Neoplasms

Symptoms and General Pathology

All Conditions

Musculoskeletal Diseases

Neoplasm Metastasis

Bone Diseases

Neoplastic Processes

No Intervention is required for this study

No Intervention

Hesham Abdelbary, MD

The skeletal system is one of the most common sites for metastatic spread of many malignancies. Metastatic bone disease (MBD) can be associated with a significant reduction in quality of life due to debilitating pain and pathologic fractures. Multiple providers are involved in treating patients with MBD which can result in fragmented and delayed delivery of care. This fragmentation also leads to poor outcomes and patient experience. This project will assess whether it is feasible to integrate a multidisciplinary Rapid Access Metastatic Bone Disease Program (RAMP) at the Investigator's institution to improve the delivery of care to patients presenting with pelvic and lower extremity MBD. The goals of RAMP are: 1) Improve outcome and quality of care provided to MBD patients. 2) Improve patients experience through the participant's treatment journey. 3) Avert extra health care costs caused by unplanned admissions through ER and decrease redundancies due to unnecessary multiple clinic visits and double-ordering of diagnostic tests. This project will be designed to optimize the use of existing clinic resources more efficiently. Cancer patients and their loved ones will be actively engaged in the design of this project to better achieve its goals.

More than 140,000 new cases of cancer are diagnosed annually in Canada, with nearly half of which metastasize to bone. The skeletal system is one of the most common sites for metastatic spread of many visceral malignancies, especially cancers originating from breast, prostate, lung, thyroid and kidney. Hematologic malignancies, such as multiple myeloma and lymphoma, also primarily manifest with multiple aggressive lytic lesions in the bone. A Skeletal Related Event (SRE) is the term given when a metastatic lesion arises in bone. With advances in effective systemic treatment and supportive care, the duration of survival of patients with bone metastases has improved substantially. This improvement in survival can be accompanied by significant morbidity and reduction in quality of life secondary to pain, pathologic fracture, and spinal cord compression from SREs. Pain and impaired mobility occur in approximately 65%-75% of patients with bone metastases. SREs are also associated with high economic burden secondary to increased costs of treatment and high rates of hospitalizations. It is estimated that a single episode of SRE can cost the medical system 36,462 USD. The current literature reflects significant diversity in the approach of diagnosing and treating MBD. Therefore, numerous studies have advocated the need for a multidisciplinary clinic to co-ordinate the diagnosis, treatment, and rehabilitation of patients with MBD patients. This strategy has also been proposed to improve the delivery of early and multimodal palliative management for patients in a cost effective approach.

Aims and Objectives: The aims of this project are: 1) Assess feasibility of establishing and integrating a multidisciplinary Rapid Access Metastatic Bone Disease Program (RAMP) at the Investigator's institution to improve the delivery of care to patients presenting with pelvic and lower extremity MBD. 2) Centralize referrals and streamline clinical care pathways for patients diagnosed with MBD to pelvis and lower extremity. 3) Assess improvement in outcome and patient experience. The objectives of this project are: 1) Establish a core multidisciplinary RAMP team to develop a patient-centered clinical care pathway for diagnosis and treatment. 2) Establish a standardized and rapid referral process for RAMP. 3) Triage consults and coordinate their integration into pre-existing weekly "musculoskeletal oncology" clinic at the cancer center. 4) Develop a centralized registry for patients presenting to RAMP to assess provider performance and evaluate the success of established clinical care pathways.

Project to Assess Feasibility of a Rapid Access Metastatic Bone Disease Program

A Pilot Project to Assess the Feasibility of Integrating a Multidisciplinary Rapid Access Metastatic Bone Disease Program (RAMP) at The Ottawa Hospital

This metric can be captured by collaborating with our electronic chart experts (MOSAIQ) to create a field for RNs to document this item, which can then be tracked.

Identifying the rate of compliance from the ER, oncology (Medical, radiation and hematology), as well as primary physicians in directing referrals to RAMP. The goal is a compliance rate of 80%. This will be measured by capturing the consults for MBD of the pelvis and lower extremity that were referred outside RAMP referral pathway.

The admission rate and triage of the musculoskeletal oncology clinic for MBD patients will help us identify the current systems true clinic capacity.

This benefit will be measured by achieving wait time \< 7 days for patients to be assessed for a pending pathologic fracture. The wait time will be captured by the RAMP registry which will keep meticulous track of all referral, visits and treatment dates.

This data will be captured by patients filling validated ESAS and patient.This data will be captured by patients filling validated ESAS and patient satisfaction questionnaires. These questionnaires will be collected during phase I (planning) of this project, and will be compared to surveys obtained during phase II(execution). We anticipate an improvement in patient satisfaction.

