Radical prostatectomy is a well-established treatment option in the management of localized and locally advanced prostate cancer. An extended lymphadenectomy is performed in case of substantial risk for lymph node involvement. When biochemical recurrence (BCR) occurs, salvage radiotherapy (SRT) is performed. The benefit in terms of BCR-free survival (FS) and metastasis-FS by adding 6 months of androgen deprivation therapy (ADT) compared with SRT only has already been established. Retrospective evidence suggests that a longer schedule of ADT may be more beneficial compared with 6 months. This multicenter open-label randomized trial will include patients who need SRT after experiencing BCR post-radical prostatectomy with lymphadenectomy and pN0-status. Patients will be randomized for ADT duration (6 vs 24 months). Primary end point is distant metastasis-FS.

Clinical Trial Registration: NCT04242017 (ClinicalTrials.gov)

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Mottet N, Bellmunt J, Briers E et al. EAU-ESTRO-SIOG Guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur. Urol. 71(4), 618–629 (2017).
MedlineGoogle Scholar
2. Simon RM, Howard L, Freedland SJ et al. Adverse pathology and undetectable ultrasensitive prostate-specific antigen after radical prostatectomy: is adjuvant radiation warranted? BJU Int. 117(6), 897–903 (2016).
Medline CASGoogle Scholar
3. Rans K, Berghen C, Joniau S et al. Salvage radiotherapy for prostate cancer. Clin. Oncol. (R. Coll. Radiol.) 32(3), 156–162 (2020). • Provides an overview on the available data on salvage radiation therapy.
Medline CASGoogle Scholar
4. Fossati N, Karnes JF, Cozzarini C et al. Assessing the optimal timing for early salvage radiation therapy in patients with prostate-specific antigen rise after radical prostatectomy. Eur. Urol. 69, 728–733 (2016).
MedlineGoogle Scholar
5. Fossati N, Robesti D, Karnes JF et al. Assessing the role and optimal duration of hormonal treatment in association with salvage radiation therapy after radical prostatectomy: results from a multi-institutional study. Eur. Urol. 76, 443–449 (2019). •• Shows that long-term hormonal therapy might be beneficial for patients having two or more adverse clinical or pathological characteristics, when treated with salvage treatment with radiotherapy after radical prostatectomy.
MedlineGoogle Scholar
6. Carrie C, Mangné N, Burvan-Provost P et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncol. 20, 1740–1749 (2019). •• This open-label randomized controlled trial shows that the combination of salvage radiotherapy (SRT) with short-term androgen deprivation significantly reduced the risk of biochemical or clinical progression and metastasis-free survival compared with radiation therapy alone.
Medline CASGoogle Scholar
7. Van den Broeck T, van den Bergh RCN, Briers E et al. Biochemical recurrence in prostate cancer: the european association of urology prostate cancer guidelines panel recommendations. Eur. Urol. 6, 231–234 (2020).
Google Scholar
8. Jackson WC, Schipper MJ, Johnson SB et al. Duration of androgen deprivation therapy influences outcomes for patients receiving radiation therapy following radical prostatectomy. Eur. Urol. 69, 50–57 (2016). •• This retrospective analysis shows that some patient experiencing biochemical recurrence after radical prostatectomy might benefit from a longer duration of androgen deprivation therapy associated to SRT.
MedlineGoogle Scholar
9. Wiltshire C, Brockx KK, Haider MA et al. Anatomic boundaries of the clinical target volume (prostate bed) after radical treatment. Int. J. Radiat. Oncol. Biol. Phys. 69(4), 1090–1099 (2007).
MedlineGoogle Scholar
10. Poortmans P, Bossi A, Vandeputte K et al. Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. Radiother. Oncol. 84, 121–127 (2007).
MedlineGoogle Scholar
11. Sidhom M, Kneebone A, Lehman M et al. Post-prostatectomy radiation therapy: consensus guidelines of the Australian and New Zealand radiation oncology genito-urinary group. Radiother. Oncol. 88, 10–19 (2008).
MedlineGoogle Scholar
12. Michialski J, Lawton C, El Naqa I et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2, 361–368 (2010).
Google Scholar
13. Ost P, De Meerleer G, De Gersem W et al. Analysis of prostate bed motion using daily cone-beam computed tomography during postprostatectomy radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 79(1), 188–194 (2011).
MedlineGoogle Scholar
14. Ost P, Lumen N, Goessaert AS et al. High-dose salvage intensity-modulated radiotherapy with or without androgen deprivation therapy after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur. Urol. 60, 842–849 (2011).
MedlineGoogle Scholar
15. Fonteyne V, De Neve W, Vileirs G et al. Late radiotherapy-induced lower intestinal toxicity (RILIT) of intensity-modulated radiotherapy for prostate cancer: the need for adapting toxicity scales and the appearance of the sigmoid colon as co-responsible organ for lower intestinal toxicity. Radiother. Oncol. 84(2), 156–163 (2007).
MedlineGoogle Scholar
16. Stephenson AJ, Scardino PT, Eastham JA et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J. Natl Cancer Inst. 98, 715–717 (2006).
MedlineGoogle Scholar
17. Fossati N, Karnes JF, Colicchia M et al. Impact of early salvage radiation therapy in patients with persistently elevated or rising prostate-specific antigen after radical prostatectomy. Eur. Urol. 73, 436–444 (2018).
MedlineGoogle Scholar
18. King CR, Spiotto MT. Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int. J. Radiat. Oncol. Biol. Phys. 71(1), 23–27 (2008).
MedlineGoogle Scholar
19. Ost P, Lumen N, Goessaert AS et al. High-dose salvage intensity-modulated radiotherapy with or without androgen deprivation therapy after radical prostatectomy for rising or persisting prostate-specific antigen: 5-years results. Eur. Urol. 60(4), 842–849 (2011).
