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Platinum Priority – Editorial and Reply from Authors
Referring to the article published on pp. 998–1008 of this issue

Adjuvant or Immediate External Irradiation After Radical Prostatectomy with Pelvic Lymph Node Dissection for High-Risk Prostate Cancer: A Multidisciplinary Decision

By: Michel Bolla

European Urology, Volume 63 Issue 6, June 2013, Pages 1009-1010

Published online: 01 June 2013

Abstract Full Text Full Text PDF (105 KB)

Refers to article:

Selecting the Optimal Candidate for Adjuvant Radiotherapy After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis

Firas Abdollah, Nazareno Suardi, Cesare Cozzarini, Andrea Gallina, Umberto Capitanio, Marco Bianchi, Maxine Sun, Nicola Fossati, Niccolò Maria Passoni, Claudio Fiorino, Nadia Di Muzio, Pierre I. Karakiewicz, Patrizio Rigatti, Francesco Montorsi and Alberto Briganti

Accepted 18 October 2012

June 2013 (Vol. 63, Issue 6, pages 998 - 1008)

Abdollah et al. [1] selected, from a cohort of 6357 patients who underwent radical prostatectomy with extended pelvic lymph node dissection in the same institution between 1988 and 2008, a series of 1049 patients with pathologically advanced prostate cancer (PCa). The aim was to evaluate the impact of risk prognostic factors on survival with a regression analysis, and then to evaluate the relationship between adjuvant radiotherapy (ART) and survival according to the number of selected risk factors. The adjuvant treatments were based on the clinical judgment of each treating physician according to clinical and cancer characteristics after discussion with the patient. The following distribution was noted: no treatment (n=370), ART (n=243), ART plus androgen deprivation therapy (ADT) (n=288), and ADT alone (n=148). In all, only pathologic Gleason score ≥8, pT3b/T4 stage, and positive lymph node count ≥1 (pN1) were independent predictors of cancer-specific mortality (p≤ 0.02). The cumulative number of these predictive factors was used to develop a risk score and ranged from zero to three, with the following breakdown: zero (43.6%), one (22.1%), two (20.7%), and three (13.6%); only patients with a risk score ≥2 benefited from ART with lower cancer-specific mortality and overall mortality rates (p=0.006).

Despite the fact that all variables have been included in the multivariable analyses, the methodology is subject to bias, which may lessen the relevance of the results and their potential clinical impact: (1) the absence of a pathologic review, since the Gleason score has changed along time and a Gleason score was a criterion of eligibility for ART and/or ADT; (2) the mixture of pN0 and pN1 patients who do not share the same outcome; (3) the lack of any clinical guidelines to tailor adjuvant treatments; (4) the difference in the choice of the planning target volume, the techniques of external irradiation, and the dose range; (5) the heterogeneity of ADT modalities and the duration of ADT; (6) the absence of a report of morbidity for adjuvant treatments, especially as the authors emphasize the potential morbidity of ART; and (7) the lack of prostate-specific antigen (PSA) values after surgery. Therefore, the comparison with randomized trials devoted to ART after radical prostatectomy with pelvic lymph node dissection [2], [3], and [4] is a challenge, because those trials dealt with pT2 R1 pN0, pT3a–4 R0–1 pN0 patients with irradiation focused on the prostatic bed with conventional doses (60–64Gy) without ADT in the experimental arm. To facilitate the comparison with daily practice, we will consider the indication of ART for patients classified as pN1 M0, who may harbor a coexistent systemic risk, and then for pN0 patients, in whom the risk of relapse is more local.

For pN1 patients, although the authors claim a benefit for ART alone, the use of ART remains controversial; the evidence of a benefit from randomized trials is needed, likely from an ART/ADT combination, as in breast cancer [5]. Indeed, Da Pozzo et al. [6] showed in a cohort of 250 pN1 patients with a median follow-up of 91.2 mo that patients treated with ART/ADT (n=129) had better cancer-specific survival (p<0.001) compared with patients receiving ADT. Lawton et al. [7] reported in a subset analysis of 173 patients (cT3/pT3) with biopsy-proven lymph nodes, randomly allocated between radiation therapy (RT) plus long-term adjuvant ADT with luteinizing hormone–releasing hormone agonist (n=98) and RT alone (n=75), a gain in overall survival (p=0.03) in favor of the combined approach. At the present time, the combined approach with long-term ADT is considered a 2b level of evidence in the European Association of Urology guidelines [8]; the radiotherapy technique has to be optimized with intensity-modulated radiotherapy, taking into account the new definition of the pelvic lymph node areas [9].

