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Adjuvant and Salvage Radiotherapy After Prostatectomy for Prostate Cancer: A Literature Review
Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 4, pp. 972–979, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2008.07.026
CRITICAL REVIEW
ADJUVANT AND SALVAGE RADIOTHERAPY AFTER PROSTATECTOMY FOR PROSTATE CANCER: A LITERATURE REVIEW DAVID PASQUIER, M.D., PH.D.,* AND CHARLES BALLEREAU, M.D., M.SC.y * Department of Radiation Oncology, Centre Galile´e, Clinique de la Louvie`re, Lille, France; and y Department of Urology, Clinique de la Louvie`re, Lille, France Purpose: Given that postprostatectomy recurrence of prostate cancer occurs in 10–40% of patients, the best use of immediate postoperative radiotherapy (RT) in high-risk patients and salvage RT for biochemical recurrence remains a topic of debate. We assessed the levels of evidence (in terms of efficacy, prognostic factors, and toxicity) for the following treatment strategies: immediate postoperative RT alone, salvage RT alone, and the addition of androgen deprivation therapy to the two RT strategies. Methods and Materials: A systematic literature search for controlled randomized trials, noncontrolled trials, and retrospective studies between 1990 and 2008 was performed on PubMed, CancerLit, and MEDLINE. Only relevant articles that had appeared in peer-reviewed journals were selected. We report on the levels of evidence (according to the National Cancer Institute guidelines) supporting the various treatment strategies. Results: Immediate postoperative RT improves biochemical and clinical progression-free survival (Level of evidence, 1.ii) but has no significant effect on metastasis-free survival or overall survival. A pathologic review is of particular importance for correctly analyzing the treatment strategies. Low-grade morbidity has been significantly greater in the postoperative groups, but no severe toxicity has been observed. The influence of immediate postoperative RT on postprostatectomy continence appears to be slight; therefore, immediate postoperative RT should be considered in patients with major risk factors for local relapse (Level of evidence, 1.ii). On the basis of extensive retrospective data, salvage RT is effective in biochemical relapse after prostatectomy; some patients with few adverse prognostic factors might also benefit from salvage RT (Level of evidence, 3.ii). The addition of androgen deprivation therapy to immediate postoperative or salvage RT has only been supported by weak, retrospective data (Level of evidence, 3.ii). Conclusion: Prospective randomized trials are needed to compare immediate postoperative RT with salvage RT and to assess the value of androgen deprivation therapy in this setting. Ó 2008 Elsevier Inc. Prostate cancer, Prostatectomy, Radiotherapy, Adjuvant radiotherapy, Salvage radiotherapy.
salvage RT (efficacy and prognostic factors), and the combination of these two RT schedules with ADT.
INTRODUCTION Radical prostatectomy is the most common first-line treatment of prostate cancer. About 40% of radical prostatectomy patients with adverse prognostic features will develop biochemical recurrence. The attitude of physicians when faced with patients with a strong risk of local recurrence varies considerably and remains a topic of debate. Recent prospective data support immediate postoperative radiotherapy (RT) in such patients. On the basis of retrospective data, salvage RT is commonly used in patients with biochemical recurrence. The impact of the addition of androgen deprivation therapy (ADT) to these RT schedules is unclear. The aim of this literature review was to assess the levels of evidence in support of the following treatment strategies: immediate postoperative RT (efficacy, prognostic factors, and toxicity),
METHODS AND MATERIALS A systematic search for controlled, randomized trials, noncontrolled trials, retrospective studies, and case reports between 1990 and 2008 was performed on PubMed, CancerLit, and MEDLINE using the following MeSH headings: prostate cancer, prostatectomy, radiotherapy, adjuvant radiotherapy, postoperative, salvage therapy, and other keywords. Relevant articles identified in the literature search, found in personal files, or cited in reports and reviews were retrieved and reviewed. The levels of evidence (according to the National Cancer Institute guidelines [1]) supporting the different treatment strategies are specifically reported in the present report.
Reprint requests to: David Pasquier, M.D., Ph.D., Department of Radiation Oncology, Centre Galile´e, 69 rue de la Louvie`re, Lille 59000 France. Tel: (+33) 32-853-5353; Fax: (+33) 32-853-5365; E-mail: [email protected]
Conflict of interest: none. Received April 7, 2008, and in revised form June 27, 2008. Accepted for publication July 10, 2008. 972
0.001
Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; SWOG = Southwestern Oncology Group; PSA = prostate-specific antigen; NR = not reported.
0.16 NR 0.06 NR 0.001 NR 4.5 385 (307 with undetectable PSA) pT3 R0 or R1 tumors p German trial (11) p
pT3N0M0 tumors and $1 pathologic risk factors: capsular perforation, positive surgical margins, seminal vesicle invasion
431 (425 eligible)
10.6
<0.0001 65 vs. 36 (median, 10.3 vs. 3.1) <0.001 72 vs. 54
0.004 61 vs. 47
0.6 Median, 14.7 vs. 13.2
0.6 Median, 14.7 vs. 13.8
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p SWOG 87-94 (10)
94 vs. 94 85 vs. 75 74 vs. 52 5 pN0M0 tumors and $1 pathologic risk factors: capsular perforation, positive surgical margins, seminal vesicle invasion EORTC 22911 (9)
Patients (n) Inclusion criteria Study
1,005 (968 eligible)
Metastasis-free survival (%) Clinical progressionfree survival (%) Biochemical progression-free survival (%) Median follow-up (y)
Table 1. Characteristics and results of three randomized trials of postoperative radiotherapy
In the present report, the terms ‘‘postoperative RT,’’ ‘‘immediate postoperative RT,’’ ‘‘postoperative irradiation,’’ and ‘‘adjuvant RT’’ have been used interchangeably. Certain clinical trials of postoperative RT included patients with measurable prostate-specific antigen (PSA) levels; therefore, the term ‘‘immediate postoperative RT’’ should be preferred to ‘‘adjuvant RT.’’ Although immediate postoperative RT has been used to reduce the risk of recurrence for several years now, only a few retrospective series or case reports were found (2–8). However, in 2005 and 2006, two large, randomized, controlled studies (9, 10) were published in full and a third (11) was published in abstract form; hence, retrospective series on this topic have not been discussed. The European Organization for Research and Treatment of Cancer (EORTC) study (9) was initiated in 1992 and closed in 2001. A total of 1,005 patients were included and randomized into an immediate postoperative RT group (60 Gy of conventional RT delivered within 6 weeks) or a ‘‘wait and see’’ group. The primary endpoint was biochemical relapse-free survival in an intention-to-treat analysis. The clinical TNM category was Stage T1, T2, and T3 in 17%, 65%, and 17% of the patients, respectively. The World Health Organization histopathologic grade was 1, 2, and 3 in 12.5%, 63%, and 24% of the patients, respectively. Capsular perforation, seminal vesicle invasion, and positive surgical margins were present in 77%, 25.5%, and 63% of the patients, respectively. Of the patients, 16% had positive margins only. In 10.7% of the patients, the postoperative PSA levels remained >0.2 ng/mL. The median follow-up period was 5 years (Table 1). Biochemical progression-free survival was significantly greater in the immediate postoperative RT group, with a 5-year biochemical progression-free survival rate of 52.6% and 74%, respectively (p < 0.0001). Postoperative RT also decreased the incidence of local and regional failure. The cumulative incidence at 5 years was 5.4% and 15.4% in the RT and ‘‘wait and see’’ groups, respectively (p < 0.0001). Longer follow-up is necessary to assess metastasis-free survival and overall survival. In 2006, the results of the American, randomized Southwestern Oncology Group (SWOG) study (10) were published, with a longer median follow-up period (10.6 years) and a primary endpoint of metastasis-free survival. A total of 431 patients were enrolled between 1988 and 1997. Patients with a very low risk of pelvic node involvement were not required to undergo lymphadenectomy. An undetectable PSA level was not required at enrollment. Patients were randomized into either an immediate postoperative RT group (60– 64 Gy, delivered within 6–7 weeks) or a ‘‘wait and see’’ group. The Gleason score was #6, 7, and 8–10 in 51%, 36%, and 13% of the patients, respectively. Extracapsular extension or positive surgical margins were present in 67% of the patients, and seminal vesicle invasion was seen in 33%; 22% of the patients presented with all three adverse histopathologic features. One-third of the patients had a detectable PSA level ($0.2 ng/mL) after surgery. Immediate postoperative RT significantly improved biochemical relapse-free and clinical progression-free survival but not metastasis-free or overall survival. Biochemical relapse occurred in 64% and 35% of the patients in the observation and RT groups, respectively. The median PSA relapse-free survival time improved significantly with RT (10.3 years for RT and 3.1 years for observation, p < 0.001). The median metastasis-free survival time was slightly improved (14.7 years for RT vs. 13.2 years for observation), and the hazard ratio (HR) with immediate postoperative RT was 0.75. However, these results were nonsignificant but strongly indicative (p = 0.06; Table 1). Immediate postoperative RT also significantly lengthened the interval to the initiation of ADT. After 5 years, respectively, 21% and 10% of
