Category Archives: Prostate

ProtecT and survival: what do we make of major prostate cancer trial?

Simon Crompton

Simon Crompton

It’s a study worthy of headlines, and it got them. The early results of the ProtecT trial have been published – and they’re important if only because this is the first randomised study comparing three common approaches to localised prostate cancer: surgery, radiotherapy and active surveillance.

The news stories have been clear on the main finding of the trial: “Monitoring of prostate cancer as effective as treatment”; “Prostate cancer patients live just as long with no treatment, experts have revealed”. The stories followed the upbeat lead of press releases from the researchers’ own institutions, the universities of Bristol and Oxford: “Active monitoring is as effective as surgery and radiotherapy, in terms of survival at 10 years, reports the largest study of its kind,” they said.

The researchers found that around 1% of the 1,643 men with localised prostate cancer had died after ten years, regardless of whether they had undergone a prostatectomy, radiotherapy or a programme of regular testing to check for progression (active surveillance). And those on active surveillance had the added benefit of avoiding the severe side effects that can result from treatment. Positive about the benefits of monitoring over intervention, then.

Increased risk of metastasis

But if you’d read the editorial in the New England Journal of Medicine accompanying the study’s publication, you might believe you were reading about entirely different research. This focused on the finding that, although similar numbers in each group survived at ten years, those in the active surveillance group were more than twice as likely to have metastases and disease progression.

To the editorial author, radiation oncologist Anthony V D’Amico, an increased risk of metastasis in active surveillance was the most significant conclusion to be drawn from the research.

“Therefore, if a man wishes  to avoid metastatic prostate cancer and the side effects of its treatment,” he wrote, “monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.”

No definitive conclusions

The fact is that, though important, these results are still too limited for anyone to be able to draw definitive conclusions about the merits of active surveillance. If anything, they seem to have further polarised the stances of those set on opposite sides in the prostate cancer overtreatment debate.

So next, to move on, we need to see what happens beyond 10 years in terms of mortality. And we need a more stratified breakdown of what happened to men with different Gleason scores (indicators of cancer aggression). The men included in the active surveillance group in this study had higher Gleason scores than would normally be eligible for active surveillance – so the overall results may not reflect this approach accurately.

The headlines, of course, never reveal the full story.

Filling the knowledge gap on active surveillance

Simon Crompton

Simon Crompton

Active surveillance of men with localised prostate cancer is becoming increasingly popular. It is an observational approach, involving regularly testing, allowing men with low risk prostate cancer the opportunity to avoid or delay aggressive treatments.

Potentially, it’s of huge benefit to thousands of men: a recent study indicated that just 1% of men whose low risk prostate cancer is managed through active surveillance go on to die of the disease.

But, as delegates in Milan at last month’s third ESO Conference on Active Surveillance for Low Risk Prostate Cancer discussed, a big question looms: how do you identify the right men for active surveillance? Clearly, the implications of incorrectly defining “low risk” are major.

The problem is that you have to follow men for a long time to discover whether their prostate cancer will, in the end, prove life-threatening. The likelihood of cancer causing death depends on both the tumour (aggressiveness and extent) and the patient (age and co-morbidities). Without long-term studies characterising the type of disease and person suitable for active surveillance, selection is difficult.

How to define low risk?

In their absence, researchers are trying to find predictors of disease progression to support risk-based selection of patients. Existing prediction models help but, as Ewout Steyerberg from the Centre for Medical Decision Making at Erasmus University pointed out in Milan, much stronger predictors are needed to separate low risk from high risk patients.

The answers are likely to come from large studies analysing existing data from men with prostate cancer – and in particular a major study funded by the Movember Foundation, known as the Global Action Plan 3 project, or GAP3.  Movember has five GAP projects, but GAP3 specifically addresses the question of how you select the right men for active surveillance.

It aims to create a global consensus on selecting and monitoring men with low risk prostate cancer through studying the cases of 10,491 men across 19 institutions worldwide. This is the largest prostate cancer active surveillance database, comprising the majority of the world’s active surveillance patient data.

The significance of GAP3 to preventing overtreatment in prostate cancer cannot be underestimated. Today, one and a half years into the project, all the data from participating centres has been uploaded into a central database. Each patient’s clinical history and biospecimen, imaging and biomarker data is being analysed.

This analysis, due to be complete in August this year, will feed into a simultaneous expert review of all current active surveillance guidelines available around the world, leading to a new consensus guideline setting out which patients are suitable for active surveillance, and what are the most effective ways of monitoring them.

