Erectile Function after SBRT

Erectile function after radiation is of great interest to many men trying to decide between surgery and radiation, and to decide among the several radiation treatment options. Dess et al. reported the outcomes of men who received stereotactic body radiation therapy (SBRT), often known by the brand name CyberKnife.

Between 2008 and 2013, 273 patients with localized prostate cancer were treated at Georgetown University. All patients filled out the EPIC questionnaire at baseline, which includes several questions on erectile function. The authors focused on the question asking whether erections were firm enough for intercourse, irrespective of whether they used ED meds. A similar questionnaire, SHIM, was also used, but results were similar. Answers were tracked over time with analyses at 2 years and at 5 years. Importantly, the median age at baseline was 69 years. At 2 years:

• About half the men had functional erections at baseline
• Among those with functional erections at baseline, 57% retained potency
• The largest loss occurred by 3 months after treatment, with about 2/3 retaining potency at 3 months
• 2/3 retained potency at 3 months regardless of age
• Men under 65 suffered no further loss of potency, even after 5 years
• Men 65 and over continued to lose potency
• About half retained potency at 2 years
• About 40% retained potency at 5 years

The authors also looked at other causes of erectile dysfunction, including partner status, BMI, diabetes, cardiovascular disease,  depression, baseline testosterone levels, and baseline use of ED meds. None of those, except BMI, had a statistically significant effect in this patient population at 2 years post treatment.  Some gained importance by 5 years, but because they are age dependent, and also affect baseline ED, none except BMI were independently important after baseline function and age were accounted for. A few known risk factors for ED were not included: medications (e.g., beta blockers, testosterone supplementation, etc.), smoking, and substance abuse. Some of that data was collected and may be included in a subsequent analysis.

There is a source of statistical error called colinearity, which arises when 2 variables, like baseline potency and age, are substantially interlinked. Although they were independently associated with erectile function, there is considerable overlap, especially when patient age was over the median (69). It may be useful to separate the effect of one from the other. This is accomplished by using age-adjusted baseline erectile function in the same way that economists look at inflation-adjusted GNP. I hope the authors will look at this. As we saw, an analysis of brachytherapy utilizing a different technique showed that half of the loss of potency among men who had brachytherapy was due to aging.

The effect of age on potency preservation cannot be overemphasized. Undoubtedly, radiation can cause fibrosis in the penile artery, and fibrosis is worse in older men. But, contrary to a prevalent myth, those radiation effects occur very early. Following that early decline, the declines in potency are primarily attributable to the normal effects of aging (which include occlusion of the vasculature supplying the penis.) As we've seen in other studies, most of the radiation-induced ED will show up within the first two years, and probably within 9 months of treatment. This was shown for 3D-CRT in the  ProtecT clinical trial,  for brachytherapy, for SBRT, and for EBRT.

Looking at other reports of potency preservation following SBRT, the Georgetown experience (57% potency preservation) seems to be on the low end. There has only been one report of lower potency preservation: 40% at 3 years among 32 patients. An earlier report from Georgetown reported 2-year potency preservation at 79% at 24 months. Dr. Dess explained that the earlier report included men with lower potency at baseline. However, because baseline potency is highly associated with post-treatment potency, the outcomes should be in the other direction. The discrepant data are puzzling. At 38 months post treatment, Bernetich et al. reported potency preservation in 94% among 48 treated patients. Friedland et al.  reported 2-year potency preservation at 82%. Katz reported potency preservation of 87% at 18 months. Although, different patient groups may respond differently, it is difficult to understand why potency preservation was so much lower in the current study. These discrepancies argue for a more standardized approach to analyzing erectile function after treatment, and the present study makes a good start towards that goal.

Compared to other radiation therapies, SBRT fares well. Evans et al. looked at SBRT at Georgetown and two 21st Century Oncology locations and compared it to low dose rate brachytherapy (LDR-BT) and IMRT as reported in the PROSTQA study. At 2 years, among patients who had good sexual function at baseline, EPIC scores declined by 14 points for SBRT, 21 points for IMRT, and 24 points for LDR-BT( the minimum clinically detectable change on that measure is 10-12 points). There has been only one randomized trial comparing extreme hypofractionation to moderate hypofractionation. In that Scandinavian trial, they used an older technique called 3D-CRT, which would never be used today to deliver extreme hypofractionation (at least I hope not!). In spite of the outmoded technology, sexual side effects of of the two treatments were not different. In an analysis from Johnson et al. comparing SBRT and hypofractionated IMRT, the percent of patients reporting minimally detectable differences in sexual function scores was statistically indistinguishable in spite of the SBRT patients being 5 years older.