MedlineGoogle Scholar
20. Goenka A, Magsanoc JM, Pei X et al. Long-term outcomes after high-dose post-prostatectomy salvage radiation treatment. Int. J. Radiat. Oncol. Biol. Phys. 84(1), 112–118 (2012).
MedlineGoogle Scholar
21. De Meerleer G, Fonteyne V, Meersschout S et al. Salvage intensity-modulated radiotherapy for rising PSA after radical prostatectomy. Radiother. Oncol. 89(2), 205–213 (2008).
MedlineGoogle Scholar
22. Ost P, Fonteyne P, Villeirs G et al. Adjuvant high-dose intensity-modulated radiotherapy after radical prostatectomy for prostate cancer: clinical results in 104 patients. Eur. Urol. 56(4), 669–667 (2009).
MedlineGoogle Scholar
23. Gahdjar P, Hayoz S, Bernhard J et al. Acute toxicity and quality of life after dose-intensified salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: first results of the randomized trial SAKK 09/10. J. Clin. Oncol. 33(35), 4158–4166 (2015).
MedlineGoogle Scholar
24. Qi X, Gao X-S, Li H-Z et al. Toxicity and biochemical outcomes of dose-intensified post-operative radiation therapy for prostate cancer: results of the randomized phase III trial. Int. J. Radiat. Oncol. 106(2), 282–290 (2020).
Medline CASGoogle Scholar
25. Katz MS, Zelefsky MJ, Venkatraman ES et al. Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J. Clin. Oncol. 21(3), 483–489 (2003).
MedlineGoogle Scholar
26. Briganti A, Karnes RJ, Joniau S et al. Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. Eur. Urol. 66(3), 470–486 (2014).
Google Scholar
27. Stish BJ, Pisanky TM, Harmsen WS et al. Improved metastasis-free and survival outcomes with early salvage radiotherapy in men with detectable prostate-specific antigen after radical prostatectomy for prostate cancer. J. Clin. Oncol. 34(32), 3864–3871 (2016). • Shows the benefit of early SRT in terms of biochemical recurrence, distant metastases, cancer-specific mortality and all-cause mortality.
MedlineGoogle Scholar
28. Stephenson AJ, Scardino PT, Kattan MW et al. Predicting outcome of salvage radiation therapy for recurrence prostate cancer after radical prostactectomy. J. Clin. Oncol. 25(15), 2035–2041 (2007).
MedlineGoogle Scholar
29. Tandulkar RD, Agrawal S, Gao T et al. Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy. J. Clin. Oncol. 34, 2648–3654 (2016).
Google Scholar
30. Abugharib A, Jackson WC, Tumati V et al. Very early salvage radiotherapy improves distant metastasis-free survival. J. Urol. 197(3), 662–668 (2017).
MedlineGoogle Scholar
31. Baumgarten L, Borchert A, Sood A et al. Impact of timing on salvage radiation therapy adverse events following radical prostatectomy: a secondary analysis of the RTOG 9601 cohort. Urol. Oncol. 8, e17.22–e38.22 (2020).
Google Scholar
32. Rodin D, Drumm M, Clayman R et al. Risk factors for disease progression after postprostatectomy salvage radiation: long-term results of a single-institution experience. Clin. Genitourin. Cancer 16(1), 21e1–27e1 (2018).
Google Scholar
33. Markowski MC, Chen Y, Feng Z et al. PSA doubling time and absolute PSA predict metastasis-free survival in men with biochemically recurrent prostate cancer after radical prostatectomy. Clin. Genitourin. Cancer 17(6), 470–475 (2019).
MedlineGoogle Scholar
34. Simmons MN, Stephenson AJ, Klein EA. Natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. Eur. Urol. 51, 1175–1184 (2007).
MedlineGoogle Scholar
35. Campbell SR, Agrawal S, Tom MC et al. Impact on post-prostatectomy prostate specific antigen (PSA) kinetics on outcomes of salvage radiotherapy. Int. J. Rad. Oncol. Biol. Phys. 105(1), S38–S39 (2019).
Google Scholar
36. Roberts SG, Blute ML, Bertstralh EJ et al. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin. Proc. 76(6), 576–581 (2001).
Medline CASGoogle Scholar
37. Spratt DE, Evans MJ, Davis BJ et al. Androgen receptor upregulation mediates radioresistance after ionizing radiation. Cancer Res. 75, 4688–4696 (2015).
Medline CASGoogle Scholar
38. Bolla M, de Reijke TM, Van Tienhoven G et al. Duration of androgen suppression in the treatment of prostate cancer. N. Engl. J. Med. 360, 2516–2527 (2009).
Medline CASGoogle Scholar
39. Bolla M, Van Tienhoven G, Warde P et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 11, 1066–1073 (2010).
Medline CASGoogle Scholar
40. D'Amico AV, Chen MH, Renshaw AA et al. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 299, 289–295 (2008).
MedlineGoogle Scholar
41. Denham JW, Steigler A, Lamb DS et al. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans–Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol. 6, 841–850 (2005).
Medline CASGoogle Scholar
42. Horwitz EM, Bae K, Hanks GE et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a Phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J. Clin. Oncol. 26, 2497–2504 (2008).
Medline CASGoogle Scholar
43. Jones CU, Hunt D, McGowan DG et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N. Engl. J. Med. 365, 107–118 (2011).
Medline CASGoogle Scholar
44. Roach M III, Bae K, Speight J et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J. Clin. Oncol. 26, 585–591 (2008).
MedlineGoogle Scholar
45. Pilepich MV, Winter K, Lawton CA et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma-long-term results of Phase III RTOG 85-31. Int. J. Radiat. Oncol. Biol. Phys. 61, 1285–1290 (2005).
Medline CASGoogle Scholar
46. Shipley WU, Seiferheld W, Lukka HR et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N. Engl. J. Med. 376(5), 417–428 (2017). •• This double-blind, placebo-controlled trial shows that adding 24 months of antiandrogen therapy (bicalutamide) to SRT improved overall survival significantly compared with salvage radiation plus placebo.
MedlineGoogle Scholar