Ottawa Hospital Research Institute

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Cohort I seeks to identify the Recommended RefleXion FDG dose (RRFD), which is the dose of administered FDG that allows for functioning of the RefleXion system. This phase of the investigation seeks to optimize the balance between minimizing patient exposure to the radiotracer and achieving satisfactory performance of the RMRS PET subsystem for BgRT. The dose levels of 15 mCi and 20 mCi (if required) will be assessed sequentially in an escalation protocol. To determine the RRFD, a modified 3+3 design will be utilized wherein meeting the Activity Concentration threshold - not dose-limiting toxicity as is typically used - will be the relevant criteria for escalating from one dose to the next. Up to 12 participants will be enrolled in Cohort I, and will undergo one RMRS imaging session and one third-party Positron Emission Tomography (PET) /CT imaging session.

After the RRFD is determined by Cohort I, Cohort II enrollment will start enrollment. Cohort II seeks to determine whether BgRT dose distributions generated from Limited Time Sample (LTS) RMRS PET images obtained at the time of treatment delivery are consistent with the approved BgRT plan. To achieve this objective, RMRS PET scans will be added to the SBRT workflow at timepoints representing some of the instances when the RMRS PET subsystem would be utilized during a BgRT workflow. Specifically, subjects will undergo RMRS PET collections at the time of planning, and then before the first and final fractions of their planned course of SBRT treatment.

Up to 22 participants will be enrolled in Cohort II, and will undergo three RMRS imaging sessions and one third-party Positron Emission Tomography (PET) /CT imaging session.

Participants will be injected with FDG at the studied dose and will undergo imaging sessions using the RMRS IDE device and a third-party Positron Emission Tomography (PET)/CT imaging device.

RMRS IDE Device

Daniel Chang, MD

Aurelie Garant, MD

The purpose of this study is to assess the performance and safety of Biology-Guided Radiotherapy (BgRT) using the RefleXion Medical Radiotherapy System (RMRS) via optimizing F18-Fluorodeoxyglucose (FDG) dosing, assessing the performance of the Positron Emission Tomography (PET) imaging subsystem for BgRT treatment planning and delivery, including its role as an interlock, and validating the dose delivery performance of the end-to-end BgRT workflow.

The performance and safety of BgRT using the RMRS will be studied by to sequential cohorts of patients with one targetable metastatic lesion in either the lungs or bone. Patients with multiple metastases can be accrued, but these investigations will focus on only one lesion per patient.

Cohort I will seek to identify the Recommended RefleXion FDG dose (RRFD), which is the dose of administered FDG - within a range concordant with the American College of Radiology and Society of Pediatric Radiology Practice Parameter for Performing PET/CT in Oncology (ACR-SPR Practice Parameter) - that allows for functioning of the RefleXion system. Keeping ALARA ("As Low As Reasonable Achievable") principles in mind, this phase of the investigation seeks to optimize the balance between minimizing patient exposure to the radiotracer and achieving satisfactory performance of the RMRS PET subsystem for BgRT. This cohort will also seek to assess RMRS PET imaging performance in comparison to a third-party diagnostic PET/CT.

To that end, dose levels of 15 mCi and 20 mCi (if required) will be assessed sequentially in an escalation protocol. Patients with at least one known FDG avid tumor in the bone or lung will be enrolled into this cohort. These patients will undergo a CT simulation in an acceptable radiotherapy treatment position and with immobilization devices as needed. After acquisition of CT images, contours for targets, OARs, and BTZ will be generated by the investigator. Next, the patient will undergo back-to-back PET scans on the RefleXion device and a third-party diagnostic PET/CT device after a single injection of FDG at the studied FDG dose level. Quantitative metrics will be collected for each lesion in order to assess the performance of the RMRS PET subsystem at that dose. Up to 12 participant will be enrolled in Cohort I. Actual delivery of radiotherapy to the patient is not part of this investigation.

The chief objective of Cohort II is to confirm that the machine-deliverable fluence generated by applying the BgRT firing filter to PET LTS images obtained at the time of a radiotherapy delivery does in fact result in an anatomic dose distribution that is consistent with the approved BgRT plan. A secondary objective is to extend this analysis by also confirming that the linear accelerator subsystem hardware is able to deliver the received machine instructions. Importantly, this investigation comprehensively emulates and assesses (without actually delivering the radiation therapy to the patient) the entire end-to-end BgRT workflow from simulation to treatment planning to, finally, dose delivery. This design also provides an opportunity to assess imaging, workflow, and the toxicity, if any, associated with multiple administrations of FDG.

