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

The myth that younger men should not pursue active surveillance

In spite of no evidence to back up their assertion, I continue to hear urologists say things like "If you were older, I'd recommend active surveillance. But because you're young, you should have surgery for your low risk prostate cancer now while your recovery will be better." We saw, in a previous article, that immediate surgery rather than active surveillance only resulted in more years of expected misery from impotence and incontinence: see: "Can a man be too young for active surveillance?"

Now, a new study from Memorial Sloan Kettering Cancer Center examines the evidence for potency preservation. The authors, who include John Mulhall, the sexual medicine specialist, demonstrate that the expected loss of erectile function is never compensated for by better recovery in younger men and the age-related decline in erectile function over the years while waiting on active surveillance.

They used a standard questionnaire, the International Index of Erectile Function 6 (IIEF6). It is sometimes called the Sexual Health Inventory for men (SHIM). There are six questions, and the best score (excellent erectile function) is 30. The questions are:

1. Over the last month, how often were you able to get an erection during sexual activity?
2. Over the last month, when you had erections with sexual stimulation, how often were your erections hard enough for penetration?
3. Over the last month, when you attempted intercourse, how often were you able to penetrate your partner?
4. Over the last month, during sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?
5. Over the last month, during sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?
15. Over the last month, how do you rate your confidence that you can get and keep your erection?

All men filled out the questionnaire before surgery and periodically for two years. They excluded high risk patients who wouldn't be eligible for active surveillance, and any men who did not have bilateral nerve-sparing surgery. Men who had hormone therapy or salvage radiation were also excluded. There were 1,103 men in their cohort of men treated with RP at MSKCC between 2009-2013. Needless to say, MSKCC has some of the best, most experienced surgeons in the world.

They first looked at the baseline scores by age to get an understanding of how erectile function declines with age. This defines the expected erectile function if there were no surgery. They also looked at actual scores after surgery for each age. The difference between actual and expected shows the true effect of surgery on erectile function, with compensation for age-related decline and for the time delay caused by active surveillance.

They found that:

• Each year increase in age reduced the IIEF6 score by -0.27
• Erectile function recovery after RP declined by -0.16 for each year older at the age of treatment

While younger men started with a higher erectile function score, and their recovery after RP was better, it was never good enough to be better than the erectile function of an older man who didn't have surgery. At all time points, they would have been better off if they had delayed treatment and stayed on active surveillance. There was no "window of opportunity" where younger age recovery exceeded what would be expected to happen if they waited.

The authors conclude:

Small differences in erectile function recovery in younger men are offset by a longer period of time living with decreased postoperative function. Better erectile recovery in younger men should not be a factor used to recommend immediate surgery in patients suitable for active surveillance, even if crossover to surgery is predicted within a short period of time.

I hope patients whose urologists spout the myth that "early surgery will lead to better long-term erectile function than delaying until he is older" will email this important study to them and ask for comment.

Vessel-sparing IMRT spares erectile function

While either nerve-sparing surgery or radiation can cause erectile dysfunction, the probability for that for any given patient is always worse after surgery. The recent ProtecT randomized clinical trial removed any doubt of that, if there ever really was any. While nerve-sparing surgery was introduced by Walsh in 1982, there has been no similar breakthrough in IMRT radiation delivery - until now.

Effects of treatments on erectile apparatus

The mechanism of erectile function is complex, involving the brain, hormones, neurotransmitters, enzymes, and nitric oxide, just to mention a few vital components. Nerve impulses must travel from the brain, through the spine, along the nerve fibers that surround the prostate and then along its length down to the corpus cavernosa (the spongy tissue inside the penis from the penile bulb to the glans). Surgery, even nerve-sparing surgery, usually disrupts the signal that must innervate the penis. "Nerve sparing" is not an all-or-nothing technique. If the cancer has grown out into the neurovascular bundles, only some of the nerves may be spared. Take away too little, and the cancer is not cured; take away too much, and permanent erectile dysfunction is assured. Sometimes surgeons send frozen slices of tissue for pathological analysis before deciding how much to remove.