Vol. 16, No. 27

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History

Received 22 April 2020

Accepted 16 June 2020

Published online 15 July 2020

Published in print September 2020

Information

Keywords

Author contributions

Study conception: G De Meerleer and S Joniau. Initial study design: G De Meerleer, S Joniau and C Berghen. Revision of study design and protocol: G De Meerleer, S Joniau, C Berghen A Laenen, G Devos, K Rans, K Goffin and K Haustermans. Study coordination: C Berghen and G De Meerleer. Drafting the manuscript: all authors. All authors read and approved the final manuscript.

Financial & competing interests disclosure

The study was an academic study without external funding. Decapeptyl® 22.5 mg injections was provided by the firm IPSEN. IPSEN was not involved in the data collection or analysis. Charlien Berghen is a PhD student at KU Leuven, receiving a grant from ‘Kom op tegen kanker’ (Stand up to Cancer). S Joniau is a senior clinical researcher of the FWO (research foundation flanders). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

Ethics approval was obtained by the Ethical Committee Research/KULeuven at 15 November 2019. All patients must sign an informed consent before entering the study.

Data sharing statement

The datasets generated and/or analyzed during the current study are not publicly available due to national privacy policy restrictions (they contain information that could compromise research participant privacy), but are available from the corresponding author on reasonable request.

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