To do this, up to 22 subjects dispositioned to undergo conventional SBRT for a single bone tumor or a single lung tumor will be enrolled. As noted previously, patients with multiple metastases can be accrued but the investigation will focus only one targeted lesion per patient. For each patient, RMRS PET collections will be added to the SBRT workflow at 3 timepoints representing the steps when the RMRS PET subsystem would be utilized during the BgRT workflow. Specifically, these timepoints will include a RMRS PET imaging-only session prior to the start of SBRT delivery that will be used to create a BgRT plan as well as RMRS PET collections before the first and final fractions of their planned course of SBRT. A single comparison third-party diagnostic PET/CT image will also be obtained on the day of the final fraction.

This is an open-label, prospective study. The study is divided into two sequential cohorts of patients with one targetable primary or metastatic lesion in either the lungs or bone. Patients with multiple metastases can be accrued, but these investigations will focus on only one lesion per patient.

Cohort I seeks to identify the Recommended RefleXion FDG dose (RRFD), which is the dose of administered FDG that allows for functioning of the RefleXion system. To that end, dose levels of 15 mCi and 20 mCi (if required) are assessed sequentially in an escalation protocol.

The RRFD identified in Cohort I is utilized in Cohort II, to emulate and assess the dose delivery performance of the end-to-end BgRT workflow.

Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (BIOGUIDE-X)

The primary endpoint determined the number of cases that received the lowest FDG dose of 15 mCi, completed the RMRS image session and established an adequate target activity concentration to enable Biology guided Radiotherapy planning. The starting dose was 15mCi which was determined based upon preliminary physics studies done prior to this study. A FDG dose escalation to 20 mCi was not required.

The number of scans/fractions where the emulated BgRT dose distribution in a phantom was consistent with the BgRT treatment plan (i.e., 95% of DVH Delivered points for the BTZ and OAR fall within bounded DVH of the approved BgRT plan). There were 9 first fractions and 8 last fractions that were analyzed.

This endpoint evaluated percent of cases where there was an agreement between the site investigator SI and an Agreement Standard (AS) for the PET modeling localization decision. Six image comparisons were performed.

This endpoint evaluated Percent of cases where there was concordance of the positive "plan proceed" decision between the BgRT PET Imaging-only session and a third-party diagnostic PET/CT.

Secondary Endpoint 3 evaluated the percent of cases where X1 PET images generated an Acceptable BgRT plan.

Secondary Endpoint 4 determined the percent of cases where the generated BgRT plan achieved acceptable quality assurance metrics in a physical phantom.

Number of fractions where there is concordance between the physical and digital phantoms of emulated BgRT delivery derived from human subject PET emissions. Concordance is defined as a standard gamma index with a goal that 90% of pixels meet the 3mm/3% deviation standard.

Number of Pre-scan images where there is agreement between a site investigator and the agreement standard for the BgRT PET PreScan localization decision (overall percent agreement). Positive percent agreement and negative percent agreement will also be reported.

Number of Scans where there is concordance of a positive localization decision between the short-duration PET PreScan and a third-party diagnostic PET/CT scan (positive percent agreement). Overall percent agreement and negative percent agreement will also be reported.

Number of Participants who experienced AEs related to bladder and bone marrow assessed by complete blood count, urinalysis and AEs specific to bladder and bone marrow determined by Common Terminology Criteria for Adverse Events (CTCAE) v5 at 72±24 hours after final FDG injection.

Workflow characterization by

1. Number of participants with PET imaging-Only scans at RRFD that meet the Activity Concentration (AC) threshold for BgRT.
2. Number of participants with PET imaging-Only scans that generate an acceptable BgRT plans.
3. Number of participants with approved BgRT plans that Passed Physics Quality Assurance.

Number of PET Pre-Scans on the Day of Fraction Delivery that Elicited a "Pass" Signal Fraction Delivery.

RefleXion Medical

Any deaths, SAE, and other adverse events that started at the time of first FDG injection or 72±24 hours after the last FDG injection were collected in this study.

Cohort I: All Participants, 5 participants with bone tumor and 3 participants with lung tumor, underwent CT simulations, received single injection of 15 mCi of FDG, underwent back-to-back RefleXion PET Imaging-Only session and third-party diagnostic PET/CT device and was followed up at 72±24 hours.