And the end result – available in perhaps 18 months’ time –  will be a web-based platform, based on the guidelines and using risk-based modelling derived from the new analysis, to help clinicians decide which patients are suitable for active surveillance.

Perhaps just as importantly, as Sophie Bruinsma from Erasmus Medical Centre pointed out in Milan, it will also provide some reassurance to men that that they have made the most sensible, risk-based decision about their disease.

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The real definition of active surveillance: what it means for a patient

Simon Crompton

Simon Crompton

It was only on the second day of ESO’s conference on active surveillance of low risk prostate cancer this weekend that the question was raised: what actually is active surveillance?

“Watchful waiting” and “active surveillance” were for many years regarded as the same thing. In fact, that Bible of medical veracity Wikipedia still equates the two – as observational approaches that allow men with low risk prostate cancer the opportunity to avoid or delay aggressive tests and treatments.

But the field has changed and specialised rapidly in the past 20 years, with the European School of Oncology taking a lead on extending knowledge in the field – organising three expert conferences, of which this was the latest. Those urologists, radiologists and public health experts attending such events are very clear that active surveillance is different from watchful waiting.

What’s the difference?

As Axel Semjonow from the University Hospital Muenster, Germany, explained: watchful waiting delays the need for palliative treatment, while active surveillance delays the need for curative treatment. Active surveillance is more likely to involve a schedule of assessment and tests, such as biopsy. Watchful waiting is more likely to apply to men with a life expectancy of less than ten years and will often follow active surveillance.

But these definitions only became widely used in 2008.

The rapid acceptance that active surveillance is an important strategy for treating low risk prostate cancer has had a lot to do with growing concerns about overdiagnosis and overtreatment in prostate cancer. For many men, biopsies, prostatectomy and radiotherapy produce effects far worse than their cancer ever would. A recent study showed that just 1% of men whose low risk prostate cancer is managed through active surveillance go on to die of the disease.

Conferences such as this are incredibly important for determining the best ways of selecting patients for active surveillance and of monitoring them while on the programme.

But active surveillance is still an emerging art, under-researched and ill-defined. The role of MRI scanning, for example, was a continual source of debate during the conference. We know a lot about its ability to diagnose prostate cancer. But in terms of its accuracy at monitoring disease progression, there are few yardsticks.

When cure seems the only goal

And, beyond the realms of such meetings, the very meaning of active surveillance is poorly understood. There are still varied definitions in scientific papers and guidelines. For prostate cancer patients, mere scientific statements of meaning do little good. Active surveillance offers many men the chance of a long and good quality of life without treatment side effects, but that might be hard to understand amid the stress of diagnosis when “cure” seems the only goal.

As several participants at the conference pointed out, amid the excitement of scientifically advancing this important field, the difficulty of patients understanding the approach and their personal risk should not be forgotten. Good communication has to be at the heart of programmes – and making sure that everyone understands what active surveillance really means today would be a good start.

Highlights from the conference:

 

We have breast cancer units – so why not prostate cancer units?

Simon Crompton

Simon Crompton

There are few certainties in prostate cancer: intense debate continues to surround the benefits and drawbacks of screening, the relative merits of surgery, brachytherapy and radiotherapy and surgery, the right times for active surveillance and radical therapies. But through all the dialogue, a plain fact is now being acknowledged that casts a light on all aspects of diagnosis, treatment and continuing support. The patient’s own preferences, personality and circumstances have a central bearing on what the “right” decisions actually are.

Thanks to the efforts of patient organisations such as Europa Donna, this principle has already received widespread recognition in the most common cancer in women, breast cancer. A new European Parliament policy in 2003 prompted the growth of specialist breast units based around patient-centred multidisciplinary care teams. This, it has become clear, is the best way to take account of a wide range of individual needs and preferences.

The most common cancer in men, prostate cancer, is not yet widely benefitting from such a re-alignment. But that may change.

ESO promotes the specialist model

The specialist unit model is particularly well suited to prostate cancer and its convoluted decision-making. Not only does it provide specialist care and support at every stage – whether it be active surveillance, surgery and radiotherapy side effects or palliative care. It can also help patients recognise emotional needs that might not otherwise be addressed – and studies show that men are less likely than women to recognise the need for help.

These are all points that have been made with some force by the European School of Oncology’s Prostate Cancer Programme, led by Riccardo Valdagni, Scientific Director of the Division of Radiotherapy 1 and the Prostate Cancer Programme at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. The programme developed the concept of prostate cancer units (PCUs), and in an influential article in the European Journal of Cancer in 2011 set out the concept and what was involved in terms of professional education and experience. The central principle is specialist care, multi professional care.

