Background
Chemoradiotherapy (CRT) in oesophageal cancer
Rational for standard chemotherapy agents
Cetuximab and anti-EGFR therapies
Endpoint assessment
Main research question
Methods/Design
Study Design
Participant Eligibility
Inclusion Criteria Patients meeting the following criteria can be included in the trial: |
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1. Histologically confirmed carcinoma of the oesophagus (adenocarcinoma or squamous cell or undifferentiated carcinoma) or Siewert Type 1 tumour of the gastro-oesophageal junction (GOJ) or Siewert Type 2 with no more than 2 cm mucosal extension into the stomach. |
2. Age 18 or over |
3. Have been selected to receive potentially curative definitive CRT by a specialist Upper GI MDT including a designated Upper GI surgeon. |
4. Not suitable for surgery either for medical reasons or through patient choice. |
5. Tumours staged with both endoscopic ultrasound (EUS) and spiral CT scan to be T1-4, N0-1 confirming localised, non-metastatic disease (both within 7 weeks prior to randomisation, but the most recent within 4 weeks). An attempted but failed or contra-indicated EUS is acceptable. Tumours should be staged according to the 6th edition of the American Joint Committee on Cancer's (AJCC) Cancer Staging Manual |
6. Total disease length (primary and lymph nodes) less than or equal to 10 cm defined by EUS or CT if EUS attempted but failed or contra-indicated. |
7. WHO Performance status 0-1 |
8. Adequate cardiovascular function for safe delivery of CRT in the opinion of the principal investigator |
9. Adequate respiratory function for safe delivery of CRT in the opinion of the Principal Investigator |
10. Adequate bone marrow and hepatic function (within 1 week prior to randomisation): |
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L |
• White blood cell count ≥ 3 × 109/L |
• Platelets ≥ 100 × 109/L |
• Haemoglobin (Hb) ≥ 10 g/dL (patients' Hb should be corrected to > 10 g/dl before treatment) |
• Adequate liver function (within 1 week prior to randomisation) |
• Serum bilirubin ≤ 1.5× ULN |
• ALT/AST ≤ 2.5× ULN |
• ALP ≤ 3× ULN |
11. Adequate renal function (within 1 week prior to randomisation): Glomerular filtration rate (GFR) assessed by EDTA clearance to be > 40 mL/min (or estimated by Cockcroft-Gault formula to be > 60 mL/min) |
12. Patients who are fit to receive all protocol treatment. |
13. Patients who are able and willing to administer capecitabine. |
14. Patients who are of child bearing age are willing to use contraception. |
15. Patients who have completed baseline quality of life questionnaires |
16. Patients who have provided written informed consent prior to randomisation |
Exclusion Criteria
If any of the following criteria apply, patients cannot be included in the trial: |
1. Patients who have had previous treatment for invasive oesophageal carcinoma or gastro-oesophageal junction carcinoma (not including PDT or laser therapy for high grade dysplasia/carcinoma in-situ). |
2. Patients with metastatic disease i.e. M1a or M1b according to UICC TNM version 6. |
3. Patients with any previous treatment for malignancy which will compromise ability to deliver definitive mediastinal CRT or may compromise survival (does not include patients with squamous cell carcinoma). |
4. Patients who have had a previous malignancy during the previous 5 years |
5. Patients with significant (> 2 cm) extension of tumour into the stomach |
6. Patients with unstable angina or uncontrolled hypertension or cardiac failure or other clinically significant cardiac disease |
7. Patients who have had major surgery or major trauma in the 4 weeks prior to randomisation. |
8. Patients who have been treated with a monoclonal antibody in the 4 weeks prior to randomisation. |
9. Patients who have been treated with radiotherapy in the 3 months prior to randomisation |
10. Patients who need continued treatment with a contraindicated concomitant medication or therapy |
11. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency |
12. Patients with hearing impairment or sensory-motor neuropathy of WHO grade > 2 |
13. Women who are pregnant |
Sample Size Considerations
Phase II
Phase III
Method of Randomisation
Outcome Measures
Phase II
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Toxicity: will be scored using the NCI CTCAE v3.0 and RTOG late radiation morbidity scoring criteria at baseline, during treatment and at pre-specified time points on follow-up. Serious adverse events will be monitored "real-time" by the Chief Investigator and TMG.
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Feasibility: will be measured through the number of protocol dose modifications and delays.
Phase III
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HRQL: This aspect of the trial aims determine whether cetuximab in addition to CRT:
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◦ improves generic and disease specific aspects of HRQL following treatment than CRT alone. Specific HRQL domains that are expected to be better in the experimental group are: physical and role function, fatigue, dysphagia and eating restrictions
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◦ is associated with poorer HRQL during treatment. Specific HRQL domains that are expected to be worse in the experimental arm include: dyspnoea, skin rashes and diarrhoea.
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Cost effectiveness: A cost-utility analysis of cetuximab in addition to CRT in oesophageal cancer will be performed from the perspective of the UK National Health Service, but with consideration also given to patient and family related costs. The cost-effectiveness will be considered using two time horizons: within trial and lifetime. In order to undertake the latter a decision-analytic model will be developed to assess the costs and effects over the lifetime of patients. The model will be a Markov model and the transition probabilities will be based on parameter estimates derived from the trial (and other sources from within the literature). The within trial component will involve a comparison of the additional costs associated with the use of cetuximab in the treatment regimen ± any changes in resources utilised elsewhere. Costs of cetuximab will be based on discussions with clinicians and finance staff, while other healthcare resources utilised by patients during the study period will be collected via the healthcare resource utilisation log administered during treatment and at follow-up. At each of the 3-4 weekly visits, patients will be asked to indicate whether they have had any contacts with their GP, practice nurse, community nurse or attended hospital either as an outpatient or in-patient. They will be asked whether the contact was connected to their condition or for any other purpose. The involvement of others in providing transport and/or support will also be logged. In addition, they will be asked to indicate the medication they have been taking during the 3-4 week period. Consultations with healthcare professionals will be costed using published sources of unit costs and healthcare resources utilised will be added to the respective treatment costs in each arm. Quality adjusted life years (QALYs) will be derived from survival data generated during the second stage of the trial and from the EQ-5D scores collected at baseline, during treatment and at follow-up. A patient diary will also be used to collect additional data. These data will then be used to populate the lifetime model.
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RTTQA: A detailed QA program will be in place to ensure adherence to the protocol (see RTTQA section below). Major and minor deviations will be collected.
Data collection
Statistical analysis
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Descriptive statistics of the patient characteristics within each treatment group
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A CONSORT flow diagram of enrolment, intervention allocation, and follow-up
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Tables of toxicities at each timepoint (baseline, end of each treatment cycle, then Month 6, 9, 12, 16, 20, 24, 36, 48, 60)
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Treatment compliance during each cycle (in terms of proportions of patients with delay/reduction to CRT) within each treatment group. An exploration of predictors of poor compliance will be performed.