Proximal FEmur Reconstruction or Internal Fixation fOR Metastases (PERFORM) Randomized Controlled Trial
Phase: NA
Conditions: Metastatic Bone Disease
Sponsor: Michelle Ghert, MD

CLINICAL RESEARCH PROTOCOL 
 
 
 
Study Protocol 
 
 
 
Version 1.0 
 
 
 
This study is registered on ClinicalTrials.gov 
Identification No.: XXXX 
 
 
Principal Investigator: 
Michelle Ghert, MD 
Methods Center: 
 
Department of Surgery Methods Center 
McMaster University 
711 Concession Street 
Lakeview Lodge | Level 3, Room 6 
Hamilton, ON L8V 1C3 
Funding Sponsors: 
 
National Institutes of Health: National Institute 
of Arthritis and Musculoskeletal and Skin 
Diseases (NIH/NIAMS) 
Canadian Cancer Society (CCS) 
McMaster Surgical Associates (MSA) 
 
  
 
 
This Study Protocol is the confidential intellectual property of the PERFORM Principal 
Investigator, Steering Committee and McMaster University, and cannot be used in any 
form without the expressed permission of the Principal Investigator. 

Version 2.0 
 
Page 2 of 29 
13 FEB 2025 
Signature Page 
 
Reviewed and Approved by: 
Michelle Ghert 
Principal Investigator 
Signature: 
Date: 
 

Version 2.0 
                                                                                                    Page 3 of 29 
13 FEB 2025 
Table of Contents 
Signature Page ......................................................................................................................................... 2 
List of Abbreviations ............................................................................................................................... 5 
Study Summary ........................................................................................................................................ 6 
1.0 
Introduction .................................................................................................................................. 7 
1.1 Burden of Metastatic Bone Disease of the Proximal Femur .............................................. 7 
1.2 Current Surgical Treatment of Skeletal Metastases to the Proximal Femur ................. 7 
1.2.1 Rationale for Resection and Reconstruction ........................................................................ 8 
1.3 The Need for the Trial ................................................................................................................... 8 
1.4 Stakeholder Engagement and Collaboration ......................................................................... 8 
1.5 Evidence for Current Practice .................................................................................................... 9 
1.6 Clinical Equipoise.......................................................................................................................... 9 
1.6.1 Patient Population of Clinical Equipoise ............................................................................... 9 
1.6.2 Zone of Clinical Equipoise ...................................................................................................... 9 
1.6.3 Life Expectancy of Target Population ................................................................................... 9 
1.7 Most Relevant Patient-Reported Outcome Measures (PROMs) ........................................ 9 
1.8 Hierarchal Composite Outcome .............................................................................................. 10 
1.9 Summary of Background and Rationale ............................................................................... 10 
2.0 Study Objectives ............................................................................................................................. 10 
2.1 Research Objectives ................................................................................................................... 10 
2.1.1 Primary Research Objective ................................................................................................. 10 
2.1.2 Secondary Research Objective ............................................................................................ 10 
2.2 Subgroup Objectives .................................................................................................................. 11 
3.0 Study Design .................................................................................................................................... 11 
3.1 Pragmatic-Explanatory Continuum ........................................................................................ 11 
3.2 Outcome Measures ..................................................................................................................... 12 
3.2.1 Primary Outcome: Hierarchal Composite Outcome .......................................................... 12 
3.2.2 Secondary Outcomes ............................................................................................................ 12 
3.2.3 Cost-Effectiveness Outcomes ................................................. Error! Bookmark not defined. 
4.0 Study Methods and Procedures .................................................................................................. 12 
4.1 Study Setting ................................................................................................................................ 12 
4.2 Trial Population ............................................................................................................................ 13 
4.3 Recruitment and Informed Consent ....................................................................................... 13 
4.4 Randomization ............................................................................................................................. 15 
4.5 Study Interventions ..................................................................................................................... 15 
4.5.1 Internal Fixation ...................................................................................................................... 15 
4.5.2 Resection and Reconstruction ............................................................................................. 15 
4.5.3 Standardization of Perioperative Care ................................................................................ 16 
4.6 Data Collection and Participant Follow-Up........................................................................... 16 
4.6.1 Maximization of Follow-Up .................................................................................................... 18 
4.7 Protecting Against Sources of Bias ....................................................................................... 18 
4.7.1 Data Monitoring ...................................................................................................................... 18 
4.7.2 Adjudication of Outcomes ..................................................................................................... 19 
4.7.3 Allocation Concealment and Blinding .................................................................................. 19 
4.7.4 Minimization of Crossovers of Trial Interventions ............................................................. 19 
5.0 Statistical Plan ................................................................................................................................. 20 
5.1 Sample Size Determination ....................................................................................................... 20 

Version 2.0 
                                                                                                    Page 4 of 29 
13 FEB 2025 
5.2 Statistical Methods...................................................................................................................... 20 
5.2.1 Analysis Plan Overview ......................................................................................................... 20 
5.2.2 Primary Outcome Analysis .................................................................................................... 20 
5.2.3 Secondary Outcomes Analyses ........................................................................................... 21 
5.2.3 Subgroup Analyses ................................................................................................................ 21 
5.2.5 Sensitivity Analyses ............................................................................................................... 21 
6.0 Data Collection and Management ............................................................................................... 22 
6.1 Data Transmission ...................................................................................................................... 22 
6.2 Data Integrity ................................................................................................................................ 22 
6.2.1 Data Transmission ................................................................................................................. 22 
6.2.2 Data Integrity ........................................................................................................................... 22 
6.2.2 Data Preservation and Sharing ................................................................................................ 23 
7.0 Ethical Considerations ................................................................................................................... 23 
7.1 Research Ethics Approval ........................................................................................................ 23 
7.2 Informed Consent Form ............................................................................................................. 23 
7.3 Confidentiality .............................................................................................................................. 23 
7.4 Protocol Amendments ............................................................................................................... 24 
7.5 Safety and Adverse Events ....................................................................................................... 24 
7.5.1 Definitions ................................................................................................................................ 24 
7.5.2 Clinical Site Reporting ........................................................................................................... 25 
7.5.3 Participant Safety and Monitoring ........................................................................................ 25 
8.0 Knowledge Dissemination ............................................................................................................ 26 
9.0 Secondary and Sub-Study Manuscripts ................................................................................ 26 
10.0 References ...................................................................................................................................... 27 
 
 
 

Version 2.0 
                                                                                                    Page 5 of 29 
13 FEB 2025 
List of Abbreviations 
 
AE 
 
Adverse Event 
CAC 
 
Central Adjudication Committee 
CEAC  
Cost-Effectiveness Acceptability Curve 
CI 
 
Confidence Interval 
CONSORT 
Consolidated Standards Of Reporting Trials 
CRF 
 
Case Report Form 
DAMOCLES Data Monitoring Committees: Lessons, Ethics, Statistics 
DSMB  
Data and Safety Monitoring Board 
HiREB  
Hamilton Integrated Research Ethics Board 
ICEMAN 
Credibility of Effect Modification Analyses 
IRB 
 
Institutional Review Board 
LTFU  
Loss to Follow-Up 
LY 
 
Life Years 
PARITY 
Prophylactic Antibiotic Regimens In Tumor surgerY Trial 
PERFORM 
Proximal FEmur Reconstruction or Internal Fixation fOR Metastases Trial 
PRECIS-2 
Pragmatic-Explanatory Continuum Indicator Summary 
PROM  
Patient-reported Outcome Measures 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PROPr  
Preference scoring system 
QALY  
Quality Adjusted Life Years 
RCT 
 
Randomized Controlled Trial 
REB 
 
Research Ethics Board 
SAE 
 
Serious Adverse Event 
SAFETY 
Surveillance AFter Extremity Tumor surgerY Trial 
 
 

Version 2.0 
                                                                                                    Page 6 of 29 
13 FEB 2025 
Study Summary 
 
Title 
Proximal FEmur Reconstruction or Internal Fixation fOR Metastases Randomized Controlled 
Trial 
Short Title 
PERFORM 
Methodology 
Multi-centre, parallel-arm superiority randomized controlled trial (RCT) 
Coordinating Centre 
This trial will be centrally coordinated by the Department of Surgery Methods Centre at 
McMaster University in Hamilton, ON, Canada.  
Clinical Sites 
20-30 clinical sites across Canada, the United States and internationally. 
Primary Objective 
The overall objective of the PERFORM trial is to determine the effect of resection and 
reconstruction on patient-important outcomes compared to internal fixation for the 
stabilization of an impending or realized pathologic fracture in patients with metastatic bone 
disease of the proximal femur. We hypothesize that resection and reconstruction will result 
in improved outcomes as assessed by a hierarchal composite outcome at one year post 
randomization. 
Secondary Objectives 
We will assess each component of the hierarchal composite outcome as independent 
endpoints, as well as the composite outcome at three- and six-months post-surgery. We will 
also assess the PROMIS-PROPr (PROMIS-Preference) utility score encompassing mental 
and physical health, and quality of life at baseline, six months, and 12 months. 
Treatment Groups 
This trial will compare two surgical interventions to stabilize an impending or realized 
pathologic fracture:  
1. Resection and reconstruction with an endoprosthesis or arthroplasty (intervention); or 
2. Internal fixation utilizing intramedullary nails, plates and screw fixation +/- tumor curettage 
(comparator).  
Trial Outcome 
The definitive primary outcome will be a patient-centered hierarchal composite endpoint 
consisting of: 
1. Mortality at 12 months 
2. PROMIS Global Physical Function (patient-reported outcome measure) at 4 months 
3. Days at Home at 12 months 
Follow-Up 
Trial patients will be followed for one-year post-surgery. 
Sample Size 
334 patients 
Estimated Trial 
Duration 
Trial Initiation: January – December 2025; Enrolment: June 2025 – December 2028; Follow 
up: December 2029  
Significance 
Due to the rapidly evolving landscape of cancer survivorship, the traditional methods of 
stabilizing bones in the setting of metastatic bone disease may no longer be meeting the 
standard of outcomes required for cancer patients who can now live for years with their 
disease. A growing body of retrospective evidence suggests the advantages of resection and 
reconstruction over internal fixation for disease control and other cancer-related, surgical, 
and quality-of-life outcomes, although all current recommendations are based on low-level 
evidence. The PERFORM trial has the potential to effect significant change in clinical practice 
and improve the surgical, functional, and quality-of-life outcomes of patients with metastatic 
bone disease of the proximal femur. However, the introduction of a more invasive, yet more 
durable, procedure would represent a paradigm shift in the approach to this orthopaedic 
patient population and, therefore, must be supported by high-quality, concrete evidence. 
 
