Increasing focus on the appropriate definition (and management) of prostate “cancer”

As many readers will be aware, there has been a recent and increasing focus on whether abnormal pathological findings on biopsy classified as Gleason grade 3 + 3 = 6 should really be classified as “cancer” at all. This also has major implications for its management.

This topic came up at the National Institutes of Health Concensus Conference on active surveillance in December. Oppenheimer has suggested that a more appropriate term for this set of findings should be “prostatic epithelial neoplasia” (PEN). Esserman et al. have suggested the innovative term IDLE (“indolent lesions of epithelial origin”) to encompass the types of early pathological finding observed in both prostate and breast cancers.

A new opinion piece in BJU International by Nickel and Speakman (a Canadian and a Britsh urologist, respectively) also suggests (pretty bluntly) that the time has come to take a stand on this issue and (perhaps more appropriately) on the associated consequence — how one should manage low- and very low-risk prostate cancer. The article itself can only be read if one is a subscriber to BJU International, but a summary of the article is available on the MedPage web site.

Nickel and Speakman apparently acknowledge that:

Whether Gleason 6 is really a cancer or not is a [moot] point, one that can only be debated, at this time.

Perhaps more importantly, they continue as follows:

We continue to over-diagnose and subsequently over-treat unfortunate men who are labelled with a ‘lethal’ cancer, when in fact they will probably never die from it. It is a fact, however, that some men continue to die from prostate cancer, so we must try and direct our therapies to those men, a task that will only be possible through enlightened discussion coupled with basic and clinical research. We need to change our paradigm when dealing with Gleason 6 pattern diagnosis, whether it is a low-risk cancer, a benign disease associated with a high risk of developing real potentially lethal cancer, or a true prostate cancer precursor. Let ’s find a way to treat only those men who are destined to die from this serious cancer and relieve some of the psychological burden and significant morbidity from those men who should never have been labelled as having a lethal cancer in the first place. Let us make the case and put in the effort to develop improved prostate cancer screening for the higher grade prostate cancers, while at the same time relegating low volume Gleason 6 to the status of no more than a significant risk factor. Let us decide as a profession to stop the push for inappropriate, expensive, inopportune and perhaps even unethical radical therapies for a condition that by itself does not kill our patients.

It is clear that — even within the profession of urology — a serious debate has now, finally, begun about whether current modes of treatment for what is formally described as low-risk or very low-risk prostate cancer are even ethical … whether we should call it something else or not! This serious debate within the urology community (and the radiation oncology community) is overdue.

There seems to be little doubt that Nickel and Speakman have laid out their position in a deliberately assertive and combative style because they are tired of the response they have received over the years from those in the urology community who they describe as “urological Luddites.” This won’t make them any friends, but it may be what is needed to get this discussion out onto the main podium at major cancer meetings. It is perhaps worth noting that, since Nickel and Speakman work in Canada and England, they are paid employees of national health systems and are their incomes are not primarily defined by how many prostates they remove surgically or how many Greys of radiation they deliver per month.

14 Responses

  1. Positions! Load! Aim! Commence firing!

  2. I do not believe that calling low grade cancer not cancer in an effort to help men avoid therapy is really the solution to over-treatment. We know that 6-8% of men with Gleason 3 + 3 disease, managed conservatively, die from their disease in 10 years. That could be because they either had Gleason pattern 4 or 5 that was not known at diagnosis, it later developed, or possibly that some of them will indeed progress. Regardless, calling it something different is not really being truthful. How about creating a standardized education piece that all men are required to see that talks about the results of the randomized studies (PIVOT and Scandinavian trials), showing no survival advantage for treating low-risk disease in 10 years. Unless something like that occurs, men will continue to be subjected to biased information from doctors who benefit much more from administering definitive treatment than they do from conservative therapy.

  3. Gerry:

    So to be the Devil’s advocate, I would argue that it is ridiculous to tell the 92-94% of men who have Gleason 3 + 3 disease and who do not die from their disease within 10 years if managed conservatively that they definitively do have “cancer,” thereby justifying a widespread psychosocial belief that all “cancer” must be treated as though it will kill you tomorrow. Words matter.

