A practice guideline report on adjuvant RT following prostatectomy in patients with pT3 or margin-positive prostate cancer was originally completed by the Program in Evidence-Based Care Genitourinary Disease Site Group (PEBC GU DSG) in February 2008. The systematic review, as originally published in February 2008, can be found in Section 2B of this Evidencebased Series. A systematic review manuscript based on that report was published in July 2008 (1). With the availability of new evidence, the GU DSG chose to conduct an update of the evidence and recommendations in the fall of 2009. A review of the evidence published since February 2008 is presented here, Section 2A, of this report.
The evidence-based series guidelines developed by Cancer Care Ontario's PEBC use the methods of the Practice Guidelines Development Cycle (2). For this project, the core methodology used to develop the evidentiary base was the systematic review. Evidence was selected and reviewed by two members of the GU DSG and methodologists.
This systematic review is a convenient and up-to-date source of the best available evidence on the role of adjuvant RT following prostatectomy in patients with pathologic T3 or margin-positive prostate cancer. The body of evidence in this review is primarily comprised of randomized controlled trial (RCT) data; therefore, recommendations by the DSG are offered. That evidence, along with the original evidence reviewed in Section 2B, forms the basis of a clinical practice guideline developed by the GU DSG found in Section 1 of this evidence-based series. The systematic review and companion recommendations are intended to promote evidence-based practice in Ontario, Canada. The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the PEBC is editorially independent from its funding source.

# Literature Search Strategy
Relevant articles published since February 2008 were identified by searches of MEDLINE (2008 -September 2009 week 1), EMBASE (2008 -2009 week 37), and the Cochrane Library (2009, Issue 4). The updated MEDLINE and EMBASE search strategies are detailed in Appendix 1.
The conference proceedings of the 2008 and 2009 annual meetings of the American Society of Clinical Oncology, the American Society for Radiation Oncology, the American Urological Association, and the European Association of Urology were also searched for relevant trials.

# Study Selection Criteria
The study selection criteria used in the original systematic review (See Section 2B) were adopted for the 2010 update. This included RCTs, systematic reviews, or clinical practice guidelines in which adjuvant RT in the immediate postoperative period after radical prostatectomy was compared to observation, with other therapies including RT and ADT held in reserve for salvage. The patients had prostate cancer and were found at prostatectomy to have either extracapsular extension (now more commonly referred to as extraprostatic extension), seminal vesicle invasion, positive surgical resection margins, or more than one of these features.

# Synthesizing the Evidence
Assessment of study quality followed the same procedure as in the original systematic review (See Section 2B).
OS, prostate cancer-specific survival, metastasis-free survival, bPFS, locoregional recurrence-free survival, time to initiation of ADT, acute and late toxicity, and quality of life were the outcomes of interest, as in the original systematic review. When data were available on these outcomes from two or more trials, meta-analysis of the trial data was planned using the Review Manager software (RevMan 5.0.22) provided by the Cochrane Collaboration. 1 

# Literature Search Results
In the original search, a total of 14 reports (3-16) representing three randomized trials satisfied the eligibility criteria. The main reports of the two trials were published as full articles (6,10) and the other trial was published as an abstract (14).
A literature search update was conducted in September 2009. New reports of two RCTs contributed to the evidence base: longer term follow-up of the Southwest Oncology Group (SWOG) 8794 trial (17), and the full publication of the German Cancer Society ARO 96-02/AUO AP 09/95 trial (18), previously available only as a meeting abstract. Post-hoc analyses of the SWOG trial were also identified (19,20). Three systematic reviews (21)(22)(23) and a practice guideline (24) met the selection criteria, but did not contain any new trials. A Cochrane review protocol (25) was identified, but the systematic review is not yet available.

# Trial Characteristics
No new results from the European Organization for the Research and Treatment of Cancer (EORTC) 22911 trial (6) have been published since the original version of the systematic review was completed. The GU DSG contacted the EORTC trial committee in October 2009 and at that time there was no definite timeline in place for an updated trial report. While the initial report of SWOG 8794 (10) was based on analysis at a median followup of 10.6 years, the updated report published in 2009 (17) extends median follow-up to 12.6 years. The ARO/AUO trial was published in a full report in 2009 (18). Study characteristics in the updated reports remained the same as the original reports. Major characteristics of the three trials (6,17,18) are summarized in Table 1. The updated trial data are shown in italics. 

