Combination of chemoTherapy aNd chemoradioTherapy for adenocarcinoma of the OESophagus and gastro-oesophageal junction with oligometastatic disease

Rationale: Metastatic adenocarcinoma of the oesophagus or gastro-oesophageal junction (GOJ) has a dismal prognosis and is associated with a poor quality of life (QoL), mainly due to locoregional complaints such as dysphagia and odynophagia. The recently published FLOT3-study showed that in selected patients with limited metastatic disease, induction chemotherapy followed by surgery may prolong survival. Furthermore, in the (potentially) curatively treated patients, chemotherapy (CT), consisting of a combination of Fluorouracil, Leucovorin, Oxaliplatin and doceTaxel (FLOT) is currently a standard of care as peri-operative treatment for adenocarcinomas of the stomach and GOJ. On the other hand, neoadjuvant chemoradiation (CRT) according to the CROSS regimen improves locoregional control, QoL and survival in patients with resectable oesophageal and GOJ tumours. After CRT, 23% of patients have a pathologically complete response (pCR). The combination of systemic CT (FLOT) with mainly locoregional acting CRT (CROSS) is an attractive treatment option for patients with limited metastatic disease, aiming for better survival, but also better locoregional control and thus improved QoL. It is currently unknown however whether FLOT CT can be safely combined with CROSS CRT. This phase II study investigates the safety and feasibility of the combined, sequenced regimen.

Objective: To assess the safety and feasibility of a multimodal combination of FLOT CT with CROSS CRT.

Study design: Phase II, prospective single-centre intervention study

Study population: Patients aged 18-75 years old with resectable adenocarcinoma of the oesophagus or GOJ with limited distant metastatic disease (e.g. retroperitoneal or supraclavicular lymph node metastases, limited visceral metastases).

Intervention: In total 20 patients will be included. All patients will start with four courses of FLOT in 2-week cycles. Patients with progressive disease will be excluded from further study and treated according to the decision of the multidisciplinary tumour board. Patients with stable or regressive disease will continue with CROSS CRT (weekly administration of five cycles of carboplatin and paclitaxel with concurrent radiotherapy). After this time-point in the study, further treatment, if any, is determined in our multidisciplinary tumour board according to guidelines and institutional practice and not by the study protocol. The options include best supportive care, continuation of chemotherapy and treatment of the primary tumour and/or metastases (by local ablative therapies and/or surgery).

Main study parameters/endpoints: Primary endpoint is the tolerability of the combined regimens (defined as the number of patients that complete the administration of four cycles of FLOT CT and the full CROSS CRT regimen). Secondary outcomes are the number of patients that have progressive disease after four cycles of FLOT CT, disease control rate (DCR) and objective response rate (ORR), both according to RECIST 1.1, serious adverse events and adverse events according to Common Terminology Criteria for Adverse Events (CTCae) v4.0, cumulative administered dose of FLOT and number of cycles of carboplatin/paclitaxel administered as part of CROSS CRT, progression free survival [PFS], overall survival [OS], number of patients with a clinically complete response, QoL, the number of patients proceeding to local therapy of distant metastases and/or oesophagectomy.

We hypothesize that it is feasible and safe to test the proposed FLOT-CROSS in a planned future phase III trial, defined as a success rate or at least 40% (success defined as completion of all four FLOT chemotherapy cycles and all CROSS CRT sessions).

In the first stage, 11 patients will be accrued. If there are 3 or fewer successes in these 11 patients, the study will be stopped (success defined as completion of all four FLOT cycles and all CROSS CRT sessions). Otherwise, 9 additional patients will be accrued for a total of 20.

The combination of two standard-used regimens consisting of CRT (CROSS) with CT (FLOT) is studied. A first clinical response evaluation (CRE-1) will take place 4-6 weeks after the last CT cycle using CTneck/chest/abdomen. Only patients who have stable disease or regression of disease according to RECIST criteria, will be eligible for continuation in the study. A second clinical response evaluation (CRE-2) will take place 4-6 weeks after the last CRT session using a combination of endoscopy with bite-on-bite biopsies, EUS-FNA of suspected lymph nodes and CTneck/chest/abdomen. The on-study treatment stops for all patients after CRE-2. After this timepoint in the study, further treatment decisions are made in our multidisciplinary tumour board.

Chemotherapy:

Patients receive chemotherapy according to the FLOT4 regimen, starting with 4 courses according to the standard schedule:
1.Docetaxel (50 mg/m2) in 250 ml NaCl 0.9% i.v. for 1 h, d1
2.Oxaliplatin (85 mg/m2) in 500 ml G5% i.v. for 2 h, d1
3. Leucovorin (200 mg/m2) in 250 ml NaCl 0.9% for 1 h, d1
4. 5-FU (2600 mg/m2) continuous infusion for 24 h, d
Repeated every two weeks (q2w), following the treatment schedule.

Chemoradiotherapy:

Patients receive chemoradiation according to the CROSS regimen, which consists of weekly administration of five cycles of CT (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m2] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week). Chemoradiation will start no earlier than 4 weeks but within 8 weeks after the last FLOT cycle.