- Active surveillance for prostate cancer: a systematic review of contemporary worldwide practices
- AS patient selection
- TNM stage
- PSA level
- Number/percentage of positive cores
- Summary of systematic review
- Prostate Cancer Treatment: What to Know About Active Surveillance
- Prostate Cancer Treatment: When Watching May Be Enough
- Active Surveillance in Prostate Cancer
Active surveillance for prostate cancer: a systematic review of contemporary worldwide practices
Prostate cancer (PC) is the second most common cancer diagnosis and the fifth leading cause of cancer mortality in men (1). In 2012, 1.09 million men were diagnosed worldwide, thus representing a substantial public health burden.
The use of prostate specific antigen (PSA) testing and improvements in diagnostic procedures such as imaging and ultrasound guided biopsy have led to a significant increase in early diagnosis of localized, low-risk PC (LRPC), ranging from 10–80% of all men diagnosed with PC worldwide (1), and a subsequent decrease in PC mortality (2-4).
A substantial proportion of men with LRPC do not need treatment with surgery or radiation, but can be carefully monitored—an approach known as active surveillance (AS).
Overtreatment of LRPC is of concern, not only because of the physical and psychological morbidity associated with radical treatment, but also because of the economic healthcare burden (5,6).
AS is considered a safe alternative to immediate treatment and is endorsed by national medical organizations and guideline groups as a viable management option for men with LRPC (7).
More specifically, AS for LRPC can be defined as a treatment strategy of close monitoring through blood tests (PSA), digital rectal examination (DRE), imaging and prostate biopsy, with conversion to curative treatment if progression occurs (8,9). Large cohort studies have shown that with appropriate patient selection, risk of dying from PC in men on AS is low: 0.
1% to 5.7% over 10–15 years (Table 1). However, inconsistency in selection and adherence to AS remains. Studies suggest that patient preference (23,24), physician (25,26), family and peer group influence (27,28), National guidelines (29,30) and local practices (31,32) all influence this process.
There is also no doubt that anxiety surrounding disease progression also plays a significant role (33-35) in influencing long-term AS adherence. It is reported that cancer continues to cause more fear than debt, knife crime, Alzheimer’s disease and unemployment (36). Unsurprisingly therefore, studies continue to report that 1.
6% to 38% of men opt AS often with no or little evidence of disease progression within 5 years (Table 1).
Table 1 Overview of large cohort active surveillance studies
However, in the last 10 years a trend towards AS adoption in LRPC has been reported by many large database studies, with some variation still noted between countries, practices and physicians (37). Most notable are the upward trends seen in North America, Australia and Europe.
In 2015, Cooperberg and Carroll reviewed US trends in AS reporting from the US CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database. This demonstrated a sharp rise in the uptake of AS, from 10% over the past 20 years to 40% in 2010–2013 (4).
This was replicated in Europe with the Swedish National PC Register reporting a rise from 40% to 74% between 2009 and 2014 (30) and in Australia, where the Victorian PC Registry (38) reported a 16% rise in AS uptake between the first half of 2010 and second half (23.9% to 39.7%).
This level (39%) was maintained over the following 2 years further increasing in 2015 up to 42.8% (39). This was also demonstrated in hospitals reporting on radical prostatectomy in both Canada and Germany.
In Canada (Toronto), Louis and authors (40) reported a steady decline in the number of radical prostatectomies carried out for LRPC from 2007 (40.6%) to 2012 (13.6%), whilst in Germany the Martini Clinic (41) demonstrated a similar decrease for low-risk Gleason score 6 cancer in 2014 (12.1%) in comparison to 52.2% in 2000.
However, this increase is not universal. In contrast, a 2014 survey (42) of 2,133 Japanese urologists suggested that 26.9% reported no use of AS for LRPC and another 50.6% reported using AS in 18 months).
We identified 119 unique citations; of these 83 were excluded as review articles, commentaries, narratives, abstracts or where median follow-up was less than 18 months.
Full-text screening was carried out on 36 articles, of which 23 were excluded, rendering 13 articles included (Figure 1—PRISMA diagram) each describing a unique AS cohort.
