Contemporary treatment options for patients with clinically localized prostate cancer include radical prostatectomy, radiotherapy, and active surveillance. Surgery can be curative for approximately two-thirds of patients choosing radical prostatectomy.1 However, men with adverse pathologic findings at the time of radical prostatectomy, such as the presence of positive surgical margins, extraprostatic extension, or seminal vesicle invasion,2,3 experience up to a 60% risk of recurrence at 10 years and may require subsequent radiation therapy.2
In three well-powered randomized controlled trials, adjuvant radiotherapy was associated with a lower risk of recurrence for men with adverse pathologic findings at the time of surgery, compared to a ‘watch and wait’ approach (SWOG S8794,4,5 EORTC 229116,7 and ARO 96-028,9). A randomized multi-institutional study of adjuvant radiotherapy for pathologically-advanced prostate cancer after radical prostatectomy (SWOG S8794), post-operative radiotherapy (P-RXT) after radical prostatectomy (Px) improves progression-free survival (PFS) in pT3NO prostate cancer (PC) (EORTC 22911), and a Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: (ARO 96-02/AUO AP 09/95). On the basis of these studies, joint guidelines were published by the American Urological Association (AUA) and the American Society for Radiation Oncology (ASTRO) recommending adjuvant radiotherapy for patients with adverse pathologic findings.2 More recently, the FINNPROSTATE trial, "Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension (FINNPROSTATE)", was published, addressing a similar question and yielding similar results.10 In a recent meta-analysis including all four of these trials, use of adjuvant radiotherapy (compared to a permissive post-operative treatment approach with late salvage) was associated with consistent, and statistically significant, improvements in biochemical recurrence-free survival, but uncertain benefits in metastasis-free survival and no benefit in overall survival.11 Further, this analysis demonstrated that the routine use of an adjuvant approach is associated with high rates (35-60%) of overtreatment. Thus, in spite of the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) guidelines, many experts do not support the routine use of adjuvant radiotherapy,12,13 due to concerns of overtreatment with associated toxicity, and due to limitations in the design, analysis, and interpretation of these studies.
Another commonly utilized strategy is salvage radiotherapy in which radiation is only administered at the time of early recurrence. Salvage radiotherapy has been shown to provide durable cancer control rates for patients at high risk for progression to metastasis14 and to decrease the risk of prostate cancer-related mortality compared with observation.15 The benefit is maximized when radiotherapy is administered early following recurrence detected by a rise in the serum prostate-specific antigen (PSA) (biochemical recurrence),15,16 so-called early salvage radiotherapy.
Until very recently, there were no randomized data to compare adjuvant and early salvage radiotherapy. Observational data and decision modeling analyses had suggested equivalence of these two approaches,17 with benefits to the salvage therapy approach due to lower rates of toxicity and resource utilization.
Following presentation at the European Society of Medical Oncology (ESMO) 2019 meeting, four relevant manuscripts have been published to address this question including three randomized controlled trials and a prospectively planned meta-analysis of these data. The remainder of this manuscript will detail these studies.
Randomized Controlled Trials: RADICALS-RT, GETUG-AFU 17, RAVES
RADICALS-RT18
The RADICALS-RT, "Timing of radiotherapy after radical prostatectomy (RADICALS-RT)", randomized controlled trial was an international, Phase III, multicenter, open-label trial implemented at 138 trial-accredited centers in Canada, Denmark, and the United Kingdom. Patients with non-metastatic adenocarcinoma of the prostate were eligible for the trial if they had undergone radical prostatectomy, had postoperative PSA of 0.2 ng/mL or less, and at least one specified risk factor (ie. pathological T-stage 3 or 4, Gleason score 7–10, positive margins, or preoperative PSA of 10 ng/mL or more). Participants were randomly assigned within 22 weeks after radical prostatectomy to receive either adjuvant radiotherapy to the prostate bed with or without pelvis, or close observation with salvage radiotherapy to the prostate bed with or without pelvis given in the event of PSA biochemical progression, defined as either two consecutive rising PSAs with a PSA of ≥ 0.1 ng/mL, or three consecutive rising PSAs. Radiotherapy to the prostate bed used a dose-fractionation schedule of either 66.0 Gy in 33 fractions or 52.5 Gy in 20 fractions.
