Cryoablation Combined With Stereotactic Body Radiation Therapy for the Treatment of Painful Bone Metastases, the CROME Trial

Study Overview
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Brief Summary
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This trial compares cryoablation combined with stereotactic body radiation therapy to stereotactic body radiation therapy alone to see how well they work in treating patients with pain from cancer that has spread to the bones (bone metastases). Bone is a common site of metastasis in advanced cancer, and bone metastases often result in debilitating cancer-related pain. The current standard of care to treat painful bone metastases is radiation therapy alone. However, many patients do not get adequate pain relief from radiation therapy alone. Another type of therapy that may be used to provide pain relief from bone metastases is cryoablation. Cryoablation is a procedure in which special needles are inserted into the tumor site. These needles grow ice balls at their tips to freeze and kill cancer cells. The goal of this trial is to compare how well cryoablation in combination with radiation therapy works to radiation therapy alone when given to cancer patients to provide pain relief from bone metastases.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the efficacy of cryoablation in combination with stereotactic body radiation therapy (SBRT) or SBRT only for the treatment of painful bone metastases. SECONDARY OBJECTIVES: I. To assess for narcotics utilization by daily morphine equivalent dose. II. To assess duration of pain response reported by International Pain Response Criteria. III. To assess for local tumor control. IV. To assess for changes in patient quality of life with Brief Pain Inventory (BPI) score. V. To assess for adverse event rates. VI. To assess incidence and severity of adverse events/toxicity. VII. To assess technical success for cryoablation. EXPLORATORY OBJECTIVE: I. To investigate the local microenvironmental changes following SBRT and cryoablation combined with SBRT to bone metastases. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients undergo stereotactic body radiation therapy for 1 fraction. ARM B: Patients undergo cryoablation. Within 10 days after cryoablation, patients undergo stereotactic body radiation therapy for 1 fraction. After completion of study treatment, patients are followed up at 1, 2, 3, 4, 8, 12, 16, 20, and 24 weeks.

Official Title
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Cryoablation Combined With Stereotactic Body Radiation Therapy for the Treatment of Painful Bone Metastases

Conditions
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Castration-Resistant Prostate Carcinoma, Metastatic Colorectal Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Metastatic Prostate Carcinoma, Metastatic Renal Cell Carcinoma, Metastatic Sarcoma, Metastatic Thyroid Gland Carcinoma, Metastatic Urothelial Carcinoma, Stage IV Colorectal Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8

Intervention / Treatment
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* Procedure: Cryosurgery
* Other: Quality-of-Life Assessment
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have a primary diagnosis of malignancy and radiographic evidence of bone metastases. Eligible tumor histologies include the following malignancies with low alpha/beta ratios: renal cell carcinoma, urothelial carcinomas, castration-resistant prostate cancer, sarcoma, thyroid carcinoma, colorectal carcinoma, and melanoma A target lesion the meets the following criteria: The target lesion must be amenable to both cryoablation and SBRT, as determined by the study principal investigators (PIs) The target lesion must be =< 7cm The pain due to the target lesion must be at least 4/10 based on the BPI pain scale Pain from the metastatic site must correlate with an identifiable tumor on computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US) imaging Life expectancy >= 3 months Platelet count > 50,000/mm^3 within 6 weeks of screening International normalized ratio (INR) < 1.5 within 6 weeks of screening If taking antiplatelet or anticoagulation medication, it must be able to be discontinued 48 hours prior to the procedure or at the discretion of the PI (e.g., aspirin, ibuprofen, low molecular weight heparin [LMWH] preparations) Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) within 6 weeks of screening Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization. Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization All lines of prior systemic therapy are permissible. Standard concurrent chemotherapy, immunotherapy, or targeted therapy are permissible Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Prior locoregional therapy to target lesion, including ablation of any modality, embolization, radiation, or surgery Patient may not be receiving any other investigational agents. Standard concurrent chemotherapy, immunotherapy, or targeted therapy will be allowed Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, interstitial lung disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or nursing women; women of childbearing potential unless using effective contraception as determined by the investigator Target lesions that involve the spinal column or calvarium Absolute neutrophil count < 1000 mm^3 within 6 weeks of screening Active infection Presence of confirmed pathologic fracture at the target lesion not amenable to percutaneous stabilization Lesions that involve a weight-bearing long bone of the lower extremity with the tumor causing > 50% loss of cortical bone. Lesions involving the hands and feet

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (SBRT)<br>Patients undergo stereotactic body radiation therapy for 1 fraction. | Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo stereotactic body radiation therapy<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|
| Experimental: Arm B (cryoablation, SBRT)<br>Patients undergo cryoablation. Within 10 days after cryoablation, patients undergo stereotactic body radiation therapy for 1 fraction. | Procedure: Cryosurgery<br>* Undergo cryoablation<br>* Other names: cryosurgical ablation;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Stereotactic Body Radiation Therapy<br>* Undergo stereotactic body radiation therapy<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain response | Defined as complete or partial response as reported by the International Pain Response Criteria at the site of the treated bone metastasis based on the BPI pain score and daily morphine equivalent (MEDD). Will be summarized separately for each treatment arm with associated 95% exact confidence intervals. | At 12 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily morphine equivalent (MEDD) |  | Baseline, assessed up to 24 weeks post-treatment | 
| Duration of response | Will be assessed by performing area under the curve (AUC) analysis of Brief Pain Inventory (BPI) pain scores. | Up to 24 weeks post-treatment | 
| Local control | Will be determined by imaging evidence of residual viable tumor. Standard of care cross-sectional imaging and bone scintigraphy will be performed at 3 month intervals. | Up to 24 weeks post-treatment | 
| Rate and severity of adverse and serious related adverse events | Point estimates and two-sided 95% confidence intervals will be generated for procedural related adverse events. | Within 30 days of the last study treatment | 
| Technical success for cryoablation | Will be determined by identifying on intra-procedural imaging when the leading edge of the ice successfully extends beyond the tumor margin by at least 5 mm. | Up to 24 weeks post-treatment |