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Referring to the article published on pp. 1133–1139 of this issue

Intermediate- and High-Risk Prostate Cancer: A Plea for High-Dose, High-Precision Intensity-Modulated Radiotherapy With a Modulated Duration of Androgen Deprivation Therapy

By: Michel Bolla

European Urology, Volume 60 Issue 1, December 2011, Pages 1140-1141

Published online: 01 December 2011

Abstract Full Text Full Text PDF (77 KB)

Refers to article:

Dose Escalation for Prostate Cancer Radiotherapy: Predictors of Long-Term Biochemical Tumor Control and Distant Metastases–Free Survival Outcomes eulogo1

Michael J. Zelefsky, Xin Pei, Joanne F. Chou, Michael Schechter, Marisa Kollmeier, Brett Cox, Yoshiya Yamada, Anthony Fidaleo, Dahlia Sperling, Laura Happersett and Zhigang Zhang

Accepted 11 August 2011

December 2011 (Vol. 60, Issue 6, pages 1133 - 1139)

Zelefsky et al [1] report a retrospective analysis of 2251 patients with T1–3 N0–X M0 prostate cancer (PCa) divided into groups of 571 low-risk (22.4%), 1074 intermediate-risk (42.1%), and 906 high-risk (35.5%) patients, according to the National Comprehensive Cancer Network classification. Patients were scanned in the treatment position and anatomic data were transferred to the 3D treatment planning system, where prostate and seminal vesicles were delineated and then surrounded by a security margin. They were treated with three-dimensional (3D) conformal radiotherapy (CRT) or intensity-modulated radiotherapy (IMRT), performed on prostate and seminal vesicles only.

During irradiation, a multileaf collimator adapts automatically and continually to the contours of the target volume seen by each beam. IMRT requires specific software because movement of the leaves during irradiation allows for adaptation of the dose to be delivered and provides concave isodose curves, particularly at the anterior part of the rectum. In the study by Zelefsky et al [1], the prostate dose ranged from 64.8 to 86.4Gy; doses >81Gy were delivered in the last 10 yr by image-guided IMRT. Complete androgen deprivation therapy (ADT) with a luteotrophin hormone-releasing hormone agonist and antiandrogen was given to 1249 patients (49%) at the discretion of treating physician (623 high-risk patients [69%], 456 intermediate-risk patients [42%], and 170 low-risk patients [30%]). ADT duration was 3 mo for low-risk patients and 6 mo for intermediate- and high-risk patients, starting 3 mo prior to radiotherapy (RT) and continued during RT.

End points were 10-yr biochemical disease-free survival (BDFS) and distant metastases–free survival (DMFS). With an 8-yr median follow-up, the 10-yr BDFS of each risk group was significantly influenced by dose escalation: 84% (>75.6Gy) versus 70% for low risk (p=0.04), 76% (>81Gy) versus 57% for intermediate risk (p=0.0001), and 55% (>81Gy) versus 41% for high risk (p=0.0001). Six-month ADT also influenced the BDFS of intermediate- and high-risk patients, with 55% versus 36% for high-risk patients (p<0.0001). In multivariate analysis, dose >81Gy (p=0.027) and ADT (p=0.052) were significant predictors of DMFS, but none of these parameters influenced PCa mortality or overall survival (OS). Grade 3–4 acute or late toxicity was very low and was published elsewhere [2].

Despite 20% of patients being lost to follow-up [1], these results were in keeping with those in the literature [3]. In daily practice, IMRT is a gold standard, provided that quality assurance criteria are implemented, and as stated by the authors, dose escalation >86Gy is possible through the combination of IMRT plus high-dose-rate brachytherapy [3] and [4]; however, we have to wait for the results of phase 3 trials. In light of these results, would there be a space for RT alone with regard to intermediate-risk patients, and what would be the optimized combination of RT and ADT for high-risk patients?

For intermediate-risk PCa, no data promote definitive RT. A retrospective analysis of 1044 patients with intermediate-risk patients (n=782) or high-risk patients (n=262) treated with dose-escalated RT, brachytherapy, or high-dose-rate brachytherapy plus pelvic external-beam RT showed that the 8-yr locoregional failure rate was 5% with or without ADT and the 8-yr cause-specific survival was 97% with ADT versus 99% without (p=0.20) [4]. Regarding phase 3 randomized trials comparing high-dose RT with and without ADT, GETUG 14 studied 377 intermediate-risk patients who were randomized to receive high-dose (80Gy) 3D-CRT with or without IMRT ±4 mo of complete ADT. Preliminary results with a median follow-up of 37 mo showed a 3-yr BDFS or clinical disease-free survival of 92% (combined approach) versus 86% (p=0.09) and a 3-yr BDFS of 97% and 91%, respectively (p=0.04) [5].

