Patient and clinical data
We reviewed the medical records of 652 patients with ESCC who received definitive CCRT at Sun Yat-sen University Cancer Center, in Guangzhou, Guangdong, China between January 2010 and December 2012. Among 652 patients, 73 ESCC patients were identified to have fistulae. The patients were diagnosed according to the American Joint Committee on Cancer tumor, node, and metastasis (TNM) classification (7th edition). All the patients who met the following inclusion criteria were included in this study: (1) confirmed thoracic ESCC by pathologic analysis; (2) no previous cancer treatments and no distant metastases; (3) Eastern Cooperative Oncology Group (ECOG) performance status ≤2; (4) a complete evaluation, including physical examination, computed tomography (CT) scanning of the chest and abdomen, an upper gastrointestinal barium meal exam, and endoscopic ultrasound of the esophagus; and (5) meglumine diatrizoate mucilage (MDC) leakage with/without endoscopy for fistulae assessment.
Clinical data collected from each patient included ECOG performance status, a nutrition assessment, age, sex, primary esophageal tumor location, clinical stage and T category of primary tumor, radiation dose, CCRT regimen, and tumor response to CCRT.
Enteral nutrition support and assessment
Before, during, and after CCRT, all patients were evaluated by clinical nutritionists using nutrition risk screening (NRS). Patients were evaluated in terms of undernutrition and disease severity, according to whether they are absent, mild, moderate, or severe, making a total score of 0–6; patients with a total score of ≥3 were classified as nutritionally at-risk. Undernutrition was estimated using three variables used in most screening tools: body mass index (BMI), percent of recent weight loss, and change in food intake. Diseases like hip fracture, chronic diseases, and tumor were scored 1; major abdominal surgery, stroke, diabetes, and hematologic malignancy were scored 2; head injury and bone marrow transplantation were scored 3 . Increased NRS score indicated improved nutritional status of patients than before. When diagnosed with a malignant fistula, patients were administered enteral nutrition support. The patients either received nasal feeding or underwent a percutaneous endoscopic gastrostomy (PEG), and therefore dietary intake could be adjusted and to achieve energy balance and minimize weight loss based on patient weight that was continuously monitored.
Intacted protein enteral nutrition powder formula (Danone; Paris, France) was used for nasal feeding (each 500-mL bottle provides 20 g of protein and 500 kcal of energy). Oral and/or enteral energy-rich and protein-rich supplements were added when needed. At all measurement points, the PEG stoma site was observed and care advice was given when needed. Nutritional supplements were administered until 4–8 weeks after fistula closure.
All laboratory test values, including hemoglobin level and serum albumin level, were determined in the clinical laboratories of Sun Yat-sen University Cancer Center.
Radiotherapy and concurrent chemotherapy
During radiotherapy, the techniques used for patient immobilization, simulation, and treatment planning were performed according to a standard protocol in the Department of Radiotherapy at Sun Yat-sen University Cancer Center for esophageal carcinoma patients receiving three-dimensional conventional radiotherapy (3D-CRT) . With the patient in the supine position, a cradle for immobilization was made with a vacuum. Individual patients were scanned from the atlas (C1) to the second lumbar vertebra (L2) level to cover the entire neck, lung, esophagus, and celiac lymph node regions. CT scans were performed with 0.5-cm thickness slices. Briefly, the gross tumor volume (GTV-esophagus) consisted of lesions diagnosed by biopsy or subsequent CT scans; tumor regions described on endoscopy but not observed on CT were also included in the GTV-esophagus. The criteria for GTV of positive lymph nodes (GTV-ln) based on CT scans were as follows: short axis size ≥10 mm, a lymph node with an infiltrative margin, or central necrosis. Two clinical target volumes (CTVs) for the patients were defined: CTV1 comprised GTV-ln and 2 cm proximal and distal to the GTV-esophagus; CTV2 comprised the supraclavicular and mediastinal lymph nodes, GTV-ln, and 4 cm proximal and distal to the GTV-esophagus. PTV1 was defined as a 5-mm margin added to CTV1; PTV2 was defined as a 5-mm margin added to CTV2 . All patients had a 3D-CRT treatment plan that was calculated by the Pinnacle treatment planning system, and they were treated with a 6-MV linear accelerator (MIMiC; Nomos Corp., Sewickly, PA, USA). The median dose was 60 Gy for GTV (range, 46–68 Gy), 55 Gy for PTV1 (range, 40–68 Gy), and 46 Gy for PTV2 (range, 40–54 Gy). Dose constraints for critical organs were as follows: the maximum spinal cord dose <46 Gy, mean lung dose <17 Gy, and the lung volumes irradiated above 20 Gy (V20) <30%.
Two regimens of chemotherapy were used in the study: (1) concurrent chemotherapy consisted of cisplatin (20 mg/m2 per day) and 5-FU (500 mg/m2 per day), every 3 weeks; (2) docetaxel-based regimens consisted of docetaxel (60 mg/m2 per day) and cisplatin (60 mg/m2 per day), every 3 weeks; or concurrent chemotherapy comprising cisplatin (25 mg/m2 per day) and docetaxel (25 mg/m2 per day), weekly [15, 16].
Follow-up and treatment response assessment
The beginning of the follow-up period was defined as the last date of CCRT treatment. During the follow-up period, patients underwent a chest CT scan every 3 months, an upper digestive tract endoscopy and an abdominal ultrasonography every 6 months for 2 years after CCRT, and a subsequent chest CT scan, an endoscopy, and an abdominal ultrasonography every 6 months thereafter. Bone scans were performed when patients were suspected to have bone metastases. The rates and time to treatment response or distant metastasis, duration of OS and local relapse were recorded.
MDC leakage evaluation and/or endoscopy were performed every 2–3 weeks from the diagnosis of malignant fistulae until 4 weeks after fistula closure.
Tumor response evaluations were performed 1–3 months after CCRT according to response evaluation criteria in solid tumors (RECIST) definitions. For the primary tumors, the responses include complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) [15, 19]. Multiple failures comprised both local and distant failures after CCRT. Acute toxicity was graded using the National Cancer Institute Common Toxicity Criteria (version 4.0).
The study endpoint was OS, which was calculated as the time from the last date of radiotherapy to the date of death from any cause or to the date of the last visit before September 30, 2013. Continuous variables, such as age, hemoglobin level, serum albumin level, and radiation dose, were normalized as the sample median and then analyzed as nominal categorical variables. Each variable was assessed first in univariate analysis, and variables that reached a P value of less than 0.05 were further evaluated in multivariate analysis. Survival curves were plotted using the Kaplan–Meier method. We fitted the proportional hazards model using Cox regression. After testing for variable interactions, a forward stepwise elimination procedure was used to determine the best-fitting model. In the multivariate analysis, P values less than 0.05 were considered statistically significant. All statistical analyses were performed using SPSS 19.0 software (IBM, Chicago, IL, USA).
Our thoracic multi-disciplinary team discussed the treatment of all patients. Written informed consent was not obtained; instead, all clinical records were anonymized and de-identified prior to analysis. The entire study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center.