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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 newly released 2022 prostate cancer guidelines. Today, we are discussing the role of radical prostatectomy for patients with prostate cancer. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. This section is divided into three, so we are first going to give an overview of the role of surgical intervention in prostate cancer, a discussion of operative techniques and their adverse effects, and then a brief discussion on the role of pelvic lymph node dissection, as well as its technical considerations.

By way of overview, the NCCN guidelines panel states that radical prostatectomy is an appropriate choice for any patient whose cancer appears to be clinically localized to the prostate. However, we know that surgery is not the appropriate choice for every patient, and certainly should be restricted to those with a life expectancy of more than 10 years. When we look at the data from Dr.[inaudible 00:01:05] and others, it is unclear whether the underlying disease biology of prostate cancer or the treatment efficacy of radical prostatectomy drive the overall low prostate cancer-specific mortality rates that we see for patients undergoing radical prostatectomy. Surgery is actually the only intervention with a proven survival benefit compared to an observational approach in localized prostate cancer.

These data come from the Scandinavian Prostate Cancer Group 4 trial, which has multiple publications, and here we are highlighting 23 and 29 years of follow-up. This trial enrolled 695 patients with early-stage, non-screen detected prostate cancer and randomized them to radical prostatectomy or watchful waiting. At 23 years of follow-up, 200 of 347 men randomized to radical prostatectomy had died, of whom 63 died of prostate cancer. Among those who were randomized to watchful waiting, 247 of 348 had died, and 99 of those were from prostate cancer. So looking at prostate cancer-specific mortality, the relative rate of 0.56 for those who received radical prostatectomy, associated with a statistically significant benefit and a number needed to treat of 8. At 29 years of follow-up, results are essentially similar, though, as expected, the proportion of the cohort who had died increased.

Now, when we look at translating this to individual patients, the use of radical prostatectomy compared with watchful waiting confer to a mean of 2.9 years of life gain. So patients, on average, lived nearly 3 years longer. However, we can take this even further. That was the results for the overall cohort, and when we look at men aged 65 or less at the time of their prostate cancer diagnosis, the number needed to treat dropped from 8 down to 4. In addition to these prostate cancer-specific mortality benefits, we see that radical prostatectomy is associated with improved overall survival, particularly among younger patients with more aggressive disease, as well as a decreased risk of metastasis and of local progression. And those features may have important implications for patients' quality of life and the burden of treatment and of disease on their life.

The NCCN guideline panel then moved to discuss the role of high-risk and very high-risk patients receiving radical prostatectomy. They emphasized that surgery may be beneficial for some of these patients, but that we do need to consider the risks of systemic disease and the need for multimodal therapy. And so they highlight data from a cohort of 842 patients who underwent radical prostatectomy on the basis of Gleason 8 to 10 and disease on biopsy.  And worse long-term outcomes were seen among those with a PSA over 10, clinical stage T2b or greater, and Gleason 9 or 10 disease, as well as those with an increasing number of cores involved or over 50% core involvement. And so when we look at those five adverse features, if we compare patients with high-grade histology who either had or did not have those additional adverse features, we see that both biochemical recurrence-free survival and disease-free survival vary quite dramatically.

And so those who have none of those five adverse features have a 10-year biochemical recurrence-free survival of 31% and 10 years disease-specific survival of 75%. Whereas if they had those adverse features, biochemical recurrence-free survival falls to 4% and disease-specific survival falls to 52%. Additionally, surgery may be indicated following a biochemical failure after initial radiotherapy. So the guideline panel focuses on primary external beam radiotherapy, though certainly there is a role following focal therapies or brachytherapy as well. And it's important, however, to acknowledge and counsel our patients appropriately that morbidity is higher for salvage radical prostatectomy than an initial primary radical prostatectomy, in particular, rates of incontinence, erectile dysfunction, bladder neck contracture are higher. The literature is quite varied here, and certainly not homogenous, but 10-year quoted overall survival in the guideline ranges from 54-89% in 10-year and cancer-specific survival from 70-83% for patients undergoing salvage radical prostatectomy. The guideline panel further emphasizes that selection of these patients is critical, and salvage radical prostatectomy should probably only be performed by experienced surgeons.

We are now going to move to consider some operative techniques and adverse effects that are important when counseling our patients and undertaking radical prostatectomy. In terms of the surgical approach, the guideline panel emphasizes that durable long-term cancer control has been seen with both retropubic and perineal approaches, although in general, the perineal approaches have fallen out of favor. They further emphasize that both laparoscopic and robotic-assisted radical prostatectomy are considered comparable to conventional approaches, including open retropubic surgery.

When we look at characteristics associated with long-term outcomes, the guideline panel emphasizes that high-volume surgeons in high-volume centers genuinely achieve superior outcomes. And this is a relatively recent systematic review assessing the volume-outcome relationship in radical prostatectomies. You can see in this table 4, and we'll highlight here, high-volume surgeons have improved outcomes across a range of endpoints, including perioperative outcomes and the need for long-term salvage oncologic therapies, as well as urinary continence. And so, it's definitely important to consider the role of referral to high-volume surgeons, to improve outcomes for our patients.

