Predicting outcomes on active surveillance for intermediate-risk patients

It is now clear that men who meet NCCN criteria for very low- and low-risk forms of prostate cancer are almost invariably good candidates for initial management on active surveillance (i.e., just monitoring as opposed to immediate treatment). Equally, men with high-risk prostate cancer are almost invariably poor candidates for active surveillance. (However, if they are elderly or at significant risk for death from other causes within the next 5 to 10 years, they may be well managed on watchful waiting or “observation”, which is not the same thing as active surveillance at all.)

By comparison, there is still a great deal of discussion and controversy about the role of active surveillance in the management of men with NCCN intermediate-risk prostate cancer — and most particularly those with “favorable” forms of intermediate-risk prostate cancer, which basically means men with not more than one of the following:

  • A PSA level of 10–20 ng/ml or
  • A clinical stage of T2b or T2c or
  • A Gleason score of 3 + 4 = 7  (i.e., ISUP grade group 2) and with at most 50 percent of biopsy cores positive for cancer (but preferably much less and with only a small amount of Gleason pattern 4 as a secondary pattern in one or two biopsy cores).

What Savdie et al. (of The Vancouver Prostate Centre in Vancouver, Canada) have done is to show how use of either the NCCN risk groups or the CAPRA score, in their cohort of 651 prostate cancer patients initially managed on active surveillance, were able to project risk for progression of disease among men with differing types of intermediate-risk prostate cancer.

An explanation of the UCSF Cancer of the Prostate Risk Assessment Score or CAPRA score, together with examples of its practical use is given on this web page. The CAPRA system defines low-risk patients as being those with a CAPRA score of 0 to 2 and intermediate-risk patients as those with a CAPRA score of 3 to 5.

In their cohort of patients, Savdie et al. assigned all their patients placed on active surveillance both an NCCN risk category and a CAPRA score at time of diagnosis. The patients were then rigorously followed over time and relevant clinical, biochemical and pathological characteristics, progression to definitive invasive treatment, and pathologic progression on follow-up biopsies were compared among these groups.

Here is what they found:

  • 144/651 men in their cohort were initially diagnosed with NCCN intermediate-risk prostate cancer of any type.
  • Average (median) follow-up was 4.5 years (but the range was from 0.6 to 19.1 years).
  • 259/651 patients (39.7 percent) received definitive treatment (but we are not told how many were advised to have such treatment and how many simply chose to do this).
  • Initially predicted rates of definitive treatment for the intermediate-risk patients were
    • 50 percent at 5 years
    • 66 percent at 10 years
  • Actual rates of definitive treatment were
    • No different between the NCCN low-risk and NCCN intermediate-risk groups of patients
    • Higher in CAPRA intermediate-risk (CAPRA score 3 to 5) compared to CAPRA low-risk (CAPRA score 0 to 2) groups of patients (P = 0.025)
  • Compared to NCCN “favorable” intermediate-risk patients
    • NCCN “unfavorable” intermediate-risk patients were twice as likely to receive definitive intervention (hazard ratio = 2.07).
  • In the entire cohort of 651 patients, two characteristics were independent predictors of cessation of active surveillance on multivariate analysis:
    • The percentage of biopsy cores positive of cancer
    • The presence of ISUP grade group 2 or higher on initial biopsy
  • In the intermediate group of 144 patients, only one characteristic was an independent predictor of cessation of active surveillance on multivariate analysis:
    • The percentage of biopsy cores positive for cancer
  • Only 1/144 patients (0.7 percent) diagnosed with intermediate-risk prostate cancer developed metastatic disease.
  • Actuarial overall survival was
    • 98.6 percent at 5 years
    • 94.1 percent at 10 years
  • There were two prostate cancer-specific deaths in the entire cohort (at 18.7 and 19.1 years of follow-up).

Savdie et al. conclude, based on the data from their 19-year-long cohort of active surveillance patients that

  • An increasing percentage of core involvement and the presence of Gleason pattern 4 are both predictors of increased risk of prostate cancer progression.
  • For men with intermediate-risk prostate cancer, NCCN “favorable” criteria and the CAPRA score can both be used to predict those more likely to remain on active surveillance for the long term.

