Low volume, Gleason 3 + 4 = 7 disease: is active surveillance a realistic option?

It would be easy to misinterpret (or at least “over-interpret”) a recent paper from the group at Johns Hopkins about the pathological outcomes of men initially diagnosed with very low-, low-, or “favorable” intermediate-risk localized disease and treated by immediate radical prostatectomy.

This new paper by Patel et al. is entitled “Adverse pathologic findings for men electing immediate radical prostatectomy: defining a favorable intermediate-risk group” and has recently been published in JAMA Oncology.

The question that the authors set out to address is this one:

Is there a subset of men with Gleason 3 + 4 = 7 intermediate-risk prostate cancer with favorable characteristics to minimize risk of adverse pathologic findings at surgery?

To try to answer this question, Patel et al. carried out a retrospective analysis of data from 6,721 men, all of whom had initially been diagnosed with clinically localized very low-risk (VLR), low-risk (LR), and low-volume intermediate-risk (LVIR)  prostate cancer (as defined by the NCCN guidelines) between January 2005 and July 2016, and who had elected to be treated by radical prostatectomy by one of 15 different surgeons at Johns Hopkins during that time frame.

During the same time frame, Johns Hopkins was following 2,052 men with VLR and LR prostate cancer on active surveillance — but their active surveillance cohort excluded any men with LVIR prostate cancer.

The authors found that, of the 6,721 men who elected to have radical prostatectomy at Johns Hopkins:

  • The rates of adverse pathological findings were:
    • 60/1,264 (4.7 percent) among the men with VLR prostate cancer
    • 280/4,849 (5.8 percent) among the men with LR prostate cancer
    • 150/608 (24.7 percent) among the men with LVIR prostate cancer
  • A pathological Gleason score score of 4 + 3 = 7 or higher was the most common reason for such pathological findings, occurring in
    • 50/271 men (18.4 percent) of all men with LVIR prostate cancer at diagnosis who met all VLR criteria except biopsy grade at time of diagnosis
    • 108/508 men (21.3 percent) of all men with LVIR prostate cancer at diagnosis who met all LR criteria except biopsy grade at time of diagnosis

In other words, the men initially diagnosed with low-volume, intermediate-risk prostate cancer who underwent elective surgery were at significantly higher risk for adverse pathological findings than the men with very low- and low-risk prostate cancer, and the most common adverse pathological finding among these men was a pathological Gleason score of 4 + 3 = 7 or higher.

The authors use these and other data to draw the following, very reasonable conclusions that, based on this study:

  • One in four men who are diagnosed with low-volume, Gleason 3 + 4 = 7 prostate cancer (i.e., Gleason Group 2) on biopsy and who undergo immediate elective prostatectomy will be found to have more adverse pathology at the time of surgery.
  • Traditional clinical and pathological criteria were not useful in identification of a “favorable” subset of men with low volume, intermediate-risk prostate cancer who might be better candidates than others for management on active surveillance.
  • Active surveillance may place men with low volume, intermediate-risk prostate cancer (including a Gleason score of 3 + 4 = 7 or Gleason Group 2) at risk for adverse outcomes that could potentially have been avoided with immediate intervention.

However, the authors are also very careful to point out two things that did not happen “routinely enough” among this cohort of patients — magnetic resonance imaging (MRI) and molecular/genetic/genomic testing.

In addition, there is no suggestion in this paper that any of the 6,721 patients underwent a repeat biopsy prior to their surgery to try to confirm the presence or absence of Gleason 4 + 3 = 7 tissue (something that is strongly recommended for all men who enter a well-conducted active surveillance protocol, and ideally by use of an MRI- or MRI/TRUS fusion-guided biopsy).