 
 
 

Version 2.0 
                                                                                                    Page 7 of 29 
13 FEB 2025 
1.0 Introduction 
 
1.1 Burden of Metastatic Bone Disease of the Proximal Femur 
Over 16 million individuals are currently living with cancer of any type in North America alone, with the annual 
incidence estimated at 2 million in 2023.1,2 Cancer patients are living longer with metastatic disease in almost all 
cancer types due to improved oncologic control as a result of advancements in cancer therapies.3  The skeleton 
is among the most common anatomic locations for metastatic cancer, and the long-term survival of cancer 
patients with bone metastases has more than tripled in the last quarter of a century.4 It is estimated that there 
are over 300,000 individuals presently living with bone metastases in North America.5 Among cancer patients 
with bone metastases – or metastatic bone disease (MBD) – the proximal femur represents the most common 
location in the appendicular skeleton and a source of substantial morbidity.6 
 
1.2 Current Surgical Treatment of Skeletal Metastases to the Proximal Femur 
The proximal femur is exposed to the highest mechanical forces in the body. While bone-modifying agents and 
radiotherapy can be used to manage pain, the risk of proximal femur fracture remains high due to cancer induced 
bone fragility. Prophylactic surgery is the 
cornerstone of treatment to protect the 
mechanical integrity and stability of the bone. 
While surgical treatment is unlikely to increase 
life expectancy, surgical stabilization can 
improve the quality of the patient’s remaining life 
by relieving pain and maintaining or regaining 
function. The traditional surgical approach for 
MBD in the proximal femur is the stabilization of 
the pathologic bone with internal fixation 
(Figure 1). The advantages of internal fixation 
include its simplicity, low morbidity, and 
relatively low cost.4 Retrospective data also 
suggests a low rate of surgical site infections 
following internal fixation, likely due to the 
minimally invasive nature of the procedure. 
However, disease recurrence after internal 
fixation is becoming increasingly common and 
can result in devastating implant failures; 
deleterious effects on function, mobility, and quality of life; and a subsequent need for revision surgery.7 

Version 2.0 
                                                                                                    Page 8 of 29 
13 FEB 2025 
1.2.1 Rationale for Resection and Reconstruction 
Alternatively, resection and reconstruction with an endoprosthesis is an orthopaedic surgical technique gaining 
in popularity for MBD of the proximal femur (Figure 2).8 The advantages of resection with endoprosthetic 
reconstruction include the immediate stability of the bone 
without the need for bone healing; and the removal of all local 
disease during the procedure, reducing the risk for local 
disease relapse and the need for post-operative local 
radiotherapy.4,6 The available evidence, provided by 
retrospective comparative studies, has found that revision 
rates due to disease relapse may be up to three times lower 
with resection and reconstruction than with internal 
fixation.7,9–12 Therefore, resection and reconstruction may 
avoid the harmful effects on function, mobility and quality of 
life that result from implant failure and revision surgeries. A 
recent systematic review of retrospective data highlighted the 
relative durability of resection and reconstruction, an 
important consideration in a population with increasing life 
expectancies.13 However, given the complexity and duration 
of these procedures, they are costly and patients are at a 
higher risk of peri-operative complications, such as hip dislocation and surgical site infection.4 
 
1.3 The Need for the Trial 
Due to the rapidly evolving landscape of cancer survivorship, the traditional methods of stabilizing bones in the 
setting of MBD may no longer be meeting the standard of outcomes required for patients who often live for years 
with their disease. A growing body of retrospective evidence suggests the advantages of resection and 
reconstruction over internal fixation for disease control and other cancer-related, surgical and quality-of-life 
outcomes. However, all current recommendations are based on low-level evidence.14 
 
Moreover, we recently conducted a modified Delphi study to develop a consensus-based research agenda. From 
this process that included 80 delegates consisting of orthopaedic oncologists and patients from 18 countries, we 
identified the most feasible and important research questions to enhance patient care.15 The evaluation of 
surgical options for MBD ranked in the top three research questions out of a preliminary list of nearly 200.15,16 
 
1.4 Stakeholder Engagement and Collaboration 
We have pioneered a patient-engagement paradigm in prospective orthopaedic oncology clinical research that 
has included patient and caregiver engagement throughout the research continuum and adheres to the ten-step 
Comparative Effectiveness Research/Patient-Centered Outcomes Research Framework for Continuous Patient 
Engagement.17 In the Surveillance AFter Extremity Tumor surgerY (SAFETY) trial, we partnered with sarcoma 
patients from the onset of the trial’s development to ensure that their perspectives were reflected in all stages 
including the identification of the research question itself. We have continued this paradigm in the PERFORM 
trial through the engagement of advanced cancer patients and caregivers in the research question development, 
trial design and the identification and ranking of outcomes that are important to them. 
Our research consortium published the Prophylactic Antibiotic Regimens In Tumor surgerY (PARITY) 
international randomized controlled trial, which demonstrated, for the first time, that despite the challenges 
associated with prospective clinical research in small sub-specialties like orthopaedic oncology, investigator-
initiated clinical trials in this field are indeed possible with international collaboration.18 Through our conduct of 
both the PARITY and SAFETY trials, our consortium has grown to over 60 clinical sites across Canada, the 
United States, Argentina, Australia, Austria, Belgium, Brazil, Egypt, Germany, India, Italy, Malaysia, the 
Netherlands, Portugal, Singapore, South Africa, Spain, Sweden, and the United Kingdom. 

Version 2.0 
                                                                                                    Page 9 of 29 
13 FEB 2025 
 
1.5 Evidence for Current Practice 
A comprehensive clinical practice guideline on the management of MBD of the femur,14 which required an 
exhaustive systematic review of the available evidence, concluded that: 1) failures due to local disease relapse 
are increasingly common after internal fixation for MBD of the proximal femur; 2) there are potentially lower risks 
of re-operation due to disease relapse with resection and reconstruction; and 3) a clinical zone of equipoise can 
be identified in which surgeons are comfortable with both procedures.9,10,19–22 This data guided baseline risk 
estimates, expected treatment effect and eligibility criteria for the PERFORM trial. Through collaboration with the 
International MBD Registry, we have determined that: 1) the intertrochanteric and subtrochanteric regions of the 
proximal femur are the most common locations for surgical MBD in the proximal femur; 2) resection and 
endoprosthetic reconstruction is increasingly being used in these cases; and 3) the remaining cases were 
managed with arthroplasty and either intramedullary nailing, plating or curettage. It is important to note that the 
available evidence does not provide meaningful information on patient-reported outcomes in MBD of the proximal 
femur. Therefore, the PERFORM trial will also make important progress in the improvement of patient-centered 
care for this surgical population. 
 
1.6 Clinical Equipoise  
 
1.6.1 Patient Population of Clinical Equipoise 
The target population for the PERFORM trial will be any adult person with MBD of the proximal femur in the 
intertrochanteric and/or subtrochanteric regions with an impending or realized pathologic fracture. The practical 
application of a protocol that reliably defines and identifies this population in the zone of clinical equipoise has 
been further discussed through multiple investigator meetings and a cross-sectional survey of the field. 
 
1.6.2 Zone of Clinical Equipoise 
The size and extent of metastatic lesions in the intertrochanteric and/or subtrochanteric regions of the femur may 
dictate if a lesion is ‘too advanced’ for which internal fixation would not provide sufficient stability. Previous work 
in Japan has suggested that transverse destruction greater than 50% of the width of the bone and/or soft-tissue 
involvement dictate the use of an endoprosthesis over internal fixation.19 Our survey work and investigator 
meeting discussion has resulted in a zone of equipoise of no more than 75% bone destruction and no less than 
25% bone destruction.23 The presence of a pathologic fracture versus an impending fracture may result in a 
differential treatment effect in the internal fixation group, as the proximal femur in these cases is inherently less 
stable. Therefore, we plan to stratify randomization based on this variable.  
 