Dess et al. also looked at sexual aid utilization in a separate study on the effect of SBRT. They found:

• 37% were already using sexual aids at baseline
• 51% were using sexual aids at 2 years
• 55% were using sexual aids at 5 years
• 89% of users say they were helped by them at baseline, 2 years and 5 years
• 86% used PDE5 inhibitors only (i.e., Viagra, Cialis, Levitra or Stendra)
• 14% combined a PDE5 inhibitor with other sexual aids (e.g., Trimix, MUSE, or a vacuum pump)

Erectile function is well-preserved following SBRT, and seems to be as good or better than after IMRT, moderately hypofractionated IMRT, or LDR brachytherapy. Based on reports of a protective effect of a PDE5 inhibitor, patients should discuss their use with their radiation oncologist starting 3 days before radiation and continuing for 6 months after. High levels of exercise and frequent masturbation may have protective effects as well.

With thanks to Daniel Spratt and Robert Dess for allowing me to see the full texts of their studies

Patient-reported outcomes from ProtecT - the first randomized trial comparing surgery, radiation, and active surveillance

While there were no differences in 10-year mortality when patients were randomized to surgery (RP), external beam radiotherapy (EBRT), and active surveillance (AS) (see this link), the side effects patients suffered from those treatments differed markedly. Johnson et al. have published the patient-reported outcomes of the ProtecT trial in the New England Journal of Medicine (see this link).

In the ProtecT trial, all participants (or actually 85% of them) filled out a series of validated questionnaires (EPIC and others) that probed issues of urinary function, rectal function, sexual function, and general health. I will ignore the overall health, vitality and mental status questions for now. Suffice it to say that they did not differ among therapies, nor were they very much affected by them. Questionnaires were filled out before the biopsy (the baseline), and at 6 and 12 months after randomization, and annually thereafter until 6 years from the initial biopsy.

What is especially interesting is seeing how equivalent patients (they are equivalent because they were randomized to the 3 treatments) did over the 6 years after receiving each treatment. This means that, for the first time, the side effect profiles are completely comparable (well, almost) and almost without bias.

Some messy data

I say "almost" because there was some switching of treatments that did occur. 22% of the men did not get the therapy they were originally randomized to, and they self-selected some other therapy or no therapy. However, in the analysis they are treated as if they got therapy that they were originally intended to get. Strange, huh?

In addition, they may have received salvage therapy after biochemical failure, and 55% of those assigned to AS did get a radical therapy eventually. So for each intended therapy:

• Among those 291 men who started on AS but got radical treatment: 49% had surgery, 33% had radiation as specified, and 18% had another kind of radiation or HIFU
• Among those 391 men who started on RP, 14 (4%) had adjuvant or salvage radiation, and 1 went on lifelong androgen deprivation therapy (ADT) within a year.
• Among those 405 men who started on EBRT,  3 had salvage RP, 14 (3%) went on lifelong ADT, and 1 had HIFU.

Whether men had the assigned therapy or not, and irrespective of any other therapy they had, they are included with the group they were originally assigned to. It's messy.

Fortunately, there's hope in sight. In one of the Appendices (Section S3), they added the note:

"In future analyses, we intend to present patient-reported outcomes according to treatment received and an economic evaluation including assessment of therapies received for treatment impacts, as well as details about the reasons for change of management in the active monitoring arm to further inform individual and clinical decision-making"

That will give us a much truer picture of the side effects associated with the treatments they actually received.

The treatments

RP was open and nerve sparing. While most men now have robotic surgery rather than open surgery, it seems to make little difference, except for some higher incidents of issues arising during the operation (see this link).

AS did not have required follow-up biopsies, so their side effects may be a little better than on contemporary AS programs. Biopsy complications are never long-lasting anyway.

EBRT was different from contemporary standards. The dose was lower (74 Gy vs. 80 Gy), so there may have been fewer complications due to dose. They used an older delivery technique (3D-CRT vs IMRT) which had higher rates of side effects. And it was given together with short term (3-6 months) of ADT, which would certainly increase the early sexual side effects. ADT is seldom given to favorable risk patients today.

note: all of the patient-reported outcomes include the effect of whatever remedies they used to treat them.

1. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AS or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 20% were incontinent by the end of two years, with little improvement from that point.

For EBRT, incontinence peaked at 5% at 6 months. Remember, this was 3D-CRT - a technology that has greater toxicity than the IMRT predominantly in use now. It hovered around 3-4% thereafter.

For AS, incontinence also peaked at 4% at 6 months, and stayed at that level for the next couple of years. From then, it steadily rose to 8% by the end of the 6 year study. Remember that for the purposes of this trial, men were still included in the AS cohort whether they were eventually treated or not. By 6 years, more than half the men had been treated, primarily with surgery.