When radiation causes erectile dysfunction, the mechanism is very different. Nerves are relatively impervious to radiation; however, blood vessels and other endothelial tissue may be affected. The blood that supplies the penis comes to it through the "pudendal arteries" that flow downwards on either side of the prostate (in the "neurovascular bundle"). The blood enters the penis at the penile bulb (the part that extends inside the pelvis) and engorges the tissue of the corpus cavernosa. Radiation may cause an inflammatory reaction in the linings of the blood vessels and in the tissue of the corpus cavernosa. Over a period of months, the inflammation may result in scar tissue that restricts blood flow, and the impedes the ability of the spongy tissue of the corpus cavernosa to expand and contract elastically.

For years, there has been somewhat conflicting evidence about whether radiation's effect on erectile dysfunction can be mitigated by reducing the dose to the penile bulb (see this link). Consequently, radiation oncologists set a dose constraint for the penile bulb, but that was not a full solution. Many radiation oncologists have wondered whether the dose to the pudendal arteries and to the other parts of the corpus cavernosa could be  restricted to preserve erectile function without sacrificing oncological effectiveness. Innovations in MRI-based planning and super-precise (sub-millimeter) beam delivery have enabled that.

Vessel-sparing IMRT

Spratt et al. at the University of Michigan conducted a clinical trial on 135 patients treated between 2001 to 2009 to see whether "vessel sparing" IMRT could better preserve erectile function while achieving equal cancer control. As others have, they used a T2 MRI to delineate the contours of the penile bulb and corpus cavernosa. Their innovation was to use contrast-enhanced MRI-angiography to delineate the pudendal arteries that run near the prostate apex. The MRI images were fused with CT scan images and dose goals were set based on those. Intermediate and high risk patients were treated with low dose rate brachy (seed) boost therapy before they received IMRT; low risk patients received IMRT alone. A treatment margin of 1 cm was set for patients receiving IMRT only. It was lowered to 0.5 cm for those receiving brachy boost therapy.

Key patient and treatment characteristics included:

• Age = 63 (median)
• Baseline erectile function: IIEF score ≥ 16 (mild or no ED)
• Risk: Low - 39%, Intermediate - 53%, High -9%
• Gleason score: 3+3 - 44%, 3+4 - 33%, 4+3 - 13%, 8-10 - 9%
• Treatment: IMRT alone - 39%, brachy boost - 61%
• Dose: IMRT - 75.6-79.2 Gy, brachy boost - 110 Gy I-125 seeds + 45 Gy IMRT
• Pelvic dose: 45 Gy (high risk only)
• 6-month ADT: yes -33%, no - 67%

Potency preservation

During a median follow-up of 8.7 years, patients filled out questionnaires and doctors evaluated their erectile function at 2 years and 5 years. They were also queried about their use of erectile medicines and aids. Their responses were matched to the results of the PROSTQA study, matched for age, baseline potency, and other sexual risk factors. The percent of men who had erections firm enough for intercourse 2 years after treatment were:

• 78% if they had vessel-sparing IMRT
• 42% if they had conventional IMRT
• 24% if they had nerve-sparing prostatectomy

Other measures of erectile function at baseline, 2 years and 5 years included:

• No sexual aid use: 88%, 47%, 44%
• IIEF score ≥16 (no or mild ED): 100%, 70%, 67%
• High/very high confidence in getting and keeping an erection: 63%, 40%, 33%
• Potent without aids: 80%, 45%, 35%
• Potent with aids: 20%, 41%, 53%
• Impotent: 0%, 14%, 12%

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 EBRT. Perhaps the authors will make an attempt to separate the effect of patient aging in a future analysis. The University of Michigan should be able to accomplish this using their age-adjusted sexual domain EPIC scores.

It's worth noting that potency preservation was no different for those who had the brachy boost or IMRT only. It was better for younger men, men with higher baseline performance, and those who did not have adjuvant ADT.

Oncological outcomes

At 5 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 100%
• High risk: 98%

At 10 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 89%
• High risk: 88%

One could not ask for better outcomes!

Conclusion

It appears that vessel-sparing IMRT is a vast improvement over conventionally targeted IMRT in terms of preservation of erectile function, and based on this, should be adopted as standard practice for all patients who might benefit. Interestingly, potency preservation is similar to that reported for SBRT (see this link) and for high dose rate brachytherapy (see this link). That is not at all surprising because both of those therapies use much narrower margins than those used for IMRT, typically 2-3 mm vs. 10 mm for IMRT, and the biologically effective dose to the vascular tissue of the pudendal arteries are lower. With SBRT, intra-fractional motion is tracked, thus avoiding dose to nearby structures. With HDR brachytherapy, the gland is immobilized with catheters that prevent doses to the nearby vessels and organs. Hopefully, equally excellent results can be achieved with hypofractionated IMRT,  but that remains to be proved in future trials. With salvage IMRT, the entire prostate bed is treated, so I do not know if radiation to the pudendal arteries can be similarly avoided.