1.6.3 Life Expectancy of Target Population 
Our previous work, the survey results, and stakeholder discussions have indicated that a life expectancy of at 
least six months would be reasonable for clinicians to consider both surgical options. 19,23  Since life expectancy 
will be based on an estimated clinical judgement, clinicians have expressed that they feel comfortable with this 
timeline. In addition, functional outcomes and early oncologic events are best assessed within 4-6 months post-
operatively, as functional improvements tend to reach a stable threshold at this time in this patient population.24  
 
1.7 Most Relevant Patient-Reported Outcome Measures (PROMs) 
When selecting PROMs for the PERFORM trial, it was important to consider the outcomes that are most relevant 
to the patient population being evaluated. We have conducted a virtual focus group with eight members of our 
patient and caregiver advisory group to facilitate the selection of the most relevant and patient-focused PROMs. 
Focus group participants included advanced cancer patients with metastatic disease and caregivers of this 
patient population who had diverse backgrounds and experiences. The arising discussion was confidential and 
moderated by one of our collaborators specializing in PROMs methodology to ensure that all participants were 

Version 2.0 
                                                                                                    Page 10 of 29 
13 FEB 2025 
able to safely share their perspectives. The discussion was recorded and transcribed for thematic analysis. The 
main themes from the focus group that emerged were: the impact of treatment on their daily life, being 
independent and living a normal life, and the impact of the cancer treatment on their quality of life. Based on the 
analysis of the focus group and the literature, it was determined that the most important outcomes for the 
PERFORM trial would be the following, and these were later ranked based on further work with clinicians and 
patient representatives (see Section 1.8 below): 
 
• 
Mortality within 12 months 
• 
Days at home within 12 months 
• 
Physical function as assessed by a PROM at 4 months  
 
1.8 Hierarchal Composite Outcome 
The utilization of hierarchal composite endpoints provides benefits for both statistical and clinical interpretation 
as it helps to establish a ranking system among individual outcomes within the composite, thereby addressing 
concerns regarding endpoint equivalence that can arise with traditional composites. Dr. Nathan O'Hara is an 
expert in research methodology and has led our team in the use of behavioral economic techniques to identify 
patient preferences for outcomes.33-35 To achieve this, we have virtually conducted a discrete choice experiment 
as part of our stakeholder engagement framework to quantify the outcome priorities of the target population. This 
process involved individual stakeholders being presented with hypothetical comparisons of different outcomes 
after surgical management of MBD of the proximal femur, such as a minimum clinically important difference in a 
PROM, disease relapse requiring re-operation, re-operations for other indications, or mortality. By pooling 
responses from our sample of 86 stakeholders for this planning step, we have determined the relative importance 
of the various outcomes and the minimum significant differences that patients desire that would allow them to 
choose the more invasive surgery.  
Please refer to 3.2 Outcome Measures for the results of the discrete choice experiment to determine the 
hierarchal composite outcome. 
 
1.9 Summary of Background and Rationale 
The population of those living with MBD of the proximal femur is growing precipitously due to the changing 
landscape of cancer survivorship. The traditional methods of stabilizing bones in the setting of MBD may no 
longer be meeting the standard of outcomes required for patients who can now live for years with their disease 
and are at risk of outliving their femoral hardware. A growing body of retrospective evidence suggests the 
advantages of resection and reconstruction over internal fixation for disease control and other cancer-related 
and surgical outcomes. As such, there is an increasing need to understand the best surgical approach to MBD 
of the proximal femur. 
2.0 Study Objectives 
 
2.1 Research Objectives 
2.1.1 Primary Research Objective 
The primary objective of the PERFORM trial is to determine if resection and reconstruction improves patient-
important outcomes compared to internal fixation for patients with MBD of the proximal femur. We hypothesize 
that resection and reconstruction will result in greater improvements as assessed by a hierarchal composite 
outcome at 1 year. 
 
2.1.2 Secondary Research Objective 
We will assess the individual components of the composite outcome as independent endpoints, as well as the 
composite outcome at three- and six-months post-surgery as secondary outcomes. We will also assess the 

Version 2.0 
                                                                                                    Page 11 of 29 
13 FEB 2025 
PROMIS-PROPr (PROMIS-Preference) utility score - encompassing mental and physical health, and quality of 
life at baseline, six months, and 12 months.  
 
2.2 Subgroup Objectives 
We will explore two clinically relevant subgroups based on life expectancy at baseline and fracture status. Life 
expectancy will be dichotomized as life expectancy greater than one year versus less than one year, and fracture 
status will be classified as either impending fracture or pathologic fracture. We hypothesize that patients with a 
longer life expectancy and those with an impending fracture prior to surgery will have greater treatment benefits 
from the more invasive surgical procedure. 
3.0 Study Design 
The PERFORM trial will be a multi-centre, parallel two-arm superiority randomized controlled trial of patients with 
MBD of the proximal femur who require surgical management of an impending or realized pathologic fracture. 
Participants will be randomized in a 1:1 manner to undergo surgical management with either resection and 
reconstruction or internal fixation. Details on the surgical procedures are provided in 4.5 Study Interventions 
below. 
 
3.1 Pragmatic-Explanatory Continuum 
Based on the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) toolkit, the PERFORM trial 
design favors a highly pragmatic approach, and the trial is designed to determine if the interventions work under 
usual conditions, as opposed to under ideal conditions. The PRECIS-2 tool uses a five-point Likert scale in nine 
domains to evaluate the continuum of design choices where a score of five is ‘very pragmatic,’ while a score of  
one suggests ‘very explanatory.’ The PERFORM trial design scores either four or five in all domains (Table 1). 
 
Table 1. PERFORM Trial PRECIS-2 Score 
Domain 
Score 
Rationale 
Eligibility 
Who is selected to participate in the trial? 
4 
The eligibility criteria are broad and include most patients with MBD of the proximal femur. 
Recruitment 
How are participants recruited into the 
trial? 
5 
All eligible patients treated at each participating clinical site will be approached to participate during their pre-
operative appointment/assessment when surgical management options are discussed. However, trial consent will 
ideally not be obtained until closer to the start of surgery (and immediately prior to randomization). This decision 
follows the principle of obtaining consent and enrolling patients as late as possible prior to the start of the 
intervention in order to avoid missing eligible patients, as well as to avoid the inclusion of ineligible patients. 
Setting 
Where is the trial being conducted? 
4 
Recruitment will take place at multiple sites in Canada, the United States, and internationally. However, although 
both surgical procedures are standard practice for all orthopaedic oncology surgeons, some surgeons may not have 
equal experience with both procedures. To mitigate the risk of either selection or performance bias, only clinical 
sites that demonstrate equivalent expertise availability will be invited to participate. Therefore, although MBD can 
be treated at either secondary or tertiary care centres, it is likely that only tertiary care centres will be involved in 
the trial.  
Organization 
What expertise and resources are needed 
to deliver the intervention? 
4 
The interventions may require some adjustments to clinical care delivery (particularly with respect to surgeon 
expertise), but it will not require any increase in care providers. A trial conduct training session will be provided to 
all participating clinical sites before they begin enrolment. 
Flexibility (Delivery) 
How should the intervention be 
delivered? 
5 
The interventions will be delivered in a manner consistent with standard practice. The Methods Centre is not 
dictating the specifics of the surgical implants, as different centres have different implants available. 
Flexibility (Adherence) 
What measures are in place to make sure 
participants adhere to the intervention? 
4 
Both surgical interventions fall within the spectrum of accepted practice. The trial consent process will take place 
after eligibility is confirmed and immediately prior to surgery to prevent unplanned conversions between the trial 
arms and withdrawals of consent immediately prior to surgery. 
Follow-Up 
How closely are participants followed-up? 
5 
Post-surgical follow-up is an important element of oncologic care. The follow-up schedule aligns with the standard 
follow-up practice and adheres to all relevant guidelines. Generous visit windows have been developed to 
accommodate the clinic schedules of investigators and participant availability. 
Primary Outcome 
How relevant is it to participants? 
5 
The components of the primary hierarchal composite outcome have been validated by MBD patients as being both 
important and relevant. The ranked approach also aligns with clinical practice, as patients and care providers are 
typically interested in the treatment effect on multiple outcomes with a defined hierarchy. The primary outcome 
will not require specialized expertise beyond the treating physicians for diagnosis. 
Primary Analysis 
To what extent are all data included? 
5 
All available trial data will be used for analysis following the intention-to-treat principle. 
 

Version 2.0 
                                                                                                    Page 12 of 29 
13 FEB 2025 
3.2 Outcome Measures 
 
3.2.1 Primary Outcome: Hierarchal Composite Outcome 
The primary outcome for the PERFORM trial will be a patient-centered hierarchal composite endpoint, including 
the four constructs we identified in our stakeholder and patient engagement framework: 1) Mortality as assessed 
at 12 months, 2) Physical function as assessed at 4 months using the Patient-Reported Outcomes Measurement 
Information System (PROMIS®) Global Physical Function score, and 3) Number of days at home as determined 
at 12 months. The data (Table 2) below has been extrapolated from the literature and will be hierarchically 
assessed in the order listed below. The hierarchal order was determined by discrete choice experiment 
responses from surgeons, caregivers and patient partners (n=86) that allowed for prioritization of the outcomes 
within the hierarchy.  
 
Table 2. Expected Proportion of Outcomes in the Sample (Stratified by Treatment Arm) 
Level 
Outcome 
Expected Outcomes 
Overall 
Internal Fixation 
Resection and 
Reconstruction 
1 
Mortality at 12 months 
30% 
30% 
30% 
2 
PROMIS Global Physical Function (patient-reported 
outcome measure) * at 4 months 
3.5 
4.0 
3.0 
3 
Days at Home ** at 12 months 
320 
300 
340 
* Higher values = better function, minimal clinically important difference is 0.5. ‘To what extent are you able to carry out your everyday physical 
activities such as walking, climbing stairs, carrying groceries or moving a chair?’ (Range 5: completely to, 1: not at all).  
** Days with no interaction with the healthcare system, patient diary reported 
3.2.2 Secondary Outcomes 
We will also assess each component listed in Table 2 above as independent endpoints and the composite 
outcome at three- and six-months post-surgery as secondary outcomes. Another key secondary outcome will be 
the PROMIS-PROPr (PROMIS-Preference) utility score - encompassing mental and physical health, quality of 
life at baseline, six months, and 12 months. This secondary outcome aligns with our patient and caregiver 
qualitative research themes. The PROMIS-PROPr combines scores from seven PROMIS domains into a single 
preference-based score (also called a health utility score), which captures the preferences of the general adult 
population. The total number of items that the patient answers are 31. This instrument gives four different scores: 
health utility score, domain level scores (one for each of the following domains: physical function, anxiety, 
depression, fatigue, sleep disturbance, social roles and activities, pain interference, cognition, and pain intensity), 
physical component score, and a mental component score. 
 
