagnosis, prior administration of surgery or non-cisplatin based chemotherapy, and incomplete data on the treatment response and survivals.

Pre-treatment work-up
Pre-treatment procedures included complete physical examination, electrocardiography, and blood and pulmonary function tests. Baseline nutritional assessment was operationalized with the NRS-2002 under the recommendation of the ESPEN for hospitalized patients. The NRS-2002 is based on three variables: weight loss, BMI, amount of food intake in the preceding week in addition to the patient's age and the severity of the underlying disease. Patients are classified as being at nutritional risk (score ≥3) or not (score <3) according to the total score obtained. [10,18] Baseline PS was assessed using the ECOG scale which categorized patients' level of functioning into 5 levels. [19] A patient's BMI was calculated and classified according to the Asian-specific BMI cutoff values as follows: underweight (<18.5 kg/ m 2 ); normal weight (18.5-22.9 kg/m 2 ); overweight and obese (≥23.0 kg/m 2 ). [20] The extent of disease evaluation included endoscopy of the esophagus, barium swallowing, endoscopic ultrasonography, enhanced computed tomography (CT), positron emission tomography/ CT (PET/CT, if available), bronchoscopy (to exclude tracheoesophageal fitula) and bone scan (if clinically indicated). Metastatic lymph nodes were defined as ≥1 cm in their greatest diameter on CT imaging. Clinical stages (II-IVa) were diagnosed according to the 2002 American Joint Committee on Cancer staging system (version 6.0, AJCC).

Treatment schedule
A total of 132 patients (65.3%) received threedimensional conformal radiotherapy (3D-CRT) and the other 70 patients were treated with intensity-modulated radiation therapy (IMRT). The preplanned radiation dose was 54.0-60.0 Gy, which was given as 30 fractions of 1.8-2.0 Gy each once a day 5 days per week. The definitions of gross tumor volume (GTV), clinical target volume (CTV), planning target volume (PTV) and dose-volume constraints of normal tissues have been described previously. [21] All patients received cisplatin-based chemotherapy combined with 5-fluorouracil (5-Fu) or paclitaxel (PTX). In the PF (5-Fu+Cisplatin) group, 110 patients received two cycles of PF regimen at 4-week intervals. Cisplatin at 75 mg/ m 2 was administered intravenously on Day 1 and Day 29 with standard hydration, followed by 5-Fu at 1000 mg/m 2 per day administered by continuous intravenous infusion on days 1-4 of each cycle. In the TP (PTX+Cisplatin) group, 92 patients also received the same preplanned dose of cisplatin, followed by PTX at 135 mg/m 2 i.v. administered for 3 hours on day 1 and day 29 with standard premedications. Dose modification of dCRT or suspension of treatment was considered if any grade 4 toxicities occurred and restarted when toxicities recovered to grades ≤2.

Nutritional support
According to the NRS-2002 suggestion, patients identified as scores of 1-2 received individualized diet counseling and support to help maintain nutritional status, whereas those with risk scores ≥3 received nutritional intervention including oral nutritional supplements, EN, and/or PN. All patients were reviewed weekly throughout the treatment course. Patients who developed severe dysphagia during the treatment course received nasogastric tube placement, depending on the treatment week in which this occurred.

Treatment assessment and follow-up
Clinical response was assessed according to the RECIST (Response Evaluation Criteria in Solid Tumors) system 6-8 weeks after the completion of treatment. CR was defined as the disappearance of all target lesions on CT images, PR was defined as a ≥30% decrease in the sum of the longest diameter of target lesions, PD was defined as a ≥20% increase in the sum of the longest diameter of target lesions and SD was defined as neither sufficient shrinkage to qualify for PR nor a sufficient increase to qualify for PD. [22] The National Cancer Institute Common Toxicity Criteria (version 3.0) was used to score acute treatment toxicity. [23] Follow-up modalities included physical examination, blood test, upper endoscopy, enhanced CT of the neck (mandatory for cervical EC), chest, abdomen, and pelvis. Follow-up evaluations were performed every 3 months for the first year, every 6 months for the second year, and then on a yearly basis.

Statistical analysis
The cutoff date of the last follow-up was December 31, 2016 for the censored data analysis. OS was determined as the time that elapsed from the date of dCRT initiation to the last follow-up or to the date of death. Progression-free survival (PFS) was defined as the interval between the first day of treatment and the date of documented failure or the date of the last follow-up for those remaining. Survival curves were generated using the Kaplan-Meier method and compared with the logrank test. Correlation between the baseline NRS-2002 scores and ECOG PS was estimated using the Spearman rank correlation coefficient (ρ). Response to dCRT was categorized as 1 (CR+PR) and 2 (SD+PD) for the purpose of analysis. A univariate analysis was performed to identify the predictive factors for the response to dCRT on one hand and to OS and PFS on the other hand. Variables identified with a 2-sided P value <0.10 on univariate analysis were included in the multivariate analyses. Multivariate analysis of the predictive factors for the response to dCRT was performed using binary logistic regression with calculation of the hazard ratio (HR) and a confidence interval (CI) of 95%. Multivariate analysis of the predictive factors of OS and PFS were performed using a Cox regression model. P<0.05 was accepted as statistically significant. All statistical analyses were conducted using IBM SPSS for Windows version 22.0 (SPSS, Armonk, New York, USA).

Author contributions
MF designed the study; QyW, TS, JbL, ShL and CX conducted the research; QyW, TS and WkY analyzed data; QyW, TS and HqW wrote the paper. QyW and MF had final responsibility for content.