Cohort I: Recommended RefleXion FDG Dose (RRFD) Cohort

Cohort II: The RRFD was determined in Cohort 1 as 15 mCi, aftter which enrollment began for Cohort II. In Cohort II each participant, (4 with bone tumor and 5 with lung tumor), underwent RefleXion PET image-only sessions at three different timepoints. Each participant received a FDG injection of 15 mCi, prior to each image acquisition:

The timepoints were as follows:

1. At the time of enrollment: RefleXion PET image-only

2: At SBRT First Fraction (Standard of Care): RefleXion PET Prescan #1

3: At SBRT Last Fraction (Standard of Care): RefleXion PET Prescan #2 plus a Third-party PET/Scan.

The participants were then followed-up at 72 ± 24 hours after final FDG injection.

Cohort II: Delivery Emulation Cohort

Cohort I: Each participant (5 participants with bone tumor and 3 participants with lung tumor) underwent a CT simulation, then received a single injection of 15 mCi of FDG then underwent back-to-back RefleXion PET Imaging-Only session and third-party diagnostic PET/CT device. Each participant was then followed up at 72±24 hours after the imaging-only session.

Total

Age, Categorical

Cohort I & Cohort II

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Debradenise Brooks

Statistical analysis of the primary endpoint is not applicable to Cohort I. A modified 3+3 design was utilized wherein meeting the activity level threshold, not dose-limiting toxicity, is the endpoint. The RRFD is primarily based upon the lower FDG dose level where 5 to 6 out of 6 subjects have an Activity Concentration greater than 5 kBq/ml."

Cohort I: Recommended RefleXion FDG Dose (RRFD)

The number of patients that received 15 mCi FDG dose and completed the RMRS image session.

Cohort I Recommended RefleXion FDG Dose (RRFD) to Enable the Use of BgRT Planning.

Cohort II: The RRFD was determined in Cohort 1 as 15 mCi, after which enrollment began for Cohort II. In Cohort II each participant, (4 with bone tumor and 5 with lung tumor), underwent RefleXion PET image-only sessions at three different timepoints. Each participant received a FDG injection of 15 mCi, prior to each image acquisition:

The timepoints were as follows:

1. At the time of enrollment: RefleXion PET image-only

2: At SBRT First Fraction (Standard of Care): RefleXion PET Prescan #1

3: At SBRT Last Fraction (Standard of Care): RefleXion PET Prescan #2 plus a Third-party PET/Scan.

The participants were then followed-up at 72 ± 24 hours after final FDG injection.

Cohort II - Emulated Delivery population evaluable scans

Cohort II: Delivery Emulation

Cohort I: Recommended RefleXion FDG Dose

The number of participants that received 15 mCi FDG dose injection and completed the RMRS image session.

Cohort I: Endpoint 1 Percent Agreement Between SI and AS for BgRT PET Imaging-only Session

Cohort I Endpoint 2: Percent of Cases X1 PET vs. Third-party Diagnostic PET/CT Image Comparison

Cohort I Endpoint 3: Biology Guided Radiotherapy (BgRT) Plan Generation

Cohort I: RRFD Cohort

Cohort I Endpoint 4: Percent of Cases Where the Intended Dose Distribution of BgRT Plan Was Achieved in the Physical Phantom.

17 scans for nine (9) subjects were used to measure the percent of fraction concordance between physical and digital phantoms of emulated BgRT delivery

Cohort II Endpoint 1 Percent of Fractions With Concordance Between Physical and Digital Phantoms

Cohort II: The RRFD was determined in Cohort I as FDG dose of 15 mCi. Following this Cohort II enrollment began.

Each participant, 4 participants with bone tumor and 5 participants with lung tumor, underwent RefleXion PET image only sessions at three different timepoints. Prior to each the image collection the participant received a single dose injection of 15 mCi of FDG.

1. At the time of enrollment: RefleXion PET image-only

2: At SBRT First Fraction (Standard of Care): RefleXion PET Prescan #1

3: At SBRT Last Fraction (Standard of Care): RefleXion PET Prescan #2 plus a Third-party PET/Scan.

The subject was then followed-up at 72 ± 24 hours after final FDG injection.

Cohort II Inter-observer agreement for Localization decision on RMRS PET Pre-Scan image

Cohort II Endpoint 2 Localization Decision

Positive Agreement

Overall agreement

Cohort II: Emulated Delivery Cohort

Comparison of short-duration PET CRR01 vs. Third-party Pet/CT

Cohort II Endpoint 3 Image Concordance (Cohort II)

Cohort II Endpoint 4 Toxicity Related to FDG Administrations

Number of participants with PET imaging-Only scans at RRFD meeting the AC threshold for BgRT.

b. Number of participants PET imaging sessions which lead to acceptable BgRT plans.

c. Number of participants approved BgRT plans that go on to pass physics quality assurance