I agree that pT3–4 pN0 patients with Gleason score 8–10 (risk score: 2) do need ART. In the randomized trials that have been mentioned, which consistently show a 50–60% reduction in the risk of PSA progression, the main eligibility criteria was pT3 (pT2R1, pT3–4 for the European Organization for Research and Treatment of Cancer [EORTC] trial). In the Southwest Oncology Group (SWOG) trial [2] that compared ART with observation in pT3 pN0 patients, ART did improve metastasis-free survival (p=0.016) and overall survival (p=0.023), contrary to the ARO and EORTC trials, which displayed better local control and biochemical disease-free survival. In the EORTC trial, designed 20 yr ago, the 10-yr results showed that patients with positive surgical margins seem to benefit from ART to a greater extent than patients with negative or close margins; and in terms of clinical progression-free survival, ART seems to be detrimental in patients ≥70 yr, without any definite reasons for this apparent negative effect [3]. This latter impact was not reported in the SWOG or ARO trials and is not seen in daily practice. The tolerance of ART is quite good; in the ARO trial with pT3 disease and undetectable PSA, tridimensional conformal radiotherapy was given with a low risk of late toxicity (0–3%) [4].

At the current time, the treatment policy for pT3–4 pN0 patients must take into account the PSA value after surgery to separate patients with undetectable PSA from patients with a detectable PSA who are at very high risk of relapse and who require a combined approach [10], with perhaps a dose escalation.

Nevertheless, no trial has shown so far that immediate RT is better than early salvage RT; thus, for R0 patients with Gleason score <8 and an undetectable PSA, many surgeons prefer to wait for a biochemical relapse and start RT as soon as the patient's PSA concentration reaches 0.2 ng/ml. RT can begin even earlier thanks to ultrasensitive assays that are able to detect a PSA concentration as low as 0.01 ng/ml—the lower the concentration, the better the outlook [11].

In conclusion, the decision whether to proceed with adjuvant RT for high-risk PCa (pT3–4 pN0–1 M0) after radical prostatectomy or to postpone RT as an early salvage procedure in case of biochemical relapse remains difficult. In daily practice, the urologist should explain to the patient before radical prostatectomy that adjuvant irradiation could be applied if the patient has negative prognostic risk factors. Ultimately, the decision to treat needs a multidisciplinary approach to determine the optimal timing of radiotherapy when used and to provide justification when not used, which will help in the discussion between the referent physician and the patient.

Conflicts of interest

Michel Bolla is a board member of Janssen and has received payment for lectures, including service on speakers bureaus, from Ipsen and Astellas.

References

  • [1] F. Abdollah, N. Suardi, C. Cozzarini, et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: a long-term survival analysis. Eur Urol. 2013;63:998-1008 Abstract, Full-text, PDF, Crossref.
  • [2] J.M. Thompson, C.M. Tangen, J. Paradelo, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduced risk of metastases and improves survival: long term follow-up of a randomized trial. J Urol. 2009;181:956-962
  • [3] M. Bolla, H. Van Poppel, B. Tombal, et al. Postoperative radiotherapy after radical prostatectomy for high risk prostate cancer: long term results of a randomized controlled trial (EORTC trial 22911). Lancet. 2012;380:2018-2027 Crossref.
  • [4] T. Wiegel, D. Bottke, U. Steiner, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy alone in pT3 prostate cancer with undetectable prostate specific antigen. ARO 9602/AUO AO 09/95. J Clin Oncol. 2009;27:2924-2930 Crossref.
  • [5] M. Overgaard, M.B. Hansen, J. Overgaard, et al. Postoperative radiotherapy in high risk postmenopausal breast-cancer patients given adjuvant tamoxifen. Lancet. 1999;353:1641-1648 Crossref.
  • [6] L.F. Da Pozzo, C. Cozzarini, A. Briganti, 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 Abstract, Full-text, PDF, Crossref.
  • [7] C.A. Lawton, K. Winter, D. Grignon, et al. Androgen suppression plus radiation versus radiation alone for patients with D1/pathologic node-positive adenocarcinoma of the prostate: updated results on national prospective randomized trial Radiation Therapy Oncology Group 85–31. J Clin Oncol. 2005;23:800-807 Crossref.
  • [8] A. Heidenreich, J. Bellmunt, M. Bolla, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localized disease. Eur Urol. 2011;59:61-71 Abstract, Full-text, PDF, Crossref.
  • [9] C.A. Lawton, J. Michalski, I. El-Naqa, et al. RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiation Oncology Biol Phys. 2009;74:383-387 Crossref.
  • [10] Shipley WU, Hunt D, Lukka HR, et al. Initial report of RTOG 9601: a phase III trial in prostate cancer: effect of anti-androgen therapy with bicalutamide during and after radiation therapy on freedom from progression and incidence of metastatic disease in patients following radical prostatectomy with pT2-3 NO disease and elevated PSA levels. Paper presented at: 2011 Genitourinary Symposium, February 17–19, 2011; Orlando, FL, USA.
  • [11] A.J. Stephenson, M. Bolla, A. Briganti, et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. Eur Urol. 2012;61:443-451 Abstract, Full-text, PDF, Crossref.

Footnotes

Department of Radiation Oncology, Grenoble University Hospital, Grenoble, France

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