Early Salvage Therapy for Patients With Advanced Features for Biochemical Relapse After Radical Prostatectomy for Localized Prostate Carcinoma In Correlation With Supposed Molecular-genetic Parameters of Higher Aggressiveness

Study Overview
=================
Brief Summary
-----------------
The primary objective of the trial is to compare the impact and safety of delayed salvage therapy (dSRT, i.e., SRT initiated at PSA values of 0.4-0.5 ng/ml) to those of early salvage therapy (eSRT, i.e., at PSA levels of 0.2 ng/ml) in patients with biochemical relapse after radical prostatectomy. The secondary objective of the trial is to perform analysis of the subgroups of patients to determine which patients are most likely to benefit from dSRT Exploratory objective of the trial is to determine whether selected molecular genetic parameters (172 candidate genes and molecular alterations) and known clinical parameters can be used to identify potential predictors of worse prognosis in patients with known risk factors for relapse after radical prostatectomy, thereby augmenting and refining patient stratification, optimizing their therapy, and clarifying the proper timing of multimodal therapy

Official Title
-----------------
Early Salvage Therapy for Patients With Advanced Features for Biochemical Relapse After Radical Prostatectomy for Localized Prostate Carcinoma In Correlation With Supposed Molecular-genetic Parameters of Higher Aggressiveness

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Radiation: Early salvage radiotherapy (eSRT)
* Radiation: Delayed Salvage radiotherapy (dSRT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: > 18 years of age Pathologically confirmed invasive prostate carcinoma with minimal 1 risk factor (RF) after radical prostatectomy (RP) Patient refuses the adjuvant therapy after normalization of urinary function within 6 month after RP Signed informed consent to participate in the study and (where necessary) consent to participate in the translational part of the research (not a requirement) ECOG 0 - 1 pT2 and minimal 1 risk factor (RF): R1 (PSM), and/or Gleason score (4+3=7) 8-10 and/or ISUP grade group 3-5 pT3a /pT3b with or without one RF No evidence of suspicious pelvic lymph nodes by initial diagnostic: cN0 and/or pN0 No evidence of suspicious distant metastases by initial diagnostic: M0 Patient with decline of PSA level to undetectable PSA levels (< 0,1 ng/ml) or around 0,2ng/ml and with another decreasing trends so that the PSA level decline within 12-24 weeks after RP to undetectable levels (< 0,1 ng/ml) and with renewed increase of PSA >0,2 ng/ml (BCR= biochemical relapse) without any clinical relapse on PSMA PET/CT No hormonal therapy prior and /or after the radical prostatectomy Patient suitable and fit for subsequent radiotherapy with high likelihood of good compliance to the follow-up Exclusion Criteria: Life expectancy (based on Charlson comorbidity index) < 10 years Patient not fit for the therapy History of other cancer (other than a radically removed non-melanoma skin carcinoma) Previous pelvic irradiation Active immunosuppressive medication History of hormone therapy prior to randomization cN1 and/or pN1 and M1 PSA-persistence after RP (PSA 12-weeks after RP > 0.1 ng/ml or no decreasing trend described in Inclusion criteria)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A balanced design is used for the 1:1 randomization into two arms A and B:
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A- early salvage radiotherapy (eSRT)<br>Early salvage radiotherapy (eSRT) will be administered immediately after the confirmation of the biochemical relapse (prostate-specific antigen PSA level increase to ≈ 0,2 ng/ml) after radical prostatectomy with defined risk factors and no clinical recurrence signs on prostate specific membrane antigen positron emission tomography and computed tomography (PSMA PET/CT). | Radiation: Early salvage radiotherapy (eSRT)<br>* eSRT administered immediately after the confirmation of the biochemical relapse (PSA ≈ 0.2ng/ml). 66-70Gy will be delivered to the bed of prostate. Radiotherapy will be optionally accompanied by androgen deprivation therapy.<br>|
| Experimental: Arm B- delayed salvage radiotherapy (dSRT)<br>The patient is by the biochemical relapse analysis (PSA level 0,2 ng/ml) referred for further follow-up of PSA values. dSRT is initiated, if PSA further increase to values of ≥ 0.4 ng/ml is confirmed and the presence of a potential clinical relapse is excluded with repeated PSMA-PET-CT in line with standard procedures | Radiation: Delayed Salvage radiotherapy (dSRT)<br>* dSRT administered if PSA levels increase to ≥ 0.4 ng/ml. 66-70Gy will be delivered to the bed of prostate. Radiotherapy will be optionally accompanied by androgen deprivation therapy.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | Defined as a time to re-documented biochemical relapse after salvage therapy (bRFS), demonstration of clinical relapse (i.e.,local relapse /lRFS/, locoregional relapse /lrRFS/, distant relapse /MFS/) and/or death from any cause. | Analysed 3 years after randomisation of the last patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carcinoma-specific survival (CSS) |  | Analysed 5/10 years after randomization of the last patient. | 
| Overall survival (5y- and 10y- OS) |  | Analysed 5/10 years after randomization of the last patient. | 
| Incidence of treatment-related acute and late toxicity | Comparison of the incidence of treatment-related acute and late toxicity between patients after early/ delayed salvage therapy. Acute and late toxicity will be assessed and graded using Common Terminology Criteria for Adverse Events (CTCAE). | Analysed 5 years after randomization of the last patient. | 
| Health-related quality of life (QoL) assessment. | The analysis of the QoL of both study ARMs will be made based on EORTC validated questionnaires (QLQ-C30 and QLQ-PR25). QLQ-C30 was developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease. The EORTC QLQ-PR25 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 25 items specifically related to prostate cancer. | Analysed 5 years after randomization of the last patient. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
biochemical relapse, prostate carcinoma, salvage therapy