Reflux after esophagectomy with gastric conduit reconstruction in the posterior mediastinum for esophageal cancer: original questionnaire and EORTC QLQ-C30 survey

Reflux after esophagectomy with gastric conduit reconstruction in the posterior mediastinum for... SUMMARY Reflux following an esophagectomy with gastric conduit reconstruction in the posterior mediastinum is a clinically significant problem. In this study, we investigated the frequency and impact of reflux on the quality of life (QOL) among 158 patients who underwent an esophagectomy for esophageal cancer using an original questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30). Reflux frequency was assessed using the original questionnaire. The number of patients who complained of reflux every day, two or three times a week, once a week, or less than once a week was 16 (10.1%), 21 (13.3%), 26 (16.5%), and 60 (38.0%), respectively. Out of 35 patients (22.2%) reported no reflux symptoms. Patients were divided into two groups: those with reflux ≥ once/week (63 patients) and those with low frequency of symptoms (95 patients). Time elapsed following surgery was the only factor to influence reflux frequency. Reflux frequency decreased within two years of surgery; however, the frequency plateaued after more than two years. QOL was assessed using the EORTC QLQ-C30. The ≥ once/week reflux group had a significantly lower global health status score than the low-frequency reflux group (59.6 ± 24.2 vs. 70.8 ± 20.7; P = 0.007). In addition, the ≥ once/week reflux group had a significantly lower social functioning score than the low-frequency reflux group (81.6 ± 24.1 vs. 88.4 ± 19.8; P = 0.035). Regarding symptoms, the ≥ once/week reflux group had significantly higher scores for fatigue, nausea, and vomiting, dyspnea and insomnia compared to the low-frequency reflux group (fatigue: 42.4 ± 21.9 vs. 28.9 ± 18.4, P < 0.001; nausea and vomiting: 17.3 ± 17.1 vs. 4.9 ± 10.6, P < 0. 001; dyspnea: 29.2 ± 26.0 vs. 21.7 ± 26.8, P = 0.043; insomnia: 22.2 ± 31.1 vs. 10.5 ± 21.7, P = 0.015). Thus, reflux after an esophagectomy was associated with a lower QOL. INTRODUCTION Recently, the prognosis of esophageal cancer (EC) has improved with the development of multimodal therapies that combine surgery, chemotherapy, and radiotherapy. Shapiro et al. reported that the median overall survival of patients who received neoadjuvant chemotherapy plus surgery was 48.6 months.1 Moreover, Yamasaki et al. reported that the two-year recurrence-free survival rate of patients with neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy plus surgery was 64.1%.2 Surgery plays a particularly important role in combined modality therapy for EC. The commonest surgical procedure for EC is an esophagectomy with gastric conduit reconstruction. However, studies have reported that patients who undergo this procedure are at risk for developing functional disorders, such as delayed gastric emptying, dumping syndrome, reflux, and dysphagia.3 Specifically, reflux is a clinically significant problem for patients who have undergone an esophagectomy and gastric conduit reconstruction because it can cause esophagitis and aspiration pneumonia.4 In addition, reflux is associated with the development of Barrett's metaplasia and metachronous cancer in the esophageal remnant.5–7 To the best of our knowledge, there are no reports that have systematically investigated the symptoms of reflux following an esophagectomy. Therefore, this study sought to use an original questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30) to investigate the frequency and impact of reflux on the quality of life (QOL) of patients who underwent a subtotal esophagectomy and gastric conduit reconstruction for EC. PATIENTS AND METHODS Patients and inclusion criteria Between April and September 2013, 231 patients who had undergone an esophagectomy for EC visited the outpatient department at our institution. Of these 231 patients, 186 patients were enrolled in the study after meeting the following criteria: (1) a subtotal esophagectomy and gastric conduit reconstruction was performed; (2) curative resection (R0) was achieved; (3) adjuvant chemotherapy was not administered after the surgery or at the time of enrollment; (4) there were no signs of recurrence after the surgery; and (5) no active malignancy was present at the time of enrollment. Since 28 patients did not answer the questionnaires, a total of 158 patients were included as the study population. In addition to these 158 patients, 14 patients who underwent gastric conduit reconstruction by the retrosternal route and 15 patients who underwent reconstruction using the right-side colon or jejunum by the antesternal route were also surveyed. This study was approved by the ethics committee of Osaka University and informed consent was obtained from all participating patients. Study population and data collection Two questionnaires (an original questionnaire and the EORTC QLQ-C30) were distributed to patients at the time of outpatient assessment. Patients were invited to fill out and sign the questionnaires while in the department and to return them to a collection box. Patient characteristics, operative outcomes, and complications were retrospectively collected. Patient characteristics include age, sex, primary tumor location, histological type, pathological stage, preoperative therapy type, body mass index (BMI) at the time of the survey and the time elapsed following surgery. Operative outcomes included the operation time, blood loss, fields of lymph node dissection, methods of thoracic approach, and anastomotic location. Regarding complications, anastomotic leak, recurrent laryngeal nerve palsy, atrial arrhythmia, chyle leak, pneumonia, and pneumothorax were examined during the in-hospital postoperative period. The presence of anastomotic stricture was examined until the time of enrollment. The original questionnaire The original questionnaire is shown in Supplementary File 1. The questionnaire consisted of 21 questions and asked about the following items: Questions 1 to 7 asked about the frequency, type (acid, bitter, saliva, food) and timing of reflux; Question 8 asked about the length of time between dinner and going to sleep; Questions 9 to 19 asked about potential symptoms caused by reflux; and Questions 20 to 21 asked about the patients’ dietary intake after the esophagectomy. Reflux assessment and frequency The presence of reflux was defined by either the regurgitation of food, saliva or other material and/or an acidic or bitter taste within the mouth according to the results of the original questionnaire. Patients without reflux were defined as those who answered that nothing was regurgitated. The frequency of reflux was defined as the rate at which the most commonly reported symptom occurred. Patients were divided into two groups: those with reflux ≥ once/week and those with low frequency of symptoms. In accordance with Shibuya et al.,8 the ≥ once/week reflux group consisted of patients who experienced