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Adjuvant and Salvage Radiation for Advanced Prostate Cancer: A Discussion During the ESOU 2010 Meeting
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 401–405
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Adjuvant and Salvage Radiation for Advanced Prostate Cancer: A Discussion During the ESOU 2010 Meeting Henk G. van der Poel a,*, Steven Joniau b a
Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands
b
Department of Urology, Leuven University, Leuven, Belgium
Article info
Abstract
Keywords: Prostate cancer Salvage Adjuvant radiation Prostatectomy
Adjuvant radiation therapy (RT) for advanced localised prostate cancer (PCa) is now supported by the findings from three randomised controlled trials, having shown improved biochemical recurrence–free survival rates in three trials and an improved metastases-free survival in one trial. Patients with positive surgical margins are most likely to benefit from adjuvant radiotherapy. In this article, the three trials are compared and the control groups scrutinised. Salvage RT at the time of a biochemical or local recurrence is still valid and seems particularly beneficial for men with more rapidly rising prostate-specific antigen values prior to salvage treatment, when disease-specific survival is considered. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31205122553; Fax: +31205122554. E-mail address: [email protected] (H.G. van der Poel).
1.
Introduction
The evidence for the value of additional radiation therapy (RT) to the prostate fossa after prostatectomy has been accumulating in recent years. Although earlier retrospective analyses revealed a disease progression advantage for adjuvant RT in >70% of the studies, a survival advantage was only observed in 2 out of 10 studies [1]. Three large randomised controlled trials have now been published on the topic of adjuvant RT (Tables 1–3) [2–5]. All three trials showed a benefit in biochemical recurrence (BCR)–free survival for the adjuvant RT group of at least 15% at 5 yr. Whereas the largest (European Organisation for Research and Treatment of Cancer [EORTC]-22911; n = 1005) [3] and the smallest (ARO-96-02; n = 307) [5] trials were powered to detect a benefit in BCR-free survival, the Southwest Oncology Group (SWOG)-S8794 trial [4] with 431 randomised patients had as its primary end point metastasis-free survival. The inclusion criteria were similar with the exception that in the EORTC trial, pT2R1 patients were
also included; in the other two trials, only pT3 cancers with or without a positive resection margin were included. Patients with pN1 cancers were excluded in all three trials. The presence of patients with a positive surgical margins (PSM) was relatively high in all three trials, ranging from 63% to 68%. Of note is the fact that the randomised population differed with respect to the postoperative prostate-specific antigen (PSA) level prior to randomisation for adjuvant RT among the three trials. In the German ARO96-02 trial, only men with a PSA <0.1 ng/ml were eligible for randomisation, whereas in the EORTC trial, 11% had a PSA level >0.2 ng/ml prior to randomisation. In the SWOG trial, this percentage was even higher (34%), indicating that in the EORTC and SWOG trials, a substantial number of patients received ‘‘salvage’’ RT (SRT) for a non-normalised PSA levels rather than adjuvant RT. In a subanalysis of the SWOG trial, Swanson et al. [6] showed that men in all categories of postprostatectomy PSA level (<0.2, 0.2–1.0, and >1.0 ng/ml) showed improvement in metastases-free survival, suggesting that although less effective, SRT may be
1569-9056/$ – see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2010.02.012
402
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 401–405
Table 1 – Inclusion criteria for the three randomised controlled trials for adjuvant radiation therapy
ARO-96-02 [5] EORTC-22911 [3] SWOG-S8794 [4]
n
TNM
Patients with a PSM at prostatectomy, %
Patients with a postoperative PSA >0.2 ng/ml, %
Interval of prostatectomy to adjuvant RT, d
307 1005 431
pT3N0 pT2R1–pT3N0 pT3N0
68 63 67 (with EC)
0 11 16
81 112 <122
Dose of adjuvant radiation, Gy
60 60 60–64
PSM = positive surgical margin; PSA = prostate-specific antigen; RT = radiation therapy; EORTC = European Organisation for Research and Treatment of Cancer; SWOG = Southwest Oncology Group; EC = extracapsular disease.
Table 2 – Treatments of patients in the control arms for the three randomised controlled trials for adjuvant radiation therapy
ARO-96-02 [5] EORTC-22911 [3] SWOG-S8794 [4]
n
Median follow up, mo
Patients receiving salvage RT in the control arm, %
PSA level at salvage RT in the control arm
307 1005 431
54 60 152
– 55 33
– – 1
Interval to salvage RT, yr
– 2.2 2
RT = radiation therapy; PSA = prostate-specific antigen; EORTC = European Organization for Research and Treatment of Cancer; SWOG = Southwest Oncology Group.
