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Chris Wallace: Hello, and thank you for joining us for this UroToday discussion of the recent updates in the NCCN Clinical Practice Guidelines in oncology focusing on prostate cancer. As of the newest version of the 2023 Guidelines, published September 16th, 2022, there's a new section focused on quality of life and shared decision-making, which we're going to discuss today.

I'm Chris Wallace, an assistant professor in the Division of Urology at University of Toronto. Joining me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia.

As we launch into this recent update to the prostate cancer guidelines, we really have a focus here on principles of quality of life and shared decision-making, as they influence prostate cancer treatment choice.

One of the first principles that the NCCM panel emphasizes is that, it's important before embarking on prostate cancer treatments to measure baseline disease specific function, and this includes urinary, sexual, and bowel function. While this can be done qualitatively, the panel recommends that it's preferable to use the standardized patient reported outcome measure, such as the EPIC-26.

And so, we'll highlight here the EPIC-26, which was developed and validated by a group led by Dr. Sanda. This really represents a pared down version of the original EPIC-50 to try and make it more accessible for patients. And the goal here really, to facilitate both health-related quality of life research across a broad range of prostate cancer research and practice settings, but also to provide guidance in clinical care. And importantly, the authors in this derivation study found that there's a high correlation between the results of the EPIC-50, which is relatively longer, more burdensome, and the EPIC-26, both with respect to urinary incontinence, as well as urinary irritative and obstructive symptoms, bowel function, sexual function, and vitality and hormonal domains. And so this, as of 2010, really supported the use of this pared down version, the EPIC-26, for both research and clinical care.

And then you can see here, an example of what you may ask your patient when using the EPIC-26, and this is the sort of standard questionnaire form. And we allow patients to fill this in on their own time without a physician by directly monitoring as it provides more representative analysis. And you can see that we move from a urinary function through to bowel function, sexual function, and hormonal questions. And these are relatively easy for patients to fill out without a significant A test response burden.

Principle number two is that, treatment for patients with localized prostate cancer should be acknowledged to have risks and side effects that must be considered in the context of the risk posed by the disease. And so, we really have to weigh the risks and benefits of therapy, given what we know about the oncologic risk of disease progression.

And as we move this into practice, principle number three becomes important, as baseline urinary, sexual, and bowel function, are strongly associated with functional outcomes following treatment for those patients who do offer therapy, and we need to use this for informed patient counseling.

And so, when we try to integrate these and we look at the data behind them, there are a number of key studies, including work from Dr. Sanda, the NC process group, CESAR cohort, and the ProtecT trial. We'll run through each of these in turn.
And so, among the first studies here was work from Dr. Sanda and colleagues published in New England Journal Medicine in 2008, which prospectively examined outcomes for 1200 men, as well as importantly, 625 spouses and partners. And they looked both before and after radical prostatectomy, brachytherapy or external beam radiation therapy. But the goal of identifying determinants of health related to quality of life after primary therapy, and to measure the effect of these determinants and satisfaction with the outcome of treatment.

And you can see here, that there are, as expected, changes in quality of life after primary treatment. And so we have here in the columns, each of the three treatment modalities, and then across the rows different domain scores. And so, you can see in column A that prostatectomy is associated with dramatic declines in sexual function immediately after surgery, some of which recover, but recover better in the nerve sparing cohort. In terms of urinary incontinence, there's a big dip at two months for surgically treated patients, which then recovers over time, but not quite back to baseline. Small effects on urinary irritation or obstruction scores, minimal effects on bowel or vitality scores.

For the radiation patients, those receiving radiation with ADT see a dramatic decline in their sexual function scores, whereas, those who treated with radiotherapy alone see less of a decline. In terms of urinary incontinence, there's minimal effects here, but we do see with radiation an effect on urinary irritation in the early post-treatment period. Similarly, there's an effect on a bowel and rectal function, and those receiving hormones have a decrease in their vitality scores. Similar trends are observed for the brachytherapy group.

