Stahl 2005.

Methods	Randomized controlled study
Participants	Histologically proven squamous cell carcinoma of the upper and mid‐third esophagus (no exact definition given on tumor location from dental ridge); age < 70 years, WHO performance status 0 to 1. Locally advanced disease (T3‐4, N0‐1, M0 according to endoscopic ultrasound and computed tomography); June 1994 to May 2002; Germany (multi‐center) 172 participants (138 male, 34 female) Median observation time: 6 years Participants randomized/analysed in this meta‐analysis: 172/172
Interventions	Induction chemotherapy, followed by preoperative chemoradiation versus induction chemotherapy, followed by chemoradiation alone. Both groups received induction chemotherapy, consisting of three courses of bolus fluorouracil (500 mg/m²), leucovarin (300 mg/m²), etoposide (100 mg/m²), cisplatin(30 mg/m²) days 1 to 3 every 3 weeks. Intervention group: After induction chemotherapy, preoperative concomitant chemoradiotherapy was given as detailed below. Chemotherapy: Cisplatin (50 mg/m²) , etoposide(80 mg/m²) on days 2 to 8 Radiotherapy: 2 Gy per fraction, 5 fractions per week to a total dose of 40 Gy. Radiotherapy clinical target volume included gross tumor with 5 cm craniocaudal margin and 2 cm transverse margin. Supra‐, infraclavicular, and lower cervical lymph nodes were included for upper thoracic tumors. AP and PA fields were used in conjunction with three‐dimensional planning. Surgery: transthoracic esophagacteomy was performed 3 to 4 weeks after chemoradiation. Resection included para‐esophageal, paracardial, left gastric, and celiac nodes (two‐field lymphadenectomy) Control group: after induction chemotherapy, definitive chemoradiotherapy was given. Chemotherapy: Cisplatin (50 mg/m²), etoposide(80 mg/m²) on days 2 to 8. Radiotherapy: 2 Gy per fraction, 5 fractions per week to a total dose of 50 Gy initially. Following which, a boost was delivered. Radiotherapy boost to reduced volume: For T4 and obstructing T3 tumors, a total external beam dose of 65 Gy was delivered. (i.e. 15 Gy delivered using 1.5 Gy twice a day, 6‐hour intervals, over 5 days) For T3 and non‐obstructing tumors, external beam dose to a total of 60 Gy, followed by intracavitary brachytherapy (two fractions of 4 Gy high dose rate administered with a 4 to 7 day interval; prescribed to 5 mm depth from applicator to pre‐radiotherapy tumor length and 5 mm superior and inferior margin) Radiotherapy clinical target volume for the initial phase included gross tumor with 5 cm craniocaudal margin and 2 cm transverse margin. Supra‐, infraclavicular, and lower cervical lymph nodes were included for upper thoracic tumors. Radiotherapy clinical target volume (external beam) for the boost phase included gross tumor with 2 cm craniocaudal margin and 1 cm transverse margin. AP, PA, and oblique fields were used in conjunction with three‐dimensional planning.
Outcomes	overall survival, local progression free survival, treatment‐related mortality
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence was generated using a computerized randomization program.
Allocation concealment (selection bias)	Low risk	Allocation was done at a central site (Institute for Medical Informatics, Biometry and Epidemiology, University Clinics Essen)
Blinding of participants and personnel (performance bias) All outcomes	High risk	The risk of bias for the primary outcome (overall survival) is objective and therefore low. However, the risk of bias from lack of blinding was high for local progression‐free survival.
Blinding of outcome assessment (detection bias) All outcomes	High risk	The risk of bias for the primary outcome (overall survival) is objective and therefore low. However, the risk of bias from lack of blinding was high for local progression‐free survival.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	The prespecified primary outcome was reported
Other bias	Unclear risk	Quality assurance of radiotherapy planning and delivery were not reported. Type and quality of surgeries performed were not audited or reported.

Key: AP = anterior‐posterior ; PA = posterior‐anterior