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Christopher Wallis: Hello, and thank you for joining us for this UroToday discussion of the NCCN Clinical Practice Guidelines in Oncology with a focus on the most recent 2022 version of the prostate cancer guidelines. Today we are discussing comparisons of local therapy options as well as follow-up for patients that are diagnosed with prostate cancer. I'm Christopher Wallis, Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zachary Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.

This is the outline for the three topics we will be covering in this presentation. First, when we look at the comparison of treatment options in localized disease, the NCCN Guideline Panel highlights that there are several large prospective population-based or cohort-based studies, which allow for comparisons of external beam radiation therapy, brachytherapy, radical prostatectomy, observation, and/or active surveillance.

The first that they highlight is the CEASAR cohort initially published by Dan Barocas and colleagues based on three-year data of 2,500 men. As you can see in the two figures to the right, highlighting urinary incontinence and sexual function, radical prostatectomy is associated with early greater declines in urinary and sexual function, compared with radiotherapy, active surveillance maintained the best outcomes throughout the initial three year time period. Active surveillance, however, was associated with increased urinary irritative symptoms.

The second cohort published at the same time as the CEASAR cohort comes from North Carolina and was published by Dr. Chen and colleagues. This looked at just over 1,100 men and compared three-year outcomes. We can see using active surveillance as a comparator, that radical prostatectomy is associated with worse erectile function and worse continence. External beam radiotherapy was associated with worse erectile function, worse urinary obstruction or irritative function, and worse bowel function. Finally, brachytherapy was associated with worse erectile function and worse urinary obstruction or irritation.

Finally, we come to a paper from Dr. Hoffman and colleagues. These investigators again used the CEASAR cohort that Dr. Barocas had published looking at five-year outcomes. The authors concluded the most functional differences were minimal between the approaches, although patients treated with radical prostatectomy had worse incontinence by five years.

We can now think about other local therapies that may be employed in prostate cancer. And the rationale here is to try and reduce the toxicity associated with the treatment of localized prostate cancer while maintaining adequate cancer control. The NCCN Clinical Practice Guidelines Committee makes two clear statements here. First that cryotherapy or other local therapies are not recommended as routine primary therapy, due to the lack of long-term data. And second that the panel recommends only cryosurgery or HIFU as local therapy options in the setting of radiotherapy recurrence in the absence of metastatic disease.

We are going to talk through a number of these modalities briefly here to give some context, but again, these are not guideline-recommended as initial treatment.  So cryotherapy is a minimally invasive approach, which damages tissue due to local freezing effects, and in a variety of studies conducted among patients with low-risk disease, five-year biochemical disease-free survival ranges from 65% to 92%. One study suggested that in patients with unilateral disease based on pre-treatment evaluation, cryotherapy and radical prostatectomy may give similar results. A randomized control trial in which all patients received neoADT, and then they were randomized to cryotherapy or external beam radiotherapy showed no difference in three-year overall survival or disease-free survival, meeting that criterion for comparable cancer control. However, instead of improved functional outcomes, there was actually worse sexual function in the cryotherapy group in this study.

In patients with locally advanced disease in comparison to external beam radiotherapy and cryotherapy, showed worse cancer control with cryotherapy, although disease-specific survival and overall survival were similar. In contrast to this primary treatment paradigm, you can also consider the role of cryotherapy in recurrent disease, following radiation. And in this setting, biochemical disease-free survival rates are pretty reasonable with one-year rates of 95%, three-year rates of 72%, and five-year rates of 47%. Notable adverse events include urinary retention, urinary incontinence, and rectourethral fistula.

I am now going to hand it over to Zach to walk us through some more local therapy options, including first HIFU, as well as talk through the role of ongoing monitoring for patients with prostate cancer, following their initial diagnosis and treatment.

Zachary Klaassen: Thanks, Chris. So, we will talk about High-intensity Focus Ultrasound or HIFU. This was studied in several studies in the initial disease state. This was a multi-institutional study of 111 patients with localized disease. They found that radical treatment-free survival at two years was 89%. And continence was preserved in 97% of men at 12 months and erectile dysfunction was preserved in 78% of men at 12 months. Of note, the Grade three complication rate for these patients was 13%. In another larger prospective cohort of 625 patients, among which the majority had intermediate or high-risk disease, the failure-free survival at five years was actually quite good at 88%, but the pad-free continence rate at five years was 98%.

Additionally, HIFU has been studied in radiation recurrent disease and a prospective registry. They noted a median biochemical recurrence-free survival of 63 months, a five-year OS rate of 88%, and a five-year cancer-specific survival rate of 94%. In this series, there was a Grade three or four complication rate of 33.6%, and in a second registry study, 48% of men undergoing HIFU after radiation were able to avoid ADT with a median follow-up of 64 months.

