Standard Treatment +/- SBRT in Solid Tumors Patients With Between 1 and 5 Bone-only Metastases

Study Overview
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Brief Summary
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Bone metastases occur frequently during the evolution of solid tumors, either isolated or associated with visceral metastases. The incidence varies between 20 and 85% depending on the primary cancer. Breast, prostate, and lung cancers are responsible for 70% of bone metastases. Cancer with bone metastases compared to other metastatic sites is considered as associated with a better prognosis, particularly for breast and prostate cancer. Bone metastases may be present at diagnosis (synchronous metastasis) or appear at a later time (metachronous metastasis). The concept of oligometastases was proposed in patients with about 3 up to 5 metastases (without restriction on the primary site) and associated with an intermediate prognosis. It was hypothesized that local treatment with curative intent, aiming at the few metastatic sites, would yield long-term survival probabilities, along with systemic therapies. Long-term survivors have been reported after curative-intent treatment of metastasis in sarcoma and colorectal cancers with liver or lung metastasis. We chose to focus on bone metastasis because of their high incidence, their impact on the patient's quality of life and autonomy, and their accessibility to potentially curative radiotherapy. The systemic treatment of metastatic cancer includes hormonal therapy (breast and prostate cancer), biologically-targeted drugs and chemotherapy (all cancers). Stereotactic radiotherapy is a highly accurate technique was initially developed for performing the radiosurgery of brain tumors in patients for whom it was deemed be too difficult to proceed to classical excision surgery. In this process, a high total dose of radiation is delivered in a single fraction to a well-defined intra-cranial target. The concept of radiotherapy in stereotactic conditions was extended to one or several fractions delivered to small volumes primary tumors/ metastases in extra-cranial sites (Stereotactic Body RadioTherapy [SBRT]). At present, high control rates have been achieved for lung metastases. Similarly, very high local control rates have been reported in bone metastases after stereotactic radiotherapy. In this protocol, our purpose is to demonstrate, via a randomized phase III trial, that high doses of radiotherapy, delivered in stereotactic conditions to the bone metastases (between 1 and 5 metastases) in solid tumor patients is able to improve the survival without progression.

Official Title
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Extracranial Stereotactic Body Radiation Therapy (SBRT) Added to Standard Treatment Versus Standard Treatment Alone in Solid Tumors Patients With Between 1 and 5 Bone-only Metastases

Conditions
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Metastatic Breast Cancer, Metastatic Lung Cancer, Metastatic Prostate Cancer, Bone Metastases

Intervention / Treatment
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* Radiation: SBRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients older than 18 years and younger than 75 years Good general condition: WHO performance status ≤ 2 Patients with histological proof of breast, non-small cell lung, or prostate cancer Note: Histological proof can be done on the primitive tumour and/or adenopathy and/or metastatic site. Absence of co-morbidity contra-indicating radio-chemotherapy or surgery Primary tumor accessible to curative-intent treatment (surgery, chemoradiation…) for patients with synchronous metastases Patients with between 1 and 5 synchronous or metachronous bone metastases as defined by NaF-PET or conventional SPECT-CT scan and spinal MRI (if necessary) within 6 weeks before randomization) Bones metastases treatable by SBRT Primary cancer considered to be controlled or accessible to curative-intent treatment (surgery, chemoradiation…) in case of locoregional recurrence for metachronous bone oligo-metastatic disease Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy Patients who have received the information sheet, dated and signed the informed consent form Affiliated to the social security system Exclusion Criteria: Visceral metastases as defined by FDG-PET (F-Choline-PET or PSMA PET-CT for prostate cancer) and cerebral CT or MRI performed. Previous systemic therapy for metastasis for patients with metachronous metastasis. Prostate and breast cancer patients remain eligible if hormonal treatment was initiated 6 months before enrollment All bone metastasis requiring surgical treatment (spinal cord compression, fracture…) More than 5 bone metastases as defined by NaF-PET or conventional SPECT-CT scan and spinal MRI (if spinal bone metastases on NaF-PET) Previous cancer within the 5 years before inclusion (except basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix) Previous radiotherapy on bone metastasis (e.g: antalgic radiotherapy) Patient enrolled in another therapeutic trial Pregnant women or breast feeding mothers, Hypersensitivity to the active substance (FDG and NaF or F-Choline or PSMA for prostate cancer) or to any of the excipients Contraindication to MRI (in case of spinal metastases) Patients deprived of liberty or placed under the authority of a tutor. Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. Patients unable to understand the purpose of the study (language, etc.).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Systemic treatment + SBRT<br>Systemic treatment and SBRT to the bone metastases. Two SBRT schemes are allowed: 9 Gy x 3 fractions or 7 Gy x 5 fractions for axial and appendicular bones metastases. The choice is at the discretion of the investigator. | Radiation: SBRT<br>* SBRT will be added to systemic (standard) treatment of bone metastases.<br>|
| No Intervention: Systemic treatment<br>Palliative radiotherapy on bone metastases is allowed if necessary (pain, fracture, spinal cord compression…) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | To evaluate the impact of SBRT on Progression-Free Survival (PFS) at 1 year according to RECIST 1.1 and PERCIST 1.0 Criteria | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS at 2 and 3 years | Progression-Free Survival (PFS) at 2 and 3 years will be evaluated according to RECIST 1.1 and PERCIST | 2 years and 3 years after treatment | 
| Bone progression free survival at 1, 2 and 3 years | Distant bone progression at 2 and 3 years will be evaluated according to RECIST Criteria 1.1 and at 1 year according to RECIST Criteria 1.1 and PERCIST | 1, 2 and 3 years after treatment | 
| Local control at 1, 2 and 3 years | Local control will be evaluated at 1, 2 and 3 years according to RECIST Criteria 1.1 and PERCIST | 1, 2 and 3 years after treatment | 
| Cancer-specific survival | The length of time from the start of treatment for the disease until the death identified as being due to the specified cancer. | 1, 2 and 3 years after treatment | 
| Overall survival | The length of time from the start of treatment for the disease until patients are still alive. | 1, 2 and 3 years after treatment | 
| SBRT toxicities | according CTCAE 4.0 scale | 1, 2 and 3 years after treatment | 
| Patient's Quality of life | self-administered questionnaire | at baseline, 6 weeks after randomization, and 3 months, 6 months and 1, 2 and 3 years after treatment | 
| Pain score | according to Numeric Scale related to pain medication | at baseline, once a week during 2 weeks and 6 weeks after randomization, and at 3 months, 6 months and 1, 2 and 3 years after treatment | 
| Cost utility | QALYs (Quality-Adjusted Life Years) and ICERs (Incremental Cost-Effectiveness Ratios) calculation based on EQ-5D-3L questionnaire. | 6 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone-only metastases, solid tumors, SBRT