Cohort I - RRFD Cohort

Combined Cohort I (RRFD Cohort) and Cohort II (Emulated Delivery Cohort) to characterize RefleXion system functioning

Combined Cohort I + Cohort II

PET imaging-Only sessions at RRFD that meets BTZ activation concentration threshold for BgRT (5 kBq/ml)

Cohort II Endpoint 5 Workflow Characterization

Cohort II Endpoint 5d Workflow Characterization: PET Evaluations That Elicited a "Pass" Signal

Cohort II: The RRFD was determined in Cohort 1 as 15 mCi, after which enrollment began for Cohort II. In Cohort II each participant, (4 with bone tumor and 5 with lung tumor), underwent RefleXion PET image only sessions at three different timepoints. Each participant received a FDG injection of 15 mCi, prior to each image acquisition timepoint:

The timepoints were as follows:

1. At the time of enrollment: RefleXion PET image-only

2: At SBRT First Fraction (Standard of Care): RefleXion PET Prescan #1

3: At SBRT Last Fraction (Standard of Care): RefleXion PET Prescan #2 plus a Third-party PET/Scan.

The participants were then followed-up at 72 ± 24 hours after final FDG injection.

Overall Study

Subjects will undergo a single OsteoCool™ RF Ablation procedure.

The OsteoCool™ RF Ablation system is indicated in the United States (US), Europe (EUR) and Canada (CAN) for patients with metastatic malignant lesions in a vertebral body, painful metastatic lesions involving bone (in the US, patients with metastatic lesions involving the bone must have failed or were not candidates for standard therapy) and benign bone tumors such as osteoid osteomas.

OsteoCool™ RF Ablation

Sandeep Bagla, MD

This study evaluates the effectiveness of the Medtronic OsteoCool™ RF Ablation System.

The OsteoCool™ RF Ablation system has 510k regulatory clearance in the United States, Conformité Européene (CE) mark in Europe, and Health Canada Licence in Canada. The goal of this study is to collect real-world outcomes among a cohort of patients in the US, EUR and CAN with metastatic malignant lesions in a vertebral body, painful metastatic lesions involving bone (in the US, patients with metastatic lesions involving the bone must have failed or were not candidates for standard therapy), and benign bone tumors such as osteoid osteoma who receive treatment with the OsteoCool™ RF Ablation system. Additionally, the study will collect device, procedure and/or therapy related adverse events and device deficiencies. Lastly, subject outcomes (such as pain relief, quality of life, and function) will be evaluated using validated assessment measures.

Enrollment/Baseline visit, OsteoCool procedure visit and 5 post-procedure visits (3 days, 1 week, 1-, 3-, and 6-month clinic visits) and a final post-procedure study visit (12 months) for a total of 8 study related visits.

OsteoCool Tumor Ablation Post-Market Study

OsteoCool Tumor Ablation Post-Market Study (OPuS One)

Demonstrate an improvement of worst pain score (WPS) at the target treatment site in the previous 24 hours for subjects with metastatic lesions in only the thoracic and/or lumbar vertebral body(ies) as collected using the Brief Pain Inventory (BPI). The WPS is a single question from the BPI (scored from 0-10; 0=NO PAIN and 10=PAIN AS BAD AS YOU CAN IMAGINE). Lower scores indicate less pain.

Characterize change in worst pain score (WPS) at the target treatment site in the previous 24 hours for subjects with metastatic lesions in the periacetabulum, iliac crest, and/or sacrum as collected using the Brief Pain Inventory (BPI). Some subjects also had an additional thoracic/lumbar ablation. The WPS is a single question from the BPI (scored from 0-10; 0=NO PAIN and 10=PAIN AS BAD AS YOU CAN IMAGINE). Lower scores indicate less pain.

The secondary outcome is based on a mutually exclusive cohort of study subjects as compared to the primary outcome.

MedtronicNeuro

AE data are based on all available safety data (ie, based on 206 total subjects undergoing RF Ablation including 184 in only the thoracic and/or lumbar vertebral body(ies) and 22 in the periacetabulum, iliac crest, and/or sacrum).

Device, therapy, and procedure related AEs were considered reportable. Deaths due to underlying malignancy were not considered AE; all deaths were reviewed for causality by a Clinical Events Committee.

Subjects underwent a single OsteoCool™ RF Ablation procedure.

OsteoCool™ RF Ablation: The OsteoCool™ RF Ablation system is indicated in the United States (US), Europe (EUR) and Canada (CAN) for patients with metastatic malignant lesions in a vertebral body, painful metastatic lesions involving bone (in the US, patients with metastatic lesions involving the bone must have failed or were not candidates for standard therapy) and benign bone tumors such as osteoid osteomas.

