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

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 ¼ 31) or DCF þ 45 Gy radiotherapy (DCFRT, n ¼ 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.

Treatment outcome after radiochemotherapy in anal cancer patients staged with 18F-FDG-PET-CT

“…While most published studies used FDG-PET for baseline assessment of disease, there is a strong rationale to assume that changes of functional imaging parameters during radiotherapy might be a stronger predictor of outcome than baseline parameters. This has already been proven in studies for other gastrointestinal primaries such as the rectum or the esophagus [32][33]. For instance, in a multicenter study of patients with esophageal carcinoma treated with neoadjuvant chemotherapy and subsequent radiochemotherapy, PET/CT after the first chemotherapy cycle was conducted.…”

Response rate and diagnostic accuracy of early PET‐CT during neo‐adjuvant therapies in oesophageal adenocarcinoma: A systematic review and meta‐analysis

“…All patients had gastro‐oesophageal adenocarcinoma. Three studies 27,28,30 used neo‐adjuvant chemotherapy alone prior to surgery, one 29 used neo‐adjuvant chemoradiotherapy and two 14,31 used initial neo‐adjuvant chemotherapy followed by radiotherapy in metabolic non‐responders (Table 2). In total, 20/519 (3.9%) of patients progressed during neo‐adjuvant therapy and were no longer eligible for surgery.…”

“…Study sample size was not associated with the primary outcome ( P = .4583). The largest study was Barbour et al 14 with 107 patients resected, the smallest was Malik et al 29 with 37 patients resected. There was significant heterogeneity between studies ( I 2 69.1%, P = .012).…”

“…The decision to alter neo‐adjuvant therapy based on an early assessment may differentiate metabolic responders from non‐responders; the latter group could potentially be offered an alternative neo‐adjuvant therapy or simply omit the remaining cycles and proceed straight to surgery, thereby reducing the exposure to potential side‐effects of chemotherapy with or without radiotherapy and reducing the chance of progression during the interval before surgery. Several recent large‐scale interventional trials have used a PET‐directed therapy approach 14,15 …”

Biomarkers for Precision Treatment in Gastric Cancer

“…Recently, a phase 2 multicenter trial evaluated 18-FDG-PET scan after 1 cycle of doublet chemotherapy in patients with resectable gastroesophageal tumors [58]. Patients showing a metabolic response (according to the MUNICON criteria) [56] received another cycle of doublet chemotherapy followed by surgery, whereas patients without a metabolic response were randomized to receiving 2 cycles of triplet chemotherapy or concomitant triplet chemotherapy plus radiotherapy, either followed by surgery.…”