Prostate Cancer 2017: Light at the End of the Tunnel?
If you follow this blog far enough back you will read early rumblings about the futility of prostate cancer screening. The last ten years has seen a “slow growth” of international guidelines stating that this is something that we probably should NOT be doing… and yet, it remains one of the most common screening tests in primary care. In 2013 approximately 20% of middle-aged Aussie men were tested using PSA. [AIHW, Medicare]
This 2016 paper in BMJ Open illustrated the stark differences in PSA screening practice between Australian and UK based GPs. The Poms rarely screen for prostate cancer – whereas we are a bit keen in the Antipodes.
Doctors’ perspectives on PSA testing illuminate established differences in prostate cancer screening rates between Australia and the UK: a qualitative study
The rate of screening in Australia has been decreasing since about 2008 [as has the incidence of disease… beware statistical trap there! If you don’t look you won’t find it. Does it matter?? – there’s the big question!]
HERE’S A QUICK WRAP of the GUIDELINES from around the globe
2012: US Preventative Services Taskforce recommendations.
The USPSTF recommends against all PSA-based screening for prostate cancer. This recommendation applies to men in the general US population regardless of age.
2014: The Canadian Task Force on Preventive Health Care
The recommendations apply to all men without a previous diagnosis of prostate cancer.
- For men aged < 55 years, we recommend not screening for prostate cancer with the prostate-specific antigen (PSA) test. (Strong recommendation; low-quality evidence.)
- For men aged 55–69 years, we recommend not screening for prostate cancer with the PSA test. (Weak recommendation; moderate-quality evidence.)
- For men 70 years of age and older, we recommend not screening for prostate cancer with the PSA test. (Strong recommendation; low-quality evidence.)
2016: Royal Australian College of GPs Guidelines for Preventative Activities in GP
Screening of asymptomatic (low-risk) men for prostate cancer by prostate specific antigen (PSA) testing is not recommended because the benefits have not clearly been shown to outweigh the harms. This remains the case following recent large trials. Therefore, GPs have no obligation to offer prostate cancer screening to asymptomatic men.
Some men may have individual concerns about prostate cancer and may put a higher value on the possible benefits of prostate cancer screening. This requires specific discussion to address the benefits and harms (from overdiagnosis and overtreatment) of prostate cancer screening. The Royal Australian College of General Practitioners (RACGP) has produced a patient decision aid that may assist this discussion
If after an informed process, perhaps using a decision aid, a man still requests prostate cancer screening, a PSA blood test is acceptable. Digital rectal examination (DRE) is no longer recommended as it is insufficiently sensitive to detect prostate cancers early enough.
Clinicians should not test for asymptomatic prostate cancer (eg by adding the PSA test to a battery of other tests) without counselling about possible harms as well as possible benefits, and obtaining informed consent.
The NHS in the United Kingdom do not offer prostate cancer screening as part of their service. They do offer PSA testing for free to men who have seen their GP and discussed the relative risks and benefits of screening.
Here is my personal algorithm, in my mind, that makes sense when it comes to dealing with the screening question in daily practice:
So here we are, it is 2017 and for the last decade or so we seem to have become a bit stuck. We have been “keen to screen” and yet recent data would suggest we may actually be doing more harm than good. There is a bit of trend away from universal screening on the whole – but there are still plenty of men out there who find themselves in the unfortunate situation of becoming “PSA positive” and having to ask their GP… “what now?”.
Of course, in an ideal world with appropriate pre-test counselling this question would have been answered hypothetically PRIOR to the screening. However we do not live in a Panglossian paradise, things are not as they ought to be, for several reasons.
- This discussion is often short or non-existent when it comes to PSA testing
- We have not actually had good data to answer the question of “what now?”
- The reality of counselling is that most men decide for / against test no matter what we tell them, it has become part of our medical / health culture in the worried-well, First World
- Why did the Irishman wear two condoms? Just to be sure, to be sure! Even after all this counselling, I imagine most men hear the word cancer “in the genital area” and will do anything to “avoid it” – hence the extremely strong motivation to get the test. This is just the way we MEN think. That is hard to change!
