Active surveillance in men with Gleason 3 + 4 = 7 prostate cancer at diagnosis

A critical question for men with favorable intermediate-risk prostate cancer (based primarily on a Gleason score of 3 + 4 = 7) can often be, “How safe would it be for me to go on active surveillance for a while after initial diagnosis?”

So let us be very clear about one thing immediately.

A man with favorable intermediate-risk prostate cancer (e.g., a clinical stage of T1c or T2a; a PSA level of 5.0 ng/ml; and a Gleason score of 3 + 4 = 7, with 15 percent of one positive biopsy core out of 12 showing cancer) who starts on active surveillance is always going to have a higher probability of the need for later treatment if he starts on active surveillance that an otherwise identical man who has only Gleason 3 + 3 = 6 disease.

So the question about “How safe” it would be for such a man to start on active surveillance as opposed to having immediate treatment is really about how effective treatment will be later when it actually becomes necessary.

The abstract of a presentation by Kalapara et al., to be given at the upcoming annual meeting of the American Urological Association, provides us with some reassuring information that addresses this precise question.

Kalapara et al. used information from a prospective database of men on active surveillance at Monash University in Australia to look at what was found among all men in that database (enrolled between 2000 and 2017) who underwent a delayed radical prostatectomy after being initially managed on active surveillance. All the men in their active surveillance database had to have a clinical stage of ≤ T2, a PSA level of < 20 ng/ml, a Gleason score of ≤ 3 + 4 = 7,  and fewer than half of their biopsy cores showing positive indications for prostate cancer at the time of diagnosis. All the men in the database were also given a confirmatory biopsy at 1 year and surveillance biopsies at least every 3 years thereafter.

The patients who started on active surveillance and then went on to have a radical prostatectomy were divided into two groups:

  • Men who started active surveillance with a Gleason score of 3 + 3 = 6 and had surgical treatment while their Gleason score was still 3 + 3 = 6 or immediately after upgrading to a Gleason score  of ≥ 7 (Group A)
  • Men who started active surveillance with a Gleason score of 3 + 4 = 7 and those who started active surveillance with a Gleason score of 3 + 3 = 6 disease, then progressed to a Gleason score of 3 + 4 = 7 but remained on active surveillance prior to their surgery.

After patients had surgery, they were assessed as to whether their post-surgical pathology and clinical outcomes were either favorable or unfavorable. Unfavorable disease was defined as prostate cancer with a Gleason score of ≥ 4 + 3 = 7 or pathological stage T3 and biochemical failure (i.e., a post-surgical PSA level > 0.2 ng/ml).

Here is a summary of the study findings:

  • 359 men were initially enrolled on active surveillance and followed for an average (mean) of 72.9 months
    • 286 of these men started with a Gleason score of 3 + 3 = 6.
    • 73 men started with a Gleason score of 3 + 4 = 7
  • 147/359 men (40.9 percent) went on to have some form of treatment.
  • 117 of the men who went on  to have treatment elected to have a radical prostatectomy
    • 77/117 men were in Group A
    • 40/117 men were in Group B
  • There were no statistically significant differences between the men in Group A and Group B (on average) with regard to their ages, their PSA levels at diagnosis, or their times from enrollment to progression.
  • Pathological results after surgery were similar between the two groups.
    • In Group A
      • 42/77 patients (54.5 percent) had unfavorable prostate cancer.
      • 23/77 patients (29.9 percent) had a Gleason score of ≥ 4 + 3 = 7.
      • 30/77 patients (39.0 percent) had pT3 disease.
    • In Group B
      • 21/40 patients (52.5 percent) had unfavorable prostate cancer.
      • 9/40 patients (22.5 percent) had a Gleason score of ≥ 4 + 3 = 7.
      • 16/40 patients (40 percent) had pT3 disease.
  • Rates of biochemical recurrence after surgery were also similar.
    • 12/77 men in Group A (15.6 percent) had biochemical recurrence and salvage therapy was successful in 10 of these patients.
    • 6/40 men in Group B (15.0 percent) had biochemical recurrence and salvage therapy was successful in all six of these patients.
  • 2/77 men in Group A (2.6 percent) progressed to have metastatic disease.
  • No patients had died of prostate cancer.

