Active Surveillance - Time to End?

Having worked with Laurence Klotz over the two years development of the AUA/ASTRO/SUO clinical guideline for localized prostate cancer I know his thoughts well on what tests to use and when to jump off active surveillance. While six statements were focused on Active Surveillance, I'd like to point out Statement 32 and Statement 33:

Statement 32: Tissue based genomic biomarkers have not shown a clear role in active surveillance for localized prostate cancer and are not necessary for follow up. (Expert Opinion)

Statement 33: Clinicians should offer definitive treatment to localized prostate cancer patients undergoing active surveillance who develop adverse reclassification. (Moderate Recommendation; Evidence Level: Grade B)

Discussion for Statement 33: For patients who elect active surveillance as a management approach (versus watchful waiting) there is an assumption that active treatment should be initiated upon the detection of adverse features that may change the patient’s risk category. This may be due either to an incorrect original classification or to true progression from a lower-risk to a higher-risk category. Thus, if there is adverse reclassification due to the detection of a higher Gleason score than was present at the initiation of surveillance, definitive treatment should be considered. Other factors that may lead to adverse reclassification include growth of lesion on mpMRI and suspicious rises in PSA that may change PSA density. In the PIVOT and ProtecT studies, 20% and 50%, respectively, of patients who started on active surveillance received treatment within 10 years.

My notes from the panel:
At no time in our behind the scenes meetings did Laurie mention jumping from active surveillance required a 4+3 designation. Although he did state that a 4+3 should probably not be on active surveillance. In fact, he wrote this section of the guideline and we wordsmithed it together with the panel to reach a consensus. We also discussed the use of genomic tests and all agreed that we need to improve the data we have with existing available tests. And before we stated "do this if this test shows this". we all recognized that data was also limited and required more research.

If anyone would like the complete guideline here is the link. I suggest getting the unabridged PDF at the top of this webpage. I personally am not a fan of how the webpage was published and the PDF is complete:

www.auanet.org/guidelines/clinically-localized-prostate-cancer-new-(aua/astro/suo-guideline-2017)

T

Hey Allen,
You are not kidding about whether all institutions and non-institutions (private practice urology centers) but the panel was academia and the peer reviewers represented pretty much the top academia in the US and abroad. And the panel was not just AUA, it was AUA, ASTRO, and SUO and had to be broader than AUA in order for ASCO to adopt as well. There was plenty of ASCO and NCCN involved. There was nothing left aloof.

Please note that the document from Klotz you cite is a 2007 document with the most recent study citation in 2004. A lot has changed with Laurie and AS in general. Though still a good read the 25 citations in the Klutz 2007 article were expanded on greatly for our work here.

There is a lot of excitement on the available genomic tests out there but we noted that the industry is still learning the effective use for them as far as treatment course changes. I am currently on the ASCO panel elected to assess molecular biomarker guidelines and we are clearly a couple years away from issuing this guideline. Stay tuned on that one. For now if a urologist, radiation oncologist, or patient decides to use the available tests it should be done where there are trials but I know that many private practices are compensated for using them. What effect that has on bias or conflict of interest is only speculative for me.

Keep up the great work Allen. You are masterful in your blog and in your support to those who can benefit from it.

Edit: Spelling errors corrected.

Post Edited (Tony Crispino) : 1/31/2018 8:09:35 PM (GMT-7)

Tall Allen said...
Statement 33 does not in any way contradict what I said. Klotz started his protocol allowing in patients with GS 3+4. So "adverse reclassification" would have to be GS 4+3. Here's what he wrote:

Klotz said...
The authors' [Klotz et al.] approach has been to use PSADT less than 3 years (20% of patients) or grade progression to Gleason 4+3 or higher (5%).

/www.medscape.com/viewarticle/565297_6

He's made some changes since the start. He now only allows GS 3+4 if pattern 4 is less than 10%. He also eliminated PSADT < 3 years as a treatment trigger. PRIAS, in contrast, uses it.

