NEOadjuvant Trial in Adenocarcinoma of the oEsophagus and oesophagoGastric Junction International Study (Neo-AEGIS)
- Conditions
- Adenocarcinoma of the OesophagusOesophageal TumoursJunctional TumoursAdenocarcinoma of the Oesophago-gastric JunctionOesophageal Cancer
- Interventions
- Registration Number
- NCT01726452
- Lead Sponsor
- Cancer Trials Ireland
- Brief Summary
This is a multicentre phase III open-labelled, randomised controlled trial. Eligible patients will be randomised in a 1:1 fashion between neoadjuvant and adjuvant chemotherapy (Investigator's choice modified MAGIC (ECF/ECX or EOF/EOX) or FLOT regimen) and surgery or Arm B (CROSS protocol: chemotherapy with radiation therapy and surgery as per multimodal protocol).
Primary Objective:
To evaluate one, two and three year survival of patients treated with resection plus neoadjuvant and adjuvant chemotherapy versus resection plus neoadjuvant chemo radiotherapy.
Secondary Objective(s):
To evaluate the effect of both neoadjuvant regimens on clinical and pathological response rate (in particular relief of dysphagia, improvement in health related quality of life (HRQL), endoscopic regression, and CT-PET evidence of tumour response), tumour regression grade, node-positivity, post-operative pathology, disease-free survival, time to treatment failure, toxicity, post-operative complications and Health Related Quality of Life (HRQL).
Exploratory Objective(s):
Translational Research: The collection of blood and tissue samples for storage in the bio bank for future research.
- Detailed Description
Indication:
Patients with cT2-3 N0-1 M0 adenocarcinoma of the oesophagus or junction, based on clinical, CT-PET, and EUS staging, will be randomised to the modified MAGIC (ECF/ECX or EOF/EOX) or FLOT regimen and chemotherapy regimen versus the CROSS neoadjuvant chemo radiation protocol prior to surgery. Patients will be randomised to either Arm A (modified MAGIC or FLOT chemotherapy only and surgery) or Arm B (CROSS protocol: chemotherapy with radiation therapy and surgery as per multimodal protocol).
Eligible patients will be randomised in a 1:1 fashion between the modified MAGIC or FLOT regimen or the CROSS protocol.
Exploratory Study- Translational Research :
The collection of blood and tissue samples for storage in the bio bank for future research.
Patients enrolled in this trial at the St James's' Hospital site, will be invited to consent to having some of their tissue and blood taken for use in future research studies. Following consent from the patient, tissue biopsy of tumour and/or normal oesophageal tissue will be obtained for research at the same time as that biopsied for histological diagnosis. In addition, tumour and/or normal tissue will also be obtained following surgical resection. Patient blood samples will also be obtained, both before and during treatment. The identification of both tumour and circulating biomarkers will increase knowledge of the molecular mechanism(s) underlying treatment response in oesophageal cancer and may facilitate the identification of biomarkers predicting patient response to treatment.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 377
- Histologically verified adenocarcinoma of the oesophagus or oesophago-gastric junction based on endoscopy (OGD)
- CT-18FDG-PET performed in all patients for disease staging.
- EUS in all patients unless luminal obstruction precludes sensitivity of the test.
- Staging laparoscopy performed at the investigator's discretion for locally advanced AEG II and AEG III tumours .
- Pre-treatment stage cT2-3, N0-3, M0.
- Maximum tumour length should be no more than 8cm (equal to 8 cm is acceptable)
- Male/female patients aged ≥18 years
- ECOG Performance Status 0, 1 or 2 (Appendix F).
- ASA I-II (Appendix F).
- Adequate cardiac function. For all patients, an ejection fraction of > 50% is required. If patients have a known cardiac history (e.g. known ischemic disease, cardiomyopathy) an ejection fraction > 50% and cardiac clearance by a consultant cardiologist for major surgery and cancer therapies is required.
- Adequate respiratory function. Patients should have pulmonary function tests completed with a minimum FEV1 ≥ 1.5L. CPEX acceptable
- Adequate bone marrow function: absolute neutrophil count (ANC) >1.5x109/l; white blood cell count >3x109/l; platelets >100x109/l; haemoglobin (Hb) >9g/dl (can be post-transfusion).
- Adequate renal function: glomerular filtration rate >60ml/minute calculated using the Cockcroft-Gault Formula (Appendix O).
- Adequate liver function: serum bilirubin <1.5x ULN; AST <2.5x ULN and ALP <3x ULN (ULN as per institutional standard).
- Written informed consent must be obtained from the patient before any study-trial specific procedures are performed.
- Women of child-bearing potential and male subjects must agree to use an effective barrier method of contraception for up to 6 months following discontinuation of therapy. Effective contraception is defined as any medically recommended (or combination of methods) as per standard of care.
- Women of childbearing potential must have pregnancy excluded by urine or serum beta-HCG testing within 7 days prior to treatment.
- Tumours of squamous histology.
- Patients with advanced inoperable or metastatic oesophageal, junctional or gastric adenocarcinoma.
- Disease length (total length of tumour plus node) greater than 10cm (up to 10 cm will be allowed) -as measured by any modality or, if appropriate, combination of modalities-, unless in the opinion of the investigator in discussion with national RT lead, it is felt that OAR constraints are likely to be achievable.
- Any prior chemotherapy for gastrointestinal cancer.
- Prior abdominal or thoracic, chest wall or breast radiotherapy.
- Patients who are unfit for surgery or cancer treatments based on cardiac disease.