There is absolutely no doubt whatsoever that any man with low volume, intermediate-risk prostate cancer, including a Gleason score of 3 + 4 = 7, who decides that he wants to go on active surveillance as a first-line management option should be thoroughly informed that his risk for progressive disease is notably higher than that of a man with Gleason 3 + 3 = 6 disease. Indeed, The “New” Prostate Cancer InfoLink would politely suggest that any such man should only be placed on active surveillance after at least two of the following three additional tests:

  • A high-quality multiparametric MRI scan  to look for any indication that there may be cancerous lesions that did not appear on the original diagnostic biopsy
  • A repeat biopsy under MRI- or MRI/TRUS fusion-guided biopsy to assure the physician and the patient that there is no evidence of Gleason 4 + 3 prostate cancer
  • Some form of molecular/genetic/genomic test to assess other types of risk for more aggressive forms of prostate cancer

While the study by Patel et al. certainly helps to clarify the pathologic risk for adverse pathologic findings among men with low volume, intermediate-risk prostate cancer, the data from other studies (e.g., those from Klotz’s group and elsewhere) show that the risk for metastatic disease or for prostate cancer-specific mortality among men with LVIR prostate cancer and a Gleason score of 3 + 4 = 7 is relatively low (but by no means non-existent) at a median 10 years of follow-up.

The other way to look at the data presented by Patel et al. is that 75.3 percent of the men diagnosed with LVIR prostate cancer in this study did not have adverse pathological findings at radical prostatectomy.

It would certainly be wonderful if we could actually subcategorize men with LVIR prostate cancer (inclusive of a Gleason score of 3 + 4 = 7) into subgroups who really were at highly definable risk “for” and “not for” unfavorable pathological findings at time of diagnosis. Hopefully, the appropriate use of MRI scanning, repeat biopsies, and molecular/genetic/genomic testing can assist us to define such subsets of patients so that we can better inform LVIR patients whether they are or are not potentially good candidates for active surveillance.

At the end of the day, whether to treat or to monitor any form of localized prostate cancer remains the patient’s, after a thorough discussion and a shared decision-making process between doctor and patient. And — as we have already indicated above — there is certainly increased risk for the patient if he has been diagnosed with LVIR prostate cancer and a Gleason score of 3 + 4 = 7, but he may still consider that active surveillance is an acceptable risk in his particular case.

What Patel et al. do not state in this paper is that every man with a low volume, intermediate-risk prostate cancer and a Gleason score of 3 + 4 = 7 should be discouraged from considering active surveillance. What they are, very appropriately, saying is that — based on this study — they cannot as yet define a “favorable” subset of men who would be better candidates for active surveillance and that therefore all men with these characteristics who wish to consider active surveillance need to be well and thoroughly advised of the risks involved.

Editorial note: The “New” Prostate Cancer InfoLink thanks Dr. Hiten Patel and his colleagues at Johns Hopkins for kindly and promptly providing us with a full text copy of their very interesting paper. Your sitemaster freely admits his personal bias: that there is a significant subset of men who are diagnosed with LVIR, Gleason 3 + 4= 7 prostate cancer and who are potentially very good candidates for active surveillance; that as yet we cannot identify those patients with a high enough level of accuracy; that any such patient needs careful work-up and counseling about his risk before any decisions about management on active surveillance; and that any such patient needs to be monitored with great care if he chooses to be so managed.

23 Responses

  1. There seems to be increasing if not overwhelming evidence that Gleason pattern 3 tissue does not metastasize but Gleason pattern 4 does. Klotz argues that deciding to proceed with active surveillance (AS) with a diagnosed Gleason 3 +4 = 7 cancer requires considerable thought and counseling, but, in a properly-managed AS program can be successful in delaying intervention. The factors for success depend upon the total number and replication rates of the Gleason pattern 4 cells, and the use of MRI imaging and, when indicated by imaging, targeted repeat biopsies to catch significant growth of pattern 4 cells while still isolated in treatable tumors. So, yes, in some cases a Gleason 3 + 4 = 7 cancer can be managed by AS to defer treatment. As with so many factors in our disease, the devil is in the details.

