Breaking news--UK study reaffirms Active Management, surgery and radiation have similar survival rates

ProtecT trial makes strong argument for the grandaddy of Active Surveillance

By Howard Wolinsky

When British researchers launched the ProtecT study--a comparison of men who went on Active Monitoring (AM)—grandaddy of today’s Active Surveillance—or were aggressively treated with surgery or radiation--they anticipated that survival curves eventually would separate, and those who underwent radical treatment would have a survival advantage.

It didn’t happen that way.

“That was a big surprise,” Dr. Freddie Hamdy, professor of surgery and urology at the University of Oxford, lead author of the study.

Researchers from the Universities of Oxford and Bristol led the study revealed Saturday at the European Urological Association meeting Milan and in the New England Journal of Medicine. “

(Dr. Freddie Hamdy, head of the ProtecT trial.)

All three groups of patients with low-risk to favorable intermediate-risk prostate cancer had similar similar death rates 15 years after diagnosis: Roughly 2-3% of each died.

Patients who went on AM lived as long as those who were treated. AM patients had a quality of life advantage, avoiding the impotence and incontinence faced by many who were treated,

When I was diagnosed after a rising PSA with a single tiny core of low-risk Gleason 6 cancer in 2010, I faced a dilemma--one urologist was urging me to undergo aggressive treatment--which 94% of us with low-risk disease did then--or roll the dice on AS, a then little used protocol of close monitoring with PSAs, MRIs and biopsies on a regular basis. (Today, the proportion who choose to be treated is 40%—better but still high compared to the 6% in Sweden and 9% in Michigan.)

I chose AS in part based on a study showing that mortality rates amongst the Big Three options were equal five years after diagnosis, I took the leap of faith in the science and my urologist, Dr. Scott Eggener at the University of Chicago. 

(I had an early AS because MRI was incorporated into my protocol in 2011.)

My conclusion then was all things being equal in terms of death rates why bother with surgery or radiation that could damage my quality of life? QOL means the risk of experiencing impotence and incontinence from aggressive treatment.

(Wall Street Journal)

Personally, the new ProtecT study offers more support for my decision almost 13 years ago. And it has to be a boost for newly diagnosed patients with low- to favorable intermediate-risk prostate lesions. 

My old friend from covering he tobacco epidemic while I was a reporter at the Chicago Sun-Time, Clifford Douglas, JD, Director, Tobacco Research Network, University of Michigan School of Public Health, who was diagnosed with Gleason 6 (also known as Grade Group 1) agreed about the boost from the findings from ProtecT study:

“It is certainly reaffirming, yes. I was diagnosed in late-2014, so it has been over 8 years now. I have been comfortable with this choice with the expert support and guidance of my doctor, Dr. David Miller at the University of Michigan. He has guided me through it carefully and informatively, which I think is truly critical for any individual who has to make the profound treatment decisions involved.”

Hamdy said: “This is very good news. Most men with localized prostate cancer are likely to live for a long time, whether or not they receive invasive treatment and whether or not their disease has spread, so a quick decision for treatment is not necessary and could cause harm.”

“It’s also now clear that a small group of men with aggressive disease are unable to benefit from any of the current treatments, however early these are given. We need to both improve our ability to identify these cases and our ability to treat them.”

Still AS is not perfect. Although men on active monitoring (the name researchers used for the protocol) were more likely to see it progress or spread than those receiving radiotherapy or surgery, this didn’t reduce their likelihood of survival.

More bad news for those who were treated: The trial also found that the negative impacts of radiotherapy and surgery on urinary and sexual function persist much longer than previously thought – for up to 12 years.

The trial was conducted in nine UK centers and is the longest-running study of its kind. It is the first to fully evaluate: active monitoring, radical prostatectomy, and radiotherapy with hormones for men with localized prostate cancer.

Between 1999 and 2009, 1,643 men aged 50-69 years across the UK, who were diagnosed with localized prostate cancer after a PSA blood test, agreed to be randomized to active monitoring (545), radical prostatectomy (553) or radical radiotherapy (545). The research team followed the men over an average of 15 years, to measure mortality rates, cancer progression and spread, and the impact of treatments on quality of life.

They found that around 97% of the men diagnosed with prostate cancer survived 15 years after diagnosis, irrespective of which treatment they received.

The AM group, like AS groups today, had a high dropout rate. Previous research has shown that five years after diagnosis 33-50% of patients leave AM because their cancers have advanced or for a variety of reasons, such as treatment exhaustion from the demands of repeated testing and emotional distress.

In ProtecT, around a quarter of the men on AM had still not had any invasive treatment for their cancer after 15 years. So the dropout rate continues to progress—a topic that demands attention from researchers.