Table 1. Incontinence: The percent who used one or more pads per day

Time point	AS	RP	EBRT
Baseline	0%	2%	0%
6 months	4%	46%	5%
1 year	4%	26%	4%
2 years	4%	20%	4%
3 years	5%	20%	3%
4 years	7%	17%	4%
5 years	7%	17%	3%
6 years	8%	17%	4%

b. Urinary Irritation/Obstruction

The researchers examined the question of whether urination become more difficult or more frequent after therapy. One way to look at this is a set of questions on the EPIC questionnaire asking about urinary frequency and retention. On that questionnaire, a score of 100% means that function is perfect in that regard, no issues whatever.

On this dimension only EBRT had a clinically detectable effect, and it was only at the 6 month mark. EPIC score dropped from 93% to 84%. After that, it returned quickly to baseline levels.

Table 2. Urinary Irritation/Obstruction EPIC scores, where 100% would be the best possible score.

Time point	AS	RP	EBRT
Baseline	93%	92%	94%
6 months	92%	89%	84%
1 year	93%	93%	93%
2 years	92%	93%	93%
3 years	91%	93%	93%
4 years	91%	94%	93%
5 years	92%	94%	93%
6 years	92%	94%	93%

2. Rectal Adverse Outcomes

The researchers asked the trial participants about their bowel function at baseline and after treatment. There were no discernable effects of AS or RP. Bowel function among the men enrolled for EBRT declined by 6 months (from a score of 93% to 86%). Thereafter, bowel function scores returned to near baseline levels. Other than the 6 month time point, there were no significant differences among the 3 treatments.

Table 3. Bowel function EPIC scores, where 100% would be the best possible score.

Time point	AS	RP	EBRT
Baseline	92%	91%	93%
6 months	91%	92%	86%
1 year	92%	93%	90%
2 years	92%	93%	90%
3 years	92%	93%	91%
4 years	92%	93%	91%
5 years	92%	93%	90%
6 years	92%	92%	91%

3. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AS. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was reduced to 12% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 21% at 3 years but did not recover beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AS cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they elected to have radical therapies, predominantly surgery. 11% of this cohort had already elected to have radical treatment by the 6-month mark.

For the EBRT cohort, erectile function had dropped to a minimum value of 22% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 38% at 1 year, and declined to 27% by 6 years. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point	AS	RP	EBRT
Baseline	68%	65%	68%
6 months	52%	12%	22%
1 year	49%	15%	38%
2 years	47%	19%	34%
3 years	41%	21%	34%
4 years	37%	20%	32%
5 years	35%	20%	27%
6 years	30%	17%	27%

Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation

That's clearly not true for incontinence or erectile function, It is true for urinary irritation and rectal function, which are at baseline levels and similar in all cohorts at 6 years.

Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.

What we've seen here belies that myth. There is some recovery of continence up to two years later, but not thereafter. After radiation, incontinence was a minor symptom (except to those who had it, of course), but it did not increase over the years. Urinary irritation/obstruction increased at 6 months for EBRT, but returned to baseline permanently thereafter. Rectal function scores also permanently returned to baseline levels after the 6-month time point.

Myth #3: Over time, erectile function is about the same for surgery and radiation. 

As we've just seen, erectile function is much worse after surgery, and it never recovers much beyond 2 years. It is worth tracking this myth down to its source. I have even heard John Mulhall, the eminent Memorial Sloan Kettering sex specialist quote this myth.

I believe this myth started with the PROSTQA study published in 2008. Until the ProtecT trial, it was our best source of patient-reported outcomes after the various treatments. The patients were not randomly assigned, however, and differed markedly in their characteristics. Those characteristics, especially age, varied greatly with the treatments they chose. In the following table, hidden in an appendix (all the good stuff is usually back there), we can extract the following table:

Table 5. Percent with preserved erectile function sufficient for intercourse 2 years after treatment, broken down by age at treatment 

Age	RP	EBRT	BT
<50	55	100*	75*
50-59	43	52	67
60-69	27	39	44
70+	8*	30	24
Total	35	37	43
Median Age	60 years	70 years	66 years

* small sample size

Although the potency doesn’t seem to vary much between treatments in total (range 35% to 43%), it is only because the men who received EBRT and BT were older than the men who were treated with RP. Within every age group, potency preservation was higher with radiation.

There are other differences between the two studies, such as: 
• this table only includes men who were potent before therapy, which would exclude about a third of men in the ProtecT trial. This would lower all the percentages in Table 5 relative to Table 4. 
• ProtecT included only men in the 50-69 age range, while half of the findings in ProstQA came from men treated with radiation over the age of 70. 
• Finally, ProtecT didn't yet report erectile function according to the therapy or therapies they actually received.

It is gratifying to see these myths shattered. Patients are the beneficiary.