Kalapara et al. conclude that

Patients with GS 3 + 4 = 7 prostate cancer are more likely to progress to treatment on AS than those diagnosed with GS 6 disease. However, rates of unfavorable disease and BCR are equivalent between men with GS 6 and GS 3 + 4 = 7 disease who undergo delayed RP after AS. As such, our results support the safety of including selected men with GS 3 + 4 = 7 disease in AS programs.

The “New” Prostate Cancer InfoLink would point out that this cohort of “real world” patients who started on active surveillance was actually a higher-risk group of patients that those enrolled by Klotz et al. in the original Sunnybrook trial of active surveillance in that men with PSA levels as high as 19.9 ng/ml were eligible for enrollment, as were men with clinical stages T2b and T2c, and this cohort includes a higher proportion of men with Gleason 3 + 4 = 7 disease as well.

Despite the wide spectrum of patients who seem to have been eligible for inclusion in this study, the men with initial Gleason scores of 3 + 4 = 7 who went on to have surgery seem to have done just as well as the men with initial Gleason scores of 3 + 3 = 6, and this should offer a greater degree of confidence that active surveillance is a perfectly reasonable initial management strategy for men with favorable intermediate-risk prostate cancer. However, …

Even your sitemaster — who freely admits to having been a long-term advocate for active surveillance — is not sure he would consider active surveillance if he was diagnosed tomorrow with a clinical stage of T2b and a PSA level of (say) 17.0 ng/ml and a Gleason score of 3 + 4 in less than 50 percent of two positive biopsy cores out of 12 (although such patients do appear to have been eligible for inclusion in this study).

20 Responses

  1. I know they know this, so probably they will publish it, but they need to filter for sub-patterns of GP4, particularly cribriform. Even without that, thank you for the direct hit in my wheelhouse, Kalapara et al and @SM!

  2. It is interesting that the 2 mets were in the GP3 group, and I note the talk of 12-core biopsies. Suggestive of the point that it is generally better to know you have GP4 than to think you have not.

    Is there a repetition of “3 + 4” above, for “3+3”?

  3. Re “Is there a repetition of “3 + 4” above, for “3 + 3”?

    No. I don’t think so.

  4. But I KNOW so :- )

    “Despite the wide spectrum of patients who seem to have been eligible for inclusion in this study, the men with initial Gleason scores of 3 + 4 = 7 who went on to have surgery seem to have done just as well as the men with initial Gleason scores of 3 + 4 = 7”

  5. And you are right and it has been corrected.

  6. I want to share my experience in regards to active surveillance with a Gleason score (GS) of 3 + 4.

    I had GS 3 + 4 with a PSA baseline of 4.8 and then a month later it dropped to 4.2. The DRE exam showed some hardness. I was being treated for BPH by my PCP and dealing with that for about 5 years.

    In June 2017 I elected to have radical prostatectomy & pathology report, all the cancer was inside the prostate capsule. It was noted pathology examined the other tissues which were also removed. I had been referred to a local urologist/surgeon who exceeded my expectations of his intense experience and knowledge and had 2 years of robotic assistance training at Tulane. As an example of his experience, I asked how many prostatectomies he had done in the past month. His response was, “Around 22 completed”. I also asked him about me waiting since I had intermediate risk disease. I was 69 when my yearly PSA showed risk for cancer. I had four positive core samples out of 12 (three were 3 + 3 and one was 3 + 4). He said he would advise me not to do “watch and wait” because 3 + 4 was still a concern. I wanted to do more research and he felt I had about 6 months before more issues came about. I finally chose to have the da Vinci nerve-sparing RP procedure and the pathology report showed the cancer beginning in the neck of the urethra inside the prostate. I am glad I took his advise and have had three recent PSAs which were all 0.01. The expertise of the surgeon makes a difference … in my opinion. I felt this surgeon talked to me like a family member. He also said “as a patient I was in very good health for someone of 70 years old, which made a big difference. I discovered that many men who I had talked to even a couple of years younger could not have a radical prostatectomy because of their general health. I did also hear from these guys, “Oh I did not want to deal with the side effects of surgery”. Some admitted about the sexual erectile dysfunctions, then changed the subject.

