Walking the prostate cancer tightrope

There is very clear value in PSA testing in the right patient, it’s also very clear lack of value in PSA testing in the wrong patient. What we want to do is to find that little subgroup where it’s going to make a massive difference to their long-term survival, and hopefully would potentially save their lives and reduce the mortality rate of the disease

THE biggest tightrope act in men’s health – the balance between finding men with high risk prostate cancer and avoiding unnecessary therapies for those with low risk disease – is becoming less perilous for patients, urologists and GPs, thanks to a bank of “triage tests” working their way into standard practice.

While access and funding remain perennial problems, the science is moving ahead to take the heat out of decades of controversy.

A new narrative review of modern paradigms for prostate cancer detection and management, published by the MJA, details the steps that are mitigating the controversies of overtesting and overtreating that have plagued the past 10–15 years in the field (here, here, here, here, here, here, here and here).

PSA screening

“A good way to look at it is to compare prostate cancer screening in 2010 versus 2022,” said Professor Mark Frydenberg, a urologist specialising in urologic oncology and cancer surgery, who was lead author on the MJA review.

“In 2010, men would turn up to their GPs and they would have a PSA (prostate-specific antigen test) score above 4 and get referred to a urologist.

“There were no triage tests, so a PSA above 4 nearly always led to a prostate biopsy, many of which were potentially unnecessary,” Professor Frydenberg said in an exclusive podcast.

“The biopsies carried harms because they were predominantly done transrectally, which had at least a 2% severe sepsis rate leading to readmission to the hospital.

“Cancers were detected and, virtually irrespective of the grade of the tumour or the size of the tumour – because we didn’t understand the biology as well as we do now – they went on and had either radiation or surgery, with their attendant potential quality-of-life side effects.”

In 2022, Professor Frydenberg said, there are now checks and balances along the way, narrowing the group of patients who need to go on to active treatment.

“First of all, a PSA is done, and we normally encourage our GP colleagues to repeat the PSA … because in about 30% of cases, the PSA will return back to the normal range when you repeat it,” he said. “So, you automatically – just by simply repeating the test and including a free/total ratio – exclude people from even needing to be referred to a neurologist.

“These days if a patient has a repeat PSA and gets referred, the urologist now, unless there are some very extenuating circumstances, will arrange not only to do a full physical examination including a rectal examination, but would nearly always arrange a multiparametric MRI (mpMRI) of the prostate as a triage tool unless the patient was unable to have an MRI due to a metallic foreign body, pacemaker or implanted heart valve.”

Recommendations about the frequency of screening tests have also changed, with most, including the National Health and Medical Research Council (NHMRC)’s 2016 guidelines, recognising that testing every 2 years, rather than annually, is enough in asymptomatic men.

One big barrier to men’s willingness to be tested is the removal of the recommendation to have a digital rectal examination (DRE) at this early stage.

“The NHMRC 2016 guidelines have excluded the DRE as a part of routine screening, which has been a barrier to a lot of men to get tested at all, because they don’t like the exam, and has been shown to have limited predictive value as a screening tool,” said Professor Frydenberg.

In terms of age of screening, the recommendations remain focused on men aged between 50 and 70 years.

“It’s reasonable to screen men over 70, but it’s very clear that they’ve got to have at least a 7–10-year life expectancy because studies have clearly shown that there is no benefit in screening if men have a less than 7–10-year life expectancy and it would lead to unnecessary treatments and harms.”

The exception to the rule is men with a strong family history of prostate cancer, with screening recommended to start at age 45 years.

“There is quite a lot of evidence now that a single PSA at age 40–45 years of age is a predictor of future likelihood of developing prostate cancer,” said Professor Frydenberg.

“For example, if you’ve got a PSA of greater than 1.5 ng/ml at age 45, that group comprises up to 50% of prostate cancer deaths in the future. That particular group you need to be closely monitoring.”

Detection

The evidence for the diagnostic accuracy of mpMRI is now strong (here, here and here), and a Medicare rebate is available for a selected group of patients.

“What the mpMRI does is – apart from letting us know there is a lesion – it also helps us determine the size of the prostate which allows us to calculate PSA density which is the PSA divided by the volume of the prostate,” said Professor Frydenberg.

“If we have a patient with a normal looking prostate and with what we call a favourable density, usually less than 0.15, which means that you can explain the high PSA score because of the volume of the prostate, then they don’t generally go and have biopsies at all.”

Biopsy

Biopsies themselves have become safer – with a reduced risk of sepsis – and more accurate with the shift from transrectal to transperineal procedures.