Researchers said: “By the end of follow-up, 133 men (24.4%) in the active-monitoring group were alive and had neither received radical treatment nor started androgen-deprivation therapy. Of these men at the time of diagnosis, 17 (12.8%) were considered to have intermediate or high-risk disease according to the D’Amico criteria and 14 (10.5%) had Gleason grade group 2 disease or higher …”

Patients from all three groups reported similar overall quality of life, in terms of their general mental and physical health. But the negative effects of surgery or radiotherapy on urinary, bowel and sexual function were found to persist much longer than previously thought.

Co-investigator, Professor Jenny Donovan, from the University of Bristol, said: “Patients and doctors now have the necessary information on the long-lasting side effects of treatments to better understand the trade-offs between their benefits and harms. Survival no longer needs to be considered when deciding on treatment – as that’s the same for all three options. Now men diagnosed with localized prostate cancer can use their own values and priorities when making the difficult decisions about which treatment to choose.”

The trial has also highlighted defects in current methods to predict which prostate cancers are likely to grow quickly and spread. Initially, all those recruited to the trial were diagnosed with localized cancer and 77% of them were deemed low risk.

A reassessment using more modern methods showed that a far greater number would now be considered intermediate-risk – and in around 30% of men, the disease had spread beyond the prostate already. 

This means that the participants in the study had higher grade and stage disease than was thought initially. Despite this finding, mortality was still low, even when men with intermediate disease delayed or did not have radical treatment. Some of the men who subsequently died of their prostate cancer had been assessed as low risk at diagnosis, which the researchers highlight as an issue of concern.

Professor Peter Albers, chair of the EAU’s Scientific Congress Office and a urologist at Düsseldorf University, said: “The fact that the greater progression of disease seen under active monitoring didn’t translate into higher mortality will be both surprising and encouraging to urologists and patients. Active monitoring and biopsy protocols today are much more advanced than at the time this trial was conducted, so it’s possible we could improve on these outcomes still further. It’s an important message for patients that delaying treatment is safe, especially as that means delaying side effects as well.”

“But it’s also clear that we still don’t know enough about the biology of this disease to determine which cancers will be the most aggressive and more research on this is urgently needed.”

ProtecT reported in 2016 that after ten years follow-up, men whose cancer was being actively monitored were twice as likely to see it progress or metastasize than those in the other groups. The assumption had been that this might lead to a lower survival rate for men on active monitoring over a longer time period. However, the results from the 15-year follow-up show that this isn’t the case and that survival rates remain similarly high across all groups.

In an editorial in the New England Journal, Dr. Oliver Sartor, of the Departments of Medicine and Urology, Section of Hematology and Medical Oncology, Tulane Medical School, New Orleans, noted that diagnosis and treatment of prostate cancer has changed significantly since the ProtecT trial started.

He said: “Active monitoring as performed in the ProtecT trial should not be used today. We can do better by adding serial multiparametric MRI assessments. The increased rate of metastasis that was noted in the active-monitoring group would likely be diminished with the active surveillance protocols that are being used today.

“Surveillance for low-risk prostate cancer is more accepted today than in 1999, although at times patients remain anxious about leaving a cancer untreated. However, treating anxiety by removing a prostate often creates larger problems. Various forms of focal therapy are increasingly being used, especially now that tumors can be better visualized and potentially targeted with the use of advanced imaging techniques.aken together, the management of localized prostate cancer has undergone a wholesale change since 1999 when the ProtecT trial was started. Even so, the results of this trial provide valuable data to inform decision making in the large group of men with low- or intermediate-risk prostate cancer.”

Kevin Ginsburg, MD, a urological oncologist at Wayne State and a leader in the AS group in the MUSIC program, a leader in AS, said: “If we look at the 15-year outcomes of ProtecT, in which men were randomized to Active Monitoring (important: this is not the same as active surveillance, it’s very bad AS, not what we do in 2023) vs surgery vs RT, the risk of death from prostate cancer was similar among all groups - about 2% at 15 years. 77% of this cohort was GG 1 and 23% was GG2 or higher. You could imagine that most of those death events were driven by the non-GG1 disease. 

“As seen in ProtecT, some men with GG1 disease at diagnosis will die of prostate cancer, but that is likely the consequence of having missed higher grade and higher stage disease or progressing to higher grade and higher stage disease, not necessarily that GG1 disease in and of itself causing the death. I think the general consensus is that GG1 disease, in the absence of higher risk or higher grade disease, just does not have the ability to spread and kill. 

“Sadly, they have not broken down the risk of metastasis from ProtecT by grade group yet. I am very interested for these data.”

So we patients and our doctors got many more answers from ProtecT, leading to more questions.

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