Clinical “success” and the management of low-risk, localized prostate cancer

Historically, “success” in the treatment of localized prostate cancer was the elimination of all evidence of cancer from the patient’s prostate and other nearby tissues — through radical surgery or radiation therapy of some type. But the increasing acceptance of active surveillance and the evolution of focal forms of therapy have introduced whole new ways of thinking about the “successful” management of low- and even intermediate-risk, localized disease.

Let’s see if we can accurately define the potential opportunities (and the potential problems) today.

Harry has been monitoring his PSA since he was 48 years old, a year after his dad was diagnosed with Gleason 7 disease at age 68. (His dad had a radical prostatectomy and — now aged 77 — claims he is entirely satisfied with the outcome. His mother has a different point of view. She says Harry’s Dad still needs a pad all the time, and that they never had sex again after his surgery.)

Since his first PSA test in 2002, which was 1.1 ng/ml, Harry’s PSA has gradually risen to 2.6 ng/ml this year, and when it hit 2.6 ng/ml his urologist recommended a free PSA test. The result showed a free PSA of 18 percent, which suggests an increased risk for prostate cancer compared to BPH, but the strong possibility that this is low volume, non-aggressive disease. Harry and his urologist decide that — at 56 years of age and otherwise in excellent health — a biopsy would be a good idea. The biopsy is positive in 2/12 cores, Gleason 3 + 3 in both cores, with significantly more cancer in one of the two cores. The second positive core contains a minimal amount of cancer. Both positive cores come from the right base area of his prostate.

What are Harry’s options for the management of his prostate cancer today? Well they fall into two very general categories:

  • Methods intended to “cure” his cancer (i.e., completely eliminate all prostate cancer cells)
    • Radical surgery (open or minimally invasive)
    • External beam radiation therapy (IMRT, IGRT, SBRT, PBRT, etc.)
    • Brachytherapy
    • Whole gland high-intensity focused ultrasound (HIFU) (investigational in the US)
    • Whole gland cryotherapy
  • Methods intended to control his cancer over time (i.e., minimize risk for clinically significant, progressive disease)
    • Focal therapy with HIFU (investigational in the US)
    • Focal therapy with cryotherapy
    • Focal therapy with laser ablation
    • Other forms of focal therapy (e.g., phototherapy)
    • Active surveillance

The important point here is the distinction between treatments designed to eliminate all organ-confined prostate cancer and prostate-related tissue (“curative” therapies) and forms of management that may not be curative because they are designed primarily to manage the risk that the patient will have progressive (clinically significant)  prostate cancer through careful monitoring or through the elimination of signs of cancer that seem to place the patient at possible risk for progressive disease.

All focal therapies for prostate cancer come with the understanding that they may leave behind small areas of cancer that were not evident on biopsy and that cannot currently be identified with accuracy by any known imaging technique. Thus the goal of such focal therapies can not truly be described as curative. The goal is to eliminate the evident index lesion or lesions that predispose the patient to the risk for progressive disease, thereby minimizing risk.

A new article by Ahmed and Emberton, two leading UK-based surgeons with strong interests in the potential of focal therapy for prostate cancer, has laid out the importance of the concepts of cancer control as opposed to curative treatment in discussing the future development of clinical trials to assess the effectiveness and safety of evolving forms of focal therapy.

They point out that the ideal form of management of localized prostate cancer requires the development of a novel therapy with the ability to minimize risk for progressive disease (in other words, it should have the “curative” impact of radical prostatectomy) while optimizing quality of life (in other words, the side effects should be no worse than those of active surveillance). At least in theory, some forms of focal therapy might be able to meet this standard.

This idea that prostate cancer needs to be “cured” in some men (because they have aggressive forms of disease that need aggressive forms of therapy in order to save their lives) but only needs to be “controlled” in others (because they have relatively less aggressive forms of the disease that should just be prevented from becoming clinically significant) is not unique to prostate cancer. It is already being applied to other forms of cancer for which we are able to recognize specific characteristics that place patients at higher or lower levels of risk for progressive disease that might lead to cancer-specific death.