Overall survival (%)
Immediate postprostatectomy RT
92 vs. 93
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the patients in the observation and RT groups had received hormonal therapy (p < 0.001). A third randomized trial (with apparently favorable results for immediate postoperative RT for Stage pT3 patients) has only been published in abstract form (11). This German trial (ARO 96-02) was flawed by an unusual methodology in which randomization was performed immediately after surgery. Patients with a detectable PSA level just before postoperative RT were excluded from the trial, leading to possible baseline imbalances between the intervention and ‘‘wait and see’’ arms. A total of 385 patients were randomized into the postoperative RT group (60 Gy) or the ‘‘wait and see’’ group. An undetectable PSA level was not achieved in 78 patients, who then left the trial and underwent RT. The biochemical relapsefree survival rate was 72% and 54% in the RT and ‘‘wait and see’’ arms, respectively (p = 0.001; Table 1). Prognostic factors for response to immediate postoperative RT. In the EORTC trial (9), patients were stratified at randomization because of extracapsular extension, surgical margin status, and seminal vesicle invasion. In contrast, the SWOG trial stratified patients according to the tumor extent (tumors at inked surgical margins or beyond the anatomic capsule vs. tumors within the seminal vesicles vs. tumor at both the inked surgical margins or beyond the anatomic capsule and within the seminal vesicle) and by preprostatectomy hormonal therapy (10). In the first EORTC trial publication, a benefit from immediate postoperative RT was found for all pathologic risk groups (9). These data were confirmed in a subsequent analysis by Collette et al. (12). No statistically significant heterogeneity was found in the treatment effect across the stratified patient groups, although the benefit from postoperative RT in the surgical marginnegative, extracapsular extension-positive subgroup appeared to be closer to an HR of 1. In a sense, these results heralded those published after a central review of the histologic slides from a proportion of the patients (13). Pathologic review data were available for 552 patients, and surgical margin status was the strongest predictive factor of improved biochemical progression-free survival after immediate postoperative RT. The HR for the treatment benefit in the group with positive surgical margins was 0.38 (p < 0.0001) but was not significantly different from 1 in patients with negative surgical margins. However, this subset analysis was not planned a priori, and the prognosis of patients whose specimens were reviewed centrally was significantly better than those of patients whose specimens were not reviewed centrally, which might have introduced bias into these results (13). In the SWOG trial, immediate postoperative RT significantly improved biochemical progression-free survival and recurrence-free survival in each group (tumor beyond the anatomic capsule or positive margins, seminal vesicle invasion, or tumor at both the inked surgical margins or beyond the anatomic capsule and within the seminal vesicle) (10). In a subsequent analysis, the role of postoperative PSA was analyzed. The HR for treatment failure for patients receiving RT was 0.35, 0.67, and 0.51 for patients with a PSA level <0.2, 0.2–1, and >1 ng/mL, respectively; these HRs were not significantly different, and thus, all patients groups benefited from RT (14). Toxicity. The prospective evaluation of late toxicity is more relevant than retrospective evaluations; therefore, only the results of prospective, controlled trials have been discussed. In the EORTC trial, the Radiation Therapy Oncology Group (RTOG)/EORTC late radiation morbidity scoring scheme was used to assess late adverse effects (9). In the SWOG trial, however, the scale used to assess late complications was not specified, and rectal and urethral strictures were reported but not graded (10).
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The influence of immediate postoperative RT on continence is a matter of debate. In the EORTC trial, the prevalence of Grade 3 urethral stricture and incontinence was 1.5% in both the postoperative RT and ‘‘wait and see’’ groups. Incontinence was not specifically assessed, but a 100-patient interim analysis showed no difference in complete urinary continence when the latter was measured using patient interviews and objective pad weighing tests (15). In the SWOG trial, total urinary incontinence was more frequent in the postoperative RT group than in the ‘‘wait and see’’ group’’ (6.5% vs. 2.8%, respectively), but this difference was not significant (p = 0.11). In contrast, the incidence of urethral stricture was significantly more frequent in the postoperative RT group than in the observation group (17.8% vs. 9.5%, respectively, p = 0.02) (10). In these two controlled trials, low-grade, non-urinary morbidity was significantly more frequent in the postoperative RT group. In the EORTC trial (9), all grades of late effects (Grades 1–3) were more frequent in the postoperative RT group, but no severe toxicity (Grade 4) was observed. No significant difference was found between the postoperative RT and observation groups in terms of all types of Grade 3 toxicity (4.2% vs. 2.6%, respectively, p = 0.07). In the SWOG trial (10), late effects were more frequent in the RT group than in the observation group (23.8% vs. 11.9%, respectively, p = 0.002), with rectal complications (proctitis or bleeding) occurring in 3.3% of the patients in the former group. In the German trial, the Grade 2 late rectal complication rate was 1% (11). Quality of life was not analyzed in the EORTC trial. In the SWOG trial, quality of life was assessed in a subgroup of patients, but the results are not yet available. Sexual function was not evaluated in either of these two trials. Conclusion. In three randomized trials, immediate postoperative RT improved biochemical/clinical progression-free survival in high-risk patients (Level of evidence, 1.ii) but had no significant influence on metastasis-free survival or overall survival. The followup of the EORTC trial was too short and the SWOG trial appeared to be underpowered to validly assess overall survival. The power of the SWOG trial is open to question because the primary endpoint was initially metastasis-free survival but a lower-than-expected event rate prompted extension of the follow-up period and changed the number of patients for inclusion. Above all, the statistical analysis in the SWOG trial was one-sided in contrast to the two-sided test in the EORTC study. Given the median metastasis-free survival observed in the SWOG’s ‘‘wait and see’’ arm, a two-sided analysis with an HR of 1.25 would have required the inclusion of 2,900 patients (10). These two trials used different inclusion criteria. About 33% and 11% of the patients in the SWOG and EORTC trials, respectively, had a detectable persistent PSA level after surgery and therefore should have been classified as having undergone postoperative RT rather than adjuvant RT (9, 10). In the German trial, patients with a detectable PSA level were excluded from the study after randomization and underwent RT (11). This prompts us to suggest that to correctly evaluate adjuvant RT, only patients with no detectable disease (i.e., with undetectable PSA levels) should be selected. Although immediate postoperative RT benefited all treated patients in the German and SWOG trials (10, 11), the benefit appeared to be greatest in patients with positive surgical margins (13). However, a large proportion of the pathology specimens in the SWOG trial were not centrally reviewed. We believe that adjuvant RT should be considered for patients with Stage pT3 tumors with negative margins. A central review might help to accurately evaluate the role of histologic findings (i.e., grade and stage) in general and that of positive surgical margins in particular, as in the subset analysis in
Adjuvant and salvage RT after prostatectomy d D. PASQUIER AND C. BALLEREAU
the EORTC trial (13). Likewise, we suggest performing a meta-analysis of the individual data from the three trials to refine the prognostic factors; the analysis of the data from pooled patients with undetectable PSA levels should be of particular interest. In routine clinical practice, pathologists might have to reduce interobserver variability as much as possible. Although low-grade morbidity was significantly greater in the postoperative RT groups, no severe toxicity has been observed (Level of evidence, 1.ii). Postoperative RT appears to have a slight influence on postprostatectomy continence and stricture (Level of evidence, 1.ii).