Table 3 – Follow-up data for the three randomised controlled trials for adjuvant radiation therapy
ARO-96-02 [5] EORTC-22911 [3] SWOG-S8794 [4]
n
Primary end point
307 1005 431
BCR BCR Metastasis-free survival
Median Definition of BCR for adjuvant follow-up, mo BCR (PSA, ng/ml) and control arms, yr 54 60 152
0.1 0.2 0.4
5 (28% vs 46%) 5 (21% vs 44%) 10 (47% vs 70%)
Metastasis development, yr 2% vs 3.1% 5 (6.1% vs 6.3%) 10 (27% vs 35%)
OS
– 90.8% vs 91.5% 10 (74% vs 66%)
BCR = biochemical recurrence; PSA = prostate-specific antigen; OS = overall survival; EORTC = European Organization for Research and Treatment of Cancer; SWOG = Southwest Oncology Group.
beneficial to improving metastases-free survival. However, the relatively high number of men with a non-normalised PSA after surgery (PSA >0.2 ng/ml) may result in an underestimation of the true value of adjuvant RT. 2.
Delayed radiation therapy
In light of these results, it is of interest that not all men in the nonadjuvant arm of the trials were treated with SRT by the time of BCR. In the EORTC trial, 55% of men with a rising PSA level received delayed or SRT to the prostatic fossa, whereas in the SWOG trial, this group constituted 33%. This difference means that the trials essentially are not evaluating the question of whether adjuvant RT is superior to SRT because in the control arm, only half of the men at most received RT at the time of PSA recurrence. In the German trial, which had an end point of BCR—similar to the EORTC trial end point—the percentage of men receiving SRT was not reported. Therefore, neither trial is useful for evaluating the role of SRT in comparison to adjuvant RT; indeed, the authors of the EORTC trial suggest that SRT may be equivalent to adjuvant RT, provided that the PSA level is <1 ng/ml [3]. Basically, only the SWOG trial was powered to address the issue of delayed RT, as metastasis-free survival was the primary end point. Particularly in the SWOG trial, men in the control arm were less likely to receive SRT (33%). Still, it took a median follow-
up of >12 yr before metastasis-free survival improved in the adjuvant arm, suggesting that in men with a life expectancy <10 yr, adjuvant RT might not be useful [2,4]. The median interval to SRT was 2 yr and 2.2 yr for the SWOG and EORTC nonadjuvant RT arms, respectively. In the SWOG study, 23% of men had a PSA level >1.5 ng/ml prior to SRT. From earlier analysis [7], it is clear that a higher PSA level at SRT predicted poorer response. Men with a PSA level <0.5 ng/ml at the time of SRT had a 48% BCR-free survival at 6 yr, which stills seems considerably lower than observed in the adjuvant RT arm of the three clinical trials but within the range of the nonadjuvant RT arms (44–52%), suggesting that the control groups in all three trials may reflect current clinical practice with respect to SRT use. 3.
Biochemical recurrence
It is also of interest to look at the definitions of biochemical recurrence in the three trials. In the ARO-96-02 trial, BCR was defined as 0.1 ng/ml, whereas in the EORTC-22911 and SWOG-S8794 trials, BCR was defined as a PSA level of 0.2 ng/ml and 0.4 ng/ml, respectively. Whether this difference in BCR definition is the reason for the observed lower BCR rate in the EORTC trial (21% at 5 yr) in comparison to the ARO-96-02 trial (28% at 5 yr) remains unclear, but it seems not likely because in the SWOG-S8794 trial—where BCR was
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 401–405
defined as a PSA >0.4 ng/ml—a 30% 5-yr BCR rate was found in the adjuvant RT arm (Tables 1–3). 4.
