Randomised phase II trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma (SEED)

Abstract

Background: Chemotherapy is associated with a survival benefit in advanced gastric cancer. Several options exist, including EOX. The regimen docetaxel, cisplatin and 5‐fluorouracil (DCF) is toxic and modifications have been developed. In our institution CTX was a standard treatment from 2004 to 2012 when it was replaced by EOX. Afterwards, a randomised trial with CTX was conducted. Methods: SEED was a prospective, single‐center, phase 2 trial in unresectable HER2‐negative esophagogastric adenocarcinoma. Patients were randomised to either docetaxel 60 mg/m2, carboplatin AUC5 and capecitabine 1000 mg/m2 bd for 14 days q4w (CTX) or epirubicin 50 mg/m2, oxaliplatin 130 mg/m2 and capecitabine 625 mg/m2 bd for 21 days q3w (EOX). Treatment continued until progression, intolerance or a maximum of 9 cycles. The primary endpoint was 1‐year‐survival for patients treated with CTX. The trial sought to accept (lower boundary 55%) or reject (higher boundary 40%) CTX for further study without making direct comparisons to EOX. Secondary endpoints included OS, PFS and grade 3/4 toxicities. Results: From 2014 to 2019 a total of 98 patients were randomised (49 in each arm). The median age was 63 (36‐79). Male/female: 79/19; ECOG PS (0/1): 46/52; oesophageal/ GEJ/gastric: 29/44/25; metastatic/non‐metastatic: 96/2. As of 26 April 2019, 85 patients had died. The estimated 1‐year survival was 32% (95% CI 19‐46) for CTX and 39% (95% CI 25‐52) for EOX. The median PFS and OS was 6.2 months (95% CI 5.2‐7.2) and 9.2 months (95% CI 7.2‐11.2), respectively, for CTX, and 5.2 months (95% CI 3.5‐7.0) and 10.2 months (95% CI 7.9‐12.4), respectively, for EOX. Grade 3/4 related toxicities in>5% were neutropenia (78%), febrile neutropenia (25%), diarrhoea (8%) and fatigue (6%) for CTX, and neutropenia (49%), febrile neutropenia (10%), peripheral neuropathy (8%) and nausea (8%) for EOX. There were no treatment‐related deaths. Conclusions: CTX resulted in a 1‐year‐survival rate of 32% and so is rejected for further study. Also, CTX had a high rate of febrile neutropenia. CTX is not recommended for patients with esophagogastric cancer, except selected patients intolerant of other standard therapies, and then only with G‐CSF support.