# Trial Quality
The results of the trial quality assessment are summarized in Table 2. The three trials met all of the trial quality criteria. 
The updated report on the SWOG trial (17) presented new data for the outcomes of OS and metastasis-free survival. The ARO/AUO trial (18) did not provide new time-to-event analyses beyond those reported in the 2007 abstract. Trial results are summarized in Table 3, and proceeding text only addresses outcomes with updated results. 

# Overall Survival
While the original 2006 report of the SWOG trial (10) showed no difference between treatment groups for OS, the updated report in 2009 (17) showed a significant improvement in overall survival with adjuvant RT (hazard ratio 0.72; 95% confidence interval 0.55 to 0.96; p=0.023). At the time of the update, 88 of 214 men randomized to adjuvant RT had died versus 110 of 211 men randomized to observation. Ten-year OS was 74% and 66% for those randomized to adjuvant RT and observation, respectively. Median survival was 15.2 years with adjuvant RT and 13.3 years with observation.
No new results from the EORTC 22911 trial have been published since the initial version of this review was completed. Only short term (five-year) results from the 2005 trial publication are available (6). At the time of publication, 43 deaths had occurred in the observation arm and 46 deaths in the adjuvant RT arm (HR, 1.09; 98% CI, 0.67 to 1.79; p=0.6796). This represents an event rate for death of only 8.9%. In view of the immaturity of these results, the GU DSG felt that inclusion of these data in a meta-analysis was inappropriate and no such meta-analysis has therefore been undertaken. Longer term results from the EORTC trial are awaited and once available will be incorporated into a meta-analysis with the SWOG 8794 results.

# Metastasis-Free Survival
Only the SWOG trial (17) provided data on this outcome. In the updated report, adjuvant RT reduced death or metastatic disease by 29% compared with observation (HR, 0.71; 95% CI, 0.54 to 0.94; p=0.016). Ten-year metastasis-free survival was 71% in those randomized to adjuvant RT and 61% in those randomized to observation.

# Acute and Late Toxicity
The full report of the ARO/AUO trial (18) did not report early and late toxicity data separately; instead, cumulative rates of toxicity over the entire follow-up period were reported. In the adjuvant RT group, one patient experienced grade 3 GU (bladder) adverse effects, three patients (2%) experienced grade 2 GU adverse events, and two patients (1.4%) experienced grade 2 gastrointestinal adverse effects. No adverse effects  grade 2 were experienced by the observation group. Overall, the cumulative rate of adverse effects for bladder and rectum  grade 1 was 21.9% in the adjuvant RT group and 3.7% in the observation group (p<0.0001). The updated report of the SWOG trial (17) did not include toxicity outcomes.

