A randomised Phase II/III trial to study radiotherapy dose escalation in patients with oesophageal cancer treated with definitive chemo-radiation with an embedded Phase II trial for patients with a poor early response using positron emission tomography (PET)

INTERVENTION: Product Name: Capecitabine Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: capecitabine CAS Number: 154361509 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 150‐500 Product Name: Paclitaxel Pharmaceutical Form: Concentrate and solvent for concentrate for solution for infusion INN or Proposed INN: Paclitaxel CAS Number: 33069‐62‐4 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 6‐ Product Name: Carboplatin Pharmaceutical Form: Product Name: Cisplatin Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Cisplatin CAS Number: 15663‐27‐1 Other descriptive name: cis diamminedi‐ chloroplatinum (II) Concentration unit: mg/m2 milligram(s)/square meter Concentration type: equal Concentration number: 60‐ Product Name: Fluorouracil Pharmaceutical Form: Solution for injection/infusion INN or Proposed INN: 5 Fluorouracil CAS Number: 51‐21‐8 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: equal Concentration number: 200‐ CONDITION: Non operable oesophageal cancer patients ; MedDRA version: 19.1 Level: LLT Classification code 10030151 Term: Oesophageal cancer System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04] SECONDARY OUTCOME: Secondary end point(s): 1. Do participants receiving high dose radiotherapy live longer without the disease (progression free survival (PFS) rate)? PFS will be assessed during the follow‐up visits. Suspected disease progression will be confirmed by CT/endoscopic assessment. This information will be collected on the trial CRFs. ; 2. Do participants that do not respond to early chemotherapy treatment live longer without their disease if they switch to a different chemotherapy regimen? PFS will be assessed during the follow‐up visits. Suspected disease progression will be confirmed by CT/endoscopic assessment. This information will be collected on the trial CRFs.; 3. Is it safe to deliver high dose radiotherapy in this patient group? We will assess this by carefully monitoring any side‐effects that the patients have and grading them according to a very specific set of toxicity criteria; the NCI Common Terminology Criteria for Adverse Events. Patients receiving the higher dose of radiotherapy will have additional assessments after radiotherapy to monitor toxicities. The toxicity profile between the two different chemotherapy regiments received by the PET non‐responders will also be compared.; 4. Do patients receiving high dose radiotherapy have a reduced quality of life? It is expected that although a high dose of radiography may lead to better disease control, increased toxicity and side effects (and poorer quality of HRQL) maybe experienced during treatment. We will answer this question by looking at questionnaires (EORTC QLQ‐C30 and EORTC QLQ‐OES18) completed throughout the trial by trial participants.; 5. Has the trial protocol been followed in this trial? The study aims to look at how well the patient has followed the protocol (treatment compliance). This will be assessed across all trial arms by looking at protocol deviations noted by the site and those raised by QC checks. ; 6. Is it cost effective to treat patient with high dose radiotherapy relative to the health benefits (if any)? Is it cost effective to switch to a non‐standard chemotherapy regimen in patients who do not respond to standard chemotherapy (as defined by the day 14 PET scan)? We will answer this question by looking at questionnaires (EQ‐5D and health utilisation log) completed by trial participants.; 7. Can we use blood and tissue samples to tailor patient treatment and predict patient outcomes in future? Samples will be collected from consenting patients and will used to answer these research questions as part of the T‐SCOPE2 sub study.; 8. Do patients with different types of oesophageal cancers (adenocarcinoma and squamous cell carcinoma) respond differently to a) an increase in radiotherapy dose and b) a change in chemotherapy regimen? This will be assessed towards the end of the trial.; 9. Can a special CT scan (4D CT) be used to help account for breathing movement during radiotherapy? This will only been done at certain sites. ; 10. We would like to know more about the patients’ experienced of being on the different trial arms and how they felt about the trial. A proportion of patients will be invited to take part in interviews as part of the optional embedded qualitative study described in more detail in section A11.; ; ; Timepoint(s) of evaluation of this end point: Overall survival and progression free survival: this will be assessed at each visit. Patients will be flagged using HSCIC. ; ; Safety: SAEs and toxicities will be presented to the IDMC for a recommendation as to whether or not to continue the trial after 40 patients have completed trial treatment. Toxicity will be measured using the CTCAE V4 at baseline, after each treatment cycle, and follow up visits. Patients in the dose escalation arm will have additional assessments post RT to monitor toxicities. ; ; Quality of Life assessment will be captured through the EORTC QLQ‐C30 and EORTC QLQ‐OES18 questionnaires administered at baseline, at the end of treatment, and at 6, 12 and 24 months.; ; Health economic data will be collected using EQ‐5D plus data on health resource usage. INCLUSION CRITERIA: 1.17 years of age or older. 