Multi-centre trials in Orthopaedic Oncology: Dream or Reality?

1. Multi-centre trials in Orthopaedic Oncology:Dream or Reality? Michelle Ghert, MD, FRCSC Associate Professor Department of Surgery McMaster University

2. 22 year-old male with sarcoma right femur

17. Deep infection in total joints • Approximately 1% risk • AAOS guidelines: 24 hours of gram positive coverage with pre-operative dosing

18. Tumour prosthesis: higher risk • Patients are myelo-depleted due to chemotherapy • Surgeries are long and the wound is open for several hours • Large foreign body • Large dead space • Loss of protective soft-tissue coverage

20. What is the magnitude of the problem?

22. Systematic Review • Deep infection rate 9.5% (95% confidence interval: 8.1% to 11%) • Comparison to primary arthroplasty: 1%

25. Systematic Review Conclusions • The risk for deep infection following tumour prosthesis is high, X10 that of total joints • Antibiotic regimens vary from publication to publication • There no published guidelines to direct management

26. What antibiotic regimens do we use?

28. Duration of antibiotics

29. Results

30. PARITY Survey conclusions • Practice patterns vary considerably with respect to antibiotic regimen, dosages and duration • Majority of surgeons are willing to change practice • Overwhelming support for a multi-centre clinical trial

31. Hierarchy of Evidence Randomized Trials Less Bias Level 1 Prospective Cohort Studies Level 2 Level 3 Case Control Studies Level 4 Retrospective Case Series Opinion Level 5 More Bias

32. RCTs in Orthopaedic Oncology • Orthopaedic Oncology multi-center randomized controlled trials: • Radiation Oncology: one trial, 150 patients • Medical Oncology: 72, methodologically poor • Surgical Oncology: NONE • There is a lot of talk about RCTs in Orthopaedic Oncology, but no doing

33. Why do we need multi-centre trials?

34. Tibial Shaft Fractures (SPRINT)

35. Multicenter RCT’s • Advantages • Level 1 Evidence • more centers = More Patients • shorter study recruitment time • increased generalizability of results • collaboration between centers, countries and continents

36. Multicenter RCT’s • Disadvantages • They are Hard to Do • Complex organization • Very Expensive

37. But not impossible…. • Cardiology • OASIS-6 RCT • 13000 pts (JAMA, 2006) • 447 hospitals • 41 countries

38. But not impossible…. • Intensive Care Medicine • PROTECT (DVT prophylaxis) • Canadian Critical Care Trials Group • 4000 pts • North America/Australia

39. But not impossible… • Neonatal Medicine • Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. • N=910 infants • 32 centers • NA, Austalia, NZ, China • JAMA. 2003

40. Has it been done in Orthopaedic Surgery? • SPRINT Trial (Tibial Shaft Fractures) • 1339 patients recruited, 95% F/U

42. Challenges in Surgical Trials

43. Can Surgeons be Blinded?

44. Who can be blinded?Patient and outcome assessors

45. Expertise Bias

46. Expertise Bias • Surgeons tend to stick to procedures that they are good at • Difficult to convince surgeons to develop new techniques • Solution: patients are allocated to provider, not procedure

47. But can it be done anyways?

48. Center for Evidence-Based Orthopaedics

49. SPRINT trial: 1339 patients, 95% follow-up • FLOW trial: 2200 patients recruited, target 2200 • FAITH trial: 900 patients, target 1000 • TRUST trial: 600 patients, target 1000 • HEALTH trial: 350 patients, target 1400 • INORMUS and PRAISE prospective studies: 9000 patients • All trials are funded by NIH/CIHR • 150 centers around the world