Metastasis-free and overall survival
Recently, the SWOG trial data have been updated. With a median follow-up of 152 mo, this is the trial with the longest follow-up. Although in the initial publication (at a median follow-up of 130 mo) no significant overall survival (OS) advantage was observed [2], in the most recent update, a significant hazard ratio of 0.72 for adjuvant RT was found [4]. This finding translates into an estimated 10-yr OS of 74% for adjuvant RT versus 66% for the nonadjuvant arm. These findings have been criticised in editorials by Cheng et al. [8] and Chun [9]. In the SWOG-S8974 trial, metastasis-free survival was defined as time from randomisation to metastasis or death resulting from any cause. This definition may have led to an overestimation of the presence of metastasis and explains why the number needed to treat with adjuvant RT to prevent one patient with metastasised disease was 12 versus 9.1 to prevent one patient from dying. If death (from prostate cancer [PCa]) is always associated with metastasised disease, it seems difficult to explain why adjuvant RT would be less effective in preventing metastasis than in preventing death. It was also put forward that the number of high Gleason sum score tumours (Gleason sum score 8–10) in the observation arm was higher than in the adjuvant RT arm. Whether this seeming imbalance in Gleason sum scores would have affected outcome is unclear. The authors, however, correctly remarked that randomisation should correct for this imbalance. The fact that preoperative PSA levels >10 ng/ ml were less likely in the observation arm (47%) and slightly lower than in the adjuvant RT arm (59%) suggests that a serious imbalance may not have been present. 5.
Predictors of response
Additional analyses of all three clinical trials on adjuvant RT studied predictors of response. In the SWOG-S8794 trial, the level of postprostatectomy PSA and disease extension (defined as seminal vesicle invasion [SVI]) were not predictive of a metastases-free survival advantage to adjuvant RT, suggesting that all men benefited equally from early RT [4]. In the ARO-96-02 trial, in an unplanned subanalysis, men with a PSM at prostatectomy, preoperative PSA level >10 ng/ml, non-SVI tumours, and a lower PSA doubling time (PSA DT) were significantly more likely to benefit from adjuvant RT with respect to BCR-free survival [5]. Van der Kwast et al. [10] showed in a subanalysis from the EORTC-22911 trial that in particular men with a PSM benefited from adjuvant RT with respect to BCR. PSM location was not predictive of response to adjuvant radiation.
Gleason sum score, the presence of SVI, surgical margin status, the presence of lymph node metastases, and PSA DT as well as radiation dose and hormonal treatment [7]. A nomogram based on these clinical characteristics predicted for 6-yr progression-free survival (PFS) probability. In this nomogram, a decrease in PSA DT was associated with an increased risk of clinical progression. Recently, data on OS and SRT have become available. Interestingly, Trock et al showed in a group of men with a median follow-up of 9 yr after prostatectomy that the benefit of SRT for PCa-specific mortality was particularly seen in men with a PSA DT <6 mo who obtained SRT to the prostate fossa within 2 yr after a PSA rise [11]. These data suggest that local disease control may prolong PCa-specific survival in men formerly thought to be at risk for systemic disease progression and less likely to benefit from (salvage) RT. This finding may possibly be explained by the fact that men with slowly progressing disease—although at risk of systemic progression—may not benefit from SRT because the risk of development of lethal PCa in these cases may be low. Certainly, longer follow-up is needed to answer this question, but it seems in line with findings in, for example, breast cancer. In a recent multi-institutional matched-control analysis of adjuvant and salvage postoperative RT for pT3–4N0 PCa, Trabulsi et al. [12] have demonstrated a BCR-free survival advantage in favour of adjuvant RT compared to SRT. Interestingly, in a multivariate Cox regression analysis, adjuvant versus SRT were not independent predictors in metastatic PFS when corrected for adverse clinical and pathologic factors. 7.
Radiation treatment in node-positive disease
Whereas in PCa the presence of more extensive/systemic disease is considered a contraindication for local treatment, a meta-analysis in breast cancer treatment showed that the OS benefit of adjuvant RT after mastectomy was highest in women with node-positive disease [13]. This observation raises the question of whether men with nodal disease during prostatectomy could benefit from adjuvant or SRT. The three mentioned randomised clinical trials excluded men with node-positive disease; therefore, retrospective evaluations are the only data to address this question. Da Pozzo et al. [14] found in a retrospective analysis of 250 men with node-positive PCa after prostatectomy that local radiation of the prostate fossa in addition to hormone therapy (HT) improved PCa-specific survival, with a hazard ratio of 0.38 at a median follow-up of 96 mo in comparison to HT only. In this study, prostate fossa–only radiation was given, and the role of pelvic radiation in node-positive disease remains unanswered, as it remains unanswered in men with primary radiation for PCa and node-positive disease. 7.1.
6.