    The Best to You and Yours!

  2. After re-reading this post and reading the abstract of the paper, to further understand the point of the study it would be helpful to have defined the “findings of adverse pathology” upon surgery. Were these upgrades in the Gleason scores, increases in tumor volume, extensions outside the prostate margin? Without having access to the full paper, this seems ambiguous. And, what one would ultimately like to know would be the time to recurrence and ultimate cancer-specific survival of the men in each risk group.

    All men in the study apparently had Gleason 3 + 4 = 7 on the original biopsy. How many had the Gleason score changed upon surgical pathology? If that was significant, is the lesson, once again, that what really is happening is inaccurate sampling and pathology in initial biopsies. Access to the full paper might be more enlightening. Otherwise this seems to simply confirm that presence of Gleason pattern 4 tissue upon biopsy must seriously be considered in whether or not to do active surveillance and that for the other staging data, the existing stratification of VLR, LR, and LVIR risk groups provides a useful gradation of risk.

    Finally, as I recall. most prostate cancer programs and the NCCN Guidelines do not include Gleason 3 + 4 = 7 in the VLR (very low risk) or LR (low risk) categories. So, what new was really learned from this study?

  3. Dear Jon (and others):

    (1) On re-reading the original post myself, I realize I had initially, mistakenly stated that all patients in this study had a Gleason score of 3 + 4 = 7 at diagnosis. That is not correct. Only the men with low volume, intermediate-risk (LVIR) prostate cancer had a Gleason score of 3 + 4 = 7 (Gleason group 2) at diagnosis. My error … and I have adjusted the above text accordingly. Thank you for drawing this to my attention.

    (2) In the full text of the paper, the authors state that, “The primary outcome was adverse pathologic findings at radical prostatectomy, defined as Gleason score of at least 4 + 3 = 7 (GG ≥ 3), seminal vesicle invasion (pT3b), or lymph node metastasis (pN1); this outcome was selected based on universal acceptance that AS is inappropriate for patients harboring such features.”

    (3) Obviously it would be nice to know what the long-term outcomes of these patients was, but equally (since some of them were treated as recently a year ago) that isn’t a possibility as yet.

    (4) The importance of this study, in my view, is that it comes from a center that has a very high reputation for the quality of the pathological examination of both biopsy specimens and pathological specimens. In other words, one can be pretty confident of the accuracy of the levels of upgrading found at the time of post-surgical pathology compared to the original biopsy pathology.

    (5) I would concur with your suggestion that this study confirms “that presence of Gleason pattern 4 tissue upon biopsy must seriously be considered in whether or not to do active surveillance and that for the other staging data, the existing stratification of VLR, LR, and LVIR risk groups provides a useful gradation of risk.” However, I would also take the view that it provides a high quality measure of that risk at the time of any decision whether or not to initiate management on active surveillance: which is about 1 in 4 or about 25%.

  4. “they cannot as yet define a ‘favorable’ subset of men who would be better candidates for active surveillance and that therefore all men with these characteristics who wish to consider active surveillance need to be well and thoroughly advised of the risks involved.”

    To reframe the question; I do not wonder if there is a greater risk from 3 + 4 = 7. At a given 3 + 4 = 7 starting point, what is the improvement in outcomes from radical prostatectomy? It is not that there is greater risk, the question is the delta in risk.

  5. Yes Mike … but an accurate answer to that question would require a randomized clinical trial of active surveillance against radical prostatectomy in something like 750 or more patients with LVIR and Gleason 3 + 4 = 7 disease on biopsy who were followed for at least 10 years (and maybe a lot longer). I don’t think such a trial is even feasible. It took the best part of 20 years to do the ProtecT trial in the UK and that was enrolling men with any type of diagnostically localized disease in men with a Gleason score of 7 or lower on biopsy.

    Men in the US have never been very willing to be randomized to treatment or non-treatment for prostate cancer.

