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. (But be warned, this is a relatively long article.)

The screening protocol for men under 50 years of age that is now advocated by Memorial Sloan-Kettering Cancer Center (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 to 30 percent 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 percent). 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 Sunnybrook active surveillance trial has demonstrated the safety of that protocol. Klotz reported that of the 993 patients, there were only 15 deaths (1.5 percent) due to prostate cancer. When he pooled together several active surveillance studies, he found that the combined disease-specific survival rate was 99.7 percent. A Gleason score of 8 to 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 Sunnybrook trial 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.

A

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 Cancer Center male life expectancy survey, we can see that for a 45-year-old man in excellent health diagnosed with a Gleason score of 3 + 3, a 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 10 years, and a 4 percent chance of dying of something else. Even if he lets it go for 15 years, he only has a 3 percent chance of dying of prostate cancer, and an 8 percent 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.

B

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 level. 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 active surveillance 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 are 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?

 

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.

C

*Extrapolated numbers.
Sources: A. Hunter DJ, et al., see p. 4. B. Younger cohort is from Johns Hopkins prostatectomy patients (Rogers et al.); older cohort is from the University of Chicago (Shikanov et al.). C. Column A − Column B. D. Sunnybrook outcome data, assuming plateau continues. E. Column C × Column D. F. Social Security actuarial tables.

If he chooses active surveillance (AS) at 45 and manages to stay on AS for the next 25 years without treatment (a 55 percent probability), his expected loss of continence (incorporating the probability of being able to go that long without treatment) is minimized, at only 6 percent. 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, but 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 those numbers.

D

*Extrapolated numbers.
Sources: A. Keyes M, et al. B. Alemozaffar M, et al. (see supplemental content: eTable3; 97% had nerve-sparing surgery).

Our fully potent, 45-year-old man has a 55 percent chance of retaining his potency if he has an immediate radical prostatectomy. So, about 45 percent of 45-year-old men will lose potency if they elect an immediate radical prostatectomy as opposed to AS. Those 45 percent will live with that impotence for 34 years.

If he chooses AS instead of the radical prostatectomy, what happens in the next 5 years? He has some small natural deterioration of potency, roughly a 6 percent expected loss. If he has the radical prostatectomy 5 years from now, his expected potency will be less too, at 49 percent. Therefore, his expected loss of potency nets out exactly the same (at 45 percent) if he remains on AS for the full 5 years. But he has only a 76 percent 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 percent — 11 percentage points less than if he had the radical prostatectomy 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 percent 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 percent. 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 disease, 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. Urinary incontinence is a very low-probability side effect of radiation therapy, 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 radical prostatectomy or intensity-modulated radiation therapy (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 co-morbidities (see this link).

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

  • IMRT: 8.6% at 5 years, 11.2 percent at 8 years, and 10 years (76 percent of 10-year total by 5 years)
  • Brachytherapy: 4.3 percent at 5 years, 8 years, and 10 years (100 percent of 10-year total by 5 years)
  • Radical prostatectomy: 3.1 percent at 5 years, 3.7 percent at 8 years, and 5.5 percent at 10 years (56 percent 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 percentages experiencing grade 2 or higher rectal toxicities by 5 years, 8 years, and 10 years after treatment were:

  • IMRT: 7.8% percent at 5 years, 8 and 10 years (100 percent of 10-year total by 5 years)
  • Brachytherapy: 1.7% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
  • Radical prostatectomy: 0 percent at 5 years, 8 years, and 10 years (100 percent of 10-year total by 5 years)

We have seen in a previous commentary that erectile dysfunction due to radiation therapy was lower than for radical prostatectomy 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. However, it is a moot point in most situations because younger, low-risk patients are seldom offered (or consider) radiation therapy.

Conclusions

I should be clear that 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 (finasteride/Proscar or dutasteride/Avodart) may be able to delay or even reverse progression in men with low-risk prostate cancer. 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 2 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 stereotactic body radiation therapy (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.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

10 Responses

  1. I say no! Quality of life. Live now ! 49 when I started AS.

  2. 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

    But we should all know that “conventional wisdom”, a.k.a. PSA screening, has never been shown to “save lives”, so we should read the term “conventional wisdom” in an ironic sense.

  3. Great article. Diagnosed at 50 (now 54) and will active surveillance for as long as possible. I feel for all those men who are now coming to the realisation that they had radical treatment when they really didn’t need it.

  4. Dear David:

    With great respect, we actually do not know whether PSA screening may be able to “save lives” on average or not.

    What we know is that the trials conducted to date were very poorly designed and (generally) poorly conducted and have certainly not shown that such screening leads to improvements in either prostate cancer-specific or overall survival. It would require the latter to actually prove that any form of screening actually extended life on average.

