The improvements in quality of life measurements and International Prostate Symptom Score (IPSS) in patients following prostatic artery embolization (PAE) are “far superior” to those due to the placebo effect, a new study just published in European Urology, the official journal of the European Association of Urology (EAU), concludes. Publishing a paper positively describing PAE in a urology journal has historically been difficult for interventional radiologists, and co-author Tiago Bilhim (Hôpital Saint-Louis, Lisbon, Portugal) tells Interventional News that this publication “might help our way into the urology guidelines with PAE”.
The most recent EAU guidelines for the diagnosis and treatment of men with lower urinary tract symptoms (LUTS)/ benign prostatic hyperplasia (BPH), published in 2017, are cautious when describing the potential clinical role of PAE, saying that the selection of LUTS patients who will benefit from the procedure still needs to be defined, and highlighting that PAE is technically demanding. The European guidelines state: “A multidisciplinary team approach of urologists and radiologists is mandatory as the basis for future RCTs [randomised controlled trials] of good quality with long-term follow-up in order to integrate this treatment option into the spectrum of efficient, minimally invasive treatment options.”
Bilhim says that the present study is the “kind of research” called for by the European urology community in order to accept PAE into their guidelines for the treatment of LUTS due to BPH. He therefore hopes that this research, which he says demonstrates that PAE is not a placebo procedure, “will be a fundamental study to raise the level of evidence of PAE to treat LUTS due to BPH, and to help get PAE in the [European] urology guidelines.”
In the USA, the American Urological Association (AUA) also mention PAE in their guidelines, published in The Journal of Urology—but only to explicitly not recommend the procedure outside the context of a clinical trial. Interventional radiologists have been advocating for the procedure’s acceptance by urologists, with several prominent figures in this community calling for more widespread awareness of the safety and efficacy of this minimally invasive treatment option for select LUTS/ BPH patients.
The authors of this recent publication therefore underline the importance of sharing their data with the urology community, writing: “PAE is considered experimental in the urology guidelines. For a novel technique such as PAE to be considered as a first-line option, sham-controlled trials are very helpful, and hence the present study.”
In light of the positive outcomes observed in the PAE group, they believe “The results of this clinical trial will be a reference for future research consensus panels and guidelines on the management of LUTS/BPH.”
Speaking to this newspaper in May 2019, Ari Isaacson (Department of Radiology, University of North Carolina, Chapel Hill, USA) highlighted the importance of interventional radiologists publishing their work in urology specific journals, as a way of communicating their views directly to this community. However, he reported that this is challenging: “We have attempted to [publish in a urology journal] several times; it is very difficult to get a PAE paper in a urology journal”. Riad Salem (Northwestern University, Chicago, USA), who is one of few US interventional radiologists that has published a PAE paper in a urology journal, supports this assertion, commenting earlier this year: “In my 20 years of publishing over 330 papers, getting accepted into a urology journal was the most difficult, challenging, controversial process I have ever been through. The reviews were replete with opinions that seemed to have been made before even reading the study. We tried several times, and finally got accepted into the fourth urology journal. This was a prospective, phase II, FDA [US Food and Drug Administration]-approved study, so it met all the high level criteria, but it was still dismissed by many urology journals.”
However, the European urology community has been more welcoming, as Bilhim describes. “The overall experience was very positive,” he says. “We received very constructive reviews from urology experts in the field of BPH that helped make the manuscript better. We wanted to target the urology community because the major goal of this manuscript was to prove to the urology community that PAE is not a sham procedure, and is in fact safe and effective for the treatment of LUTS, without compromising sexual function.
“The major goal of this study was to raise the level of evidence for PAE as a safe technique to treat LUTS due to BPH, so that PAE can be considered as [an] effective alternative in the urological guidelines for patient management. The submission process in the urology journal was similar to standard scientific journals and it took around four to six months from submission to final acceptance.”