    Do I have an answer to the dichotomy? No. I don’t. Do I think a highly public debate is essential? Yes, I do.

    I do not believe (sadly) that the level of scientific education (or indeed literacy) in America is good enough to think that asking men to read detailed educational booklets is going to be an appropriate resolution to this issue. That might work in somewhere like Sweden, but not here. We are an emotion-driven culture, not a rational one.

  4. This article is a Perfect justification to hemi-ablation using HIFU.

    I was initially diagnosed with Gleason 3 + 3 and prior to HIFU (after a sutuaration biopsy) as Gleason 3 + 4.

    First, a conclusion: 3 + 3 may turn to be 3 + 4. Second, a note: in case cancer is in the apex, I guess even 3 + 3 or less is too risky.

    My alternatives were:

    1. RP or any other scary procedure (scary due to results)
    2. Active surveillance, which I did not opt for since I would hate to live on a barrel of gunpowder.
    3. Full gland HIFU, which (in my opinion) has the best results compared with the above procedures, yet is risky and new.
    4. HIFU hemi-ablation

    I opted for HIFU hemi-Ablation (in January 2008), due to the high success rate (~100%), being a light procedure (not a major criterion), expected preservation of quality of life in all aspects, and, in worst case, assuming that even if there are cancer cells on the other lobe, progress is very slow and I will keep being on active surveillance with a close to clean prostate and the procedure can be repeated.

    I am happy that I opted for this treatment.

    I manage to maintain erection even with 1 lobe. I have no continence problems. My PSA level is floating ~1.3 for the past 4 years. I have had no other side effects.

    Thanks Dr. Emberton, UK


    Noting that everyone dies, everyone dies only once, and only one of many competing agents gets to kill us, let’s take a step back. Let us not conflate today’s conservatively treated with tomorrow’s proposed conservatively treated. These are “apples” and “oranges.”

    To date, most conservatively treated have been men with competing illness, e.g., heart disease. This is one reason they died of things other than prostate cancer.

    What happens if you take men without competing illness and withhold the prostate cancer treatment they are getting today? One clear possibility is that fewer will die of the other illnesses that they do not have and the death rate from prostate cancer will go up.

    When assessing an individual patient, it’s not enough to look at Gleason scores. One has to look at competing illnesses, among other things.

    “Percent dead from prostate cancer” is a somewhat academic way to measure the desired effect, I think. Better to talk about time to death, which is what most patients are focused on (when is the last time a patient said “Gee, can you arrange it so I die of lung cancer instead of my prostate cancer?”)

    We need better staging, markers, and clinical trials.


    Changing “cancer” to “Condition Happy” in no way relieves the doctor from communicating to the patient the clinical implications of the condition. If changing words will help the patient to listen and receive communication, then fine and we should change the names of all scary conditions to “Conditions Happy.” This will have temporary effect, as our grandchildren will one day come to see “Condition Happy” as “the thing what killed grandpa.”

    Some cases of appendicitis resolve spontaneously, i.e., do not require invasive surgery. Would changing “appendicitis” to “AEN: Appendiceal Endothelial Neoinflammasia” reduce the over-treatment of appendicitis?

  6. Wish there was a “like” button. I like what Dr Krongrad had to say.

  7. Every discussion on over-treatment and screening and active surveillance and watchful waiting and … ends up with the one point that everyone, from every side of the prostate cancer industry seems to agree on:

    We need more an better tools to diagnose the disease more accurately (or perhaps to use existing available tools better?)

    Hopefully, bringing some robust views into the arena expressed by people other than men with the disease will ultimately lead to this happening?

  8. I agree with the two — actually three — themes seen these comments. First, the medical profession must become more patient-centered. This means ensuring that the patient has all and understands all the information to make a informed decision. And that the patient truly shares in the treatment decision-making process. Second, targeted focal therapies (TFTs) must be really considered for treatment of low-risk Gleason 6 cancers. With these treatments you get the best of both worlds; the cancer is gone, but you have good quality of life. Third, is what Dr Krongard brings up about longevity. What if you don’t think you’re going to die from some other condition in 10 or maybe 15 years; will prostate cancer kill you before your expected death?

