Episode 3 – Dr Daniel Lin

I’m Joseph Ischia

I’m Nathan Lawrentschuk.

And we’re talking urology where we pick the eyes out of the landmark papers that guide our practice everyday. Our goal is to empower doctors to develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient.

We are all about “bringing the literature to life”.

JOSEPH: Today we are looking at a paper from the Canary PASS cohort of patients undergoing active surveillance for their prostate cancer. The title of the paper is “Outcomes of Active Surveillance for Clinically Localized Prostate Cancer in the Prospective, Multi-Institutional Canary PASS Cohort” published in the Journal of Urology in February 2016 with first author Lisa Newcomb. We were lucky enough to catch up with Senior author Dan Lin who gave us some insights in to this great paper on predicting who will have adverse pathology after a period of AS.

DAN: My name is Dan Lin, I am the chief of urological oncology and a professor of urology at the University of Washington in Seattle and am part of the prostate program down there.

NATHAN: In the absence of better screening tests, AS is the answer to overtreatment of insignificant prostate cancer detected in the PSA era. But now there has been a shift in thinking with AS which Dan highlights.

DAN: For many years we thought that active surveillance was a strategy to avoid over treatment. Place men on and avoid over treatment. But I think that strategy has changed now, we’ve conquered that. We know that that’s going to happen, now the strategy is to identify the virulent disease amongst the background of insignificant disease. So now we accept that we are going to avoid over treatment, we are doing that better; now we have a sea of men with imminent disease -we’ve got to find the bad apples in them. Now it’s a strategy to avoid under treatment of those men. So before it was an avoiding over treatment, now it’s really avoiding under treatment.

NATHAN: Australia, Canada and parts of Europe have been avid adopters of AS, but the proportion of men in the United States is still very low according to Dan.

DAN: I think that the figure use to be somewhere in the 10% range, although recently Matt Cooperberg and others published some JAMA as well as there was a big series in Michigan looking at the uptake of active surveillance now. I think that now for low risk patients, it’s now gone from that 10-15% to about nearing 40%, so I think that it’s getting there; but for the typical low risk patient at most 40% probably more like 20-25%.

JOSEPH: So if we accept that AS is the best initial treatment for low risk prostate cancer, how do we spot the bad actors. i.e. which low risk cancers will not stand the test of time and would be better treated upfront.

NATHAN: We currently use risk stratification based on PSA, DRE, and Gleason score and are happy to survey men with low risk or very low risk cancers. The future promises advances in MRI, genetic analysis of tissue specimens, or even liquid biopsies.

JOSEPH: But AS is currently the best we have and there are a number of cohorts such as the Toronto, Hopkins, and UCSF cohorts, that point to its long-term safety. Today, we are looking at the Canary PASS cohort from 9 high volume institutions in Canada and the United States. This study looks at 905 men with two primary aims:

1. To evaluate outcomes of men on AS, and
2. Determine significant predictors of progressing to curative treatment.

NATHAN: The eligibility criteria were very inclusive. Certainly more broad than most other published criteria. To be eligible for AS, men only had to satisfy two broad criteria: have biopsy confirmed prostate cancer, and cT1-2 disease.

DAN: We intentionally chose a broad criteria. Primarily because the major intent of this canary pass trial was bio market research. So we needed some men that might choose to be in active surveillance that were slightly higher risk as proof or principle for some of the bio markers that we were choosing to examine. That was one reason. The other was that again we wanted to have a real world application of active surveillance, just because they chose active surveillance with slightly higher risk disease we wanted to maintain them and see how they did for a natural history experiment of active surveillance.

JOSEPH: This is an important first point- there was no restriction on Gleason grade, and number cores, or percentage of core involved. It was only what would be considered reasonable for AS according to the treating clinician.

NATHAN: The key outcome was adverse disease reclassification, which meant any increase in Gleason grade on repeat biopsy, or an increase in biopsy tumor volume, which was a binary outcome, defined as an increase in the percentage of positive cores from less than 34% to more than 34%. Men with disease reclassification were offered curative treatment.

JOSEPH: I think that is a really interesting point. There was no protocol trigger for treatment based on PSA changes alone or increases in tumour volume if they didn’t cross the 34% threshold. So if they started with 40% cores involved and went to 100% with no change in Gleason grade then no protocol enforced trigger to treat. We asked Dan why they chose these criteria.

DAN: So there’s a couple of reasons. One – we do have the NCCN guidelines and the NCCN guidelines or the Epstein criteria of lets say 2 or less cores or 3 or less cores or a percentage of an individual core, we have a lot of debate about whether they include volume because as you said; the primary driver of tumour biology is grade. Volume might be a surrogate for a bigger tumour volume, maybe a surrogate for a hidden grade,

NATHAN: Exactly. However, many men did go on to receive treatment at the discretion of the surgeon based on this increase in tumour volume.