403
Dose, target volume, and toxicity
Salvage radiation therapy
Earlier data suggest that the efficacy of SRT depends not only on the pre-RT PSA level but also on the prostatectomy
The three randomised trials on adjuvant RT all apply doses <66 Gy, currently the most frequently used dose for adjuvant and SRT. It should be mentioned that comparable
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EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 401–405
to results from dose escalation studies in primary RT for PCa, an increased dose in the salvage setting may improve biochemical response without compromising local toxicity [15,16]. Doses up to 70 Gy showed better BCR-free rates than a higher dose with a median tissue culture infectious dose (ie, the dose to achieve 50% BCR-free survival) of 66.8 Gy for SRT. Even higher doses may be considered, particularly when using better imaging techniques such as with fiducial markers [17]. The fact that 9% of men still develop a local recurrence after adjuvant RT at 60 Gy supports the notion of increasing dose and target volume [6]. Evaluation of target volume delineation showed that variations up to 65% may be present among different radiotherapists in cases of adjuvant or SRT to the prostatic fossa [18,19] despite the presence of guidelines [20]. With respect to this, local toxicity should not be disregarded. In the EORTC-22911 study, 3.1% of men had to interrupt adjuvant RT because of local complaints, mainly diarrhoea. Although grade 3 or 4 toxicity for both adjuvant and SRT to the prostate fossa is rare, it was almost doubled in the adjuvant arm of the EORTC-22911 study (2.6% vs 4.2%) and SWOG-S8794 study (urethral stricture [risk ratio (RR): 1.9], incontinence [RR: 2.3]).
References [1] Ganswindt U, Stenzl A, Bamberg M, Belka C. Adjuvant radiotherapy for patients with locally advanced prostate cancer—a new standard? Eur Urol 2008;54:528–42. [2] Thompson Jr IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006;296:2329–35. [3] Bolla M, Van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005;366:572–8. [4] 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;181:956–62. [5] 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;27:2924–30. [6] Swanson GP, Hussey MA, Tangen CM, et al. Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007;25:2225–9. [7] 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;25:2035–41.
8.
Ongoing trials
[8] Cheng T, Heng DY, Stewart D. Re: adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized
Three ongoing trials will shed light on the question of the need for additional HT to adjuvant or SRT. The Radiotherapy and Androgen Deprivation in Combination after Local Surgery (RADICALS) trial randomises men between adjuvant and SRT and no, 6 mo, or 2 yr of additional androgen ablation in the United Kingdom and Canada [20,21]. In May 2009, the EORTC-30041-22042 trial opened to study the effects of 64-Gy adjuvant RT with or without 6 mo of luteinising hormone-releasing hormone agonist (LHRHa) treatment in pT2R1 and pT3R0/R1 N0M0 patients after prostatectomy. Finally, the RTOG 96-01 study, which completed accrual in 2003, studies the benefit of adjuvant RT with or without 2 yr of additional bicalutamide.
clinical trial: I. M. Thompson, C. M. Tangen, J. Paradelo, M. S. Lucia, G. Miller, D. Troyer, E. Messing, J. Forman, J. Chin, G. Swanson, E. Canby-Hagino and E. D. Crawford. J Urol 2009;182:2531–4. [9] Chun TY. Reply by author. Re: adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial: I. M. Thompson, C. M. Tangen, J. Paradelo, M. S. Lucia, G. Miller, D. Troyer, E. Messing, J. Forman, J. Chin, G. Swanson, E. Canby-Hagino and E. D. Crawford. J Urol 2009;182:2532. [10] 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;25:4178–86. [11] Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008;299:2760–9.
9.
Conclusions
Adjuvant RT improves BCR-free and metastases-free survival in men with pT3 and R1 disease after prostatectomy. Men with a PSM after prostatectomy at any location benefit most from adjuvant RT. Men with nodal disease may see a benefit for PCa survival when RT is combined with androgen ablation. Men with a rapid PSA rise may still benefit from SRT for PCa survival when salvage treatment is started early in the progression.
[12] 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: 1298–302. [13] Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. [14] 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;55:1003–11.
Conflicts of interest The authors have nothing to disclose.
[15] King CR, Spiotto MT. Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys 2008;71:23–7. [16] King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys
Funding support
2008;71:346–50. [17] Schiffner DC, Gottschalk AR, Lometti M, et al. Daily electronic portal
None.
imaging of implanted gold seed fiducials in patients undergoing
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 401–405
radiotherapy after radical prostatectomy. Int J Radiat Oncol Biol Phys 2007;67:610–9. [18] Mitchell DM, Perry L, Smith S, et al. Assessing the effect of a contouring protocol on postprostatectomy radiotherapy clinical target volumes and interphysician variation. Int J Radiat Oncol Biol Phys 2009;75:990–3.