 
 
4.0 Study Methods and Procedures 
 
4.1 Study Setting 
Under the leadership of the Principal Investigator, our trial team within the Department of Surgery Methods 
Centre at McMaster University will centrally manage the PERFORM trial. For the definitive trial, we intend to 
recruit patients from approximately 20-30 clinical sites across Canada and the United States, as well as select 
international sites with whom we have a history of productive collaboration. Clinical sites will be carefully 
screened prior to receiving an offer to participate in the trial. The clinical site inclusion criteria will be: 1) adequate 
research personnel and infrastructure to manage the trial; 2) sufficiently high MBD volume to complete enrolment 
within the trial timeline (defined as greater than or equal to 12 eligible patients per year); 3) commitment from all 
or most of the site’s orthopaedic oncologists to participate in the trial and that they are comfortable with 
randomizing all eligible patients (i.e. no potential bias); and 4) access to the required equipment for the two 

Version 2.0 
                                                                                                    Page 13 of 29 
13 FEB 2025 
surgical procedures. The exclusion criteria are: 1) lack of interest in the trial; 2) anticipated challenges with 
complying with the protocol; 3) conflicting studies that would inhibit patient participation; 4) financial or contractual 
constraints; and 5) exceptionally poor performance in the PARITY and/or SAFETY trial(s), if applicable. We will 
remain mindful of the geographic location and expected participant demographics of each clinical site to ensure 
that the trial sample is geographically and demographically diverse, and that it adequately reflects the spectrum 
of patients with MBD.  
 
4.2 Trial Population 
Extensive background work has established a zone of equipoise in which surgeons would consider both surgical 
approaches (reconstruction or internal fixation) to be equally appropriate. This background work included a 
survey of the field23 and three investigator meetings. The zone of equipoise, therefore, provides inclusion and 
exclusion criteria that are acceptable to the field (Table 4). All patients 18 years of age or older who present with 
MBD of the proximal femur and who require surgery will be screened. Patients with Multiple Myeloma and 
Lymphoma will also be screened and included, if eligible. 
 
 Table 4: Inclusion and exclusion criteria  
Inclusion Criteria 
Exclusion Criteria 
Life expectancy of at least 6 months 
Lesions isolated to the femoral neck  
Lesions in the proximal femur (femoral neck, 
intertrochanteric region, subtrochanteric region, and 
combinations thereof) 
Lesion with any femoral head involvement 
Low or intermediate risk for perioperative morbidity 
and/or mortality 
High risk for perioperative morbidity and/or mortality 
No more than 75% and no less than 25% bone loss 
Multidisciplinary decision that resection of the entire lesion would be 
indicated 
Mutual (patient and physician) decision to perform surgical 
management of an impending or realized pathologic 
fracture due to MBD of the proximal has been made. 
 
 
 
4.3 Recruitment and Informed Consent 
Ethics approval will be obtained at the Methods Centre and at each clinical site before recruitment begins. Each 
participating clinical site’s locally responsible investigator will oversee the administration of the trial at the site 
level. To screen MBD patients for eligibility, the locally responsible investigator, along with designated personnel, 
will develop a site-specific patient enrolment plan. Typically, this plan will include participation in patient rounds 
and a review of weekly clinic schedules for patients with MBD of the proximal femur. While the management of 
MBD patients can vary between sites, patients will typically become eligible and will be screened once the 
surgical management options have been discussed with the patient. The sequence of care a MBD patient 
typically undertakes is outlined in Figure 3 below. 
 
The initial introduction of the trial to patients will take place after the discussion of surgical management options 
has occurred. At this time, patients will be provided with the participant information sheet and informed consent 
form. Given the surgical nature of the trial interventions, consent to participate in the trial must occur prior to the 
start of surgery. Therefore, to facilitate an improved consent process that prevents undue decision-making stress 
for patients awaiting surgery for their impending or realized pathologic fractures, the consent process will, when 
possible, take place at a later time either on the local inpatient ward (if the patient was admitted from the 
outpatient clinic or emergency room) or via telephone/email (if the patient was discharged and is to return to the 
hospital at a later date for surgery). This decision also follows the principle of obtaining consent and enrolling 
patients as late as possible prior to the start of the intervention to avoid missing eligible patients, as well as to 
avoid the inclusion of ineligible patients.  
 

Version 2.0 
                                                                                                    Page 14 of 29 
13 FEB 2025 
Trial personnel at each clinical site will obtain informed consent from patients prior to randomization. Either 
electronic, written, or verbal consent via telephone may be obtained, as approved by the local ethics committee. 
If a patient is unable to provide informed consent (e.g., language restriction or due to their disease), informed 
consent will be obtained from their proxy, if available. If a patient leaves clinic prior to being invited to participate 
in the trial, the local trial personnel site may obtain verbal consent via telephone or electronic consent via email, 
as per local ethics committee approval. Upon providing informed consent, participants will be followed in the trial 
for one year. However, they may withdraw their consent at any time. 
 
The process of obtaining and documenting informed consent will be completed in accordance with local Good 
Clinical Practice recommendations. Consent procedures will comply with the appropriate ethics committee and 
any applicable regulations. At minimum, the following process will be observed by delegated personnel to obtain 
informed consent:  
▪ 
Present trial information in a manner that is understandable to the potential trial patient/proxy;  
▪ 
Discuss the trial with the potential trial patient/proxy and answer any questions they ask;  
▪ 
Allow the potential trial patient/proxy an opportunity to discuss participation with others, if desired;  
▪ 
Confirm that the potential trial patient/proxy understands the risks and benefits of participating in the trial 
and that their participation is voluntary;  
▪ 
Complete and obtain the appropriate signatures on the approved Informed Consent Form and collect 
contact information from the trial patient/proxy; and  
▪ 
Provide the trial patient/proxy with a copy (paper or electronic) of the signed Informed Consent Form. 
 
Trial personnel at clinical sites will be trained to approach any and all potentially eligible patients (should they 
agree to be approached). They will receive ongoing training at annual Investigators Meetings and monitoring 
visits, with guidance from our patient partners and trial team. 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. Typical Sequence of Care of MBD Patients 
 
 
Key Personnel 
Interventions 
Detect Bone Pain or Break 
 
Patient 
Self-assessment 
Discuss with Medical Oncologist 
or Emergency Room Physician 
 
Physician, Nurse, 
Physician Assistant 
Medical assessment, imaging, blood tests 
Refer to Orthopaedic Oncology 
Surgeon 
 
Surgeon, Nurse, 
Radiologist 
Medical assessment 
Diagnosis and Staging 
 
 
Surgeon, Nurse, 
Radiologist 
Imaging, biopsy 
Trial Intervention: Surgery  

Version 2.0 
                                                                                                    Page 15 of 29 
13 FEB 2025 
Resection and Endoprosthetic Reconstruction OR Internal Fixation 
Surgery 
 
Surgeon, Nurse, 
Anesthetist, Medical Oncologist, 
Radiation Oncologist 
Tumor excision or fixation, anesthetic, 
antibiotics 
Post-Surgical Recovery  
 
Surgeon, Nurse, 
Anesthetist 
Pain medication, antibiotics, monitoring 
Discharge 
 
Family, Friends 
Pain medication, wound care 
Rehabilitation 
 
Family, Friends, Physical Therapist, 
Occupational Therapist, Wound Care 
Clinics/Nurses 
Physical therapy 
Full Recovery 
 
Yes 
 
 
 
 
 
Patient 
discharged 
from 
Orthopaedic 
Oncology surgeon’s care 
No 
 
OUTCOME: Death, limited physical function, 
many days in hospital, and/or local cancer 
recurrence 
 
 
4.4 Randomization 
 
After providing informed consent, participants will be randomized in a 1:1 ratio to receive either resection and 
reconstruction or internal fixation. A centralized web-based randomization system (www.randomize.net) will be 
used to ensure the concealed allocation of participants. Treatment allocation will be determined using random 
variable block sizes to avoid a substantial imbalance in the number of participants assigned to each treatment 
group. To ensure balance across groups for any key prognostic and treatment-related variables, such as regional 
differences in MBD management, the randomization process will be stratified by: 1) impending or pathologic 
fracture, and 2) clinical site. 
 
4.5 Study Interventions 
 
 
4.5.1 Internal Fixation 
If the participant is randomized to the Internal Fixation treatment arm, the surgery will involve the stabilization of 
the remaining bone with either an intramedullary nail, plate or screw fixation. All standard surgical principles of 
stable internal fixation will be followed. The type of fixation, the surgical approach, and the intra-operative use of 
cement and other adjuvants for disease control will be at the treating surgeon’s discretion. We will, however, 
record these surgical details on the trial CRFs.  
 
4.5.2 Resection and Reconstruction 
If a participant is randomized to the Resection and Reconstruction treatment arm, a proximal femoral resection 
or hip arthroplasty will be carried out as per standard surgical practice. The type of endoprosthesis used for 
reconstruction will be at the treating surgeon’s discretion. Acetabular reconstruction (if any), the surgical 

Version 2.0 
                                                                                                    Page 16 of 29 
13 FEB 2025 
approach, and the intra-operative use of cement and other adjuvants for disease control will also be at the 
discretion of the treating surgeon. We will, however, record these surgical details on the trial CRFs. 
 
4.5.3 Standardization of Perioperative Care 
The random assignment will only specify the type of surgical procedure. To ensure that differences in pre-, peri- 
and post-operative regimens across clinical sites do not impact trial outcomes, the following key aspects will be 
standardized. Pre-operatively, prophylactic antibiotics will be administered within one hour of the start of the 
procedure, with the specific antibiotic at the discretion of the treating surgeon. Post-operatively, antibiotics will 
continue for 24 hours with the specific choice of antibiotic and regimen at the discretion of the treating surgeon. 
Thromboprophylaxis will be prescribed, with the specific agent at the discretion of the treating surgeon. All 
participants will be mobilized within 24 hours of surgery; weightbearing will be advanced as per the treating 
surgeon’s best judgment. The type of anesthesia will be left at the discretion of the local care team. Due to a 
lack of evidence favoring a particular approach, we will not standardize the use of post-operative hip precautions, 
physiotherapy/rehabilitation programs and pain management – rather, they will be left at the discretion of the 
treating surgeon. We will, however, record details of all these variables on the trial CRFs.  
 
