Timing of Radiotherapy After Radical Prostatectomy (RADICALS-RT) Journal Club - Zachary Klaassen and Christopher Wallis

January 24, 2021

The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. In this UroToday Journal Club, Christopher Wallis and Zachary Klaassen discuss the RADICALS-RT trial Lancet Oncology publication looking at the timing of radiotherapy following radical prostatectomy which aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. The primary outcome for RADICAL-RT was disease-specific survival and a key secondary outcome was freedom from distant metastases. In 2011, the primary outcome of RADICALS-RT was changed to freedom from distant metastases following a review of the expected event rate based on other publications.

Biographies:

Christopher J.D. Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center


Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we're discussing the RADICALS-RT trial looking at the timing of radiotherapy following radical prostatectomy. I'm Chris Wallis, a Fellow in urologic oncology at Vanderbilt. And with me today is Zach Klaassen, an Assistant Professor at the Medical College of Georgia. This is the citation from the recently published RADICALS-RT trial in The Lancet, with Dr. Parker as the lead author.

Most UroToday readers will know that there's a fairly extensive body of literature looking at the role of adjuvant radiotherapy in men with prostate cancer. This began with the initial EORTC 22911 and subsequent to SWOG trial. Somewhat later, the ARO 96-02 trial was published and in the last year and a half, the FinnProstate Group published their work. In each of these trials, they compare the strategy of postoperative adjuvant radiotherapy compared to an approach that was primarily observation-based with a late delayed intervention with either radiation therapy or hormonal therapy.

Some of these trials used true adjuvant approaches requiring an undetectable PSA in the end of the ARO trial, whereas EORTC and SWOG included patients with detectable PSAs post-operatively.

These data together, we see that the use of an adjuvant approach compared to this lead intervention conferred a benefit in terms of biochemical progression-free survival equivocal benefits in terms of metastasis-free survival, and no benefit in terms of overall survival. In spite of these somewhat equivocal benefits, guidelines from the AUA and ASTRO have recommended that physicians should offer adjuvant radiotherapy to all men with adverse pathological findings at the time of prostatectomy, namely seminal vesicle invasion, positive surgical margins, or extra prosthetic extension.

In spite of these guidelines, most physicians have not practiced in this manner. And so, many have followed an approach initially outlined by Dr. Trock and colleagues from Johns Hopkins, using a salvage radiotherapy approach.

Following Dr. Trock's initial publication, subsequent data showed that the use of early salvage radiotherapy was associated with improved outcomes compared to leader intervention. And so, the goal of the RADICALS-RT trial was to compare the efficacy and safety of adjuvant radiotherapy after radical prostatectomy, compared to a policy of observation with early salvage radiation at the time of biochemical progression.

This is a schema of the RADICALS-RT trial design. We'll go through the details a little bit further, but in short, these are men following radical prostatectomy with undetectable PSAs and in the 4 to 24 weeks postoperatively, they were approached for enrollment and randomization. To be eligible, they had to have one or more high-risk features, namely pT3/4 disease, Gleason score of 7-10, preoperative PSA greater than 10, or positive surgical margins. Randomization was two adjuvant radiotherapy or salvage radiotherapy. Approach with radiation initiated at the time of PSA failure.

And as you can see, the threshold for salvage radiation was two consecutive rises and absolute PSA value over 0.1 or three consecutive rises, regardless of absolute PSA value. So again, to highlight, this is an international Phase III, randomized controlled trial conducted primarily in the UK and in Canada. The RADICALS trial actually has two separate randomizations. We're discussing here the RADICALS-RT, looking at postoperative radiotherapy. There is a subsequent nested randomization assessing concurrent ADT, the RADICALS-HG trial, which is currently still ongoing and not yet reported.

For both of these RADICALS trials, patient-level inclusion criteria included men with non-metastatic prostate cancer, who had underwent prior radical prostatectomy had undetectable, post-operative PSA, and one or more of these higher-risk features for postoperative recurrence. Again, randomization was conducted in a one-to-one fashion to adjuvant or an observation-based approach, and stratification was performed according to Gleason score, margin status, radiotherapy schedule, and we'll talk about that in a moment, as well as study center.

