Background
Methods/design
Objectives
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Primary endpoint
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○ Androgen deprivation therapy free survival ADT will be started in both arms at time of polymetastatic disease, local progression (defined below) or symptoms. In case of a metachronous oligometastatic recurrence in arm A, a retreatment with radiotherapy or surgery is allowed. Calculation will start from randomization until ADT is started.
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Secondary endpoints
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○ Quality of life scoring using the EORTC QLQ-C30 supplemented with QLQ-PR25. Raw scores will be transformed to a linear scale ranging from 0 to 100. The results will be presented in accordance with recent guidelines for reporting HRQOL RCTs [11].
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○ Assessment of quality-adjusted-life-years with the EuroQol classification system (EQ-5D) [12]. A written consent to use this system has been obtained from the EuroQol Group Foundation.
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○ Acute and late toxicity due to radiotherapy will be scored using the Common toxicity criteria version 4.0 [13]. Surgical complications will be scored using Clavien-Dindo Classification [14]. Other surgical related morbidity (intra-operative complications (blood loss, injury to pelvic or intra-abdominal organs…) and duration of hospital stay) will also be recorded.
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○ Time to castration-resistant disease is calculated from randomization until development of castration-resistant disease as defined by the EAU guidelines [1].
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○ Progression-free survival:
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▪ 3 types of progression are defined and definitions of progression are used and registered according to the recommendations of the prostate cancer clinical trials working group [10]. Calculation will start from randomization until progression or death.
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▪ PSA or biochemical progression:
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In case of decline from baseline: record time from randomization to first PSA increase that is ≥25% and ≥ 2 ng/ml above the nadir OR that is ≥25% and rises above the pre-treatment PSA value and which is confirmed by a second value 3 or more weeks later.
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In case of no decline from baseline: PSA increase that is ≥25% and ≥ 2 ng/ml after 3 months if baseline PSA is ≥2 ng/ml. PSA increase that is ≥25% after 3 months if baseline PSA is < 2 ng/ml.
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Local progression for soft-tissue and bone lesions: Each metastasis is a target lesion independently assessed for response with the RECIST criteria [15]. In addition, metastases (particularly osseous) with a metabolic complete response on bone or PET scan are scored as complete response in the absence of progression on CT scan.
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▪ Distant progression: appearance of new metastatic lesions.
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Prostate cancer specific survival will be calculated from randomization until PCa death. Overall survival will be calculated from randomization until death from any cause.
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Time to first symptomatic event will be calculated from randomization until the event of symptoms due to metastatic disease.
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Inclusion criteria
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Histologically proven diagnosis of PCa
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PCa patients with a biochemical recurrence following treatment with curative intent (radical prostatectomy, primary radiotherapy or a combination of both) as defined by the EAU guidelines [1].
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A maximum of 3 extracranial metastases in any organ system diagnosed on choline PET-CT.
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Controlled primary tumor
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○ Patients in the postoperative setting should have received postoperative radiotherapy to the prostate bed. In case the PSA > 2 ng/ml in the postoperative setting patients are eligible if a multiparametric MRI of the prostate bed rules out a local relapse or a negative biopsy of the prostate bed is performed37. Patients after primary radiotherapy should undergo MRI of the prostate according to the European Society of Urogenital Radiology (ESUR) guidelines to rule out local relapse [16]. In case of a suspicious lesion, a biopsy should confirm local recurrence and patients should be referred for local salvage prostatectomy when distant metastases are ruled out. If MRI rules out local relapse, patients are eligible.
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WHO performance state 0-1
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Age ≥18 years old
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Willing to provide a signed informed consent
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Patient presented at the multidisciplinary tumour board of the local hospital in which the therapy will be given.
Exclusion criteria
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Serum testosterone level <50 ng/ml
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Symptomatic metastases
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Patients with oligometastases that have been previously treated.
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PSA rise while on active treatment (LHRH-agonist, LHRH-antagonist, anti-androgen, maximal androgen blockade, oestrogen)
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Previous treatment with a cytotoxic agent for PCa
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Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids,…)
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Disorder precluding understanding of trial information or informed consent
Evaluation and randomization
Interventions
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Defined as 3-monthly clinical examination and serum PSA measurement. Restaging will be performed in case of symptomatic progression or PSA progression:
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▪ A PSA increase that is =25% and = 2 ng/ml if baseline PSA is =2 ng/ml.
