Clinical Challenge: Radiotherapy After Prostatectomy

Should men who undergo radical prostatectomy receive adjuvant radiation treatment? It's not a simple question with a straightforward answer.

According to Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center in Charlottesville, previous studies evaluating the effect of adjuvant radiotherapy have presented a "mixed picture" about its benefits. These trials showed that adjuvant radiotherapy after radical prostatectomy achieved a reduced risk of disease recurrence, but only one – the SWOG 8794 trial – showed a survival benefit.

"So there has been controversy about the true utility [of adjuvant radiotherapy] and an increased adoption of salvage radiotherapy, meaning treating patients when there is evidence of biochemical or PSA recurrence," Dreicer told MedPage Today. "So you are now theoretically treating people at true risk, with evidence that you could still cure some of those patients. Therefore, over time, what evolved was a paradigm where more patients were not getting adjuvant therapy, but were being treated at PSA relapse."

It is in this context that a series of trials – RADICALS, RAVES, and GETUG-AFU17 -- comparing adjuvant and early salvage radiotherapy after prostatectomy were conducted, the results of which (along with a meta-analysis and review) were recently published in The Lancet.

That review and meta-analysis found that adjuvant radiotherapy resulted in no event-free survival (EFS) benefit compared to salvage therapy, with an absolute difference of just 1 percentage point in the 5-year EFS rates between the adjuvant and salvage radiotherapy groups (89% and 88%, respectively)

The RADICALS trial included 1,396 men with localized prostate cancer associated with at least one high-risk characteristic (pathologic T-stage 3 or 4, Gleason score 7-10, positive surgical margins, or preoperative PSA ≥10 ng/mL) and randomized them to either adjuvant radiotherapy (697 men) or early salvage radiotherapy (699 men). Five-year biochemical progression-free survival (bPFS) was 85% with adjuvant therapy and 88% with salvage therapy, representing a nonsignificant 10% increase in the risk of biochemical progression in the adjuvant group (95% CI 0.81-1.49, P=0.56).

A second trial – RAVES – included 333 patients with high-risk features. Results there were also a toss-up, with 5-year bPFS of 86% with adjuvant radiotherapy versus 87% with salvage radiotherapy (HR 1.12, 95% CI 0.65-1.90, P=0.15).

GETUG-AFU17 included 424 patients randomized to immediate or delayed radiotherapy after radical prostatectomy. After a median follow-up of 75 months, patients receiving the adjuvant radiotherapy had a 5-year EFS of 92% versus 90% for those who underwent delayed radiation therapy (HR 0.81, 95% CI 0.48-1.36).

"What the meta-analysis and RADICALS shows and suggests is that, in that group of intermediate-risk patients, there was no defined meaningful clinical benefit to adjuvant radiotherapy, and that based on this data there was a reasonable suggestion supporting the urologic oncology community in using salvage radiotherapy for the majority of these kinds of patients," Dreicer said. He had one caveat, though: "Follow-up is still somewhat limited and... there might be even higher risk patients who were included in this [analysis] where adjuvant radiotherapy may still be beneficial, but you can't sort them out."

Anthony V. D'Amico, MD, PhD, of Brigham and Women's Hospital and Dana Farber Cancer Institute in Boston, along with Derya Tilki, MD, of the University Hospital Hamburg-Eppendorf, Hamburg, Germany, provided a commentary in The Lancet in which they also noted that limitations and potential confounders in the three studies suggest there still could be a role for adjuvant therapy in high-risk prostate cancer patients.

D'Amico told MedPage Today that while the studies support the use of early salvage radiotherapy for many patients after prostatectomy, they "may have missed a benefit in men who are at highest risk for dying from prostate cancer -- and the benefit is adjuvant radiotherapy."

He said a careful look at patient eligibility in the three trials shows that they enrolled a large cohort of men who had prostate cancer with favorable risk features. He pointed to the RADICALS trial in particular, whose only adverse risk factors were a preoperative PSA over 10 ng/mL or Gleason score 7.

At the same time there was "a subset of men with high-risk disease – specifically seminal vesicle invasion, extracapsular extension, and Gleason 8, 9, or 10, who were not represented to any high degree in these studies," D'Amico said. Specifically, the percentage of men in these studies that had high risk features ranged from 9% to 17%. "So any benefit could be missed in these patients because it would get washed away by the overwhelming number of favorable risk men in these studies."

Going forward, D'Amico said research needs to focus on that high-risk group – patients with Gleason score 8-10 and pT3b or higher. "That group may still benefit from adjuvant therapy," he said. "And there are ongoing efforts in this area."

For now, said Dreicer, "the urologic oncology community will look at this [as] additional evidence that salvage radiotherapy is a more appropriate way in lieu of adjuvant radiotherapy, because you limit the number of patients who will get radiotherapy-related side effects, while probably not necessarily losing the potential to impact the disease for patients who need treatment.... The [physicians] who focus on this disease have evolved towards salvage radiotherapy as a more standard approach. So, I don't think this will dramatically change what we do since we've been moving in that direction."

D'Amico pointed out that in Europe adjuvant therapy "is done, it's all salvage now."

"Here, there may be an effect – maybe not as big as in Europe," he said. "I don't know if it is going to impact the high-risk group since there is concern among urologists and radiation oncologists and medical oncologists who do this that this group may be at risk for dying and this is the one chance you may have to impact that because if you wait until it is salvage, it is too late. But I do think this might drop the rate of adjuvant in high-risk men."

"I'm not saying that people are going to die as a result of that," he added. "I'm just saying there may be a benefit that is lost, and until we know for sure my recommendation would be to offer adjuvant to men with those high- risk features until we have proof that salvage is not different than adjuvant in that group."

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