1 2 3 4 5 7 8 9 10 11 12 13 14 6 6 PATIENTS AND METHODS Patients Referral to our institute was accomplished as a result of agreements between hospitals affiliated to the Comprehensive Cancer Centre South in the Netherlands to concentrate surgical care of patients with esophageal cancer. The protocol of this prospective clinical phase II trial was approved by the Medical Ethics Committee, and from all patients written informed consent was obtained. All consecutive patients with a potentially resectable stage II and III esophageal cancer who were referred to our Centre between January 2002 and November 2004 were found eligible. 9 9 Pretreatment staging evaluation included clinical examination, upper gastrointestinal endoscopy with histological biopsies of the tumor, computed tomography (CT) scan of chest and upper abdomen, and ultrasound of the neck. Endoscopic ultrasound (EUS) was performed when a T1 tumor could not be excluded by conventional techniques. More recently, PET imaging was introduced to exclude distant metastases. Neoadjuvant Treatment 2 2 Radiotherapy was performed with a linear accelerator with a minimal photon energy of 6 MV. The total dose of 45 Gy was given in 25 fractions of 1.8 Gy once daily, starting on day 1. The radiation fields encompassed the primary tumor and enlarged lymph nodes, if any, defined by endoscopy, CT scan, and EUS, surrounded by 5-cm proximal and distal margins and a 2-cm radial margin. Neoadjuvant treatment was given on a fully outpatient base. 15 Surgery Surgery was planned 6–8 weeks after completion of neoadjuvant treatment. For tumors in the distal third of the esophagus, a transhiatal approach was used whenever possible. A thransthoracic Ivor-Lewis technique was used for tumors in the proximal and middle third of the esophagus. Esophagogastric continuity was reestablished using the stomach with a cervical anastomosis in all patients. A feeding jejunostomy was placed, and enteral feeding was started 24 hours after surgery. Data Collection The following data were prospectively collected: age, sex, WHO performance status, location of the tumor, histology of the tumor, comorbidity, toxicity of neoadjuvant treatment, type of resection, and postoperative course and complications. Histological Examination 16 17 Statistical Analysis P RESULTS Patient Characteristics 1 TABLE 1. Patient characteristics  n Age (years)   Median 60   Range 34–75 Sex   Male 44   Female 6 WHO performance status   Median 1   Range 0–2 ASA classification   I 24   II 24   III 2   IV – Tumor location   Upper third 2   Middle third 1   Lower third 47 Histology   Adenocarcinoma 42   Squamous cell carcinoma 8 Toxicity Related to Neoadjuvant Treatment Forty-two patients (84%) completed full neoadjuvant treatment. Three patients discontinued chemotherapy prematurely due to grade II hand-foot syndrome, four patients due to esophagitis, and one due to grade IV leucopenia. Forty-seven patients (94%) received at least 5 weeks chemotherapy; the remaining three patients discontinued chemotherapy in week 4. Full dose of radiotherapy was received by 49 patients (98%). Grade III leucopenia occurred in 23 patients (46%), without febrile episodes. No other hematologic toxicity was recorded. All 50 patients experienced esophagitis, usually mild (≤ grade 2). A total of 13 patients (26%) needed nasogastric enteral feeding. Infection of the indwelling central venous catheter occurred in two patients. There were no neoadjuvant treatment related deaths. However, one patient died of myocardial infarction 3 weeks after completing neoadjuvant treatment. Postoperative Complications Surgery was performed after a median of 8.1 weeks (range 6.0–17.9 weeks). No significant difference was observed between responders (TRG 1–3) and nonresponders (TRG 4–5) with respect to the time between the end of chemoradiation and surgery. Two patients showed metastatic disease at the time of surgery; hence, 47 patients underwent surgery with a curative intention. Transhiatal esophageal resection was performed in 44 patients; a transthoracic Ivor-Lewis resection was performed in three patients. n n n n n 2 TABLE 2. Postoperative complications Type of complication No. of patients (%) Major anastomotic leakage 5 (11) Pulmonary 15 (32)  Pneumonia 7  Emphysema 4  ARDS 1  Mediastinal infection 1  Trachea-esoph fistula 1  Chylothorax 1 Recurrent nerve palsy   Permanent 1 (2)   Temporary 4 (9) Cardiac arrhythmias 3 (6) Wound infection 2 (4) Diaphragmatic hernia 1 (2) Hospital stay (days)   Median 15   Range 9–83 ICU/MCU stay (days)   Median 2   Range 2–18 Ventilation time (days)   Median 1 Range 0–9 Pathologic Response to Neoadjuvant Treatment 3 4 TABLE 3. Pathological stage of patients treated with neoadjuvant chemoradiation and surgery Stage, ypTNM No. of patients (%) 0 18 (38.3) I 6 (12.8) II a 12 (25.5) II b 4 (8.5) III 7 (14.9) TABLE 4. Tumor regression grade (TRG) of patients treated with neoadjuvant chemoradiation and surgery a No. of patients (%) 1—Absence of histologically identifiable residual cancer and fibrosis extending through the different layers of the esophageal wall 18 (38.3) 2—Presence of rare residual cancer cells scattered through the fibrosis 11 (23.4) 3—Increase in the number of residual cancer cells, but fibrosis still predominated 9 (19.1) 4—Residual cancer outgrowing fibrosis 7 (14.9) 5—Absence of regressive changes 2 (4.3) a 17 Survival and Pattern of Failure 1 2 FIG. 1. n  FIG. 2. n  P 3 FIG. 3. n n P  Recurrent disease was found in 20 patients surviving postoperatively (20 of 43, 47%) Five of them were still alive at the time of the analysis. Recurrence was only locoregional in three patients. Distant metastases occurred in 16 patients, and in one patient recurrence presented with locoregional and pulmonary metastases. To date 22 patients have died. Of these 22 patients, three died from nondisease-related causes and were presumed disease free. Of the 19 patients who had disease-related deaths, four patients died of postoperative complications, and three patients died of complications from local recurrence, whereas 12 patients died due to systemic failure that included metastases to lung, liver, brain, and bone. DISCUSSION 6 4 18 22 4 19 22 23 P 5 7 24 25 6 2 2 2 2 2 26 P 23 We decided to perform surgery after at least 6 weeks to achieve an adequate downstaging and permit maximal recovery; in addition, surgery was postponed in some patients due to a slow recovery from the chemoradiation. We believe that the timing of surgery is important. Performing an esophagectomy too soon after neoadjuvant chemoradiation may lead to increased morbidity due to prolonged myelosuppression and hence an increased risk for developing postoperative complications. 4 19 20 22 27 29 6 7 25 30 3 8 9 30 31 In conclusion, although the discussion regarding the value of neoadjuvant therapy is ongoing, the neoadjuvant treatment regimens used for the last 20 years produced only modest benefit, at best. Improving chemoradiation regimens as in our study, by incorporating modern chemotherapeutics such as paclitaxel in combination with modern 3-D conformal radiotherapy seems to be promising. Further improvement of the systemic therapy seems to be critical as survival is mainly determined by recurrences at metastatic sites. Data of ongoing phase III trials including novel chemoradiation protocols have to be awaited in the near future.