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[20] 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 2007;84:121–7. [21] Parker C, Sydes MR, Catton C, et al. Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): a new
[19] Wiltshire KL, Brock KK, Haider MA, et al. Anatomic boundaries of
Medical Research Council/National Cancer Institute of Canada
the clinical target volume (prostate bed) after radical prostatecto-
phase III trial of adjuvant treatment after radical prostatectomy.
my. Int J Radiat Oncol Biol Phys 2007;69:1090–9.
BJU Int 2007;99:1376–9.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Adjuvant and Salvage Radiation for Advanced Prostate Cancer: A Discussion During the ESOU 2010 Meeting Henk G. van der Poel a,*, Steven Joniau b a
Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands
b
Department of Urology, Leuven University, Leuven, Belgium
Article info
Abstract
Keywords: Prostate cancer Salvage Adjuvant radiation Prostatectomy
Adjuvant radiation therapy (RT) for advanced localised prostate cancer (PCa) is now supported by the findings from three randomised controlled trials, having shown improved biochemical recurrence–free survival rates in three trials and an improved metastases-free survival in one trial. Patients with positive surgical margins are most likely to benefit from adjuvant radiotherapy. In this article, the three trials are compared and the control groups scrutinised. Salvage RT at the time of a biochemical or local recurrence is still valid and seems particularly beneficial for men with more rapidly rising prostate-specific antigen values prior to salvage treatment, when disease-specific survival is considered. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel. +31205122553; Fax: +31205122554. E-mail address: [email protected] (H.G. van der Poel).
1.
Introduction
The evidence for the value of additional radiation therapy (RT) to the prostate fossa after prostatectomy has been accumulating in recent years. Although earlier retrospective analyses revealed a disease progression advantage for adjuvant RT in >70% of the studies, a survival advantage was only observed in 2 out of 10 studies [1]. Three large randomised controlled trials have now been published on the topic of adjuvant RT (Tables 1–3) [2–5]. All three trials showed a benefit in biochemical recurrence (BCR)–free survival for the adjuvant RT group of at least 15% at 5 yr. Whereas the largest (European Organisation for Research and Treatment of Cancer [EORTC]-22911; n = 1005) [3] and the smallest (ARO-96-02; n = 307) [5] trials were powered to detect a benefit in BCR-free survival, the Southwest Oncology Group (SWOG)-S8794 trial [4] with 431 randomised patients had as its primary end point metastasis-free survival. The inclusion criteria were similar with the exception that in the EORTC trial, pT2R1 patients were
also included; in the other two trials, only pT3 cancers with or without a positive resection margin were included. Patients with pN1 cancers were excluded in all three trials. The presence of patients with a positive surgical margins (PSM) was relatively high in all three trials, ranging from 63% to 68%. Of note is the fact that the randomised population differed with respect to the postoperative prostate-specific antigen (PSA) level prior to randomisation for adjuvant RT among the three trials. In the German ARO96-02 trial, only men with a PSA <0.1 ng/ml were eligible for randomisation, whereas in the EORTC trial, 11% had a PSA level >0.2 ng/ml prior to randomisation. In the SWOG trial, this percentage was even higher (34%), indicating that in the EORTC and SWOG trials, a substantial number of patients received ‘‘salvage’’ RT (SRT) for a non-normalised PSA levels rather than adjuvant RT. In a subanalysis of the SWOG trial, Swanson et al. [6] showed that men in all categories of postprostatectomy PSA level (<0.2, 0.2–1.0, and >1.0 ng/ml) showed improvement in metastases-free survival, suggesting that although less effective, SRT may be
1569-9056/$ – see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2010.02.012
402
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 401–405
Table 1 – Inclusion criteria for the three randomised controlled trials for adjuvant radiation therapy
ARO-96-02 [5] EORTC-22911 [3] SWOG-S8794 [4]
n
TNM
Patients with a PSM at prostatectomy, %
Patients with a postoperative PSA >0.2 ng/ml, %
Interval of prostatectomy to adjuvant RT, d
307 1005 431
pT3N0 pT2R1–pT3N0 pT3N0
68 63 67 (with EC)
0 11 16
81 112 <122
Dose of adjuvant radiation, Gy
60 60 60–64
PSM = positive surgical margin; PSA = prostate-specific antigen; RT = radiation therapy; EORTC = European Organisation for Research and Treatment of Cancer; SWOG = Southwest Oncology Group; EC = extracapsular disease.