reflux one or more times a week, while the low-frequency reflux group consisted of patients who did not experience reflux at all, or less than once a week. QOL assessment QOL was assessed on the basis of the EORTC QLQ-C30 (in Japanese). The EORTC QLQ-C30 includes one global health status, five functional scales (physical, role, emotional, cognitive, and social), and nine symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The scores were converted into a 0–100 scale, according to the EORTC Scoring Manual. A higher global health status score represents a higher QOL, and a higher functional scale score represents a higher level of function. Conversely, a higher symptom scale score represents a higher level of symptoms. This study received permission from the EORTC to use the QLQ-C30. Statistical analysis The following postoperative complications were evaluated according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4: anastomotic leak, recurrent laryngeal nerve palsy, chyle leak, pneumothorax, and pneumonia. Adverse events of Grade 2 or greater were defined as complications. Anastomotic stricture was defined as a stricture requiring balloon dilation. Tumors were staged according to the seventh edition of the tumor-node-metastasis (TNM) classification system of the International Union Against Cancer (UICC). All data from the questionnaire responses were entered into Microsoft Office Excel 2010 (Microsoft, Redmond, USA). All data analyses and calculations were performed using the JMP 10 (SAS Institute Inc., Cary, NC, USA) and Excel. Values were expressed as the mean ± standard deviation (SD). The significance of differences between the two groups was estimated with the Mann-Whitney U test and a chi-squared test. Multivariate logistic regression analysis was performed to identify the independent risk factors for reflux after esophagectomy. All differences were considered statistically significant at the level of P < 0.05. RESULTS Classification of high and low reflux frequency for 158 patients Table 1 shows the reflux frequency of the 158 total patients. There were 35 patients (22.2%) who did not report reflux and 123 patients (77.8%) who reported reflux. The number of patients who complained of reflux every day, two or three times a week, once a week, or less than once a week was 16 (10.1%), 21 (13.3%), 26 (16.5%), and 60 (38.0%), respectively. Of those patients reporting reflux, patients who experienced reflux less than once a week (n = 95, 60.1%) were classified as having low-frequency reflux while the remaining patients (n = 63, 39.9%) experienced reflux at least once a week. Table 1 The reflux frequency in 158 patients and the classification into the ≥ once/week reflux group and low-frequency reflux group   Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)    Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)  View Large Table 1 The reflux frequency in 158 patients and the classification into the ≥ once/week reflux group and low-frequency reflux group   Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)    Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)  View Large Patient characteristics, operative outcomes, and postoperative complications associated with reflux frequency The patient characteristics, operative outcomes, and postoperative complications in patients who experienced reflux ≥ once/week and low-frequency reflux group are presented in Table 2. Of the 158 total patients, 151 patients (95.6%) had squamous cell carcinoma. Of the remaining seven patients, three patients had carcinosarcoma, two patients had adenocarcinoma, one patient had neuroendocrine carcinoma, and one patient had basaloid carcinoma. Table 2 Patient characteristics, operative outcomes, and postoperative complications in all 158 patients and the comparison between the ≥ once/week reflux group and low-frequency reflux group   Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815    Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Ce, cervical esophagus; CT, chemotherapy; CRT, chemoradiotherapy; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; SCC, squamous cell carcinoma; Ut, upper thoracic esophagus; VATS, video-assisted thoracoscopic surgery. View Large Table 2 Patient characteristics, operative outcomes, and postoperative complications in all 158 patients and the comparison between the ≥ once/week reflux group and low-frequency reflux group   Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815    Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Ce, cervical esophagus; CT, chemotherapy; CRT, chemoradiotherapy; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; SCC, squamous cell carcinoma; Ut, upper thoracic esophagus; VATS, video-assisted thoracoscopic surgery. View Large In regard to time elapsed following surgery, there was a statistical difference between the patients who experienced reflux ≥ once/week and low-frequency reflux group. Although the difference was not statistically significant, the rate of anastomotic stricture and recurrent laryngeal nerve palsy in the ≥ once/week reflux group was about twice as high compared to the low-frequency reflux group. Relationship between reflux frequency and time elapsed following surgery Figure 1 shows the relationship between reflux frequency and time elapsed following surgery. Within one year of the esophagectomy, there were more patients in the ≥ once/week reflux group (56.4%) than in the low-frequency reflux group (43.6%). In contrast, after more than one year since the esophagectomy, there were more patients in the low-frequency reflux group than in the ≥ once/week reflux group. The proportions of patients in the ≥ once/week reflux group were 41.4% within 1–2 years (by comparing with the proportion within one year, P = 0.220), 34.6% within 2–3 years (P = 0.085), 32.0% within 3–4 years (P = 0.048), 27.3% within 4–5 years (P = 0.022) and 35.3% after 5 years (P = 0.144). Fig. 1 View largeDownload slide The relationship between reflux frequency and time elapsed following surgery (n.s., not significant; *P < 0.05). Fig. 1 View largeDownload slide The relationship between reflux frequency and time elapsed following surgery (n.s., not significant; *P < 0.05). Multivariate logistic regression analysis for risk factors of reflux after esophagectomy Table 3 shows the multivariate logistic regression analysis for risk factors of reflux after esophagectomy. Parameters with P < 0.2 among those shown in Table 2 were selected in the multivariate analysis. Time elapsed following surgery was classified in ≥ one year and < one year. Atrial arrhythmia was not included in the multivariate analysis because the frequency of atrial arrhythmia was quite low and atrial arrhythmia was considered to be unrelated to reflux. The analysis identified the time elapsed following surgery (OR = 2.42, 95% CI 1.14–5.22, P = 0.022) as an independent factor associated with reflux after esophagectomy. Table 3 The multivariate logistic regression analysis for risk factors of reflux after esophagectomy   OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)          OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)        OR, odds ratio: 95%CI, 95% confidence interval. View Large Table 3 The multivariate logistic regression analysis for risk factors of reflux after esophagectomy   OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)          OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)        OR, odds ratio: 95%CI, 95% confidence interval. View Large Relationship between reflux frequency and QOL The relationship between reflux frequency and QOL was investigated by evaluating the differences in the QLQ-C30 scores between patients who experienced reflux ≥ once/week and low-frequency reflux group. The comparison of the global health status scores and functional scale scores between the two groups is shown in Table 4. The ≥ once/week reflux group had a significantly lower global health status score than that of the low-frequency reflux group (59.6 ± 24.2 vs. 70.8 ± 20.7; P = 0.0072). In addition, the ≥ once/week reflux group had a significantly lower social functioning score than that of the low-frequency reflux group (81.6 ± 24.1 vs. 88.4 ± 19.8; P = 0.035). The comparison of the symptom scale scores between the two groups is shown in Table 5. The ≥ once/week reflux group had significantly higher scores of fatigue, nausea, and vomiting, dyspnea, and insomnia than those in the low-frequency reflux group (fatigue: 42.4 ± 21.9 vs. 28.9 ± 18.4; P < 0.001; nausea and vomiting: 17.3 ± 17.1 vs. 4.9 ± 10.6, P < 0. 001; dyspnea: 29.2 ± 26.0 vs. 21.7 ± 26.8, P = 0.043; insomnia: 22.2 ± 31.1 vs. 10.5 ± 21.7, P = 0.015). Table 4 Comparison of the global health status and functional scales between the ≥ once/week reflux group and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035  View Large Table 4 Comparison of the global health status and functional scales between the ≥ once/week reflux group and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035  View Large Table 5 Comparison of the symptom scales between the ≥ once/week reflux and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217  View Large Table 5 Comparison of the symptom scales between the ≥ once/week reflux and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217  View Large Reflux frequency among patients that underwent reconstruction via the antesternal or retrosternal route The average times elapsed from surgery to questionnaire response in patients reconstructed by the retrosternal route and by the antesternal route were 81.2 ± 42.6 months and 35.2 ± 46.2 months, respectively. The time elapsed following surgery in patients reconstructed by the retrosternal route was greater because this approach had been commonly used in our institution 10 years ago, but is now rarely performed. Table 6 presents the reflux frequency of the 14 patients who underwent gastric conduit reconstruction by the retrosternal route and the 15 patients who underwent reconstruction using the right-side colon or jejunum by the antesternal route. Out of the 14 patients reconstructed by the retrosternal route, 6 (42.9%) indicated that reflux occurred one or more times per week. Only one (6.7%) of the 15 patients reconstructed by the antesternal route indicated that reflux occurred one or more times per week. Table 6 Reflux frequency among the 14 patients constructed by the retrosternal route and 15 patients by the antesternal route   Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)    Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)  View Large Table 6 Reflux frequency among the 14 patients constructed by the retrosternal route and 15 patients by the antesternal route   Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)    Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)  View Large DISCUSSION This study examined the reflux frequency and QOL of patients who underwent a subtotal esophagectomy and gastric conduit reconstruction for EC. Of the 158 patients enrolled in the study, 77.8% complained of postoperative reflux and 39.9% were found to regurgitate one or more times a week. Reflux frequency was associated with diminished QOL and the symptoms of fatigue, nausea and vomiting, dyspnea, and insomnia. Furthermore, the study found that the time elapsed following surgery was the only factor to influence reflux frequency. Reflux frequency decreased within two years of surgery; however, this decrease plateaued after more than two years. This study showed that the rate of anastomotic stricture and recurrent laryngeal nerve palsy in the ≥ once/week reflux group was about twice as high compared to the low-frequency reflux group. The inflammation at the site of anastomosis induced by reflux might be associated with anastomotic stricture, and the dysphagia caused by recurrent laryngeal nerve palsy might be associated with reflux. The relationship of reflux to anastomotic stricture and recurrent laryngeal nerve palsy was not statistically significant in this study, and further studies with more cases are needed to reveal the relationship. After an esophagectomy, reflux has been reported to be related to night time cough, breathing difficulty, compromised sleep, aspiration, and recurrent pneumonia.3,9 This study showed the higher scores of fatigue, dyspnea, and insomnia scales in the ≥ once/week reflux group on the EORTC QLQ-C30 questionnaire and was consistent with previous reports. To prevent reflux, patients are instructed to not lie down immediately after eating, to ensure a longer period of time between dinner and going to bed, and to sleep with their head up. However, as indicated by the results of this study, education on reflux prevention is limited in its ability to reduce the occurrence of reflux. There are several reports of surgical procedures that can be performed to prevent postoperative reflux.3,4,10,11 For example, we have successfully created an antireflux valve using an endoscopic suturing system (OverStitch; Apollo Endosurgery, Austin TX, USA) within animal models.12 In addition, we have applied this procedure to the patients with severe reflux after an esophagectomy for EC. We have investigated reflux in patients who underwent gastric conduit reconstruction by the retrosternal route and patients who underwent reconstruction using the right-side colon or jejunum by the antesternal route. Although the sample sizes were small, these results suggest that while reconstruction by the retrosternal route did not decrease reflux, reconstruction by the antesternal route significantly decreased reflux. These findings are consistent with those of previous studies.13,14 This study has several limitations. First, the study was retrospective and was conducted at only one institution. At our institution, whole stomach has been used as gastric conduit and cervical anastomosis has been performed using a 25-mm diameter circular stapler in most cases. Moreover pyloric drainage procedures have not been routinely performed. For example, the level of anastomosis is reported to influence reflux