    As a prostate cancer survivor, I dealt with all of these elements. I had low-risk Gleason 6 cancer. I was educated on all treatments available ranging from prostectomy to active surveillance. Figuring out how long I thought I was going to live, I chose TFT, because I saw it as middle ground; getting rid of the cancer, but still preserving quality of life.

  9. A biopsy that shows prostatic epithelial neoplasia (PEN) is not “condition happy.” “Condition happy” is a biopsy which is benign. PEN is a condition which needs further contemplation and perhaps additional workup to see whether it is aggressive enough to deserve the designation of “cancer” and thereby be a deserving candidate for treatment.

  10. I suggest we are missing one aspect of renaming low-risk disease.

    By omitting the word “cancer,” active surveillance may become a more acceptable form of treatment for men with low- or very low-risk disease and a very small amount of identified cancer in the biopsy. This second qualifier is an important aspect; a man with 1 or 2 mm out of 12 or more cores may be labeled IDLE or PEN; if he has 3 + 3 = 6 cancer in many cores, and much in length, this is unlikely to be IDLE or PEN.

    Frequently we encounter men with minimal 3 + 3 = 6 cancer who are so psychologically intimidated by “the C-word,” that they over-react to the diagnosis, as (on occasion) do their medical counselors. Taking the sting out of a low-risk diagnosis may encourage less invasive treatment like active surveillance.

  11. So if you have a Gleason of 6, what’s a guy supposed to do while these doctors argue over words? Wait for it to go to 8? The whole point is not just the Gleason score, but the aggressiveness of the cancer. What is the PSA doubling time? If it’s faster than X years you must do something. What is X? This should be the focus of discussion, not on words but the decision points.

  12. There’s no ‘happy’ ever again for a man and the people who love him once the “what’s wrong with this prostate” cycle begins. The closest thing there is to “happy” are 6 month periods of ambiguity while trying not to think too much about the the anxiety-ridden, quickly approaching horizon of the next round of testing, which will inevitably only produce more anxiety and ambiguity.

    The closest thing to definitiveness is inevitably bad news, a diagnosis of a high Gleason score and/or a high volume of cancer in the prostate. In this situation, all outcomes are horrible. If the cancer is truly contained within the prostate, the treatment options available are intended to destroy his most intimate relationship for extended periods of time or forever in the name of destroying the cancer. If the cancer is metastatic, the ending of his life has begun — while reprieves may be extended, the extension is at the cost of being completely neutered as a human being, upending his hormonal chemistry in a way that changes personality, energy, interests, and emotions, and produces chronic anxiety while awaiting the inevitable failure of treatment.

    For men with low-grade, low-volume, and/or arguably indolent prostate “cancer,” the prospects are not as imminently terrifying, but neither is there genuine relief or hope. If treated using conventional radical therapies, they can either kiss their sexual function goodbye immediately by scheduling surgery or choose the slow goodbye and spend a couple to a half a dozen years watching with sadness their potential for physical and emotional intimacy slowly fade to memory as the radiation poisoning kills everything in its path — whether it was diseased or not. At best, some of the diminution in quality of life can be minimized — at least for a little while — through persistent, intensive medicalization of life’s most intimate functions.

    For men trapped in a cycle of suspected but to-date undiagnosed disease, there is the chronic tension and anxiety about what are safe and reasonable next steps and about how to assign meaning and weight to a series of tests, which are confounded both in context of each other and of how the diagnostic results present over time. Benign diseases with overlapping symptoms are difficult or impossible to treat. Thus, there’s no solving a case of prostatitis or BPH, without taking the risk of masking a more malignant condition. Solving one issue merely serves to make the risk of another more malevolent. Diagnostic results that come back negative cannot be celebrated. They can only be understood as a higher or lower probability of a random biopsy needle missing a cancer or of an elevated PSA value being attributable to both cancer and other diseases of the prostate. Then there’s the dreadful realization that the only possible outcome of the diagnostic process is an eventual cancer diagnosis because the ambiguity in existing diagnostic techniques only allows for cancer to be ruled in, but never ruled out. If a man starts this process relatively early in life, in his mid-40s or early 50s, he will literally have decades to live worrying — worrying about being under- or over-diagnosed, worrying about being under- or over-treated, worrying about disease progression and death, and worrying about how to live with the brutish, maiming consequences of treatment.