The idea is catching on. When I recently interviewed Per Anders Abrahamsson from the European Association of Urology, he said he supported PCUs, adding that non-prostate specialists had been treating the condition for too long. “We are definitely behind the concept of units. In many countries already, for example the UK, you now have to operate a certain number of cases a year and demonstrate follow-up and outcome to be allowed to carry out a procedure. I am convinced this is what will happen in all European countries.”

New paper sets the way forward

In August, the case for Europe-wide PCUs moves a step onwards with the publication of a new position paper from ESO in Critical Reviews in Oncology/Hematology, setting out the core criteria for defining the units in European countries. The criteria have been compiled by the PCU Initiative in Europe Task Force, established by ESO in 2012 to set standards for quality comprehensive prostate cancer care and designating care pathways in PCUs.

As Riccardo Valdagni says in the paper, there is a general cultural shift towards multiprofessional working which should win a consensus among the uro-oncologic community. But the influence of those who stand to benefit most could be crucial.

“The efforts of patient advocacy groups in increasing patients’ awareness about the importance of being treated and followed up in top quality centers are key elements for the success of the initiative,” he writes.

 

 

 

 

 

 

In praise of academic cancer treatment studies

roger Wilson

Guest blogger – Roger Wilson, Honorary President of Sarcoma Patients Euronet

 

 

 

 

 

 

 

 

 

As a patient working in cancer research for over ten years now, one thing has slowly become more and more apparent.

 

The greatest patient benefit accrues from studies which are academically led. A

bold statement which needs a bit of unpicking.

 

Pharmaceutically led studies dominate our attention because of the scale of

investment and the power of the public relations team. They may well be led by

talented academic clinicians but the protocol has been driven by commercial

requirements even if it is an early phase study. The reality is that larger and

larger amounts of money are being committed to studies which benefit fewer

and fewer patients.

 

I am not decrying all that effort. My personal view is that if a new drug can

benefit just one patient let us have that drug. However I don’t have deep

pockets, any more than any healthcare system does, so that principle has some

weaknesses – as does the current pharmaceutical business model.

 

Beyond numeric significance

Academically led studies, which draw funding from government, charities or

philanthropic sources, may have a component from pharma providing free

access to drugs. These studies can also draw on treatments more widely

available in the market such as generic versions of previously patented drugs.

 

Academic studies will be seeking to find better ways of treating patients using

more clinically relevant outcomes and taking fuller account of the whole patient.

They are not seeking solely to identify the numeric significance of a treatment.

This sets academic studies apart from highly publicised drug studies with

registration objectives.

 

The EORTC (a charity) is an important provider of academic studies. The

European Commission is funding studies through its R&D programme.

Governments support studies, often providing funding to a university hospital.

An important source for such studies is the UK, where local funding from Cancer

Research UK is a critical component. Occasionally one trial will stand out.

 

Two extra years from an off-patent drug

STAMPEDE is a ‘basket’ study looking at a range of drugs in treating advanced

prostate cancer. It is a 7,000 patient multi-arm study. It could not be run by

pharma. Its first results published at ASCO 2015 looked at docetaxel, which is

now off patent. The drug was given earlier than it is in current practice. An OS

(overall survival) improvement of 24% and ‘failure free’ survival of 38%

translates into significant clinical benefit, improving patient longevity by a

median of just under two years.

 

The Chief Investigator, Professor Nick James from University of Warwick, said

“Our headline conclusion would be that docetaxel should be considered as

routine practice in men with newly diagnosed metastatic disease. With non-

metastatic disease, there remains uncertainty as to whether there’s a survival

benefit or not but it certainly improves failure-free survival by a substantial

amount.”

 

Pharma company researchers would give their right arms for results like that in

a cohort of patients as large as this. It will change clinical practice without

truckloads of expensive documentation being required by EMA.

 

So let’s pay more attention to academic studies. They can change things in big

ways and have the potential to provide patient benefit far beyond the seemingly

eternal procession of pharma company registration studies targeting smaller and

smaller cohorts of patients.

Roger Wilson blogs at http://rogerwilson.me.uk/

More pieces in the prostate puzzle

Simon Crompton

Simon Crompton

When are the costs of surgery too great? It’s long been a burning question in prostate cancer, and papers presented over the past few days at the European Association of Urology’s conference in Madrid have added a few more pieces to the risk versus benefits jigsaw.

Speaking recently to Per-Anders Abrahamsson, the association’s Secretary General, for an article to be published in Cancer World, I was told about the current gaping holes in research in prostate cancer. For example, there is no randomised trial comparing radiation therapy with surgery – which constantly gets in the way of good clinical decision-making.

