Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial

• Published in: Annals of oncology Vol. 31; no. 2; pp. 236 - 245
• Main Authors: Barbour, A.P., Walpole, E.T., Mai, G.T., Barnes, E.H., Watson, D.I., Ackland, S.P., Martin, J.M., Burge, M., Finch, R., Karapetis, C.S., Shannon, J., Nott, L.M., Varma, S., Marx, G., Falk, G.L., Gebski, V., Oostendorp, M., Wilson, K., Thomas, J., Lampe, G., Zalcberg, J.R., Simes, J., Smithers, B.M., Barbour, A., Walpole, E., Mai, T., Watson, D., Karapetis, C., Barnes, L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2020
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - radiotherapy; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; chemotherapy; Cisplatin - therapeutic use; Docetaxel - therapeutic use; Esophageal Neoplasms - drug therapy; Fluorouracil - therapeutic use; gastro-oesophageal junction adenocarcinoma; Humans; metabolic response; neoadjuvant therapy; Neoplasm Recurrence, Local; oesophageal adenocarcinoma; Positron Emission Tomography Computed Tomography; Treatment Outcome; gastro-oesophageal junction adenocarcinoma; metabolic response; chemotherapy; neoadjuvant therapy; oesophageal adenocarcinoma
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1016/j.annonc.2019.10.019

Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. ACTRN12609000665235. •EMR 5-year survival >50%.•Docetaxel + CF improves histological responses for MNR.•DCF + RT improves survival for MNR.