Functional and Quality-of-Life Impacts of Prostatectomy, Radiotherapy, and Active Monitoring: Patient-Reported Outcomes from the ProtecT Trial, Journal Club - Rashid Sayyid & Zachary Klaassen

March 27, 2023

Rashid Sayyid and Zach Klaassen discuss the New England Journal of Medicine publication "Patient-Reported Outcomes 12 Years After Localized Prostate Cancer Treatment." The Prostate Testing for Cancer and Treatment (ProtecT) trial evaluated prostatectomy's functional and quality-of-life impacts, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. Patients with low to intermediate-risk prostate cancer have excellent survival outcomes irrespective of the treatment chosen. The ProtecT trial showed that at 15 years, the prostate cancer mortality rate was 2.7%. To inform patient decision-making, accurate data regarding short, medium, and long-term urinary function, sexual function, bowel function, and quality of life is needed. The trial aimed to provide this data to inform patient decision-making and minimize associated treatment regret. ProteT provides evidence about the long-term effects of treatments on prostate cancer, allowing patients and clinicians to make informed and prudent treatment decisions.


Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a first year urologic oncology fellow at the University of Toronto, along with Dr. Zack Klaassen, assistant professor and program director of The Medical College of Georgia. We'll be presenting the most recent report from the ProtecT trial looking at patient-reported outcomes 12 years after localized prostate cancer treatment. This article was recently published in the Open Access New England Journal of Medicine Evidence paper on March 11, 2023, the same day as the oncologic outcome report was published.

We know that patients with low to intermediate risk prostate cancer have excellent survival outcomes irrespective of the treatment chosen. And this was demonstrated in the most recent updated ProtecT trial that showed that at 15 years, the prostate cancer mortality rate was 2.7% and was non significantly different irrespective of the initial treatment patients were assigned to. As such, we need accurate data regarding the short, medium, and long-term urinary function, sexual function, bowel function, and quality of life. And this is critical to inform patient decision-making and minimize associated treatment regret.

The most recent update from ProtecT looking at the patient-reported outcome measures was published by Donovan et al in the New England Journal of Medicine in 2016. And if we look at the different domains and we focus on urinary function, looking at patients who need at least one pad per day, we see that there were some differences between the three arms. The red curve represents the radical prostatectomy arm, and we see that there was an initial hit that was much more significant in this arm compared to the other two. Now, this tailed off but still it's six years, there was a significant difference with 17% of patients requirement at least one pad per day in the radical prostatectomy arm, compared to 4% and 8% in the radiation therapy and active monitoring arms.

Looking at sexual function, again, this is the reverse. We see that there was a significant drop in the radical prostatectomy arm, a lesser but also pronounced drop in the radiotherapy arm. And by six years, we see that only 17% of patients in the radical prostatectomy arm reported erection firmness, compared to 27% with radiotherapy and 30% with active monitoring.

Now when we look at the bowel function score, there were no differences between the three yards, although with regards to fecal incontinence, it may be a little worse at six years in the radiotherapy arm at 8%, but one may argue that this difference is not clinically meaningful when compared to 5% active monitoring arm and 3% in the radical prostatectomy arm.

Overall, the ProtecT trial, the Prostate Testing for Cancer and Treatment, was funded by the NIH and the University of Oxford. And it invited 82,429 men between the ages of 50 and 69 years, but a life expectancy of at least 10 years. No other malignancies except skin cancer, and all patients were eligible for treatment. These men received invitations from 337 primary care centers between 1999 and 2009. And these men were invited to have a PSA test. And if the PSA was between 3 and 20 ng/ml, patients were invited to undergo rectal exam and a 10-core TRUS-guided biopsy at one of nine secondary care centers. Now, for patients who had a benign biopsy, they were invited to undergo a repeat biopsy if their f/t ratio was less than 11% or they had evidence of ASAP or HGPIN on the biopsy. Now, if that repeat biopsy was also still negative, then these patients were excluded from the trial and they were managed by their primary care physician.

Eventually, localized prostate cancer was diagnosed in 2600 men. And of these 2600, about 1643 were randomized to either active monitoring, prostatectomy, or radiotherapy with three to six months of neoadjuvant ADT.

Looking now at the patient-reported outcome measures, these were completed at baseline at six months, and then annually. And there were four main domains that were assessed. If we look at the table on the left, the first domain was urinary function and quality of life. The second domain was sexual function and quality of life. Third was bowel function and quality of life, and the fourth was generic health status, anxiety, depression, and cancer-related quality of life.

And if we look at the box on the right, these were the questionnaires and the scales that were used for the purposes of this study. Of note, clinically-meaningful differences between the groups were not pre-specified by the authors, and they did that on purpose to allow the readers themselves to reach their own conclusions of what essentially accounts for a clinically-meaningful difference.
For the statistical analyses, the intention-to-treat principle was followed, and essentially irrespective of what patients received afterwards, all participants were analyzed as per their initial treatment assignment. And given that we had repeated measurements in the same patients, so essentially the same patient had their outcomes measured at, let's say, six months and then a year afterwards, and then two and a half years. Given the repeated measures, they performed a two-level mixed-effect models where the higher level was the participant and the lower level was the repeated measures themselves. If the responses were binary, meaning yes, no, they used a logistic model. And if it was a continuous response, they used a linear model. And then for each outcome, they tested the null hypothesis of no difference in response in the means or the odds across the three groups over the seven to 12 years of follow up.

