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Background

Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer: The REAL 2 Trial.

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Background

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  1. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer: The REAL 2 Trial D Cunningham, S Rao, N Starling, T Iveson, M Nicolson, F Coxon, G Middleton, F Daniel, J Oates, AR Norman et al on behalf of the NCRI Upper GI Study Group, UK

  2. Background • ECF is widely used in the UK/Europe for the treatment of advanced oesophagogastric cancer • Activity has been demonstrated in 2 randomised trials involving 800 patients with advanced oesophago-gastric cancer1-3 • Associated with response rates of ~40%, median overall survival of ~9 months and one year survival of ~35% • Addition of anthracycline to CF in gastric cancer supported by Cochrane meta-analysis4 1Webb A, et al. J Clin Oncol 1997;15:261–7;2Waters JS, et al. Br J Cancer1999;80:269–72 1997; 3Ross et al. J Clin Oncol 2002;20:1996–20044Wagner et al. Cochrane Database Syst Rev 2005:2; CD004064

  3. REAL-2 study design UK NCRI cooperative group study 63 centres: mostly UK, 2 Australian Epirubicin Cisplatin 5-FU RANDOMISATION Patients with locally advanced or metastatic oesophago-gastric cancer(chemonaive) Epirubicin Cisplatin Xeloda (capecitabine) Epirubicin Oxaliplatin 5-FU Epirubicin Oxaliplatin Xeloda(capecitabine) Stratified for: - Centre - Locally advanced versus metastatic - PS 0/1 versus 2

  4. June 2000 Phase II pilot study 4 centres n=80 Oct 2001 Planned interim analysis1 Protocol planned capecitabine dose escalation* *X dose escalated: 500 mg/m2 bd 625 mg/m2 bd in X containing arms Planned 2nd interim analysis - dose escalation confirmed (n=204)1 Oct 2002 Continued accrual to 600 patients 2003-2005 Increased accrual to 1000 patients 1Sumpter et al BJC 92(11): 1976-83

  5. E E C C F X REAL 2: 2 x 2 randomisation Epirubicin 50 mg/m2 iv Cisplatin 60 mg/m2 iv Capecitabine 625 mg/m2/bd q 3 weeks Epirubicin 50 mg/m2 iv Cisplatin 60 mg/m2 iv PVI 5-FU 200 mg/m2/d* q 3 weeks E E Epirubicin 50 mg/m2 iv Oxaliplatin 130 mg/m2 ivPVI 5-FU 200 mg/m2/d* q 3 weeks Epirubicin 50 mg/m2 iv Oxaliplatin 130 mg/m2 ivCapecitabine 625 mg/m2/bd q 3 weeks O O F X Planned treatment duration 24 weeks (8 cycles) CT scan baseline, 12 weeks and 24 weeks * PVI 5FU delivered by central venous access catheter

  6. Primary Endpoints • Overall survival, non-inferiority: 1) Capecitabine over PVI 5-FU (ECX + EOX versus ECF+ EOF ) 2) Oxaliplatin over Cisplatin (EOF + EOX versus ECF + ECX) - 80% power to demonstrate non-inferiority (1 sided a 0.05) based on a one year survival for ECF of 35% required 1000 patients (250 per arm) - Upper limit of hazard ratio for experimental arms compared to standard arm should be less than 1.23 • Overall survival between the four regimens

  7. Secondary endpoints • Progression free survival • Overall response rates • Toxicity (CTC version 2.0) • Quality of Life (EORTC QLQ-C30)

  8. Eligibility criteria • Adeno-, squamous or undifferentiated carcinoma • Oesophagus, gastroesophageal junction or stomach • Metastatic or locally advanced disease • Chemonaive (including adjuvant) • No prior radiotherapy other than adjuvant where relapse is outside the radiotherapy field • Uni-dimensionally measurable disease • Age > 18 years • ECOG 0-2 • Adequate haematological and biochemical parameters • Adequate cardiac function • Written informed consent

  9. Analysis Populations Total Randomised Intention to Treat Population (ITT) n=1002 ECFn=263 ITT ECXn= 250 ITT EOFn=245 ITT EOXn=244 ITT Ineligible/ Withdrawn* n= 14 Ineligible/ Withdrawn* n= 9 Ineligible/ Withdrawn* n= 10 Ineligible/ Withdrawn* n= 5 Per protocol population n= 249 Per protocol population n= 241 Per protocol population n= 235 Per protocol population n= 239 Per Protocol Population (PPP) n= 964 * Withdrawn prior to receiving any treatment

