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Zachary Klaassen: Hello, and thank you for joining us for this UroToday NCCN clinical practice guidelines in oncology, focusing on prostate cancer and specifically radiation therapy. My name is Zach Klaassen, I'm an Assistant Professor in the Division of Urology at the Medical College of Georgia. And with me is Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto.

The NCCN Prostate Cancer Guidelines specific to radiotherapy is a large section. And today we will be discussing the final three parts of this part of the guidelines, including brachytherapy, proton therapy, and radiation for distant metastasis. So first talking about brachytherapy. Brachytherapy involves placing radioactive sources into the prostate tissue, and has traditionally been used in low-risk disease, but is increasingly being used in high-risk and locally advanced disease.  Several advantages for brachytherapy are listed here, including it is completed in just one day, in appropriately selected patients it offers adequate cancer control, and the risk of incontinence and erectile dysfunction is minimal in the short-term follow-up. As well, there are several disadvantages to brachytherapy, including the need for general anesthesia, the risk of acute urinary retention, as well as irritative voiding symptoms for up to one year, and the risk of a bladder neck contracture from the therapy.

Typically there are two methods of brachytherapy which are listed here, including the low dose-rate which includes placement of permanent seeds into the prostate gland. This includes a short-range of radiation which allows low dose delivery to cancer and avoids excessive radiation to the bladder and the rectum. For low dose-rate, the risk of incontinence and rectal dysfunction is minimal in the short-term follow-up. For high dose-rate or HDR, this includes temporary insertion of a radiation source in the prostate, which has been associated with a lower risk of urinary frequency, urgency, and rectal pain compared to LDR.  However, irritative voiding symptoms for one year are possible as well as the risk of a bladder neck contracture.

Several initiatives have been used to improve brachytherapy, including improving the accuracy for prostate localization, including several techniques such as CT, ultrasound, implanted fiducial markers, as well as electromagnetic targeting and tracking. Also, the endorectal balloons have been used to improve prostate immobilization as well as perirectal spacer materials to decrease rectal toxicity.

Looking at brachytherapy alone for localized disease, this is an option for patients with very low, low, or favorable intermediate-risk prostate cancer. And generally, high-risk patients have been poor candidates for brachytherapy alone. Randomized trials comparing brachytherapy to radical prostatectomy or external beam radiotherapy are limited. However, one study did look at brachytherapy versus radical prostatectomy published in the Canadian Journal of Urology in 2017. This was a single-center trial in Italy looking at 165 patients with low-risk prostate cancer that were randomized to LDR brachytherapy with iodine versus radical prostatectomy.  The two-year biochemical-free survival rates were the same between these two groups with 96.1% after brachytherapy and 97.4% after radical prostatectomy. At six months of follow-up, continence was noted to be better in the brachytherapy group, whereas potency was better in the radical prostatectomy group.

Now we will switch to talking about brachytherapy boost. With regards to LDR or HDR, brachytherapy can be added as a boost to external beam radiotherapy plus ADT in men with unfavorable intermediate high or very high-risk prostate cancer. Combining external beam radiotherapy with brachytherapy allows dose escalation while minimizing acute and late toxicity.  Indeed improved biochemical control is achieved over EBRT or ADT in randomized control trials, but with a higher toxicity rate.

This is the ASCENDE Trial, which looked at androgen suppression combined with elective nodal and dose-escalated radiation therapy. This included 398 men with intermediate or high-risk prostate cancer. All these men were initially treated with 12 months of ADT plus 46 Gy pelvic external beam radiotherapy. And then they were randomized to two methods of dose escalation, including a dose-escalated external beam radiotherapy boost, the 78 Gy versus an LDR brachytherapy boost.  The primary endpoint for this trial was biochemical progression-free survival, looking at the LDR versus external beam radiotherapy boost arms. And you can see that this was higher for LDR at 86% at seven years compared to 75% in the EBRT boost arm which you can see in the Kaplan-Meier figure to the right. Importantly there was no difference in cancer-specific or overall survival regardless of their boost modality.

Looking at the addition of ADT to brachytherapy and external beam radiotherapy, adding two to three years of ADT is common for these patients. And the results of this trimodality approach are excellent with nine-year progression-free survivals of 87% and disease-specific survival of 91%.  However, the benefit of ADT above and beyond what brachytherapy and external beam radiotherapy can provide in terms of benefit is still debated.

This is a study published in JAMA in 2018 looking at the utility of multimodality therapy. This study had 1,809 men. It was a multicenter study, a retrospective cohort design of men with Gleason 9 and 10 prostate cancer. Multimodality therapy of external beam radiotherapy plus brachytherapy plus ADT was associated with improved prostate cancer-specific mortality and longer time to distant metastasis than radical prostatectomy or external beam radiotherapy plus ADT alone. And you can see that on the right in this figure, looking at prostate cancer-specific survival with improved survival for those including EBRT brachytherapy and ADT.

Next, we will discuss salvage brachytherapy which can be considered in men with biochemical recurrence after external beam radiotherapy. There was a retrospective study of 24 men published in 2009 who had external beam radiotherapy as primary therapy and permanent brachytherapy after biochemical recurrence. And this study reported a cancer-free survival rate of 96% and a biochemical relapse-free survival rate of 88%. There was a Phase 2 trial published in 2014 looking at salvage HDR brachytherapy after external beam radiotherapy, and their five-year outcomes included a relapse-free survival rate of 68.5%, a distant metastasis-free survival rate of 81.5%, and a cause-specific survival rate of 90.3%.

