Studies support early salvage radiotherapy after prostatectomy
medwireNews: Data from the phase 3 RADICALS-RT, RAVES, and GETUG-AFU 17 trials and the ARTISTIC meta-analysis suggest that observation with early salvage radiotherapy should be the standard of care for men undergoing radical prostatectomy for localized or locally advanced prostate cancer.
The authors of the studies explain that although prior clinical trials have shown a benefit of adjuvant radiotherapy versus observation in this population, the findings are difficult to interpret as a large proportion of the observed participants did not receive salvage radiotherapy, and thus the optimal timing of postoperative radiotherapy remains to be determined.
All three of the current trials therefore compared adjuvant radiotherapy, initiated within 3–6 months after surgery, with salvage radiotherapy triggered at a prostate-specific antigen (PSA) level of 0.1 ng/mL or three consecutive rises without reaching this cutoff in RADICALS-RT, at 0.2 ng/mL in RAVES, and at over 0.2 ng/mL in GETUG-AFU 17.
The radiotherapy schedule across both arms was similar in the three studies, delivering either 64 Gy in 32 fractions or 66 Gy in 33 fractions, with RADICALS-RT also permitting a schedule of 52.5 Gy in 20 fractions. A total of 93%, 95%, and 97% of participants in the adjuvant radiotherapy arm of the RADICALS-RT, RAVES, and GETUG-AFU 17 studies, respectively, initiated radiotherapy, as did 32%, 50%, and 54% of those in the salvage radiotherapy arm.
Acknowledging the difficulty of adequately powering the trials to evaluate longer-term outcomes, the investigators teamed up with the ARTISTIC group, who use “a prospective framework for adaptive meta-analysis (FAME), which reduces the likelihood of bias in the selection of studies, assessment of risk of bias, outcome definition, and in the timing and conduct of planned analyses.”
Here we summarize the key results of each of the four studies.
The trial recruited 1396 men who underwent radical prostatectomy for nonmetastatic disease at one of 138 centers in Canada, Denmark, Ireland, or the UK, and had a postoperative PSA level no higher than 0.2 ng/mL and at least one of the following risk factors: pathologic T stage 3 or 4; Gleason score of 7–10; positive margins; or preoperative PSA of at least 10 ng/mL.
After a median follow-up of 4.9 years, biochemical progression-free survival (PFS) was comparable between the adjuvant and salvage radiotherapy groups, with 5-year rates of 85% and 88%, respectively.
The adjuvant and salvage radiotherapy arms also did not differ significantly in terms of initiation of non-protocol hormone therapy, with respective rates of 7% and 8% at 5 years.
Matthew Sydes (MRC Clinical Trials Unit at UCL, London, UK) and co-researchers report in The Lancet that the data remain immature for the trial’s primary endpoint of freedom from distant metastases and overall survival.
The incidence of early (<2 years) and late (≥2 years) Radiation Therapy Oncology Group toxicity was higher among adjuvant- than salvage radiotherapy-treated men, with early grade 3–4 hematuria and urethral strictures observed at rates of 3% versus less than 1%, and 6% versus 4%, respectively.
And patients in the adjuvant group reported “a small but significant worsening” of urinary and bowel function at the 1-year mark, but not at later timepoints, say the researchers.
They therefore conclude: “In the absence of any reliable evidence that adjuvant radiotherapy does more good than harm, observation with salvage treatment for PSA biochemical progression should be the current standard of care after radical prostatectomy.”
For this noninferiority trial, Andrew Kneebone (Royal North Shore Hospital, Sydney, New South Wales, Australia) and colleagues enrolled 333 patients from 32 oncology centers in Australia and New Zealand. Participants had high-risk features – specifically, positive surgical margins, extraprostatic extension, or seminal vesicle invasion – on pathologic staging after radical prostatectomy and a PSA level of 0.10 ng/mL or less.
The median follow-up at the time of data cutoff was 6.1 years, and again there was no significant difference in biochemical PFS between men who received adjuvant radiotherapy and those given salvage radiotherapy, with respective 5-year rates of 86% and 87%.
The investigators highlight that the trial was terminated prematurely due to the “unexpectedly low event rates” and the prespecified criteria to demonstrate noninferiority of salvage radiotherapy were not met.
But they add: “We showed that the plausible range in absolute difference between salvage radiotherapy and adjuvant radiotherapy at 5 years was from 6·8% inferior to 8·7% superior, which satisfied our hypothesis that salvage radiotherapy was not 10% worse than adjuvant radiotherapy at 5 years.”