    On the other hand, we also know that the early detection of intermediate- and high-risk forms of prostate cancer (through the use of the PSA test) has certainly prevented a lot of men with such diagnoses from the later onset of incurable, metastatic prostate cancer. Many such patients (and many of their doctors) believe, very reasonably, that PSA testing did indeed “save” their lives as individuals.

    This is not a “black and white” issue. The closely interlinked questions are: (a) How do we appropriately identify the men whose cancers need to be identified and treated early in order to save them from the risks associated with progression and metastasis? (b) How to we ensure that we minimize the unnecessary treatment of men who may initially seem to be at risk for clinically significant prostate cancer but then, after diagnosis, appear to be at no or minimal risk for metastasis after all? (c) Can we identify with accuracy the men who may well have some cancer in their prostates but for whom even diagnosis is completely unwarranted and no biopsy is therefore justified?

    So long as we keep thinking about the risk for, diagnosis of, and management of prostate cancer in “black and white” terms, we really won’t be in a position to offer the most appropriate forms of guidance to anyone.

  5. Great article indeed! I hope your analysis will get a wide distribution. Thanks for all this well-researched work and piercing analysis!

    The point made in the conclusion about AS providing time for technology to improve also applies to what we can expect to see developing in the statistics and nomograms. In other words, as selection of AS patients and technology to manage them (such as 5-ARI drug use, imaging, genetic testing) continues to improve at Sunnybrook under Dr. Klotz’s guidance, we can expect the numbers for patients for whom no treatment was recommended (the first table) to improve over their already impressive levels. Likewise, the chances of dying of prostate cancer per the MSKCC nomogram will continue to decline even further from the reported also impressively low percentages.

    I am curious how many urologists (the typical prostate cancer entryway doctors) still advise their younger patients who are suitable for active surveillance to choose treatment instead. I too suspect that recommending treatment for young patients is still conventional wisdom, however ill-founded. It was without doubt conventional wisdom back in 2007. In September 2007 at the IMPaCT conference (Innovative Minds In Prostate Cancer Today) that reviewed findings from DoD-sponsored research, Dr. Christopher Logothetis moderated a panel on “Clinical Research” that was actually focused on active surveillance, including as panelists Drs. Stephen Freedland, Fritz Schröeder, Christopher Warlick, and Laurence Klotz, all associated with major institutions with prominent active surveillance programs. Each responded to an audience question about the youngest age they would be comfortable with an AS approach. All suggested that they were more comfortable with older men using AS, though as low as men in their 50s, except Dr. Klotz; he confidently stated that he would be comfortable treating a man of any age on AS, though he would want more attentive monitoring for younger men. Some thought that his comment had an electric-like impact on the audience. That was back in the days when only about 10% of suitable men of all ages were being managed on AS. (IMPaCT was the first review conference sponsored by the US Dept. of Defense, the manager of the Prostate Cancer Research Program for Congress, under funding from the Congressionally Directed Medical Research Program. Perhaps a hundred survivor representatives –- all of whom had been voting members of research proposal selection panels –- and nearly a thousand researchers and physicians attended, including many leading experts.) In 2016 we have now advanced 9 years and a mound of research from that conference, but it is almost a sure bet that many urologists have not changed their thinking.

  6. David,

    Your link refers to work by Dr. Vinay Prasad, who seems to be making a career as a professional debunker. That would be fine if his work were sound, but it is clear that for prostate cancer it is not! For example, from my recollection, he still uses data from the PLCO trial to try to undermine the benefit of prostate cancer screening, even though that trial is now widely acknowledged to be fatally flawed as an observation opportunity for seeing benefit.

  7. Jim,

    To your point about acceptance of AS for younger patients by urologists, my urologist, Leonard Marks, who runs the active surveillance program at UCLA, had this to say, “Great piece, thanks for sharing. My first patient in the UCLA A.S. program was 31 y.o. when he was diagnosed; he is now 42 years old, has in the interim gotten married and fathered a child; and his last biopsy was negative for any sign of malignancy.”

    I would love to see a survey among urologists like the one you described.

  8. Well written. Thank you for your work and insight(s).

  9. Allen, thanks for your post about Dr. Leonard Marks at UCLA. In the past it has crossed my mind that I hadn’t seen research results from a UCLA program, which seemed odd as the LA area is such a hotbed of prostate cancer expertise. I just looked up Dr. Marks on http://www.pubmed.gov and found a trove of interesting papers on active surveillance, and other aspects of prostate cancer.

    Many thanks!

  10. Dear Jim:

    If you thought nothing had been going on at UCLA, I suggest you do a little more investigation into prostate cancer research there, starting with the work of Dr. Mark Litwin (particularly into prostate cancer care among those rather less financially advantaged than you are), of Dr. Robert Reiter, who runs one of the largest prostate cancer SPORE grant programs), and of Dr. Bill Aronson into nutrition and prostate cancer.

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