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 Table 2: Length of Time Prophylactic Antibiotics Prescribed Following Long-bone Reconstruction Type of Reconstruction24 hrs48 hrs3-7 daysUntil Suction Drain Removed Tumor prosthesis25 (35.7%)13 (18.6%)3 (4.3%)29 (41.4%) Allograft18 (26.5%)13 (19.1%)11 (16.2%)26 (38.2%) Allograft-prosthesis composite17 (25.4%)12 (17.9%)9 (13.4%)29 (43.3%)

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 Prospective Cohort Studies Retrospective Case Series Case Control Studies Opinion Level 1 Level 2 Level 3 Level 4 Level 5 Less Bias 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. 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

51. PARITY Objective: To evaluate the efficacy of short- vs. long-term post-operative prophylactic antibiotic regimens on the incidence of deep infection following endoprosthetic reconstruction of lower extremity bone tumors

52. Study Design PARITY is a multi-center randomized controlled trial using a parallel two- arm design

53. Patient screened and eligible and provides informed consent Randomization Standard pre-op and intra-op antibiotics AND 24 hours post op antibiotics Standard pre-op and intra-op antibiotics AND 5 days post op antibiotics Follow-up one year

54. Eligibility Criteria Lower extremity tumour prosthesis Skeletal maturity Primary bone malignancy or benign aggressive tumor

55. Exclusion Criteria MRSA or VRE colonization Allergy to PCN or Ancef® [cefazolin] Previous local surgery (excluding biopsy) Previous local infection Systemic infection

56. Randomization 24-hour computer randomization (www.randomize.net) Pharmacist will randomize patient Stratified based on center and tumor location (femur or tibia)

60. Blinding Patients, nurses, research staff, surgeons and central adjudication committee (CAC) blinded Only pharmacist will be aware of treatment allocation

61. Primary outcome and adjudication Deep infection as defined by CDC 1992 Within one year of surgical implantation CAC: 2 Orthopaedic Surgeons and 1 Infectious Disease specialist Global Adjudicator Platform™

62. Secondary Outcomes MSTS-87 and -93 TESS Antibiotic-related complications

64. Data Management

65. STEERING COMMITTEE Overall responsibility for the trial CENTRAL ADJUDICATION COMMITTEE Review and classification of all clinical events DATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harm METHODS AND COORDINATING CENTRE Data management, daily conduct of the trial PARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocol PARITY Trial Organization Center for Evidence-Based Orthopaedics

66. Steering Committee Dr. Michelle Ghert (McMaster University) Dr. Ben Deheshi (McMaster University) Dr. Mohit Bhandari (McMaster University) Dr. Tim O’Shea (McMaster University) Dr. Jay Wunder (University of Toronto) Dr. Lor Randall (Huntsman Cancer Institute, Utah) Dr. Lehana Thabane (McMaster University) Dr. Ginger Holt (Vanderbilt University) Dr. Gordon Guyatt (McMaster University)

67. STEERING COMMITTEE Overall responsibility for the trial CENTRAL ADJUDICATION COMMITTEE Review and classification of all clinical events DATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harm METHODS AND COORDINATING CENTRE Data management, daily conduct of the trial PARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocol PARITY Trial Organization Center for Evidence-Based Orthopaedics

68. Central Adjudication Committee Dr. Ben Deheshi (McMaster University) Dr. Michelle Ghert (McMaster University) Dr. Tim O’Shea (McMaster University) Dr. Lor Randall (Huntsman Cancer Institute, Utah)

69. STEERING COMMITTEE Overall responsibility for the trial CENTRAL ADJUDICATION COMMITTEE Review and classification of all clinical events DATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harm METHODS AND COORDINATING CENTRE Data management, daily conduct of the trial PARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocol PARITY Trial Organization Center for Evidence-Based Orthopaedics

70. Data Safety Monitoring Board Dr. Peter Rose, Chair (Mayo Clinic) Dr. Brian Brigman (Duke University Medical Center) Dr. Vikram Venkateswaran (Georgetown, Ontario)

71. Power analysis Infection rate mean 9.5% Superiority of long-term antibiotics: threshold of 5% for inferiority Alpha 5%, Power 80% 431 patients per arm (862 total) Estimated sample size of 908 to account for 5% loss to follow-up, errors, drop-out etc

72. – 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

73. Pilot: Feasibility Assess recruitment – 10% of definite trial: 100 patients in 12 months Maintain follow-up (95%) and data quality Assess ability to accurately use internet-based randomization system Ensure compliance

74. Funding Orthopaedic Research & Education Foundation: PARITY has been awarded an OREF/MSTS Clinical Research Grant in Orthopaedic Oncology. PSI Foundation: PARITY has also received funding from the Physicians’ Services Incorporated Foundation Private Donation: Sarcoma Fund Canadian Cancer Society Research Institute Innovation Grant

75. Active Sites (O7 Feb 2013) Canada *Juravinski Hospital & Cancer Centre, Hamilton, Ontario, Canada *Mount Sinai Hospital, Toronto, Ontario, Canada *Ottawa Hospital, Ottawa, Ontario, Canada *McGill University Health Centre, Montreal, Quebec, Canada *Hopital Maisonneuve Rosemont, Montreal, Quebec, Canada François d’Assise et L’Hotel-Dieu de Quebec, Quebec City, Quebec, Canada *Vancouver General Hospital, Vancouver, British Columbia, Canada USA *Vanderbilt Medical Centre, Nashville, Tennessee, USA Beth Israel Deaconess Medical Centre, Boston, Massachusetts, USA Boston Children’s Hospital, Boston, Massachusetts, USA *Huntsman Cancer Institute, Salt Lake City, Utah, USA Memorial Sloan-Kettering Cancer Centre, Cornell, New York, USA UK The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK The Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK The Robert Jones Agnes Hunt Hospital NHS Foundation Trust, Oswestry, UK Oxford University Hospital NHS Trust (Nuffield Orthopaedic Centre), Oxford UK The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle UK Argentina Hospital Universitario Austral, Beuonos Aires, Argentina *actively enrolling Interested sites Canada Halifax USA Albany Medical College, Albany, New York, USA Menorah Medical Center and Mid American Sarcoma Institute, Overland Park, Kansas, USA Marshall University, Huntington, West Virginia University of Washington, Washington, USA International University Hospital of Tampere, Tampere, Finland Tel Aviv Medical Centre, Tel Aviv, Israel Nagoya University, Chikusa-ku, Nagoya, Japan Cancer Institute Hospital & the Japanese Foundation for Cancer Research, Toyko, Japan

76. Launch Sept 28 th 2012 Toronto

79. PARITY International

80. To boldly go………

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