Salvage RT Salvage RT of the prostatic fossa can be used in patients with biochemical recurrence after prostatectomy. Numerous noncontrolled studies have been published. The biochemical progression-free survival in patients with nonpalpable recurrence has varied from 10% to 55% at 5 years (16–34) (Table 2). In the published data, RT has been limited to the prostatic fossa; conformal and intensity-modulated RT should enable more tailored treatment, and guidelines for target volume definitions have recently been published (35–37). In a salvage setting, a dose of 64–68 Gy is recommended (20, 33). However, the influence of the administered dose on biochemical progression-free survival has only been studied retrospectively; therefore, randomized, dose-escalation studies (up to about 70 Gy) are necessary (38, 39). A recent retrospective study revealed superior biochemical relapse-free survival in patients with a high risk of lymph node invasion treated with whole pelvic RT compared with prostatic bed RT; this advantage was only observed in cases of ADT (40). However, given the lack of high-quality prospective data (particularly concerning toxicity), whole pelvic postoperative RT should, we believe, only be used with great caution in routine clinical practice, and inclusion of this topic in clinical trials should be favored. In palpable recurrent disease, the efficacy of salvage RT appears to be limited (16, 41, 42). Most retrospective studies have enabled the definition of prognostic factors for biochemical recurrence-free survival using univariate analysis only (because of the low number of patients). However, multivariate analysis has been possible in some studies with larger
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sample sizes (16, 19, 21, 22, 24, 25, 28–34, 40) and has yielded the following prognostic factors: preprostatectomy and pre-RT PSA levels, PSA doubling time, interval to PSA failure, Gleason score, margin status, and seminal vesicle invasion. Despite its retrospective design, one particular multicenter study merits further attention. In 2004 and 2007, Stephenson et al. (32, 33) published a multicenter series, with the more recent study featuring 1,540 patients. All patients had a pre-RT PSA level of $0.2 ng/mL at $6 weeks after radical prostatectomy followed by another still greater value, or a single PSA level of $0.5 ng/mL. The median preprostatectomy and pre-RT PSA level was 10.5 ng/mL (interquartile range, 6.6–19) and 1.1 ng/mL (interquartile range, 0.6–2.2), respectively. Extracapsular extension, positive surgical margins, seminal vesicle invasion, and positive lymph nodes were present in 65%, 51%, 24%, and 3% of the patients, respectively. The median radiation dose was 64.8 Gy (interquartile range, 63–66). Fourteen percent of the patients had undergone ADT before and/or during RT, for a median duration of 4 months. With a median follow-up of 53 months, the progression-free survival rate at 6 years was 32%. A multivariate analysis confirmed that the PSA level before RT, Gleason grade, PSA doubling time, surgical margin status, use of ADT, and lymph node metastasis were all significant prognostic factors. The 6-year disease-free survival rate was 48%, 40%, 28%, and 18% in patients with a PSA level <0.5, 0.5–1, 1–1.5, and >1.5 ng/mL, respectively. The most favorable case for salvage RT would be a patient with a low PSA level before RT, a Gleason score of 4–7, positive surgical margins, and a PSA doubling time >10 months (33). Salvage RT can be considered in some patients with a few unfavorable prognostic factors (greater Gleason score and/or shorter PSA doubling time) despite the greater risk of metastatic disease, because this approach gives a lasting response in around one-third of these individuals (33). In summary, salvage RT is effective in biochemical relapse after prostatectomy (Level of evidence, 3.ii). The prognosis factors are well known (Level of evidence, 3.ii) and enable the selection of patients for salvage RT, systemic treatment, or inclusion in clinical trials. Recent data argue in favor of early salvage RT in patients with a PSA level <1 ng/mL or even 0.5 ng/mL, although uniform criteria for defining biochemical recurrence after radical prostatectomy are still lacking. At present, debate continues as to whether the PSA
Table 2. Results for salvage radiotherapy after biochemical recurrence from selected studies Investigator
Patients (n)
Median PSA (ng/mL)
Median dose (Gy)
Biochemical recurrence-free survival
Catton et al. (16) Cadeddu et al. (17) Garg et al. (18) Pisansky et al. (19) Anscher et al. (20) Leventis et al. (21) Chawla et al. (22) Taylor et al. (23) Buskirk et al. (24) Kalapurakal et al. (25) Tsien et al. (26) Peyromaure et al. (27) Hagan et al. (28) Pazona et al. (29) Ward et al. (30) Stephenson et al. (33) Neuhof et al. (34)
22 82 78 166 89 49 54 71 368 41 57 62 91 307 211 1,540 171
2.8 4.1 1.2 0.9 1.4 2.1 1.3 0.8 0.7 0.5 1.2 2.5 4.5 0.8 0.6 1.1 1.1
60 64 66 64 66 66 64.8 70 64.8 65 65 65 64 64 64 65 60–66
19% at 5 y 10% at 5 y 65% at 3 y 46% at 5 y 50% at 4 y 24% at 5 y 35% at 5 y 66% at 5 y 35% at 8 y 57% at 5 y 30% at 8 y 42% at 5 y 55% at 5 y 40% at 5 y; 25% at 10 y 34% at 10 y 32% at 6 y 35% at 5 y
Abbreviation: PSA = prostate-specific antigen.
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level to determine recurrence after prostatectomy should be $0.2 or $0.4 ng/mL. In 2004, the Prostate Specific Antigen Working Group stated that the minimal value for considering a patient to be eligible for secondary treatment was 0.4 ng/mL confirmed by a subsequent test result of $0.4 ng/mL; this threshold was determined by the supposition that patients with a PSA of $0.4 ng/mL are at a greater risk of systemic relapse (43). These results were recently confirmed in a trial that evaluated 10 definitions for predicting metastatic progression in 3,125 patients who had undergone radical prostatectomy (44). The four best definitions for predicting metastatic progression were a PSA level of $0.4 ng/mL and increasing, a PSA level of $0.2 ng/mL and increasing, a single PSA measurement of $0.6 ng/mL, and a single PSA measurement of $0.4 ng/mL. These definitions were also associated with a greater risk of PSA progression and secondary treatment. Concerning the risk of secondary treatment or clinical recurrence, two different definitions (a PSA level of $0.4 ng/mL and increasing and a PSA level of $0.2 ng/mL and increasing) displayed similar sensitivity and specificity. In these 3,125 patients, the 7-year probability of secondary treatment or clinical recurrence using these same two definitions was 62% (95% confidence interval, 54–70) and 64% (95% confidence interval, 57–71), respectively (44). Consequently, the more sensitive definition (PSA level $0.2 ng/mL and increasing) is more appropriate in patients who are presumed to have local recurrence and who are eligible for salvage RT. When salvage RT is indicated using a more sensitive definition, it will necessarily be initiated sooner in the disease course. To date, salvage RT is the only potentially curative treatment for patients with an increasing PSA level. We believe that systemic treatment or inclusion in chemotherapy clinical trials should only be considered if salvage RT has failed to stop the recurrence. Our view even extends to salvage RT for patients with one or two adverse prognostic factors (e.g., Gleason score 8–10 and/or a PSA doubling time of <10 months, despite a low PSA level and positive surgical margins). Progression-free survival was seen in about onethird of such patients after salvage RT (33). Patients with a worse prognosis should be considered for ADT or inclusion in clinical trials, rather than for salvage RT. Immediate postoperative and salvage RT have not been compared in a prospective, controlled trial. Only retrospective data are available (16, 23, 25, 28, 45, 46); hence, no conclusions could be drawn. Supporters of salvage RT alone argue that the benefit of this technique when applied early (with a biochemical relapse-free survival rate of around 50%, with a PSA level <0.5 ng/mL) appears to be similar to that of postoperative RT (an improvement in progression-free survival of about 40–50%). They also state that salvage RT avoids giving postoperative RT to patients who do not need it. Given our current state of knowledge, this position (outside of a clinical trial) is overassertive, because the levels of evidence underpinning the two approaches are not the same (three randomized studies of postoperative RT but only retrospective studies of salvage RT). The comparison of prospective and retrospective studies with differing inclusion criteria and patients treated at different points is not reliable. Even though postoperative RT means treating patients who might not otherwise have developed a recurrence (i.e., between 36% and 54% of recurrence-free survival rates in the ‘‘wait and see’’ arms of the three randomized trials [9–11]), one potential disadvantage of salvage RT is that it misses patients (about 1 in 2, even with a PSA level <0.5 ng/mL) whose recurrence could have been prevented by postoperative RT. Only randomized trials will be able to validly compare postoperative RT and salvage RT; therefore, inclusion in the ongoing studies of this type should be encouraged.
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The design of the three published randomized trials does not enable us to answer this question, because salvage RT was not planned in the ‘‘wait and see’’ arm. The Radiotherapy and Androgen Deprivation in Combination after Local Surgery (RADICALS) is a randomized trial addressing the questions of the timing of RT (immediate vs. salvage) and the duration of ADT (none vs. 6 months vs. 24 months). Patients can be entered into one or both randomizations, and the inclusion of 4,000 patients is scheduled (47). The Groupe d’Etude des Tumeurs Uro-Genitales 17 trial is set to open soon; this France-based, randomized trial will compare immediate postoperative and salvage RT in Stage pT3, R1, pN0, and pNx patients; a 6month luteinizing hormone-releasing hormone (LHRH) analog treatment will be combined with RT in both arms. For patients with increasing PSA after prostatectomy, we need new ways to identify those presenting with local and/or metastatic recurrence. This issue is all the more tricky when the PSA level is low and the recurrent disease is low in volume. 111 In-capromab pendetide (ProstaScint) has been evaluated retrospectively in several studies. The results have been mixed, with some studies showing a better prognosis in the absence of uptake or solely intrapelvic uptake (48, 49), and others failing to reveal any link between the radioimmunoscintigraphy results and biochemical progression-free survival (50–53). The 11C-choline positron emission tomography technique appears to be of use but is handicapped by the cameras’ low spatial resolution—this makes it difficult to detect low-volume lesions and results in a poor negative predictive value (54). Magnetic resonance imaging enables the sensitive, specific detection of local recurrence (55), and dynamic contrast-enhanced magnetic resonance imaging and proton magnetic resonance spectroscopy imaging could further improve these results, particularly in patients with the lowest PSA levels (56). However, in the foreseeable future, the benefit of imaging is likely to remain moderate in patients with very low PSA levels (<0.5 ng/mL), given that none of the techniques have sufficient resolution to detect microscopic local, locoregional, or metastatic disease. In the future, biomarker profiling might prompt the development of treatments that are better tailored to each patient by providing a more detailed description of the state of disease progression (57, 58).
