PPC as a key element of clinical stage instead of T stage in localized prostate cancer?


In recent years it has become increasingly widely accepted that clinical stage is of dubious value as a prognostic factor in determining prostate cancer risk, particularly as regards the sub-stages of clinical stage T2 (i.e., T2a, T2b, and T2c) in men with localized prostate cancer. We have previously commented on a couple of papers by Reese et al. that dealt in detail with this issue.

A paper published a few months ago, by Huang et al. — and a supporting “Beyond the Abstract” commentary on the UroToday web site — have now tested the idea that clinical stage should be replaced by percentage of biopsy cores that are positive for cancer (referred to as percentage of positive cores or PPC) in clinical staging systems and in the algorithms used to project outcomes after treatment.

Huang et al. looked at data for 1,056 men, all treated between 1993 and 2004, who were initially diagnosed with clinical stage T1c-T3N0M0 prostate cancer, who had four or more biopsy cores sampled, and for whom complete biopsy core data were available. The men were all treated with external beam radiation therapy, with or without a high-dose-rate brachytherapy boost, at a single institution (the William Beaumont Hospital, Royal Oak, Michigan).

Here are the core findings of their study:

  • The median follow-up of the patients was 7.6 years.
  • Based on multivariate Cox regression analysis
    • PPC was an independent predictor of distant metastasis, prostate cancer-specific survival, and overall survival.
    • A PPC >50 percent was associated with significantly greater risk for distant metastasis (hazard ratio [HR] = 4.01).
    • The independent predictive value of PPC was still significant in men who did or did not receive androgen deprivation therapy.
    • Perineural invasion and clinical T stage were only predictive for loco-regional recurrence.
  • Combining the PPC (≤50 vs. >50% percent with National Comprehensive Cancer Network (NCCN) risk stratification
    • Improved the prognosis of risk for distant metastasis for men with intermediate-risk disease (HR = 5.44)
    • Also improved the prognosis of risk for distant metastasis for men with high-risk disease (HR = 4.39)

The authors conclude that “PPC is an independent and powerful predictor of clinical outcomes of prostate cancer” after radiation therapy and that “A risk model replacing T stage with the PPC to reduce subjectivity demonstrated potentially improved stratification.”

They also carefully note that their findings are concordant with the earlier finding s of Reese et al. (referred to above) and that most men diagnosed with prostate cancer today initially present with localized or impalpable (DRE-negative) disease. Of the 1,056 patients in the current study cohort, only 4 percent were diagnosed with clinical stage T3 disease.

The “New” Prostate Cancer InfoLink considers this to be a useful, hypothesis-generating study. Other studies would need to validate this concept if we are really going to consider replacement of clinical T stage with PPC in our current staging systems and then use these data in prognostic algorithms. Furthermore, there would need to be a consensus on exactly how we define PPC (which is differently defined by different pathology groups at this time).

As a first step, it would be interesting to know whether the model applied by Huang et al. to their cohort of radiation therapy patients is equally successful when applied to men treated with large cohorts of men treated with surgery and with primary brachytherapy.

10 Responses

  1. This process assumes the continued use of grid-based biopsies. How would men biopsied via fused MRI/ultrasound technology be staged? If specific, visible suspicious lesions are targeted won’t the percent of positives needles be disproportionately high?

  2. OK. I am confused. First, doesn’t the percent positive depend on the total number of cores taken? For example, I had 52 cores taken with six positive. That puts me in the less than 50% category. However, what if I had only had six cores taken and they hit four spots of my total six. That woud put me in the greater than 50% category. Obviously, PPC just depends on where you poke. So I don’t see how this can be predictive.

  3. Tracy:

    I don’t think the paper is addressing any of the things you are implying. All the authors are saying is that the amount of tumor found in biopsy cores is a more accurate predictor of risk and stage than current staging methodologies. Clearly how biopsies are done is one relevant factor.

  4. Chris:

    You are missing key factors here.

    First, PPC is not just about the number of positive cores. It is about the amount of cancer in the positive cores. Thus, a man with a single positive core that is 80% cancerous and all Gleason 6 may actually be at higher risk than a man with three positive cores, each of which contains only 1% of cancerous tissue, all of which is Gleason 6.

