Diagnosis and management of low-risk disease with a PSA < 4.0


There is a good deal of media noise today about a newly published study in Archives of Internal Medicine. The study addresses the “risk profiles and treatment patterns” of US prostate cancer patients diagnosed with a PSA of ≤ 4.0 ng/ml.”

Shao et al. conducted a retrospective database analysis involving 123,934 men in the Surveillance, Epidemiology, and End Results (SEER) system who were diagnosed with prostate cancer between 2004 and 2006. Age-standardized treatment rates were calculated for these patients in 5-year age strata and the odds ratios (ORs) were calculated for the use of radical prostatectomy (RP) or radiation therapy (RT) in men with low- and high-risk disease.

The basic results of the study are:

  • Men with prostate cancer and a PSA level < 4.0 ng/ml represent 14 percent of incident prostate cancer cases.
  • 54 percent of men diagnosed with prostate cancer and with PSA levels < 4.0 ng/ml have low-risk disease (clinical stage ≤ T2a, PSA level ≤ 10 ng/ml, and Gleason score ≤ 6), but over 75 percent of them received RP or RT.
  • Men with prostate cancer detected through PSA and/or DRE testing and PSA with values < 4 ng/ml were 1.49 and 1.39 times more likely to receive RP and RT, respectively, and were less likely to have high-grade disease than men who had prostate cancer detected as a consequence of signs and/or symptoms (OR, 0.67).

The authors conclude that, “Most men diagnosed with prostate cancer with a PSA threshold below 4.0 ng/ml had low-risk disease but underwent aggressive local therapy. Lowering the biopsy threshold but retaining our inability to distinguish indolent from aggressive cancers might increase the risk of overdiagnosis and overtreatment.”

Articles commenting on this study appear in a variety of sources, including The Wall Street Journal Health Blog, Medscape, MSNBC/Reuters, HealthDay, MedPage Today, and WebMD. The bottom line to all of this would seem to be relatively straightforward:

  • Are we over-treating prostate cancer? Probably … but at present no one can tell any individual patient whether his cancer is or isn’t going to place him at risk for clinically significant disease.
  • Should more men with low-risk prostate cancer be managed with active surveillance protocols? Probably … but we need better information about long-term outcomes of expectant management approaches (i.e., active surveillance and watchful waiting) so that we know what the best protocols are, particularly for younger patients with low-risk disease and a life expectancy of 25 years or more.
  • Should we raise the PSA threshold for biopsy? Probably not … because there are no good data to suggest that men with a PSA < 4 ng/ml are at substantially lower risk for clinically significant prostate cancer than men with a PSA level of > 4 ng/ml.

As we have said a thousand times before … We need a better test for prostate cancer: a test that can differentiate with selectivity and specificity between those men with indolent disease and those men with potentially clinically significant disease. And with respect to “over-diagnosis,” what is that? Treatment decisions should be made on the basis of sound clinical evidence of risk. If a patient doesn’t know he has prostate cancer (however low the risk of clinically significant disease), then how can he make a decision to monitor it rather than have it treated?

7 Responses

  1. It’s not surprising that 75% of the men diagnosed with prostate cancer in the timeframe 2004-2006 chose surgery or radiation, with active surveillance apparently not having much salience. I would be willing to make a modest bet that a substantially higher proportion of men is chosing active surveillance today.

    It’s important to remember that active surveillance results were just coming to the attention of the medical community in 2004, with patients most likely unaware of the results. The first study I know of was the Klotz report of the Toronto (Sunnybrook) results published in 2003, based on their series started in late 1995. However, that was just one study, the number of patients involved was respectable but not large, and the median follow-up period was again respectable but not long — long enough to be intriguing, but not persuasive. Also, nothing had been reported about the patients whose active surveillance determined that they did in fact need treatment.

    Additional studies began adding to the evidence. I recall the one from Johns Hopkins (Dr. H. B. Carter) as the second, followed by the series at Memorial Sloan-Kettering (Dr. Peter Scardino), then Erasmus Medical Center in the Netherlands (Dr. Schroder), then UCSF (Dr. Peter Carroll), and then M. D. Anderson (Dr. Babaian). However, this all took some time. The bottom line is that doctors, let alone patients, did not have a lot on their radar screens as they were making treatment/active surveillance decisions in the years between 2004 and 2006.