I will now turn it over to Chris who will discuss proton therapy as well as radiation to distant metastasis.

Christopher Wallis: Thanks, Zach. The NCCN Guidelines here are quite helpful to guide, I think, what are relatively common clinical questions. And so first we will discuss the role of proton-based radiotherapy. And proton therapy while has come into vogue in prostate cancer relatively recently has been used to treat cancer since the 1950s. However, there is, unfortunately, a lack of prospective data on prostate cancer. The general principle that drives the interest in proton-based therapy is that less radiotherapy dose is delivered to surrounding normal tissues, including muscle, bone, vessels, and fat that are not immediately adjacent to the prostate.

However, in prostate cancer treatment, these tissues do not routinely cause morbidity and therefore the improved side effect profile that may be associated with proton therapy is not readily clinically apparent. What is readily apparent, however, is that the cost associated with both building a proton beam facility and then ongoing proton beam treatments are substantially higher compared to the expense of building and utilizing more commonly utilized photon linear accelerated-based treatment practices.

So when we look at some prospective data, here we have a moderate size Phase 2 trial of 184 patients with low or intermediate-risk prostate cancer who received 70 Gy of hypofractionated radiotherapy using proton therapy in 28 fractions.  Four-year biochemical and clinical failure-free survival was nearly 94%. And if you could see on the right side of the screen, GU and GI toxicity rates, these are grade two or higher increasing over time and reaching nearly 15% for GU toxicity once we get three or more years out.

In terms of proton therapy, the NCCN Guidelines Panel states that there is no clear evidence to support either beneficial or detrimental effects of proton therapy compared to IMRT for either treatment efficacy or long-term toxicity. As a result, the panel recommends that conventionally fractionated prostate proton therapy can be considered as a reasonable alternative to x-ray-based regimes where clinics have appropriate technology, physics, and clinical expertise.  Although they would caution, that from a healthcare systems perspective, the increased cost should be taken into consideration.

We will now transition to discussing the role of radiotherapy for distant metastatic disease. External beam radiotherapy is an effective means of palliating isolated bone metastases. And a short course of 8 Gy in a single fraction has been found to be both as effective and less costly than 30 Gy in 10 fractions. And so the NCCN panel notes that this single course of an 8 Gy fractionation schedule may be as effective for pain palliation, but that retreatment rates are going to be higher.  As a result, other regimes, including 30 Gy in 10 fractions or 37.5 Gy in 15 fractions may be considered as alternative palliative dosing schedules based on various clinical scenarios.

And so the ORIOLE Phase 2 rial provides us with some more data on the role of radiotherapy in the oligometastatic setting. This was a Phase 2 trial randomizing 54 patients with recurrent castration-naïve prostate cancer, and one to three metastases, either SBRT or SABR or versus observation. The primary outcome was progression at six months and rates were substantially lower at 19% among those who received radiotherapy as compared to 61% in those who received observation.  The composite progression-free survival secondary endpoint was not reached among patients who received radiotherapy but was median of 5.8 months in those who received observation. You can see this in the Kaplan–Meier figure to the right of the screen.

An alternative way to administer radiotherapy instead of external beam radiotherapy is the use of systemic radiotherapy. And the most commonly utilized approach here is radium-223 on the basis of data from the ALSYMPCA trial. This Phase 3 trial randomized 921 men with symptomatic CRPC with more than two bone metastases and no visceral disease to receive either radium-223 or placebo.  As you can see on the right of the screen, the overall survival Kaplan–Meier curve, overall survivals improved for men who received radium-223 by a median of about three and a half months with a statistically significant hazard ratio of 0.70. Radium-223 is also associated with palliative benefits.

And so we can see that its use prolonged the time to the first skeletal-related event by a median of just under six months with again a statistically significant hazard ratio of 0.66. And notably, radium-223 maintained its survival benefit regardless of the use of docetaxel.  Grade 3 or 4 hematologic toxicity was relatively low despite the calcimimetic targeting, and radium-223 use improved or slowed declines in health-related quality of life providing that important patient-derived symptomatic benefit.

ERA-223 was a follow-up study conceptually, looking at the addition of radium-223 to abiraterone acetate and prednisone in the first-line treatment of patients with mCRPC. This Phase 3 trial enrolled 806 men with bone metastatic chemotherapy-naïve CRPC who were randomized to receive abiraterone with or without radium-223. The primary endpoint of SSE-free survival was not met. And notably, the combination arm was associated with a higher rate of bone fractures compared to placebo which was a somewhat unexpected finding.

The NCCN Guidelines panel, therefore, recommends radium-223 as a Category 1 treatment option in men with symptomatic bone metastases without visceral disease in the mCRPC space. Hematologic evaluation should be performed for patients before each dose is administered. And the combination of radium-223 with docetaxel has the potential for added myelosuppression, and thus should not be routinely used clinically outside the auspices of a trial. Further, given the evidence we saw from ERA-223, we need to consider bone health in patients who received radium and therefore treatment with denosumab or zoledronic acid should be considered.

We now come to the final slide here on the principles of radiotherapy highlighting roles for brachytherapy in prostate cancer. We can see that brachytherapy monotherapy is an appropriate treatment choice for patients with very low and low-risk or favorable intermediate-risk disease, whether an LDR or HDR is employed. Similarly, a brachy boost with external beam radiotherapy is appropriate for both unfavorable intermediate-risk and high and very high-risk disease, again using either LDR or HDR-based approaches.

This concludes our presentation and we hope this has provided important insights into the critical role of radiotherapy as a treatment option for patients with prostate cancer. Thank you again.