So, in terms of the intervention, radiation can be given with one of two approaches, either a 66Gy and 33 fractions, a relatively conventional approach, or a moderately hypofractionated approach in which 52.5Gy were administered in 20 fractions. For patients in the adjuvant arm, radiation was administered within two months of randomization, and within 26 weeks of radical prostatectomy. For those randomized to the salvage approach, it had to be administered within two months of evidence of biochemical progression. And so, again to highlight, is defined as a PSA greater than 0.1 with two consecutive rises or three absolute consecutive rises with an absolute threshold value.

Nodal radiotherapy could be administered at the treating physician's discretion, but it was not protocolized. And concurrent ADT could be administered per protocol if patients were randomized in that RADICALS-HT trial or at the treating physician's discretion for those who were not included in the second randomization.

The study was designed with an initial primary outcome of disease-specific survival and a secondary outcome of metastasis-free survival. However, on the basis of event rates and a power consideration, this was subsequently revised. The primary outcome was freedom from distant metastases and secondary outcomes included overall disease-specific survival, time to initiation of ADT, adverse events, and patient-reported outcomes. When the artistic collaborative was formed, the RADICALS investigators added biochemical progression-free survival as an outcome in order to allow comparison across the three trials included in the artistic collaborative.

And so in this study, this was defined as freedom from a PSA greater than 0.4, following radiotherapy, from PSA greater than two at any point following randomization, from clinical progression, or from death. And so again, we talked about the revision of this trial and its outcomes, but this is reflected in the underlying power calculation. So, initially, this trial was designed to recruit 2,600 men to give an 80% power, to detect a 5% improvement in disease-specific survival, and then was revised to recruit 1,000 men, to give an 80% power, to detect a 5% improvement in freedom from just the metastases.

And so with the coordinated assessment of biochemical outcomes, through the artistic collaborative, the authors, post-hoc, determined, they had 80% power to detect a hazard ratio of 0.7 for a five-year biochemical progression-free survival of 0.86.

So, all analyses in this trial conducted on an intention-to-treat basis using Kaplan-Meier analysis and Cox proportional hazards models. Toxicity was assessed in two time periods first in the first two years following randomization, reflecting the initial treatment period for adjuvant or radiotherapy patients; and then subsequently. Patient-reported outcomes were also assessed here.

At this point, I'll hand it over to Dr. Klaassen to discuss the results and implications of this trial.

Zachary Klaassen: Thanks, Chris. So, 1,396 patients were randomized after prostatectomy. This included 699 allocated to salvage radiotherapy and 697 allocated to adjuvant radiotherapy. There was a median follow-up of five years for those undergoing salvage with 33 patients having no data in the last 18 months but were last seen alive, and a median follow-up of 4.7 years in the adjuvant radiotherapy. Fifty-four patients with no data in the last 18 months, but last seen alive. This included 699 patients in the intention-to-treat analysis for salvage radiotherapy and 697 in the analysis for adjuvant radiotherapy.

This is a table of the baseline characteristics. You can see here, salvage radiotherapy on the left, adjuvant therapy on the right. Very standard in terms of age, with a median of 65 years, for both groups. PSA at diagnosis was comparable between the two groups as well with a median of eight for salvage radiotherapy and 7.8 for adjuvant radiotherapy.

The majority of these patients, almost half of them, had Gleason score three plus four, with about a quarter of them having four plus three. Most commonly, just over 50% for both arms was pathological T-stage 3a, 56% in salvage and 58% in adjuvant. In terms of positive margins, about two-thirds had positive margins. There was a lymph nodes positive in about 4% or 5% of these patients, more than half of them were CAPRA score intermediate. And you can see that the majority of these patients were randomized in the UK at 82%.