Of the 13 included cohort studies (10-22), 6 took place in North America (10-12,14,17,21), 5 in Europe (15,16,18,20,22), 1 worldwide (13) and 1 in Australia (19).
Figure 1 Preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram.
The general demographic and follow-up characteristics of the published AS cohorts in this review vary considerably (Table 1). The average age across the studies was 65 years old. The number of participants studied ranged from 238 to 2,494 men. The number of months’ follow-up ranged from 19 to 180 months.
The main findings in terms of AS adoption/patient selection, monitoring protocols and trigger points for intervention or re-assessment across the different AS studies are described below.
AS patient selection
Thirteen international AS programmes met our inclusion criteria, describing guidelines for AS patient selection (Table 2). These are described with respect to selection criteria the following components: (Tumour Nodes Metastases) TNM stage, PSA level, PSA density, percentage of cancer in prostate cores, number of positive cores and Gleason grading.
Table 2 Criteria for entry into active surveillance programme
All cohorts agreed eligibility for AS meant clinically localised PC, with half of the cohorts using T2a or less, two [John Hopkins (11) and Goteborg (20)] opting to follow the Epstein criteria of T1c (in at least one arm of their cohort study). At the other end of the spectrum, three studies also included patients with T2b [(St Vincent’s, Australia (19), Canary PASS (21) and Milan (22)] and two cohorts men diagnosed with T2c disease [Canary PASS (21) and Milan (22)].
Agreement between ten of thirteen cohorts suggested a PSA cut-off of 10 µg/L, the University of Toronto (17) and Royal Marsden (15) suggested an upper limit of 15–20 µg/L depending on life expectancy and age (>65 years) respectively.
Only Goteborg (20) and Canary PASS (21) suggested an acceptable PSA for intermediate-risk disease of 6. In the Canary PASS LRPC group radical treatment versus continued AS (with re-classification as intermediate-risk) were discussed as options.
Two [University of Toronto (17) and Goteborg (20)] suggested any pathological upgrade would trigger intervention. Two cohorts [Royal Marsden (15) and UCPH (18)] identified a Gleason score of ≥4+3 as the trigger point.
Only Canary PASS (21) and Goteborg (20) gave a weighting depending on very low-risk/low risk (Gleason >3+3) or intermediate/High-risk (Gleason ≥3+4) disease.
Number/percentage of positive cores
Five of the thirteen studies [MSKCC (10), UCSF (12), PRIAS (13), University of Miami (14) and Milan (22)] maintained that >2 cores positive should trigger treatment, with the UCPH (18) extending this to >3 cores positive.
St Vincent’s Australia (19) suggested that cancer found in >20% of any positive core should trigger intervention, whilst The Royal Marsden (15) and Johns Hopkins (11) suggested a higher threshold for triggering treatment: 50% and 33% respectively.
The remaining studies gave no indication of cut-off number of cores positive.
The maximum cancer length (MCL) was variable, with two centres [MSKCC (10) and John Hopkins (11)] suggesting a cut-off of 50% and two centres suggesting more conservative numbers; St Vincent’s Australia (19) suggesting a cut-off of 8 mm of cancer and the Canary PASS consortium was set at ≥34%. The University of Miami (14) defined any increase in volume of PC and in MCL as their trigger for intervention.
PSA-based triggers for intervention included PSA doubling time (PSAD) and PSA velocity (PSAV). Only two studies suggested PSAV as an important trigger, The Royal Marsden (15) suggesting a PSAV of >1 and St Vincent’s Australia (19) >0.75.
PSA doubling time was included in six studies [UCSF (12), PRIAS (13), University of Toronto (17), UCPH (18), St Vincent’s Australia (19) and Milan (22)] with a cut-off of 3 years.
The Goteborg group (20) defined the trigger as any PSA progression.
Summary of systematic review
The thirteen AS cohorts included in this review demonstrated a wide variety of descriptions of LRPC. This indicates a clear lack of consensus on defining favourable risk disease, suitability for AS and intervention thresholds.
