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Journal of Clinical Oncology, Vol 25, No 35 (December 10), 2007: pp. 5671-5672 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.2018
Adjuvant Radiotherapy After Surgery for Pathologically Advanced Prostate CancerPathology and Laboratory Medicine, Mount Sinai Hospital and University Health Network, Toronto, Canada
Statistics Department, European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium
Department of Radiotherapy, Centre Hospitalier Universitaire de Grenoble, Grenoble, France To the Editor: Two large randomized trials (European Organization for Research and Treatment of Cancer [EORTC] trial 229111 and Southwest Oncology Group [SWOG] trial 87942,3) have now reported on the beneficial outcome of adjuvant radiotherapy in patients with pathological risk factors after prostatectomy.1-3 A third German trial (ARO 96-024) was reported in abstract form at ASCO's 2005 Annual Meeting. In the SWOG and EORTC trials, pathologically advanced prostate cancer was defined as the presence of extraprostatic extension (stage pT3a or b) and/or positive surgical margins, while patients with positive lymph nodes were excluded. In the ARO trial, patients had to present with pT3 disease and normalized prostate-specific antigen (PSA) after radical prostatectomy. EORTC 22911, with 1,005 patients and a median follow-up of 5 years, reported an increase of the 5-year biochemical relapse-free survival of 21% (74% v 52.6%; hazard ratio [HR] = 0.48; P < .001) in favor of the immediate adjuvant radiotherapy arm.1 SWOG 8794, with 10 years median follow-up on 473 patients showed reduction of the biochemical relapse rate from 64% to 34.9% (HR = 0.43; P < .001) in patients with PSA less than 0.4 ng/mL postprostatectomy.2 Both trials also showed a significant reduction of risk of clinical local recurrence in the adjuvant radiotherapy arm. A similar reduction (HR = 0.4) in the biochemical relapse-free survival at 4 years also was reported in the ARO trial.4 As for distant metastasis, no conclusions could be drawn yet in EORTC 22911 as only 56 distant failures had occurred at 5 years follow-up, while SWOG 8794 (with 10 years follow-up) reported a near-significant increase of the distant-metastases–free survival in the adjuvant radiotherapy arm (HR = 0.75; P = .06).2 In the observation arm of SWOG 8794, 17% of the patients developed distant metastases, as compared with 8% in the adjuvant radiotherapy arm. The authors3 comment that this relatively low rate of systemic disease spread was unexpected at the time of trial design, and that the reduction on the rate of distant metastases resulted from the improved local control. This would imply that distant metastasis evolves from the outgrowth of residual disease after the surgery, which can be eradicated with sufficiently high doses of irradiation. Next to the notion that clinically manifested metastatic disease after prostatectomy would originate from distant micrometastases outside the small pelvis present at the time of surgery, a second wave of metastases would occur from the latent disease left in the surgical bed in high risk patients. If this holds true, it is an argument for immediate radiotherapy rather than deferral of radiotherapy after the identification of PSA failure. Swanson et al,3 however, suggest that current improvements in radiotherapy may allow the deferral of radiotherapy to the moment of PSA recurrence. The question then remains whether distant micrometastases would evolve before PSA elevation. The observed low incidence of distant metastasis (16% by year 10) in the wait-and-see arm of SWOG 8794 seems to argue against this possibility. Limiting radiotherapy to patients developing PSA failure would have as an advantage the reduction of the numbers of patients requiring radiotherapy. Indeed, both the data of EORTC 22911 and SWOG 8794 show an HR close to 0.50, in a population that has approximately 50% risk of PSA relapse by year 5, thus indicating that four patients need to be irradiated to prevent one PSA relapse to occur. An alternative approach to reduce the number of treated patients might be to identify subsets of patients who may specifically benefit from immediate adjuvant therapy. These subsets may be defined on the basis of clinical and pathological findings, though it must be kept in mind that, in addition to the grading of prostate cancers, their staging and the determination of surgical margin status is liable to interobserver variation.5 Most urologists and radiation oncologists may underestimate this potential misclassification of prostate cancers. An exploratory subgroup analysis of EORTC trial 229116 using the results of the local pathologic examinationi indicated that although pre- and postoperative PSA, differentiation grade, invasion of the seminal vesicles, and surgical margin positivity were all independent predictors for the risk of relapse in the wait-and-see group, only surgical margin status was significantly predictive for the magnitude of the benefit from immediate adjuvant radiotherapy. Like in the SWOG trial,3 the EORTC data showed no statistically significant predictive impact of the postoperative PSA level on the adjuvant treatment benefit.1 In separate reports of EORTC trial 22911 using the grading, staging, and surgical margin status determined by a central pathology review,5,7 it was shown that the margin status by review pathology was a stronger predictor than the margin status by local pathology,5 and that it was also more strongly predictive for the magnitude of the treatment benefit.7 Unfortunately, the reported data of SWOG 8794 combine extracapsular extension, seminal vesicle invasion, and positive surgical margin status in one single classification, and no results are reported for the classification by margin status only. It would be of utmost interest to validate the results from the EORTC trial, showing no predictive impact on irradiation benefit of the classification combining the three factors6 and an impact of surgical margin alone.6,7 It is also noted that the pathology of the prostatectomy specimens of a significant number of patients entered in SWOG 8794 were not centrally reviewed. Although their data might therefore reflect better the current routine diagnostics, a central review using current guidelines for grading, staging, and surgical margin status might help to perform the subset analysis required to further validate the findings in EORTC 22911 that were based on review pathology. A combined analysis would also enhance the statistical power of these analyses. Combining the data from both trials may be helpful to formulate recommendations for the design of new trials aiming to further refine the population of patients that should be offered adjuvant immediate versus deferred radiotherapy at the time of PSA relapse. Pathologists need also to address their interobserver variability in judging pathologic material, and to reduce it as much as possible by further refining their criteria and by offering educational activities. A summary of the results of the three trials is available online.8 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS We thank the European Organization for Research and Treatment of Cancer Charitable trust for supporting Laurence Collette's contribution to this publication. REFERENCES 1. Bolla M, van Poppel H, Collette L, et al: Postoperative radiotherapy after radical prostatectomy (EORTC trial): A randomised controlled trial. Lancet 366:572-578, 2005[CrossRef][Medline] 2. Thompson I, Tangen C, Paradelo J, et al: Adjuvant radiotherapy for pathologically advanced prostate cancer: A randomized Clinical Trial. JAMA 296:2329-2335, 2006 3. 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 25:2225-2229, 2007 4. Wiegel T, Bottke D, Willich N, et al: Phase III results of adjuvant radiotherapy (RT) versus "wait and see" (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP) (ARO 96-02/AUO AP 09/95). J Clin Oncol 23:16s 2005 (suppl; abstr 5060) 5. Van der Kwast TH, Collette L, Van Poppel H, et al: Impact of pathology review on stage and margin status of radical prostatectomy specimens (EORTC trial 22911). Virchows Arch 449:428-434, 2006[CrossRef][Medline] 6. Collette L, van Poppel H, Bolla M, et al: Patients at high risk of progression after radical prostatectomy: Do they all benefit from immediate post-operative irradiation? (EORTC trial 22911). Eur J Cancer 41:2662-2672, 2005[CrossRef][Medline] 7. Van der Kwast ThH, Collette L, Van Poppel H, et al: Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy (EORTC trial 22911). J Clin Oncol 25:4178-4186, 2007 8. Wikibooks: Radiation Oncology/Prostate/Randomized. http://en.wikibooks.org/wiki/Radiation_Oncology/Prostate/Randomized
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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