The addition of ADT to immediate postoperative RT and salvage RT In an adjuvant setting, the RTOG 85-31 trial evaluated the effect of ADT up to relapse vs. ADT at relapse in RT patients with an unfavorable prognosis. Patients who had undergone prostatectomy were eligible if penetration through the capsule and/or seminal vesicle invasion was documented. Patients were stratified at randomization according to the treatment type (i.e., prostatectomy or no prostatectomy). A total of 139 patients (15%) had undergone prostatectomy. Immediate adjuvant ADT improved disease-free survival and overall survival, both in the population as a whole and in patients who had undergone previous prostatectomy (59). In a secondary analysis, the biochemical failure rate (defined as a PSA level >0.5 ng/mL) was 65% and 42% in patients who received combination therapy and RT alone, respectively (p = 0.002). Local control, distant failure, and overall survival did not differ significantly (60). Although the findings of a retrospective trial argue in favor of adjuvant ADT with postoperative RT (61) (Level of evidence, 3.ii), the results of ongoing trials (e.g., the Radiotherapy and Androgen Deprivation in Combination after Local Surgery study) are eagerly awaited (47). The RTOG 00-11 study was a three-arm adjuvant trial (RT alone, RT plus LHRH agonist for 2 years, LHRH agonist alone for 2 years) but was closed prematurely owing to poor accrual (62).
Adjuvant and salvage RT after prostatectomy d D. PASQUIER AND C. BALLEREAU
In a salvage RT setting, some retrospective findings argue in favor of adjuvant ADT (Level of evidence, 3.ii) (33, 63, 64). In the series reported by Stephenson et al. (33), ADT before or during RT improved the 6-year progression-free probability on multivariate analysis. The results of the RTOG 96-01 randomized trial comparing RT in the presence and absence of 2 years of postprostatectomy ADT in patients with elevated (persistent or relapsing) PSA levels are now awaited (65). The recently opened RTOG 0534 three-arm, randomized, salvage RT trial is evaluating prostatic bed RT alone, prostatic bed RT with short-term (4–6 months) ADT, and pelvic node RT with short-term ADT (66). The GETUG 16 randomized trial comparing salvage RT in the presence and absence of ADT (administration of an LHRH analog for 6 months) is also ongoing (67).
CONCLUSION Immediate postoperative RT improves biochemical and clinical progression-free survival in high-risk patients in ran-
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domized trials but has no significant influence on metastasisfree survival or overall survival. The pathologic review of surgical margins is of particular importance in analyzing treatment choices. No severe toxicity has been observed. Although the effect of immediate postoperative RT on continence is a topic of debate, prospective data have not shown any significant deleterious influence on this symptom. Immediate postoperative RT should be considered in patients with major risk factors for local relapse. Salvage RT is effective in terms of biochemical recurrence but its use has only been supported by retrospective data. The question of the equivalence between immediate postoperative and early salvage RT has not been resolved, and randomized trials are ongoing. The addition of ADT to immediate postoperative or salvage RT must be evaluated in randomized trials before being used in routine clinical practice.
REFERENCES 1. Available from: http://www.cancer.gov/cancertopics/pdq/levelsevidence-adult-treatment. Accessed June 27, 2008. 2. Gibbons RP, Cole BS, Richardson RG, et al. Adjuvant radiotherapy following radical prostatectomy: Results and complications. J Urol 1986;135:65–68. 3. Anscher MS, Prosnitz LR. Postoperative radiotherapy for patients with carcinoma of the prostate undergoing radical prostatectomy with positive surgical margins, seminal vesicle involvement and/or penetration through the capsule. J Urol 1987;138:1407–1412. 4. Petrovich Z, Lieskovsky G, Freeman J, et al. Surgery with adjuvant irradiation in patients with pathologic stage C adenocarcinoma of the prostate. Cancer 1995;76:1621–1628. 5. Syndikus I, Pickles T, Kostashuk E, et al. Postoperative radiotherapy for stage pT3 carcinoma of the prostate: Improved local control. J Urol 1996;155:1983–1986. 6. Perez CA, Beyer DC. Blasko JC, for the American College of Radiology. Postradical prostatectomy irradiation in carcinoma of the prostate: ACR Appropriateness Criteria. Radiology 2000;215(Suppl.):1419–1439. 7. Vargas C, Kestin LL, Weed DW, et al. Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Radiat Oncol Biol Phys 2005;61:714–724. 8. Teh BS, Bastasch MD, Mai WY, et al. Long-term benefits of elective radiotherapy after prostatectomy for patients with positive surgical margins. J Urol 2006;175:2097–2102. 9. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: A randomised controlled trial (EORTC trial 22911). Lancet 2005;366:572–578. 10. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: A randomized clinical trial. JAMA 2006;296:2329-2325. 11. Wiegel T, Sto¨rkel S, Bottke D, et al. pT3 prostate cancer: Phase III study of adjuvant radiotherapy versus wait and see: Impact of pathologic review on analysis. Presented at 43th Annual ASCO Meeting, June 1–5, 2007, Chicago, IL. 12. 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 2005;41:2662–2672. 13. 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;25:4178–4186.
14. 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;25:2225–2229. 15. Van Cangh PJ, Richard F, Lorge F, et al. Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: Results of a prospective randomized study. J Urol 1998;159:164–166. 16. 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. 17. Cadeddu JA, Partin AW, DeWeese TL, et al. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 1998;59:173–178. 18. Garg MK, Tekyi-Mensah S, Bolton S, et al. Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology 1998;51:998–1002. 19. Pisansky TM, Kozelsky TF, Myers RP, et al. Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J Urol 2000;163:845–850. 20. Anscher MS, Clough R, Dodge R. Radiotherapy for a rising prostate-specific antigen after radical prostatectomy: The first 10 years. Int J Radiat Oncol Biol Phys 2000;48:369–375. 21. Leventis AK, Shariat S, Kattan M, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2001;19: 1030–1039. 22. Chawla AK, Thakral HK, Zietman AL, et al. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: Analysis of efficacy and prognostic factors. Urology 2002;59: 726–731. 23. Taylor N, Kelly JF, Kuban DA, et al. Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 2003;56:755–763. 24. Buskirk SJ, Pisansky TM, Schild SE, et al. Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: Evaluation of prognostic factors and creation of a prognostic scoring system. J Urol 2006;176:985–990. 25. Kalapurakal JA, Huang C-F, Neriamparampil MM, et al. Biochemical disease-free survival following adjuvant and salvage irradiation after radical prostatectomy. Int J Radiat Oncol Biol Phys 2002;54:1047–1054. 26. Tsien C, Griffith K, Sandler H, et al. Long term results of threedimensional conformal adjuvant and salvage radiotherapy after radical prostatectomy. Urology 2003;62:93–98.
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27. Peyromaure M, Allouch M, Eschwege O, et al. Salvage radiotherapy for biochemical recurrence after radical prostatectomy: A study of 62 patients. Urology 2003;62:503–507. 28. Hagan M, Zlotecki R, Medina C, et al. Comparison of adjuvant versus salvage radiotherapy policies for postprostatectomy radiotherapy. Int J Radiat Oncol Biol Phys 2004;59:329–340. 29. Pazona JF, Han M, Hawkins SA, et al. Salvage radiation therapy for prostate specific antigen progression following radical prostatectomy: 10-year outcome estimates. J Urol 2005;174:1282–1286. 30. Ward JF, Zincke H, Bergstralh EJ, et al. Prostate specific antigen doubling time subsequent to radical prostatectomy as a prognosticator of outcome following salvage radiotherapy. J Urol 2004;172:2244–2248. 31. Brooks JP, Albert PS, Wilder RB, et al. Long-term salvage radiotherapy outcome after radical prostatectomy and relapse predictors. J Urol 2005;174:2204–2208. 32. Stephenson A, Shariat S, Zelefsky M, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291:1325–1332. 33. Stephenson A, Scardino P, Kattan M, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035–2041. 34. Neuhof D, Hentschel T, Mischof M, et al. Long term results and predictive factors of three dimensional conformal salvage radiotherapy for biochemical relapse after prostatectomy. Int J Radiat Oncol Biol Phys 2007;67:1411–1417. 35. 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;84:121–127. 36. Miralbell R, Vees H, Lozano J, et al. Endorectal MRI assessment of local relapse after surgery for prostate cancer: A model to define treatment field guidelines for adjuvant radiotherapy in patients at high risk for local failure. Int J Radiat Oncol Biol Phys 2007;67:356–361. 37. Wiltshire K, Brock K, Haider M, et al. Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy. Int J Radiat Oncol Biol Phys 2007;69:1090–1099. 38. King CR, Spiotto MT. Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys 2008;71:23–27. 39. King R, Kapp S. Radiotherapy after prostatectomy: Is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys 2008;71:346–350. 40. Spiotto M, Hancock S, King C. Radiotherapy after prostatectomy: Improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high risk patients. Int J Radiat Oncol Biol Phys 2007;69:54–61. 41. Choo R, Mortona G, Danjouxa C, et al. Limited efficacy of salvage radiotherapy for biopsy confirmed or clinically palpable local recurrence of prostate carcinoma after surgery. Radiother Oncol 2005;74:163–167. 42. Mc Donald O, Schild S, Vora S, et al. Salvage radiotherapy for palpable locally recurrent prostate cancer after radical prostatectomy. Int J Radiat Oncol Biol Phys 2004;58:1530–1535. 43. Scher H, Eisenberger M, D’Amico A, et al. Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate specific antigen: Recommendations from the Prostate Specific Antigen Working Group. J Clin Oncol 2006;22:537–556. 44. Stephenson A, Kattan M, Eastham J, et al. Defining biochemical recurrence of prostate cancer after radical prostatectomy: A proposal for a standardized definition. J Clin Oncol 2006;24: 3973–3978. 45. Cozzarini C, Bolognesi A, Ceresoli G, et al. Role of postoperative radiotherapy after lymphadenectomy and radical retropubic prostatectomy: A single institute experience of 415 patients. Int J Radiat Oncol Biol Phys 2004;59:674–683.