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▪ A PSA increase that is =25% if baseline PSA is < 2 ng/ml.
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ADT will be started at time of polymetastatic disease, local progression (defined above) or symptoms. The type of ADT is left to the discretion of the treating physician. Both anti-androgen monotherapy, LHRH agonist or antagonists and maximal androgen deprivation therapy are allowed. Both intermittent and continuous ADT are allowed.
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All patients randomized into arm A will be presented at the multidisciplinary urology tumour board prior to treatment. The choice between SBRT or surgery will depend on localization and size of the metastases, the nearby organs-at-risk and previous treatments in the vicinity of the metastases. After reaching a consensus, the patient will be informed about the options for treatment.
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All patients will receive a CT simulation in supine position with 2 mm CT slice thickness through the tumour site. The planning simulation should cover the target and all organs at risk. A typical scan length should extend at least 10 cm superior and inferior beyond the treatment field borders. Support devices to increase patient comfort will be chosen depending on the tumour localisation. The isocenter will be determined on the CT-simulator with marking of laser lines on the patient. Imaging data will be transferred to the treatment planning system.For all lesions, the Gross Target Volume (GTV) will be defined as all visible tumor by combining iconographic and metabolic information. No additional margin will be added for microscopic spread of disease. The GTV will be expanded with 2-5 mm to the Planning Target Volume (PTV) to account for organ motion and setup error. Margins depend on the site irradiated with 2 mm margins for bony lesions, 3 mm for nodes and 5 mm for other sites. The type of organ at risk delineated depends on the localization of the metastasis. A Planning Organ at Risk Volume (PRV) expansion of 2-5 mm will be added for OAR such as the spinal cord, oesophagus, intestine,… (if applicable), and dose constraints apply to this PRV. It is strongly recommended that dose constraints not be exceeded. If a dose constraint cannot be achieved due to overlap of the target with an organ at risk or its PRV, the total dose can be lowered in order to meet the constraint.For spinal lesions, a pre-treatment axial MRI is required to assess the extent of disease and position of the cord. This must be fused with the planning CT scan.
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IMRT (static or rotational) treatment planning will be dependent the localization of the metastasis. Dose constraints for organ at risks will be in accordance with the recommendations from the report of the AAPM task group 101 [17]. A total dose of 30 Gy (80% of the maximal dose) will be delivered in 3 fractions and fractions will be separated >48 h and <96 h [18, 19]. Treatment will be prescribed to the periphery of the target (80% of the dose (=30 Gy), should cover 90% of the PTV). In case of violation of dose constraints to the organs at risk, the prescription will be adapted accordingly. If multiple targets will be irradiated and the targets are more than 10 cm apart in the cranio-caudal direction, multiple isocenters are needed with a CBCT prior to every treatment for every isocenter. Patient immobilization devices can be used according to the institutional policy.
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In order to ensure patient safety and effective treatment delivery the following measurements are taken:
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Prior to treatment, all plans are discussed and approved at the daily radiotherapy rounds after prior verification by the treating physician.
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All dose delivery for intensity-modulated plans will be confirmed before treatment by physics staff.
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At each fraction, a cone-beam CT (CBCT) will be used for patients’ set-up and target verification prior to treatment. In case of multiple isocenters, every isocenter will be verified separately with CBCT.
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Quality assurance: all plans will be verified using the Delta(4) diode array phantom prior to treatment delivery [20].
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The surgical technique to be used is at the discretion and expertise of the surgeon but must be in accordance to the best surgical practice available. A minimally invasive technique is preferred, but not obligatory. For pelvic nodal metastases, in case of a previous extended pelvic lymph node dissection (ePLND) or pelvic radiotherapy, only the suspicious lymph node will be removed. If no ePLND has been performed previously, a salvage ePLND will be preferred. In case of retroperitoneal nodes, only the suspicious node will be removed.
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ADT will be started as in arm A. In case of a metachronous oligometastatic recurrence, a retreatment with SBRT or surgery is allowed.
Follow-up
At inclusion | 3-monthly | At PSA or symptomatic progression | |
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Eligibility check | * | ||
Informed consent | * | ||
PET-CT | * | * | |
QOL questionnaire | * | * | * |
Toxicity assessment | * | * | * |
PSA measurement | * | * | * |
History and physical examination | * | * | * |