Adjuvante vs. Salvage-Strahlentherapie nach radikaler Prostatektomie

Zusammenfassung

Hintergrund: Nach radikaler Prostatektomie (RP) sind präoperativer PSA-Wert, Gleason-Score, pT-Stadium, der Status der Samenblasen und der Resektionsränder wesentliche Risiko-Indikatoren für ein biochemisches oder klinisches Rezidiv. Binnen 5 Jahren kommt es je nach Tumorstadium bei 50–70% der Hochrisikopatienten zum biochemischen Progress. Behandlungsoptionen unter diesen Bedingungen sind die adjuvante Strahlentherapie (ART, bei nicht detektierbarem PSA) oder die Salvage-Radiotherapie (SRT, bei persistierendem oder aus dem Nullbereich ansteigendem PSA). Daten laufender randomisierter Studien zum direkten Vergleich von ART und SRT sind noch nicht publiziert.

Methode: PubMed-Recherche zu ART und SRT nach RP bei Prostatakarzinom und Vergleich der publizierten Resultate beider Therapieformen.

Ergebnisse: 3 randomisierte Phase-III-Studien zeigen einen fast 20-prozentigen Vorteil bei der biochemische Progressionsfreiheit nach ART (60–64 Gy) gegenüber einer abwartenden Strategie. Bei Patienten mit Tumorstadium pT3 und positiven Schnitträndern ist der Effekt am größten. Patienten mit postoperativ persistierendem PSA oder PSA-Anstieg aus dem Nullbereich kann nach S-3-Leitlinie die SRT mit mindestens 66 Gy angeboten werden. In 30–70% der Fälle sinkt danach der PSA erneut unter die Nachweisgrenze. Damit besteht eine zweite kurative Option. Durch die niedrigere Gesamtdosis scheint die Rate der Spätfolgen nach ART geringer als nach SRT. Andererseits vermindert die SRT mögliche Wechselwirkungen mit postoperativen Komplikationen und das potentielle Übertherapie-Risiko. Die Mitbestrahlung der pelvinen Lymphabflusswege, eine zusätzliche antihormonelle Therapie und die Höhe der Gesamtdosis sowohl von ART als auch von SRT werden kontrovers diskutiert.

Schlussfolgerung: Die Wertigkeit der SRT nach PSA-Progression im Vergleich mit der ART bei PSA im Nullbereich unmittelbar postoperativ ist nicht abschließend geklärt. Die Indikation zur ART hängt von begleitenden Risikofaktoren ab, ist bezogen auf die biochemische Progressionsfreiheit jedoch durch hochrangige Evidenz gesichert. Wird bei biochemischer Progression die SRT eingesetzt, so sollte dies frühzeitig geschehen, d. h. bei möglichst niedrigem PSA-Wert.

Abstract

Background: After radical prostatectomy (RP) the pre-RP PSA value, Gleason Score, pT-stage, state of seminal vesicles and state of surgical margins are key indicators for the risk of biochemical or clinical recurrence. Depending on the tumour stage, 50–70% of the high-risk patients suffer biochemical progression. The treatment options in these circumstances are adjuvant radiotherapy (ART, for an undetectable PSA) or salvage radiotherapy (SRT, for persisting PSA or PSA re-rising above detection limits). Data from ongoing randomised trials that compare ART and SRT directly have not yet been published.

Method: A search in PubMed for ART and SRT after RP for prostate cancer was undertaken to compare the results of the 2 treatment approaches.

Results: 3 randomised phase-III studies have shown a nearly 20% advantage in terms of biochemical progression after ART (60–64 Gy) compared with a wait-and-see strategy. The largest effect was seen in patients with pT3 prostate cancer with positive surgical margins. According to the German S3-guidelines, SRT with at least 66 Gy can be offered to patients with a post-RP persisting PSA or a PSA re-rising above detection limits. 30–70% of these patients re-achieve an undetectable PSA. Thus, there is a second option for curative treatment. Due to the lower total dose, ART seems to be connected with fewer late complications than SRT. SRT, on the other hand, reduces the risk of potential interactions with post-RP complications and of overtreatment. There is a controversial discussion about the inclusion of the pelvic lymph nodes in the treatment volume, the additional application of anti-androgens and the total dose of both ART and SRT.

Conclusions: The comparison of SRT after PSA progression with ART at a PSA below the detection limits cannot yet be judged conclusively. The indication for ART depends on the associated risk factors. However, regarding freedom from biochemical progression, it is backed up by high level evidence. If SRT is applied for biochemical progression, then it should be initiated early, i. e., at the lowest PSA possible.