occurrence.15,16 However, the impact of reconstruction procedures on reflux was unclear in this study. Second, while the selection of patients was consecutive, only the patients who came to the clinic during the survey period were targeted. The survey methods may bias this study to select more symptomatic patients. Third, the patients answered the questionnaires only once. Thus, the survey was unable to assess any chronological changes in reflux symptoms. Fourth, this study showed that postoperative reflux was associated with a lower QOL; however, postoperative QOL would be affected by other factors, such as delayed gastric emptying, dumping syndrome, malnutrition, and weight loss. Finally, this study was a questionnaire survey, and responses were potentially affected by patient's impressions and psychological aspects. The association with complaint of reflux and objective measures such as endoscopic findings or pH monitoring was not investigated in this study. We are planning to conduct a prospective and consecutive multicenter study including objective parameters to better understand the frequency and occurrence of reflux symptoms. In conclusion, postoperative reflux occurred one or more times a week in approximately 40% of the patients who underwent a subtotal esophagectomy and gastric conduit reconstruction in the posterior mediastinum for EC. Reflux after an esophagectomy was associated with a lower QOL. Therefore, further research on the reduction of reflux after an esophagectomy is necessary. SUPPLEMENTARY DATA Supplementary data are available at DOTESO online. Supplemental File 1: We will ask you 21 questions about your symptoms within the last few months. Please answer all of the questions yourself by circling the number that best applies to you. References 1 Shapiro J, van Lanschot J J B, Hulshof M C C M et al.   Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol  2015; 16: 1090– 8. Google Scholar CrossRef Search ADS PubMed  2 Yamasaki M, Yasuda T, Yano M et al.   Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003). Ann Oncol  2017; 28: 116– 20. Google Scholar CrossRef Search ADS PubMed  3 Poghosyan T, Gaujoux S, Chirica M et al.   Functional disorders and quality of life after esophagectomy and gastric tube reconstruction for cancer. J Visc Surg  2011; 148: e327– 35. Google Scholar CrossRef Search ADS PubMed  4 Aly A, Jamieson G G. Reflux after oesophagectomy. Br J Surg  2004; 91: 137– 41. Google Scholar CrossRef Search ADS PubMed  5 da Rocha J R, Ribeiro U Jr, Sallum R A, Szachnowicz S, Cecconello I. Barrett's esophagus (BE) and carcinoma in the esophageal stump (ES) after esophagectomy with gastric pull-up in achalasia patients: a study based on 10 years follow-up. Ann Surg Oncol  2008; 15: 2903– 9. Google Scholar CrossRef Search ADS PubMed  6 Dunn L J, Shenfine J, Griffin S M. Columnar metaplasia in the esophageal remnant after esophagectomy: a systematic review. Dis Esophagus  2015; 28: 32– 41. Google Scholar CrossRef Search ADS PubMed  7 O’Riordan J M, Tucker O N, Byrne P J et al.   Factors influencing the development of Barrett's epithelium in the esophageal remnant postesophagectomy. Am J Gastroenterol  2004; 99: 205– 11. Google Scholar CrossRef Search ADS PubMed  8 Shibuya S, Fukudo S, Shineha R et al.   High incidence of reflux esophagitis observed by routine endoscopic examination after gastric pull-up esophagectomy. World J Surg  2003; 27: 580– 3. Google Scholar CrossRef Search ADS PubMed  9 Greene C L, DeMeester S R, Worrell S G et al.   Alimentary satisfaction, gastrointestinal symptoms, and quality of life 10 or more years after esophagectomy with gastric pull-up. J Thorac Cardiovasc Surg  2014; 147: 904– 14. Google Scholar CrossRef Search ADS   10 van der Schaaf M, Johar A, Lagergren P et al.   Surgical prevention of reflux after esophagectomy for cancer. Ann Surg Oncol  2013; 20: 3655– 61. Google Scholar CrossRef Search ADS PubMed  11 Palmes D, Weilinghoff M, Colombo-Benkmann M, Senninger N, Bruewer M. Effect of pyloric drainage procedures on gastric passage and bile reflux after esophagectomy with gastric conduit reconstruction. Langenbecks Arch Surg  2007; 392: 135– 41. Google Scholar CrossRef Search ADS PubMed  12 Yanagimoto Y, Yamasaki M, Nagase H et al.   Endoscopic anti-reflux valve for postesophagectomy reflux: an animal study. Endoscopy  2016; 48: 1119– 24. Google Scholar CrossRef Search ADS PubMed  13 Yasuda T, Shiozaki H. Esophageal reconstruction using a pedicled jejunum with microvascular augmentation. Ann Thorac Cardiovasc Surg  2011; 17: 103– 9. Google Scholar CrossRef Search ADS PubMed  14 Yasuda T, Shiozaki H. Esophageal reconstruction with colon tissue. Surg Today  2011; 41: 745– 53. Google Scholar CrossRef Search ADS PubMed  15 Kim H K, Choi Y H, Shim J H et al.   Endoscopic evaluation of the quality of the anastomosis after esophagectomy with gastric tube reconstruction. World J Surg  2008; 32: 2010– 4. Google Scholar CrossRef Search ADS PubMed  16 Kayani B, Jarral O A, Athanasiou T, Zacharakis E. Should oesophagectomy be performed with cervical or intrathoracic anastomosis? Interact Cardiovasc Thorac Surg  2012; 14: 821– 6. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Reflux after esophagectomy with gastric conduit reconstruction in the posterior mediastinum for esophageal cancer: original questionnaire and EORTC QLQ-C30 survey

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© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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Abstract

SUMMARY Reflux following an esophagectomy with gastric conduit reconstruction in the posterior mediastinum is a clinically significant problem. In this study, we investigated the frequency and impact of reflux on the quality of life (QOL) among 158 patients who underwent an esophagectomy for esophageal cancer using an original questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30). Reflux frequency was assessed using the original questionnaire. The number of patients who complained of reflux every day, two or three times a week, once a week, or less than once a week was 16 (10.1%), 21 (13.3%), 26 (16.5%), and 60 (38.0%), respectively. Out of 35 patients (22.2%) reported no reflux symptoms. Patients were divided into two groups: those with reflux ≥ once/week (63 patients) and those with low frequency of symptoms (95 patients). Time elapsed following surgery was the only factor to influence reflux frequency. Reflux frequency decreased within two years of surgery; however, the frequency plateaued after more than two years. QOL was assessed using the EORTC QLQ-C30. The ≥ once/week reflux group had a significantly lower global health status score than the low-frequency reflux group (59.6 ± 24.2 vs. 70.8 ± 20.7; P = 0.007). In addition, the ≥ once/week reflux group had a significantly lower social functioning score than the low-frequency reflux group (81.6 ± 24.1 vs. 88.4 ± 19.8; P = 0.035). Regarding symptoms, the ≥ once/week reflux group had significantly higher scores for fatigue, nausea, and vomiting, dyspnea and insomnia compared to the low-frequency reflux group (fatigue: 42.4 ± 21.9 vs. 28.9 ± 18.4, P < 0.001; nausea and vomiting: 17.3 ± 17.1 vs. 4.9 ± 10.6, P < 0. 