2.Have been selected to receive potentially curative definitive chemoradiotherapy by a specialist Upper GI MDT. 3.Histologically confirmed adenocarcinoma, undifferentiated cancer or squamous cell carcinoma. 4.Tumours of the cervical, thoracic oesophagus, or gastro‐oesophageal junction (GOJ) with proximal extent of disease no more proximal than 15cm aboral and distal extent of primary tumour no more than 2 cm beyond the GOJ. 5. Tumours staged with spiral CT scan, PET‐CT with/without endoscopic ultrasound (EUS), to be T1‐4, N‐/+ (provided total tumour length including nodes is =10). To be eligible for PET randomisation, the PET‐CT must be within 4 weeks of start date of treatment. 6. Total contiguous disease length =10cm defined by CT, EUS and/or PET. This includes =8cm primary tumour plus nodes within 2cm. 7. WHO performance status 0 or 1. 8. Adequate haematological, renal, respiratory, cardiac and hepatic func PRIMARY OUTCOME: Main Objective: There are two principal research questions within this trial. Firstly, is it effective and safe to treat oesophageal cancer patients presenting with either adenocarcinoma, undifferentiated or squamous cell carcinoma, with an elevated dose of radiotherapy? Secondly, would patients that do not respond to initial chemotherapy treatment with the standard regiment (capecitabine and cisplatin) benefit from switching to a different chemotherapy regiment (carboplatin and paclitaxel)? ; ; Primary end point(s): There are two principal research questions within this trial. Firstly, is it effective to treat oesophageal cancer patients presenting with either adenocarcinoma, undifferentiated or squamous cell carcinoma, with an elevated dose of radiotherapy? ; ; Secondly, would patients that do not respond to initial standard chemotherapy treatment (capecitabine and cisplatin) benefit from switching to a different chemotherapy regiment (carboplatin and paclitaxel)? ; ; This will be assessed by looking at the proportion of patients that do not show any evidence of remaining tumour on the 24 week CT scan and endoscopic assessment between a) the 50/60Gy radiotherapy arms, ; b) the two different chemotherapy arms (standard chemo of capecitabine+cisplatin vs alternative regimen of paclitaxel+carboplatin) within the PET non‐responders group. The PET non‐responders group refer to the group of patients that do not show a response to early standard chemotherapy treatment as determined by the 14 day PET scan.; ; Based on the outcome of the phase II data, the 50/60Gy radiotherapy arms will progress into a phase III study. This part of the study will compare the overall survival of patients receiving 50 and 60Gy of radiotherapy. ; ; As a lower percentage of patients with adenocarcinoma are expected to be recruited into the trial in comparison to patients having squamous cell carcinoma, the phase III part of the trial will recruit patients with squamous cell carcinoma only. ; Secondary Objective: The secondary research questions will be;; 1. Do participants receiving high dose radiotherapy live longer without the disease? ; 2. Do participants that do not respond to early chemotherapy treatment live longer without their disease if they switch to a different chemotherapy regimen?; 3. Is it safe to deliver high dose radiotherapy in this patient group? We will assess this by carefully monitoring any side‐effects that the patients have and grading them according to a very specific set of toxicity criteria.; 4. Do patients receiving high dose radiotherapy have a reduced quality of life? It is expected that although a high dose of radiography may lead to better disease control, increased toxicity and side effects (and poorer quality of HRQL) maybe experienced during treatment. We will answer this question by looking at questionnaires (EORTC QLQ‐C30 and EORTC QLQ‐OES18) completed by trial participants.; 5. Has the trial protocol been followed in this trial? The study aims to look a Timepoint(s) of evaluation of this end point: Both research questions will be assessed by looking at the 24 week treatment failure free survival and overall survival which will be assessed at each visit.