# Subgroup Analyses
The three trials included in this review enrolled patients with positive surgical margins, extracapsular extension, or seminal vesicle invasion. (Strictly speaking, it should be noted that a positive margin alone was not sufficient for entry into the ARO/AUO trial if unaccompanied by pathologic T3 disease.) It is therefore of interest to assess the relative benefit of adjuvant RT in subgroups defined by the presence or absence of these characteristics. Exploratory analyses across these pathologic subgroups have been published for each of the three trials. Two subgroup analyses of the EORTC trial (8,26) were considered in the initial version of this systematic review, and no further analyses have since been published. The first report (26) included all patients enrolled in the trial and used local pathology data while the second report (8) was limited to approximately half of study patients (n=552) in whom a central pathology review was performed. In each report, bPFS was the outcome of interest and analysis was performed at a median follow-up of five years. Two subgroup analyses of the SWOG trial (one published report considering those patients enrolled in the trial with seminal vesicle invasion (19) and the other an abstract considering those free of seminal vesicle invasion (20)) have appeared since February 2008. Finally, the published ARO/AUO trial report included a subgroup analysis of all trial participants performed at a median follow-up of 4.5 years (18). The outcome of interest was bPFS. The analysis took account of a central pathology review in 85% of cases, while local pathology review was employed for the remaining 15% of cases.
In each of the three trials, randomization was stratified with respect to these pathologic characteristics, whether considered singly or in combination (see Table 1). Hence, the adjuvant RT and observation arms in each trial are likely to be well balanced with respect to these characteristics. In addition, the definitions of bPFS employed across the three trials were similar. In view of this, meta-analysis of the bPFS subgroup data was performed by members of the GU DSG and is to be presented at the 2010 annual meetings of the Canadian Association of Radiation Oncology (27) and the American Society for Radiation Oncology (28). It should be noted that, of the two published post-hoc analyses of the EORTC trial (8,26), results of the one that included all trial patients (26) were included in the meta-analysis. The analysis included previously unpublished data provided by the SWOG trial investigators. These data included subgroup analyses of bPFS and OS by pathologic subgroup. Results of the pooled analysis of bPFS outcomes are summarized in Table 4, with the OS outcome data provided by the SWOG trial investigators. It is remarkable that the OS benefit of adjuvant RT observed in the overall SWOG trial population also extends to the subgroup of patients with positive surgical margins (HR, 0.68; 95% CI, 0.49 to 0.94); the subgroup with extracapsular extension (HR, 0.62; 95% CI, 0.46 to 0.84); and the subgroup with seminal vesicle invasion (HR, 0.57; 95% CI, 0.35 to 0.93). Stated alternatively, each of the three constituent pathologic subgroups included in these trials experienced a significant survival benefit from adjuvant RT that was independent of the others.
An additional comment is necessary regarding the group free of extracapsular extension. This is the only subgroup in which the HR for OS favoured observation. Absence of extracapsular extension in this context should not be assumed to be synonymous with pT2 R1 disease. As pathologic variables were coded independently in the SWOG trial database, the extracapsular extension-absent subgroup is a collection of patients with either pT2 R1 disease or pT3b R0-1 disease without coexisting capsular extension. As such, this is a very heterogeneous group, that is not representative of the population at large with organconfined, margin-positive disease, and the result is therefore not generalizable to it. It is also a small subgroup (n=85), as evidenced by the broad confidence interval. Finally, the possibility exists that this is a spurious result that has arisen from an exploratory analysis involving multiple comparisons.
For these reasons, the GU DSG cautions against overinterpretation of the outlying result seen in this subgroup.
It is noteworthy that in all six subgroups examined (positive and negative surgical margins, presence and absence of extracapsular extension, and presence and absence of seminal vesicle invasion), adjuvant RT conferred a statistically significant benefit in terms of bPFS. The magnitude of benefit was broadly similar across all groups, with the pooled HR ranging from 0.45 (in the case of patients with positive margins) to 0.61 (in the case of patients with negative margins). The finding of benefit across all subgroups conflicts with both the EORTC subgroup analysis based on central pathologic review (8) and the ARO/AUO subgroup analysis (18), in which the margin-negative population did not benefit from adjuvant RT.
It should be acknowledged finally that the population of patients enrolled in these trials with positive surgical margins may not be representative of the general population at large with positive margins following prostatectomy. While a positive margin alone was sufficient for entry into the EORTC and SWOG trials (pT3 disease was a requirement for entry into the ARO/AUO trial), relatively few patients whose only adverse feature was a positive margin were enrolled. For example, in the EORTC trial, 629 of the 1005 enrolled patients possessed positive surgical margins. Among these, in only 163 cases (26%) was the positive margin the only adverse feature present (i.e., pT2 R1 disease), while in the remaining 466 cases (74%) the positive margin occurred in the presence of either extracapsular extension of seminal vesicle invasion (i.e., pT3 R1 disease). Additional study of the impact of adjuvant radiotherapy in patients with organ-confined, margin-positive disease is therefore warranted.