  6. “(LVIR) prostate cancer (as defined by the NCCN guidelines) between January 2005 and July 2016, and who had elected to be treated by radical prostatectomy by one of 15 different surgeons at Johns Hopkins during that time frame.”

    I have a hard time believing that 100 % of the screened pool elected to have surgery. While not a randomized study, there is a pool of equally screened dropouts, how big that pool is I obviously do not know.

  7. Dear Mike:

    This was not a “screened pool” of patients at all. It was only patients who actually received surgery at Johns Hopkins during this time frame.

    Another 2,000+ patients were enrolled in an active surveillance protoicol at Johns Hopkins during that time frame, and then there were undoubtedly many others who elected to have other types of treatment or who had more advqnced disease, or weren’t candidates for surgery because of their age, etc., etc.

    This study is a retrospective analysis of data from a very specific cohort of men who all met very specific criteria and who all had a radical prostatectomy.

  8. So the old problem that 3 + 4 at biopsy includes riskier groups who inflate the riskiness of 3 + 4 at biopsy. But those who know they are 3 + 4 (26 cores, MRI-guided, multiple MRIs) are correspondingly less risky as a result.

  9. At the end of the day, it is all about how intensely (and with what level of paranoia) the individual man wants to look at his risk.

  10. … and how intensely (and with what level of stamina) he is able to heed his own counsel against generally more aggressive options pushed by doctors who want to treat the cancer not the patient. “Being accepted onto an AS protocol” is a term which illustrates. No: you are not “accepting” me; I am refusing to sign the consent forms.

  11. blogollum:

    I hear you. Being “accepted” is not a privilege being bestowed upon you. It is your right. Just be careful it is a decision, not an avoidance. Hard to tell from the inside looking out, but then it is hard to tell from the outside looking in as well.

    Good wishes to you.

  12. Hi! Last week, my father (aged 64) was diagnosed with prostate enlargement with a Gleason score of (3 + 4). Is that curable? what would be the best treatment to cure it? Kindly advise.

  13. Dear Ashok:

    If you join our social network, that is designed and set up to be able to offer this type of personal, individualized information, but we will need the answers to some more questions after you are logged in.

  14. Excellent information. I do know that men with LVIR, as I had through genomic testing, should in fact have RP. Do not wait, it is cancer and needs to be removed. AS is fine for those men with VLR or LR, anything above that point needs intervention.

  15. Dear Walt:

    (1) There is now a great deal of information demonstrating very clearly that some men with “favorable” forms of intermediate-risk prostate cancer can be managed on active surveillance for considerable periods of time. And we are getting better at being able to identify those men that we were 5 years ago.

    (2) The appropriate treatment of men with “favorable” forms of intermediate-risk prostate cancer is very much a matter for individual discussion between a patient and his physician(s). RP is quite certainly not the only management option, and the “best” decision for patient A may well not be the same as the “best” decision for patient B, even if their clinical data are very similar.

    (3) Your personal decision to have an RP may well have been the “best” decision for you, and I am absolutely not criticizing that decision. However, others in your position might very well have come to very different decisions about how they wanted to manage their cancer, and their decisions may well have been equally justifiable.

  16. What seems to be missing from the debate about active surveillance (AS) versus immediate treatment for low volume intermediate-risk prostate cancer is the increasing availability of more detailed information for staging before rushing to immediate treatment and the following consequences, whether surgery or radiation.

    I did AS for 7 years before making the personal decision that it was time for treatment. But my AS was “active” as I did not assume that AS was a “cure” alternative to treatment for my prostate cancer if it should progress. I also accepted that obtaining biopsy samples is currently the best way to do accurate staging.

    My AS included annual imaging (color Doppler with Dr. Bahn; this was before mpMRI) and color Doppler ultrasound-targeted biopsies. I charted my PSA doubling time and my PSA density using the prostate volumes from my imaging. Initially my cancer was “very low risk”. It evolved over 4 years to “low risk”.