4.6 Data Collection and Participant Follow-Up 
At baseline, we will collect pre-operative demographic and cancer-related data from various sources, including 
the participant or proxy, the participant’s medical chart, and/or the participant’s treating surgeon. The data will 
include details such as age, sex and gender, co-morbidities, life-expectancy based on surgeon estimate and pre-
surgical functional status, and anatomic characteristics of the femoral metastatic lesion. Participants will also 
pre-operatively complete the PROM questionnaires. We will document surgical details, peri-operative care, and 
in-hospital data, including the timing of surgery and any co-interventions used that may mediate treatment effects 
(such as post-operative mobilization and therapy), as well as any serious adverse events (SAEs) that occurred 
during hospitalization. After discharge, participants will be followed for one year, during which they will be 
assessed by their treating surgeon at two and six weeks; four, six and nine months; and one-year post-surgery. 
At each visit, we will document physical therapy, ability to ambulate, re-operations, hospitalizations, and SAEs. 
PROM data will be collected at all visits; however, the burden is low due to the short nature of the questionnaire. 
The utility score from the PROPr: PROMIS®-Preference Scoring System will be collected at baseline and 6 and 
12 months. Trial data will be securely stored in the trial database accessible only to authorized personnel. See 
Table 4 below: 
 

Version 2.0 
                                                                                                    Page 17 of 29 
13 FEB 2025 
Table 4. Study Flow 
 
CATEGORY 
STEPS 
DATA COLLECTED 
 
Recruitment 
Identification of Patients 
 
Assessment of Patient Eligibility 
Screening Data 
Informed Consent 
Informed Consent Form 
 
 
Pre-Operative 
(Baseline) 
Pre-Operative 
(Baseline) 
 
RANDOMIZATION 
 
Demographics 
Cancer-related data 
PROMIS®-PROPr questionnaire 
PROMIS® Physical Function 
Internal  
Fixation 
Resection and 
Reconstruction 
 
 
 
 
 
 
 
 
Follow Up  
Visits 
Peri-Operative 
Peri-Operative 
Surgical details 
Peri-operative care 
Serious Adverse Events (SAEs) 
 
 
2 Week 
 
2 Week 
Follow-Up Data Package: 
X-rays; PROMIS® Physical Function 
questionnaire; Demographics, health-
related questions, Mortality Status; 
Patient-reported days at home; 
Recurrence of cancer; SAEs 
 
6 Week 
 
6 Week 
 
Follow-Up Data Package: 
X-rays; PROMIS® Physical Function 
questionnaire; Demographics, health-
related questions, Mortality Status; 
Patient-reported days at home; 
Recurrence of cancer; SAEs 
 
4 Month 
 
4 Month 
 
Follow-Up Data Package: 
X-rays; PROMIS® Physical Function 
questionnaire; Demographics, health-
related questions, Mortality Status; 
Patient-reported days at home; 
Recurrence of cancer; SAEs 
6 Month 
 
 
6 Month 
Follow-Up Data Package: 
X-rays; PROMIS® Physical Function 
questionnaire; Demographics, health-
related questions, Mortality Status; 
Patient-reported days at home; 
Recurrence of cancer; SAEs PROMIS®-
PROPr questionnaire 
 
9 Month 
 
9 Month 
 
Follow-Up Data Package: 
X-rays; PROMIS® Physical Function 
questionnaire; Demographics, health-
related questions, Mortality Status; 
Patient-reported days at home; 
Recurrence of cancer; SAEs 
 
12 Month 
 
12 Month 
 
Follow-Up Data Package: 
X-rays; PROMIS® Physical Function 
questionnaire; Demographics, health-
related questions, Mortality Status; 
Patient-reported days at home; 
Recurrence of cancer; SAEs PROMIS®-
PROPr questionnaire 
PROMIS®: Patient-Reported Outcomes Measurement Information System; PROPr: PROMIS®-Preference Scoring System 
 
 
 

Version 2.0 
                                                                                                    Page 18 of 29 
13 FEB 2025 
 
 
4.6.1 Maximization of Follow-Up 
Post-surgical follow-up is an important element of oncologic care. Therefore, given that our trial follow-up visits 
align with the standard follow-up practice, we anticipate only minimal losses to follow-up in our MBD population. 
Nonetheless, the importance of trial compliance both at the beginning of the trial and at each trial visit will be 
explained to participants. The following procedures will be implemented to minimize losses: 
 
▪ 
Any otherwise eligible patient who is likely to present problems with maintaining follow-up will be excluded; 
▪ 
At the time of randomization, each participant will be asked to provide their contact information, as well as 
the contact information for their family physician and three alternate contacts; 
▪ 
If a participant refuses to return for an assessment, they will be asked if they are willing to provide follow-
up data via telephone;  
▪ 
If a participant cannot be reached, their status regarding the primary trial outcome will be assessed by 
reviewing their medical chart; and 
▪ 
Trial personnel will remind participants via telephone/email of upcoming clinic visits. 
 
4.7 Protecting Against Sources of Bias 
 
Our pragmatic trial design carefully balances the internal validity of our eventual results and their generalizability 
to MBD patients beyond our participating clinical sites. We have carefully considered sources of possible bias 
and safeguards that we might put in place. To ensure internal validity, we will leverage the experience and 
advanced clinical trial infrastructure of our trial team. These include procedures for maximizing recruitment, 
maintaining follow-up, ensuring protocol adherence, and the central adjudication of outcomes, which are detailed 
in the sections below. When possible, we will blind outcomes assessors and data analysts. Bias could intrude 
through co-intervention, in particular, differential peri-operative management. We will, therefore, mandate a 
specific peri-operative management protocol (see 4.5.3 Standardization of Perioperative Care). The 
generalizability of our results is supported by the diversity of our participating hospitals, the screening of all MBD 
patients, and the surgical procedures used daily for MBD across North America and worldwide. 
 
4.7.1 Data Monitoring 
In addition to our strategies to maximize participant retention, we will also implement a Data Monitoring Plan to 
prevent missing data and protect the integrity of the data quality. Ongoing remote data monitoring will be 
conducted by our trial team. Specifically, we will monitor the trial database for missing data, inconsistent or 
implausible data, enrolment rates, the distribution of key data points (e.g., life-expectancy based on surgeon 
estimate, pre-surgical functional status, and anatomic characteristics of the lesion), follow-up rates, the number 
and type of outcomes (e.g., lower than anticipated trial events), and protocol deviations reported by each clinical 
site. Findings from the remote data monitoring will be distributed to the Principal Investigator, as well as to the 
site investigator and personnel at the respective clinical site. Our trial team will work collaboratively with the 
clinical site personnel and site investigators to resolve all identified issues, which may necessitate an ad hoc in-
person monitoring visit. 
 
If an in-person site monitoring visit is required, items that will be reviewed at each monitoring visit will include: 
trial master files, trial procedures, screening data and data verification of 20% of the enrolled trial patients, which 
will be increased if significant issues are identified. Our trial team will also carefully monitor participants’ records 
to ensure that they received the correct interventions. Findings from each monitoring visit will be recorded and 
distributed to the trial Principal Investigator, as well as to the investigator and personnel at the respective clinical 
site. Our trial team will work collaboratively with the clinical site personnel and site investigators to resolve all 
identified issues. Re-training of clinical site personnel will be provided as necessary. 

Version 2.0 
                                                                                                    Page 19 of 29 
13 FEB 2025 
 
We achieved a 95% follow-up rate in our PARITY trial in which patients with MBD of the femur were included. 
Since all MBD patients who have undergone surgical management for an impending or realized pathologic 
fracture require post-surgical follow-up, we anticipate a similar loss to follow-up (LTFU) rate in the PERFORM 
trial. As in our previous trials, patients will only be withdrawn if they no longer consent to participate or if clinical 
site personnel are unable to contact them after several attempts for their one-year follow-up visit. Over the course 
of the trial, clinical site personnel will receive frequent quality control reports generated by the Methods Centre 
personnel who will summarize missing or overdue data. Our trial team will follow-up regarding these reports, as 
well as inform the Principal Investigator who may escalate them to the site investigator to develop a plan to 
submit the overdue data. If necessary, we will conduct in-person monitoring visits to collect any missing or 
overdue data points. 
 
4.7.2 Adjudication of Outcomes  
The use of Central Adjudication Committees (CAC) in randomized controlled trials significantly increases data 
quality and reduces inaccuracies by minimizing biased outcome assessment and between-site variability. The 
membership and responsibilities of the PERFORM CAC will be detailed in the PERFORM CAC Charter. Briefly, 
the PERFORM CAC will be comprised of three orthopaedic oncologists, a medical oncologist and a radiation 
oncologist. Using pre-defined decision rules that will be documented in the PERFORM CAC Charter, the 
PERFORM CAC will adjudicate: 1) case eligibility; 2) unplanned re-operations; 3) local recurrence; 4) serious 
adverse events and 5) mortality (cause of death). The CAC will reach a consensus on all reviewed cases. All 
decisions made by the Committee will be final. We anticipate that the PERFORM CAC will meet quarterly to 
review trial events that require adjudication. 
 