The next study published at the same time is the first report of the CEASAR cohort, which Zach is going to summarize, is the NC process group. And this is population-based cohort study examining just over 1100 men in North Carolina, of whom approximately 28% received active surveillance, 40% received radical prostatectomy, 22% received external beam radiation, and about 10% received brachytherapy. All patients received quality of life assessment using the prostate cancer symptom indices at baseline, three, 12, and 24 months after therapy. And the goal was to provide a cross treatment comparison here.

And using the active surveillance as a comparator, we saw sexual dysfunction scores worsened at three months for all three groups of patients receiving therapy. And when we look at specific treatment related effects at three months, we see worse incontinence for those receiving surgery, worse urinary obstruction and irritative symptoms for those receiving external beam radiation or brachytherapy, and worse bowel symptoms for those receiving external beam therapy. Importantly, the authors found that by 24 months, there were minimal differences between these treatment groups and those treated with active surveillance.

I'm now going to hand it over to Zach to walk us through the results from a few more studies in this domain, and walk through other principles in terms of shared decision-making.

Zach Klaassen: Thanks so much, Chris. As Chris alluded to, this is the CEASAR trial, which is a third out of the four studies important for principles two and three. And this is work led by Dr. Dan Barocas at Vanderbilt. And this was a prospective population-based cohort of 1386 men with favorable risk disease, and 619 men with unfavorable risk prostate cancer. And these investigators used patient reported outcomes including EPIC-26 up to five years after treatment, with the goal of comparing functional outcomes associated with treatments over the five years after treatment. And this was published in JAMA in 2020.

So this is the favorable risk disease cohort. And you can see here, that nerve sparing prostatectomy is in red, external beam radiotherapy is in dark blue, low-dose brachytherapy is in light blue, and active surveillance is in orange. And so, looking at the top, sexual function, this is really recapitulating the previous studies that Chris talked about, but sexual function, we see a dip for nerve sparing radical prostatectomy, which then comes up almost back to baseline at about 60 months, and sort of a progressive decline in sexual function for those undergoing external beam radiotherapy.

With regards to urinary incontinence, again, we see a dip at six to 12 months for those undergoing surgery, with some recovery, but not quite to the level of those receiving other treatments. With regards to urinary irritative symptoms, we see the biggest effect on those undergoing low dose brachytherapy, with recovery of function about two years after treatment. And for bowel function, slight decreases for those receiving either external beam radiotherapy and low-dose brachytherapy, but again, recovering function several years after treatment. With regards to hormone function, really minimal to no difference across the treatment groups.

This is the unfavorable risk disease group based in CEASAR. And so here, we're looking at, because of the more aggressive disease, just radical prostatectomy versus external beam radiotherapy with ADT. And so, moving up to the top in sexual function for both treatments, we see a decrease in function, at about six to 12 months, with some recovery over the course of follow up. With urinary incontinence, certainly not surprisingly with the radical prostatectomy group, we see a decrease of six to 12 months with minimal recovery, but not quite to the level of those receiving external beam radiotherapy.

For irritative symptoms, really minimal effects for both treatment groups. And for bowel function, we see a decrease, slight decrease at about six months for those receiving external beam radiotherapy, with general recovery occurring around two years.

Again, not surprisingly, among the men receiving external beam radiotherapy plus ADT, we see a decrease in hormone function compared to radical prostatectomy, but a recovery in hormone function roughly three to four years after treatment.
The final study in this group of four is the ProtecT trial, which was published by Dr. Donovan and colleagues in New England Journal Medicine in 2016, and this was 1643 men who completed a questionnaire before diagnosis, as well as at six and 12 months thereafter, and an annual follow up. These investigators assessed urinary bowel and sexual function, as well as specific effects on quality of life, including anxiety and depression, with the goal in of investigating the effects of active monitoring, radical prostatectomy, and radiotherapy with hormones, on patient reported outcomes.