Patient selection (Table 2): despite all studies agreeing that a clinically localised PC diagnosis was defined as T2 disease and the majority of studies agreeing on a PSA threshold of 6 in 62% of studies, number of percentage increase in positive cancer cores was identified in 69% of the cohorts, MCL and PSA doubling time of
Prostate Cancer Treatment: What to Know About Active Surveillance
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Because certain prostate cancers grow very slowly, your doctor might determine that it’s not ly to present a significant threat to you. This is particularly true if a prostate cancer is localized, meaning it hasn’t spread beyond the prostate.
If that’s the case, you and your doctor can discuss getting regularly tested instead of undergoing treatment right away. Doctors call this approach active surveillance. By not rushing into treatment for a cancer that may not cause you any harm, this approach helps many men avoid treatment-related side effects.
Active surveillance , or active monitoring, means your doctor will monitor you closely, watching to see how the cancer progresses, if at all. This is primarily for cancers that doctors classify as:
- Very low risk for causing symptoms
To monitor a low-risk prostate cancer, someone on active surveillance could undergo:
- Rectal exam : Every six months
- PSA test : Twice a year. This blood test, commonly used to screen for prostate cancer, measures how much prostate-specific antigen (PSA) is in your blood.
- Biopsy : Once a year (until and unless your doctor determines a less frequent biopsy is warranted)
- MRI scan : Necessary in some cases to show more details of a cancer if your doctor has any questions or concerns from your test results
Prostate Cancer Treatment: When Watching May Be Enough
Your doctor will consider many factors before deciding whether this approach is right for you. This includes:
- Gleason score : This scoring system grades how aggressive a prostate cancer is. It also gives doctors hints as to how ly a cancer is to spread. Gleason scores less than 7 are considered lower risk and might be appropriate for active surveillance.
- Biopsy results : A prostate biopsy (removing tissue samples from the prostate) is the only definitive way to diagnose prostate cancer today. After a prostate biopsy, your doctor will count how many of the samples contain cancer. For biopsies that show three or fewer samples (or cores) with cancer, your doctor might recommend watching you before starting treatment.
- PSA results : A PSA test is the standard way doctors assess prostate cancer risk. Doctors use PSA test results along with information about your prostate size to measure your PSA density. If PSA density is less than 0.15, you might not need treatment right away.
- Physical characteristics : Another way your doctor will assess prostate cancer is through a rectal exam. If he or she can’t feel a cancer (via a hard nodule, for example), that’s another sign that could point to active surveillance as a possible treatment approach.
Active Surveillance in Prostate Cancer
Raoul S. Concepcion, MD, FACS:
Historically, using traditional ultrasound-guided 12-core biopsy, we understage and we undersample. Where we sample just with our little 12 cores, we sample less than 1% of the prostate. We have a range anywhere from 8% to 25%, upgrading and upstaging—and this is the Johns Hopkins’s data. Again, this is speaking to the heterogeneity of the disease, and speaking to the lack of a good imaging technique and biopsy technique. We understand that, again, there has never been any head-to-head trials with these tests, but the most recent joint guidelines from AUA (American Urological Association), SUO (Society of Urologic Oncology, and ASTRO (American Society for Radiation Oncology), despite this undergrading and understaging, basically said that they didn’t see a need for molecular testing in the low-risk patient. Glen, what are your thoughts on that?
Glen Gejerman, MD, DABR: I think the NCCN guidelines, talking about the low- to very low-risk, that’s perhaps where it has the greatest utility. Those are really the patients who struggle. Do they need to have a definitive treatment with all the attendant side effects? Whether it’s radiation or surgery, these patients do have significant quality of life issues.
If you have a low PSA, and are either very low- or low-risk your Gleason score, everyone’s looking for one additional piece of information. A genomic test can eventually prove this, but we’re not there yet. I agree that the company has done a very good job putting datasets together, but we need to validate it in a much larger group of patients in the real world. If we could do that, that would make patients and the physicians much more comfortable with the decision. “You can wait. You don’t need treatment now. We’ll put you on active surveillance and follow that protocol.”
Raoul S. Concepcion, MD, FACS: Mike and Evan, as medical oncologists, obviously, you guys generally, historically, are not involved in the decision making for the localized people with low-grade disease.