“Importantly, we know that about 25–30% of prostate cancers are actually anterior. The problem with transrectal biopsies was the needle may not have even reached the anterior part of the prostate,” said Professor Frydenberg.

“Now we can direct the needles appropriately into that area or any other area of suspicion as detected by the MRI. As a result, the grading of the tumours is much more accurate because you’re now actually targeting a lesion and you can be very confident about what you’ve got on your sample.”

Active surveillance

Recommendations around active surveillance have changed.

“Active surveillance used to only be done for small volume, Gleason 6 disease,” said Professor Frydenberg.

“What we now recognise is that any volume Gleason 6 is reasonably safe to manage with surveillance because it’s biologically relatively inactive. Based on recent guidelines, even small volume, low intermediate risk disease is reasonably safe to be managed with surveillance as well.

“If you’ve got a very small volume Gleason 7, as long as it’s what we call a Gleason 3+4, rather than a 4+3, that patient, at least in the short to medium term, is reasonably safe to manage with surveillance as well.

“The guidelines are expanding because we’re beginning to realise that what we’re trying to find are the people with the higher Gleason 7s and the Gleason 8s and above, because they’re the high/intermediate and high-risk cancers that clearly need treatment.”

What do we call it

Any doctor knows that the word “cancer” elicits an anxiety response in patients that may prevent them from absorbing important information allowing them to make a reasoned, informed decision about management and treatment.

If a man has a lower Gleason score than requires active treatment, should we be calling it cancer?

“It’s an incredibly topical question at the moment,” said Professor Frydenberg.

“As soon as you mention the word cancer, you get an immediate anxiety response from patients and their families. Intuitively, they think ‘I’ve got a malignancy, it’s curable, why don’t we go ahead and cure,’ not understanding that the evolution of that cancer might be over a 20- or 30-year period.

“There’s certainly a lot of push in the urologic world right now to come up with an alternate name.”

The counselling skills of the managing doctor are really important at this point, says Professor Frydenberg.

“Probably the most powerful thing that I can ever tell my patients is that I’m not going to give them advice that I would not take myself,” he said.

“I’ll say, ‘if I had this diagnosis, personally, there is not a chance I would have any treatment for this’.

“That tends to relax them a little bit because, they automatically think that they’re coming to a surgeon, so they’re going to end up with a diagnosis and an operation.

“It’s really powerful when you, as a surgeon, say, ‘no, that’s the wrong thing for you, and I wouldn’t do it myself’.”

Novel agents and therapies

If a man has high risk disease, treatment options have broadened beyond the surgery–radiation binary.

“Ten years ago, the only real option for we had was androgen deprivation therapy,” said Professor Frydenberg. “There’s now a whole plethora of novel anti-androgen drugs available.

“It’s become standard of care that, if possible, you want to intensify standard hormone therapy with luteinising hormone-releasing hormone (LHRH) agonists together with one of these new novel anti-androgens because they’re much less toxic than chemotherapy.

“A lot of the current trials are looking at triplet therapy, where if you’ve got an extremely high risk metastatic disease, would we be better to have the standard LHRH agonist together with the novel anti-androgens together with chemotherapy.”

Access

Of course, as in all the Australian health care system, access to the latest diagnostic tools and available therapies can be problematic outside the big cities.

Does Joe Blow in rural Queensland have the same opportunities for accurate, prompt diagnosis and treatment as Jack Blow in Melbourne?

“They may not at the moment,” says Professor Frydenberg.

“Unfortunately, there are a lot of cost-related issues with this. Thankfully, MRI and PET (positron emission tomography) scans now are largely funded by Medicare, but getting good quality MRI and PET scanning, especially in regional Australia, is still difficult.

“The other thing is the cost of the treatments. At the moment, while some of the treatments like the novel agents under certain circumstances are covered by the [Pharmaceutical Benefits Scheme], a lot isn’t.

“For example, we know that anti-androgens together with hormone therapy have been proven without a doubt to improve long-term survival. The problem is patients, whether they’re in metropolitan or regional Australia, have to self-fund the anti-androgens as they are not covered on the PBS, and it’s expensive, anything up to $5000 or $6000 a month.

“So, it’s not only access in the country, but I think economically, even within metropolitan areas of Australia, there are a lot of people that just can’t afford a lot of the treatments that are best practice.

“There are still a lot of things that are unfunded, that are becoming very mainstream in urologic and medical oncology practice.”

Science and best practice are working to reduce overtesting, overtreating and unnecessary harms to men, making the management of prostate cancer less of a minefield for patients and practitioners. Now it’s up to governments to make those best practices more accessible for all Australian men.

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