GU Cancers 2021 | SPORT: P-SABR versus PPN-SABR for localized prostate cancer

The SPORT trial is entitled the stereotactic prostate radiotherapy trial, a randomized feasibility study comparing prostate stereotactic radiotherapy to prostate and pelvic nodal stereotactic radiotherapy and patients with unfavorable intermediate-risk or high-risk prostate cancer. This is a single-center feasibility study that I think is very current and will be of interest to the prostate and radiotherapy community.

We know that stereotactic radiotherapy is the direction of travel for localized prostate cancer. There is now a number of very large reported trials demonstrating the safety and the efficacy of stereotactic radiotherapy particularly for low-risk and intermediate-risk prostate cancer. Indeed, that has become a standard of care in many countries and in many centers, but there is a gap in the evidence-base, particularly for patients with high-risk localized prostate cancer, and I think this is important because the radiobiology of higher risk disease may be slightly different to low-intermediate and intermediate-risk disease. Also the area that we treat is also different in that we tend to encompass more of the seminal vesicles, which makes our radiotherapy treatment fields larger, and many centers, including my own, treat the pelvic lymph nodes for patients with high-risk prostate cancer and that’s a much bigger volume than would be treated if we treat the prostate alone.

We want to examine the feasibility of carrying out a randomized clinical trial of stereotactic radiotherapy to the prostate or to the prostate and pelvic lymph nodes. We elected to enroll 30 patients; a half to get prostate only stereotactic radiotherapy and half to get prostate and nodal stereotactic radiotherapy, and the primary objective was feasibility. Could we recruit, would it be suitable for patients and for clinicians? Could we technically deliver the radiotherapy to the pelvic lymph nodes? And was the toxicity acceptable? The acute clinician-reported toxicity and patient-reported toxicity.

All patients had an unfavorable intermediate-risk or high-risk prostate cancer and all patients had image-guided radiotherapy with gold fiducial markers and had a perirectal spacer gel inserted to reduce dose to the rectum. In the third cohort of 10 patients, because toxicity was low, we also amended the trial to permit a dose escalation to the dominant endoprosthetic lesion, escalating dose up to 45 gray or even 50 gray if it was a peripheral lesion. So, the dose to the prostate overall for the trial was 40 gray, the prostate EDV 36.25 gray, and the pelvic nodal dose was 25 gray with the DIL boost to 45 to 50 gray. And these were weekly treatments over five fractions.

To summarize the results briefly, the recruitment target was met. We recruited the 30 patients on time as planned and all patients, it was technically feasible to deliver the radiotherapy to both the prostate and the pelvic lymph nodes, even with the use of tight radiotherapy dose constraints. We could boost the dominant endoprosthetic lesion in most patients up to 45 gray, in some patients up to 50 gray. But again, our strict organs at risk constraint tended to limit the dose that we could boost to.

All patients have now been followed up for two and a half years, so we have clinician and patient reported toxicities, both acute and late for all patients and we see an interesting signal. Obviously, the trial is not powered to detect the differences in the two groups, but both in clinician-reported and patient-reported outcomes we see increased late urinary and bowel toxicity for patients treated with pelvic lymph node stereotactic radiotherapy. For instance, with late side effects and patient-reported outcome measures, about one third of patients have a minimally clinically important change in their bowel quality of life in the prostate group, two-thirds in the prostate and radiotherapy group.

Just to finally mention our biomarkers, so we looked at citrulline as a measure of small bowel damage, and there was quite a profound drop in the short term in the pelvic nodal group, whereas we did not see that in the prostate only group. Similarly, with H2AX, a measure of double-strand breaks and peripheral blood mononuclear cells, we saw a much higher increase in patients treated with pelvic and prostate nodal radiotherapy one hour after the first radiotherapy dose. So, we need to evaluate these biomarkers in larger studies, but we hope that these may act as a signal for patients that are more susceptible to longer term toxicity from radiotherapy in future studies.

So, the next steps we need to do are a multicenter randomized controlled trial, and we are actively developing that in the UK to test stereotactic radiotherapy either to the prostate and seminal vesicles, or to the prostate seminal vesicles and pelvic lymph nodes for patients with high-risk prostate cancer. We hope that that will be a game changer to make radiotherapy more deliverable for man with high-risk prostate cancer.