The primary outcome for RADICAL-RT was disease-specific survival and a key secondary outcome was freedom from distant metastases. In 2011, the primary outcome of RADICALS-RT was changed to freedom from distant metastases following a review of the expected event rate based on other publications. Biochemical progression-free survival was defined as freedom from PSA of 0.4 ng/mL or greater following postoperative radiotherapy, or PSA of more than 2.0 ng/mL at any time, or clinical progression, or initiation of non-protocol hormone therapy, or death from any cause. The trial had ~80% power to detect a hazard ratio of 0.70 if 5-year biochemical progression-free survival was 0.86 in the early salvage group. All analyses were done on an intention-to-treat basis.
This trial accrued 1,396 patients over 9 years from November 22, 2007, through December 30, 2016, with participants being randomly assigned to an adjuvant radiotherapy (n=697) or salvage radiotherapy policy (n=699). The median age was 65 years (IQR 60–68) and the median PSA at diagnosis was 7.9 ng/mL. Median PSA at randomization was undetectable in both randomized groups, and the median follow-up was 4.9 years at the time of data freeze. At the time of analysis, 223 (32%) of 699 patients allocated to the salvage radiotherapy group started radiotherapy within 5 years after randomization. There were 169 biochemical progression events were reported—87 events in patients in the adjuvant radiotherapy group and 82 in patients in the salvage radiotherapy group. There was no difference between the adjuvant and salvage groups in terms of biochemical progression-free survival (hazard ratio [HR] for adjuvant radiotherapy 1.10, 95% confidence interval [CI] 0.81–1.49; p=0.56). The 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group. At the time of analysis, data for the primary outcome measure of freedom from distant metastasis were not sufficiently mature, which was the same for overall survival. Radiation Therapy Oncology Group (RTOG) toxicity events were more commonly reported in the group randomized to adjuvant radiotherapy in comparison with the salvage radiotherapy group. The majority of diarrhea, proctitis, and cystitis events were low severity, with grade 3 or 4 events reported for approximately 1% of patients. Patient-reported outcome measures for urinary and bowel function showed similar results for both groups at baseline, with a small but significant worsening of symptoms with adjuvant radiotherapy one year after randomization, which then normalized in later years.
GETUG-AFU 1719
The GETUG-AFU 17, "Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17)", was a randomized, open-label, multicenter, Phase III trial completed at 46 French hospitals. Inclusion criteria included men with localized adenocarcinoma of the prostate treated with radical prostatectomy with or without pelvic lymph node dissection who had pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection), and those who had positive surgical margins. Patients were randomized (1:1) to either immediate adjuvant radiotherapy or delayed salvage radiotherapy at the time of biochemical relapse. Importantly, postoperative radiotherapy was combined with short-term hormonal therapy in both study groups (6 months of triptorelin). All patients had radiotherapy planned for 7 weeks at a dose of 66 Gy in 33 fractions of 2 Gy, five days per week. Pelvic lymph nodes could be treated at a dose of 46 Gy in 23 fractions of 2 Gy, five days per week. Biochemical relapse before initiating salvage radiotherapy was defined as a PSA level greater than 0.2 ng/mL confirmed after four weeks.
The primary outcome for GETUG-AFU 17 was event-free survival, assessed as the time from random assignment to the first documented event, either disease relapse (locoregional or metastatic), biochemical progression, or death. Secondary outcomes were overall survival, metastasis-free survival, and incidence of acute and late toxic effects. The study was designed to show a 10% increase in the 5-year event-free survival rate, from 60% with early salvage radiotherapy to 70% with adjuvant radiotherapy (HR 0.70).