So this is broken down, each slide, by each of these domains. So this is the urinary function. The color scheme here is radical prostatectomy in red, radiotherapy in orange, and active monitoring in blue. As you can see here in panel A, B, and C looking at incontinence, we do see worse incontinence for those receiving radical prostatectomy, with recovery almost back to the other two treatment options, at around five to six years. In terms of urinary score, we do see a dip in those receiving radical prostatectomy as well as radiotherapy, but again, recovery at about one to two years, compared to active monitoring. With regards to voiding score, we do see some slight worsening for those receiving radiotherapy, but again, recovery which is comparable as well, for those looking at urinary symptoms of quality of life, as well as nocturia, which we see worsening for radiotherapy, but again, recovery back to baseline, after about one to two years after treatment.

With regards to sexual function, generally here we see that the firmness score is affected by radical prostatectomy and radiotherapy, roughly six to 12 months after therapy with some recovery. We do see this correlating again with the erectile dysfunction and the sexual function score. When we look at sexual bother score, we do see that men receiving treatment, either radical prostatectomy or radiotherapy, do have a worsening of sexual bother score at around six months, with some recovery around three to four years after treatment, which also correlates with the sexual quality of life scores in the bottom left panel E.

With regards to bowel function, again, we see a slight decrease for radical radiotherapy for both bowel function score, bowel bother score, and particularly, we see this with loose stools, compared to radical prostatectomy or radiotherapy. And again, very little difference in treatments between fecal incontinence and bowel habits. But we do see, interestingly, in Panel E looking at bloody stools, we do see a slight increase over time for those receiving radiotherapy, which does persist up to 72 months since randomization.

Finally, looking at ProtecT health related quality of life, this is assessing physical health score, mental health score, has an anxiety score, and has depression score, and we see very little difference at all between radical prostatectomy, radiotherapy, and active monitoring for these items.

So the final principle in this session is looking at shared decision-making regarding initial management of localized prostate cancer, which should include an explanation of the potential benefits and potential harms of each option.

To delve into this a little bit further, this specifically discussing shared decision-making, the provider should explain the likelihood of cure, recurrence, disease progression, and disease specific mortality with each management option, taking into account disease severity and competing risks. It should also include an explanation of the effects of treatment, discussing the side effects of each treatment and predicted impact of quality of life, including the quality of life of urinary, sexual, or bowel function. And the patient preferences should be elicited and should be incorporated into the management decision. So the NCCN panel relied heavily on the AUA white paper, which was updated in 2022, led by Dr. Danil Makarov, and this basically takes on the SHARE approach to decision-making for clinically localized disease.

And so, using the SHARE acronym, the NCCN recommends that we should seek our patient's participation. This includes having a conversation with the patient and their family members. We should help the patient explore and compare treatment options. This may start with a discussion amongst the urologists, and then should also include options for second opinions and other specialists, such as radiation oncologists.

We should assess our patient's values and preferences, understanding the impact of what quality of life versus length of life may look like. And really, getting an idea of what their values are when they go through treatment.

Importantly, we should reach a decision with the patient. By the time they've gone through the process of discussing with other providers, it's important to actually come up with a decision for the patient, and also allowing your patient to evaluate their decision. So taking time to have a follow-up appointment to confirm that their questions are answered, and that they're truly comfortable with the decision that they've made.

So to summarize this session, this is a relatively new section of the NCCN Guidelines, looking at quality of life and shared decision-making. It's important that localized treatment for prostate cancer is associated with side effects and must be weighed in the context and risk of disease. As we've discussed extensively today, these side effects include urinary, sexual, bowel function. We should be using a standardized tool, such as EPIC-26, to assess patient quality of life and function at baseline and throughout the treatment and follow-up.

And importantly, as we just discussed, we should use shared decision-making when discussing treatment options with the patients and their families.

We thank you very much, and we hope you enjoyed this NCCN update, looking specifically at quality of life and shared decision-making for localized prostate cancer.