    How circumstances have changed! Now we have a number of leading centers updating their impressive results; we have a large number of patients in these series; and we have a reasonably robust amount of follow-up. Perhaps most importantly for patients, we have prestigious organizations endorsing active surveillance as the go-to strategy for low-risk patients, or at least as a leading option.

    I too would like to see a definitive test for aggressiveness versus indolence of prostate cancer. However, I’m seeing the current situation much differently from the “bottom line” summary of the media reports: “… at present no one can tell any individual patient whether his cancer is or isn’t going to place him at risk for clinically significant disease …” I’m convinced that active surveillance — basically putting the cancer on strict probation under a no-nonsense probation officer — DOES go a very long way toward answering this question for most low-risk patients. For that reason, I’m convinced that the over-TREATMENT problem can be solved, provided the active surveillance option is appropriately connected with the screening/diagnosis process. I’m having trouble understanding why the medical establishment does not also see this. Can anyone help answer that?

    I’m aware the active surveillance results are not conclusive and that data are still rapidly accumulating, but the outlines of the results look quite clear.
    Thanks for bringing this study to our attention!

  2. Jim:

    (1) You are no longer a scared and newly diagnosed patient. Indeed, even by patient standards you are educated in the extreme. Your viewpoint is no longer the one you had a week after your initial diagnosis! Men with cancer want to have it taken out. They have been taught that cancer will kill them.

    (2) The “medical establishment” (as represented by people like Dr. Catalona and Dr. Walsh) don’t buy the active surveillance concept at all — at least, not for anyone under about 75 years of age.

  3. Sitemaster,

    I do understand your points, but I believe the prostate cancer world has already experienced a sea change in favor of active surveillance. Only a few years ago the research to support it just was not there — choosing active surveillance was a more dicey choice. Fortunately, that has changed.

    I truly expect that newly diagnosed men, who are not fond of a substantial risk of impotence and incontinence, will begin to seriously consider and choose active surveillance now that the word is out. A quote from a Nixon official comes to mind, perhaps Chuck Coleson, that when you have someone by his [private parts], the heart and mind will follow. Many will still be spooked, just as you have described, and will opt for major therapy without really condsidering active surveillance, but increasing numbers will choose it. As our golf buddies and co-workers become active surveillance veterans in greater numbers, a greater proportion of us will choose it. As our buddies get sound support on the Internet, they will choose it in increasing numbers.

    As for the age thing, one of the great aspects of being a “consumer reviewer” — aka survivor representative — on the proposal review panels for the CDMRP is that you got invited to the IMPaCT Conference in September 2007. There was a panel with doctors representing several of the major active surveillance programs, including Dr. Klotz, Dr. Schroder, and Dr. [Westfield?] representing the Johns Hopkins Program (now at the University of Wisconsin). Dr. Schroder is known for accepting patients as young as 55 in his series, and Johns Hopkins, at least until recently, favored men close to 70 or above. But during the audience question opportunity I was able to ask the panel about age, and Dr. Klotz said he was comfortable having a man of any age on AS. He added that he would like to see younger men have better staging data, and that he monitored such men more closely. Dr. Charles “Snuffy” Myers stated last year that he had more than 30 men under age 40 on AS in his practice.

    I am not aware of Dr. Walsh’s current posture toward AS, but I have not seen any credible argument from Dr. Catalona opposing it — just opinion statements. Do you know of any credible opposition from either of these two worthy doctors, or any others?

  4. On the other hand there are the few patients I have met that had clearly low-risk prostate cancer at biopsy, and even still they chose RP, … and good thing. One went from G6 to G9, the other from G6 with 1 in 16 cores less than 5% to G7 stage T3b post-RP. Probably why Walsh and Catalona are not biting into the AS cake.

    From a retrospective viewpoint I am with you on the “probablies.” From one case to the next, there will be missed opportunities for some patients who will end up worse off because of the cancer — far worse than the side effects would ever be in some form of early intervention. This will conflict with the Hippocratic oath for many doctors on either side of the AS debate.

