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

A. P. Barbour, E. T. Walpole, G. T. Mai, E. H. Barnes, D. I. Watson, S. P. Ackland, J. M. Martin, M. Burge, R. Finch, C. S. Karapetis, J. Shannon, L. M. Nott, S. Varma, G. Marx, G. L. Falk, V. Gebski, M. Oostendorp, K. Wilson, J. Thomas, G. LampeJ. R. Zalcberg, J. Simes, B. M. Smithers, A. Barbour, E. Walpole, T. Mai, D. I. Watson, C. S. Karapetis, L. Barnes

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Abstract

Background: 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 and methods: 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). Results: 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. Conclusions: 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. Trial registration: ACTRN12609000665235.

Original languageEnglish
Pages (from-to)236-245
Number of pages10
JournalAnnals of Oncology
Volume31
Issue number2
DOIs
Publication statusPublished - Feb 2020

Keywords

  • chemotherapy
  • gastro-oesophageal junction adenocarcinoma
  • metabolic response
  • neoadjuvant therapy
  • oesophageal adenocarcinoma

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    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., ... Barnes, L. (2020). 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. Annals of Oncology, 31(2), 236-245. https://doi.org/10.1016/j.annonc.2019.10.019