There are several other emerging therapies that are not quite well described as of yet. Focal Laser ablation has been described, as well as Vascular Targeted Photodynamic therapy. VTP was previously compared to active surveillance in a low-risk prostate cancer cohort in a randomized fashion, with a median follow-up of two years. Noting that disease progression was 28% in the VTP cohort and 58% in the active surveillance cohort. And the subsequent negative prostate biopsy rate was 49% in the VTP cohort and 15% in the active surveillance cohort. The most common serious adverse event in this intervention was urinary retention in three of 206 patients.

Next, we'll discuss disease monitoring. So these recommendations are from a combination of this guideline, as well as the survivorship guideline regarding common consequences of cancer and cancer treatment. And, particularly with men with prostate cancer, there are several important aspects to consider. So, the first is cardiovascular disease risk assessment, as well as including anxiety, depression, trauma, distress, dealing with hormone-related symptoms, as well as sexual dysfunction, which is usually a side effect of any treatment that we use for these men. It's also important for clinicians during the disease monitoring and survivorship phase of the process to promote physical activity, weight management, and immunization status.

In terms of surveying patients after initial definitive therapy, if treatment is for intent to cure, PSA testing should be done every six to 12 months times 5 years, and then annually thereafter. For patients with a high risk of recurrence, PSA testing can be done every three months. In a paper from Dr. Pound and colleagues, patients that recurred after radical prostatectomy, 45% recurred within two years, 77% within five years and 96% recurred within the first 10 years. So, this really highlights the need for long-term follow-up for these patients. As we know as clinicians, local recurrence can be morbid and annual DRE is recommended for prostate cancer recurrence and for colorectal cancer detection. However, if the PSA is undetectable, these physical exams usually can be omitted.

With regards to patients with castration-naïve disease on ADT, the intensity of monitoring is usually determined by the response to ADT and external beam radiation therapy. However, follow-up should include physical exams, history, and PSA every three to six months. Imaging should certainly be performed for patients that are symptomatic or have an increase in PSA. Previous studies have shown that the relative risk of bone metastasis or death increases as the PSA doubling time decreases. This inflection point has been estimated at about eight months for PSA doubling time, and therefore in patients with a PSA doubling time less than this, bone imaging should be performed more frequently.

With regards to patients with localized disease under observation, the intensity of monitoring should follow the same recommendations as to patients with castration-naïve disease on ADT. However, physical examinations and PSA are typically performed only every six months.

Patients that progress should have several workup items noted.  And these patients that progress, castrate testosterone should be documented for patients advancing on ADT. This should be done to confirm that they are actually castrated based on their hormone therapy. If patients have a serum PSA of less than 50, additional imaging can include a bone scan, a CT chest, abdominal and pelvic CT, or MRI. Additionally, the guidelines note that a choline or fluciclovine study can be ordered to further identify soft tissue and bones.

As for the most recent update in September 2021, version 1.2022 of the NCCN guidelines they have made several changes, noting that there are multiple PSMA radiopharmaceuticals at various stages of investigation and the NCCN guidelines recommend DCFPyL and gallium-PSMA-11. Additionally, they state that PSMA-PET/CT can be considered an alternative to standard imaging for staging detection of BCR and work up for progression as conventional imaging is not a prerequisite for their use.

This is the algorithm provided by the guidelines looking at disease monitoring. This essentially summarizes the last several slides I've discussed. If we look at initial definitive therapy, as noted PSA every six to 12 months for five years, then every year. DRE every year, but maybe omitted if PSA is undetectable. If the patient has a recurrence post radical prostatectomy and is classified as PSA persistent recurrence, then follow the guidelines for this which we discussed in a different NCCN discussion, as well as post-radiotherapy. If they have a PSA recurrence or positive DRE, they will then follow the algorithm for radiation therapy recurrence. For those with radiographic evidence of metastatic disease without PSA persistence or recurrence, they should have a biopsy of the metastatic site. Among men that are N1 on ADT or localized on observation, they should have a physical exam plus a PSA every three to six months with imaging triggers for symptoms or increasing PSA. For those that progress, if they are N1, M0, they should follow the M0 CRPC algorithm, and for those that are M1, they should follow the M1 CRPC algorithm.

So in summary, comparative data suggests differing but meaningful toxicity burdens with the use of radical prostatectomy and radiotherapy in localized disease. Cryotherapy or other local therapies are not recommended as routine primary therapy as there is a lack of long-term data. Certainly following curative-intent treatment, long-term monitoring is required due to the potential for late recurrence.

Thank you very much for joining us. We hope you enjoyed this UroToday discussion of the NCCN prostate cancer guidelines, looking at definitive therapy as well as disease monitoring.