Many men ‘can safely be spared’ adjuvant radiotherapy after prostatectomy, analysis shows
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Adjuvant radiotherapy after prostatectomy did not improve outcomes compared with observation and salvage radiotherapy for men with prostate cancer, according to results of three studies published in The Lancet and The Lancet Oncology.
A systematic review and meta-analysis of the randomized phase 3 trials, also published in The Lancet, concluded that adjuvant radiotherapy conferred no EFS benefit in localized or locally advanced disease and that men could safely avoid this treatment and related adverse effects, including increased risk for urinary morbidity.
“Our findings suggest that following surgery, patients whose cancer is confined to the prostate, or has spread only to nearby tissues or organs, can safely be spared routine postoperative radiotherapy and its associated side effects,” Claire L. Vale, MD, principal research fellow at University College of London in the United Kingdom, said in a press release. “Radiotherapy need only be given to men if they show early signs that the cancer may be returning.”
RADICALS-RT trial
Radical prostatectomy — the standard treatment for men with clinically localized prostate cancer — typically is followed by postoperative radiotherapy to the prostate bed. However, the optimal timing of radiotherapy after surgery is unknown.
Men with no residual disease can receive adjuvant radiotherapy early to lower the risk for subsequent occurrence. Salvage radiotherapy can be given later to men who develop a rising PSA concentration.
Some theories suggest earlier adjuvant radiotherapy could be more effective than salvage radiotherapy in stopping biological progression; however, it may result in more treatment-related morbidity.
Christopher C. Parker, MD, MRCP, consultant clinical oncologist with The Royal Marsden NHS Foundation Trust and Institute of Cancer Research in the United Kingdom, and colleagues randomly assigned 1,396 men (median age, 65 years; interquartile range [IQR], 60-68) with localized prostate cancer to salvage radiotherapy (n = 699) or adjuvant radiotherapy (n = 697).
All men had at least one risk factor for biochemical progression after radical prostatectomy. Stratification factors included Gleason score, margin status, planned radiotherapy schedule (52.5 Gy in 20 fractions or 66 Gy in 33 fractions) and study center.
Freedom from distant metastases served as the primary outcome. Researchers also analyzed biochemical PFS, freedom from nonprotocol hormone therapy, safety and patient-reported outcomes.
Median follow-up was 4.9 years (IQR, 3-6.1).
Overall, 649 men in the adjuvant group received radiotherapy within 6 months of randomization, whereas 228 in the salvage group received radiotherapy within 8 years.
A total of 169 biochemical progression events occurred. Results showed 5-year biochemical PFS of 85% in the adjuvant group and 88% in the salvage group (HR = 1.1; 95% CI, 0.81-1.49).
Similar percentages of men in the adjuvant group (93%) and salvage group (92%) remained free of nonprotocol hormone therapy at 5 years (HR = 0.88; 95% CI, 0.58-1.33). However, men in the adjuvant group reported worse urinary incontinence at 1 year (mean score, 4.8 vs. 4; P = .002).
Six percent of men in the adjuvant group and 4% of those in the salvage group reported grade 3 or grade 4 urethral stricture within 2 years.
“The good news is that in future, many men will avoid the side effects of radiotherapy,” Parker said in the press release. “These include urinary leakage and narrowing of the urethra, which can make urination difficult. Both are potential complications after surgery alone, but the risk is increased if radiotherapy is used, as well.”
RAVES trial
The randomized, noninferiority RAVES trial included 333 men (median age, 64 years) enrolled across 32 oncology centers in Austria and New Zealand who had undergone radical prostatectomy for adenocarcinoma of the prostate with pathologic staging showing high-risk features. All men had an ECOG performance status of 0 or 1 and postoperative PSA concentration of 0.1 ng/mL or less.
Researchers assigned the men to adjuvant radiotherapy (n = 166) or salvage radiotherapy (n = 167).
Median follow-up was 6.1 years (IQR, 4.3-7.5).
An independent monitoring committee recommended halting enrollment prematurely because of low event rates.
Results showed 50% of patients in the salvage group had radiotherapy triggered by a PSA of 0.2 ng/mL or higher.
The intent-to-treat analysis showed 25 biochemical progressions in the adjuvant radiotherapy group and 30 in the salvage group.
Researchers reported similar rates of 5-year freedom from biochemical progression in the adjuvant and salvage groups (86% vs. 87%; stratified HR = 1.12; 95% CI, 0.65-1.9).
The salvage group had a lower rate of grade 2 or worse genitourinary toxicity (54% vs. 70%) and a slightly lower rate of grade 2 or worse gastrointestinal toxicity (10% vs. 14%).
GETUG-AFU 17 trial
In the randomized, open-label GETUG-AFU 17 trial, researchers randomly assigned 424 men (median age, 64 years) with localized prostate cancer across 46 hospitals in France to adjuvant radiotherapy (n = 212) or salvage radiotherapy (n = 212) after radical prostatectomy. All men had an ECOG performance status of 1 or less and pathologically staged pT3a, pT3b or pT4a, pNx or pN0 disease.
The study called for 718 participants, but an independent monitoring committee recommended early enrollment termination because of low event rates.
Median follow-up from randomization was 75 months (IQR, 50-100) in the adjuvant group and 78 months (IQR, 52-101) in the salvage group.
Fifty-four percent of men in the salvage group started study treatment after biochemical relapse.
Results showed 5-year EFS rates of 92% (95% CI, 86-95) in the adjuvant group and 90% (95% CI, 85-94) in the salvage group (HR = 0.81; 95% CI, 0.48-1.36).
Acute grade 3 or higher toxicities occurred among 3% of patients in the adjuvant group and 2% of patients in the salvage group. The adjuvant group had higher rates of late grade 2 or worse genitourinary toxicities (59% vs. 22%), genitourinary adverse events (27% vs. 7%; P < .0001) and erectile dysfunction (28% vs. 8%; P < .0001).
Meta-analysis
For the systematic review and meta-analysis of the three trials, Vale and colleagues used a harmonized definition of EFS as the time from randomization until the first evidence of biochemical progression, clinical or radiographical progression, initiation of a nontrial treatment, death due to prostate cancer, or a PSA level of at least 2 ng/mL at any time after randomization.
After a median follow-up ranging from 60 to 78 months, and based on 270 events, results of 2,153 total patients across the trials showed no evidence of EFS improvement with adjuvant radiotherapy vs. early salvage radiotherapy (HR = 0.95; 95% CI, 0.75-1.21) and only a 1 percentage point change in 5-year EFS (89% vs. 88%).
These studies support the use of early salvage radiotherapy as opposed to adjuvant radiotherapy for many men after radical prostatectomy. However, there is an exception for men at a high risk for progression, who comprised less than 20% of participants in these trials, Derya Tilki, MD, professor of urology at University Hospital Hamburg in Germany, and Anthony V. D’Amico, MD, PhD, professor of radiation oncology at Harvard Medical School and chief of the division of genitourinary radiation oncology at Dana-Farber Cancer Institute, wrote in an accompanying editorial.
“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,” they wrote.
References:
- Kneebone E, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30456-3.
- Parker CC, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31553-1.
- Sargos P, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30454-X.
- Tilki D and D’Amico AV. Lancet. 2020;doi:10.1016/S0140-6736(20)31957-7.
- Vale CL, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31952-8.
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