Anyone planning on having IMRT should forward a copy of this study to his radiation oncologist, and ask to discuss it at their next meeting. Of course, for men who are low risk, active surveillance will cause no erectile dysfunction and no loss of ejaculate.

Toxicity equal for SBRT and conventional external beam radiation

There has been some question as to whether the toxicity of delivering very high doses of external beam radiation per treatment (or fraction) in fewer fractions (called “extreme hypofractionation” or SBRT) would be high compared to conventional dose rates per fraction. While SBRT practitioners have reported very low toxicity rates (see table in this link), there has always been some doubt because there may have been some bias in how patients were selected in the various studies.

The HYPO-RT-PC trial was the first trial ever to randomly assign patients to one kind of radiation or the other. Between 2005 and 2015, they enrolled 1200 intermediate-risk patients in Scandinavia to receive either:

1.  Conventional fractionation: 78 Gy in 39 fractions
2. SBRT: 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

There were a few differences from some US practices:

• “Intermediate risk” was defined as one or two of the following 3 risk factors:

1. Stage T1c-T3a (T3a is a high risk factor in the commonly used US definition)
2. PSA> 10 ng/ml (PSA> 20 ng/ml is a high risk factor in the commonly used US definition)
3. Gleason score ≥7 (Gleason scores greater than 7 are a high risk factor in the commonly used US definition)

• 80% of the men were treated with a technology called 3D-CRT, which is seldom used for external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic.

• SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

The toxicity results are based on 866 patients who had 2-year follow-up results. There were some differences in acute toxicity:

• Acute urinary toxicity was 27.6% for the SBRT group and 22.8% for the conventional fractionation group, but the difference was not statistically significant.
• Acute rectal toxicity was 9.4% for the SBRT group and 5.3% for the conventional fractionation group. The difference was statistically significant, but narrowed by 3 or 6 months.

Neither physician-reported toxicity nor patient-reported late-term toxicity differed by the fractionation schedule they received. By two years:

• Late-term urinary side effects were reported by 5.4% of the SBRT group and 4.6% of the conventional fractionation group. The difference was not statistically significant.
• Late term rectal side effects were reported by 2.2% of the SBRT group and 3.7% of the conventional fractionation group. The difference was not statistically significant.
• Impotence was reported by 34% of both groups, up from 16% at baseline.
• Patient-reported bother from urinary, rectal and sexual side effects were not different.

Given their use of the largely outmoded 3D-CRT technology, it was not surprising that acute toxicity would be elevated. I’m frankly surprised that late-term toxicity was not higher for SBRT.

They plan to present their findings on oncological outcomes at a future time.

Can a man be too young for active surveillance?

There is a “conventional wisdom” that active surveillance (AS) is only for older men, and that younger men are better off having immediate radical treatment, typically prostatectomy (RP). By “better off” we mean that there is a better chance at cancer control, or that the side effects of treatment, particularly incontinence and impotence, will be milder if treated earlier. Let’s turn a spotlight on that conventional wisdom, and see if it holds up under scrutiny.

The screening protocol for men under 50 years of age that is advocated by Memorial Sloan Kettering (see this link and this one), and recently discussed here, has important implications for active surveillance. Autopsy studies have demonstrated prostate cancer incidence of 20-30% in men under 50, mostly low grade and indolent. With increased screening of this young cohort, there will be an increase in the current incidence rate (now at about 10%). These men will increasingly be urged by their urologists to seek radical treatment, primarily surgery. If their screening protocol is widely adopted, there is great danger of over-treatment for this age group.

Oncological Control

With up to 20 years of follow-up, the Klotz Active Surveillance Trial has demonstrated the safety of that protocol. Klotz reported that of the 993 patients, there were only 15 deaths (1.5%) due to prostate cancer. When he pooled together several active surveillance studies, he found that the combined disease-specific survival rate was 99.7%. A Gleason score of 8-10 on confirmatory biopsy and a PSA doubling time of less than 3 years were associated with mortality, indicating the importance of close monitoring and follow-up biopsies on any active surveillance protocol.