Allen, wouldn't "adverse reclassification" include a change from favorable intermediate risk to unfavorable intermediate risk? Say, you were 3+4 and pattern 4 was 5%. With just a little pattern 4, you are almost 3+3 and could qualify for AS... sounds reasonable.

But if pattern 4 rose to 40% or PSA jumped to 15 (2 intermediate risk factors), I would think just logically that remaining on AS might not be sound reasoning any more... even though you are still 3+4...unless of course there were hard statistical data to prove that it was OK!

Hence adverse reclassification may not be strictly be grade progression to 4+3, but a reclassification from favorable to unfavorable

Allen, you bring up another interesting point. These days with the MRI fusion biopsies, biopsies are more targeted and more accurate and fewer needles are put into less interesting areas of the prostate MRI wise. To me, this would mean a higher hit rate and would affect stats like the number of positive cores although probably less so, the proportion of Gleason 4. Conversely, the untargeted biopsy would almost seem fairly limited in determining the actual Gleason score. Do they use MRI fusion biopsies differently from random biopsies?

Earlier, I wasn't suggesting using PSA kinetics. Rather a PSA beyond 10 seems to be threshold, which is used to help reclassifying intermediate risk from favorable to unfavorable

Tall Allen said...
When you try to use a PSA change to change the risk level, you are using PSA kinetics. As I said, most programs are not doing that anymore. If the PSA goes from 10 to 15 (which is indeed PSA kinetics), it doesn't change the patient's appropriateness for AS, it just signals the further inspection is warranted.

Allen, you misunderstand me I wasn't talking about the change in PSA, but simply about PSA exceeding an absolute level of 10ng/ml, which was historically an intermediate risk factor. Also, having more than one intermediate risk factor was a criteria for unfavorable intermediate risk which could be a reason to stop AS. I am aware that the absolute level of 10ng/ml is one of the weaker criteria for intermediate risk and completely agree with you (and Klotz) that one has to look at a multitude of factors, especially Genetic testing. Klotz actually talks about this in one of his papers co-published in 2017, which has some further insights into his views:

For intermediate risk men additional biopsy features may be useful to define a ‘low-intermediate’ risk category. A recent analysis utilizing data from the Surveillance, Epidemiology, and End Results program (SEER) showed that 27.6% of men with clinical intermediate risk prostate cancer might actually have pathologic high-risk disease (T3-4 or Gleason 8-10).(28) They were able to further sub stratify the intermediate risk category into favorable or unfavorable intermediate risk by percentage of biopsy cores involved with carcinoma. Intermediate risk men with ≤50% cores positive had 18.2% occult high risk disease while men with ≥50% positive cores had 34.2% risk. When considering AS, men with intermediate risk features will likely need to be further stratified and reserved for those with lower intermediate risk features (a minority of positive biopsy cores, only Gleason 3+4). Several studies suggest that PSA levels > 10 as the sole intermediate risk factor may not correlate with higher risk for adverse pathology or biochemical recurrence after RP in the face of low grade disease especially when PSA density is considered.(29, 30) The latest publication from ISUP recommends that pathologists record the percent of Gleason pattern 4 for patients with 3+4 disease which may help risk stratify men with intermediate risk features for AS.(31)

A further consideration is the significance of very small proportion of Gleason 4 in men with Gleason 7 cancer. A study by Huang et al reported that in those patients with <=5% Gleason 4 pattern on biopsy, the distribution of radical prostatectomy grade was identical to the patients with Gleason 3+3. Undoubtedly tangential cut of a Gleason 3 acinus, which misses the lumen, may give the appearance of Gleason 4 pattern, and is responsible for artifactual upgrading in many of these cases, particularly where tumor volume is small. Thus patients with <=5% Gleason 4 should be considered excellent surveillance candidates.(32) Intermediate risk patients with low PSA density appear to behave like low risk patients. Advances in risk assessment utilizing molecular testing and innovative imaging to predict and identify cancers with higher grade or volume upfront will help limit risk and expand patient selection criteria for AS.