Radiation Therapy After Radical Prostatectomy: Strike Early, Strike Hard! The Case for Adjuvant Radiation Therapy

NE W POINT-COUNTERPOINT SE CT IO N Radiation Therapy After Radical Prostatectomy: Strike Early, Strike Hard! The Case for Adjuvant Radiation Therapy Dov Kadmon, MD Scott Department of Urology, Baylor College of Medicine, Houston, TX With a large local tumor, when surgical extirpation results in a positive surgical margin, adjuvant radiotherapy is the routine approach for a variety of solid tumors, such as head and neck cancers, rectal cancer, lung cancer, and breast cancer. With prostate cancer, however, surgery and radiotherapy are considered as alternative single-modality treatments, and their combination is far less enthusiastically embraced. Despite a trend toward earlier clinical diagnosis of prostate cancer since the introduction of prostate-specific antigen (PSA) screening, modern surgical series continue to show a 15%–25% incidence of positive surgical margins. Postoperative radiotherapy, whether delivered as “adjuvant therapy" shortly after surgery or as “salvage therapy" when serum PSA becomes detectable, effectively improves local control and prolongs disease-free survival. [Rev Urol. 2002;4(2):87–89] © 2002 MedReviews, LLC Key words: Prostate cancer • Prostatectomy • Positive surgical margins • Radiotherapy omplete eradication of the primary tumor is one of the basic tenets in oncology. When there is a large local tumor and when surgical extirpation results in a positive surgical margin, adjuvant radiotherapy is routinely considered for a variety of solid tumors. This approach is used with, for example, head and neck cancers, rectal cancer, lung cancer, and breast cancer. When it comes to prostate cancer, however, surgery (radical prostatectomy) and radiotherapy are considered most often as alternative single-modality treatments, and their combination is far less enthusiastically embraced. C VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 87 The Case for Adjuvant Radiation Therapy continued The Significance of Positive Surgical Margins Impact of Postprostatectomy Radiotherapy Despite a trend toward earlier clinical diagnosis of prostate cancer since the introduction of prostate-specific antigen (PSA) screening, modern surgical series continue to show a 15%–25% incidence of positive sur- Most of the retrospective studies in the literature suggest that postoperative radiotherapy, whether delivered as “adjuvant therapy" shortly after surgery or as “salvage therapy" when serum PSA becomes detectable, Complete eradication of the primary tumor is one of the basic tenets in oncology. gical margins.1 It remains a wellestablished fact that, whereas patients whose tumors are confined to the prostate have excellent (over 90%) 5-year disease-free survival, patients with positive surgical margins have a 28%–49% incidence of biochemical (PSA) failure within 5 years of surgery.2,3 Patterns of Postprostatectomy “PSA Recurrence" Clinical observations have documented two distinct patterns of “PSA recurrence." Most patients whose cancer recurs within 2 years of surgery and whose serum PSA rises rapidly develop clinical metastases, with or without local recurrences. On the other hand, patients whose serum PSA becomes detectable more than 2 years after surgery and who display a slow PSA rise present predominantly with local recurrences.4 effectively improves local control and prolongs disease-free survival.5 There are no data yet to document an improved overall survival, although studies in other tumors, breast cancer for instance, clearly show improved survival.6 Analysis of the literature also shows that the earlier the radiotherapy is delivered after surgery, the better the outcome. Thus, if radiotherapy is given when patients develop palpable local recurrences, it is rarely, if ever, the outcome of “adjuvant" radiotherapy given to patients postoperatively before their serum PSA becomes detectable (usually within 3 to 12 months after prostatectomy) with that of “salvage" radiotherapy given subsequently when serum PSA has begun to rise, concluded that “adjuvant" radiotherapy results were superior.5 We have recently reviewed our own experience with 44 men who received postoperative adjuvant radiotherapy within a year of their surgery. All had positive surgical margins but undetectable serum PSA. They received a median dose of 60 Gy to the prostatic bed. Biochemical no-evidence-of-disease (bNED) results in this group of patients were compared with findings from an observational group of 189 men from the same time period (1989–1995) from the Specialized Program for Research Excellence (SPORE) database who had positive surgical margins and undetectable PSA levels after prostatectomy. Both The earlier the radiotherapy is delivered after surgery, the better the outcome. effective. On the other hand, when “salvage" radiotherapy is given because of a detectable serum PSA, the lower the serum PSA level before radiotherapy, the better the outcome.5 Furthermore, most series comparing groups were similar in terms of age, preoperative PSA, Gleason score, extracapsular extension, and seminal vesicle involvement. After a median follow-up of 60.4 months, 4 men (9%) in the adjuvant therapy group Main Points • Over 90% of patients whose tumors are confined to the prostate have 5-year disease-free survival; patients with positive surgical margins have a 28%–49% incidence of biochemical failure within 5 years of surgery. • Most patients whose cancer recurs within 2 years of surgery and whose serum prostate-specific antigen (PSA) rises rapidly develop clinical metastases, with or without local recurrences. • Patients whose serum PSA becomes detectable more than 2 years after surgery and who display a slow PSA rise present predominantly with local recurrences. • Radiotherapy given when patients develop palpable local recurrences is rarely, if ever, effective; when “salvage" radiotherapy is given because of a detectable serum PSA, the lower the serum PSA level before radiotherapy, the better the outcome. 88 VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY The Case for Adjuvant Radiation Therapy developed detectable serum PSA compared with 54 men (28.6%) in the observational group. This was statistically significant (P = .0012; log rank test). Statistical analysis including all men in the study showed that a Gleason score of 7 or higher and absence of radiotherapy were statistically significant risk factors for PSA failure (analysis of variance: P = .0001).7 The Biological Rationale for Early Adjuvant Radiotherapy These observations from retrospective studies are consistent with the biology of radiotherapy as well as with the biology of the tumor. First of all, radiotherapy is most effective when the tumor burden is small. One would expect the local tumor burden to be smallest shortly after the radical prostatectomy. Secondly, by delaying the radiotherapy until the serum PSA becomes detectable, we are allowing the residual tumor not only to establish itself in the prostate bed but also to metastasize. Consequently, it is conceivable that for some patients, “salvage" radiotherapy occurs too late, when the immediate postoperative window of opportunity has been lost. What percentage of patients fall into this category is unclear. Only large phase III studies conducted in a prospective, randomized fashion may be able to answer this question in the future. References 1. 2. 3. 4. 5. 6. 7. Mettlin C, Murphy G, Lee F, et al. Characteristics of prostate cancer detected in the American Cancer Society—National Prostate Cancer Detection Project. J Urol. 1994;152:1737–1740. Ohori M, Wheeler T, Kattan M, et al. Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol. 1995;154:1818–1824. Van Den Ouden D, Bentvelsen F, Boeve E, Schroder F. Positive margins after radical prostatectomy: correlation with local recurrence and distant progression. Br J Urol. 1993;72:489–494. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate specific antigen after anatomic radical retropubic prostatectomy. Urol Clin North Am. 1997;24:395–410. Catton C, Gospodarowicz M, Warde P, et al. Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol. 2001;59:51–60. Overguard M, Hansen P, Overguard J, et al. Post-operative radiotherapy in high-risk postmenopausal women with breast cancer. N Engl J Med. 1997;337:949–955. Bastasch ND, Butler EB, Aupsberger NE, et al. Adjuvant radiation therapy improves disease-free survival in high-risk men with undetectable PSA [abstract 34]. Radiology. 2001;221(suppl):225. VOL. 4 NO. 2 2002 REVIEWS IN UROLOGY 89