It is worth noting how long men entering the Klotz study were able to stay on active surveillance before their progression characteristics indicated that radical treatment was required. Most of the progression was found in the first 5 years after entering the program, and reached a plateau by 15 years.

Time on AS	Percent for whom no treatment was recommended
5 years	75.7%
10 years	63.5%
15 years	55.0%
20 years	55.0%

Age was not a risk factor for prostate cancer mortality. Klotz said, “Younger patients were not at increased risk of prostate cancer mortality.” In fact, in younger men, the risk of non-prostate cancer mortality was almost six times higher than the rate of prostate cancer mortality.

It’s important to understand how slowly low-risk prostate cancer typically progresses in young men, even without active surveillance; that is, even without an intention to treat if the cancer progresses. Based on the Memorial Sloan Kettering Nomogram, we can see that for a 45 year-old man in excellent health diagnosed with a Gleason score of 3+3, PSA of 4 ng/ml, and nothing felt on a digital rectal exam, he has a zero chance of dying of prostate cancer in the next ten years, and a 4% chance of dying of something else. Even if he lets it go for 15 years, he only has a 3% chance of dying of prostate cancer, and an 8% chance of dying of something else.

It has been observed that there are rare and virulent forms of prostate cancer that are more prevalent in men under 50, and particularly among younger African-American men (see this link and this link). This is irrelevant to the discussion of active  surveillance  because those men will seldom be good  candidates for active surveillance from the outset. And if they do get in, clinical progression will be noticed in any active surveillance protocol at a very early time. Still, it is a reasonable precaution to screen men under 50 for genetic markers when there is a family history of early prostate cancer; for example, Oncotype Dx, Prolaris, TMPRSS2-ERG fusion, PTEN loss, or BRCA2 mutations.

Advancing age at the time of diagnosis is associated with a worse prognosis. In an analysis of 205,551 cases in the SEER database (see this link), 15-year prostate cancer mortality rates increased steadily with age at diagnosis.

Age Group	15-year PC mortality
≤50	2.3%
51-60	3.4%
61-70	4.6%
≥71	6.3%

Once again, this observation is irrelevant to a discussion of active surveillance. Age was not found to be a prognostic factor after accounting for Gleason score, tumor stage and PSA. The higher risk older men would probably not meet the entry criteria for active surveillance (although, depending on co-morbidities, they may be good candidates for watchful waiting). Those older men with more virulent disease that do get into an AS program would most likely be soon found to progress and be safely treated in time.

Based on oncological prognosis, younger age should not be used to decide between active surveillance and radical therapy.

Continence

An argument for treatment for younger men has been that there is a higher chance of continence preservation after surgery among younger men who already have better continence. Let’s see what the real-world numbers look like.

Continence naturally declines with age. Population-based continence statistics on younger men is scarce, but we can reasonably assume that moderate to severe incontinence is a rare occurrence in a 45 year-old man, and for our purposes, let us suppose that a 45 year old, just diagnosed with low-risk prostate cancer, is fully continent. What decision maximizes his lifetime expected continence?

Age	A. No natural moderate or severe incontinence	B. Expected lasting continence for men treated at that age	C. Percent losing continence due to RP at that age	D. Probability of staying on AS if started at 45	E. Expected loss of continence due to decision to initially have RP rather than AS	F. Life expectancy (years)
45	100%	80%	20%	100%	20%	34
50	92%*	79%	13%	76%	10%	30
55	84%	74%	10%	64%	6%	25
60	81%	70%*	11%	55%	6%	21
65	79%	66%	13%	55%	7%	18
70	74%	63%	11%	55%*	6%	14
75	74%*	59%	15%	55%*	8%	11

Sources:

A.     https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1060034/?page=4

B.     Younger cohort is from Johns Hopkins prostatectomy patients, older cohort is from University of Chicago: http://www.jurology.com/article/S0022-5347(06)01930-6/abstract http://www.jurology.com/article/S0022-5347(10)00017-0/abstract

C.     Column A – Column B

D.    Klotz, assuming plateau continues

E.     Column C x Column D

F.     Social Security actuarial tables

* extrapolated figures

Our fully continent 45 year-old man has about an 80% chance of retaining his continence if he has an immediate RP.  So, about 20% of 45 year-old men will lose continence if they decide for RP rather than AS. Those 20% will live with that loss of continence for 34 years.