JOSEPH: For the statistical analysis, the usual variables were looked at: Age, race, Gleason score and tumor volume, PSA, PSA density, Clinical T-stage, BMI, and FHx of prostate cancer. And cases were stratified by NCCN risk criteria at diagnosis.

NATHAN: Although PASS uses broad eligibility criteria, most participants (87%) met NCCN criteria for very low risk or low risk cancer at diagnosis. 94% had a Gleason score of 6 or less. We asked Dan if he thought men with any Gleason pattern 4 were suitable for AS?

DAN: We think so. I think that what you mentioned there about the percentage of pattern 4 is amazingly under-utilised or under appreciated, the fact that somebody can have 95% 3 with 5% 4 (if you had 3+4) which would qualify for I think your agreed minority of 4, or 51% 3 and 49% 4 (the 3+4) but it’s a lot of 4, and I think we’re going to get to the bottom of some of that with the molecular analysis that we do.

JOSEPH: And the cohort wasn’t just full of all old codgers either. 37% were less than 60, and 89% were less than 70. We asked Dan if he had any concerns about AS in young men?

DAN: A couple of parts to that answer. If one looks at one of the predictors of reclassification or progression, it’s age. I mean older age men actually somewhat paradoxically have a higher chance of having higher grade disease later, so in some ways having a younger man – is that protective – not really. However, the second part of that answer is, I will tell men, I’m sure you tell your patients as well; if they’re young and they want active surveillance particularly if they have more high volume disease, that it’s probably not a matter of if they’ll get treated it’s probably a matter of when.

JOSEPH: Young men have the most to gain regarding erectile dysfunction and continence if you can delay curative treatment.

DAN: Exactly. They say often at times to me “let me get to retirement” or “give me the next 5-7 years without side effects”, this is very common and I hear it a lot.

JOSEPH: That’s right: Doc, give me 5-7 years and I’ll hang up the boots, put the cue in the rack, sing with Flaccido Domingo, take gold at the Lake Flaccid Olympics, Disappointing Miss Daisy….

NATHAN: Median follow-up is short at only 28 months. 216 men (24%) experienced adverse disease reclassification, which was mostly due to increased grade. Of these 216 men, 115 received curative treatment, 83 of these men decided to remain on AS or were considering treatment, and 18 dropped out of PASS without confirmed treatment. We asked Dan why men would choose to stay on AS after upgrading.

DAN: Yeah, this is not surprising. If one looks at the 2-3 major series of active surveillance that being Hopkins, the Toronto series or UCSF series, it’s pretty common that men that have evidence of grade progression decide to stay in active surveillance. I think it’s partially because they are having microscopic bits of pattern 4 disease, 3+4 disease that are in one biopsy and they decide to stay on. What’s interesting is if one looks at the men that actually go from a Gleason 6 to a little bit of Gleason 7 and they stay on active surveillance, sometimes the next biopsy – right back to Gleason 6, maybe even low volume. So, one can see some heterogeneity there of the biopsy and I think that’s probably why people are staying on cause they’re just hanging in there.

JOSEPH: So I think we get to one the key questions. Have these men that went on to curative treatment “failed” AS?

DAN: No I don’t think so. I think that they’ve actually had a success on active surveillance because they’ve maintained themselves off, half of them have been with no treatment have no side effects of course for 10 years. And then, they are identified as having either progression, or they themselves decide okay I’m done with surveillance and it hasn’t been a failure they just feel done with surveillance and want to move on to treatment.

JOSEPH: And in the 689 participants who did not experience disease reclassification, 560 remained on AS, whereas 55 received treatment (mostly due to increased tumour volume but not crossing the 34% threshold), and 74 dropped out of study follow-up.

Nathan: overall 170 (19%) participants received treatment. 105 men had surgery, 59 receiving radiation, 3 receiving hormones and 1 treated with cryotherapy.

JOSEPH: There is always one!!

NATHAN: There were no distant metastases or PCa deaths. The probability of a patient remaining on AS at 2 years was 88%, at 5 years was 71%, and at 10 years was 50%.

JOSEPH: On multivariate Cox proportional hazards modeling, three variables were significantly associated with grade reclassification: percentage of cores containing cancer at diagnosis, BMI and PSA density.

NATHAN: Why percentage of cores?

DAN: I think that most of us think there is a bit of a surrogate for higher volume disease and higher volume disease has been shown to have higher grade disease ultimately, if one looks in the radical prostatectomy’s certainly as a predictor of upgrading in radical prostatectomy

JOSEPH: And why was BMI a predictor of poor outcome?

DAN: I think that if you ask the tumour biologists, the ones that are interested in insulin growth factor or inflammation and so forth; they say that body mass index or obesity is again a surrogate for inflammation, for metagenesis, for other things that will effect human biology, there’s a whole other school of the endocrine schools, so body mass index changing the hormonal milieu within the prostate. I don’t know which is true but all I know is that we are one of the first ones to show that BMI was associated with reclassification.

NATHAN: PSA density is something we don’t often calculate or hear about. Dan thinks we are missing an important point.