001; dyspnea: 29.2 ± 26.0 vs. 21.7 ± 26.8, P = 0.043; insomnia: 22.2 ± 31.1 vs. 10.5 ± 21.7, P = 0.015). Thus, reflux after an esophagectomy was associated with a lower QOL. INTRODUCTION Recently, the prognosis of esophageal cancer (EC) has improved with the development of multimodal therapies that combine surgery, chemotherapy, and radiotherapy. Shapiro et al. reported that the median overall survival of patients who received neoadjuvant chemotherapy plus surgery was 48.6 months.1 Moreover, Yamasaki et al. reported that the two-year recurrence-free survival rate of patients with neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy plus surgery was 64.1%.2 Surgery plays a particularly important role in combined modality therapy for EC. The commonest surgical procedure for EC is an esophagectomy with gastric conduit reconstruction. However, studies have reported that patients who undergo this procedure are at risk for developing functional disorders, such as delayed gastric emptying, dumping syndrome, reflux, and dysphagia.3 Specifically, reflux is a clinically significant problem for patients who have undergone an esophagectomy and gastric conduit reconstruction because it can cause esophagitis and aspiration pneumonia.4 In addition, reflux is associated with the development of Barrett's metaplasia and metachronous cancer in the esophageal remnant.5–7 To the best of our knowledge, there are no reports that have systematically investigated the symptoms of reflux following an esophagectomy. Therefore, this study sought to use an original questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30) to investigate the frequency and impact of reflux on the quality of life (QOL) of patients who underwent a subtotal esophagectomy and gastric conduit reconstruction for EC. PATIENTS AND METHODS Patients and inclusion criteria Between April and September 2013, 231 patients who had undergone an esophagectomy for EC visited the outpatient department at our institution. Of these 231 patients, 186 patients were enrolled in the study after meeting the following criteria: (1) a subtotal esophagectomy and gastric conduit reconstruction was performed; (2) curative resection (R0) was achieved; (3) adjuvant chemotherapy was not administered after the surgery or at the time of enrollment; (4) there were no signs of recurrence after the surgery; and (5) no active malignancy was present at the time of enrollment. Since 28 patients did not answer the questionnaires, a total of 158 patients were included as the study population. In addition to these 158 patients, 14 patients who underwent gastric conduit reconstruction by the retrosternal route and 15 patients who underwent reconstruction using the right-side colon or jejunum by the antesternal route were also surveyed. This study was approved by the ethics committee of Osaka University and informed consent was obtained from all participating patients. Study population and data collection Two questionnaires (an original questionnaire and the EORTC QLQ-C30) were distributed to patients at the time of outpatient assessment. Patients were invited to fill out and sign the questionnaires while in the department and to return them to a collection box. Patient characteristics, operative outcomes, and complications were retrospectively collected. Patient characteristics include age, sex, primary tumor location, histological type, pathological stage, preoperative therapy type, body mass index (BMI) at the time of the survey and the time elapsed following surgery. Operative outcomes included the operation time, blood loss, fields of lymph node dissection, methods of thoracic approach, and anastomotic location. Regarding complications, anastomotic leak, recurrent laryngeal nerve palsy, atrial arrhythmia, chyle leak, pneumonia, and pneumothorax were examined during the in-hospital postoperative period. The presence of anastomotic stricture was examined until the time of enrollment. The original questionnaire The original questionnaire is shown in Supplementary File 1. The questionnaire consisted of 21 questions and asked about the following items: Questions 1 to 7 asked about the frequency, type (acid, bitter, saliva, food) and timing of reflux; Question 8 asked about the length of time between dinner and going to sleep; Questions 9 to 19 asked about potential symptoms caused by reflux; and Questions 20 to 21 asked about the patients’ dietary intake after the esophagectomy. Reflux assessment and frequency The presence of reflux was defined by either the regurgitation of food, saliva or other material and/or an acidic or bitter taste within the mouth according to the results of the original questionnaire. Patients without reflux were defined as those who answered that nothing was regurgitated. The frequency of reflux was defined as the rate at which the most commonly reported symptom occurred. Patients were divided into two groups: those with reflux ≥ once/week and those with low frequency of symptoms. In accordance with Shibuya et al.,8 the ≥ once/week reflux group consisted of patients who experienced reflux one or more times a week, while the low-frequency reflux group consisted of patients who did not experience reflux at all, or less than once a week. QOL assessment QOL was assessed on the basis of the EORTC QLQ-C30 (in Japanese). The EORTC QLQ-C30 includes one global health status, five functional scales (physical, role, emotional, cognitive, and social), and nine symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The scores were converted into a 0–100 scale, according to the EORTC Scoring Manual. A higher global health status score represents a higher QOL, and a higher functional scale score represents a higher level of function. Conversely, a higher symptom scale score represents a higher level of symptoms. This study received permission from the EORTC to use the QLQ-C30. Statistical analysis The following postoperative complications were evaluated according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4: anastomotic leak, recurrent laryngeal nerve palsy, chyle leak, pneumothorax, and pneumonia. Adverse events of Grade 2 or greater were defined as complications. Anastomotic stricture was defined as a stricture requiring balloon dilation. Tumors were staged according to the seventh edition of the tumor-node-metastasis (TNM) classification system of the International Union Against Cancer (UICC). All data from the questionnaire responses were entered into Microsoft Office Excel 2010 (Microsoft, Redmond, USA). All data analyses and calculations were performed using the JMP 10 (SAS Institute Inc., Cary, NC, USA) and Excel. Values were expressed as the mean ± standard deviation (SD). The significance of differences between the two groups was estimated with the Mann-Whitney U test and a chi-squared test. Multivariate logistic regression