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46. Jani A, Kao J. Postprostatectomy adjuvant versus salvage radiotherapy: A complication-adjusted number-needed-to-treat analysis. Cancer 2005;103:1833–1842. 47. Parker C, Clarkey N, Loguez J, et al. RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery). Clin Oncol 2007;19:167–171. 48. Proano JM, Sodee DB, Resnick MI, et al. The impact of a negative (111.indium-capromab pendetide scan before salvage radiotherapy. J Urol 2006;175:1668–1672. 49. Kahn D, Williams RD, Manyak MJ, et al. for the ProstaScint Study Group. 111Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. J Urol 1998;159:2041–2047. 50. Nagda SN, Mohideen N, Lo SS, et al. Long-term follow-up of 111 In-capromab pendetide (ProstaScint) scan as pre-treatment assessment in patients who undergo salvage radiotherapy for rising prostate-specific antigen after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 2007;67:834–840. 51. Thomas CT, Bradshaw PT, Pollock BH, et al. Indium-111- capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy. J Clin Oncol 2003;21: 1715–1721. 52. Wilkinson S, Chodak G. The role of 111Indium-capromab pendetide imaging for assessing biochemical failure after radical prostatectomy. J Urol 2004;172:133–136. 53. Liauw SL, Weichselbaum R, Zagaja G, et al. Salvage radiotherapy after prostatectomy biochemical failure: Does pre-treatment radioimmunoscintigraphy help select patients with locally confined disease? Int J Radiat Oncol Biol Phys 2008;71: 1316–1321. 54. Scattoni V, Picchio M, Suardi N, et al. Detection of lymph node metastases with integrated 11C choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: Results confirmed by open pelvic retroperitoneal lymphadenectomy. Eur Urol 2007;52:423–429. 55. Sella T, Schwartz L, Swindle P, et al. Suspected local recurrence after radical prostatectomy: Endorectal coil imaging. Radiology 2004;231:379–385. 56. Sciarra A, Panebianco V, Salciccia S, et al. Role of dynamic contrast enhanced magnetic resonance (MR) imaging and proton MR spectroscopic imaging in the detection of local recurrence after radical prostatectomy for prostate cancer. Eur Urol 2008;54:589–600. 57. Parekh DJ, Ankerst DP, Troyer D, et al. Biomarkers for prostate cancer detection. J Urol 2007;178:2252–2259. 58. Bensalah K, Montorsi F, Shariat S. Challenges of cancer biomarker profiling. Eur Urol 2007;52:1601–1609. 59. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma— Long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285–1290. 60. Corn B, Winter K, Pilepich M. Does androgen suppression enhance the efficacy of postoperative radiotherapy? A secondary analysis of RTOG 85-31. Urology 1999;54:495–502. 61. Eulau SM, Tate DJ, Stamey TA, et al. Effect of combined transient androgen deprivation and irradiation following radical prostatectomy for prostatic cancer. Int J Radiat Oncol Biol Phys 1998;41:735–740. 62. RTOG trial 0011: Phase III randomized study of adjuvant therapy for high risk pT2-3N0 prostate cancer. Available from: http://www.rtog.org/. Accessed June 27, 2008. 63. King C, Presti J, Gill H, et al. Radiotherapy after radical prostatectomy: Does transient androgen suppression improve outcomes? Int J Radiat Oncol Biol Phys 2004;59:341–347. 64. Tiguert R, Rigaud J, Lacombe L, et al. Neoadjuvant hormone therapy before salvage radiotherapy for an increasing post-radical
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prostatectomy serum prostate specific antigen level. J Urol 2003; 170:447–450. 65. RTOG trial 9601: A phase III trial of radiation therapy with or without Casodex in patients with PSA elevation following radical prostatectomy for pT3N0 carcinoma of the prostate. Available from: http://www.rtog.org/. Accessed June 27, 2008. 66. RTOG trial 0534: A phase III trial of short term androgen deprivation with pelvic lymph node or prostate only radiotherapy
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(SPORT) in prostate cancer patients with a rising PSA after radical prostatectomy. Available from: http://www.rtog.org/. Accessed June 27, 2008. 67. GETUG 16 trial: Phase III randomized study of adjuvant radiotherapy with versus without concurrent goserelin in patients who have undergone surgery for recurrent or refractory prostate cancer. Available from: http://www.cancer.gov/clinicaltrials. Accessed June 27, 2008.
doi:10.1016/j.ijrobp.2008.07.026
CRITICAL REVIEW
ADJUVANT AND SALVAGE RADIOTHERAPY AFTER PROSTATECTOMY FOR PROSTATE CANCER: A LITERATURE REVIEW DAVID PASQUIER, M.D., PH.D.,* AND CHARLES BALLEREAU, M.D., M.SC.y * Department of Radiation Oncology, Centre Galile´e, Clinique de la Louvie`re, Lille, France; and y Department of Urology, Clinique de la Louvie`re, Lille, France Purpose: Given that postprostatectomy recurrence of prostate cancer occurs in 10–40% of patients, the best use of immediate postoperative radiotherapy (RT) in high-risk patients and salvage RT for biochemical recurrence remains a topic of debate. We assessed the levels of evidence (in terms of efficacy, prognostic factors, and toxicity) for the following treatment strategies: immediate postoperative RT alone, salvage RT alone, and the addition of androgen deprivation therapy to the two RT strategies. Methods and Materials: A systematic literature search for controlled randomized trials, noncontrolled trials, and retrospective studies between 1990 and 2008 was performed on PubMed, CancerLit, and MEDLINE. Only relevant articles that had appeared in peer-reviewed journals were selected. We report on the levels of evidence (according to the National Cancer Institute guidelines) supporting the various treatment strategies. Results: Immediate postoperative RT improves biochemical and clinical progression-free survival (Level of evidence, 1.ii) but has no significant effect on metastasis-free survival or overall survival. A pathologic review is of particular importance for correctly analyzing the treatment strategies. Low-grade morbidity has been significantly greater in the postoperative groups, but no severe toxicity has been observed. The influence of immediate postoperative RT on postprostatectomy continence appears to be slight; therefore, immediate postoperative RT should be considered in patients with major risk factors for local relapse (Level of evidence, 1.ii). On the basis of extensive retrospective data, salvage RT is effective in biochemical relapse after prostatectomy; some patients with few adverse prognostic factors might also benefit from salvage RT (Level of evidence, 3.ii). The addition of androgen deprivation therapy to immediate postoperative or salvage RT has only been supported by weak, retrospective data (Level of evidence, 3.ii). Conclusion: Prospective randomized trials are needed to compare immediate postoperative RT with salvage RT and to assess the value of androgen deprivation therapy in this setting. Ó 2008 Elsevier Inc. Prostate cancer, Prostatectomy, Radiotherapy, Adjuvant radiotherapy, Salvage radiotherapy.
salvage RT (efficacy and prognostic factors), and the combination of these two RT schedules with ADT.