GETUG-AFU 17 enrolled 424 patients between March 7, 2008, and June 23, 2016, at 46 French centers. The plan was to enroll 718 patients, with 359 in each study group, however, early trial termination was recommended secondary to low event rates. At that time of accrual cessation, only 12 (5%) of 242 events needed for the primary outcome analysis had been reported; at that time 424 patients had been randomly allocated, 212 to the adjuvant radiotherapy group and 212 to the salvage radiotherapy group. At the time of analysis, 54% of patients in the salvage radiotherapy group had initiated radiotherapy after biochemical relapse.
For the primary outcome analysis, 58 events were reported, 25 in the adjuvant radiotherapy group and 33 in the salvage radiotherapy group. The 5-year event-free survival rate was 92% (95% CI 86–95) in the adjuvant radiotherapy group and 90% (85–94) in the salvage radiotherapy group (HR 0.81, 95% CI 0.48–1.36; p=0.42). Although data was not mature, the 5-year overall survival was 96% (95% CI 92–98) in the adjuvant radiotherapy group and 99% (96–100) in the salvage radiotherapy group (HR 1.60, 95% CI 0.71–3.60; p=0·25). Acute toxic effects were reported in 87% of patients in the adjuvant radiotherapy group and 44% of patients in the salvage radiotherapy group. Late genitourinary adverse events were reported by 73% of patients in the adjuvant radiotherapy group and 29% of patients in the salvage radiotherapy group.
RAVES20
The RAVES trial, "Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES)", was a Phase III, randomized, controlled, non-inferiority trial completed at 32 oncology centers across Australia and New Zealand. Eligible patients were at least 18 years of age and had undergone radical prostatectomy for prostate adenocarcinoma with pathological staging showing high-risk features defined as either positive surgical margins, extra prostatic extension, or seminal vesicle invasion. Patients were also required to have a postoperative PSA of 0.10 ng/mL or less, and to be able to start radiotherapy within four months of radical prostatectomy. The dose in both the adjuvant and salvage radiotherapy groups was 64 Gy in 32 fractions. Adjuvant radiotherapy was given within six months of radical prostatectomy and salvage radiotherapy was given within four months of a PSA measurement of 0.20 ng/mL or more. For both groups, biochemical progression was diagnosed on the first occasion following radiotherapy when PSA was 0.40 ng/mL or more and increasing.
The primary endpoint for RAVES was freedom from biochemical progression, and secondary endpoints were time to initiation of androgen deprivation therapy (ADT), time to local, regional, and distant progression, and overall survival. Additional secondary endpoints (not reported in this first analysis) were quality-of-life outcomes, anxiety and depression, adverse events, disease-specific survival, quality-adjusted life-years, and cost-utility. In terms of a power calculation, salvage radiotherapy would be considered to be non-inferior to adjuvant radiotherapy if the 5-year freedom from biochemical progression was at most 10% lower than that for adjuvant radiotherapy (ie. >64%).
Between March 27, 2009, and December 31, 2015, there were 333 patients randomly assigned to treatment adjuvant radiotherapy (n=166) and salvage radiotherapy (n=167); the median follow-up was 6.1 years (IQR 4.3–7.5). In the intention-to-treat analysis, there were 25 biochemical progressions in the adjuvant radiotherapy group and 30 biochemical progressions in the salvage radiotherapy group. The 5-year freedom from biochemical progression was 86% (95% CI 81–92) in the adjuvant radiotherapy group compared to 87% (82–93) in the salvage radiotherapy group (unstratified HR 1.15 [95% CI 0.67–1.95). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (54%) than in the adjuvant radiotherapy group (70%; OR mixed 0.34, 95% CI 0.17–0.68; p=0.0022).