This curve shows the time to starting radiotherapy, and you can see here, as expected adjuvant very soon after prostatectomy, and then the salvage group in the blue curve, quite a few in the first year or two, and then sort of leveling off with no median time reached during the salvage radiotherapy timing. This is the biochemical progression-free survival curves. You can see here, adjuvant radiotherapy is in red and salvage radiotherapy is in blue, and this was a hazard ratio for adjuvant radiotherapy of 1.10 with an insignificant 95% confidence interval of 0.81 to 1.49.

This curve shows freedom from non-protocol hormone therapy, and you can see here very similar curves. The hazard ratio for adjuvant radiotherapy was 0.88. Once again, a non-significant 95% confidence interval of 0.58 to 1.33.

These are the results of the toxicity. If you can see here, we'll focus on the left side of the table. These are early, less than two years after treatment, and you can see here, the salvage radiotherapy and adjuvant radiotherapy on the right. In terms of diarrhea, 16% in the salvage group, 38% in the adjuvant group; proctitis, 7% in salvage, 22% in adjuvant; cystitis, 12% in salvage and 25% in the adjuvant group; hematuria, 4% in salvage and 11% adjuvant radiotherapy, and very comparable low rates of urethral stricture.

When we look at the late toxicities on the right side of this table, we can see here that patients that had adjuvant radiotherapy had more diarrhea than salvage radiotherapy at 17% versus 8%. Similar again for proctitis, 13% versus 5%, as well as cystitis, 13% versus 7%. Hematuria also more common in late toxicity for adjuvant radiotherapy, 12% versus 4%.

So once again, we see, as we summarize this table that patients that received adjuvant radiotherapy, by definition, very close to the time of the radical prostatectomy, did have more toxicity.

These are the results of the patient-reported outcome measures in terms of urinary incontinence and fecal incontinence. On the left side of this curve is urinary incontinence on the right side is fecal incontinence. And you can see here that the adjuvant radiotherapy had statistically significant worse patient-reported outcomes at one year for both urinary and fecal incontinence, but these became insignificant with more time, as you can see here in year five.

So several discussion points from the RADICALS-RT trial, and we see here that in the initial analysis of this trial, there was no benefit of adjuvant radiotherapy after radical prostatectomy and the low metastatic event rate in the control group suggests poor improvement in this group. The RADICALS-RT trial differs from SWOG 8794 and EORTC 22911 in that these two trials compared adjuvant radiotherapy to observational alone. So, this is a much different design and a much more clinically applicable design in the RADICALS-RT group.

We do not yet have good quality evidence concerning the effect of postoperative radiotherapy timing on long-term outcomes, such as freedom from disease metastasis. Although the biochemical progression-free survival is not a surrogate for freedom from disease metastasis, trials of prostate radiotherapy typically show a greater treatment effect in terms of biochemical progression-free survival than for longer-term outcomes.

Several strengths of the RADICALS-RT trial, this is the largest RCT of adjuvant radiotherapy after radical prostatectomy, and it mandates salvage radiotherapy in the control group. This is powered to study, in due course, the long-term outcomes of freedom from disease metastasis as well. Several limitations of the trial is that right now, follow-up is insufficient to reliably report long-term outcomes at this point. And during recruitment, new evidence suggesting men receiving salvage radiotherapy benefit from the addition of hormone therapy, as has been suggested in the RTOG 9601, the GETUG-16 trial.

So, in conclusion, the RADICALS-RT trial has not yet shown any benefit for adjuvant radiotherapy in comparison to salvage radiotherapy for PSA biochemical progression. Adjuvant radiotherapy initially does increase the risk of comorbidities and side effects within one year, but then subsequently, does not increase the risk of urinary or bowel morbidity. But, in the absence of evidence that adjuvant radiotherapy does more good than harm, observation with salvage radiotherapy for biochemical progression should be the standard of care.

Thank you for your attention. We hope you enjoyed this UroToday Journal Club on the RADICALS-RT trial.

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