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

Overview

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

Interventions

• Radiation Early salvage radiotherapy (eSRT)
  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.
• Radiation Delayed Salvage radiotherapy (dSRT)
  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.

Primary outcome measures

• Event-free survival (EFS) [Time frame: Analysed 3 years after randomisation of the last patient.]

Secondary outcome measures (4)

• Carcinoma-specific survival (CSS) [Time frame: Analysed 5/10 years after randomization of the last patient.]
• Overall survival (5y- and 10y- OS) [Time frame: Analysed 5/10 years after randomization of the last patient.]
• Incidence of treatment-related acute and late toxicity [Time frame: Analysed 5 years after randomization of the last patient.]
• Health-related quality of life (QoL) assessment. [Time frame: Analysed 5 years after randomization of the last patient.]

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Kneebone A, Fraser-Browne C, Duchesne GM, Fisher R, Frydenberg M, Herschtal A, Williams SG, Brown C, Delprado W, Haworth A, Joseph DJ, Martin JM, Matthews JHL, Millar JL, Sidhom M, Spry N, Tang CI, Turner S, Wiltshire KL, Woo HH, Davis ID, Lim TS, Pearse M. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, ph PMID 33002437
• Tao R, Dai J, Bai Y, Yang J, Sun G, Zhang X, Zhao J, Zeng H, Shen P. The prognosis benefits of adjuvant versus salvage radiotherapy for patients after radical prostatectomy with adverse pathological features: a systematic review and meta-analysis. Radiat Oncol. 2019 Nov 9;14(1):197. doi: 10.1186/s13014-019-1384-z. PMID 31706339
• Wiegel T, Bartkowiak D, Bottke D, Bronner C, Steiner U, Siegmann A, Golz R, Storkel S, Willich N, Semjonow A, Stockle M, Rube C, Rebmann U, Kalble T, Feldmann HJ, Wirth M, Hofmann R, Engenhart-Cabillic R, Hinke A, Hinkelbein W, Miller K. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014 Aug;66(2):243-50. doi PMID 24680359
• Bhindi B, Lokeshwar SD, Klaassen Z, Klotz L, Wallis CJD. Systematic review and meta-analysis of trials evaluating the role of adjuvant radiation after radical prostatectomy for prostate cancer: Implications for early salvage. Can Urol Assoc J. 2020 Oct;14(10):330-336. doi: 10.5489/cuaj.6440. PMID 32432529
• Bolla M, van Poppel H, Tombal B, Vekemans K, Da Pozzo L, de Reijke TM, Verbaeys A, Bosset JF, van Velthoven R, Colombel M, van de Beek C, Verhagen P, van den Bergh A, Sternberg C, Gasser T, van Tienhoven G, Scalliet P, Haustermans K, Collette L; European Organisation for Research and Treatment of Cancer, Radiation Oncology and Genito-Urinary Groups. Postoperative radiotherapy after radical prostat PMID 23084481
• Hackman G, Taari K, Tammela TL, Matikainen M, Kouri M, Joensuu T, Luukkaala T, Salonen A, Isotalo T, Petas A, Hendolin N, Bostrom PJ, Aaltomaa S, Lehtoranta K, Hellstrom P, Riikonen J, Korpela M, Minn H, Kellokumpu-Lehtinen PL, Pukkala E, Hemminki A; FinnProstate Group. Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer P PMID 31375279
• Sanda MG, Cadeddu JA, Kirkby E, Chen RC, Crispino T, Fontanarosa J, Freedland SJ, Greene K, Klotz LH, Makarov DV, Nelson JB, Rodrigues G, Sandler HM, Taplin ME, Treadwell JR. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part II: Recommended Approaches and Details of Specific Care Options. J Urol. 2018 Apr;199(4):990-997. doi: 10.1016/j.juro.2018.01.002. Epub 2018 Jan 10. PMID 29331546
• McClelland S 3rd, Sandler KA, Degnin C, Chen Y, Mitin T. Adjuvant vs. salvage radiation therapy in men with high-risk features after radical prostatectomy: Survey of North American genitourinary expert radiation oncologists. Can Urol Assoc J. 2019 May;13(5):E132-E134. doi: 10.5489/cuaj.5470. Epub 2018 Oct 15. PMID 30332590

Identifiers

NCT: NCT05232578 · ESTABLISH 2021 Trial v03.2021

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