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. Materials/Methods: 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 2year locoregional progression-free survival (LRPFS). Results: 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. Conclusion: 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.

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TPS4191 Background: LAPC represents a major challenge with no standardized chemotherapy (CT) and radiotherapy (RT) treatment. Phase 2 studies (LAPACT/NEOLAP) indicated efficacy of FFX and GA, although addition of conventionally fractionated RT remains controversial. Phase 3 LAP07 trial obtained a reduction of progression free survival (PFS), albeit with no overall survival (OS) advantage. Since in metastatic pancreatic cancer we recently attained with GA/FFX sequential combination (GABRINOX) high objective response rate and promising OS with acceptable toxicity and no limiting neurotoxicity, we proposed in LAPC to complement GABRINOX with SMART, recently recognized beneficial in pancreatic tumors by a retrospective multicenter study (OS at 2 years) and our prospective registry study (dosimetric benefit of adaptation). In a first step (SEQ1), we will evaluate GABRINOX efficacy and select patients without progression for a second step (SEQ2), to evaluate feasibility and tolerance in patients without disease progression after SEQ1. Secondarily we will evaluate CT tolerance (SEQ1), acute toxicities and dosimetric results (SEQ2) and for both SEQ1+2, late toxicities, response to treatment, PFS, OS and quality of life (QoL). Methods: Naive patients with confirmed non-metastatic unresectable adenocarcinoma by centralized reading (WHO 0/1) and adequate organ function will receive in SEQ1 two cycles of GABRINOX, GA (1000 mg/m2, 125 mg/m2) on days 1, 8, and 15 followed by FFX on day 29 and 43. After 3-4 weeks, patients without progression or unacceptable toxicity will benefit from SMART (5 fractions of 10 Gy/day over 5 consecutive days). Specific dummy-run, contouring quality assurance and dosimetric plans will precede post-treatment monitoring every 6 weeks for 6 months for non-progressive patients and then every 2 months until progression: radiological assessment, biological markers (circulating tumor DNA) and QoL evaluation. Co-primary endpoints include success of SEQ1 (non-progression at 4 months, RECIST v1.1) and that of SEQ2 as absence of acute digestive non-toxicity rate > grade 3 (NCI-CTCAE v5.0) within 90 days. Based on Fleming design with maximal inefficacy (p0) of 70% and 90% (α = 2.5% and β = 5%) we need 98 and 70 patients (SEQ1 and SEQ2), and total of 103 cases considering those entering in SEQ 2 (70%) and non-evaluable patients. Success rate, toxicities (by treatment sequences) and safety (System Organ Class) by patient and cycle will be considered while dosimetry will be correlated with gastro-intestinal toxicities. Median follow-up, OS and PFS will be expressed as medians and rates with 95% CI while QoL will be explored by QLQ-C30 and QLQ-PAN26 analyses using the time to definitive deterioration. From 2021, we included 5 patients (NCT04570943). Clinical trial information: NCT04570943.

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