The investigators propose redefining this concept by focusing on volume rather than the number of metastases. To achieve this, the investigators aim to determine the Maximum Tolerated Volume (MTV) of metastatic lesions treatable with SRT (Stereotaxic radiotherapy) in a phase 1 study. In this study, the investigators will recruit patients with high-volume metastatic disease in bones or lymph nodes and progressively irradiate a volume-escalated subset of the total lesions. The selection will prioritize lesions at higher risk of causing pain or complications, such as fractures, spinal compression, or vascular compression. The investigators hypothesis is that SRT targeting multiple metastases (with a total volume ≤ MTV) will extend the duration without refractory pain and/or tumor-related complications in patients with castration-resistant and chemo-refractory prostate cancer.
Metastatic prostate cancer with clinical progression after the use of androgen-receptor pathway inhibitor, chemotherapy or any other life-prolonging therapy. Patient could have been treated previously by RadioLigand Therapy (RLT).
Performance Status < 3
Bone and/or lymph node metastases based on conventional (CT and bone scan) or metabolic imaging
Bone and/or lymph node metastases suitable for SRT, according to the investigator
Evidence of symptomatic metastases to the lungs, brain, peritoneum or liver
Evidence of diffuse metastatic spread to the bone marrow (e.g. positive super bone scan) or the cerebral spinal fluid as per bone scan (no lumbar puncture required).
Evidence of presence of symptomatic spinal cord compression with indication of neurosurgical decompression.
Patient with symptomatic and/or high-risk tumor volume-to-bone marrow reserve ratio > 50%
Single group
Stereotactic body radiotherapy (SBRT)
RadiationThe acceptable regimens are: * 27 Gy / 3 fractions / 3 fractions per week * 35 Gy / 5 fractions / 3 fractions per week An interval of at least 24 hours should be kept between two consecutive fractions. Prescription must be defined on 80% isodose or higher, maximum dose up to 130% of the isodose prescription. At least 90% of the Planning Target Volume should receive the prescribed dose. A coverage of \<90% of the Planning Target Volume will be considered as acceptable deviation, and coverage of \<80% of the target volume as an Unacceptable Deviation. At least 90% of the Gross Tumoral Volume should receive the prescribed dose. Only a part of the Gross Tumoral Volume\_Total could be considered for radiation, depending on the ratio with Bone Marrow Reserve. High-risk and/or symptomatic metastases will be prioritized over other metastases. Anatomic bone marrow reserve (BMR) will be first determined for each patient: BMR = Total trabecular bone - (Total trabecular bone ∩ GTV\_Total)
Maximum tolerated volume (MTV)
The MTV will be defined as the highest volume that can be treated with an acute toxicity of grade \< 3 (CTCAE V5.0 scale) in one third of patient and will allow us to determine the recommended phase II volume under the assumption that higher volumes are likely to be more toxic. The maximum tolerated Volume (MTV) is defined as the volume at which 2 Dose-Limiting Toxicity (DLT) were observed among 3 to 6 patients. DLT are considered as: * Death clearly related to irradiation * Intractable pain despite oral or intravenous opioids and/or corticosteroids (EVA \> 4 and increase of 2 from EVA baseline) * Any new grade ≥ 3 toxicity (CTCAE V5.0 scale) compared to baseline among: * Anemia * Febrile Neutropenia * Hemorrhage within grade ≥3 thrombocytopenia * Any gastro-intestinal-related disorder * Any genito-urinary-related disorder * Pneumonitis Bone marrow reserve will be determined by CT-base automatic tool.
Number of toxicity related to radiotherapy as assessed by CTCAE v5.0
Acute (≤ 12 weeks) and late (\>12 weeks) toxicity will be evaluated according to NCI-CTCAE v5 grading
Recommended volume for irradiation by SRT for phase-II
The Recommended Volume (RV) corresponds to the volume of the level immediately below the MTV. This Recommended Volume for irradiation by SRT will then be applied for phase 2.
Pain relief assessed by EVA scale
Global pain evaluation (EVA) will be measured at baseline, 1-, 3- and 6-month following SRT. Score is 0 (no pain) to 10 (maximal pain)
Time to first pejorative event among tumour-related complication (bone, neurological or vascular compression) and/or death
Time to first worsening event due to tumor progression (as seen on thoraco-abdomino-pelvic CT scan): including bone displacement, spinal cord or neurological compression, and vasculo-lymphatic compression will be assessed.
To assess the functioning bone marrow reserve at baseline and after SRT
Functioning bone marrow reserve is quantified on 99Tc-sulfur colloid SPECT-CT by automatic delineation at baseline and at 3 months after SRT (GTV\_Total/functioning BMR)
To compare the anatomical and functioning assessment of the bone marrow reserve
Comparison of the tumor volume-to-bone marrow reserve ratio: GTV\_total/functioning BMR and GTV\_Total/anatomic BMR
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