Now – here is another COMMON question that comes up all the time in teaching. The screening guidelines should only be applied to “asymptomatic men” – i.e.. those who have no symptoms of prostate cancer. As we all know, prostate cancer is usually asymptomatic until its later stages. The big fly in the ointment is that MANY of our older men have symptoms related to their lower urinary tract (LUTS) e.g.. slow stream, difficulty voiding, retention, uncomplicated UTIs etc. And… here is the rub: these are not symptoms of “prostate cancer” – they are symptoms of benign prostatic hyperplasia (BPH) and should NOT be used to describe a man as “symptomatic” and hence in need of investigation for cancer. They should prompt investigation for BPH and appropriate treatment, but not PSA testing as such. Many Urologist may not agree with this statement. However:
- The presence of LUTS were not exclusion criteria for the big trials that have given us all the data in recent years around PSA screening. Having BPH symptoms did not exclude men from the trials, hence we can include them in our population in which we can apply the data.
- There are a few studies which have looked at this question.[Collin, BJUI ; Gothenburg RST]; And it would seem that in men who have a raised PSA those whom also have LUTS have a LOWER rate of prostate cancer diagnosed than men without symptoms. This makes sense as we would expect men with bulky, benign prostate glands to produce more PSA and hence the test become too sensitive and less specific in this group. Some would advocate using a much higher threshold in men with “prostatism” – one paper suggested a cut-off of 20 ng – which is pretty high!
On the whole I think we should just ignore LUTS as a risk factor. The incidence is very common, it will mess with your mind and you will end up “accidentally screening” too many men causing false positives in this group. Treat their bladder troubles, refer them on but be aware that a PSA with muddy the waters so to speak… just consider men with typical BPH symptoms to be “asymptomatic” when it comes to PSA screening for cancer. Carry on.
Enter the PROTECT trial – published in NEJM in September 2016. This is a really useful trial for us as GP s who are counselling men as to what a PSA ping might mean.
1643 men with localised prostate cancer diagnosed after PSA screening were randomised to one of 3 groups.
- Active monitoring: regular PSA levels, with a trigger to review if the level increased by 50% within 12 months.
- Radical prostatectomy
They were initially randomised, but were allowed to switch therapies as the disease course clinically dictated. They were followed up for 10 years. Here is what happened per 100 men over 10 years [from Table 1 of the paper] in a series of infographics created for your viewing pleasure. [Feel free to download and print these out, this is a good way to present complex information to patients I reckon.]
There was no significant difference in the primary outcome – prostate cancer related mortality [including treatment related deaths – a better metric IMHO]. There was also no overall mortality difference with just over 1% dying in all three groups – i.e.. these men with an actual diagnosis of prostate cancer had a 99% 10-year survival! That is pretty low given that the mean age of 62 years.
Although the “disease progression” was not the primary outcome for which this trial was powered we can guess at the relative effect sizes of each intervention.
If you bundle surgery and radiotherapy together as “radical” initial treatments then the NNT to avoid the development of metastatic disease is about 30 in comparison to “monitoring alone”.
The NNT to prevent “clinical progression” for a radical approach compared to initial surveillance was 9.
It should be noted that 41% of the men in the “monitoring” group never got any intervention and lived happily ever after. Same mortality rate, never progressed to need radio… fairytale ending!
For me these are numbers worth knowing. We should have these available when it comes to counselling men about their choices, risk and fears around PSA testing.
OK, are you still with me? One more concept I want to throw out there when it comes to screening for prostate cancer and what to do when the PSA comes back over the magic line.
The trial I want to discuss here is the PROMIS trial. Published in the Lancet, January 2017. The official title was, like the trial, hard to get your head around: Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study
This trial is tricky to understand but offers a new hope I think to those men who are in the “what now?” place having tested “PSA positive”.
First – you need to understand that the current “reference Gold standard” for diagnosis of prostate cancer is usually a TRUS (transrectal, ultrasound guided biopsy).
