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.

Half of long-term erectile function (EF) loss after brachytherapy (BT) is due to aging.

One of the most important things we patients want to know about any treatment is what kind of potency we can expect afterwards. Urinary and rectal dysfunctions are often measured and reported by investigators, but sexual dysfunction is rarely reported or measured.

While there is at least some consensus on the use of the National Cancer Institute-defined common terminology criteria for adverse events (CTCAE 4.0) to grade urinary and rectal adverse events, there seems to be no consensus on how to measure sexual dysfunction. It is reported in a wide variety of different, non-comparable ways, if it is reported at all.

Several definitions are used in studies: IIEF/SHIM, EPIC-sexual status score, erection sufficient for intercourse, actual intercourse in the last month, and/or whether erection aids are needed or helpful. Often results are given among men who were previously potent or high-scoring only. Others report return to baseline function, where “return” may be defined as anywhere from within 1 point on IIEF/SHIM to any value within the population standard deviation.

From the patient’s point of view, we would love to have a nomogram that could predict our probability of potency after any given treatment. 

In 2011, Alemozaffar et al. (see The New Prostate Cancer InfoLink article) reported comparable figures on erectile function at two years after surgery (RP), external beam radiotherapy (EBRT), and brachytherapy (BT). They found that functional erection preservation could be predicted for each kind of therapy based on pre-treatment sexual function (EPIC scores), age, and a few other variables that varied with the type of treatment. However, there is a problem in the way they used baseline EPIC scores and age in their predictive model. The problem is that EPIC score is not independent of age - it is a function of age, especially in the age group studied. This problem, called covariance, violates a basic assumption of the model. The problem of covariance could have been fixed by using an age-adjusted EPIC score (much as we use inflation-adjusted constant dollars in economic analyses). The University of Michigan, which did the validation study, must have a validated file of EPIC scores by age for a random sample of healthy men. Those scores, expressed as a%, can become an indexing factor that will be divided into each respondent’s EPIC score according to his age.

We can easily see the “age problem” in the following table from the appendix (eTable3) of their study.

Percent of men with functional erections after 2 years

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.

Conventional wisdom is that radiation erodes potency slowly over time, while surgery affects potency at the beginning with some return over the first two years. The study only looked at potency at a single point in time, 2 years after treatment. This may obscure the long-term effect of radiation treatment on erectile function. This is more than just a technicality. As we measure potency after treatment for say 5 or 10 years, we want to be able to separate treatment effects from age effects. In the 60-75 age range that includes most treated patients, we expect potency to deteriorate naturally as we age, but what portion of that deterioration is because of the treatment?

Katz and Kang, in a 7-year follow-up study of quality of life following SBRT treatment, found that there was a brief early decline and recovery followed by a gradual long-term decline (see Figure 5). After 7 years, potency was about 67% of their original EPIC score. The authors point out: “In fact, potency preservation rates after SBRT are only slightly worse than what one would expect in a similar cohort of men in this age group, who did not receive any radiotherapy.” However, they made no attempt to separate the effects of treatment from the effect of natural aging.

In a new analysis of the erectile function after low dose rate (LDR) brachytherapy, Keyes et al. made the first such attempt to separate the impact of the two effects. They analyzed the erectile function of 2,929 favorable risk brachytherapy patients treated between at the British Columbia Cancer Agency between 1989-2012.

• ·      The men were categorized at the baseline visit by their doctors as having full (79%), partial (8%) or no (13%) erectile function. The men were re-categorized on follow-up visits by their doctors.
• ·      The men self-evaluated potency on follow-up visits using the Sexual Health Inventory for Men (SHIM) questionnaire.
• ·      All men in the study had at least 10 months of follow up and as long as 14.1 years (median 3.5 years).
• ·      44% had adjuvant ADT. It typically began 3 months before treatment and continued 3 months after, and was given to men with larger prostates or higher risk. It was rarely used after 2005.
• ·      The median age was 66 at treatment.
• ·      33% had hypertension, 10% had diabetes.
• ·      Expected erectile function by age without treatment was predicted in two ways:

o   1. The Massachusetts Male Aging Study (MMAS) predicts annual impotence rates of:

§  12.4 cases per 1000 for men 40-49

§  29.8 cases per 1000 for men 50-59

§  46.4 cases per 1000 for men 60-69

§  These were estimated in 5-year increments.

o   2. Baseline erectile function of men 5 years older was used as the level expected if there had been no treatment.

The authors report the following results:

• ·      There was a large decline in erectile function (EF) at the first (6 week) follow-up visit:

o   EF loss of 25-35% if they had no ADT. The authors attribute this to trauma and psychological factors rather than dose to erectile vasculature and structures.

o   EF loss of 80-85% if they had adjuvant ADT

• ·      The EF of those who didn’t have ADT continued to decline gradually.
• ·      The EF of those treated with adjuvant ADT rose back up to the level of the other men at the 2-year mark, and then similarly declined.
• ·      Among men fully potent at baseline, about 50% were fully potent at 5 years and an additional 10% were partially potent.
• ·      Among men fully potent at baseline, about 40% were fully potent at 7 years and an additional 15% were partially potent.
• ·      The following table shows potency by age group after 7 years.

Age Group	Percent with full EF after 7 years
<55	80
55-59	76
60-64	53
65-69	41
70-74	22
>74	13

• ·      About 30% of the fully potent men used PDE5 inhibitors.
• ·      Diabetes and hypertension significantly affected EF, radiation dose did not.
• ·      The following table shows actual and expected potency losses due to by age group.

Age group at 5 years post BT	EF loss* due to BT+age (percent)	EF loss due to age (avg expected)†	Loss due to age as% of total loss
<60	22	13	59
60-64	38	18	47
65-69	58	26	45
70-74	75	40	53
>74	93	55	59

* among those with normal EF at baseline

† average of MMAS and 5-year older EF in study cohort at baseline

• ·      About half of the long-term decline in EF was due to normal aging effects.
• ·      Most of the steep early decline is due to BT; most of the gradual later decline is due to aging.

This study goes a long way towards providing the data patients need to make a treatment decision. The patient wants to know, for each potential treatment, what his odds are of preserving functional erections at some future point in time. To build a database capable of answering his question, clinicians offering each treatment will have to collect the following data at baseline and follow-up visits:

• ·      EPIC score (age adjusted)
• ·      Age at treatment
• ·      Co-morbidities: cardiovascular disease, hypertension, diabetes, neuropathy, depression, hypogonadism
• ·      Medications: beta blockers, testosterone supplementation, ADT, opiates, adrenergics, etc.
• ·      Smoking
• ·      Substance abuse
• ·      Obesity
• ·      Married/sex partner

I am hopeful that someday clinicians will arrive at a consensus about collected the data, measuring and reporting potency. Patients can further this goal by letting their doctors know that this is important to them. Judging by how seldom reports like this are published, many doctors think it is not very important.

note: Thanks to Dr. Mira Keyes, Head of the Provincial Prostate Brachytherapy Program of the British Columbia Cancer Agency, Vancouver Cancer Centre for making the full text of the article available to me. 

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.