Ahmed and Emberton describe a “pragmatic” clinical trial structure in which patients with localized prostate cancer could be randomized to one or other of two concurrent clinical trials if they met appropriate study criteria:

  • Trial A would be a trial of a specific form of focal therapy vs. “curative” therapy (e.g., radical prostatectomy).
  • Trial B would be a trial of the same specific form of focal therapy vs. active surveillance

These two “paired” trials would potentially be appropriate for any patient with low- or intermediate-risk forms of prostate cancer. Depending on patient preference and physician recommendation, a patient might be more acceptant of or eligible for Trial B or Trial A, but since the trial structures would otherwise be the same, it should be possible to compare data at least some data across the two trials. At the same time, it should be easier to recruit patients to such paired trials than to a three-arm trial in which patients could be randomized to any one of active surveillance, “curative” treatment, or “focal” treatment.

We are going to need to be able to know with some degree of certainty whether “control” of localized prostate cancer in some manner is as effective (and presumably safer) than “cure” for well-defined patients with low- and intermediate-risk prostate cancer if we are to minimize the recognized “over-treatment” of localized disease. These issues will become even more important over the next two decades. The trial concept laid out by Ahmed and Emberton represents an interesting approach to this problem. Of course it would be even better if we could find a pharmaceutical or biological agent that stopped the evolution of low- and intermediate-risk forms of prostate cancer, but we suspect that such an agent is not on the near horizon.

What is Harry going to do in the meantime? Unfortunately he is faced with the same question as about 150,000 other American men with low- or intermediate-risk prostate cancer will be faced with this year: “What is the best thing for me to do?” At present we have no good answer … just a series of opinions based on specific points of view.

4 Responses

  1. Too bad for the men in the RPP arm who will inevitably suffer the full consequences of what is — by definition of the study itself — a fully failed technique in regards to QoL.

  2. Tracy:

    I don’t think that’s a very fair comment. There are many men who do extremely well after surgery, with complete and rapid return of full continence and good recovery of erectile function. This is particularly the case for younger men and for the men who are treated by the more highly skilled and dedicated surgeons.

    It’s not as though patients are forced to enter clinical trials. If they don’t wish to participate they can just say, “No thank you.”

  3. Mike,

    You, yourself, have said — I believe as recently as in the past week or so — that the RRP industry needs to be more honest with men about the inevitable impact of RRP on quality of orgasm and penile shrinkage and Peyronie’s disease. Recovery of erectile function is different than these nearly universal outcomes, right?

    No, patients aren’t forced to participate in the clinical trials, but they lose the possibility of getting into one of the focal therapy arms of the trials if they won’t put themselves at risk of the RRP.

    I understand RRP is an behemoth industry unto itself. But the goal should be to quit subjecting men with low grade, non-aggressive cancers to RRP and its inevitable consequences.

  4. I am sorry. You’ve lost me. If men don’t want to risk going into the RRP arm of such a two-part trial, they can volunteer for the active surveillance vs. focal therapy arm. Or they can not enter a trial at all. Focal cryoablation is already available in the USA. Other forms of focal therapy are available in several European countries. You don’t have to be treated within a clinical trial.

    In addition, I would respectfully suggest that the correct goal is to ensure that each patient is able to obtain the best possible treatment based on his clinical characteristics and his psychological/emotional mindset about the available treatments. There are plenty of very smart men, who, when presented with all of the relevant information in a completely unbiased manner, still elect radical surgery as their first choice for low-risk, non-aggressive prostate cancer because they just don’t want to live with the cancer at all. You probably wouldn’t recommend that. I probably wouldn’t do that. But many men do and are very well aware of the risks and the potential consequences. That is their choice, and they have a right to that choice.

    Furthermore, Peyronie’s disease is most certainly not a “universal” outcome of radical surgery, and nor is “penile shrinkage.” We aren’t even clear to what extent Peyronie’s disease is a consequence of radical surgery.

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