Table 2 – Treatments of patients in the control arms for the three randomised controlled trials for adjuvant radiation therapy
ARO-96-02 [5] EORTC-22911 [3] SWOG-S8794 [4]
n
Median follow up, mo
Patients receiving salvage RT in the control arm, %
PSA level at salvage RT in the control arm
307 1005 431
54 60 152
– 55 33
– – 1
Interval to salvage RT, yr
– 2.2 2
RT = radiation therapy; PSA = prostate-specific antigen; EORTC = European Organization for Research and Treatment of Cancer; SWOG = Southwest Oncology Group.
Table 3 – Follow-up data for the three randomised controlled trials for adjuvant radiation therapy
ARO-96-02 [5] EORTC-22911 [3] SWOG-S8794 [4]
n
Primary end point
307 1005 431
BCR BCR Metastasis-free survival
Median Definition of BCR for adjuvant follow-up, mo BCR (PSA, ng/ml) and control arms, yr 54 60 152
0.1 0.2 0.4
5 (28% vs 46%) 5 (21% vs 44%) 10 (47% vs 70%)
Metastasis development, yr 2% vs 3.1% 5 (6.1% vs 6.3%) 10 (27% vs 35%)
OS
– 90.8% vs 91.5% 10 (74% vs 66%)
BCR = biochemical recurrence; PSA = prostate-specific antigen; OS = overall survival; EORTC = European Organization for Research and Treatment of Cancer; SWOG = Southwest Oncology Group.
beneficial to improving metastases-free survival. However, the relatively high number of men with a non-normalised PSA after surgery (PSA >0.2 ng/ml) may result in an underestimation of the true value of adjuvant RT. 2.
Delayed radiation therapy
In light of these results, it is of interest that not all men in the nonadjuvant arm of the trials were treated with SRT by the time of BCR. In the EORTC trial, 55% of men with a rising PSA level received delayed or SRT to the prostatic fossa, whereas in the SWOG trial, this group constituted 33%. This difference means that the trials essentially are not evaluating the question of whether adjuvant RT is superior to SRT because in the control arm, only half of the men at most received RT at the time of PSA recurrence. In the German trial, which had an end point of BCR—similar to the EORTC trial end point—the percentage of men receiving SRT was not reported. Therefore, neither trial is useful for evaluating the role of SRT in comparison to adjuvant RT; indeed, the authors of the EORTC trial suggest that SRT may be equivalent to adjuvant RT, provided that the PSA level is <1 ng/ml [3]. Basically, only the SWOG trial was powered to address the issue of delayed RT, as metastasis-free survival was the primary end point. Particularly in the SWOG trial, men in the control arm were less likely to receive SRT (33%). Still, it took a median follow-
up of >12 yr before metastasis-free survival improved in the adjuvant arm, suggesting that in men with a life expectancy <10 yr, adjuvant RT might not be useful [2,4]. The median interval to SRT was 2 yr and 2.2 yr for the SWOG and EORTC nonadjuvant RT arms, respectively. In the SWOG study, 23% of men had a PSA level >1.5 ng/ml prior to SRT. From earlier analysis [7], it is clear that a higher PSA level at SRT predicted poorer response. Men with a PSA level <0.5 ng/ml at the time of SRT had a 48% BCR-free survival at 6 yr, which stills seems considerably lower than observed in the adjuvant RT arm of the three clinical trials but within the range of the nonadjuvant RT arms (44–52%), suggesting that the control groups in all three trials may reflect current clinical practice with respect to SRT use. 3.
Biochemical recurrence
It is also of interest to look at the definitions of biochemical recurrence in the three trials. In the ARO-96-02 trial, BCR was defined as 0.1 ng/ml, whereas in the EORTC-22911 and SWOG-S8794 trials, BCR was defined as a PSA level of 0.2 ng/ml and 0.4 ng/ml, respectively. Whether this difference in BCR definition is the reason for the observed lower BCR rate in the EORTC trial (21% at 5 yr) in comparison to the ARO-96-02 trial (28% at 5 yr) remains unclear, but it seems not likely because in the SWOG-S8794 trial—where BCR was
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 401–405
defined as a PSA >0.4 ng/ml—a 30% 5-yr BCR rate was found in the adjuvant RT arm (Tables 1–3). 4.
