Tailor Prostate Cancer Tx by Adverse Effects Profile

Pam Harrison

March 21, 2017

Each treatment for localized prostate cancer has its own distinct adverse effects profile, and physicians need to consider the comparative harms of each strategy when deciding which course is best suited for individual patients. This is the message from two separate studies and an accompanying editorial, all published online March 21 in the Journal of the American Medical Association.

"To date, men with clinically localized prostate cancer have never been better informed about the trade-off they have to make between oncological outcomes and now clearly defined potential adverse effects of available treatments," Freddie Hamdy, MD, University of Oxford, United Kingdom, writes in the editorial.

"These new studies provide a useful addition to the evidence, which will help physicians and patients to make difficult decisions about the management of this ubiquitous disease," he adds.

In the larger of the two studies, Daniel Barocas, MD, MPH, Vanderbilt University Medical Center, Nashville, Tennessee, and multicenter colleagues report outcomes among 2550 men with intermediate- or high-risk disease who underwent either radical prostatectomy, external-beam radiation therapy (EBRT), or active surveillance. The patients were followed for 3 years.

Surgery had the greatest adverse effects on sexual performance, they report.

"At 3 years, the adjusted mean sexual domain score for radical prostatectomy decreased more than for EBRT," the investigators report. The mean difference in scores between the patients who underwent surgery and those who underwent radiation therapy was -11.9 points; the mean difference was -16.2 points between those who underwent surgery and those who were under active surveillance.

In contrast, decline in the same sexual domain scores for men undergoing EBRT and those under active surveillance was not clinically relevant, at a difference of -4.3 points, they add.

Surgery was also more likely to cause urinary incontinence than either EBRT or active surveillance, especially in men who did not have urinary incontinence at baseline, the investigators note.

More men, at 14%, were also likely to report having either moderate or big problems with urinary leakage compared with the 5% to 6% of men in the other two treatment arms.

On the other hand, urinary irritative symptoms improved following surgery, whereas those symptoms showed little or no improvement in patients who received radiation or who were under active surveillance.

"Decline in bowel domain score was not common," the study authors continue.

At 6 months, mean scores in bowel domains were significantly worse among men treated with EBRT than in the other two groups, but at 12 months, there was little difference between the three groups.

Only the radiation group showed decrements in hormonal function, but these patients had all received androgen deprivation therapy, so this was expected.

Health-related quality-of-life scores were not significantly different between the three treatment groups at study endpoint, investigators add.

"These findings may facilitate counselling regarding the comparative harms of contemporary treatments for prostate cancer," researchers conclude.

Second Study

In the second study, Ronald Chen, MD, MPH, University of North Carolina at Chapel Hill, and multicenter colleagues followed 1141 men with newly diagnosed prostate cancer who were treated with radical prostatectomy, EBRT, brachytherapy, or active surveillance.

Scores for sexual, urinary, and bowel function at 24 months were all propensity-weighted, and the patients were stratified for baseline levels of function.

"At 3 and 12 months but not 24 months, patients who received external beam radiotherapy and brachytherapy had increased sexual dysfunction compared with active surveillance," the study authors observe.

However, sexual function was more likely to deteriorate after surgery; more than half of the patients (57%) who had normal sexual function at baseline reported poor sexual function 24 months after undergoing prostatectomy.

This compares with 27.2% of the men treated with EBRT, 34.2% for those who received brachytherapy, and 25.2% for those who were under active surveillance. (Among those assigned to active surveillance, almost 19% received some form of treatment within 24 months.)

Only about 20% of the men who received brachytherapy and who had no obstructive or irritative urinary symptoms at baseline still had no symptoms 24 months after brachytherapy.

This was much lower than approximately half of men who underwent either surgery or radiation therapy and who reported no obstructive or irritative symptoms 24 months after treatment.

Only about a third of the men who had no problems with urinary incontinence prior to surgery still had good urinary control 2 years later.

This was again much lower than the proportion of men who retained good urinary control 24 months after EBRT (73%) and brachytherapy (65%).

Close to 43% of the men who had normal bowel function prior to radiation therapy maintained good bowel function at 2 years, as did some 47% of the men who underwent brachytherapy and 57% of the men who underwent either prostatectomy or active surveillance.

"Physicians can use these data to provide more individualized counselling of their patients regarding expected outcomes of patients with similar levels of baseline function," the study authors reiterate.

Overall Outcomes

The findings from these two studies generally agree with each other, Dr Hamdy comments in the editorial.

Despite the fact that men involved in the current studies received more contemporary treatment options, he notes that the findings were "remarkably consistent" with those from the landmark ProtecT (Prostate Testing for Cancer and Treatment) study, which was published last year. Dr Hamdy was the principal investigator of that study.

The consistency of findings across all three studies shows "that all options carry risk of adverse effects that affect quality of life," Dr Hamdy comments.

Given the fact that all treatments for prostate cancer have some adverse effects, Dr Hamdy suggests a way in which physicians can best use this information to help patients come to a decision regarding their treatment.

"First, each man can take time to assess carefully with his treating physician the risk of receiving treatment or active surveillance taking into account the tumor risk category and his general health," Dr Hamdy advises.

Second, physicians need to review the main adverse effects that men might expect once they choose any one of the treatment options, at least in the short term: sexual function and urinary incontinence are worse after surgery and may persist over time; bowel problems are typically worse after radiation; and sexual dysfunction can be expected with androgen deprivation therapy.

Lastly, physicians need to remind men that even if they choose active surveillance and avoid adverse events initially, "there is a natural decline in urinary and sexual function symptoms over time," Dr Hamdy points out, "and the adverse effects of radical treatments will be experienced when those treatments are received."

How to "ProtecT" Men From Harm

In a separate opinion piece on findings from the ProtecT trial, Daniel Spratt, MD, University of Michigan, in Ann Arbor, argues that the "most powerful message" from ProtecT is how physicians can protect men from the adverse effects of radical therapy without jeopardizing oncologic outcomes.

The conclusion to be drawn from the ProtecT study, as expressed in the accompanying editorial, was that the higher risk for metastases seen in the active surveillance arm of the study supports the use of active surveillance only in patients with a relatively short life expectancy.

"Rather than concluding that radical therapy is the best choice, I would argue that the logical answer would be to select the appropriate patients for active surveillance and to optimize active surveillance strategies to avoid the small (approximately 3.5%) absolute increased risk of distant metastasis seen in ProtecT," Dr Spratt writes.

"Optimizing active surveillance will help to avoid or delay the often permanent adverse effects from radical treatment," he reaffirms.

Dr Hamdy and Dr Barocas have disclosed no relevant financial relationships. Dr Chen has received grants and personal fees from Accuray and personal fees from Astellas and Medivation. Dr Spratt has served on an advisory board for Dendreon.

JAMA. Published online March 21, 2017. Study 1, Abstract; Study 2, Abstract; Editorial

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