Schlüsselwörter

Prostatakarzinom - radikale Prostatektomie - adjuvante Strahlentherapie - Salvage Strahlentherapie - Review

Key words

prostate cancer - radical prostatectomy - adjuvant radiotherapy - salvage radiotherapy - review

• Literatur

• 1 Leitlinienprogramm Onkologie der AWMF DKeVuDKeV Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinom 2014 http://leitlinienprogramm-onkologie.de/uploads/tx_sbdownloader/LL_Prostata_Langversion_3.0.pdf
• 2 Wiegel T, Lohm G, Bottke D et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome – results of a retrospective study. Int J Radiat Oncol Biol Phys 2009; 73: 1009-1016
• 3 Stephenson AJ, Shariat SF, Zelefsky MJ et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004; 291: 1325-1332
• 4 Anscher MS, Clough R, Dodge R. Radiotherapy for a rising prostate-specific antigen after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys 2000; 48: 369-375
• 5 Lotan Y, Roehrborn CG. Clearance rates of total prostate specific antigen (PSA) after radical prostatectomy in African-Americans and Caucasians. Prostate Cancer Prostatic Dis 2002; 5: 111-114
• 6 Audenet F, Seringe E, Drouin SJ et al. Persistently elevated prostate-specific antigen at six weeks after radical prostatectomy helps in early identification of patients who are likely to recur. World J Urol 2012; 30: 239-244
• 7 Lohm G, Lutcke J, Jamil B et al. Salvage radiotherapy in patients with prostate cancer and biochemical relapse after radical prostatectomy: Long-term follow-up of a single-center survey. Strahlenther Onkol. 2014
• 8 Wiegel T, Bartkowiak D, Bottke D et al. PSA persistence after radical prostatectomy as a predictive factor of clinical relapse-free and overall survival. 10-years data of the ARO 96-02 trial. Int J Radiat Oncol Biol Phys 2014; in press
• 9 Heidenreich A, Bastian PJ, Bellmunt J et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol 2014; 65: 124-137
• 10 Roehl KA, Han M, Ramos CG et al. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol 2004; 172: 910-914
• 11 Stephenson AJ, Wood DP, Kattan MW et al. Location, extent and number of positive surgical margins do not improve accuracy of predicting prostate cancer recurrence after radical prostatectomy. J Urol 2009; 182: 1357-1363
• 12 Liauw SL, Pitroda SP, Eggener SE et al. Evaluation of the prostate bed for local recurrence after radical prostatectomy using endorectal magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2013; 85: 378-384
• 13 Shekarriz B, Upadhyay J, Wood Jr DP et al. Vesicourethral anastomosis biopsy after radical prostatectomy: predictive value of prostate-specific antigen and pathologic stage. Urology 1999; 54: 1044-1048
• 14 Rossi Jr CJ, Joe Hsu IC, Abdel-Wahab M et al. ACR appropriateness criteria postradical prostatectomy irradiation in prostate cancer. Am J Clin Oncol 2011; 34: 92-98
• 15 Wiegel T, Bartkowiak D, Bottke D et al. 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;
• 16 Bolla M, van Poppel H, Tombal B et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380: 2018-2027
• 17 Thompson Jr IM, Tangen CM, Paradelo J et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006; 296: 2329-2335
• 18 Van der Kwast TH, Bolla M, Van Poppel H et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007; 25: 4178-4186
• 19 Thompson IM, Tangen CM, Paradelo J et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009; 181: 956-962
• 20 Stephenson AJ, Bolla M, Briganti A et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. Eur Urol 2012; 61: 443-451
• 21 Briganti A, Joniau S, Gandaglia G et al. Patterns and predictors of early biochemical recurrence after radical prostatectomy and adjuvant radiation therapy in men with pT3N0 prostate cancer: implications for multimodal therapies. Int J Radiat Oncol Biol Phys 2013; 87: 960-967
• 22 Connolly JA, Shinohara K, Presti Jr JC et al. Local recurrence after radical prostatectomy: characteristics in size, location, and relationship to prostate-specific antigen and surgical margins. Urology 1996; 47: 225-231
• 23 Miralbell R, Vees H, Lozano J et al. Endorectal MRI assessment of local relapse after surgery for prostate cancer: A model to define treatment field guidelines for adjuvant radiotherapy in patients at high risk for local failure. Int J Radiat Oncol Biol Phys 2007; 67: 356-361
• 24 Malone S, Croke J, Roustan-Delatour N et al. Postoperative Radiotherapy for Prostate Cancer: A Comparison of Four Consensus Guidelines and Dosimetric Evaluation of 3D-CRT Versus Tomotherapy IMRT. Int J Radiat Oncol Biol Phys 2012; 84: 725-732
• 25 Chua B, Min M, Wood M et al. Implementation of an image guided intensity-modulated protocol for post-prostatectomy radiotherapy: planning data and acute toxicity outcomes. Journal of medical imaging and radiation oncology 2013; 57: 482-489