    In the sixth year a targeted biopsy found for the first time Gleason 3 + 4 tissue in the index tumor. My evaluation as to the next step included having the color Doppler ultrasound images available for the position and increasing size of the index tumor, observed changes in the PSA doubling time, and changes in the PSA density. Having that information available led me to decide to not continue AS with Gleason 3 + 4. But that decision was not based on “fear” of Gleason 3 + 4 but rather having the ancillary staging data available. If the only factor had been finding a limited amount of Gleason 3 + 4 in the targeted biopsy, I would have continued AS.

    My initial treatment choice following research during AS was brachytherapy. After 6 years of AS the increasing data for SBRT convinced me to choose that treatment. Four years after SBRT my PSA is 0.086 and continuing to decrease. A recent color Dopplker ultrasound image shows a dense prostate with an intact margin, clean seminal vesicles, no tissue anomalies, no sign of cancer in any of the original areas (at ending AS the index tumor was Gleason 3 + 4, another small tumor 3 + 3 on the right, another smaller 3 + 3 on the left).

    So my personal “bottom line” is that AS can be a valid alternative to initial definitive treatment if one takes advantage of the current tools for staging. And, proactive surveillance (not “fear”) can provide indications if and when one needs to move from AS to successful treatment.

  17. John’s personal story above is precisely on point. AS is not a “treatment” for prostate cancer of any risk level. It is a means to defer treatment and to then manage if and when one needs treatment. For some men treatment may turn out never be necessary at all.

  18. I am impressed with Jon’s listing and evaluation of his data points. An “active” that requires an active patient or an active physician.

    In comparison, my data points for the last 7 years consist of PSA scores and occasional DREs. In my case, I like to believe, that is more driven by my personal factors (a repetitive injury that has morphed into more of an auto-immune disorder; 7 years for bladder lining to return to normal after cancer treatment) that would require some pretty drastic news to change my mind about holding the cards I have.

    I can’t help but wonder if the increase in AS looks more like my story or Jon’s.

  19. Dear Michael:

    Your situation sounds more like “watchful waiting” to me than “active surveillance”, but I would need to know a lot more detail before I could understand the precise situation. You say you have had “cancer treatment”. Was that for your prostate cancer or for some other form of cancer (e.g., bladder cancer?).

  20. I’m not all that sure of the watchful part, but not unreasonable in my individual case.

    Yes bladder cancer, preceded with 14 years of Raynauds that spread from hands. Raynauds that was active into the mid and high 90 degrees. My response to injury is drastic blood flow reduction. After the bladder cancer path more treatment is not at all appealing so more data really may not be all that useful, or locally all that available. Removal of prostate stones dropped PSA from 14 to 4-6 range in the 7 years since, but also left painful adhesions which are with me every day. Did not mean to get off track.

    In large part I was really thinking of the Hammer and Nail post; looking for your current take upon how well the current toolbox is being used as AS spreads. Jon’s or my experience the more common?

  21. @Jon Nowlin:

    What got you “on the train” in the first place? An elevated PSA on screening? If so, what level? Your path sounds a lot like mine, but with an earlier biopsy. What was your PSADT when you chose treatment?

    Separate but related, I take the view based on my own experience and others that true grade progression 3-4 is more than the 1% p.a. that I have seen quoted.

  22. Dear Michael:

    I really don’t think your experience and Jon’s experience are comparable because you have the extensive prior history which Jon did not have. This “changes everything” in relation to how you are being monitored compared to someone like Jon.

    All I can really tell you is that Jon clearly made every effort to ensure that he was being monitored over time on a rigorous form of active surveillance. THis is what AS would look like at the majority of high-quality, academic medical centers. MY suspicion is that AS at a lot of community centers is not as rigorous, but has become a lot more rigorous now than it was (say) 3 to 5 years ago.

  23. Just a side bar. Thank you for your response.

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