Exclusive Chemoradiotherapy With or Without Radiation Dose Escalation in Esophageal Cancer: Multicenter Phase 2/3 Randomized Trial CONCORDE (PRODIGE-26)

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Increasing dose of chemoradiotherapy in locally advanced esophageal cancer unsuitable for surgery has been a matter of debate in the last 2 decades. Advances in tumor staging and radiation targeting with modern imaging and IMRT should allow further testing exclusive radiation dose escalation in esophageal cancer.We performed a multicenter, randomized, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 28 centers in France between 07/06/2011 and 11/10/2019. Eligible participants had confirmed stage I-III biopsy proven esophageal carcinoma, ECOG 0-2 and sufficient caloric intake. Patients were randomly assigned (1:1) to receive 50Gy in 25 fractions over 5 weeks (standard arm) or 66Gy in 33 fractions over 6.5 weeks (experimental arm). Elective nodal irradiation (40Gy) was delivered in both groups. Concomitant chemotherapy was FOLFOX-4 for 3 courses followed by 3 adjuvant courses. Random allocation to treatment groups was done by a central computerized randomization procedure by minimization, stratified by center, histology, weight loss, and technique of radiotherapy. The primary endpoint was 2-year locoregional progression-free survival (LRPFS).109 participants were randomly allocated to the 50Gy arm and 108 to the 66Gy group (intention-to-treat population). 177 men (81.6%) and 40 women (18.4%) were included with a mean age of 62.6 years (± 7.8). 191 patients (88.4%) had squamous cell cancer and 25 (11.6%) has adenocarcinoma. Most of the patients had stage III tumors (74% vs 26% for stage I-II). IMRT was delivered in 169 patients (80.1%) and 3D conformal in 42 patients (19.9%). 59 patients (54.1%) have died in the 50Gy group and 65 patients (60.2%) in the 66Gy group with a median follow up 35.3 months (range: 2.0-65.7) and 35.5 months (range: 1.3-60.7), respectively. Median overall survival was 25.2 months (95% CI 17.8-NR) in the 50Gy group and 23.5 months (14.5-32.2) in the 66Gy group (HR 1.14, 95% CI 0.82-1.59; P = 0.44). Median LRPFS was 16.2 months (95% CI 10.9-26.0) in the 50Gy group and 18.4 months (12.2-25.7) in the 66Gy group (HR 1.03, 95% CI 0.75-1.40; P = 0.88). The 2-year LRPFS rates were 42.7% (95% CI 33.2%-51.8%) and 43.8% (95% CI 34.1%-54.1%). No significant differences were recorded in the rates of late adverse events between the treatment groups (P = 0.14). The rates of grade 3/4 toxicities in the 50Gy group were 29.5%/0% and 24.0%/5.3% in the 66Gy group. 5 toxic deaths (4.6%) occurred in the 50Gy group and 7 (6.7%) in the 66Gy group. One and 2 toxic deaths out of the 5 in the 50Gy were related to radiotherapy or chemotherapy, respectively. Two and 3 out of the 7 toxic deaths in the 66Gy were related to radiotherapy or chemotherapy, respectively.Dose escalated chemoradiotherapy delivering 66Gy is not more toxic than 50Gy but did not improve locoregional progression-free survival. Chemoradiotherapy delivering 50Gy should be definitely admitted as a standard dose.