analysis was performed to identify the independent risk factors for reflux after esophagectomy. All differences were considered statistically significant at the level of P < 0.05. RESULTS Classification of high and low reflux frequency for 158 patients Table 1 shows the reflux frequency of the 158 total patients. There were 35 patients (22.2%) who did not report reflux and 123 patients (77.8%) who reported reflux. The number of patients who complained of reflux every day, two or three times a week, once a week, or less than once a week was 16 (10.1%), 21 (13.3%), 26 (16.5%), and 60 (38.0%), respectively. Of those patients reporting reflux, patients who experienced reflux less than once a week (n = 95, 60.1%) were classified as having low-frequency reflux while the remaining patients (n = 63, 39.9%) experienced reflux at least once a week. Table 1 The reflux frequency in 158 patients and the classification into the ≥ once/week reflux group and low-frequency reflux group   Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)    Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)  View Large Table 1 The reflux frequency in 158 patients and the classification into the ≥ once/week reflux group and low-frequency reflux group   Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)    Reflux frequency    Everyday  Two or three times a week  Once a week  Less than once a week  No reflux  No of patients  16  21  26  60  35  Classification  ≥once/week reflux group (n = 63)  Low-frequency reflux group (n = 95)  View Large Patient characteristics, operative outcomes, and postoperative complications associated with reflux frequency The patient characteristics, operative outcomes, and postoperative complications in patients who experienced reflux ≥ once/week and low-frequency reflux group are presented in Table 2. Of the 158 total patients, 151 patients (95.6%) had squamous cell carcinoma. Of the remaining seven patients, three patients had carcinosarcoma, two patients had adenocarcinoma, one patient had neuroendocrine carcinoma, and one patient had basaloid carcinoma. Table 2 Patient characteristics, operative outcomes, and postoperative complications in all 158 patients and the comparison between the ≥ once/week reflux group and low-frequency reflux group   Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815    Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Ce, cervical esophagus; CT, chemotherapy; CRT, chemoradiotherapy; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; SCC, squamous cell carcinoma; Ut, upper thoracic esophagus; VATS, video-assisted thoracoscopic surgery. View Large Table 2 Patient characteristics, operative outcomes, and postoperative complications in all 158 patients and the comparison between the ≥ once/week reflux group and low-frequency reflux group   Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815    Total (n = 158)  ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Age  68.2 ± 8.4  67.2 ± 9.3  68.9 ± 7.8  0.412  Sex        0.340   Male  137 (86.7%)  57 (90.5%)  80 (84.2%)     Female  21 (13.3%)  6 (9.5%)  15 (15.8%)    Location        0.204   Ce  4 (2.5%)  2 (3.2%)  2 (2.1%)     Ut  28 (17.7%)  16 (25.4%)  12 (12.6%)     Mt  77 (48.7%)  28 (44.4%)  49 (51.6%)     Lt  49 (31.1%)  17 (27.0%)  32 (33.7%)    Histological type        0.869   SCC  151 (95.6%)  60 (95.2%)  91 (95.8%)     Other  7 (4.4%)  3 (4.8%)  4 (4.2%)    PStage        0.827   0  19 (12.0%)  9 (14.3%)  10 (10.5%)     I  50 (31.6%)  19 (30.2%)  31 (32.6%)     II  53 (33.5%)  23 (36.5%)  30 (31.6%)     III  25 (15.8%)  8 (12.7%)  17 (17.9%)     IV  11 (7.1%)  4 (6.3%)  7 (7.4%)    Preoperative therapy        0.578   None  34 (21.5%)  16 (25.4%)  18 (18.9%)     CT  105 (66.5%)  39 (61.9%)  66 (69.5%)     CRT  19 (12.0%)  6 (12.7%)  11 (11.6%)    Body mass index (kg/m²)  19.5 ± 2.4  19.5 ± 2.5  19.4 ± 2.3  0.639  Time elapsed following surgery (months) (mean ± SD)  31.7 ± 23.9  27.8 ± 25.7  34.4 ± 22.4  0.023  Operation time (min) (mean ± SD)  442.0 ± 70.5  441.1 ± 71.2  442.5 ± 70.4  0.742  Blood loss (g) (mean ± SD)  617.1 ± 366.2  625.2 ± 391.2  611.8 ± 350.7  1.000  Lymph node dissection        0.055   Two field  80 (50.6%)  26 (41.3%)  54 (56.8%)     Three field  78 (49.4%)  37 (58.7%)  41 (43.2%)    Surgical approach        0.500   Open  110 (69.6%)  42 (66.7%)  68 (71.6%)     VATS  48 (30.4%)  21 (33.3%)  27 (28.4%)    Anastomotic location        0.350  Intrathoracic  5 (3.2%)  3 (4.8%)  2 (2.1%)    Cervical  153 (96.8%)  60 (95.2%)  93 (97.9%)    Complications  Anastomotic leak  9 (5.7%)  3 (4.8%)  6 (6.3%)  0.680  Anastomotic stricture  16 (10.1%)  9 (14.3%)  7 (7.4%)  0.158  Atrial arrhythmia  3 (1.9%)  0  3 (3.2%)  0.154  Pneumonia  10 (6.3%)  5 (7.9%)  5 (5.3%)  0.499  Pneumothorax  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Recurrent laryngeal nerve palsy  12 (7.6%)  7 (11.1%)  5 (5.3%)  0.154  Chyle leak  3 (1.9%)  1 (1.6%)  2 (2.1%)  0.815  Ce, cervical esophagus; CT, chemotherapy; CRT, chemoradiotherapy; Lt, lower thoracic esophagus; Mt, middle thoracic esophagus; SCC, squamous cell carcinoma; Ut, upper thoracic esophagus; VATS, video-assisted thoracoscopic surgery. View Large In regard to time elapsed following surgery, there was a statistical difference between the patients who experienced reflux ≥ once/week and low-frequency reflux group. Although the difference was not statistically significant, the rate of anastomotic stricture and recurrent laryngeal nerve palsy in the ≥ once/week reflux group was about twice as high compared to the low-frequency reflux group. Relationship between reflux frequency and time elapsed following surgery Figure 1 shows the relationship between reflux frequency and time elapsed following surgery. Within one year of the esophagectomy, there were more patients in the ≥ once/week reflux group (56.4%) than in the low-frequency reflux group (43.6%). In contrast, after more than one year since the esophagectomy, there were more patients in the low-frequency reflux group than in the ≥ once/week reflux group. The proportions of patients in the ≥ once/week reflux group were 41.4% within 1–2 years (by comparing with the proportion within one year, P = 0.220), 34.6% within 2–3 years (P = 0.085), 32.0% within 3–4 years (P = 0.048), 27.3% within 4–5 years (P = 0.022) and 35.3% after 5 years (P = 0.144). Fig. 1 View largeDownload slide The relationship between reflux frequency and time elapsed following surgery (n.s., not significant; *P < 0.05). Fig. 1 View largeDownload slide The relationship between reflux frequency and time elapsed following surgery (n.s., not significant; *P < 0.05). Multivariate logistic regression analysis for risk factors of reflux after esophagectomy Table 3 shows the multivariate logistic regression analysis for risk factors of reflux after esophagectomy. Parameters with P < 0.2 among those shown in Table 2 were selected in the multivariate analysis. Time elapsed following surgery was classified in ≥ one year and < one year. Atrial arrhythmia was not included in the multivariate