Clinicians and patients are also short of information to weigh about the long-term side effects of treatments – and research presented at EAU showed that the evidence that clinicians currently act on might also be misleading. Take the incidence of erectile dysfunction following prostate removal surgery. The standard way of measuring erectile dysfunction is by the International Index of Erectile Function (IIEF), but researchers from the Herlev Hospital in Copenhagen realised that this might not take into account the sudden change in erectile dysfunction brought about by prostate surgery.

So they added another simple question to the survey: “Is your erectile function as good as before the surgery? (yes/no)”

The difference it made to responses from prostate surgery patients was striking. Responding to the IIEF survey without the additional question, nearly 24% of patients registered no decline in their erectile function after surgery. But when they were asked the additional question, just 7% said their erections were as good as before surgery.

That’s quite a difference for quite a lot of people. Such evidence could have a major influence on decisions about whether or not to have a radical prostatectomy.

Also presented at the conference was evidence about another kind of cost associated with prostate surgery: urinary incontinence. A team of doctors from the University of Nijmegen, the Netherlands, have used health insurance data to reveal the extent of post-operative incontinence and the costs of dealing with it. On a purely financial basis, the information is interesting enough: the average cost of incontinence pads is €210 each year (another study calculated that the 20 year additional cost of incontinence for a man after prostate surgery is close to €50,000).

But more important were the findings about the percentage of men suffering urinary incontinence in the first year after a urology procedure or follow-up. For men undergoing watchful waiting/active surveillance, it was 8%. For those undergoing prostate removal it was 80%, persisting into a second year for 40%.

Patient information about prostate surgery rarely specifies such figures, often offering vague reassurance that “most men” see a quick improvement in continence after surgery – as if it would be wrong to frighten them too much. As more evidence becomes available to fill in the picture on complex decisions, it’s only right that it should be shared with those it affects most.

Is it time to curb the charity fear factor?

Simon Crompton

Simon Crompton

Last week I received a press release from the British Dental Health Foundation, aiming to raise awareness about mouth cancer. It had asked 2500 people to give the words they most associated with cancer. “Deadly”, “devastating” and “scary” were the three most common answers – although the word “curable” was also up there, said the foundation hopefully.

The survey got me thinking about cancer and the fear factor, particularly in the light of recent cancer charity fundraising campaigns in the UK. Ringing disconcertingly in my ears even at this moment are the appeals of Movember to fight prostate cancer and a national Cancer Research UK campaign telling us to “Stand Up To Cancer” (catchphrase: “It’s payback time”) which culminated in a national fundraising telethon in October.

Strong emotions

Stand Up to Cancer was a celebrity-focused effort to encourage the public to give to cancer research. But its telethon illustrated how charity fundraising can become fear-based. The heart-rending story of a young footballer being struck down by a medulloblastoma was repeated throughout the evening. A long comedy segment encouraged all men to get their prostate checked, until a casual query to the resident doctor revealed that it was only worth doing if you were in a high risk group.

The dramatic climax was when one presenter gave a monologue about the people he knew who had died of cancer, yelling “You know what, f*** you cancer.” “You’re like a seventies entertainer, you’ve touched a lot of people,” he said, “and there are ongoing operations to get rid of you.”

It was genuine, and reflected the feelings of many people touched by cancer. But it also demonstrated that, for all the good that cancer fundraising can achieve, there is a risk that it can perpetuate distorted and unhelpful messages – because they are the most effective way of getting people to give.

Research funded by Cancer Research UK has made a big difference to the lives and prospects of many patients, and it deserves every penny it can get. But as I watched Stand Up to Cancer I thought of those thousands of people who will receive a cancer diagnosis and the hundreds of thousands who are living with cancer, and I wondered how the message about the disease being deadly, a bully, the enemy within, impacts on them?

Evidence-based decisions

The message given out by Cancer Research UK’s excellent website has a very different aim: to give accurate information to help people take good decisions, based not on fear but on evidence.

I received a thoughtful response to my last blog post about the need for evidence-based decision-making about screening to prevent overdiagnosis. Dr Nicole Guiochet wrote that such arguments about risks and benefits are hard for healthy people because they have a fixed view about diagnosing cancer early. “He or she cannot imagine nor understand he or she will die with another illness because cancer remains the most frightening of all, even if detected early,” she wrote.

She is right, and public fear of cancer is entirely understandable. But does someone have to address the charity fundraising question: are the messages being sent out by the highly competitive world of fundraising holding back good understanding and good decision-making about cancer? Yes, the money raised does a lot of good, but is stoking up the fear factor too big a cost for those living with cancer or about to receive a diagnosis?

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