If he chooses AS instead of RP, what happens in the next 5 years? He has some small natural deterioration of continence, roughly an 8% expected loss. If he has an RP 5 years from now, his expected continence is about the same at 79%. Therefore, his net expected loss of continence will be 13% if he remains on AS for the full 5 years. But he has only a 76% chance of staying on AS for the first 5 years. Therefore, his expected loss of continence due to the decision to go on AS at 45 and get treated at 50 is 10% - only half as much as if he had the RP at 45. And he will expect to live with that incontinence for fewer years.

If he chooses AS at 45 and manages to stay on it for the next 25 years without treatment (a 55% probability), his expected loss of continence (incorporating the probability of being able to go that long without treatment) is minimized, at only 6%. And he will only have to suffer the loss for 14 years.

With respect to preserving continence, the 45 year old man is better off going on AS and staying on it as long as he can. What’s more, it can be easily shown with a similar continence analysis that a man diagnosed with low risk prostate cancer at any age, is better off choosing AS over immediate treatment.

We have ignored the stress incontinence that persists even after “full” continence is restored. 34 years is a long time to worry about leakage every time a man coughs, sneezes, laughs or plays sports.

Potency Preservation

Potency is better preserved by prostatectomy while the patient is younger and fully potent. Is our 45-year old man, newly diagnosed with low risk prostate cancer and fully potent, better off having a prostatectomy immediately, or choosing AS? Let’s run the numbers.

Age	A. Expected potency without prostatectomy	B. Expected lasting potency for men treated at that age	C. Percent losing potency due to RP at that age	D. Probability of staying on AS if started at 45	E. Loss of potency due to decision to initially have RP rather than start with AS	F. Life expectancy (years)
45	100%	55%	45%	100%	45%	34
50	94%*	49%*	45%	76%	34%	30
55	87%	43%	44%	64%	28%	25
60	82%	35%*	47%	55%	26%	21
65	74%	27%	47%	55%	26%	18
70	60%	18%*	42%	55%*	23%	14
75	45%	8%	37%	55%*	20%	11

Sources:

A.     http://www.brachyjournal.com/article/S1538-4721(15)00003-3/pdf

B.     http://jama.jamanetwork.com/article.aspx?articleid=1104401 Supplemental content: eTable3 (97% had nerve-sparing surgery)

C.     Column A – Column B

D.    Klotz, assuming plateau continues

E.     Column C x Column D

F.     Social Security actuarial tables

* extrapolated figures

Our fully potent 45 year-old man has a 55% chance of retaining his potency if he has an immediate RP.  So, about 45% of 45 year-old men will lose potency if they decide for RP rather than AS. Those 45% will live with that impotence for 34 years.

If he chooses AS instead of RP, what happens in the next 5 years? He has some small natural deterioration of potency, roughly a 6% expected loss. If he has an RP 5 years from now, his expected potency will be a less too, at 49%. Therefore, his expected loss of potency nets out exactly the same (at 45%) if he remains on AS for the full 5 years. But he has only a 76% chance of staying on AS for the first 5 years. Therefore, his expected loss of potency due to the decision to go on AS at 45 and get treated at 50 is 34% - 11 percentage points less than if he had the RP at 45. And he will expect to live with that impotence for fewer years.

If he chooses AS at 45 and manages to stay on it for the next 25 years without treatment (a 55% probability), his expected loss of potency (incorporating the probability of being able to go that long without treatment) is only half of the expected loss due to immediate treatment, at only 23%. And he will only have to suffer the loss for 14 years.

With respect to preserving potency, the 45 year-old man is better off going on AS and staying on it as long as he can. What’s more, it can be easily shown with a similar potency analysis that a man diagnosed with low-risk prostate cancer at any age, is better off choosing AS over immediate treatment.

This analysis ignores other important sexual side effects that would certainly weigh against immediate prostatectomy. Those sexual side effects include loss of penile length and girth, climacturia, Peyronie’s, venous leak, dry orgasms, anorgasmia, and dysorgasmia. Baseline erectile function is seldom restored fully. Loss of libido and psychologically induced loss of erectile function and depression are common results of all the aforementioned. Even when erectile function can be induced chemically, there is significant cost attached to 34 years of ED medicines or injections.

