PEACE V: Salvage Treatment of OligoRecurrent Nodal Prostate Cancer Metastases

Study Overview
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Brief Summary
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A proportion of prostate cancer (PCa) patients develop relapse following curative local treatment. Regional nodal recurrence is an emerging clinical situation since the introduction of new molecular imaging methods in the restaging of recurrent prostate cancer. More specifically, a subgroup of these patients is being diagnosed with a recurrence confined to the regional lymph nodes and limited in number (oligorecurrence) using choline or PSMA PET-CT. As there are no specific treatment recommendations for these type of patients, different treatment approaches are currently used, mostly focusing on local ablative treatments using radiotherapy or surgery. These treatments are coined metastasisdirected therapy (MDT). MDT in combination with or without temporary ADT could delay the subsequent risk of progression, and even cure limited regional nodal recurrences. Consequently, lifelong palliative ADT, with its toxicity and excess in non-cancer mortality might be postponed. The proposed trial randomizes patients with oligorecurrent nodal prostate cancer following primary PCa treatment to either metastasis-directed therapy (MDT) (salvage lymph node dissection, sLND or stereotactic body radiotherapy, SBRT) or MDT plus whole pelvis radiotherapy (WPRT: 45 Gy in 25 fractions).

Detailed Description
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A proportion of prostate cancer (PCa) patients develop a local, regional (N1) or distant (M1) relapse following curative local treatment. For both local and distant relapses, different treatment recommendations are made in the guidelines (EAU guidelines 2016). However, the entity regional nodal recurrence is not mentioned in the guidelines but is an emerging clinical situation since the introduction of choline and more recently PSMA PET-CT in the restaging of recurrent prostate cancer. More specifically, a subgroup of these patients is being diagnosed with a recurrence confined to the regional lymph nodes and limited in number (oligorecurrence) using choline or PSMA PET-CT. As there are no specific treatment recommendations for these type of patients, different treatment approaches are currently used, mostly focusing on local ablative treatments using radiotherapy or surgery. These treatments are coined metastasisdirected therapy (MDT). MDT in combination with or without temporary ADT could delay the subsequent risk of metastases, and even cure limited regional nodal recurrences. Consequently, lifelong palliative ADT, with its toxicity and excess in non-cancer mortality might be postponed. The proposed trial randomizes patients with oligorecurrent nodal prostate cancer following primary PCa treatment to either metastasis-directed therapy (MDT) (sLND or SBRT) or MDT plus WPRT. In the recurrent PCa setting, 2 recent trials have suggested a progression-free and even survival benefit of adding temporary ADT to local salvage prostate bed radiotherapy. Consequently, this positive effect might also be applicable for regional recurrences. Although the optimal duration of ADT is unknown, a minimal duration of 6 months of ADT seems advisable in this setting and will be mandatory for both arms. This trial will improve our insights in the pattern of recurrence following these treatment modalities with the expectation that WPRT will reduce the number of nodal relapses, improving metastasis-free survival and postponing the need for palliative systemic treatments while maintaining quality-of-life. The current phase II trial will try to establish a golden standard in the treatment of oligorecurrent nodal PCa.

Official Title
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PEACE V: A Randomized Phase II Trial for the Salvage Treatment of OligoRecurrent Nodal Prostate Cancer Metastases (STORM)

Conditions
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Prostate Cancer, Prostate Cancer Metastatic, Metastatic Cancer, Oligometastatic Cancer