Approximately a third of men who screen positive will go on to have a “positive” biopsy. The trouble is that we know that there is a wide range of disease trajectory with prostate cancer. The biopsy alone doesn’t really tell us who has the aggressive, life-threatening cancer and who has the slow-burning, less malignant form. Pathology samples taken at radical prostatectomy can help sort this out with lymph node analysis etc – but that is clearly a select and biased way of sorting it out. Hence the need for a new Gold standard to use as a rule to assess our testing strategies.
So the PROMIS investigators looked at:
Men who were “prostate virgins: – i.e.. never had intervention or investigation before. This included men with:
- an elevated serum PSA (up to 15 ng/mL) within previous 3 months,
- suspicious digital rectal examination,
- suspected organ confined stage T2 or lower on rectal examination,
- or family history
- they excluded men who could not have an MRI or anaesthetic for whatever reason and men on 5-a reductase inhibitors
So what they did in essence was to compare traditional TRUS against an MRI.
They introduced a new reference standard called template prostate mapping biopsy [TPM-biopsy]. This involves placing a 5mm grid over the prostate and sampling every 5 mm to get a more accurate representation of the pathology within the gland. This is a much more sensitive test than traditional TRUS. As such the detection of cancer was higher (70%) in this study. Obviously many of these will be “over diagnosis” of small, clinically insignificant disease (30% in this series).
The authors predefined a clinically significant cancer as a Gleason score of 4 or more OR a maximal core length of > 6mm. Using this definition of “significant” the TPM-biopsy yielded 40% in this population. This definition was used to calculate the test characteristics of the other tests.
They investigated something called a multi parametric MRI. The MP-MRI included a series of different MRI modalities and Gadolinium enhancement as a sort of “virtual biopsy” to screen for disease AND then compared this to the traditional TRUS (10 – 12 core samples) with the TPM-biopsy as a reference standard for both.
So what did they find?
Comparing the MP-MRI to a traditional TRUS-biopsy with the fancy [not for primetime] TPM-biopsy as reference standard:
So have a gander at the numbers here. You will see that the MRI is quite sensitive, whereas the traditional TRUS is equally specific. These tests are complementary. They each have characteristics that allow you to answer different questions.
Do you want to be reassured and “rule out” clinically significant disease – then the MRI is your test. A negative MRI could be quite useful to decide if you should consider “watchful waiting” as per the ProTECT trial.
However, the authors took the analysis further and postulated that the MRI could be used as a screening tool prior to further biopsy and could in fact be used to guide TRUS to improve it’s detection of significant disease. The study found that “blind TRUS had a sensitivity of only 48% which is not really very reassuring given it has been the gold standard for a long time!
They concluded that in this population if they had used the MRI results to guide counselling up to 27% of men could avoid an invasive biopsy. I think this is a useful test for that reason alone. The rates of side-effects from TRUS and subsequent complications is not negligible. In this paper 1% developed sepsis from a UTI, 10% got urinary retention and 14% developed erectile dysfunction (requiring medication, injection therapy or devices). Most men go into screening with no concept of these risks.
In summary -this is just one trial. Don’t change your practice just yet! However, I think this is a glimpse into the future. Maybe there is another option. Could this MRI decrease the need for biopsy, maybe inform our choices when it comes to choosing between treatment and “wait n see”. The addition of MRI may make the detection of “real” disease much more accurate – and result in less harm, more benefit for us all?
So how might the “PSA-Positive Patient Protocol” look in a few years if this MRI thing becomes more available / integrated and the trial is validated? Here is my glimpse into the future – I am probably wrong, but that is the problem about the future… it is tough to predict.
OK. A lot of ideas and data to sift through there!
I think there may be be some light at the end of the PSA tunnel, a way ahead other than the current paradigm which exposes a lot of men to invasive testing and potentially surgery that may not improve quality of life for some.
Love to hear your thoughts.
Try and tell this to the ‘Movember’ industry.