Total OsteoCool™ RF Ablation

Subjects underwent a single OsteoCool™ RF Ablation procedure. All ablations were in the Thoracic/Lumbar Spine.

OsteoCool™ RF Ablation in Thoracic/Lumbar Spine

Subjects underwent a single OsteoCool™ RF Ablation procedure. At least one ablation was in the Periacetabulum/Iliac Crest/Sacrum. Some subjects also had RF Ablation in the Thoracic/Lumbar in the same procedure.

OsteoCool™ RF Ablation in Periacetabulum/Iliac Crest/Sacrum

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

United States

Canada

France

Germany

Region of Enrollment

Worst pain score (WPS) at the target treatment site in the previous 24 hours was collected using the Brief Pain Inventory (BPI). The WPS is a single question from the BPI (scored from 0-10; 0=NO PAIN and 10=PAIN AS BAD AS YOU CAN IMAGINE). Lower scores indicate less pain.

Wost Pain Score

The baseline analysis population is based on all subjects treated with RF Ablation.

Eric Grovender

An improvement from baseline to 3 months post radiofrequency ablation in worst pain score will be demonstrated with an outcome which is statistically lower than zero.

Subjects with metastatic lesions in only the thoracic and/or lumbar vertebral body(ies).

Change of Worst Pain Score: Thoracic/Lumbar Spine RF Ablation

Change in Worst Pain Score: Periacetabulum, Iliac Crest, and/or Sacrum RF Ablation

Behaviors and Mental Disorders

Pain

Neoplasms, Second Primary

Quality of Life

The current standard treatment will be prescribed, i.e. a 3D-conformal radiotherapy of a single fraction dose of 8.0 Gy to the metastasis with a planning target volume (PTV) margin for set-up and positioning uncertainties of 1 cm. This can be performed at any linear accelerator.

Within the framework of stereotactic body radiotherapy, a single fraction dose of 20.0 Gy will be delivered to the metastasis using a PTV margin of 3-5 mm based on high-precision image-guided radiotherapy (IGRT). Therefore, only linear accelerators with the European Organization for Radiotherapy \& Oncology advisory committee on radiation oncology practice (ESTRO-ACROP) specifications for SBRT can be accepted. A risk-adapted approach will be applied, aiming for the highest possible dose no less than 16 Gy, while respecting the tolerances of critical organs at risk (e.g. spinal cord, cauda equina, brainstem etc.).

Treatment will be prescribed to the periphery of the target, i.e. 80% of the dose should cover 95% of the PTV. The organ at risk (OAR) dose constraints will be in accordance with the recommendations from the report of the American Association of Physicists in Medicine (AAPM) task group 101. Image-guidance will consist of cone-beam CT in combination with 6 degrees of freedom corrections using robotic couch.

Stereotactic body radiotherapy

In the standard setting, 95% of the PTV should receive 95% of the prescribed dose while near maximum dose (Dnear-max) in the PTV should not exceed 107%. Image-guidance will consist of portal images showing the relevant bony anatomy.

3D-conformal radiotherapy

Dirk Verellen, PhD

This is a phase III randomized-controlled, single-blind study comparing the standard schedule for antalgic radiotherapy of a single fraction of 8.0 Gy delivered through three-dimensional conformal radiotherapy (3D-CRT) to a single fraction of 20.0 Gy delivered through stereotactic body radiotherapy (SBRT). The primary aim of this trial is to double the complete response rate. Secondary aims are to compare general response rates, duration of pain response, acute and late toxicity, HRQoL through patient-reported outcome measures (PROMs), pain flare, and re-irradiation need.

All subjects will be randomly assigned in a 1:1 ratio to receive either a single fraction of 8.0 Gy to the painful bone metastasis through 3D-CRT (control arm) or a single fraction of 20.0 Gy to the painful bone metastasis through SBRT (experimental arm).

A Trial to Improve Quality of Life With Stereotactic Body Radiotherapy for Patients With Painful Bone Metastases

A Phase III Randomized-controlled, Single-blind Trial to Improve Quality of Life With Stereotactic Body Radiotherapy for Patients With Painful Bone Metastases

Pain response at the treated index site at 1 month after radiotherapy (RT), as defined by the consensus statement.