Intervention / Treatment
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* Radiation: whole pelvic radiotherapy
* Radiation: metastasis-directed treatment
* Procedure: salvage Lymph Node Dissection
* Drug: androgen deprivation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven initial diagnosis of adenocarcinoma of the prostate Biochemical relapse of prostate cancer following radical local prostate treatment (radical prostatectomy, primary radiotherapy or radical prostatectomy +/- prostate bed adjuvant/ salvage radiotherapy) according to the EAU guidelines 2016. Following radical prostatectomy, patients with a biochemical relapse are eligible in case a nodal relapse is detected in the pelvis even in the absence of prior postoperative prostate bed radiotherapy (adjuvant or salvage). In case of a suspected local recurrence following primary radiotherapy, a biopsy should confirm local recurrence and patients with a confirmed local recurrence are eligible in case they also undergo a local salvage therapy. If imaging rules out local relapse, patients are eligible. Nodal relapse in the pelvis on choline, PSMA or FACBC PET-CT with a maximum of 3 positive nodal lymph nodes. The upper limit of the pelvis is defined as the aortic bifurcation. WHO performance state 0-1 Age >18 years Absence of 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 Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. Exclusion Criteria: Bone or visceral metastases Para-aortic lymph node metastases (above the aortic bifurcation) Local relapse in the prostate gland or prostate bed not suitable for a curative treatment Previous irradiation of the pelvic and or para-aortic nodes Serum testosterone level <50ng/dl or 1.7 nmol/L at time of randomization Symptomatic metastases Lymph node metastases in previously irradiated areas resulting in dose constraint violation Contraindications to pelvic radiotherapy (chronic pelvic inflammatory bowel disease) Contraindications to androgen deprivation therapy PSA rise while on active treatment with (LHRH-agonist, LHRH-antagonist, anti-androgen, estrogen Previous treatment with cytotoxic agent for PCa Treatment during the past month with products known to influence PSA levels (e.g. fluconazole, finasteride, corticosteroids,…) Other active malignancy, except non-melanoma skin cancer or other malignancies with a documented disease-free survival for a minimum of 3 years before randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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 |
| --- | --- |
| Other: MDT + ADT<br>Metastasis-directed therapy (salvage lymph node dissection OR stereotactic body radiotherapy) + 6 months androgen deprivation therapy | Radiation: metastasis-directed treatment<br>* stereotactic body radiotherapy<br>Procedure: salvage Lymph Node Dissection<br>* metastasis-directed treatment<br>Drug: androgen deprivation therapy<br>* LHRH-agonist (+ anti-androgen) or antagonist for a duration of 6 months<br>|
| Experimental: MDT + WPRT + ADT<br>Metastasis-directed therapy (salvage lymph node dissection OR stereotactic body radiotherapy) + whole pelvic radiotherapy + 6 months androgen deprivation therapy | Radiation: whole pelvic radiotherapy<br>* addition of prophylactic whole pelvic radiotherapy to a local metastasis-directed treatment<br>Radiation: metastasis-directed treatment<br>* stereotactic body radiotherapy<br>Procedure: salvage Lymph Node Dissection<br>* metastasis-directed treatment<br>Drug: androgen deprivation therapy<br>* LHRH-agonist (+ anti-androgen) or antagonist for a duration of 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastases-free survival | Metastasis-free survival will be defined as the time between randomization and the appearance of a metastatic recurrence (any M1) as suggested by choline, FACBC or PSMA PET-CT or death due to any cause | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Progression free survival | Clinical Progression-free survival is defined as time between randomization and the appearance of a new recurrence (any N1 or M1) as suggested by PET-CT, symptoms related to progressive PCa, or death due to any cause | 2 year | 
| Biochemical progression-free survival | For patients who had previous RP at initial diagnosis, a biochemical recurrence is defined by any confirmed PSA rise above 0.20 ng/ml with a confirmatory rise at least 2 weeks later. For patients who had previous RT to the prostate at initial diagnosis, a biochemical recurrence is defined as the nadir + 2ng/ml (Phoenix definition). Non-responders are considered to have a biochemical recurrence in case a second measurement at least 2 weeks later confirms a rising PSA | 2 year | 
| Toxicity: acute toxicity | Radiotherapy toxicity will be assessed according to NCI CTCAE v4.0. | 3 months | 
| Toxicity: late toxicity | Radiotherapy toxicity will be assessed according to NCI CTCAE v4.0. | 2 year | 
| Patient reported QOL as per EORTC-QLQ C30 | Validated questionnaire assessing different health-related parameters (psychological, physical and social well-being) in cancer patients | 2 year | 
| Patient reported QOL as per EORTC-QLQ PR25 | Validated questionnaire assessing the health-related QOL of prostate cancer patients | 2 year | 
| Prostate cancer-specific survival | Cancer specific survival will be read as the time from trial randomization to the date of death due to prostate cancer | 5 year | 
| Overall survival | Overall survival will be read as the time from trial randomization to the date of death from any cause | 5 year | 
| Time to start of hormonal treatment | Time to hormonal treatment is defined as the time from trial randomization to start of hormonal treatment | 2 year | 
| Time to castration-resistant disease | Time to castration resistant disease is defined as the time from trial randomization until castration resistant status | 5 year | 
| economical evaluation | Assessment of quality-adjusted-life-years with the EuroQol classification system (EQ-5D-5L) | 2 year | 
| Sensitivity/specificity of PET-CT for the detection of nodal recurrences: limited to patients undergoing surgery | Sensitivity/specificity of PET-CT | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy, metastasis-directed therapy