The major data come from two phase 3 trials. The Boston trial with 204 T1b–2b intermediate- or high-risk patients who received 3D-CRT (70Gy) ±6 mo of complete ADT showed that the 7-yr OS was 74% (combined approach) versus 61% (p=0.01) [6]. A Radiotherapy Oncology Group (RTOG) trial accrued 1979 T1b–T2b patients who received conventional RT (66Gy) ±4 mo complete ADT; the 10-yr OS was 62% (combined approach) versus 57% (p=0.03), but the gain was limited to intermediate-risk men [7]. Considering the potential bias of retrospective series, the feasibility of high-dose IMRT, and the local and spatial combination of ADT with RT, as assessed by phase 3 results, it seems wise to propose short-term complete ADT (4–6 mo) with image-guided IMRT (78Gy). Patients who are reticent to receive ADT because of comorbidities or because they hope to preserve their sexual health may be offered image-guided IMRT (around 80Gy) or the promising combined IMRT–brachytherapy approach.

For high-risk PCa, the results reported by Zelefsky et al [1] show that IMRT combined with short-term ADT improves BDFS and DMFS but does not influence PCa mortality or OS. Individualization of high-risk localized PCa (T1–2 N0–X M0 with poor prognostic factors, Gleason score >7 and/or baseline prostate-specific antigen >20ng/ml) and of locally advanced PCa (T3–4 N0–X M0) is desirable to modulate the duration of ADT and the RT regimen accordingly. The concept of dose escalation is acquired even with ADT, as shown by the trial of Zapatero et al [8] with a cohort of 416 patients treated by 3D-CRT with ADT; 181 low-risk patients received RT alone, 160 intermediate-risk patients received 4–6 mo of adjuvant ADT, and 75 high-risk patients received long-term ADT. The BDFS of high-risk patients was 63% for a dose<72Gy versus 84% dose ≥72Gy (p=0.003). There is not yet consensus on dose level, but 78–80Gy could be delivered by image-guided IMRT.

For locally advanced PCa, pelvic lymph node irradiation is recommended with a dose of around 50Gy, all the more as it was realized in RTOG and European Organization for Research and Treatment of Cancer (EORTC) phase 3 randomized trials, which showed a positive impact on OS. ADT duration of 6 mo is enough for high-risk localized PCa patients but should be >2 yr for locally advanced PCa patients with a World Health Organization score of 0–2 and no significant comorbidity, according to EORTC 22863 and 22961 trials [9] and [10].

The 10-yr results of EORTC 22863 showed a striking gain in OS of 58.1% with 3-yr ADT versus 39.8% with conventional RT alone (p=0.0004) and a decrease in 10-yr PCa mortality of 10.3% with long-term ADT versus 30.4% with RT alone (p<0.001), with no significant difference in cardiovascular mortality [9]. The equivalence trial, EORTC 22961, has definitely shown that the combination of 6 mo of ADT with 3D-CRT (70Gy) provides inferior OS compared with 3D-CRT plus 3 yr of ADT. At a median follow-up of 6.4 yr, the 5-yr OS was 84.8% for the 3-yr ADT arm and 81% for the 6-mo ADT arm, with an estimated hazard ratio of 1.42 (p=0.008) [10].

Beyond techniques and figures, the time and the regular practice of a multidisciplinary approach for urologists and radiation oncologists, based on shared levels of evidence, will help tailor the personalized treatment plan of every patient.

Conflicts of interest

The author has received honoraria from Janssen for attending advisory board meetings and from Astellas for conference participation.

References

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  • [2] M.J. Zelefsky, E.J. Levin, M. Hunt, et al. Incidence of later rectal and urinary toxicities after three dimensional conformal radiotherapy and intensity modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:1124-1129 Crossref.
  • [3] P.A. Kupelian, J. Ciezki, A.R. Chandana, et al. Effect of increasing radiation doses on local and distant failures in patients with localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008;71:16-22 Crossref.
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  • [6] A.V. D’Amico, M.H. Chen, A.A. Renshaw, M. Loffredo, P.W. Kantoff. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299:289-295 Crossref.
  • [7] C.U. Jones, D. Hunt, D.G. McGowan, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365:107-118 Crossref.
  • [8] A. Zapatero, F. Valcarcel, F.A. Calvo, et al. Risk-adapted androgen deprivation and escalated three-dimensional conformal radiotherapy for prostate cancer: Does radiation dose influence outcome of patients treated with adjuvant androgen deprivation? A GICOR study. J Clin Oncol. 2005;23:6561-6568 Crossref.
  • [9] M. Bolla, G. van Tienhoven, P. Warde, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomized study. Lancet Oncol. 2010;11:1066-1073 Crossref.
  • [10] M. Bolla, T.M. de Reijke, G. Van Tienhoven, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360:2516-2527 Crossref.

Footnotes

Clinique Universitaire de Cancérologie-Radiothérapie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France

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