Trial findings: PAE superior to sham procedure
Lead author João Pisco (Hôpital Saint-Louis, Lisbon, Portugal), who died in March 2019 after completion of the trial, and co-authors set out to assess the safety and efficacy of PAE “above and beyond the placebo effect” compared to with a sham procedure for the treatment of LUTS/BPH. They conducted a parallel-group, single-blind, sham-controlled superiority randomised clinical trial in 80 men, aged 45 or above, with severe LUTS/BPH non-responsive to medical treatment between 2 September 2014 and 3 March 2018 at Hôpital Saint-Louis, Lisbon, Portugal, with an efficacy assessment at six months after randomisation. This was followed by an open extension phase, where all 38 patients of the sham trial arm who completed the single-blind period crossed over to the PAE arm (underwent the procedure). A final evaluation was conducted at 12 months after randomisation. One patient in the PAE group and three in the sham group did not complete the study.
Patients were randomised 1:1 upon successful catheterisation of a prostatic artery to either PAE or a sham PAE procedure without embolisation. Pisco and colleagues describe the procedure: “In the PAE group, Bead Block (BTG plc, London, UK) 300–500mm was used; in the sham group, after catheterisation of one prostatic artery, the catheter was removed and no particles were injected, but there was a wait of some minutes before the removal of the catheter in order to avoid revealing the treatment arm to patients of the sham group.” All procedures were performed by five interventional radiologists with between three and 10 years of experience in PAE.
The investigators performed an intention-to-treat analysis of all randomised patients. The co-primary outcomes were the change from baseline to six months in the IPSS and the quality of life score at six months, analysed with analysis of covariance and t test, respectively.
At six months, patients in the PAE arm had a greater improvement in IPSS than patients in the sham arm. For those that underwent PAE, the decrease from baseline to month six in IPSS was 17.1±7.25. In comparison, the decrease in IPSS from baseline to six months for patients who underwent the sham procedure was only 5.03±8.13 (difference between groups in changes from baseline: 13.2, 95% confidence interval [CI]: 10.2–16.2, p<0.0001). After six months, the mean IPSS in the PAE group was 8.75±5.73, and 21.9±7.34 in the sham arm.
This pattern was also true of improvements in quality of life: for patients treated with PAE, mean quality of life score at six months was 3.48±1.38, while for patients treated with the sham procedure, mean quality of life score at six months was 1.35±1.12 (difference in the means of quality of life scores between groups at month six: 2.13, 95% CI: 1.57–2.68, p<0.0001).
The occurrence of adverse events was similar between the two groups: 16 events in 14 patients (35%) after PAE, and 17 events in 13 patients (32.5%) following the sham procedure. One serious adverse event took place in the sham group during the open period.
“The results of this randomised clinical trial provide clear evidence that the improvement experienced by patients after PAE is due to a real treatment effect that is much larger than the placebo effect associated with the procedure,” Pisco et al summarise. “The marked and sustained amelioration in all primary and secondary outcomes, with no negative influence on erectile function, offers strong evidence that PAE, through the reduction it imposes on prostate size and possibly because of several other mechanisms, actually modifies the course of LUTS/BPH, and this explains the high clinical success rates reported so far with this treatment.”
PAE “still in the investigational phase” but this study “fills the gap in the evidence base”
Setting out the case for PAE, Pisco et al write: “PAE is a minimally invasive treatment that has been shown in many observational studies and meta-analyses to be safe and effective, reducing LUTS/BPH. In addition, many phase II trials without controls already exist, showing the safety and efficacy of PAE for BPH.
“However,” they add, “LUTS/BPH is known to be very susceptible to placebo treatments, and conclusive demonstration of efficacy will require randomised controlled trials, but until now only three randomised clinical trials of PAE have been published, all comparative to TURP [transurethral resection of the prostate], and none has conclusively demonstrated the efficacy of PAE in LUTS/BPH.” They therefore conclude that, prior to their present study, PAE was “still in the investigational phase”, as “as evidence of efficacy compared with standard treatment has not yet been clearly demonstrated and randomised placebo-controlled clinical trials have not previously been conducted.”
The authors conclude that “The single-blind period of this randomised clinical trial fills the gap in the evidence base on the treatment effect of PAE by demonstrating both clinically and statistically significant differences in patients treated with PAE as compared with patients submitted to a sham procedure. In addition, the trial open extension period offers evidence of sustainability of effects up to 12 months.”
Nonetheless, they concede that “major questions still remain”, especially regarding the durability of the treatment effect. Pisco et al call for non-inferiority clinical trials providing data on long-term outcomes after PAE in large patient cohorts, and say that future research should focus on providing comparative studies of PAE with surgery or medical care with appropriate cohort sizes and long-term follow-up.