A significantly higher proportion of patients in the adjuvant than salvage radiotherapy group experienced genitourinary toxicity of at least grade 2 (70 vs 54%), but the rates of gastrointestinal toxicity of this severity were similar (14 vs 10%), as was the incidence of grade 2 or worse erectile dysfunction, which the researchers note was high in both groups (98 vs 96%).
“In conclusion, early salvage radiotherapy results in similar biochemical control to adjuvant radiotherapy, spares approximately half of men from pelvic radiotherapy, and is associated with significantly lower amounts of genitourinary toxicity,” write Kneebone et al in The Lancet Oncology.
GETUG-AFU 17 trial
This trial – which was also reported in The Lancet Oncology and also closed early due to low event rates – was conducted at 46 French hospitals and comprised 424 men with pathologically staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection) disease, positive surgical margins, and a postsurgical PSA concentration no higher than 0.10 ng/mL.
Participants were followed up for a median of 75 months, during which time there was no significant between-group difference in the primary endpoint of event-free survival (EFS); the 5-year EFS rates were 92% and 90% in the adjuvant and salvage radiotherapy arms, respectively.
Overall survival at the 5-year mark was also comparable, with corresponding rates of 96% and 99%, reports the team led by Paul Sargos, from Institut Bergonié in Bordeaux, France.
As observed in the other two trials, adjuvant radiotherapy was associated with higher rates of acute (87 vs 44%) and late (92 vs 42%) adverse events relative to salvage radiotherapy, with significant differences between the groups in the incidence of early and late grade 2 or worse genitourinary, but not gastrointestinal, toxicities.
Sargos and colleagues say that “although our analysis lacked statistical power,” these findings show that “[s]alvage radiotherapy could spare men from overtreatment and associated radiotherapy-induced toxic effects.”
They add: “This delayed approach would be preferred unless adjuvant radiotherapy was superior to salvage radiotherapy according to long-term oncological outcomes.”
The preplanned meta-analysis included data on all 2153 participants of the three trials and found no evidence of improved EFS with adjuvant versus early salvage radiotherapy, where EFS was defined as the first evidence of biochemical PFS (PSA ≥0.4 ng/mL after postoperative radiotherapy), clinical or radiologic progression, initiation of a non-trial therapy, death from prostate cancer, or a PsA level of 2.0 ng/mL at any timepoint after random assignment.
As reported in The Lancet, there was an absolute difference of just 1 percentage point in the 5-year EFS rates between the adjuvant and salvage radiotherapy groups, at 89% and 88%, respectively.
The findings were “broadly consistent across trials,” and there did not appear to be “any indication of a benefit of adjuvant radiotherapy in any of the subgroups assessed,” say Claire Vale (University College London, UK) and co-authors.
“Until data on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy as it offers the opportunity to spare many men radiotherapy and its associated side-effects,” they comment.
The team suggests that “[g]uidelines and policy should be reviewed to reflect this.”
Applicable to all men?
The authors of an accompanying commentary, also published in The Lancet, say that “the four studies represent an important step forward and support the use of early salvage as opposed to adjuvant radiotherapy for many patients after radical prostatectomy.”
But they note that the eligibility criteria of RADICALS-RT, the largest of the three trials, “included patients who would not receive adjuvant radiotherapy in typical clinical practice because of the low risk of recurrence,” possibly diluting a potential benefit of the adjuvant approach.
Moreover, “immortal time bias could have led to missing a benefit of adjuvant radiotherapy in biochemical [PFS] in high-risk subgroups,” such as those with Gleason score 8–10 and pathologic stage T3b or higher, say Derya Tilki (University Hospital Hamburg-Eppendorf, Germany) and Anthony D’Amico (Brigham and Women’s Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, USA).
And they conclude: “Pending longer follow-up of the RADICALS-RT study to evaluate the metastasis-free survival endpoint in high-risk subgroups, we believe it is prudent to consider adjuvant radiotherapy in these patients.”
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Lancet 2020; doi:10.1016/S0140-6736(20)31553-1
Lancet Oncol 2020; 21: 1331–1340
Lancet Oncol 2020; 21: 1341–1352
Lancet 2020; doi:10.1016/S0140-6736(20)31952-8
Lancet 2020; doi:10.1016/S0140-6736(20)31957-7