    In the current construction of what it means to have prostate cancer or to be at high risk of having prostate cancer, there is no such thing as “condition happy.” There is only a spectrum of intensity of fear, anxiety, dread, pain, and loss. Using a term like “PEN” won’t save men and the people who love them from a place on this spectrum, but it might buy them some time before they have to subject themselves to physically punishing effects of current standards of treatment.

  13. For George Johnson:

    A Gleason 6 does mot metamorphose into a Gleason 8 with time; my understanding is that the nature of the cancer cells do not change — once a 3, always a 3. There could be 4 or 5 type cells present and they may grow with time — even take over the Gleason 3 cancer, but the cells themselves retain their type.

  14. I, too, wish there was a way to simply agree with positions stated so well by others. This is what can happen when you are 50 years old and you have been fully informed. Based on the outcome, which approach would have led me where? Think about it, because it seems there are those who believe I need not have known — for awhile.

    I was a Gleason 5 guy, low volume, and with reluctant agreement of my doctors, a happy watchful waiter — who was monitored every 3 to 4 months depending upon travel.

    For 18 months or so, my PSA stayed flat or dropped a little, depending on whether it was done in Florida or New England. New England normal was 4.8. Florida normal was 2.8 to 3.4. Slope was quite flat and that bothered the doctors in New England, because that could mean a special kind of problem. My New England doctor asked me to fly up for an extensive biopsy.

    This time the initial 3 + 3 Gleason score was changed to 4 + 3 by second opinion pathology. Volume in all cores. High volume (75% and higher) in 12 or 13 of 18 cores. (This lends credence to idea that higher Gleason cancers may exist and they have to grow or we have to get more fortunate in finding them early enough to move.)

    What I am about to describe happens all too often to young professionals in small staff and large dollar volume businesses. Men between 45 and 55 with “moderately aggressive cancer are in a crazy minefield of unknowns at work, young families still at home or in college. They do not fit the mold of the old idea of a typical prostate cancer patient. And these are the very ones that early screening finds — so do we screen them? If they have “moderately aggressive” disease do we tell them?

    On the upside, more younger guys would not have to hide yet another medical condition that men (and women) hide from employers for as long as they can. They hold back and hide their cancer for as long as they can, any depression, etc., etc. It may not belong here, but in the end we come full circle with the question, “Where would not knowing had a better outcome?”

    My initial diagnosis was confirmed on my 50th birthday. I was 52 when the more extensive biopsy was done. I changed from a very happy watchful waiter — with an increasingly successful, 3-year-old, international consulting business (means lots and lots of travel) to “How do I treat this new monster bear and not lose my business/income?” We had five children: four daughters ages 12 to 25 and one son aged 27. Tuition, braces, clothing, shelter, food, etc., a major consumer of my income.

    I wish that sexual intimacy — which had been our frequent and adventurous special time reserved for the two of us had been the only concern. We were concerned about income, savings, and high deductibles as I moved into what were supposed to have been that final peak earnings run to a comfortable retirement.

    So how do I tell existing and new clients who needed real help over the next 6 months — millions at stake for them — that I would be unavailable for a while, and would have to pare back the 65 hours a week on site at multiple locations in the USA, Canada, and Western Europe? We all know that the second choice guy who can show up is more effective than the first choice guy that can not. I would have to pick and prepare my competitors to go do the work I set up.

    In an important, but eventually limited way, I was rescued by old consulting friends in Florida. They had great benefits and needed a gray-haired guy they trusted to take young consultants on the road, expand their experiences and increase revenue. I could phase my clients into their business with the right to break away from them if I was cured and could go back on my own. The clients that I developed for them remained theirs. Seemed fair to me. Much lower deductibles, but 35 percent less income. On the other hand, clients would not wander away while I was receiving treatment. I trained up youngsters to cover in groups of two.