DAN: I think that it’s not used enough at all. It’s under recognised, I think it’s under reported and I also think that many don’t even calculate the PSA density. And I think there is an issue with that. If one looks at almost every paper for active surveillance, either single institution or multiple institution, if you look at that PSA density really rises to the top.

JOSEPH: And now we get to the crux of the matter. How many men had bad pathology on their RP specimen?

Nathan: Well, of the 105 men, 35 had adverse pathological features at surgery including primary Gleason pattern 4-5, EPE, SVI or lymph node metastasis.

JOSEPH: How did the guy with cryo go?

NATHAN: I could guess, but I won’t. Importantly there was no significant relationship between risk classification at diagnosis and adverse pathology at surgery.

DAN: The core of the matter is, at the beginning of their diagnosis where they are very low risk or low risk, later on if they had a radical prostatectomy they also still had about a 30 -35% chance of having adverse pathology. That’s pretty scary actually. So even if they were 1 core very low risk, low PSA density, the very low risk by NCCN category; they still have the same chance of having an adverse pathology. That really argues for biomarker work. That argues for better work in understanding the genomics and genetics and molecular biology that surround this disease.

JOSEPH: So what can we take away from all this?

NATHAN: Active surveillance is an effective strategy to mitigate overtreatment by delaying or avoiding primary therapy. Multiple series have demonstrated no or very low PCa specific mortality.

JOSEPH: The problem is that we don’t know who is safe to survey and what are the best triggers to avoid the dreaded “missed opportunity to cure”. Who are we doing a disservice to?

DAN: We have within our cohort many men that have been treated of course, and at the time of their radical prostatectomy if we look at their pathology and we’ve had a couple that were node positive, so the question that goes through my mind and all our minds of course is – did we miss the window of curability? Because we know that node positive disease is by and large incurable and so are these men that we could have operated on much sooner. So I think that those men who have poor pathology either by primary pattern 4 disease or worse or extra prostatic disease – those are the men that could we have identified them earlier, did we do them a dis-service by following them for sometimes 2-4 years until they were treated.

NATHAN: Most if not all of these disease reclassifications are unlikely to be due to actual disease evolution; most often due to under sampling of the prostate during biopsy.

JOSEPH: I think one of the hardest things to reconcile is the poorer outcomes associated with increases in tumour volume, but just say it is all Gleason 6 cancer which is not lethal. Is it just a surrogate marker of hidden higher grade? Perhaps we just need better imaging to help detect the significant cancers. We asked Dan if he thought one day MRI would replace tumour volume as a predictor:

DAN: I do. I think that grade will start to dominate. If MRI still proves that the positive predictor value for high grade or pattern 4 disease, really shows that the PPV is high and then we’re starting to hit lesions with minimal numbers or cores but they’re high grade, then certainly it’s going to change the game quite a bit.

NATHAN:  There are several limitations of this study. Mainly, the short follow-up where evaluation of the impact of AS on the more established disease specific end points, such as PCa metastasis or mortality, is not possible.

DAN: If you look at Klotz’ series or Hopkin’s series, they’re really following them for 10-15 years and we are pretty early in our study. I think that again we’re about bio markers and probably early progression, so I think that as you know the risk of mortality form low risk prostate cancer is amazingly low, it should be low, it was 1.5% in the Toronto series and 0.15% in the Hopkins series. These are again after 10-15 years follow-ups. So we are relatively young. I think we will get there eventually but it’s just going to take some time.

JOSEPH: One of the criticisms of AS concerns the adverse outcomes after delayed curative treatment. However, there is no guarantee that upfront treatment would have saved all these men from non-organ confined disease or further progression. There are still men with adverse disease in the immediate treatment arms of the PIVOT and Swedish prostatectomy trials.

DAN: Not many men have node positive disease, I think the T3 rate is in that kind of 20% range and I hear you on that, but not many node positive. So I agree with to a certain extent. Take a theoretical 100 men, they go on active surveillance and then down the line you’re going to treat 30-40 of them and half of those so we’re down to 15 or 20 that have issues, where as if you took the same 100 men and just did it right up front you’re right, there would be 15 or 20 that might have some issues.

JOSEPH: So lets look at the take home messages:

1. Even with very broad inclusion criteria, probability of a patient remaining on AS at 5 and 10 years after diagnosis was 71% and 50%, respectively.
2. With a median follow-up of 28 months, around 6% of men who undergo curative treatment will have adverse pathological features such as primary Gleason pattern 4-5, EPE, SVI or lymph node metastasis.
3. And, predictors of grade reclassification while on AS are 1. percentage of cores containing cancer at diagnosis, 2. BMI and 3. PSA density.

NATHAN: Thank you for listening.

JOSEPH: I hope you found this interesting and if you have any questions, comments or feedback, or want the full list of euphomisms for impotence, please get in touch with us at talkingurology@gmail.com. Of course, negative feedback can be sent to Sepp Blatter c/o FIFA past presidents who will transcribe it to the back of $100 non-consecutive bills and forward it to us.

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