Skipping Radiotherapy After Surgery for
Prostate Cancer

Zosia Chustecka

September 28, 2019

BARCELONA, Spain — Radiotherapy can be withheld after surgery for prostate cancer and given only if there are signs of biochemical recurrence of disease, instead of being given automatically to all patients.  

This is the new advice from prostate cancer radiation experts discussing new data presented here at the European Society of Medical Oncology annual meeting.

These new data include the first results from the largest trial to compare salvage with adjuvant radiotherapy (the RADICALS-RT trial), and also the results of a prospective meta-analysis of three such studies (ARTISTIC).

They show that withholding radiotherapy and monitoring men after they have had a prostatectectomy, and giving early salvage radiotherapy (sRT) when the first signs of biochemical recurrence are seen, produces early outcomes that appear to be slightly better than giving adjuvant radiotherapy to all patients.

"Maybe 'better than' is not quite the right term to use," commented discussant Gert de Meerleer, MD, radiation oncology at University Hospital Leuven, Belgium.

"They are most probably equal," he said, but the advantage of the salvage therapy approach is that you spare many men from undergoing radiotherapy, with its adverse effects.

However, he emphasized that these men must be monitored closely and salvage radiotherapy must be given "early" — he said that for him, this means when the prostate specific antigen (PSA) levels reach 0.2 ng/mL "at the very max."

Chris Parker, MD, from the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London, UK, who presented results from RADICALS-RT study, said the results have already changed clinical practice at his institution.

"This is our new policy — early salvage radiotherapy at the first sign of a rise in PSA," he said.

Commenting on the new data in an ESMO statement, Xavier Maldonado, MD, from the Vall d'Hebron University Hospital, Barcelona, Spain, said, "These are the first results to suggest that postoperative radiotherapy for prostate cancer could be omitted or delayed in some patients."

"This will shorten the duration of treatment for these patients and allow better use of resources, since today's radiotherapy is technically sophisticated and therefore expensive," he said.

"However, strict follow-up will be needed to identify patients requiring salvage radiotherapy," he added.

First Results from RADICALS-RT

RADICALS-RT is the largest trial so far to compare salvage with adjuvant radiotherapy, Parker noted. It involved 1396 patients with a median follow-up of 5 years.

These were patients who had undergone a radical prostatectomy, and had post-op PSA ≤0.2 ng/mL, and one or more of the following: pathologic T (pT) 3/4, Gleason score 7 to 10, pre-op PSA ≥10ng/mL, and positive margins.

Meerleer described this patient population as being at intermediate or low-intermediate risk of disease recurrence. In his discussion, he commented that "Parker described them as typical patients after surgery," but he pointed out that in other countries patients with more advanced disease also undergo surgery. 

These men were randomly assigned to receive adjuvant radiotherapy (aRT) or to be followed by observation and to receive salvage radiotherapy (Obs+sRT) only if they reached a threshold, which was either two consecutive rises of PSA and PSA levels >1ng/mL, or three consecutive rises in PSA levels.

After 5 years, only one third (33%) of this group had received radiotherapy.

In view of that, it is not surprising that the toxicity reported was less in the salvage radiotherapy group, Parker commented.

Self-reported urinary incontinence was worse at 1 year, in 5.3% of the aRT groups vs 2.7% of the OBs+sRT group (P =.008), and grade 3/4 urethral stricture was reported at any time in 8% vs 5% (P =.03).

Parker said it was too early to present results for the primary endpoint of freedom-from-distant metastases (FFDM), as not enough events had taken place.

So he presented results for the secondary endpoint of biochemical progression free survival (bPFS), which was defined as PSA >0.4 ng/mL following radiotherapy, PSA >2.0 ng/mL at any time, clinical progression, initiation of non-protocol hormone therapy, or death from prostate cancer.  

This endpoint of bPFS at 5 years was seen in 85% of patients in the aRT group vs 88% for Obs+sRT, with a hazard ratio [HR] of 1.10 (95% confidence interval [CI] 0.81 - 1.49, P = .56).

"The results suggest that radiotherapy is equally effective whether it is given to all men shortly after surgery or given later to those men with recurrent disease," Parker said in a statement.

"There is a strong case now that observation should be the standard approach after surgery, and radiotherapy should only be used if the cancer comes back," he added.

"The good news is that in [the] future, many men will avoid the side effects of radiotherapy," added Parker. "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."

However, Parker also emphasized that longer follow-up is needed, and that the primary endpoint of FFDM is still to be reported. It may be that there is a role for adjuvant radiotherapy in some subgroups of this patient population.

ESMO commentator Maldonado agreed, and said some patients may still require adjuvant radiotherapy to avoid a very early local relapse and potential subsequent metastases. Future research should focus on identifying such patients, he suggested.

"We need to develop genomic classifiers to help decide the best management strategy for each patient — whether it should include surgery and/or radiotherapy, and at which time points," he said.

Confirmation From Meta-analysis

Confirmation of these results followed in the next presentation, in which Claire Vale, PhD, from the MRC Clinical Trials Unit, University College London, UK, reported results from the ARTISTIC meta-analysis.

This combined the results from RADICALS-RT with two other similar studies, RAVES and GETUG-AFU17.

All three trials compared adjuvant RT with salvage RT in men who had undergone a radical prostatectomy. Patient characteristics were balanced within trials and overall, Vale commented. The median age was 65 years and most (77%) had a Gleason sum score of 7.

Across the 3 trials, 1074 men were randomly assigned to aRT and 1077 to sRT.

To date, 395 men (37%) have undergone sRT. Median follow-up ranged from 47 to 61 months.

The meta-analysis reported event-free survival (EFS), and Vale pointed out that the vast majority of first events across all the trials are biochemical failures.

Based on 245 events, the meta-analysis shows no evidence that EFS is improved with aRT compared to sRT (HR, 1.09; 95% CI, 0.86 - 1.39, P = .47), Vale reported.

This translates to a potential absolute difference of 1% at 5 years in favor of sRT (95% CI, 2% in favor of aRT to 4% in favor of sRT).

Vale concluded that this meta-analysis of data from the three trials suggests that salvage radiotherapy and adjuvant radiotherapy "offer similar outcomes."

"However, sRT spares many men from receiving RT, and associated side effects," she pointed out.

"Results of the ARTISTIC meta-analysis confirm those of RADICALS, and provide greater evidence to support the routine use of observation and early salvage radiotherapy," Vale said in a statement.

Parker reports relationships with AA, Bayer, and Janssen. Meerleer reports relationships with Astellas, Bayer, Ferring, Ipsen, and Janssen. Vale has disclosed no relevant financial relationships.

European Society for Medical Oncology (ESMO) 2019 Annual Meeting: Abstracts LBA49_PR (RADICALS-RT) and LBA48_PR (ARTISTIC). Presented September 27, 2019.

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