  7. Dear William:

    There are no “rights” or “wrongs” here. Other men like you might have very reasonably made any one of several other possible decisions — inclusive of staying on active surveillance for longer and then having treatment some time later when there were initial signs of disease progression. These are very personal and individualized decisions.

    Having said that, there is no doubt at all that the skill and the experience of the physician is always important when it comes to having any type of treatment … and the “skill” part is a very important part. Not all surgeons who have done lots of radical prostatectomies are necessarily good at this operation.

  8. The UK NHS standard of care is manifestly shifting now in the face of studies such as this and greater confidence in imaging. As always, based on a statistically insignificant sample of 1.

  9. I appreciate this posting but, for myself, recently diagnosed with six cores at Gleason 6 and one core at Gleason 3 + 4, there are a few important factors missing.

    In determining whether one might be a good candidate for active surveillance genome testing of one’s specific cancer cores can determine rate of progression of your specific cancer biopsy. … That is, now, a very valuable piece of information missing from this study as well as extremely helpful in determining a choice of active surveillance.

    A new friend with a Gleason 3 + 4 found this genetic testing very valuable. … He has now gone 5+ years under active surveillance as part of the Memorial Sloan-Kettering Cancer Center program of active surveillance. His decision relied importantly on the fact that the rate of progression based on Prolaris data had him at well under 3 percent per year for growth. …

    The other important factor missing here is one need not jump immediately to radical prostatectomy after progression. For myself, even if I progressed to a Gleason 4 + 3, the option of radiation therapy is still a viable one — albeit more stringent than treating earlier. …

  10. Dear Mark:

    Please do not misunderstand the posting above. It addresses a report of data from a specific, retrospective study that was presented nearly 18 months ago, and that includes data from patients back to 2000, when there were no widely available genetic/genomic test data relate to active surveillance, let alone anything that could help anyone to use such data to project risk. Data from this study therefore could not be used to assess risk for these patients based on genetic/genomic data.

    The question of who is a “good” candidate for AS has as much to do with an individual patient’s attitude to risk as it does with the data we can currently generate to suggest risk levels. There are many physicians, for example, who would tell someone like you that any patient with seven positive biopsy cores, including one that is Gleason 3 + 4 = 7, shouldn’t be on AS at all. On the other hand, you have clearly decided that you are fine with this, and I would consider that to be a very reasonable decision (but I can’t tell you that it is “right” or “wrong”).

    Furthermore, no one who is expert in this field is under the illusion that surgery is the “only” treatment option if a man like you were to progress to having a single core of Gleason 4 + 3 as opposed to 3 + 4. There are now multiple potential options, including several types of radiation therapy and other forms of treatment. The primary objective of AS is to defer treatment until treatment (of some type is still to be determined). It is not to defer surgery until a urologist thinks surgery is necessary.

    We are still in the early stages of learning how best to categorize patients as being excellent, good, reasonable, and less good candidates for active surveillance. New data are being published almost monthly. Genomic/genetic data of different types are certainly useful, as are data from different types of imaging test, and other new types of test still in development. This is all a work in progress.

  11. I am 67. I have been recently diagnosed with prostate cancer (in February 2020). My PSA levels were as follows: Dec. 2019, 4.1; PSA Jan. 2020, 4.4 ng/ml. Urologist ordered biopsy, which was done in Feb. 2020. The results were:

    — R side, Gleason 3 + 3 = 6, 1 out of 4 cores, 5%
    — L side, Gleason 3 + 4 = 7, 3 out of 4 cores, 15%

    As of right now (April 2020) I have chosen active surveillance (AS), I also completed an Oncotype DX test (score 26), so as of right now I am involved with AS.

