PROPHYLACTIC ANTIOBIOTIC REGIMENS IN TUMOR SUGERY (PARITY)

Multi-centre trials in Orthopaedic Oncology:Dream or Reality?Michelle Ghert, MD, FRCSCAssociate ProfessorDepartment of SurgeryMcMaster University

22 year-old male with sarcoma right femur

Deep infection in total jointsApproximately 1% riskAAOS guidelines: 24 hours of gram positive coverage with pre-operative dosing

Tumour prosthesis: higher risk

Patients are myelo-depleted due to chemotherapySurgeries are long and the wound is open for several hoursLarge foreign bodyLarge dead spaceLoss of protective soft-tissue coverage

What is the magnitude of the problem?

Systematic ReviewDeep infection rate 9.5% (95% confidence interval: 8.1% to 11%)Comparison to primary arthroplasty: 1%

Systematic Review ConclusionsThe risk for deep infection following tumour prosthesis is high, X10 that of total jointsAntibiotic regimens vary from publication to publicationThere no published guidelines to direct managementWhat antibiotic regimens do we use?

Duration of antibioticsTable 2: Length of Time Prophylactic Antibiotics Prescribed Following Long-bone ReconstructionType of Reconstruction24 hrs48 hrs3-7 daysUntil Suction Drain RemovedTumor 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%)Results

PARITY Survey conclusionsPractice patterns vary considerably with respect to antibiotic regimen, dosages and durationMajority of surgeons are willing to change practiceOverwhelming support for a multi-centre clinical trialHierarchy of EvidenceRandomized TrialsProspective Cohort StudiesRetrospective Case SeriesCase Control StudiesOpinionLevel 1Level 2Level 3Level 4Level 5Less BiasMore Bias31RCTs in Orthopaedic OncologyOrthopaedic Oncology multi-center randomized controlled trials:Radiation Oncology: one trial, 150 patientsMedical Oncology: 72, methodologically poorSurgical Oncology: NONEThere is a lot of talk about RCTs in Orthopaedic Oncology, but no doingWhy do we need multi-centre trials?Tibial Shaft Fractures (SPRINT)

34Multicenter RCTsAdvantagesLevel 1 Evidencemore centers = More Patientsshorter study recruitment timeincreased generalizability of resultscollaboration between centers, countries and continents35Multicenter RCTsDisadvantagesThey are Hard to DoComplex organizationVery Expensive36But not impossible.Cardiology OASIS-6 RCT13000 pts (JAMA, 2006)447 hospitals41 countries

37But not impossible.Intensive Care Medicine PROTECT (DVT prophylaxis)Canadian Critical Care Trials Group 4000 pts North America/Australia

38But not impossibleNeonatal Medicine Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. N=910 infants

32 centersNA, Austalia, NZ, China

JAMA. 2003

39Has it been done in Orthopaedic Surgery?SPRINT Trial (Tibial Shaft Fractures)1339 patients recruited, 95% F/U

40

Challenges in Surgical Trials

Can Surgeons be Blinded?

43Who can be blinded?Patient and outcome assessors

Expertise Bias

Expertise BiasSurgeons tend to stick to procedures that they are good atDifficult to convince surgeons to develop new techniquesSolution: patients are allocated to provider, not procedureBut can it be done anyways?

Center for Evidence-Based Orthopaedics

SPRINT trial: 1339 patients, 95% follow-upFLOW trial: 2200 patients recruited, target 2200FAITH trial: 900 patients, target 1000TRUST trial: 600 patients, target 1000HEALTH trial: 350 patients, target 1400INORMUS and PRAISE prospective studies: 9000 patientsAll trials are funded by NIH/CIHR150 centers around the world

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

Study DesignPARITY is a multi-center randomized controlled trial using a parallel two-arm design

Patient screened and eligible and provides informed consentRandomizationStandard pre-op and intra-op antibiotics AND 24 hours post op antibioticsStandard pre-op and intra-op antibiotics AND 5 days post op antibioticsFollow-up one yearFollow-up one yearEligibility CriteriaLower extremity tumour prosthesisSkeletal maturityPrimary bone malignancy or benign aggressive tumor

Exclusion CriteriaMRSA or VRE colonizationAllergy to PCN or Ancef [cefazolin]Previous local surgery (excluding biopsy)Previous local infectionSystemic infection

Randomization24-hour computer randomization (www.randomize.net)Pharmacist will randomize patientStratified based on center and tumor location (femur or tibia)

BlindingPatients, nurses, research staff, surgeons and central adjudication committee (CAC) blindedOnly pharmacist will be aware of treatment allocation

Primary outcome and adjudicationDeep infection as defined by CDC 1992Within one year of surgical implantationCAC: 2 Orthopaedic Surgeons and 1 Infectious Disease specialistGlobal Adjudicator Platform