    So we moved to Orlando and I had an obligation for 6 months on the road from Sunday afternoon to Saturday morning for 23 of those 26 weeks. Then I could be treated. PSA doubled during those 6 months. Plenty of time alone in airplanes, rental cars, and hotel rooms to fret about surgery, brachytherapy, EBRT, whatever. (I wondered what had happened since 1993 when most radiation onccologists wouldn’t touch a 50-year-old guy with seeds or EBRT to 1996-97 when many radiation oncologists were doing that more and more. But I was happy with seeds. Shorter downtime, back to work yippie, dippie doo.

    After the 6 months of waiting, again for both economic and lifestyle choices, we chose brachytherapy — 80 iodine seeds. The joker in the deck was that my PSA was doubling every 5 to 6 months. We seemed to be running behind the cancer, trying to catch up.

    Suddenly, my radiation oncologist and urologist agreed that the seed implantation must be preceded by 4 weeks of EBRT (which allowed me to work — good thing — show full productivity under duress and all that Type A stuff). This would be followed within a week by the seeds.

    My PSA continued to climb, so they delayed the seed implantation for 10 days to decide what to do. The conservative strategy would have been to complete two more weeks of EBRT and see what happened. The aggressive strategy was twice as many seeds, using palladium seeds, and loading up the apex, most of prostate, and a significant concentration at the periphery. Quite a jolt on top of the EBRT, but I think they knew it was out or almost out, so go hard. Cannot fault them one bit for that. My docs were going for the cure for me.

    When I returned to work, the sale of the small company to a big international firm had been completed. A really good deal for the owners. Based on the 6-month spurt in revenue and the increase in the number of effective consultants, the owners received six times revenue for that year.

    Under new ownership, the demands were higher than ever, and I wasn’t able to get too far from bathrooms, tired more easily, and needed some down time each day. That was okay, because these were/are my friends — but my healthy work had sweetened the deal for a lucrative buyout. That happened and the demands increased beyond my physical ability to meet them, buy we plugged away expecting a cure. Odds for cure were “fantastic.”

    Well, PSA nadir was 2.1. Anything above 1.0 was considered trouble ahead. All doubt was removed 90 days later when it hit 2.8. Another 90 days later, 3.8. Didn’t get it. ADT kicks in.

    The acquiring company was not happy about the side effects of ADT in 1996, so a series of memorable conversations ensued. The message was clear — either stay here and be pushed until you quit or accept long-term disability of 50% of my income and no benefits. A 50% reduction in income that had been cut 35% a year earlier to have less money, more benefits, more security.

    I wasn’t ready to do that. Disability insurance called and asked me why I thought I couldn’t work. I said that I could with a reasonable accommodation that my clients supported. At worst, I offered to figure a way to work 50% of the time for the 50% as long as it would still be there when I might really need it. After talking to the new owners, the insurance company called back and told me that it was disability or nothing. This does happen out here — especially to relatively young prostate cancer guys asking how we can be half-pregnant. We need to start educating employers. We need more confidential Employment Assistance programs. I haven’t even started yet on the impact on the children and their mother.

    So I ask, 13 to 14 years down the road, which would be more miserable — a sugar-coated diagnosis that would not be true or the misery of treatment to cure me that fails, destroys plumbing, fives the Seminole Chop to intimacy/vitality and Gator bites to mind, body, and spirit from antiquated ADT (Zoladex and Casodex followed by the Zoloft 50-100-150, followed by the Oxy, followed by the temazepam plus amitriptylene plus 30 other meds a day). Is this the misery they seek to protect me from, but what about 3 hard years of dying that I was totally unprepared for. Have cake, eat cake.

    I am still amazed that we do not have more widely available alternatives after 15 years. I am still amazed that we have to fight to get prostate cancer research going for a cure/vaccine — that managing what we call it and limiting the number of men screened is our best effort. We can do better; we must do better for our sons and grandsons and the guys that marry our daughters.

    Rambling introduction from a surprise “survivor ’til now” who was a good candidate for watchful waiting that failed; treatment with curative intent that failed; still taking ADT around 60% of the time — with side effects. Happy to be alive. Want to help search for cure/vaccine + better forms of ADT that are covered by insurance and Medicare + emotional support for people in transition + end of life comfort. I’ll stuff mail, lick stamps, whatever for those going for these things.

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