INTRODUCTION Radical prostatectomy is the most common first-line treatment of prostate cancer. About 40% of radical prostatectomy patients with adverse prognostic features will develop biochemical recurrence. The attitude of physicians when faced with patients with a strong risk of local recurrence varies considerably and remains a topic of debate. Recent prospective data support immediate postoperative radiotherapy (RT) in such patients. On the basis of retrospective data, salvage RT is commonly used in patients with biochemical recurrence. The impact of the addition of androgen deprivation therapy (ADT) to these RT schedules is unclear. The aim of this literature review was to assess the levels of evidence in support of the following treatment strategies: immediate postoperative RT (efficacy, prognostic factors, and toxicity),
METHODS AND MATERIALS A systematic search for controlled, randomized trials, noncontrolled trials, retrospective studies, and case reports between 1990 and 2008 was performed on PubMed, CancerLit, and MEDLINE using the following MeSH headings: prostate cancer, prostatectomy, radiotherapy, adjuvant radiotherapy, postoperative, salvage therapy, and other keywords. Relevant articles identified in the literature search, found in personal files, or cited in reports and reviews were retrieved and reviewed. The levels of evidence (according to the National Cancer Institute guidelines [1]) supporting the different treatment strategies are specifically reported in the present report.
Reprint requests to: David Pasquier, M.D., Ph.D., Department of Radiation Oncology, Centre Galile´e, 69 rue de la Louvie`re, Lille 59000 France. Tel: (+33) 32-853-5353; Fax: (+33) 32-853-5365; E-mail: [email protected]
Conflict of interest: none. Received April 7, 2008, and in revised form June 27, 2008. Accepted for publication July 10, 2008. 972
0.001
Abbreviations: EORTC = European Organization for Research and Treatment of Cancer; SWOG = Southwestern Oncology Group; PSA = prostate-specific antigen; NR = not reported.
0.16 NR 0.06 NR 0.001 NR 4.5 385 (307 with undetectable PSA) pT3 R0 or R1 tumors p German trial (11) p
pT3N0M0 tumors and $1 pathologic risk factors: capsular perforation, positive surgical margins, seminal vesicle invasion
431 (425 eligible)
10.6
<0.0001 65 vs. 36 (median, 10.3 vs. 3.1) <0.001 72 vs. 54
0.004 61 vs. 47
0.6 Median, 14.7 vs. 13.2
0.6 Median, 14.7 vs. 13.8
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p SWOG 87-94 (10)
94 vs. 94 85 vs. 75 74 vs. 52 5 pN0M0 tumors and $1 pathologic risk factors: capsular perforation, positive surgical margins, seminal vesicle invasion EORTC 22911 (9)
Patients (n) Inclusion criteria Study
1,005 (968 eligible)
Metastasis-free survival (%) Clinical progressionfree survival (%) Biochemical progression-free survival (%) Median follow-up (y)
Table 1. Characteristics and results of three randomized trials of postoperative radiotherapy
In the present report, the terms ‘‘postoperative RT,’’ ‘‘immediate postoperative RT,’’ ‘‘postoperative irradiation,’’ and ‘‘adjuvant RT’’ have been used interchangeably. Certain clinical trials of postoperative RT included patients with measurable prostate-specific antigen (PSA) levels; therefore, the term ‘‘immediate postoperative RT’’ should be preferred to ‘‘adjuvant RT.’’ Although immediate postoperative RT has been used to reduce the risk of recurrence for several years now, only a few retrospective series or case reports were found (2–8). However, in 2005 and 2006, two large, randomized, controlled studies (9, 10) were published in full and a third (11) was published in abstract form; hence, retrospective series on this topic have not been discussed. The European Organization for Research and Treatment of Cancer (EORTC) study (9) was initiated in 1992 and closed in 2001. A total of 1,005 patients were included and randomized into an immediate postoperative RT group (60 Gy of conventional RT delivered within 6 weeks) or a ‘‘wait and see’’ group. The primary endpoint was biochemical relapse-free survival in an intention-to-treat analysis. The clinical TNM category was Stage T1, T2, and T3 in 17%, 65%, and 17% of the patients, respectively. The World Health Organization histopathologic grade was 1, 2, and 3 in 12.5%, 63%, and 24% of the patients, respectively. Capsular perforation, seminal vesicle invasion, and positive surgical margins were present in 77%, 25.5%, and 63% of the patients, respectively. Of the patients, 16% had positive margins only. In 10.7% of the patients, the postoperative PSA levels remained >0.2 ng/mL. The median follow-up period was 5 years (Table 1). Biochemical progression-free survival was significantly greater in the immediate postoperative RT group, with a 5-year biochemical progression-free survival rate of 52.6% and 74%, respectively (p < 0.0001). Postoperative RT also decreased the incidence of local and regional failure. The cumulative incidence at 5 years was 5.4% and 15.4% in the RT and ‘‘wait and see’’ groups, respectively (p < 0.0001). Longer follow-up is necessary to assess metastasis-free survival and overall survival. In 2006, the results of the American, randomized Southwestern Oncology Group (SWOG) study (10) were published, with a longer median follow-up period (10.6 years) and a primary endpoint of metastasis-free survival. A total of 431 patients were enrolled between 1988 and 1997. Patients with a very low risk of pelvic node involvement were not required to undergo lymphadenectomy. An undetectable PSA level was not required at enrollment. Patients were randomized into either an immediate postoperative RT group (60– 64 Gy, delivered within 6–7 weeks) or a ‘‘wait and see’’ group. The Gleason score was #6, 7, and 8–10 in 51%, 36%, and 13% of the patients, respectively. Extracapsular extension or positive surgical margins were present in 67% of the patients, and seminal vesicle invasion was seen in 33%; 22% of the patients presented with all three adverse histopathologic features. One-third of the patients had a detectable PSA level ($0.2 ng/mL) after surgery. Immediate postoperative RT significantly improved biochemical relapse-free and clinical progression-free survival but not metastasis-free or overall survival. Biochemical relapse occurred in 64% and 35% of the patients in the observation and RT groups, respectively. The median PSA relapse-free survival time improved significantly with RT (10.3 years for RT and 3.1 years for observation, p < 0.001). The median metastasis-free survival time was slightly improved (14.7 years for RT vs. 13.2 years for observation), and the hazard ratio (HR) with immediate postoperative RT was 0.75. However, these results were nonsignificant but strongly indicative (p = 0.06; Table 1). Immediate postoperative RT also significantly lengthened the interval to the initiation of ADT. After 5 years, respectively, 21% and 10% of
Overall survival (%)
Immediate postprostatectomy RT
92 vs. 93
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the patients in the observation and RT groups had received hormonal therapy (p < 0.001). A third randomized trial (with apparently favorable results for immediate postoperative RT for Stage pT3 patients) has only been published in abstract form (11). This German trial (ARO 96-02) was flawed by an unusual methodology in which randomization was performed immediately after surgery. Patients with a detectable PSA level just before postoperative RT were excluded from the trial, leading to possible baseline imbalances between the intervention and ‘‘wait and see’’ arms. A total of 385 patients were randomized into the postoperative RT group (60 Gy) or the ‘‘wait and see’’ group. An undetectable PSA level was not achieved in 78 patients, who then left the trial and underwent RT. The biochemical relapsefree survival rate was 72% and 54% in the RT and ‘‘wait and see’’ arms, respectively (p = 0.001; Table 1). Prognostic factors for response to immediate postoperative RT. In the EORTC trial (9), patients were stratified at randomization because of extracapsular extension, surgical margin status, and seminal vesicle invasion. In contrast, the SWOG trial stratified patients according to the tumor extent (tumors at inked surgical margins or beyond the anatomic capsule vs. tumors within the seminal vesicles vs. tumor at both the inked surgical margins or beyond the anatomic capsule and within the seminal vesicle) and by preprostatectomy hormonal therapy (10). In the first EORTC trial publication, a benefit from immediate postoperative RT was found for all pathologic risk groups (9). These data were confirmed in a subsequent analysis by Collette et al. (12). No statistically significant heterogeneity was found in the treatment effect across the stratified patient groups, although the benefit from postoperative RT in the surgical marginnegative, extracapsular extension-positive subgroup appeared to be closer to an HR of 1. In a sense, these results heralded those published after a central review of the histologic slides from a proportion of the patients (13). Pathologic review data were available for 552 patients, and surgical margin status was the strongest predictive factor of improved biochemical progression-free survival after immediate postoperative RT. The HR for the treatment benefit in the group with positive surgical margins was 0.38 (p < 0.0001) but was not significantly different from 1 in patients with negative surgical margins. However, this subset analysis was not planned a priori, and the prognosis of patients whose specimens were reviewed centrally was significantly better than those of patients whose specimens were not reviewed centrally, which might have introduced bias into these results (13). In the SWOG trial, immediate postoperative RT significantly improved biochemical progression-free survival and recurrence-free survival in each group (tumor beyond the anatomic capsule or positive margins, seminal vesicle invasion, or tumor at both the inked surgical margins or beyond the anatomic capsule and within the seminal vesicle) (10). In a subsequent analysis, the role of postoperative PSA was analyzed. The HR for treatment failure for patients receiving RT was 0.35, 0.67, and 0.51 for patients with a PSA level <0.2, 0.2–1, and >1 ng/mL, respectively; these HRs were not significantly different, and thus, all patients groups benefited from RT (14). Toxicity. The prospective evaluation of late toxicity is more relevant than retrospective evaluations; therefore, only the results of prospective, controlled trials have been discussed. In the EORTC trial, the Radiation Therapy Oncology Group (RTOG)/EORTC late radiation morbidity scoring scheme was used to assess late adverse effects (9). In the SWOG trial, however, the scale used to assess late complications was not specified, and rectal and urethral strictures were reported but not graded (10).