  10. Patient Demographics (PPP)

  11. Events • Median duration of follow-up is 17.1 months for all patients • There have been 850 events in the whole cohort • The 60-day all-cause mortality is similar between arms

  12. Administration of study treatment

  13. Overall Survival (Per-protocol): Fluoropyrimidine comparison HR 0.86 (0.8 – 0.99) HR for ITT population = 0.88 (0.77 – 1.00) p= 0.058

  14. Overall Survival (Per-protocol): Platinum comparison HR 0.92 (0.8 – 1.1) HR for ITT population = 0.91 (0.79-1.04) p=0.159

  15. Multivariate analysis • Factors included in the model • PS, Extent of disease, Age • Factors excluded from the model • Primary site, Gender, Histology Non-Inferiority still maintained

  16. Survival by Regimen (ITT)

  17. Survival by Regimen ECF vs EOX (ITT)

  18. Progression-free survival (ITT)

  19. Best overall Response

  20. Grade 3/4 Haematogical Toxicities * p <0.05 in comparison with ECF ** p<0.01 in comparison with ECF

  21. Non-haematologic Grade 3/4 Toxicities * p <0.05 in comparison with ECF ** p<0.01 in comparison with ECF

  22. Peripheral Neuropathy

  23. Quality of Life • QoL at baseline was balanced between the arms • No differences in QoL scores (p>0.01) between arms for any change from baseline to 12 weeks

  24. Conclusions • The primary objective of the trial was met: • Capecitabine is not inferior to 5-FU • Oxaliplatin is not inferior to Cisplatin • In these triplet regimens • Capecitabine could replace PVI 5-FU • Oxaliplatin could replace Cisplatin • The use of EOX is associated with improved efficacy over ECF

  25. Acknowledgements: Participating Centres Hammersmith Hospital Wexham Park & Heatherwood Hospitals Portsmouth Oncology Centre Wythenshaw Hospital, Manchester Queen Elizabeth Hospital, Kings Lynn Clatterbridge Centre for Oncology Royal Devon & Exeter Hospital Beatson Oncology Centre, Glasgow Birmingham Heartlands Hospital Charing Cross Hospital, London Leicester Royal Infirmary Worthing Hospital Nottingham City Hospital Princess Royal Hospital, Hull Royal Cornwall Hospital Huddersfield RoyalInfirmary Queen Elizabeth Hospital, Adelaide Australia Ipswich Hospital Guys Hospital, London Airedale Hosp, Yorkshire North Devon District Hospital Warrington Hospital, Cheshire The University Hospital, Aintree Hospital Western General Hospital, Edinburgh Ninewells Hospital, Dundee Bradford Royal Infirmary Manor Hospital, Walsall Russells Hall Hospital, Dudley The Middlesex Hosp, London Flinders Medical Centre, Australia St Bartholomews & the London Hospitals, London Northampton Centre for Oncology Hospital Hairmyres Hospital, E Kilbride Derby Royal Infirmary Southport & Formby District General Hospital West Suffolk Hospital Dorset County Hospital, Dorchester Royal Marsden Hospital, Surrey/London Northern Centre for Cancer Treatment, Newcastle Dorset Cancer Centre, Bournemouth/Poole Southampton General & Salisbury District Hospitals St Lukes Cancer Centre, Guildford Aberdeen Royal Infirmary Ysbyty Gwynedd Hospital, Bangor James Cook Hospital, Middlesborough Velindre Hospital, Wales Plymouth Oncology Centre, Derriford Hospital North Middlesex Hospital, London St Georges Hospital, London Kent Oncology Centre, Maidstone Mount Vernon Hospital, Watford Glan Clwyd Hosp, Rhyl Broomfield Hospital, Chelmsford Weston Park Hospital, Sheffield Princess Alexandra Hospital, Harlow Addenbrookes Hospital, Cambridge Christie Hospital, Manchester Churchill Hospital, Oxford Peterborough District Hospital Southend Hospital Sussex Oncology Centre, Brighton The study was supported by Hoffman-La Roche and Sanofi-Aventis

  26. And finally….. Thanks to all the patients who participated in this trial

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