Number of participants with increase in pain score of 2 or more above baseline at the treated site with stable OMED, or an increase of 25% or more in OMED compared with baseline with the pain score stable or 1 point above baseline

Time until pain progression (defined as an increase in pain score of 2 or more above baseline at the treated site with stable daily oral morphine equivalent, or an increase of 25% or more in daily oral morphine equivalent (OMED) compared with baseline with the pain score stable or 1 point above baseline)

Need for re-irradiation of the treated lesion

Using the EORTC quality of life questionnaire for Bone Metastases (QLQ BM22) to measure impact of bone metastases on QoL \[min score 0 - max score 100\]. A high score represents a high level of symptomatology. The score is calculated by applying a linear transformation on the scores to each answer of the 22 question-long questionnaire (cfr. EORTC mannual).

Incidence of symptomatic pathologic fractures, radiation or surgery to bone, and spinal cord compression.

Cancer Research Antwerp

Multifractionated post-operative radiotherapy, several weeks after surgery

Radiotherapy

Julie Willeumier, MD

Gerco van der Wal, MD

Sander Dijkstra, MD PhD

Yvette van der Linden, MD PhD

Rationale: Bone metastases arise in 50% of all patients dying of cancer, increasing up to 70% in patients with breast and prostate cancer. The lesions can cause pain and fractures, leading to diminished quality of life and poorer survival. Current knowledge concerning adequate, personalized treatment of metastatic lesions of the long bones in patients with disseminated cancer is insufficient and inconclusive due to lack of large, prospective series with patient reported outcome measures. One of the debatable issues is the effectiveness of postoperative radiotherapy. It has become common practise due to professional opinion, but research evidence is lacking. It is thought that adjuvant radiotherapy improves the durability of an implant, prevents progression of the lesion, promotes bone healing, improves limb function, minimises pain and reduces the need for reoperations, however none of these are certain. Moreover, it is a burden on patient's quality of life (e.g. multiple extra hospital visits) causing toxicity and possible side effects (e.g. skin irritation). The true beneficial effect, weighing up the possible pros and certain cons, of adjuvant radiotherapy is thus unknown.

Objective: The PORT study aims to demonstrate the non-inferiority of 'surgery only' compared to surgery with adjuvant radiotherapy as treatment of impending and actual pathological fractures on the pain experienced by patients.

Study design: A multicentre, prospective, randomised non-inferiority trial nested within the OPTIMAL study.

Study population: All patients with metastases of the long bones undergoing surgery for a(n) (impending) pathologic fracture in the participating centres.

Study intervention: One study arm (A) will receive surgery with adjuvant radiotherapy; the other study arm (B) will receive surgery only.

Main study parameters/endpoints: Primary endpoint is patient reported pain according to a numeric rating scale (NRS). Clinical functioning, radiological status, complications and survival are secondary endpoints.

The PORT study aims to demonstrate the non-inferiority of 'surgery only' compared to 'surgery with adjuvant radiotherapy' for the fixation of impending and actual pathological fractures of the long bones. We hypothesize that patients without post-operative radiotherapy will not have more pain than those receiving post-operative radiotherapy. The primary efficacy endpoint will be the pain level (as measured by an eleven point numeric rating scale (NRS)) 12 weeks after treatment. Pain has been chosen as primary endpoint because it can be interpreted as a "proxy" for mechanical loosening or other complications. It was undesirable to select revision surgery as endpoint, because the number of revision surgeries will be very low in this patient population. A revision will only be performed for serious complications with large effects on the quality of life. In other cases, conservative options will be chosen over revision surgery.

Secondary endpoints are complications, quality of life and overall survival.

A secondary objective is to conduct cost-effectiveness and costs-utility analyses.

This study is a multicentre, prospective, randomised non-inferiority trial nested within the OPTIMAL study. The OPTIMAL study is the backbone of the (OPTIMAL-) PORT study, encompassing the prospective cohort and providing the infrastructure for collection patient reported outcome measures. If patients do not have an indication for surgery, they can only be included in the OPTIMAL study. If patients have an indication for surgery, they are recruited for the OPTIMAL-PORT study. However, if patients do not give consent for randomisation for radiotherapy, they can give partial consent and participate in the prospective cohort and complete questionnaires. This data will contribute to the OPTIMAL study. Details concerning the OPTIMAL study are described in the respective protocol.

The PORT trial is a non-inferiority trial between ' surgery with post-operative radiotherapy' (Arm A) with 'surgery only (no post-operative radiotherapy)' (Arm B). A non-inferiority design is appropriate for this study because we expect that the clinical outcomes with surgery only are not worse than with post-operative radiotherapy. 'Surgery only' however has evident advantages, as it will lessen the burden on patients of visiting the hospital, prevent toxicity and cost less. Furthermore, as mentioned in the introduction, the focus of treatment is on maintaining and improving quality of life. The goal is to do what is right, safe, and efficient and not to provide more care than is needed. Rethinking whether we need post-operative radiotherapy is part of achieving that goal.