• 26 Wiegel T, Bottke D, Steiner U et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol 2009; 27: 2924-2930
• 27 Spiotto MT, Hancock SL, King CR. Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys 2007; 69: 54-61
• 28 Boorjian SA, Thompson RH, Siddiqui S et al. Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol 2007; 178: 864-870 discussion 870–871
• 29 Briganti A, Karnes JR, Da Pozzo LF et al. Two positive nodes represent a significant cut-off value for cancer specific survival in patients with node positive prostate cancer. A new proposal based on a two-institution experience on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node dissection and adjuvant therapy. Eur Urol 2009; 55: 261-270
• 30 Abdollah F, Karnes RJ, Suardi N et al. Predicting survival of patients with node-positive prostate cancer following multimodal treatment. Eur Urol 2014; 65: 554-562
• 31 Briganti A, Karnes RJ, Pozzo LF et al. Combination of Adjuvant Hormonal and Radiation Therapy Significantly Prolongs Survival of Patients With pT2-4 pN+ Prostate Cancer: Results of a Matched Analysis. Eur Urol 2011; 59: 832-840
• 32 Da Pozzo LF, Cozzarini C, Briganti A et al. Long-term follow-up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy. Eur Urol 2009; 55: 1003-1011
• 33 King CR. The timing of salvage radiotherapy after radical prostatectomy: a systematic review. Int J Radiat Oncol Biol Phys 2012; 84: 104-111
• 34 Giovacchini G, Picchio M, Parra RG et al. Prostate-specific antigen velocity versus prostate-specific antigen doubling time for prediction of 11C choline PET/CT in prostate cancer patients with biochemical failure after radical prostatectomy. Clin Nucl Med 2012; 37: 325-331
• 35 Stephenson AJ, Scardino PT, Kattan MW et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007; 25: 2035-2041
• 36 Mir MC, Li J, Klink JC et al. Optimal Definition of Biochemical Recurrence After Radical Prostatectomy Depends on Pathologic Risk Factors: Identifying Candidates for Early Salvage Therapy. Eur Urol. 2013
• 37 Briganti A, Wiegel T, Joniau S et al. Early Salvage Radiation Therapy Does Not Compromise Cancer Control in Patients with pT3N0 Prostate Cancer After Radical Prostatectomy: Results of a Match-controlled Multi-institutional Analysis. Eur Urol 2012; 62: 472-487
• 38 Bernard Jr JR, Buskirk SJ, Heckman MG et al. Salvage radiotherapy for rising prostate-specific antigen levels after radical prostatectomy for prostate cancer: dose-response analysis. Int J Radiat Oncol Biol Phys 2010; 76: 735-740
• 39 King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there?. Int J Radiat Oncol Biol Phys 2008; 71: 346-350
• 40 Ohri N, Dicker AP, Trabulsi EJ et al. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer 2012; 48: 837-844
• 41 Bottke D, Bartkowiak D, Schrader M et al. Radiotherapy after radical prostatectomy: immediate or early delayed?. Strahlenther Onkol 2012; 188: 1096-1101
• 42 Ost P, Lumen N, Goessaert AS et al. High-dose salvage intensity-modulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol 2011; 60: 842-849
• 43 Goenka A, Magsanoc JM, Pei X et al. Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy. Eur Urol 2011; 60: 1142-1148
• 44 Siegmann A, Bottke D, Faehndrich J et al. Dose escalation for patients with decreasing PSA during radiotherapy for elevated PSA after radical prostatectomy improves biochemical progression-free survival: Results of a retrospective study. Strahlenther Onkol 2011; 187: 467-472
• 45 Geinitz H, Riegel MG, Thamm R et al. Outcome after conformal salvage radiotherapy in patients with rising prostate-specific antigen levels after radical prostatectomy. Int J Radiat Oncol Biol Phys 2012; 82: 1930-1937
• 46 Shipley WU, Hunt D, Lukka H et al. Initial Report of RTOG 9601: A Phase III Trial in Prostate Cancer: Anti-androgen Therapy (AAT) with Bicalutamide during and after Radiation Therapy (RT) Improves Freedom from Progression and Reduces the Incidence of Metastatic Disease in Patients following Radical Prostatectomy (RP) with pT2-3, N0 Disease, and Elevated PSA Levels. Int J Radiat Oncol Biol Phys 2010; 78: S27
• 47 Budiharto T, Perneel C, Haustermans K et al. A multi-institutional analysis comparing adjuvant and salvage radiation therapy for high-risk prostate cancer patients with undetectable PSA after prostatectomy. Radiother Oncol 2010; 97: 474-479
• 48 Ost P, De Troyer B, Fonteyne V et al. A matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2011; 80: 1316-1322
• 49 Trabulsi EJ, Valicenti RK, Hanlon AL et al. A multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pT3-4N0 prostate cancer. Urology 2008; 72: 1298-1302 discussion 1302–1304
• 50 Bolla M, van Poppel H, Collette L et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005; 366: 572-578