analysis because the frequency of atrial arrhythmia was quite low and atrial arrhythmia was considered to be unrelated to reflux. The analysis identified the time elapsed following surgery (OR = 2.42, 95% CI 1.14–5.22, P = 0.022) as an independent factor associated with reflux after esophagectomy. Table 3 The multivariate logistic regression analysis for risk factors of reflux after esophagectomy   OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)          OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)        OR, odds ratio: 95%CI, 95% confidence interval. View Large Table 3 The multivariate logistic regression analysis for risk factors of reflux after esophagectomy   OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)          OR  95%CI  P-value  Time elapsed following surgery  2.42  1.14–5.22  0.022  (<one year vs. ≥ one year)        Lymph node dissection  1.81  0.93–3.55  0.079  (Three field vs. two field)        Anastomotic stricture  2.11  0.72–6.41  0.17  (yes vs. no)        Recurrent laryngeal nerve palsy  1.81  0.53–6.56  0.34  (yes vs. no)        OR, odds ratio: 95%CI, 95% confidence interval. View Large Relationship between reflux frequency and QOL The relationship between reflux frequency and QOL was investigated by evaluating the differences in the QLQ-C30 scores between patients who experienced reflux ≥ once/week and low-frequency reflux group. The comparison of the global health status scores and functional scale scores between the two groups is shown in Table 4. The ≥ once/week reflux group had a significantly lower global health status score than that of the low-frequency reflux group (59.6 ± 24.2 vs. 70.8 ± 20.7; P = 0.0072). In addition, the ≥ once/week reflux group had a significantly lower social functioning score than that of the low-frequency reflux group (81.6 ± 24.1 vs. 88.4 ± 19.8; P = 0.035). The comparison of the symptom scale scores between the two groups is shown in Table 5. The ≥ once/week reflux group had significantly higher scores of fatigue, nausea, and vomiting, dyspnea, and insomnia than those in the low-frequency reflux group (fatigue: 42.4 ± 21.9 vs. 28.9 ± 18.4; P < 0.001; nausea and vomiting: 17.3 ± 17.1 vs. 4.9 ± 10.6, P < 0. 001; dyspnea: 29.2 ± 26.0 vs. 21.7 ± 26.8, P = 0.043; insomnia: 22.2 ± 31.1 vs. 10.5 ± 21.7, P = 0.015). Table 4 Comparison of the global health status and functional scales between the ≥ once/week reflux group and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035  View Large Table 4 Comparison of the global health status and functional scales between the ≥ once/week reflux group and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Global health status  59.6 ± 24.2  70.8 ± 20.7  0.007  Physical functioning  81.5 ± 17.9  85.0 ± 15.1  0.146  Role functioning  77.8 ± 26.2  84.8 ± 21.5  0.088  Emotional functioning  84.5 ± 17.2  89.8 ± 15.2  0.061  Cognitive functioning  77.7 ± 18.9  83.8 ± 14.8  0.062  Social functioning  81.6 ± 24.1  88.4 ± 19.8  0.035  View Large Table 5 Comparison of the symptom scales between the ≥ once/week reflux and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217  View Large Table 5 Comparison of the symptom scales between the ≥ once/week reflux and low-frequency reflux group   ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217    ≥once/week reflux (n = 63)  Low-frequency reflux (n = 95)  P-value  Fatigue  42.4 ± 21.9  28.9 ± 18.4   <0.001  Nausea and vomiting  17.3 ± 17.1  4.9 ± 10.6   <0.001  Pain  11.9 ± 18.0  7.7 ± 16.4  0.121  Dyspnoea  29.2 ± 26.0  21.7 ± 26.8  0.043  Insomnia  22.2 ± 31.1  10.5 ± 21.7  0.015  Appetite  25.1 ± 32.3  18.7 ± 25.7  0.368  Constipation  25.1 ± 25.4  20.5 ± 23.2  0.284  Diarrhoea  28.1 ± 24.2  22.2 ± 23.2  0.162  Financial difficulties  15.2 ± 26.8  9.6 ± 20.2  0.217  View Large Reflux frequency among patients that underwent reconstruction via the antesternal or retrosternal route The average times elapsed from surgery to questionnaire response in patients reconstructed by the retrosternal route and by the antesternal route were 81.2 ± 42.6 months and 35.2 ± 46.2 months, respectively. The time elapsed following surgery in patients reconstructed by the retrosternal route was greater because this approach had been commonly used in our institution 10 years ago, but is now rarely performed. Table 6 presents the reflux frequency of the 14 patients who underwent gastric conduit reconstruction by the retrosternal route and the 15 patients who underwent reconstruction using the right-side colon or jejunum by the antesternal route. Out of the 14 patients reconstructed by the retrosternal route, 6 (42.9%) indicated that reflux occurred one or more times per week. Only one (6.7%) of the 15 patients reconstructed by the antesternal route indicated that reflux occurred one or more times per week. Table 6 Reflux frequency among the 14 patients constructed by the retrosternal route and 15 patients by the antesternal route   Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)    Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)  View Large Table 6 Reflux frequency among the 14 patients constructed by the retrosternal route and 15 patients by the antesternal route   Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)    Reflux frequency    One or more times a week  No reflux or less than once a week  Patients by retrosternal route (n = 14)  6 (42.9%)  8 (57.1%)  Patients by antesternal route (n = 15)  1 (6.7%)  14 (93.3%)  View Large DISCUSSION This study examined the reflux frequency and QOL of patients who underwent a subtotal esophagectomy and gastric conduit reconstruction for EC. Of the 158 patients enrolled in the study, 77.8% complained of postoperative reflux and 39.9% were found to regurgitate one or more times a week. Reflux frequency was associated with diminished QOL and the symptoms of fatigue, nausea and vomiting, dyspnea, and insomnia. Furthermore, the study found that the time elapsed following surgery was the only factor to influence reflux frequency. Reflux frequency decreased within two years of surgery; however, this decrease plateaued after more than two years. This study showed that the rate of anastomotic stricture and recurrent laryngeal nerve palsy in the ≥ once/week reflux group was about twice as high compared to the low-frequency reflux group. The inflammation at the site of anastomosis induced by reflux might be associated with anastomotic stricture, and the dysphagia caused by recurrent laryngeal nerve palsy might be associated with reflux. The relationship of reflux to anastomotic stricture and recurrent laryngeal nerve palsy was not statistically significant in this study, and further studies with more cases are needed to reveal the relationship. After an esophagectomy, reflux has been reported to be related to night time cough, breathing difficulty, compromised sleep, aspiration, and recurrent pneumonia.3,9 This study showed the higher scores of fatigue, dyspnea, and insomnia scales in the ≥ once/week reflux group on the EORTC QLQ-C30 questionnaire and was