Secondary OutcomesMSTS-87 and -93TESSAntibiotic-related complications

Data Management

STEERING COMMITTEEOverall responsibility for the trialCENTRAL ADJUDICATION COMMITTEEReview and classification of all clinical eventsDATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harmMETHODS AND COORDINATING CENTRE Data management, daily conduct of the trialPARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocolPARITY Trial OrganizationCenter for Evidence-Based OrthopaedicsSteering CommitteeDr. Michelle Ghert (McMaster University)Dr. Ben Deheshi (McMaster University)Dr. Mohit Bhandari (McMaster University)Dr. Tim OShea (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)

STEERING COMMITTEEOverall responsibility for the trialCENTRAL ADJUDICATION COMMITTEEReview and classification of all clinical eventsDATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harmMETHODS AND COORDINATING CENTRE Data management, daily conduct of the trialPARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocolPARITY Trial OrganizationCenter for Evidence-Based Orthopaedics

Central Adjudication Committee

Dr. Ben Deheshi (McMaster University)Dr. Michelle Ghert (McMaster University)Dr. Tim OShea (McMaster University)Dr. Lor Randall (Huntsman Cancer Institute, Utah)

STEERING COMMITTEEOverall responsibility for the trialCENTRAL ADJUDICATION COMMITTEEReview and classification of all clinical eventsDATA MONITORING COMMITTEE Review of adverse events and stopping rules based on benefit and harmMETHODS AND COORDINATING CENTRE Data management, daily conduct of the trialPARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per study protocolPARITY Trial OrganizationCenter for Evidence-Based Orthopaedics

Data Safety Monitoring Board

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

Power analysisInfection rate mean 9.5%Superiority of long-term antibiotics: threshold of 5% for inferiorityAlpha 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 etcSPRINT trial: 1339 patients, 95% follow-upFLOW trial: 2200 patients recruited, target 2200FAITH trial: 900 patients, target 1000TRUST trial: 600 patients, target 1000HEALTH trial: 350 patients, target 1400INORMUS and PRAISE prospective studies: 9000 patientsAll trials are funded by NIH/CIHR150 centers around the world

Pilot: FeasibilityAssess recruitment10% of definite trial: 100 patients in 12 monthsMaintain follow-up (95%) and data qualityAssess ability to accurately use internet-based randomization systemEnsure complianceFundingOrthopaedic 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 FundCanadian Cancer Society Research Institute Innovation Grant

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, CanadaFranois dAssise et LHotel-Dieu de Quebec, Quebec City, Quebec, Canada*Vancouver General Hospital, Vancouver, British Columbia, Canada USA*Vanderbilt Medical Centre, Nashville, Tennessee, USABeth Israel Deaconess Medical Centre, Boston, Massachusetts, USABoston Childrens Hospital, Boston, Massachusetts, USA*Huntsman Cancer Institute, Salt Lake City, Utah, USAMemorial Sloan-Kettering Cancer Centre, Cornell, New York, USAUKThe Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK The Royal National Orthopaedic Hospital NHS Trust, Stanmore, UKThe Robert Jones Agnes Hunt Hospital NHS Foundation Trust, Oswestry, UKOxford University Hospital NHS Trust (Nuffield Orthopaedic Centre), Oxford UKThe Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle UK

Argentina Hospital Universitario Austral, Beuonos Aires, Argentina

*actively enrollingInterested sites

Canada HalifaxUSAAlbany Medical College, Albany, New York, USAMenorah Medical Center and Mid American Sarcoma Institute, Overland Park, Kansas, USAMarshall University, Huntington, West VirginiaUniversity of Washington, Washington, USAInternational University Hospital of Tampere, Tampere, FinlandTel Aviv Medical Centre, Tel Aviv, IsraelNagoya University, Chikusa-ku, Nagoya, JapanCancer Institute Hospital & the Japanese Foundation for Cancer Research, Toyko, Japan

Launch Sept 28th 2012 Toronto

PARITY International

To boldly goMulti-centre trials in Orthopaedic Oncology:Dream or Reality?Michelle Ghert, MD, FRCSCAssociate ProfessorDepartment of SurgeryMcMaster University

Chart187.312.7

I would participate in a multi-centre randomized controlled study assessing different antibiotic regimens in long-bone reconstruction for tumor surgeryI Would Participate in a Multi-Centre RCT Assessing Different Antibiotic Regimens in Long-bone Reconstruction for Tumor Surgery87.3 %12.7%

Sheet1I would participate in a multi-centre randomized controlled study assessing different antibiotic regimens in long-bone reconstruction for tumor surgeryYes87.3No12.7To resize chart data range, drag lower right corner of range.