As we regularly point out, active surveillance is not a form of “treatment” for prostate cancer. Rather, it is a form of initial management for prostate cancer that allows men diagnosed with lower-risk forms of the disease to delay treatment and the potential complications and side effects of such treatment until treatment becomes necessary. For some men, that delay in treatment may be brief; for others it may turn out that treatment is never needed at all.

There are no rights and wrongs here. For some men (and even some men with very low-risk disease) immediate treatment may be an imperative — even if it is not actually necessary for clinical reasons. For other men (and even some men with “unfavorable” intermediate-risk prostate cancer) deferring treatment for as long as possible may seem to be an excellent idea — even though it comes with definable risks for disease progression. What is important is that appropriate patients are advised that active surveillance is a real opportunity that they can consider and discuss with their doctors.

8 Responses

  1. A Pertinent Case Discussion from the 2016 Conference on Prostate Cancer: An Intermediate Risk Patient Desiring to Stay on Active Surveillance

    Thanks for reporting this interesting study.

    This is one of those important areas in prostate cancer where technology is advancing quickly but has not yet reached a nice, reliable steady state with clear-cut guidelines for practice. Having been a front-line participant as a survivor of a once life-threatening case since late 1999, I am in awe of how far the field has advanced, how much things have changed for the better.

    There was an interesting discussion of a case involving intermediate-risk and active surveillance at the conference by a panel of prominent doctors, who treat many prostate cancer patients. (DVD Disc 3: Case #5, 1:03:07 – 1:10:00) The panel, moderated by medical oncologist Dr. Mark Scholz, included Dr. Charles “Snuffy” Myers (medical oncology), Dr. Duke Bahn (radiology and cryosurgery), Dr. Fabio Almeida (radiology), Dr. Dan Margolis (radiology), Dr. Stan Brosnan (urology), Dr. Jacek Pinsky (medical oncology) and Dr. Henry Yampolsky (radiation oncology).

    While the case details and recommendations were quite interesting, it was hard not to be impressed by the role that genetic testing and especially mpMRI (and other) imaging played in the doctors’ thought processes in figuring out whether the patient could stay on active surveillance, which he dearly wished to do. Dr. Scholz asked: “Is it feasible? Is it questionable? Is it crazy?”

    Here is what they were dealing with (abbreviated): a patient on active surveillance for several years, now 73 years old whose PSAs through 2012 had not exceeded 3.7, with a biopsy uncovering 5% cancer, Gleason 3 + 3 = 6, but with a PSA that rose to 4.62 in 2013. A 2014 MRI (in bore) guided biopsy was negative, but, following a 2015 mpMRI indicating a lesion, a targeted biopsy found three postive cores out of eight cores taken, with 7 mm of one core positive for Gleason 3 + 4 = 7 cancer, with 20% Gleason grade 4, and the other cancers all Gleason 3 + 3 = 6. A genetic test indicated a pattern more like a Gleason 6 than Gleason 7. Radiologist Dr. Margolis described the slide showing the patient’s mpMRI results, explaining the significance of each of the parameters. (This was another illustration at the conference of how far imaging has developed over the past decade -– how remarkably precise and effective it has become.) Dr. Margolis noted that the tumor area was near the edge of the prostate and far from the rectum, an area that is hard to biopsy. A color Doppler ultrasound was also done, with results consistent with the mpMRI.

    The mpMRI was able to thoroughly examine the area that was hard to reach by biopsy, and the combination of inputs ruled out a possible benign fibromuscular stroma that apparently often looks like cancer. The panel queried the patient’s PSA doubling time and found that his PSA has been stable and fairly low. Follow-up mpMRIs every 6 months as well as free PSA and PAP were suggested as monitoring by one expert. Another contributed that monthly PSAs would be appropriate, and that having the patient on metformin, Avodart and a statin could help, that trio of drugs being a supportive tactic discussed favorably a number of times by a number of doctors at the conference. A confirmation biopsy in 2 years was suggested. The panel clearly paid close attention to the imaging information and the role of imaging in follow-up monitoring. Dr. Margolis mentioned a UCLA study he had been involved in that looked at follow-up of active surveillance patients’ ability to stay on AS based on their PSA and other monitoring data. He said that a change in the PSA, the MRI, or the functional information (I think he meant from the MRI) warranted re-evaluation with a tissue diagnosis, but that stability in these areas meant that the likelihood of progression was low, but not nil.