Meta-Analysis: The ARTISTIC Collaborative
As described above, three randomized controlled trials were contemporaneously designed and began accruing to assess the comparison of adjuvant and early salvage radiotherapy strategies, each with a different primary outcome: time free of metastasis (RADICALS-RT), event-free survival (GETUG-AFU 17), and biochemical progression (RAVES). These outcomes were selected as “intermediate” endpoints due to the difficulty of accruing and powering a trial for longer-term survival outcomes. On this basis, a collaborative was struck in 2014 which all three trials were recruiting to allow for a prospectively designed individual patient data meta-analysis of the three trials. As an intermediate step, the group planned an aggregate data meta-analysis which is what has been reported to date.21
Given that each study was designed and powered to assess a different outcome, the collaborative group defined a primary outcome of event-free survival defined as the time from randomization to the first of biochemical progression, clinical or radiographic progression, initiation of non-trial treatments, death from prostate cancer, or PSA ≥ 2.0 ng/mL at any time following randomization.
To summarize the details provided above, all trials required patients to have undergone radical prostatectomy with at least one high-risk feature, defined as stage pT3 or pT4, Gleason score 7-10, pre-operative PSA of 10 ng/mL or greater, or positive surgical margins. All patients were required to have a post-operative PSA of 0.2 ng/mL or less, unlike some of the early adjuvant radiotherapy studies. However, it is important to understand the differences between the trials. In RADICALS-RT, patients were allowed to have pT3 or pT4 disease; in GETUG-AFU 17, patients were required to have pT3 or pT4a disease and positive surgical margins; while RAVES included patients with at least one of positive surgical margins (including among patients with pT2 disease) or extracapsular extension.
In all studies, patients were randomized to receive adjuvant radiotherapy or a surveillance regime with early salvage radiotherapy administered at the time of biochemical recurrence. Treatment regimes, as detailed above, varied somewhat between studies with concomitant ADT being mandated in GETUG-AFU 17, being forbidden in RAVES, and being either at the treating physician's discretion or as part of a second randomization (RADICALS-HT) in the RADICALS trial. Also, notable are differences in study design: while RADICALS-RT and GETUG-AFU 17 were designed as superiority trials, RAVES was designed in a non-inferiority manner.
Characteristics of patients included in the systematic review mirror those of the individual trials as discussed above: patients had a median age between 64-65 years and the majority had either pT3a/b disease (79.8%), positive surgical margins (70.9%), and extracapsular extension (76.9%).
In total, 1075 included patients were randomized to adjuvant radiotherapy and 1078 to an early salvage radiotherapy strategy. Notably, 421 patients (39.1%) randomized to early salvage radiotherapy have, to date, received postoperative radiotherapy. With a data cut-off of April 22, 2020, 270 events had been recorded, the vast majority of which were PSA-driven. Pooling event-free survival results from the three trials yielded an overall fixed effect hazard ratio of 0.95 (95% confidence interval 0.75 to 1.21, p = 0.70) with an absolute difference in five-year event-free survival of 1% (95% confidence interval -2 to 3) between early salvage and adjuvant radiotherapy.
The authors then undertook a variety of pre-planned subgroup analyses. These demonstrated consistent results across subgroups defined on the basis of pre-surgical PSA less than or equal to 10 or greater than 10 ng/mL), Gleason score (7 vs. ≥ 8), seminal vesicle involvement (present vs. absent), surgical margins (positive vs. negative), and Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) risk group (intermediate vs. high) with no benefit seen to the use of adjuvant radiotherapy in any of these groups.
Conclusions
Until recently, there has been a paucity of high-quality data available to delineate the optimal timing of radiotherapy for biochemical recurrence after radical prostatectomy. Data from RADICALS-RT, GETUC-AFU 17, and the RAVES phase 3 trials, in addition to the ARTISTIC prospective systematic review and meta-analysis, have shown that standard of care for treatment of biochemical recurrence should follow an early salvage rather than an adjuvant radiotherapy approach.
Table 1. Comparison of randomized controlled trials of adjuvant versus early salvage radiotherapy
Written by: Christopher J.D. Wallis, MD, PhD, Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee; Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia
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