All patients with (impending) fractures of the long bones due to bone metastases and an operation indication will be asked to participate in the OPTIMAL cohort and provide patient reported outcomes. In addition, they will be informed about the PORT trial. Post-operatively, shortly before discharge from the hospital, they will be asked for informed consent for the PORT trial by the treating physician or a researcher. This assures a waiting period of 3-7 days between information and consent. Patients are informed that they are free to decide whether they wish to participate in the trial and will receive written information in addition to oral information. If patients do not wish to participate in the trial, they will receive standard care (which is post-operative radiotherapy in most cases). The first post-operative questionnaire will be sent 4 weeks after surgery.

Statistical analysis: To describe patient characteristics and outcomes, descriptive statistics (mean, median, standard deviation, and proportions) will be used. For univariate testing, p-values will be one tailed and considered significant if less than 0.05.

The primary endpoint of this study is pain response after surgery with or without post-operative radiotherapy. This will be expressed in absolute numbers (difference in NRS). A linear regression model to adjust for patients' characteristics will be used to compare the difference in mean pain level between the two arms with the centre from which the patient originates as a random effect.

For the analysis of non-inferiority primarily an intention to treat (ITT) will be performed. However, an ITT analysis is more likely to narrow the difference between treatments in a non-inferiority trial and yield a non-inferior result, thus a per protocol (PP) analysis is needed to cross-validate the ITT analysis.

Differences in the occurrence of complications will be compared by Fisher's exact test or chi-square test.

The QoL will be analysed using the EORTC QLQ-C15-PAL and EORTC QLQ-BM22. A comparison will be made between the baseline QoL and at predefined intervals after treatment (at 4 and 8 weeks, 3, 6 and 12 months following radiotherapy). A change of 10% of the scale width will be considered a clinically relevant change of QoL (Osoba 2005). The data will be presented as stable, worsened (≥ 10% decrease in QoL) or improved (≥ 10%increase in QOL). These time points will be compared using a Chi square test with a conservative p-value of 0.01 to correct for multiple testing. We will also evaluate the pattern of QoL as a continuous outcome over time during follow up with the mixed models approach.

Overall survival and progression free survival will be estimated by applying Kaplan-Meier's methodology analysis. Time to event will be measured from time of treatment to death or to progression of the disease. Comparisons in outcomes between treatment groups will be performed by Log Rank test.

Post-operative RadioTherapy for Patients With Metastases of the Long Bones

Post-operative RadioTherapy for Patients With Metastases of the Long Bones: a Randomised Controlled Trial

Pain will measured before treatment and after treatment on an 11-point numeric rating scale for pain. If the score differs more than 2 points between those measuring moments the change in pain is reported as significant. The number of patients in each group with a significant change in pain score will be measured.

Complications such as loosening of implant

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Project to Assess Feasibility of a Rapid Access Metastatic Bone Disease Program	NCT03134404	Metastases to B...	No Intervention	18 Years -	Ottawa Hospital Research Institute
Performance and Safety of Biology-Guided Radiotherapy Using the RefleXion Medical Radiotherapy System (BIOGUIDE-X)	NCT04788147	Cancer Tumor, Solid Cancer, Lung Cancer, Bone Metastasis to L... Metastasis to B...	RMRS IDE Device	22 Years -	RefleXion Medical
Project to Assess Feasibility of a Rapid Access Metastatic Bone Disease Program	NCT03134404	Metastases to B...	No Intervention	18 Years -	Ottawa Hospital Research Institute
OsteoCool Tumor Ablation Post-Market Study	NCT03249584	Metastasis Spin... Metastasis to B...	OsteoCool™ RF A...	18 Years -	MedtronicNeuro
A Trial to Improve Quality of Life With Stereotactic Body Radiotherapy for Patients With Painful Bone Metastases	NCT03831243	Metastasis to B... Radiotherapy Neoplasm Metast...	Stereotactic bo... 3D-conformal ra...	18 Years -	Cancer Research Antwerp
Post-operative RadioTherapy for Patients With Metastases of the Long Bones	NCT02705183	Metastasis to B...	Radiotherapy	18 Years -	Leiden University Medical Center
Project to Assess Feasibility of a Rapid Access Metastatic Bone Disease Program	NCT03134404	Metastases to B...	No Intervention	18 Years -	Ottawa Hospital Research Institute
Project to Assess Feasibility of a Rapid Access Metastatic Bone Disease Program	NCT03134404	Metastases to B...	No Intervention	18 Years -	Ottawa Hospital Research Institute

Spots Global Cancer Trial Database for metastasis to bone