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The influence of immediate postoperative RT on continence is a matter of debate. In the EORTC trial, the prevalence of Grade 3 urethral stricture and incontinence was 1.5% in both the postoperative RT and ‘‘wait and see’’ groups. Incontinence was not specifically assessed, but a 100-patient interim analysis showed no difference in complete urinary continence when the latter was measured using patient interviews and objective pad weighing tests (15). In the SWOG trial, total urinary incontinence was more frequent in the postoperative RT group than in the ‘‘wait and see’’ group’’ (6.5% vs. 2.8%, respectively), but this difference was not significant (p = 0.11). In contrast, the incidence of urethral stricture was significantly more frequent in the postoperative RT group than in the observation group (17.8% vs. 9.5%, respectively, p = 0.02) (10). In these two controlled trials, low-grade, non-urinary morbidity was significantly more frequent in the postoperative RT group. In the EORTC trial (9), all grades of late effects (Grades 1–3) were more frequent in the postoperative RT group, but no severe toxicity (Grade 4) was observed. No significant difference was found between the postoperative RT and observation groups in terms of all types of Grade 3 toxicity (4.2% vs. 2.6%, respectively, p = 0.07). In the SWOG trial (10), late effects were more frequent in the RT group than in the observation group (23.8% vs. 11.9%, respectively, p = 0.002), with rectal complications (proctitis or bleeding) occurring in 3.3% of the patients in the former group. In the German trial, the Grade 2 late rectal complication rate was 1% (11). Quality of life was not analyzed in the EORTC trial. In the SWOG trial, quality of life was assessed in a subgroup of patients, but the results are not yet available. Sexual function was not evaluated in either of these two trials. Conclusion. In three randomized trials, immediate postoperative RT improved biochemical/clinical progression-free survival in high-risk patients (Level of evidence, 1.ii) but had no significant influence on metastasis-free survival or overall survival. The followup of the EORTC trial was too short and the SWOG trial appeared to be underpowered to validly assess overall survival. The power of the SWOG trial is open to question because the primary endpoint was initially metastasis-free survival but a lower-than-expected event rate prompted extension of the follow-up period and changed the number of patients for inclusion. Above all, the statistical analysis in the SWOG trial was one-sided in contrast to the two-sided test in the EORTC study. Given the median metastasis-free survival observed in the SWOG’s ‘‘wait and see’’ arm, a two-sided analysis with an HR of 1.25 would have required the inclusion of 2,900 patients (10). These two trials used different inclusion criteria. About 33% and 11% of the patients in the SWOG and EORTC trials, respectively, had a detectable persistent PSA level after surgery and therefore should have been classified as having undergone postoperative RT rather than adjuvant RT (9, 10). In the German trial, patients with a detectable PSA level were excluded from the study after randomization and underwent RT (11). This prompts us to suggest that to correctly evaluate adjuvant RT, only patients with no detectable disease (i.e., with undetectable PSA levels) should be selected. Although immediate postoperative RT benefited all treated patients in the German and SWOG trials (10, 11), the benefit appeared to be greatest in patients with positive surgical margins (13). However, a large proportion of the pathology specimens in the SWOG trial were not centrally reviewed. We believe that adjuvant RT should be considered for patients with Stage pT3 tumors with negative margins. A central review might help to accurately evaluate the role of histologic findings (i.e., grade and stage) in general and that of positive surgical margins in particular, as in the subset analysis in
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the EORTC trial (13). Likewise, we suggest performing a meta-analysis of the individual data from the three trials to refine the prognostic factors; the analysis of the data from pooled patients with undetectable PSA levels should be of particular interest. In routine clinical practice, pathologists might have to reduce interobserver variability as much as possible. Although low-grade morbidity was significantly greater in the postoperative RT groups, no severe toxicity has been observed (Level of evidence, 1.ii). Postoperative RT appears to have a slight influence on postprostatectomy continence and stricture (Level of evidence, 1.ii).
Salvage RT Salvage RT of the prostatic fossa can be used in patients with biochemical recurrence after prostatectomy. Numerous noncontrolled studies have been published. The biochemical progression-free survival in patients with nonpalpable recurrence has varied from 10% to 55% at 5 years (16–34) (Table 2). In the published data, RT has been limited to the prostatic fossa; conformal and intensity-modulated RT should enable more tailored treatment, and guidelines for target volume definitions have recently been published (35–37). In a salvage setting, a dose of 64–68 Gy is recommended (20, 33). However, the influence of the administered dose on biochemical progression-free survival has only been studied retrospectively; therefore, randomized, dose-escalation studies (up to about 70 Gy) are necessary (38, 39). A recent retrospective study revealed superior biochemical relapse-free survival in patients with a high risk of lymph node invasion treated with whole pelvic RT compared with prostatic bed RT; this advantage was only observed in cases of ADT (40). However, given the lack of high-quality prospective data (particularly concerning toxicity), whole pelvic postoperative RT should, we believe, only be used with great caution in routine clinical practice, and inclusion of this topic in clinical trials should be favored. In palpable recurrent disease, the efficacy of salvage RT appears to be limited (16, 41, 42). Most retrospective studies have enabled the definition of prognostic factors for biochemical recurrence-free survival using univariate analysis only (because of the low number of patients). However, multivariate analysis has been possible in some studies with larger
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sample sizes (16, 19, 21, 22, 24, 25, 28–34, 40) and has yielded the following prognostic factors: preprostatectomy and pre-RT PSA levels, PSA doubling time, interval to PSA failure, Gleason score, margin status, and seminal vesicle invasion. Despite its retrospective design, one particular multicenter study merits further attention. In 2004 and 2007, Stephenson et al. (32, 33) published a multicenter series, with the more recent study featuring 1,540 patients. All patients had a pre-RT PSA level of $0.2 ng/mL at $6 weeks after radical prostatectomy followed by another still greater value, or a single PSA level of $0.5 ng/mL. The median preprostatectomy and pre-RT PSA level was 10.5 ng/mL (interquartile range, 6.6–19) and 1.1 ng/mL (interquartile range, 0.6–2.2), respectively. Extracapsular extension, positive surgical margins, seminal vesicle invasion, and positive lymph nodes were present in 65%, 51%, 24%, and 3% of the patients, respectively. The median radiation dose was 64.8 Gy (interquartile range, 63–66). Fourteen percent of the patients had undergone ADT before and/or during RT, for a median duration of 4 months. With a median follow-up of 53 months, the progression-free survival rate at 6 years was 32%. A multivariate analysis confirmed that the PSA level before RT, Gleason grade, PSA doubling time, surgical margin status, use of ADT, and lymph node metastasis were all significant prognostic factors. The 6-year disease-free survival rate was 48%, 40%, 28%, and 18% in patients with a PSA level <0.5, 0.5–1, 1–1.5, and >1.5 ng/mL, respectively. The most favorable case for salvage RT would be a patient with a low PSA level before RT, a Gleason score of 4–7, positive surgical margins, and a PSA doubling time >10 months (33). Salvage RT can be considered in some patients with a few unfavorable prognostic factors (greater Gleason score and/or shorter PSA doubling time) despite the greater risk of metastatic disease, because this approach gives a lasting response in around one-third of these individuals (33). In summary, salvage RT is effective in biochemical relapse after prostatectomy (Level of evidence, 3.ii). The prognosis factors are well known (Level of evidence, 3.ii) and enable the selection of patients for salvage RT, systemic treatment, or inclusion in clinical trials. Recent data argue in favor of early salvage RT in patients with a PSA level <1 ng/mL or even 0.5 ng/mL, although uniform criteria for defining biochemical recurrence after radical prostatectomy are still lacking. At present, debate continues as to whether the PSA
Table 2. Results for salvage radiotherapy after biochemical recurrence from selected studies Investigator
Patients (n)
Median PSA (ng/mL)
Median dose (Gy)
Biochemical recurrence-free survival
Catton et al. (16) Cadeddu et al. (17) Garg et al. (18) Pisansky et al. (19) Anscher et al. (20) Leventis et al. (21) Chawla et al. (22) Taylor et al. (23) Buskirk et al. (24) Kalapurakal et al. (25) Tsien et al. (26) Peyromaure et al. (27) Hagan et al. (28) Pazona et al. (29) Ward et al. (30) Stephenson et al. (33) Neuhof et al. (34)
22 82 78 166 89 49 54 71 368 41 57 62 91 307 211 1,540 171
2.8 4.1 1.2 0.9 1.4 2.1 1.3 0.8 0.7 0.5 1.2 2.5 4.5 0.8 0.6 1.1 1.1
60 64 66 64 66 66 64.8 70 64.8 65 65 65 64 64 64 65 60–66
19% at 5 y 10% at 5 y 65% at 3 y 46% at 5 y 50% at 4 y 24% at 5 y 35% at 5 y 66% at 5 y 35% at 8 y 57% at 5 y 30% at 8 y 42% at 5 y 55% at 5 y 40% at 5 y; 25% at 10 y 34% at 10 y 32% at 6 y 35% at 5 y
Abbreviation: PSA = prostate-specific antigen.