Metastasis-free and overall survival
Recently, the SWOG trial data have been updated. With a median follow-up of 152 mo, this is the trial with the longest follow-up. Although in the initial publication (at a median follow-up of 130 mo) no significant overall survival (OS) advantage was observed [2], in the most recent update, a significant hazard ratio of 0.72 for adjuvant RT was found [4]. This finding translates into an estimated 10-yr OS of 74% for adjuvant RT versus 66% for the nonadjuvant arm. These findings have been criticised in editorials by Cheng et al. [8] and Chun [9]. In the SWOG-S8974 trial, metastasis-free survival was defined as time from randomisation to metastasis or death resulting from any cause. This definition may have led to an overestimation of the presence of metastasis and explains why the number needed to treat with adjuvant RT to prevent one patient with metastasised disease was 12 versus 9.1 to prevent one patient from dying. If death (from prostate cancer [PCa]) is always associated with metastasised disease, it seems difficult to explain why adjuvant RT would be less effective in preventing metastasis than in preventing death. It was also put forward that the number of high Gleason sum score tumours (Gleason sum score 8–10) in the observation arm was higher than in the adjuvant RT arm. Whether this seeming imbalance in Gleason sum scores would have affected outcome is unclear. The authors, however, correctly remarked that randomisation should correct for this imbalance. The fact that preoperative PSA levels >10 ng/ ml were less likely in the observation arm (47%) and slightly lower than in the adjuvant RT arm (59%) suggests that a serious imbalance may not have been present. 5.
Predictors of response
Additional analyses of all three clinical trials on adjuvant RT studied predictors of response. In the SWOG-S8794 trial, the level of postprostatectomy PSA and disease extension (defined as seminal vesicle invasion [SVI]) were not predictive of a metastases-free survival advantage to adjuvant RT, suggesting that all men benefited equally from early RT [4]. In the ARO-96-02 trial, in an unplanned subanalysis, men with a PSM at prostatectomy, preoperative PSA level >10 ng/ml, non-SVI tumours, and a lower PSA doubling time (PSA DT) were significantly more likely to benefit from adjuvant RT with respect to BCR-free survival [5]. Van der Kwast et al. [10] showed in a subanalysis from the EORTC-22911 trial that in particular men with a PSM benefited from adjuvant RT with respect to BCR. PSM location was not predictive of response to adjuvant radiation.
Gleason sum score, the presence of SVI, surgical margin status, the presence of lymph node metastases, and PSA DT as well as radiation dose and hormonal treatment [7]. A nomogram based on these clinical characteristics predicted for 6-yr progression-free survival (PFS) probability. In this nomogram, a decrease in PSA DT was associated with an increased risk of clinical progression. Recently, data on OS and SRT have become available. Interestingly, Trock et al showed in a group of men with a median follow-up of 9 yr after prostatectomy that the benefit of SRT for PCa-specific mortality was particularly seen in men with a PSA DT <6 mo who obtained SRT to the prostate fossa within 2 yr after a PSA rise [11]. These data suggest that local disease control may prolong PCa-specific survival in men formerly thought to be at risk for systemic disease progression and less likely to benefit from (salvage) RT. This finding may possibly be explained by the fact that men with slowly progressing disease—although at risk of systemic progression—may not benefit from SRT because the risk of development of lethal PCa in these cases may be low. Certainly, longer follow-up is needed to answer this question, but it seems in line with findings in, for example, breast cancer. In a recent multi-institutional matched-control analysis of adjuvant and salvage postoperative RT for pT3–4N0 PCa, Trabulsi et al. [12] have demonstrated a BCR-free survival advantage in favour of adjuvant RT compared to SRT. Interestingly, in a multivariate Cox regression analysis, adjuvant versus SRT were not independent predictors in metastatic PFS when corrected for adverse clinical and pathologic factors. 7.
Radiation treatment in node-positive disease
Whereas in PCa the presence of more extensive/systemic disease is considered a contraindication for local treatment, a meta-analysis in breast cancer treatment showed that the OS benefit of adjuvant RT after mastectomy was highest in women with node-positive disease [13]. This observation raises the question of whether men with nodal disease during prostatectomy could benefit from adjuvant or SRT. The three mentioned randomised clinical trials excluded men with node-positive disease; therefore, retrospective evaluations are the only data to address this question. Da Pozzo et al. [14] found in a retrospective analysis of 250 men with node-positive PCa after prostatectomy that local radiation of the prostate fossa in addition to hormone therapy (HT) improved PCa-specific survival, with a hazard ratio of 0.38 at a median follow-up of 96 mo in comparison to HT only. In this study, prostate fossa–only radiation was given, and the role of pelvic radiation in node-positive disease remains unanswered, as it remains unanswered in men with primary radiation for PCa and node-positive disease. 7.1.