consistent with previous reports. To prevent reflux, patients are instructed to not lie down immediately after eating, to ensure a longer period of time between dinner and going to bed, and to sleep with their head up. However, as indicated by the results of this study, education on reflux prevention is limited in its ability to reduce the occurrence of reflux. There are several reports of surgical procedures that can be performed to prevent postoperative reflux.3,4,10,11 For example, we have successfully created an antireflux valve using an endoscopic suturing system (OverStitch; Apollo Endosurgery, Austin TX, USA) within animal models.12 In addition, we have applied this procedure to the patients with severe reflux after an esophagectomy for EC. We have investigated reflux in patients who underwent gastric conduit reconstruction by the retrosternal route and patients who underwent reconstruction using the right-side colon or jejunum by the antesternal route. Although the sample sizes were small, these results suggest that while reconstruction by the retrosternal route did not decrease reflux, reconstruction by the antesternal route significantly decreased reflux. These findings are consistent with those of previous studies.13,14 This study has several limitations. First, the study was retrospective and was conducted at only one institution. At our institution, whole stomach has been used as gastric conduit and cervical anastomosis has been performed using a 25-mm diameter circular stapler in most cases. Moreover pyloric drainage procedures have not been routinely performed. For example, the level of anastomosis is reported to influence reflux occurrence.15,16 However, the impact of reconstruction procedures on reflux was unclear in this study. Second, while the selection of patients was consecutive, only the patients who came to the clinic during the survey period were targeted. The survey methods may bias this study to select more symptomatic patients. Third, the patients answered the questionnaires only once. Thus, the survey was unable to assess any chronological changes in reflux symptoms. Fourth, this study showed that postoperative reflux was associated with a lower QOL; however, postoperative QOL would be affected by other factors, such as delayed gastric emptying, dumping syndrome, malnutrition, and weight loss. Finally, this study was a questionnaire survey, and responses were potentially affected by patient's impressions and psychological aspects. The association with complaint of reflux and objective measures such as endoscopic findings or pH monitoring was not investigated in this study. We are planning to conduct a prospective and consecutive multicenter study including objective parameters to better understand the frequency and occurrence of reflux symptoms. In conclusion, postoperative reflux occurred one or more times a week in approximately 40% of the patients who underwent a subtotal esophagectomy and gastric conduit reconstruction in the posterior mediastinum for EC. Reflux after an esophagectomy was associated with a lower QOL. Therefore, further research on the reduction of reflux after an esophagectomy is necessary. SUPPLEMENTARY DATA Supplementary data are available at DOTESO online. Supplemental File 1: We will ask you 21 questions about your symptoms within the last few months. Please answer all of the questions yourself by circling the number that best applies to you. References 1 Shapiro J, van Lanschot J J B, Hulshof M C C M et al.   Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol  2015; 16: 1090– 8. Google Scholar CrossRef Search ADS PubMed  2 Yamasaki M, Yasuda T, Yano M et al.   Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003). Ann Oncol  2017; 28: 116– 20. Google Scholar CrossRef Search ADS PubMed  3 Poghosyan T, Gaujoux S, Chirica M et al.   Functional disorders and quality of life after esophagectomy and gastric tube reconstruction for cancer. J Visc Surg  2011; 148: e327– 35. Google Scholar CrossRef Search ADS PubMed  4 Aly A, Jamieson G G. Reflux after oesophagectomy. Br J Surg  2004; 91: 137– 41. Google Scholar CrossRef Search ADS PubMed  5 da Rocha J R, Ribeiro U Jr, Sallum R A, Szachnowicz S, Cecconello I. Barrett's esophagus (BE) and carcinoma in the esophageal stump (ES) after esophagectomy with gastric pull-up in achalasia patients: a study based on 10 years follow-up. Ann Surg Oncol  2008; 15: 2903– 9. Google Scholar CrossRef Search ADS PubMed  6 Dunn L J, Shenfine J, Griffin S M. Columnar metaplasia in the esophageal remnant after esophagectomy: a systematic review. Dis Esophagus  2015; 28: 32– 41. Google Scholar CrossRef Search ADS PubMed  7 O’Riordan J M, Tucker O N, Byrne P J et al.   Factors influencing the development of Barrett's epithelium in the esophageal remnant postesophagectomy. Am J Gastroenterol  2004; 99: 205– 11. Google Scholar CrossRef Search ADS PubMed  8 Shibuya S, Fukudo S, Shineha R et al.   High incidence of reflux esophagitis observed by routine endoscopic examination after gastric pull-up esophagectomy. World J Surg  2003; 27: 580– 3. Google Scholar CrossRef Search ADS PubMed  9 Greene C L, DeMeester S R, Worrell S G et al.   Alimentary satisfaction, gastrointestinal symptoms, and quality of life 10 or more years after esophagectomy with gastric pull-up. J Thorac Cardiovasc Surg  2014; 147: 904– 14. Google Scholar CrossRef Search ADS   10 van der Schaaf M, Johar A, Lagergren P et al.   Surgical prevention of reflux after esophagectomy for cancer. Ann Surg Oncol  2013; 20: 3655– 61. Google Scholar CrossRef Search ADS PubMed  11 Palmes D, Weilinghoff M, Colombo-Benkmann M, Senninger N, Bruewer M. Effect of pyloric drainage procedures on gastric passage and bile reflux after esophagectomy with gastric conduit reconstruction. Langenbecks Arch Surg  2007; 392: 135– 41. Google Scholar CrossRef Search ADS PubMed  12 Yanagimoto Y, Yamasaki M, Nagase H et al.   Endoscopic anti-reflux valve for postesophagectomy reflux: an animal study. Endoscopy  2016; 48: 1119– 24. Google Scholar CrossRef Search ADS PubMed  13 Yasuda T, Shiozaki H. Esophageal reconstruction using a pedicled jejunum with microvascular augmentation. Ann Thorac Cardiovasc Surg  2011; 17: 103– 9. Google Scholar CrossRef Search ADS PubMed  14 Yasuda T, Shiozaki H. Esophageal reconstruction with colon tissue. Surg Today  2011; 41: 745– 53. Google Scholar CrossRef Search ADS PubMed  15 Kim H K, Choi Y H, Shim J H et al.   Endoscopic evaluation of the quality of the anastomosis after esophagectomy with gastric tube reconstruction. World J Surg  2008; 32: 2010– 4. Google Scholar CrossRef Search ADS PubMed  16 Kayani B, Jarral O A, Athanasiou T, Zacharakis E. Should oesophagectomy be performed with cervical or intrathoracic anastomosis? Interact Cardiovasc Thorac Surg  2012; 14: 821– 6. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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Diseases of the EsophagusOxford University Press

Published: Mar 28, 2018

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