    I will have another DRE in August and I am having my PSA tested monthly. I also increased my vitamin D intake from 1,000 to 10,000 IU, I will see what happens. Any comments are welcome.


  12. Dale,

    The info you need to know about your GS 3 + 4 is what percent of those cores is pattern 4. Not all pathologists report that information (although they all should, IMHO). If you have your biopsy slides sent to Jonathan Epstein’s lab at Johns Hopkins ($275), they will report that to you. If the pattern 4 is insignificant, you may feel more confident in continuing with AS.

    In a recent study, after Gleason score and PSA density were taken into account, Oncotype Dx failed to predict adverse pathology in men on AS who went on to have prostatectomy. It also did not predict upgrading on follow-up biopsy. Perhaps one of the other two genomic tests on biopsy tissue (Prolaris or Decipher) will be more predictive.

    Our best evidence from a large randomized clinical trial and a large Mendelian randomization study is that vitamin D supplementation has no effect on cancer risk. Furthermore, at the very high doses you are taking, a randomized clinical trial found vitamin D to have a deleterious effect on bone mineral density, and cause hypercalcemia and hypercalcuria. One should only supplement vitamin D if blood tests reveal abnormally low levels.

  13. I’m 60 years old and would love an honest opinion to my choice as my PSA test I had a above the limit. my biopsy I had 1 out of 12 samples come back positive 40% and was rated 3 + 4 = 7 Gleason. He did suggest the gene test but since I have no insurance I’m on AS and hope I’m making the right decision over robotic radical prostatectomy or radiation treatment.

  14. Dear Charles:

    Active surveillance is a perfectly reasonable initial management option for someone with the prostate cancer characteristics you describe. And the smaller the percentage of the Gleason pattern 4 in your single positive core, the better you might do over time. However, …

    You do need to understand that at 60 years of age the chances are significant that you will need treatment at some point in the future. Is that going to be 2, 5, or 10 years from now? No one can tell you with certainty, but if you don’t have insurance you might want to see if you can cross your fingers and hold out until you are covered by Medicare!

  15. I appreciate this article and comments! I am 68 physically active no medications, PSA in 01/21 of 7.2 confirmed 3 weeks later. This was my first PSA test since age 65 which I need to find the result but it did not trigger further action (although incredibly dumb on my part to go untested for 3 years). Gleason 3+4 (Grade Group 2) 1 core 10% (1 mm) fragmented. Focus with tumor in core 6 too small to accurately assign a percent Gleason Pattern 4. T1c T2a 1/2 lobe, bilateral. I have a Oncotype test on order. What do you think overall? Urologist wanted me to go straight to Prostatectomy. Also should I ask for a different genetic test such as the 2 mentioned above? Many thanks!. Considering HIFU with Dr. Scionti in Sarasota, I have initial phone consult tomorrow although I really want to do nothing for at least 6 months.

  16. We apologize for the delay in posting this comment/question.

  17. Jim:

    Oncotype Dx did not predict grade progression in men on AS in this study. You may be better off using Prolaris or Decipher.

    I would think the awful oncological outcomes of whole-gland HIFU (a third were NOT cured of their cancer) would put men off HIFU.

  18. Dr. Scionti (17 years performing HIFU and touts a procedure that he developed) made one comment to me that recent data in the community on oncological progression rates after radical prostatectomy, radiation, or HIFU are the same. I did not press him on this in an initial phone consultation but I will later. My interest in HIFU would be a partial removal of the prostate to preserve function, not full removal. I will also likely talk with a doctor who has done the most HIFU procedures in Georgis. MRI is next which it seems is now the recommended first step after high PSA test. Not rushing into any treatment.

  19. My take is that HIFU has a VERY small “target audience” and that outside that audience, to the extent it is applied, it is essentially a placebo for AS. I am not in that “audience” but let’s just say I had to work that out for myself to a large extent. That n =1 study suggests possible trouble ahead.

  20. Jim:

    The outcomes are far from the same in similar patients. You may be interested in what the actual numbers are.

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