    And this report is not worth much to me …. You know my position on short-term study results in prostate cancer — almost useless.

  5. Dear Jim:

    Many people in the urology community have the same reactions to active surveillance today that they had to Gerry Chodak’s research back in the late 1980s that clearly demonstrated the potential of what was then called “watchful waiting.” A few of us have been telling men for 20 years that monitoring your disease was a perfectly reasonable choice — for a significant number of people — based on the available data. Do we have more and better data now? Yes we do. Do I still think that a very high percentage of men who get treated don’t need it? Yes I do. How high is that number? I have no idea, but still very high, I suspect.

    You ask if Dr. Catalona or Dr. Walsh have published “credible data” related to active surveillance. I suppose that raises the question of “What is credible?” The point that Dr. Walsh and Dr. Catalona have been making for years is that one patient who has progressive disease after deciding to go onto active surveillance is one patient too many (let alone the few patients who have died). Whether one agrees with them or not depends on one’s point of view. It has nothing to do with the research data. I would bring to your attention that for years the majority of the prostate cancer advocacy community has argued that any death from prostate cancer is a death too many.

    The problem here is all about opinions and “absolutism” of mindsets. Even if we develop a “perfect” screening test for prostate cancer, there will still be the occasional man who dies of prostate cancer — because as humans we are less than perfect in our behavior. Equally, even if we develop “perfect” protocols for the identification of men suitable for active surveillance, there will always be some patients who slip through the cracks and have progressive disease or get diagnosed with metastatic disease.

  6. Hi Sitemaster and Tony,

    I have just a few additional thoughts.

    First, about Dr. Patrick Walsh: we may have slipped into prematurely including him with Dr. Catalona, who clearly opposes active surveillance. Dr. Walsh, on the other hand, has worked for years in the closely knit Johns Hopkins team with Dr. H. Ballentine Carter, who heads one of the world’s prominent active surveillance programs. I just checked, and Dr. Walsh is a co-author on five of Dr. Carter’s papers on active surveillance/expectant management. Has Dr. Walsh gone on record recently against AS?

    Dr. Catalona may be a lone wolf among prominent urologists in his opposition to active surveillance.

    Another thought is about that line of thought that “even one death due to lack of immediate treatment is one death too many.” It appears Dr. Catalona is on very weak ground there based on multi-institution results showing the high effectiveness of active surveillance in picking up the stealthy aggressive cases in a timely manner.

    Tony — re your reply of July 27 about a couple of stealthy aggressive cases: First, those cases probably would not have been stealthy long under diligent active surveillance. But second, some doctors want to go the extra mile in smoking out such cases in advance. Dr. Mark Scholz, as moderator, posed an apparently low-risk case to a panel of experts at the 2009 Prostate Cancer Conference sponsored by the Prostate Cancer Research Institute last September in Los Angeles. Several favored immediate treatment, but Dr. Charles Myers favored active surveillance (AS), provided a color Doppler ultrasound (CDU) did not reveal added risk. Sure enough, the CDU did reveal added risk. The case was from Dr. Scholz’s own practice, and the timely CDU steered the patient to treatment vs. AS. Clinicians like Scholz and Myers who are aggressively using AS with younger men, but coupling it with CDU, are finding that (my recollection) about 20% of such apparently low-risk men actually have cancer that merits immediate treatment. Of course, pre-screening with CDU must substantially boost the odds that AS will be successful for the remaining men.

    All that said, the prominent AS programs have achieved their remarkable success rates without CDU or comparale screening. Personally, however, I would opt for the CDU.

  7. Dear Jim:

    Dr. Walsh is very definitely “on the record” in comments he has made (in writing) about the Klotz series in Canada. Remember that Dr. Klotz’s series includes men much younger than those in the Hopkins series. Indeed there is reason to think that Dr. Carter is personally willing to use AS on men well under 65, so perhaps Dr. Walsh wasn’t willing to go there when the criteria for the Hopkins series were in development. (It is, after all, the most restrictive of all the current AS protocols.)

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