4.7.3 Allocation Concealment and Blinding 
The participants, local trial personnel and our trial team cannot be blinded to the surgical procedure, given the 
differences in surgical incisions for the procedures and the surgeon’s need to know which procedure to perform. 
However, the use of random variable block sizes will minimize the risk of selection bias. Given the obvious 
differences in hardware utilized between the two surgical procedures, it will also be impossible to blind outcomes 
assessors when adjudicating events that require the review of imaging. However, for events that do not require 
the review of imaging, outcomes assessors will be blinded. Finally, safety data reported to the PERFORM Data 
and Safety Monitoring Board (DSMB) will be compiled by a blinded data analyst who is otherwise not involved 
in the trial to ensure that the PERFORM data analyst remains blinded.  
 
4.7.4 Minimization of Crossovers of Trial Interventions 
Unplanned conversions between the two surgical procedures are unlikely, as only patients who are suitable for 
both surgical procedures will be eligible for the trial. The likelihood of crossovers is further reduced due to the 
requirement that the surgical equipment for both procedures be available at all participating clinical sites. When 
possible, local trial personnel will be present in the pre-operative holding area to obtain study consent and during 
surgery to ensure that the patient undergoes the correct surgical procedure. Nevertheless, any patients who do 
crossover will be analyzed in the group to which they were originally allocated, maintaining the intention-to-treat 
approach planned for our analysis. 
 
 
 
 
 
 
 

Version 2.0 
                                                                                                    Page 20 of 29 
13 FEB 2025 
5.0 Statistical Plan 
 
5.1 Sample Size Determination 
The use of hierarchically assessed composite outcomes is becoming more frequent in clinical trials, and it offers 
several benefits. By utilizing a pre-defined rank, statistical power increases while avoiding concerns of increased 
type I errors due to multiplicity. This ranked approach also aligns with clinical practice as patients and care 
providers are typically interested in the treatment effect on multiple outcomes with a defined hierarchy. Detailed 
simulations were performed to determine the appropriate sample size to adequately power the study. Table 5 
lists the distributional assumptions for each component of the composite outcome by treatment arm. Using 
10,000 simulations of these distributions, we determined that 300 patients (150 per group) provided over 90% 
power to detect superiority with a two-sided alpha of 5% tested with the U-statistic described by Bebu and Lachin 
26. To account for up to 10% attrition, the trial plans to enroll 334 patients. 
 
Table 5 : Input for sample size estimation. 
Rank Outcome 
Resection and 
Reconstruction 
Internal Fixation 
1 
Death within 12 months 
30% 
30% 
2 
Physical function (ability to perform everyday activities) by 4 months 
 
Unable to do 
5% 
10% 
 
With much difficulty 
20% 
25% 
 
With some difficulty 
40% 
40% 
 
With little difficult 
25% 
20% 
 
Without any difficulty 
10% 
5% 
3 
Days at home within 365 days, mean (SD) 
340 (20) 
300 (20) 
 
 
5.2 Statistical Methods 
 
5.2.1 Analysis Plan Overview 
While conducting the analyses, the data analysts will remain blinded to treatment allocation. The analysis and 
reporting of the trial will follow the CONSORT criteria (www.consort-statement.org).  The process of participant 
enrolment and flow through the study will be summarized using a flow diagram. Participant demographics and 
baseline outcome variables will be summarized using descriptive statistics reported as mean (standard deviation) 
or median (interquartile range) for continuous variables depending on the distribution, and count (percent) for 
categorical variables.  All analyses will use the intention-to-treat principle. We do not plan to conduct a formal 
interim analysis for efficacy, as the trial will not be stopped early for benefit due to the risk of overestimating 
treatment effects.  Secondary analyses will be exploratory with no adjustments for multiple comparisons. 
 
5.2.2 Primary Outcome Analysis 
We will hierarchically assess the primary composite outcome using the Win Ratio method. The Win Ratio method 
is based on the principle that each participant in the clinical trial is compared with every other participant within 
each stratum in a pairwise manner. All-cause mortality comparisons will be time-to-event and local cancer 
recurrence will allow for recurrent events using a frailty model. The pairwise comparison proceeds in a hierarchal 
fashion – for example, starting with mortality, followed by physical function, followed by days at home, and finally 
by local cancer recurrence when participants cannot be differentiated on an outcome of higher importance. If 
two paired participants both experienced a local cancer recurrence, we will assume a greater frequency of 
recurrences to be worse. If two paired participants have the same mortality status or frequency of recurrences, 
we will assume earlier events are worse. For each pairwise comparison, the treatment groups are assigned a 

Version 2.0 
                                                                                                    Page 21 of 29 
13 FEB 2025 
win, loss, or tie. The Win Ratio is the frequency of a favorable outcome in participants assigned to resection and 
reconstruction divided by the frequency of a favorable outcome in participants assigned to internal fixation with 
a 95% CI and corresponding p-value calculated using the methods described by Finkelstein and Schoenfeld.  
 
5.2.3 Secondary Outcomes Analyses 
We will analyze all-cause mortality with a Cox proportional hazards model, re-operation for disease relapse and 
other indications with frailty models to account for recurrence, and patient-reported outcomes using linear 
regression models. 
 
5.2.3 Subgroup Analyses 
We will explore two clinically relevant subgroups based on life expectancy at baseline and fracture status. Life 
expectancy will be dichotomized as life expectancy of greater than or equal to one year versus less than one 
year, and fracture status will be classified as either impending fracture or realized pathologic fracture. We 
hypothesize that participants with a longer life expectancy and those with an impending fracture prior to surgery 
will have greater treatment benefits from the more invasive surgical procedure. We will stratify our primary model 
by the subgroup covariate to assess the presence of effect modification. We will assess the credibility of any 
observed subgroup effects using the Instrument to assess the Credibility of Effect Modification Analyses 
(ICEMAN) criteria.  
 
5.2.4 Health Economic Analysis 
An economic evaluation of this trial will be conducted to compare the one-year costs and outcomes between the 
two treatment allocations.  QALYs will be utilized as the primary outcome, as is recommended in many countries 
(e.g., Canada, the United Kingdom and the United States)27–29.  Life years (LYs) will be used as a secondary 
outcome. 
 
For the base case analysis, Canadian unit costs will be applied to the economic data collected as part of the trial 
to estimate the direct (e.g., hospitalizations, surgeries) and indirect costs (e.g., productivity losses) associated 
with the two treatment allocations. QALYs will be derived using the health utility scores from the PROMIS-PROPr 
questionnaires collected in the trial using an area under the curve.  The base case analysis will use the Canadian 
algorithm to derive the PROMIS-PROPr health utility scores30.  Multiple cost-effectiveness acceptability curves 
(CEACs) presenting the probability of each of the treatment allocations to be cost-effective at several willingness-
to-pay thresholds (e.g., $50,000 or $100,000 per QALY gained) will be used to summarize uncertainty.  Costs 
and outcomes will be discounted at 1.5% as per the recommendations of the current Canadian guidelines, and 
results will be presented from both a payer (e.g., Ministry of Health) and a societal perspective27.  Scenario 
analyses will be conducted to explore the impact of varying key assumptions on the results (e.g., using unit costs 
from the United States, discount rate of 3%).  The analysis will be conducted and reported according to best 
practices for economic evaluations of healthcare technologies (e.g., how to deal with missing or censored 
data)31,32. 
 
5.2.5 Sensitivity Analyses 
Assessment of the sensitivity or robustness of the findings to the key assumptions is essential in clinical trials. 
The following sensitivity analyses will be performed:  
 
1) Baseline Prognostic Imbalance Analysis: This analysis will assume a baseline prognostic imbalance between 
the treatment groups. Adjusted analyses, employing Cox regression models, will be utilized to examine and 
control for the possible influence of patient factors that might be associated with the elements of the 
hierarchal composite outcome. 
2) “As-Treated” Analysis: This sensitivity analysis will account for crossovers in the surgical intervention. The 
actual surgical intervention will be the independent variable. 
 

Version 2.0 
                                                                                                    Page 22 of 29 
13 FEB 2025 
6.0 Data Collection and Management 
The study CRFs are the primary data collection instrument for the study.  Participating clinical sites will be 
provided with the study CRFs prior to the initiation of local enrolment. All data requested on the CRFs must be 
recorded, and any missing data must be explained. 
 
6.1 Data Transmission  
 
6.1.1 Electronic Data Capture System – Trial Database 
We will utilize the REDCap Cloud system as the PERFORM trial database.  All data will be stored on the secure 
server with no data stored locally on the user’s computer. Unauthorized access to the system is restricted by 
means of a firewall and data encryption protection applied to all communications and data transmissions. Regular 
system maintenance ensures security risks are minimized.  The database will store clinical trial data entered by 
local site personnel from the PERFORM CRFs. Data will be organized according to trial visit. The preliminary 
visit schedule is as follows (with permissible visit windows if applicable):  
• 
Screening,  
• 
Baseline,  
• 
2-Week Follow-Up (1 – 3 weeks post-surgery),  
• 
6-Week Follow-Up (4 – 8 weeks post-surgery),  
• 
4-Month Follow-Up (3 – 5 months post-surgery),  
• 
6-Month Follow-Up (5 - 7 months post-surgery),  
• 
9-Month Follow-Up (8 - 11 months post-surgery), and  
• 
1-Year Follow-Up (≥ 12 months post-surgery). 
 
6.1.2 Randomization System 
 
The Randomize.Net randomization system requires internet access and can be used on any device that can 
connect to the internet (e.g., computer, tablet, smartphone). Randomize.Net is a comprehensive randomization 
service for clinical trials that allows clients to define features and customize them specific to their trial, including 
stratification, multiple treatments, block sizes, masking and participating clinical site identifiers (in order for the 
system to generate unique participant identifiers). Online support is available for questions regarding set-up, 
updates and problems using the system. The database will store the stratification trial data entered by local site 
personnel, as well as the treatment allocation and unique participant identifier generated by the randomization 
system.  
 