Radiation

The choice is not nearly as clear when the decision is between AS and radiation therapy (either external beam or brachytherapy) for young low-risk patients. Incontinence is a very low probability side effect of radiation, and potency preservation is much better within every age group, chronic side effects of any kind are rare with modern technology. It is often argued that we don’t know how cancer control will change with 25+ years of follow-up after dose-escalated radiation. As we have seen (see this link), recurrence rates did not reach a plateau for RP or IMRT; however, if we were to examine low-risk patients only, it is likely that long-term results would be more stable for both surgery and radiation.

It is worth mentioning that there is another bit of “conventional wisdom” that does not hold up under scrutiny of the medical evidence. Many urologists incorrectly state or imply that the side effects of radiation are progressive and won’t show up for many years. Under that scenario, a 45 year-old man treated with radical radiation would eventually wind up with impotence 10 years later, as well as urinary and rectal problems. The PROSTQA study (see this link) of men treated in 1999 showed that most of the radiation-induced toxicity showed up early, and that much of the “late-term toxicity” observed may actually have been attributable to age, diabetes, and comorbidities (see this link).

The percent experiencing grade 2 or higher urinary toxicities (excluding incontinence) by 5 years, 8 years, and 10 years after treatment was:

• ·      IMRT: 8.6% at 5 years, 11.2% at 8 years, and 10 years (76% of 10-year total by 5 years)
• ·      BT: 4.3% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
• ·      RP: 3.1% at 5 years, 3.7% at 8 years, and 5.5% at 10 years (56% of 10-year total by 5 years)

Ironically, we would conclude  (erroneously) from the above that it is prostatectomy, rather than radiation, that has cumulative urinary side effects that progress most over time.

The percent experiencing grade 2 or higher rectal toxicities by 5 years, 8 years, and 10 years after treatment was:

• ·      IMRT: 7.8% at 5 years, 8 and 10 years (100% of 10-year total by 5 years)
• ·      BT: 1.7% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
• ·      RP: 0% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)

We have seen in a previous commentary that erectile dysfunction due to radiation was lower than for RP within every age group, that it occurred within the first 9 months following treatment, and that half of the observed deterioration over time was due to the normal aging process.

The case for active surveillance and against radical treatment at a younger age is less convincing if radiation is the treatment of choice. It is for currently mostly a moot point because younger low-risk patients are seldom offered radiation therapy.

Conclusions

I have been personally influenced by the testimony of a 45 year-old man in my prostate cancer support group who was inconsolable and under treatment for suicidal ideation after the loss of continence and potency. Younger men who are single and suddenly find themselves to be impotent and incontinent often despair of finding a mate, and younger men who are married sometimes find their marriages on shaky ground.

It is also important to remember that the longer one is able to stay on AS, the higher the probability a cure will emerge from all the research now in the field. Already it seems that 5ARis (Proscar or Avodart) may delay or even reverse progression in low risk PC. There are a number of hormonal medicines and immunotherapies already being tested that might prove to be even more potent.

AS protocols are already improving, and will continue to be safer. Many institutional protocols now dictate that the first follow-up biopsy should be multiparametric MRI-targeted and/or targeted using a transperineal mapping biopsy. To avoid the danger of excessive biopsies in younger men, many institutions have moved off of the original protocol of annual biopsies. After the first follow-up biopsy, what happens next depends on what happened before. If there were no signs of any progression, the next biopsy can be two years later; after that, maybe 4 years with just an imaging study in between, etc. I know that even Johns Hopkins, which had the strictest AS protocol, relaxed their position on annual biopsies.

We have now seen that starting with AS is a more rational decision than starting with RP for all low risk men. However, the decision is often not a rational one, but is based on fear, traditional “baggage” carried over from other cancers, and the influence of loved ones, relatives and friends. In the end, the young patient must decide what he is most comfortable doing. Maybe it will be AS, maybe SBRT or brachytherapy, maybe surgery. What I am uncomfortable with is his doctor making those life-changing decisions for the patient, and ruling out any options without evidence. The low-risk patient certainly has plenty of time to investigate all options thoroughly for himself before coming to a decision. Taking one’s time often allows one to put emotions in perspective. Leaving all options open until one is ready to decide is the best stance to take. I have only seen treatment regret in men who didn't take the time to do that.