The multi-variable models that are comparing the groups assessed the outcomes, adjusting for age, the log-transformed baseline PSA, the Gleason score, and then the nine study centers. Again, there was no adjustment for multiplicity performed in this study. And this has the downstream effect of an increased risk of a type 1 error (i.e. false positive) for between-group comparison, so the authors were more likely to find differences irrespective whether they were present or not. Missing data was not imputed and this was assumed to be missing at random given that they were similar across the three groups. And the follow-up data completion was quite impressive in this study. Also, baseline measurements were not included for in the covariates, and that's because some questionnaires were added and some were removed during the study period. But irrespective of that, the baseline patient-reported outcome measures were similar across the three groups. And at this point, I will turn it over to Zach to discuss the results and the discussion.

Zachary Klaassen: Thanks so much for that great introduction, Rashid. This is basically going to be a series of slides that has very similar looking pictures to these graphs here, and we're going to walk through several of the domains including urinary sexual bowel and overall health-related quality of life. We'll start with the urinary function and impact on quality of life. What we can see with regards to incontinence score on the left is that not surprisingly, there was worse incontinence for radical prostatectomy patients, which then did level out but was ultimately a little bit higher than the active monitoring and radiotherapy arms.

However, when we look at the EPIC one pad or more per day, and this is comparing patients from seven versus 12 years, we see that among all three groups, the pad per day requirement went up from seven to 12 years most notably in the radical prostatectomy group, 18%, followed at 24% at 12 years, radiotherapy, 3% up to 8% at 12 years, active monitoring, 9% up to 11% at 12 years. One of the key take home points I think from this study is that up to 12 years after radical prostatectomy, one quarter of men will have more than or equal to one pad per day of incontinence.

The second set of slides looking at urinary function looks at the incontinence as a moderate or severe interference with life, and this is at 12 years time. Radical prostatectomy patients, 15%, radiotherapy patients, 7%, and active monitoring patients, 11%.
Looking at the third slide for urinary functioning outcomes of quality of life, in the bottom left, we see nocturia. Again, this is a comparison of seven years of follow-up versus 12 years of follow-up. All these patients had worse nocturia at 12 years compared to seven. We see 27% of radical prostatectomy versus 34% at 12 years, radiotherapy, 37% versus 48% at 12 years, active monitoring, 37% versus 48% at 12 years. In the top right, we see the impact on quality of life in which patients responded somewhat or a lot affecting their quality of life. This range from 7-11% for radical prostatectomy, 5-7% for radiotherapy, and 7-11% for active monitoring.

Switching gears to sexual function, this is the EPIC: Erection Firmness scale on the left side panel. And again, this is comparing erection firmness at seven years versus 12 years. We see as you can see in the graph here that for all three groups, the metrics converge to roughly 13-17% at 12 years. But, we see that there's a drop from 18% for radical prostatectomy down to 13-17%, a significant drop for radiotherapy and active monitoring at 27% at seven years, radiotherapy, and 30% for active monitoring at seven years.

Looking at the bottom left, this is the quality of life severe impact of sexual function at seven years. And this is quite sobering data when we look at severe impact on quality of life from a sexual function standpoint, at 42% of radical prostatectomy patients at seven years, 30% for radiotherapy, and 37% for active monitoring. So clearly, these patients among all these groups have significant downstream effect on quality of life from sexual function.

Looking at the bowel function impact on quality of life, radical radiotherapy is in yellow, and we can see that both for bowel function score and bowel bother score on the right, that there's an initial decrease in function score within about one to two years after treatment. But as you can see, these lines do converge with additional follow up with the radical prostatectomy and active monitoring arms.

Looking at fecal incontinence, and this is fecal leakage at 12 years on the right side of the screen. Radical prostatectomy, 6% of patients with fecal leakage at 12 years, 12% of radiotherapy patients, and 6% of active monitoring. Again, this is another one of these long-term follow-ups which is important to counsel our patients, that 12 out of a hundred men with radiotherapy will have fecal incontinence up to 12 years after treatment.

Looking at the final EPIC analyses for bowel function, bloody stools and bowel habits, both again with a little bit worse for radiotherapy in the first several years, but leveling out with radical prostatectomy and active monitoring in the final eight to 12 years of follow-up, as you can see on the figures on this screen.

Switching gears to health-related quality of life with on the left is physical health score, we can see that it's basically overlapping amongst all three patient groups. A slight decrease from years of randomization, zero up to 12, but essentially quite stable. And again, with mental health score for all three groups, overlapping and essentially stable throughout the 12 years of follow up.
Looking at anxiety on the left and depression on the right, we see some variability between the three groups, but again, relatively low numbers and quite consistent between the three groups, active monitoring, radical prostatectomy, and radiotherapy.

With regards to discussion points from this patient-reported outcome metrics for ProtecT, the immediate and short-term effects of treatments are well-documented, with some authors concluding that side effects are attenuated by two to five years. But what we saw in this analysis from ProtecT with the longest follow up to date on patient-reported outcomes of seven to 12 years, these men can have long-term side effects.

And sort to recap some of the highlights from the results we just discussed, urinary leakage requiring pads, 24% of patients undergoing radical prostatectomy by year 12. Sexual function was best in the active monitoring group, worse in the radical prostatectomy group. But as we discussed, these do converge around 12 years of follow-up to be about the same regardless of treatment modality. Importantly, fecal leakage increased in year seven to 12 for radiotherapy, again with 12% of patients at 12 years of follow-up having fecal leakage after radiotherapy. So not surprisingly, it's important for patients to have this information to avoid decisional regret associated with treatment adverse effects when they're discussing treatment with their clinicians.

In conclusion, ProtecT provides robust evidence about continued impacts of treatments in the long term. And these data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits, and enable better informed and prudent treatment decisions.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club of the ProtecT patient-reported outcome metrics recently published in New England Journal of Medicine evidence.