At this point in time, I am going to hand it off to Zach to walk us through some other technical considerations in radical prostatectomy, as well as the adverse effects.

Zachary Klaassen: Thanks, Chris. This looks at a JAMA paper that was assessing minimally invasive radical prostatectomy. This included a cohort study from SEER-Medicare data of 8,837 patients. And they found that minimally invasive radical prostatectomy was associated with a shorter length of stay, decreased need for transfusions, fewer complications, however, higher incidence of erectile dysfunction and incontinence. A subsequent meta-analysis suggested, however, that improved 12-month urinary continence was achievable with robotic prostatectomy.

Another trial that was published in Lancet in 2016, looked at the randomized comparison of robotic and open radical prostatectomy, enrolling 326 men treated by two high-volume surgeons. The outcomes showed that early urinary function and ED complications were comparable at 6, 12, and 24 months, as well as positive margin rates being comparable as well. However post-operative care was non-standardized, which limited the ability to assess oncological outcomes in this randomized trial.

The prostate cancer outcomes study, which was published in the New England Journal of Medicine about a decade ago, assessed long-term patient-reported outcomes among 1,655 men with localized prostate cancer. These patients were treated with either radical prostatectomy or external beam radiotherapy. And you can see here, that in the short-term 2 to 5-year follow-up, radical prostatectomy was associated with increased incontinence and erectile dysfunction. Compared to external beam radiotherapy, radical prostatectomy had decreased incidence of bowel dysfunction. In a long-term follow-up, at 15 years of follow-up, there was no difference in any of these outcomes when comparing radical prostatectomy to radiotherapy.

Another study looking at the population-level data, commonly used in Ontario, Canada, looked at 30,000 patients treated with non-metastatic prostate cancer. And this study found that external beam radiotherapy had lower rates of urological procedures, however, higher rates of hospital admission, rectal and anal procedures, open surgical procedures, and increased incidence of secondary malignancies.

The next couple of slides will talk about managing toxicity associated with treatment. First is urinary incontinence, and this may be improved during radical prostatectomy by preserving the urethra beyond the prostate apex.  It also may be improved by avoiding damage to the distal sphincter mechanism, as well as bladder neck preservation, which may help in speeding the recovery of continence. Additionally, urinary control may be improved by nerve-sparing techniques at the time of the operation.

With regards to vesicourethral anastomotic strictures, this has certainly decreased substantially with modern techniques, particularly robotic-assisted radical prostatectomy, where a good anastomosis at the time of surgery is rarely associated with the subsequent anastomotic stricture. And finally, erectile dysfunction. Certainly, this is related to the degree of nerve-sparing, the age of the patient at the time of surgery, and the pre-operative erectile dysfunction. Replacement of resected nerves with nerve grafts in early studies does not appear to be effective for enhancing erectile function recovery. And several studies have looked at multiparametric MRI, which may assist with decision-making with regards to nerve-sparing at the time of radical prostatectomy.

Finally, we'll talk about lymph node dissection at the time of radical prostatectomy. The indications for pelvic lymph node dissection are typically based on a nomogram assessment, most commonly the Memorial Sloan Kettering Cancer Center nomogram, which takes into account PSA, clinical T stage, as well as Gleason sum. The NCCN guideline panel has chosen a 2% cutoff for performing a lymph node dissection, which avoids performing a lymph node dissection in 47.7% of patients, at the cost of missing 12.1% of patients that do have positive pelvic lymph nodes. This is also looked at in an updated SEER analysis of over 26,000 patients from 2010 to 2013. Again, using this 2% nomogram threshold, finding that with this threshold, you can avoid 22.5% of pelvic lymph nodes, at a cost of missing only 3% of positive nodes.

In terms of the technique, the panel suggests that this should be performed as an extended technique, and this is including removing all node bearing tissue at the external iliac vein, which makes up the anterior border, the pelvic sidewall, the lateral border, the bladder wall, which makes up the medial border, the floor of the pelvis, which makes up the posterior border, Cooper's ligament, which is the distal extent of the dissection, and the internal iliac artery, which is the proximal extent of the dissection, which you can see here in the figure to the right. Not surprisingly, increased node yield is associated with an increased likelihood of positive nodes. However, it is important to highlight, again, that the oncological benefit has not been proven with lymph node dissection, however, observational studies have suggested a survival advantage using pelvic lymph node dissection.

To summarize the radical prostatectomy section of the NCCN guidelines, radical prostatectomy is a standard of care for patients with localized prostate cancer who warrant treatment, and treatment should be considered in patients with a life expectancy of greater than 10 years. As Chris highlighted, radical prostatectomy is the only treatment with a proven survival benefit compared to observation in a randomized controlled trial, and open or minimally invasive radical prostatectomy can be considered and should be at the discretion of the surgeon and their expertise. As just highlighted, a pelvic lymph node dissection should be used when the risk of lymph node metastases is more than 2% per the available nomograms.

Thank you very much for your attention. We hope you enjoyed this UroToday discussion of the NCCN guidelines in prostate cancer, specifically regarding the use of radical prostatectomy.