6.2 Data Integrity 
 
6.2.1 Data Transmission 
Study personnel at each participating clinical site will submit the required data, as detailed on the CRFs, to the 
Methods Center using the RedCap EDC system.  Study personnel at each participating clinical site will receive 
unique login credentials (username and password) for the EDC systems and will be able to view and modify data 
for participants recruited at their respective clinical site.  Study personnel at each participating clinical site will 
receive a Study Resource Binder, which will include detailed instructions on using the REDCap EDC system.  
 
6.2.2 Data Integrity 
The REDCap EDC system uses a variety of mechanisms for checking data at the time of entry including skip 
logic, range checks and data type checks.  Data cleaning procedures will also be performed on a regular basis. 
Upon receipt of new data, Methods Center personnel will query all missing, implausible, or inconsistent data.  
Study personnel will be able to review all open queries for their respective clinical site in the system and will be 

Version 2.0 
                                                                                                    Page 23 of 29 
13 FEB 2025 
required to promptly respond.  The Study Resource Binder will include detailed instructions on addressing 
queries in the RedCap EDC system. 
 
6.2.2 Data Preservation and Sharing 
Upon the completion of the follow-up period for all trial participants, and only once all data cleaning activities 
have been completed, designated trial team members will be responsible for the notification to the Data Manager 
to remove access to the trial database for all local site personnel. Only the Data Manager, Research Manager, 
Research Assistant and Study Statistician will continue to have access to the trial database and randomization 
system. Once the data is extracted and primary analyses are completed and published, the trial team members 
will make the data available upon request to collaborators for secondary analyses.  
7.0 Ethical Considerations 
This study is to be conducted according to international standards of Good Clinical Practice, applicable 
government regulations, and institutional research policies and procedures. Both study arms fall within the 
spectrum of current standard practice, as do the standardized post-operative follow-up visits. 
 
7.1 Research Ethics Approval 
This study protocol will be submitted to a properly constituted independent ethics committee (such as a research 
ethics board [REB] or an institutional review board [IRB]), in agreement with local legal prescriptions, for formal 
approval of the study conduct. The Methods Center at McMaster University will receive ethics approval from the 
Hamilton Integrated Research Ethics Board (HiREB) prior to the distribution of this protocol and any approved 
study materials to participating clinical sites. At each participating clinical site, the decision of the appropriate 
local ethics committee concerning the conduct of the study will be made in writing to the local investigator. A 
copy of this decision will be provided to the Methods Center prior to the local commencement of this study. 
 
7.2 Informed Consent Form 
All patients eligible for this study will be provided with a Participant Information Sheet and Informed Consent 
Form describing this study and providing sufficient information for patients to make an informed decision about 
their participation in this study. The Informed Consent Form will comply with the Health Insurance Portability and 
Accountability Act, if applicable, and will be submitted with the study protocol for formal review and approval by 
the appropriate ethics committee. The formal consent of a study participant, using the ethics committee-approved 
Informed Consent Form, must be obtained prior to the subject undergoing any study procedure. 
 
7.3 Confidentiality 
Information about study participants will be kept confidential and managed in accordance with the following rules:  
 
▪ 
All study-related information will be stored securely; 
▪ 
All study participant information will be stored in locked file cabinets (for paper documents) and/or secure 
digital files, and accessible only to study personnel; 
▪ 
All paper and electronic CRFs will be identified only by a coded participant ID number and initials; and 
▪ 
All study databases will be password-protected. 
 
The communication, transmission and storage of participant data will comply with the applicable ethics 
committee. In the event that a participant revokes authorization to collect or use personal health information, the 
participating clinical site retains the ability to use all information collected prior to the revocation of participant 
authorization. For participants who have revoked authorization to collect or use personal health information, 
attempts will be made to obtain permission to collect at least vital status at the end of their scheduled study 
period. 
 

Version 2.0 
                                                                                                    Page 24 of 29 
13 FEB 2025 
7.4 Protocol Amendments 
Any amendments to the study protocol that may affect the conduct of the study or the potential safety of, or 
benefits to, participants (e.g., changes to the study objectives, study design, sample size, or study procedures) 
will require a formal amendment to the protocol. Any protocol amendments will be approved by the Principal 
Investigator, the HiREB, local ethics committees and funders (as needed). Participating clinical sites will also be 
required to submit amendment requests to their local ethics committees to obtain approval for the amendment, 
and to provide the Methods Center with a copy of this approval. Administrative changes (e.g., minor corrections 
or clarifications that have no effect on the way the study is conducted) will not need to undergo a formal 
amendment process. 
 
7.5 Safety and Adverse Events 
 
7.5.1 Definitions 
 
7.5.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness, or experience that develops or worsens in severity during 
the course of the study or can be related when there is a reasonable possibility that the event might have been 
caused by study participation. 
 
7.5.1.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event (SAE) is any AE that is any of 
the following: 
▪ 
Fatal; 
▪ 
Life-threatening; 
▪ 
Requires or prolongs hospital stay; 
▪ 
Results in persistent or significant disability or incapacity; 
▪ 
A congenital anomaly or birth defect; or 
▪ 
An important medical event. 
 
7.5.1.3 Unanticipated Problems Resulting in Risk to Participants or Others 
Any incident, experience or outcome that meets all of the following criteria will be considered an unanticipated 
problem that results in risk to participants or others: 
 
▪ 
Unexpected in nature, severity, or frequency  
▪ 
Related or possibly related to participation in research (i.e., possibly related means there is reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved 
in the research); and 
▪ 
Suggests that the research places participants or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Unanticipated problems resulting in risk to participants or others encompass more than what one usually thinks 
of as AEs. ‘Problems involving risk’ may not necessarily result in harm. For example, misplacing a participant’s 
study records containing identifiable private information introduces the risk of breach of confidentiality. 
Confidentiality may or may not be breached, but either way, this would be a reportable event. Risks to others 
must also be reported. For example, an unexpected outburst during questionnaire administration by a study 
participant that put study personnel at risk would be a reportable event. 
 

Version 2.0 
                                                                                                    Page 25 of 29 
13 FEB 2025 
7.5.2 Clinical Site Reporting 
Participating clinical sites are responsible for reporting related AEs and all SAEs (irrespective of the relatedness 
of the event to the study intervention) to the Methods Center immediately, as well as their local ethics committee 
in accordance with local reporting requirements. Unanticipated problems resulting in risk to participants or others 
are also to be promptly reported to the Methods Center and the appropriate ethics committee if required. 
 
7.5.2.1 Notifying the Methods Center 
Participating clinical sites are responsible for reporting related AEs and SAEs to the Methods Center via the 
Adverse Event Form in the REDCap Cloud database.  The original Adverse Event Forms will be kept in the 
relevant participant’s file. Significant new information on ongoing SAEs will also be promptly provided to the 
Methods Center via the REDCap Cloud system. Unanticipated problems resulting in risk to participants or others 
are also to be promptly reported to the Methods Center via telephone or email. Detailed instructions on reporting 
related AEs, SAEs or unanticipated problems resulting in risk to participants or others will be provided to study 
personnel at each participating clinical site in the Study Resource Binder. 
 
7.5.2.2 Notifying the Appropriate Ethics Committee 
Participating clinical sites are responsible for reporting SAEs and unanticipated problems resulting in risk to 
participants or others to their local ethics committee (such as an IRB or REB), or a central ethics committee, in 
accordance with local reporting requirements. Copies of each report and documentation of ethics committee 
notification and receipt will be kept in the participating clinical site’s study file. 
 
7.5.3 Participant Safety and Monitoring 
 
7.5.3.1 Participant Risks and Benefits 
Both surgical techniques and associated hardware are indicated and approved for use in MBD patients with 
impending or realized pathologic fractures of the proximal femur, and they are both commonly used across North 
America in this patient population. The typical risks of surgery, such as bleeding, infection, deep vein thrombosis 
and neurovascular injury, apply equally to participants irrespective of the trial arm. These are inherent risks within 
the operative procedures for the treatment of this condition. Additional risks associated with internal fixation 
include revision surgery as a result of implant failure or disease recurrence. Additional risks associated with 
resection and endoprosthetic reconstruction include a potential increased risk of a surgical site infection, given 
the complexity of the procedure and the more invasive nature of the procedure. Our trial’s DSMB will closely 
monitor event reporting and, should a differential risk of benefits be identified, they will consider stopping the 
trial. As in any trial, there is a potential risk of a breach of confidentiality. However, our trial team has extensive 
experience in the management of sensitive patient information and all possible precautions will be taken to 
ensure the security of these data. We will also work with clinical site personnel to ensure confidentiality is upheld 
at clinical sites. 
 
Studies show that surgical site infections are less common with internal fixation, only a few percent, compared 
to up to 10 percent with reconstruction, because it is less invasive, meaning it has smaller incisions. However, 
there is a concern that with this surgery there may an issue with increased likelihood of recurrent disease, up 
to 15 or 20 percent, compared to almost none with reconstruction. In fact, reconstruction approaches can last 
longer, which is important as people live longer with metastatic bone disease. However, these surgeries are 
complicated, may take a bit longer to complete, and can be expensive. They also have a higher chance of 
complications, like hip dislocations (a few percent) after the surgery. 
 
It is not clear at this time that one surgical technique will provide any benefit over another. However, all 
participants will receive treatment for their impending or realized pathologic fracture in a manner that is 

Version 2.0 
                                                                                                    Page 26 of 29 
13 FEB 2025 
considered acceptable and within the standard of care. They may also benefit from the additional observation 
provided, as well as trial personnel communication and patient-reported outcomes questionnaires.  
 