# INTERPRETATION AND DISCUSSION
Since the initial publication of this systematic review in 2008, updated results from one of the three included RCTs (17) are now available. At a median follow-up of 12.6 years, adjuvant RT has now been shown to confer a significant benefit in terms of both OS and metastasis-free survival. The significance of these findings warrants re-statement; for the first time, a largescale RCT has shown that an adjuvant therapy given after prostatectomy improves longevity and reduces distant failure compared to a policy of observation and salvage therapy. The magnitude of the observed benefit is substantial; median survival is prolonged by 1.9 years with adjuvant RT. A number-needed-to-treat analysis reveals that, compared to the observation and salvage strategy employed in the trial, nine courses of adjuvant RT are required to prevent one death by 12.6 years of median follow-up. Placed in context, this is similar to the magnitude of benefit seen with post-mastectomy RT given for node-positive breast cancer (29)(30)(31).
Results from the EORTC trial are not sufficiently mature to draw conclusions regarding the effect of adjuvant RT on OS in this trial. At a median follow-up of five years, only 8.9% of trial participants had died at the time of the most recent report (6). Longer term results from this trial and from the ARO/AUO trial-in which only 4% of patients have died to date-are awaited. Updates of this systematic review, and the clinical practice guideline of which it forms the basis, will be undertaken once new survival data are available.
In terms of pathologic findings, a fairly heterogeneous population of patients was enrolled in each of the three trials. They included men with positive resection margins, capsular breach, or seminal vesicle invasion, and no limitations were placed on Gleason score. The results of subgroup analysis of the SWOG trial with OS as primary endpoint are striking; the benefit in OS conferred by adjuvant RT applies not only to the trial population as a whole, but also to the individual populations of patients with a positive surgical margin, extracapsular extension, or seminal vesicle invasion when considered separately. Further, the pooled subgroup analysis of the three trials with bPFS as primary endpoint demonstrates a clear and statistically significant benefit for adjuvant RT in all subgroups. This is a new finding and is at odds with previously published post-hoc analyses of the EORTC ( 8) and ARO/AUO ( 18) trials wherein no significant bPFS benefit was seen in patients with pathologic T3 disease but negative surgical margins. On the basis of the overall trial findings as well as these subgroup analyses, it can be concluded that men found at radical prostatectomy to have any of positive surgical margins, extracapsular extension, or seminal vesicle invasion benefit from adjuvant RT. As noted above, further study of those patients with organconfined, margin-positive disease is warranted to better define the impact of adjuvant radiotherapy in this setting.

# ONGOING TRIALS
While updated results from the SWOG trial ( 17) indicate the clear superiority of adjuvant RT over the observation and salvage therapy policy employed in the trial, it remains uncertain whether the superiority of adjuvant RT would remain if it were compared to a strict policy of close surveillance with salvage RT initiated at the earliest sign of biochemical recurrence. The latter approach holds the potential advantage of avoiding RT, and its side effects, in those that do not ultimately recur biochemically following surgery. Determining which of these approaches is optimal requires well-designed phase III trials. Fortunately, three such RCTs comparing adjuvant and early salvage approaches to postoperative RT are now underway. Features of these trials, which were identified on a search of the National Cancer Institute trials registry at clinicaltrials.gov, are summarized below. The GU DSG will monitor the progress of the trials and review reported results when they become available.

# Protocol ID Title and details of trial MRC/NCIC-RADICALS-PR10 NCT00541047
Phase III randomized study of immediate vs. early salvage radiotherapy (RT) and short-vs. long-term androgen deprivation therapy in patients who have undergone local surgery for non-metastatic adenocarcinoma of the prostate.
1) RT timing randomization Arm I -immediate RT; Arm II -early salvage RT in case of PSA failure. In both arms, RT is delivered, according to clinician preference, either to 66 Gy in 33 fractions or 52.5 Gy in 20 fractions to the prostate bed.
2) Hormonal therapy during randomization Arm I -0 months; Arm II -6 months; Arm III -24 months. During the pilot phase, patients may elect to be randomized between only 2 of these 3 arms. 
In the only RCT for which long-term follow-up data are available, adjuvant RT following radical prostatectomy in patients with pathologic T3 or margin-positive prostate cancer has been shown to improve OS and reduce distant metastases compared to observation. The OS benefit extends individually to the subgroups with positive surgical margins, extracapsular extension, and seminal vesicle invasion. Longer follow-up from the other two completed RCTs is awaited and this review will be updated once new data become available.

# CONFLICT OF INTEREST
There are no known conflicts of interest.

# Funding The PEBC is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care
Ontario. All work produced by the PEBC is editorially independent from its funding source.
Copyright This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.