    However, I think the paper’s authors would be the first to tell you that there are a lot of details like this that would need to be sorted out. They aren’t suggesting putting this into practice yet. It needs careful validation as a hypothesis and then it would also require some standardization of pathologic evaluation of tissue specimens.

    Second, we already can’t apply standard staging methods to men like you who have saturation biopsies. This is about standard biopsies, based on the usual 8 to 14 cores.

  5. But the whole point of staging predictors is to understand risk and inform treatment decisions. At least at this point in time, men advised to seek MRI/ultrasound fused biopsies are those who have already had two or three or more negative biopsies but continued elevated, unexplained PSAs (see my comment on previous post on PSAs). Adoption of such a new staging procedure will inevitably (by the media, by scared patients, by lazy doctors) lead to over-interpretation of risk from intentionally focused biopsies. Again, what will it take for the prostate cancer community to address the very real problems of over-diagnosis and over-treatment? The only path they seem willing to head down is towards more and more and more of the same. What we need is a clinical specialization in measuring and managing low-risk prostate cancer. As suggested earlier this year, perhaps Gleason 6 and Gleason 3 + 4 = 7 should be considered a different disease. It’s crazy, CRAZY how committed the field is to subjecting men to over-treatment and all the pain, loss and risk that comes with it.

  6. Tracy:

    You are massively over-reacting to an entirely hypothetical model. No one is suggesting that this model be implemented without a great deal of further study that goes way beyond the concerns you are expressing. The model might, in fact, help to reduce over-treatment.

  7. I am confused here Mike — is the PPC calculation made as a function of both the number of positive cores and the amount of cancer in the positive core?

    I clearly see how the 50% calculation can be determined on the number of positive cores, but how is the amount of cancer in each core factored into the calculation?

    rd

  8. Rick:

    If you want to understand the exact details of how the authors made their calculations, I think you will need to read the full paper. I have not seen that.

  9. My point is, Mike, while there’s the occasional call for improvement in diagnostic tools as well as half-hearted calls for new techniques or improvement of existing techniques to avoid or minimize side effects, a cursory, though almost daily, review of the research and commentary in the urological research literature implies a minimal — and sometimes downright dismissive, even mocking — interest by the field of urology in the issues of over-diagnosis, over-treatment, and meaningful, lasting minimization of the side effects of treatment.

    If adequately funded serious research is happening to support better diagnostic tools, it’s not getting published. About once a quarter I read through all the clinical trials open. The vast, vast majority have nothing to do with over-diagnosis, over-treatment, or eliminating and minimizing side effects. And any potentially non-invasive and side-effect reversible treatment techniques are targeted and marketed exclusively at late-stage patients.

    More and more it appears that the urology community is working from an “economies of scale” business model. They need a lot of men to be diagnosed with prostate cancer and they need to treat a lot of those men in order to profitably treat the relatively small percentage that truly need it and to project a public message of success at “overcoming” a type of cancer.

    Once the PR is put aside, however, the current research agenda in the field does not reflect an authentic commitment to bringing to market diagnostic tools that can discriminate indolent and low-risk prostate cancer from aggressive cancers and does not indicate an interest in creating and operationalizing treatments that eliminate and minimize collateral permanent harm. The short is, clinicians would rather feed patients platitudes and give false hope — and let them go home to discover for themselves just what has been done to them — than to authentically invest in improving outcomes and avoid treating men that don’t even need treatment. It’s a very, very sad state of affairs and I see no light at the end of the tunnel.

    There are probably individual doctors out there who don’t want to unnecessarily injure men, but they’re afraid to make the position public for fear of being marginalized by the mainstream, so they’re hard to find. The disconnect is so huge between the type of outcomes clinicians say they want to achieve and what they’re actually satisfied with achieving, that it’s impossible to trust anyone in the field.

  10. Tracy:

    The reason that you aren’t seeing clinical trials of better diagnostic agents is that, frankly, basic research hasn’t come up with any. One can’t do clinical trials on things that don’t exist.

    The apparent lack of trials of “safer” treatments is a different matter, but I don’t actually know of any really potentially “safer” treatments anyway, so I am not sure what you would want to see being tested.

    I am again going to tell you that half of this problem is in the hands of patients (and their family members) who insist on treatment for prostate cancers that would be much better if monitored until treatment was actually shown to be necessary.

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