Early salvage radiotherapy appears to be a better choice after radical prostatectomy for men with prostate cancer than adjuvant radiotherapy, according to late-breaking results from the ­RADICALS-RT trial and the ARTISTIC meta-analysis of three trials that included RADICALS-RT. Observation after surgery followed by salvage radiotherapy for biochemical failure may avoid overtreatment of men who do not need radiotherapy and may spare them side effects of radiotherapy, experts noted. The results of both analyses were reported at the European Society for Medical Oncology (ESMO) Congress 2019.^1,2

Adjuvant radiotherapy administered within 4 to 6 months after radical prostatectomy has been considered a standard approach based on level 1 evidence for improved biochemical and clinical progression of disease. The optimal timing for radiotherapy after surgery remains controversial, and a sizable proportion of men will not experience biochemical (prostate-specific antigen [PSA]) failure requiring radiotherapy.

In RADICALS-RT, adjuvant radiotherapy did not improve biochemical progression-free survival or the time to future hormone therapy compared with early salvage radiotherapy. Adjuvant therapy increased urinary and bowel symptoms, findings in keeping with a recent large-scale population based report on early adjuvant radiotherapy postprostatectomy.³ “These results support early salvage radiotherapy after radical prostatectomy,” said Chris Parker, MD, of the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London, UK. “There is a strong case now that observation should be the standard approach after surgery, and radiotherapy should be used only if there is a recurrence. Longer follow-up is needed to determine whether there is an effect on survival,” he added.

Chris Parker, MD

“The good news is that in the future, many men will avoid the side effects of radiotherapy, including urinary leakage and narrowing of the urethra, both of which are potential complications after surgery alone, but the risk is increased if radiotherapy is added,” Dr. Parker noted.

RADICALS-RT Details

RADICALS-RT, a prospective phase III trial, was conducted at 150 centers in 4 different countries. It enrolled 1,396 men with at least one risk factor for disease progression (ie, pT3/4 disease, Gleason score 7–10, positive margins, or preoperative PSA level > 10 ng/mL) and postoperative PSA level ≤ 0.2 ng/mL. Men were randomly assigned 1:1 to receive adjuvant radiotherapy within 6 months after surgery or salvage radiotherapy to be triggered by two consecutive rises in PSA level. The primary outcome was freedom from distant metastases. The results presented at the ESMO Congress 2019 focused on ­biochemical-free survival and freedom from the need for hormone therapy. The median follow-up was 5 years.

The majority of patients had T3 disease, and 20% had seminal vesicle involvement. Biochemical disease progression was defined as a rise in PSA level ≥⊇0.4 ng/mL after radiotherapy.

Almost all the men randomly assigned to adjuvant radiotherapy were treated, compared with just one-third of those randomly assigned to salvage radiotherapy. Salvage radiotherapy was given relatively early, at a median PSA level of 0.2 ng/mL. More than 95% of patients had radiotherapy to the prostate bed alone, and radiotherapy could be given along with hormone therapy.

At 5 years, biochemical progression-free survival was 85% with adjuvant radiotherapy and 88% with observation and salvage radiotherapy. Freedom from nonprotocol hormone therapy at 5 years was 92% and 94%, respectively.

The investigators analyzed the salvage-therapy arm alone for freedom from distant metastases: 22 events occurred over follow-up, and 90% were free of distant metastases. “So far, there have not been sufficient events to compare freedom from distant metastases between the two arms of the trial,” Dr. Parker stated.

Noel Clarke, MBBS, FRCS, ChM

Noel Clarke, MBBS, FRCS, ChM, Professor of Urological Oncology at The Christie and Salford Royal Hospitals in Manchester, and Co–principal investigator of the RADICALS trial, added that “the RADICALS team will report on metastasis-free survival and overall suvival in the future.”

Among patients randomly assigned to observation and salvage radiotherapy, 26 deaths have occurred, most due to causes other than prostate cancer. Overall survival has not been analyzed in the adjuvant-therapy arm.

Although most urinary and bowel toxicities were low grade and relatively infrequent, they occurred more often with adjuvant therapy. Self-reported urinary incontinence was 5.3% with adjuvant radiotherapy versus 2.7% with salvage radiotherapy at 1 year. Grade 3 or 4 urethral stricture was reported in 8% vs 5%, respectively.

Confirmatory Meta-analysis

Similar findings were reported in a collaborative meta-analysis called ARTISTIC presented at the same session at the ESMO Congress.² The meta-analysis pooled results of RADICALS-RT with two similar trials: RAVES and GETUG-AFU 17. 

“Results of the ARTISTIC meta-analysis confirm those of ­RADICALS-RT and provide greater evidence to support the routine use of observation and early salvage radiotherapy,” said lead author Claire Vale, PhD, of the Medical Research Council Clinical Trials Unit, University College, London. “There is no evidence that adjuvant radiotherapy improves event-free survival compared with early salvage radiotherapy. However, early salvage radiotherapy spares many men from potentially unnecessary treatment.”

The researchers used a framework for adaptive meta-analysis (FAME) to prospectively design the study. Patient characteristics were well balanced within each trial and overall. However, the three trials differed slightly in terms of radiotherapy schedule, trigger for salvage radiotherapy, timing of salvage radiotherapy, and primary outcomes.

A total of 1,074 men were randomly assigned to adjuvant radiotherapy and 1,077 to salvage radiotherapy, of whom only 37% had initiated salvage radiotherapy during the time of the analysis. The median follow-up for the three trials ranged from 47 to 61 months.

The meta-analysis, which was based on 248 events in total, mainly ­biochemical failures, found no evidence that adjuvant radiotherapy improved event-free survival over salvage radiotherapy, with a likely absolute difference of just 1% at 5 years.

“We are mindful that these results are based largely on biochemical failures, and so there is still a need to assess long-term definitive outcomes. We also want to determine whether there is a role for adjuvant radiotherapy in some men,” Dr. Vale said.

DISCLOSURE: Dr. Parker reported a financial relationship with AAA, Bayer, and Janssen. Dr. Clarke reported financial relationships with Astellas and Janssen. Dr. Vale reported no conflicts of interest.

REFERENCES

1. Parker C, Clarke NW, Cook A, et al: Timing of radiotherapy after radical prostatectomy. ESMO Congress 2019. Abstract LBA49_PR. Presented September 27, 2019.

2. Vale CL, Brihoum M, Chabaud S, et al: Adjuvant or salvage radiotherapy for the treatment of localised prostate cancer? ESMO Congress 2019. Abstract LBA48_PR. Presented September 27, 2019.

3. Sujenthiran A, Nossiter J, Parry M, et al: Treatment-related toxicity in men who received intensity-modulated versus 3D-conformal radiotherapy after radical prostatectomy: A national population-based study Radiother Oncol 128:357-363, 2018.