- Patients with acute systemic infections.
- Patients who are receiving treatment with sorivudine or its chemical related analogues, such as brivudine which is contraindicated with capecitabine and 5-fluorouracil administration.
- Clinical COPD with significant obstructive airways disease classified by FEV1 < 1.5 L or PaO2 less than 9kPa on room air
- Known peripheral neuropathy >Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible).
- Known positive tests for human immunodeficiency virus (HIV) infection, acute or chronic active hepatitis B infection.
- Any other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix)
- Participation in other clinical trials of investigational or marketed agents for the treatment of oesophageal cancer or other diseases within 30 days from registration. UK sites please refer to Group Specific Appendix
- Women who are pregnant or breastfeeding.
- Psychiatric illness/social situations that would limit compliance with study requirements.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description A (Modified MAGIC) OR Arm A: FLOT Cisplatin / Oxaliplatin Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks. A (Modified MAGIC) OR Arm A: FLOT 5 Flourouracil/ Capecitabine Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks. A (Modified MAGIC) OR Arm A: FLOT Docetaxel Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks. B (CROSS) (41.4 Gy/23 fractions) Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive. A (Modified MAGIC) OR Arm A: FLOT Epirubicin Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks. A (Modified MAGIC) OR Arm A: FLOT Oxaliplatin Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks. A (Modified MAGIC) OR Arm A: FLOT Leucovorin Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks. B (CROSS) Paclitaxel Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive. A (Modified MAGIC) OR Arm A: FLOT 5-Fluorouracil Modified MAGIC: The modified MAGIC regimen encompasses 3 cycles of chemotherapy pre-surgery and 3 cycles post-surgery. The regimen is a combination of epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: The FLOT regimen encompasses 8 cycles of chemotherapy in total , 4 cycles of chemotherapy pre-surgery and a further 4 cycles of chemotherapy post-surgery. Each cycle of chemotherapy lasts 14 days/2 weeks. B (CROSS) Carboplatin Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.
- Primary Outcome Measures
Name Time Method Overall survival At end of trial- up to 3 years in follow up Overall survival will be calculated from the date of randomisation and an event registered on the date of death from any cause. Patients lost to follow up, or those with no death recorded on the day the database is frozen, will be censored on the date of last follow up.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (29)
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Addenbrooke's Hospital, Box 279(s4), Cambridge Biomedical Camp, Cambridge, United Kingdom
Karolinska Institutet and Karolinska University Hospital
🇸🇪Stockholm, Sweden
Nottingham City Hospital
🇬🇧Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham, United Kingdom
Centre Hospitalier Régional, Universitaire de Lille 2 Avenue Oscar Lambret, 59000
🇫🇷Lille, France
Beaumont Hospital
🇮🇪Dublin, Ireland
St. James's Hospital
🇮🇪Dublin, Ireland
Imperial College Healthcare NHS Trust St Mary's Hospital
🇬🇧London, United Kingdom
NHS Lothian, Edinburgh Cancer Centre,
🇬🇧Edinburgh, United Kingdom
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, 1056 Great Western Road, United Kingdom
Portsmouth Hospitals NHS Trust
🇬🇧Southwick Hill Road, Cosham, Hampshire, United Kingdom
Cork University Hospital
🇮🇪Cork, Ireland
Rigshospitalet
🇩🇰Blegdamsvej 9, Denmark
SLRON- St Luke's Radiation Oncology Network
🇮🇪Dublin, Ireland
University Hospital Galway
🇮🇪Galway, Ireland
University Hospitals Coventry & Warwickshire
🇬🇧Clifford Bridge Road, Walsgrave, Coventry, United Kingdom
Hull and East Yorkshire Hospitals NHS Trust, Castle Hill Hospital,
🇬🇧Cottingham, East Riding Of Yorkshire, United Kingdom
Oxford University Hospital NHS Trust Churchill Hospital
🇬🇧Headington, Oxfordshire, United Kingdom
Velindre Cancer Centre
🇬🇧Velindre NHS Trust, Velindre Road, Whitchurch, Cardiff, United Kingdom
Royal Preston Hospital
🇬🇧Sharoe Garoo Lane, Fulwood, Preston, United Kingdom
The Royal Bournemouth Hospital
🇬🇧The Royal Bournemouth And Christchurch Hospitals NHS Foundation, Bournemouth, United Kingdom
Mount Vernon Cancer Centre
🇬🇧E & N Hertfordshire NHS Trust, Rickmansworth Road, Northwood, Middlesex, United Kingdom
University Hospital Southampton NHS Foundation Trust
🇬🇧Southampton General Hospital, Division A Cancer Care, Mp307, T, Southampton, United Kingdom
Royal Surrey County Hospital
🇬🇧Guildford, Surrey, United Kingdom
Worcestershire Royal Hospital
🇬🇧Worcestershire Oncology Centre, Charles Hastings Way, Worcester, United Kingdom
Belfast Health and Social Care Trust, Northern Ireland Cancer Centre, Belfast CityHospital
🇬🇧Belfast, United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust
🇬🇧Birkenhead, Wirral, United Kingdom
University Hospitals Bristol NHS Foundation Trust
🇬🇧Bristol, United Kingdom
University Hospital Plymouth NHS Trust
🇬🇧Derriford Hospital, Derriford Road, Crownhill, Plymouth, United Kingdom
The Newcastle upon Tyne Hospital NHS Foundation TrustFreeman Hospital, Freeman Road, High Heaton
🇬🇧Newcastle upon Tyne, United Kingdom