7.5.3.2 Data and Safety Monitoring Board 
As per the principles established by the Data Monitoring Committees: Lessons, Ethics, Statistics (DAMOCLES) 
Study Group charter, we will establish a DSMB prior to the commencement of the feasibility phase of the 
PERFORM trial to oversee the safety of the trial participants and the overall conduct of the trial. The PERFORM 
DSMB will consist of members who are independent of the trial, free of conflicts with any of the investigative 
team, and will include experts in orthopaedic oncology and biostatistics, as well as an independent patient 
representative. The membership and responsibilities of the PERFORM DSMB will be detailed in the PERFORM 
DSMB Charter. Briefly, the DSMB will review accumulated safety data (i.e., SAEs) from the trial reports and 
advise the Principal Investigators and trial team on items related to trial safety. The DSMB is responsible for 
safeguarding the interests of participants, assessing the safety and efficacy of trial procedures and monitoring 
the overall conduct of the trial. 
 
8.0 Knowledge Dissemination 
The results of the study will be submitted for publication regardless of whether there are significant findings, as 
well as posted on ClinicalTrials.gov. Every attempt will be made to ensure that the amount of time between 
completion of data collection and release of study findings is minimized. Knowledge Dissemination will be 
conducted under the guidance of patient and caregiver advisors and detailed in a separate Knowledge 
Dissemination Plan.  
 
9.0 Secondary and Sub-Study Manuscripts 
We will strongly encourage requests from co-investigators to publish PERFORM secondary and sub-study 
manuscripts. The Knowledge Dissemination Plan will provide guidelines for the submission of proposals as well 
as authorship of secondary and sub-study manuscripts. 
 
 
 

Version 2.0 
                                                                                                    Page 27 of 29 
13 FEB 2025 
10.0 References 
 
1. 
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. 
doi:https://doi.org/10.3322/caac.21654 
2. 
Cancer of Any Site - Cancer Stat Facts. SEER. Accessed June 22, 2023. 
https://seer.cancer.gov/statfacts/html/all.html 
3. 
Rogers DL, Raad M, Rivera JA, et al. Life Expectancy After Treatment of Metastatic Bone Disease: An 
International Trend Analysis. JAAOS - J Am Acad Orthop Surg. 2024;32(6):e293. doi:10.5435/JAAOS-D-23-00332 
4. 
Kistler BJ, Damron TA. Latest Developments in Surgical and Minimally Invasive Treatment of Metastatic Bone 
Disease. Curr Surg Rep. 2014;2(4):49. doi:10.1007/s40137-014-0049-y 
5. 
Li S, Peng Y, Weinhandl ED, et al. Estimated number of prevalent cases of metastatic bone disease in the US 
adult population. Clin Epidemiol. 2012;4:87-93. doi:10.2147/CLEP.S28339 
6. 
Aboulafia AJ, Levine AM, Schmidt D, Aboulafia D. Surgical therapy of bone metastases. Semin Oncol. 
2007;34(3):206-214. doi:10.1053/j.seminoncol.2007.03.002 
7. 
Yu Z, Xiong Y, Shi R, et al. Surgical management of metastatic lesions of the proximal femur with pathological 
fractures using intramedullary nailing or endoprosthetic replacement. Mol Clin Oncol. 2018;8(1):107-114. 
doi:10.3892/mco.2017.1503 
8. 
Willeumier JJ, van de Sande M a. J, van der Wal RJP, Dijkstra PDS. Trends in the surgical treatment of 
pathological fractures of the long bones: based on a questionnaire among members of the Dutch Orthopaedic Society 
and the European Musculo-Skeletal Oncology Society (EMSOS). Bone Jt J. 2018;100-B(10):1392-1398. doi:10.1302/0301-
620X.100B10.BJJ-2018-0239.R1 
9. 
Gusho CA, Clayton B, Mehta N, et al. Internal fixation versus endoprosthetic replacement of the proximal femur 
for metastatic bone disease: Single institutional outcomes. J Orthop. 2021;28:86-90. doi:10.1016/j.jor.2021.11.003 
10. 
Guzik G. Oncological and functional results after surgical treatment of bone metastases at the proximal femur. 
BMC Surg. 2018;18(1):5. doi:10.1186/s12893-018-0336-0 
11. 
Sarahrudi K, Greitbauer M, Platzer P, Hausmann JT, Heinz T, Vécsei V. Surgical treatment of metastatic fractures 
of the femur: a retrospective analysis of 142 patients. J Trauma. 2009;66(4):1158-1163. 
doi:10.1097/TA.0b013e3181622bca 
12. 
Steensma M, Boland PJ, Morris CD, Athanasian E, Healey JH. Endoprosthetic treatment is more durable for 
pathologic proximal femur fractures. Clin Orthop. 2012;470(3):920-926. doi:10.1007/s11999-011-2047-z 
13. 
Di Martino A, Martinelli N, Loppini M, Piccioli A, Denaro V. Is endoprosthesis safer than internal fixation for 
metastatic disease of the proximal femur? A systematic review. Injury. 2017;48:S48-S54. doi:10.1016/S0020-
1383(17)30658-7 
14. 
Wodajo F, Colman M, Getty P. AAOS Clinical Practice Guideline Summary: Treatment of Metastatic Carcinoma 
and Myeloma of the Femur. JAAOS - J Am Acad Orthop Surg. 2023;31(3):e118. doi:10.5435/JAAOS-D-21-00888 
15. 
Schneider PJ, Evaniew N, McKay P, Ghert M. Moving Forward Through Consensus: A Modified Delphi Approach 
to Determine the Top Research Priorities in Orthopaedic Oncology. Clin Orthop. 2017;475(12):3044-3055. 
doi:10.1007/s11999-017-5482-7 

Version 2.0 
                                                                                                    Page 28 of 29 
13 FEB 2025 
16. 
Damron TA. CORR Insights®: Moving Forward Through Consensus: A Modified Delphi Approach to Determine the 
Top Research Priorities in Orthopaedic Oncology. Clin Orthop. 2017;475(12):3056-3059. doi:10.1007/s11999-017-5501-8 
17. 
Mullins CD, Abdulhalim AM, Lavallee DC. Continuous Patient Engagement in Comparative Effectiveness 
Research. JAMA. 2012;307(15):1587-1588. doi:10.1001/jama.2012.442 
18. 
The Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) Investigators. Comparison of Prophylactic 
Intravenous Antibiotic Regimens After Endoprosthetic Reconstruction for Lower Extremity Bone Tumors: A Randomized 
Clinical Trial. JAMA Oncol. Published online January 6, 2022. doi:10.1001/jamaoncol.2021.6628 
19. 
Araki N, Chuman H, Matsunobu T, et al. Factors associated with the decision of operative procedure for proximal 
femoral bone metastasis: Questionnaire survey to institutions participating the Bone and Soft Tissue Tumor Study Group 
of the Japan Clinical Oncology Group. J Orthop Sci. 2017;22(5):938-945. doi:10.1016/j.jos.2017.05.012 
20. 
Di Martino A, Martinelli N, Loppini M, Piccioli A, Denaro V. Is endoprosthesis safer than internal fixation for 
metastatic disease of the proximal femur? A systematic review. Injury. 2017;48:S48-S54. doi:10.1016/S0020-
1383(17)30658-7 
21. 
Wodajo FM. Prevention and Treatment of Pathologic Femur Fractures: Evidence as of 2019. Instr Course Lect. 
2021;70:465-474. 
22. 
Meynard P, Seguineau A, Laumonerie P, et al. Surgical management of proximal femoral metastasis: Fixation or 
hip replacement? A 309 case series. Orthop Traumatol Surg Res. 2020;106(6):1013-1023. doi:10.1016/j.otsr.2020.05.007 
23. 
Fogel J, Ng V, Schubert T, et al. A Survey to Determine the Zone of Equipoise for the Proximal FEmur Resection 
or Internal Fixation fOR Metastases (PERFORM) Randomized Controlled Trial. Published online July 26, 2024. 
doi:10.31219/osf.io/fx8qy 
24. 
Blank AT, Lerman DM, Shaw S, et al. PROMIS® scores in operative metastatic bone disease patients: A 
multicenter, prospective study. J Surg Oncol. 2018;118(3):532-535. doi:10.1002/jso.25159 
25. 
Patient Cost Estimator | CIHI. Accessed October 22, 2021. https://www.cihi.ca/en/patient-cost-estimator 
26. 
Bebu I, Lachin JM. Large sample inference for a win ratio analysis of a composite outcome based on prioritized 
components. Biostat Oxf Engl. 2016;17(1):178-187. doi:10.1093/biostatistics/kxv032 
27. 
Guidelines for the Economic Evaluation of Health Technologies: Canada (4th Edition). :76. 
28. 
National Institute for Health and Care Excellence. Guide to the Methods of Technology Appraisal 2013. National 
Institute for Health and Care Excellence (NICE); 2013. Accessed October 21, 2021. 
http://www.ncbi.nlm.nih.gov/books/NBK395867/ 
29. 
Sanders GD, Neumann PJ, Basu A, et al. Recommendations for Conduct, Methodological Practices, and Reporting 
of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine. JAMA. 2016;316(10):1093-
1103. doi:10.1001/jama.2016.12195 
30. 
Xie F, Pullenayegum E, Gaebel K, et al. A Time Trade-off-derived Value Set of the EQ-5D-5L for Canada. Med 
Care. 2016;54(1):98-105. doi:10.1097/MLR.0000000000000447 
31. 
Ramsey SD, Willke RJ, Glick H, et al. Cost-effectiveness analysis alongside clinical trials II-An ISPOR Good 
Research Practices Task Force report. Value Health J Int Soc Pharmacoeconomics Outcomes Res. 2015;18(2):161-172. 
doi:10.1016/j.jval.2015.02.001 
32. 
Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting Standards 
(CHEERS) statement. BMJ. 2013;346:f1049. doi:10.1136/bmj.f1049 

Version 2.0 
                                                                                                    Page 29 of 29 
13 FEB 2025