    The panel favored continued active surveillance for the patient. Of the five doctors who treat prostate cancer, not counting Drs. Almeida and Margolis who are radiologists, two –- Drs. Myers (“definitely” keep him on active surveillance) and Bahn stated they would keep him on active surveillance (with appropriate, careful monitoring, of course). When moderator Scholz asked if any of the panel was strongly opposed to keeping the patient on active surveillance, no one was so opposed, which Dr. Scholz clearly thought was remarkable, commenting that, “I was expecting more controversy.”

    While this discussion is focused on active surveillance for intermediate-risk patients, another alternative to traditional whole gland therapy is emerging: focal therapy. The above case is relevant to the focal therapy option as the cancer was clearly confined to the apex area, near the edge of the capsule. While such an approach would have been foolhardy in the past, there were at least two provocative illustrations of the potential of focal therapy at the conference.

    One illustration was by the eminent focal therapy expert from London, Dr. Mark Emberton; while it involved a patient not suitable for active surveillance, one can’t help thinking that if it worked for this patient it sure should work for less challenging patients with intermediate risk who had no signs of metastasis. A prominent cardio physician, a former mentor, had come to him with his own case of metastatic prostate cancer reflected in a high PSA and practically demanded that Dr. Emberton treat him focally, intending to go on to Munich for CyberKnife for one lymph node metastasis and two bone metastases. Dr. Emberton had told him that he needed to go on hormones and that “We don’t do that.” But the patient prevailed, and now, 8 years later, has no evidence of disease despite having had just focal therapy plus radiation treatment of the oligometastatic sites. Dr. Emberton did emphasize that he considered this a likely rare success in such circumstances, but he was clearly intrigued by it (2016 Conference DVD Disc 3: 2:14:40 – 2:18).

    The other illustration (“Clinical Case #2” in the Roundtable Discussion with the panel of doctors) also involved a patient well beyond the intermediate-risk status with arguable eligibility for active surveillance, but, again, if the focal approach worked for the Case #2 patient, it might work for some intermediate-risk patients. This patient had Gleason 10 cancer per Bostwick Laboratories and had been treated by Lupron and Casodex. At age 78 he had focal cryotherapy. His PSA was undetectable, but he was tired and had low libido. At some point he started taking testosterone supplementation, which would seem kind of nuts to many of us, including me. But now at age 87, with 10 years of follow-up, his PSA is 1.7, his testosterone is a healthy 483, and he is sexually active. The panel was quite skeptical of the approach and no doubt surprised to learn the outcome (2016 conference DVD Disc 3: 34:24 – 42:51)

    How fast the state of advanced practice is moving! Consider that the patient in Case #5 had cancer that was near the edge of the prostate, yet the panel’s willingness to continue active surveillance reflected confidence in radiation and supportive tactics/therapy to do the job if needed if the cancer were to penetrate the capsule -– a real change in thinking from a decade or even a few years ago when surgeons, with much justification, believed that cure was highly unlikely if the prostate were penetrated, and many doctors of all types believed that early metastases were likely to be beyond the range of radiation.

    It will be interesting to see if there are more useful developments described for such intermediate-risk patients on active surveillance at the next conference a month from now. I hope this area is addressed again.

  2. First link should be more like

  3. It has been duly corrected. Thank you.

  4. Dear Jim:

    In all honesty I think it is highly unlikely that there will ever be “nice, reliable steady state with clear-cut guidelines for practice” when it comes to the role of active surveillance in the management of “favorable” intermediate-risk prostate cancer. Patient mindset is always going to be a major factor because many men will simply be unable to consider monitoring a cancer like this … and at the other end of the scale there are going to be men like me (and the “Unreasonable Man”) who can’t really imagine why one wouldn’t!

  5. Thank you, SM: right in my wheelhouse as you know. “Only 1 IR patient developed metastatic disease (0.7%)” brought a smile to my lips. And as Allen sort of says (thank you to you too Allen), if I am that one, the science is progressing so fast that in 15 years (although it may be more like 5: I am approaching the 10th anniversary of a 3.7 ng/ml PSA) it will be better than being that one today.

  6. ADD: crossed.

    Believe me: I can imagine! I just have to pray that’s all it is.

  7. I suspect you are right.

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