6.
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Dose, target volume, and toxicity
Salvage radiation therapy
Earlier data suggest that the efficacy of SRT depends not only on the pre-RT PSA level but also on the prostatectomy
The three randomised trials on adjuvant RT all apply doses <66 Gy, currently the most frequently used dose for adjuvant and SRT. It should be mentioned that comparable
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to results from dose escalation studies in primary RT for PCa, an increased dose in the salvage setting may improve biochemical response without compromising local toxicity [15,16]. Doses up to 70 Gy showed better BCR-free rates than a higher dose with a median tissue culture infectious dose (ie, the dose to achieve 50% BCR-free survival) of 66.8 Gy for SRT. Even higher doses may be considered, particularly when using better imaging techniques such as with fiducial markers [17]. The fact that 9% of men still develop a local recurrence after adjuvant RT at 60 Gy supports the notion of increasing dose and target volume [6]. Evaluation of target volume delineation showed that variations up to 65% may be present among different radiotherapists in cases of adjuvant or SRT to the prostatic fossa [18,19] despite the presence of guidelines [20]. With respect to this, local toxicity should not be disregarded. In the EORTC-22911 study, 3.1% of men had to interrupt adjuvant RT because of local complaints, mainly diarrhoea. Although grade 3 or 4 toxicity for both adjuvant and SRT to the prostate fossa is rare, it was almost doubled in the adjuvant arm of the EORTC-22911 study (2.6% vs 4.2%) and SWOG-S8794 study (urethral stricture [risk ratio (RR): 1.9], incontinence [RR: 2.3]).
References [1] Ganswindt U, Stenzl A, Bamberg M, Belka C. Adjuvant radiotherapy for patients with locally advanced prostate cancer—a new standard? Eur Urol 2008;54:528–42. [2] Thompson Jr IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006;296:2329–35. [3] Bolla M, Van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005;366:572–8. [4] 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;181:956–62. [5] 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;27:2924–30. [6] Swanson GP, Hussey MA, Tangen CM, et al. Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007;25:2225–9. [7] 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;25:2035–41.
8.
Ongoing trials
[8] Cheng T, Heng DY, Stewart D. Re: adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized
Three ongoing trials will shed light on the question of the need for additional HT to adjuvant or SRT. The Radiotherapy and Androgen Deprivation in Combination after Local Surgery (RADICALS) trial randomises men between adjuvant and SRT and no, 6 mo, or 2 yr of additional androgen ablation in the United Kingdom and Canada [20,21]. In May 2009, the EORTC-30041-22042 trial opened to study the effects of 64-Gy adjuvant RT with or without 6 mo of luteinising hormone-releasing hormone agonist (LHRHa) treatment in pT2R1 and pT3R0/R1 N0M0 patients after prostatectomy. Finally, the RTOG 96-01 study, which completed accrual in 2003, studies the benefit of adjuvant RT with or without 2 yr of additional bicalutamide.
clinical trial: I. M. Thompson, C. M. Tangen, J. Paradelo, M. S. Lucia, G. Miller, D. Troyer, E. Messing, J. Forman, J. Chin, G. Swanson, E. Canby-Hagino and E. D. Crawford. J Urol 2009;182:2531–4. [9] Chun TY. Reply by author. Re: adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial: I. M. Thompson, C. M. Tangen, J. Paradelo, M. S. Lucia, G. Miller, D. Troyer, E. Messing, J. Forman, J. Chin, G. Swanson, E. Canby-Hagino and E. D. Crawford. J Urol 2009;182:2532. [10] 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;25:4178–86. [11] Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008;299:2760–9.
9.
Conclusions
Adjuvant RT improves BCR-free and metastases-free survival in men with pT3 and R1 disease after prostatectomy. Men with a PSM after prostatectomy at any location benefit most from adjuvant RT. Men with nodal disease may see a benefit for PCa survival when RT is combined with androgen ablation. Men with a rapid PSA rise may still benefit from SRT for PCa survival when salvage treatment is started early in the progression.
[12] 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: 1298–302. [13] Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. [14] 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;55:1003–11.
Conflicts of interest The authors have nothing to disclose.
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Funding support
2008;71:346–50. [17] Schiffner DC, Gottschalk AR, Lometti M, et al. Daily electronic portal
None.
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[19] Wiltshire KL, Brock KK, Haider MA, et al. Anatomic boundaries of
Medical Research Council/National Cancer Institute of Canada
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