In your experience and in your practice, do you get a lot of patients who will come to you, walk in and say, “Hey doctor, I got diagnosed with prostate cancer.
What do you think about this?” What is your view from a medical oncology standpoint?
Evan Y. Yu, MD: Occasionally, we’ll be the tiebreaker, right? There is the urologist who says, “You should do surgery.” You see the radiation oncologist and they say, “You should do radiation.” The patient says, “I want to see a cancer doctor.” OK, we’re supposed to break the tie.
I make most of my decisions on which treatment to move forward with side effects, quality of life, and patient desires—the issue about whether you should be treated or not. Low-risk prostate cancer should be observed. And I think the real question is, “How much benefit are in these tests?” I think you pointed out nicely that for somebody who’s low-risk, you can find out whether they’re really low-risk or whether they’re a little bit higher low-risk. And what ends up happening is people that are a little bit higher low-risk probably get some sort of treatment, rightfully or wrongfully so. I think that’s the real point. In some ways, it helps alleviate anxiety. So, we have to ask ourselves whether that’s a good reason to do a test or not.
Michael A. Carducci, MD, FACP: I have a question for Neal, though. The younger man with prostate cancer versus the older guy doesn’t want incontinence. They might want active surveillance, but they have a long life left to potentially live. Do these tests help, in that situation, make that decision or make you feel more comfortable?
Neal D. Shore, MD, FACS: Absolutely. Actually, there was a very nice paper that came out in the New England Journal of Medicine. I don’t want to misquote the hospital. It was just presented at the American Urological Association’s Annual Meeting.
Active surveillance is absolutely a reasonable approach for men diagnosed under age 55. Historically, we had this notion that, “Oh, you’re younger. You’ve got to get something because you have a longer time to live with the disease.” The key thing, as Raoul said earlier, is this is not watchful waiting. This is active surveillance.
And with the surveillance protocols, there’s not unanimity about how to best do it.
But, the way I look at it is, I don’t want to inflict the comorbidity or the consequences of surgery, or radiation in somebody who might have worsening voiding symptoms or sexual dysfunction. I don’t want somebody to progress outside the prostate. You’re going to survey them regularly with follow-up biopsies, etc. And the data are mostly single institution. It’s not super long. It’s 3 to 7 years in most institutions. It’s low, single digits—the percentages, the number of patients—if you’re reasonably surveying them. You would lose an opportunity to ultimately treat them. And the other thing that I think about is, over the course of time, we keep getting better and better with newer therapies that hopefully would be less morbid and put patients at less risk. And then, of course, there’s the issue that something can happen to you along that time that you’re being surveyed that makes it all moot anyway. I really think that the markers are very, very helpful. We could talk and debate about the economic utility, but I think the clinical utility is there. Too many of our colleagues have a hard time with the dialogue just based upon DRE, PSA, the Gleason score, and percentage and number of cores. Getting a fourth independent variable to help further that education is important to make the right decision, which could be to do active treatment. It’s not always just to do surveillance.
Raoul S. Concepcion, MD, FACS: Plus, Neal, the endpoints of some of these tests are very different. The endpoint of 1 test is basically the lihood of dying in metastatic disease at 10 years, and the lihood of progression.
The endpoint of another test is the lihood, at a set point in time—vs-à-vis the time at biopsy—the presence or absence of unfavorable or favorable histopathology.
So, again, that even adds more to the confusion in terms of some of our partners and our colleagues.
And I think the other thing that goes along with that is, even though you’re on or we may recommend active surveillance, it doesn’t necessarily mean you’ll never need to be treated. It just means that, at this point in time, at the time of the biopsy, there’s nothing to indicate that you should go ahead and move on to treatment. But, that could change in a year. And I think what’s interesting, and we don’t really have that data, is if you ordered the molecular test—I don’t think anybody would ever advocate that—molecularly, could it change? I think there are absolutely no data on that. Again, it’s another area where we want the viewing audience to understand that this is not simple. our discussion earlier on genetic testing, it’s not simple. There’s a lot of dialogue. There’s a lot of confusion. And again, I think for a lot of our colleagues, they really do have to take the time to understand the nuances of all these tests.
Transcript Edited for Clarity