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level to determine recurrence after prostatectomy should be $0.2 or $0.4 ng/mL. In 2004, the Prostate Specific Antigen Working Group stated that the minimal value for considering a patient to be eligible for secondary treatment was 0.4 ng/mL confirmed by a subsequent test result of $0.4 ng/mL; this threshold was determined by the supposition that patients with a PSA of $0.4 ng/mL are at a greater risk of systemic relapse (43). These results were recently confirmed in a trial that evaluated 10 definitions for predicting metastatic progression in 3,125 patients who had undergone radical prostatectomy (44). The four best definitions for predicting metastatic progression were a PSA level of $0.4 ng/mL and increasing, a PSA level of $0.2 ng/mL and increasing, a single PSA measurement of $0.6 ng/mL, and a single PSA measurement of $0.4 ng/mL. These definitions were also associated with a greater risk of PSA progression and secondary treatment. Concerning the risk of secondary treatment or clinical recurrence, two different definitions (a PSA level of $0.4 ng/mL and increasing and a PSA level of $0.2 ng/mL and increasing) displayed similar sensitivity and specificity. In these 3,125 patients, the 7-year probability of secondary treatment or clinical recurrence using these same two definitions was 62% (95% confidence interval, 54–70) and 64% (95% confidence interval, 57–71), respectively (44). Consequently, the more sensitive definition (PSA level $0.2 ng/mL and increasing) is more appropriate in patients who are presumed to have local recurrence and who are eligible for salvage RT. When salvage RT is indicated using a more sensitive definition, it will necessarily be initiated sooner in the disease course. To date, salvage RT is the only potentially curative treatment for patients with an increasing PSA level. We believe that systemic treatment or inclusion in chemotherapy clinical trials should only be considered if salvage RT has failed to stop the recurrence. Our view even extends to salvage RT for patients with one or two adverse prognostic factors (e.g., Gleason score 8–10 and/or a PSA doubling time of <10 months, despite a low PSA level and positive surgical margins). Progression-free survival was seen in about onethird of such patients after salvage RT (33). Patients with a worse prognosis should be considered for ADT or inclusion in clinical trials, rather than for salvage RT. Immediate postoperative and salvage RT have not been compared in a prospective, controlled trial. Only retrospective data are available (16, 23, 25, 28, 45, 46); hence, no conclusions could be drawn. Supporters of salvage RT alone argue that the benefit of this technique when applied early (with a biochemical relapse-free survival rate of around 50%, with a PSA level <0.5 ng/mL) appears to be similar to that of postoperative RT (an improvement in progression-free survival of about 40–50%). They also state that salvage RT avoids giving postoperative RT to patients who do not need it. Given our current state of knowledge, this position (outside of a clinical trial) is overassertive, because the levels of evidence underpinning the two approaches are not the same (three randomized studies of postoperative RT but only retrospective studies of salvage RT). The comparison of prospective and retrospective studies with differing inclusion criteria and patients treated at different points is not reliable. Even though postoperative RT means treating patients who might not otherwise have developed a recurrence (i.e., between 36% and 54% of recurrence-free survival rates in the ‘‘wait and see’’ arms of the three randomized trials [9–11]), one potential disadvantage of salvage RT is that it misses patients (about 1 in 2, even with a PSA level <0.5 ng/mL) whose recurrence could have been prevented by postoperative RT. Only randomized trials will be able to validly compare postoperative RT and salvage RT; therefore, inclusion in the ongoing studies of this type should be encouraged.
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The design of the three published randomized trials does not enable us to answer this question, because salvage RT was not planned in the ‘‘wait and see’’ arm. The Radiotherapy and Androgen Deprivation in Combination after Local Surgery (RADICALS) is a randomized trial addressing the questions of the timing of RT (immediate vs. salvage) and the duration of ADT (none vs. 6 months vs. 24 months). Patients can be entered into one or both randomizations, and the inclusion of 4,000 patients is scheduled (47). The Groupe d’Etude des Tumeurs Uro-Genitales 17 trial is set to open soon; this France-based, randomized trial will compare immediate postoperative and salvage RT in Stage pT3, R1, pN0, and pNx patients; a 6month luteinizing hormone-releasing hormone (LHRH) analog treatment will be combined with RT in both arms. For patients with increasing PSA after prostatectomy, we need new ways to identify those presenting with local and/or metastatic recurrence. This issue is all the more tricky when the PSA level is low and the recurrent disease is low in volume. 111 In-capromab pendetide (ProstaScint) has been evaluated retrospectively in several studies. The results have been mixed, with some studies showing a better prognosis in the absence of uptake or solely intrapelvic uptake (48, 49), and others failing to reveal any link between the radioimmunoscintigraphy results and biochemical progression-free survival (50–53). The 11C-choline positron emission tomography technique appears to be of use but is handicapped by the cameras’ low spatial resolution—this makes it difficult to detect low-volume lesions and results in a poor negative predictive value (54). Magnetic resonance imaging enables the sensitive, specific detection of local recurrence (55), and dynamic contrast-enhanced magnetic resonance imaging and proton magnetic resonance spectroscopy imaging could further improve these results, particularly in patients with the lowest PSA levels (56). However, in the foreseeable future, the benefit of imaging is likely to remain moderate in patients with very low PSA levels (<0.5 ng/mL), given that none of the techniques have sufficient resolution to detect microscopic local, locoregional, or metastatic disease. In the future, biomarker profiling might prompt the development of treatments that are better tailored to each patient by providing a more detailed description of the state of disease progression (57, 58).
The addition of ADT to immediate postoperative RT and salvage RT In an adjuvant setting, the RTOG 85-31 trial evaluated the effect of ADT up to relapse vs. ADT at relapse in RT patients with an unfavorable prognosis. Patients who had undergone prostatectomy were eligible if penetration through the capsule and/or seminal vesicle invasion was documented. Patients were stratified at randomization according to the treatment type (i.e., prostatectomy or no prostatectomy). A total of 139 patients (15%) had undergone prostatectomy. Immediate adjuvant ADT improved disease-free survival and overall survival, both in the population as a whole and in patients who had undergone previous prostatectomy (59). In a secondary analysis, the biochemical failure rate (defined as a PSA level >0.5 ng/mL) was 65% and 42% in patients who received combination therapy and RT alone, respectively (p = 0.002). Local control, distant failure, and overall survival did not differ significantly (60). Although the findings of a retrospective trial argue in favor of adjuvant ADT with postoperative RT (61) (Level of evidence, 3.ii), the results of ongoing trials (e.g., the Radiotherapy and Androgen Deprivation in Combination after Local Surgery study) are eagerly awaited (47). The RTOG 00-11 study was a three-arm adjuvant trial (RT alone, RT plus LHRH agonist for 2 years, LHRH agonist alone for 2 years) but was closed prematurely owing to poor accrual (62).
Adjuvant and salvage RT after prostatectomy d D. PASQUIER AND C. BALLEREAU
In a salvage RT setting, some retrospective findings argue in favor of adjuvant ADT (Level of evidence, 3.ii) (33, 63, 64). In the series reported by Stephenson et al. (33), ADT before or during RT improved the 6-year progression-free probability on multivariate analysis. The results of the RTOG 96-01 randomized trial comparing RT in the presence and absence of 2 years of postprostatectomy ADT in patients with elevated (persistent or relapsing) PSA levels are now awaited (65). The recently opened RTOG 0534 three-arm, randomized, salvage RT trial is evaluating prostatic bed RT alone, prostatic bed RT with short-term (4–6 months) ADT, and pelvic node RT with short-term ADT (66). The GETUG 16 randomized trial comparing salvage RT in the presence and absence of ADT (administration of an LHRH analog for 6 months) is also ongoing (67).
CONCLUSION Immediate postoperative RT improves biochemical and clinical progression-free survival in high-risk patients in ran-
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domized trials but has no significant influence on metastasisfree survival or overall survival. The pathologic review of surgical margins is of particular importance in analyzing treatment choices. No severe toxicity has been observed. Although the effect of immediate postoperative RT on continence is a topic of debate, prospective data have not shown any significant deleterious influence on this symptom. Immediate postoperative RT should be considered in patients with major risk factors for local relapse. Salvage RT is effective in terms of biochemical recurrence but its use has only been supported by retrospective data. The question of the equivalence between immediate postoperative and early salvage RT has not been resolved, and randomized trials are ongoing. The addition of ADT to immediate postoperative or salvage RT must be evaluated in randomized trials before being used in routine clinical practice.
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