Chemotherapy and chemoradiotherapy for adenocarcinoma of the esophagus and junction with oligometastases: Results of the TNT-OES-1 trial.
Authors: van der Zijden Charlène J. , Huizer Tamara J. , Eyck Ben M. , van der Gaast Ate , Van Doorn Leni , Homs Marjolein Y.V. , van Lanschot Jan J.B. , Nuyttens Joost J.M.E. , Oudijk Lindsey , Spaander Manon C.W. , Wijnhoven Bas P.L. , Mostert Bianca , Lagarde Sjoerd M. 
Published: January 2024

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Background: Chemotherapy (FLOT) and chemoradiotherapy (CROSS) are effective as neoadjuvant regimens for esophageal and junction cancer. Total Neoadjuvant Therapy (TNT) aims to increase efficacy by combining chemotherapy with chemoradiotherapy. Although TNT is increasingly used in rectal cancer, there are no data on combining FLOT and CROSS in esophageal cancer. This study aimed to evaluate the feasibility and safety of the FLOT-CROSS combination in esophageal and junction adenocarcinoma patients with oligometastatic disease. Methods: This phase-II study included patients with oligometastatic (a maximum of four lesions in up to two organs, excluding lymph nodes) esophageal adenocarcinoma. Patients were treated with four biweekly cycles of FLOT. Response was evaluated by CT-scan 4-6 weeks after completion of FLOT. If patients showed regression or stable disease (SD) based on RECIST criteria (v1.1), they received CROSS. Four to six weeks after completion of CROSS, response was assessed by CT-scan, endoscopy with biopsies and endoscopic ultrasonography. The multidisciplinary tumor board discussed whether patients could proceed to four additional cycles of FLOT or local therapy of metastases and/or esophagectomy. Primary endpoint was tolerability of FLOT-CROSS, defined as the proportion completing the full regimens. Secondary endpoints included disease control rate (DCR), objective response rate, toxicity and the proportion proceeding to local therapy of metastases and/or esophagectomy. Results: Twenty patients were included, the majority was male (85%) with a median age of 62.5 years (interquartile range 58-66) Most patients (80%) had a single metastatic lesion. 14 of 20 patients (70%) successfully completed the FLOT regimen, four are still in therapy and two patients died. Eleven of 14 patients completed FLOT-CROSS and three patients showed disease progression following FLOT. Toxicity mainly consisted of grade 1-2 leukopenia/neutropenia during FLOT, leading to treatment delay in seven patients. One patient had malaise grade 2. No grade 3-4 toxicities or treatment delays/discontinuations occurred during CROSS. Following FLOT-CROSS, seven patients underwent four additional cycles of FLOT. Six patients underwent esophagectomy and two of those also underwent local treatment of metastases. A pathologically complete response was seen in two of these six patients (33%). Three of seven patients had a clinically complete response and opted for active surveillance after shared decision making. Three months after completion of FLOT-CROSS, the DCR was 82%. Conclusions: This study showed that sequencing FLOT-CROSS in patients with oligometastatic esophageal adenocarcinoma is feasible and comes with manageable toxicity. We saw promising efficacy, with 82% having disease control three months after FLOT-CROSS. Survival data are expected mid-2024. Clinical trial information: NL9269 .