External Beam Radiation Therapy Post Surgery in Patients With Lower Extremity Bone Metastases Randomized Efficacy Trial

Study Overview
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Brief Summary
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The objective of the present study is to evaluate the effectiveness of post-operative radiation therapy in lower extremity bone metastases. This trial will compare the health outcomes of patients receiving radiation therapy after Orthopaedic surgery to patients who will not receive radiation therapy post-surgery. The primary objective of the study is to compare the need for a subsequent surgery at the same treatment site within 12 months of the initial surgery. Additionally, the need for radiation or re-irradiation, functional status, performance status, pain scores, radiologically detected local disease progression, and overall length of survival will be compared at clinical endpoints for the two study arms. It is hypothesized that those randomized to receive post-operative radiation therapy will less likely need a subsequent surgery within the 12 months after the primary surgical intervention. This may optimize the quality of life for this patient population.

Detailed Description
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The incidence of bone metastases in advanced cancer patients is substantial, representing 70% of all metastatic sites. Approximately 5-10% of all patients with bone metastases develop pathological fractures. Surgical reconstruction can be helpful following fracture or prophylactically in cases of an impending fracture. In these cases, post-operative radiation is the current clinical practice in North America and many countries around the world. Post-operative radiation has the potential to support bone healing and prevent tumor progression while also decreasing the need for subsequent orthopaedic surgeries to the same site. A recent systematic review, however, challenged the evidence on its efficacy and adoption as standard of care in this patient population. As well, post-operative radiation requires additional visits to the radiation centre (associated with added costs and efforts for both the patients and the healthcare system). There is also a pain flare phenomenon, in which up to 40% of patients receiving radiation for palliative bone metastases experience pain within 1-5 days following radiation. The pain can last for 10 days and may acutely mask potential clinical benefits of radiation. Given that there is potential negative impact to these patients who are palliative with a relatively short lifespan, it is important that the efficacy of post-operative radiation is rigorously evaluated. We propose a multicenter randomized controlled trial to assess the efficacy of post-operative radiation following orthopaedic surgery in patients with lower extremity bone metastases. 300 patients with pending or established lower extremity pathological fracture will be recruited to a trial of surgery alone vs. surgery with post-operative radiation. The primary endpoint is a second surgery to the same site within 12 months. Secondary outcomes include quality of life, pain and functional outcome markers, radiation or re-irradiation as applicable, a second surgery within 24 months for those patients alive, overall survival and cost effectiveness.

Official Title
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A Phase III Multicenter Randomized Trial Assessing the Efficacy of Post-Operative Conventional External Beam Radiation Therapy Following Orthopaedic Surgery in Patients With Lower Extremity Bone Metastases

Conditions
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Bone Metastases, Lower Extremity Fracture, Pathological Fracture, Impending Fracture

Intervention / Treatment
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* Radiation: External beam radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is the patient 18 years of age or older at the time of randomization? Does the patient have histologically or cytologically proven malignancy? Does the patient have imaging confirming presence of bone metastases corresponding to clinically painful area? Does the patient have established bone metastatic pathological fracture(s) lower extremity OR has impending pathological fracture(s)? Does patient have KPS ≥40 with estimated survival of ≥ 6 months? Was informed consent obtained? Exclusion Criteria: Did the patient have a prior impending or prior pathological fracture to the site and was previously fixed with orthopaedic surgery? Did the patient receive prior radiation to the site (external beam or stereotactic body radiation)? Did the patient have a radio-resistant tumor (renal cell carcinoma or melanoma)? Did the patient plan for radical resection of the bone metastases? Did the patient receive or is planning to receive other intra-operative tumor ablative therapies?

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to receive 1 of the 2 treatment arms.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Surgery Alone<br>Patients with lower extremity bone metastases will receive surgical fixation/reconstruction but will not receive any post-operative radiation therapy. | |
| Active Comparator: Surgery and Post-Operative Radiation Therapy<br>Patients with lower extremity bone metastases will receive surgical fixation/reconstruction and will receive any post-operative radiation therapy. | Radiation: External beam radiation therapy<br>* The post-operative radiation will cover entire prosthesis/surgical fixation device and will consist of the dose fractionation of: 20 Gy in 5 fractions or 30 Gy in 10 fractions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subsequent surgery after primary surgery | Requirement of a subsequent surgery | 12 months following the date of primary surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Re-irradiation/radiation | Requirement for re-irradiation in arm 2 or radiation in arm 1 | Weeks 2 & 6, Months 3, 6, 12, 18, and 24 | 
| Subsequent surgery (between 13 months and 24 months) | Requirement of subsequent surgery past 12 months (between 13 months and 24 months) | Between 13 months and 24 months following date of primary surgery | 
| Post-operative functional status and Karnofsky Performance Status (KPS) | The best, median, and worst post-operative functional status and KPS will be derived for each patient, and the Wilcoxin rank sum test will be used to compare the difference between treatment arms | Weeks 2 & 6, Months 3, 6, 12, 18, and 24 | 
| Post-operative pain and analgesic use | The lowest, median, and worst post-operative pain score will be derived for each patient, and the Wilcoxin rank sum test will be used to compare the difference between treatment arms. The cumulative and mean of analgesic use will presented by treatment arm. | Weeks 2 & 6, Months 3, 6, 12, 18, and 24 | 
| Radiologically determined local progression | Time to radiological local disease progression is defined as the time from randomization to the date of documented radiological logical disease progression or death whichever comes first. | Months 3, 6, 12, 18, and 24 | 
| Quality of life through functional ability | Quality of life measured measured using EORTC quality of life questionnaire (QLQ)-C15-Pal and EORTC quality of life questionnaire (QLQ)-BM22. This questionnaire includes for multi-item scales and six individual items. All items were scaled from 1 (not at all) to 4 (very much) in which a higher score indicates greater distress in symptom scales while a higher score in functional scale indicates greater functional ability. The EORTC QLQ-BM22 is a 22-item module that addresses disease symptoms related to bone metastasis. It has four subscales (painful sites, pain characteristics, functional interference and psychosocial aspects). All items were scaled from 1 (not at all) to 4 (very much), in which a higher score indicates greater distress in symptom scales while a higher score in functional scale indicates greater functional ability | Day of randomization, weeks 2 and 6, months 3, 6, 12, 18, and 24 | 
| Overall survival | Overall survival is defined as the time from randomization to the date of death from any cause, or censored at their last known alive data before or on data cutoff date | Weeks 2 & 6, Months 3, 6, 12, 18, and 24 | 
| Cost-effectiveness | Determination of the incremental cost-effectiveness by prospectively collecting economic and resource utilization information. The objective is to determine an incremental cost effectiveness ratio reported as a cost per subsequent surgery avoided for both treatment arms. The mean overall cost per patient for each of the two study treatment arms will be calculated to determine the addition cost per surgery avoided. | Weeks 2 & 6, Months 3, 6, 12, 18, and 24 |