A 'Real-World' Study of Prostate Cancer Surveillance

Nick Mulcahy

January 22, 2016

Is active surveillance a trustworthy and viable method to manage prostate cancer in a variety of practice settings — that is, outside the small group of academic centers that have pioneered and proven the approach in North America?

The answer appears to be yes — in the short run at least, according to findings from a nine-site cohort study that includes a Veterans Administration (VA) hospital and a community-based practice.

"Active surveillance is safe and a good initial strategy. About 10% to 15% of men fall off each year and transition to treatment," summarized investigator Daniel Lin, MD, a urologist at the University of Washington and Veterans Affairs Puget Sound Health Care System in Seattle.

This VA center is participating in the Canary Prostate Active Surveillance Study (PASS), the only multicenter study of active surveillance in North America. Other sites include the Eastern Virginia Medical School in Norfolk, which, despite being an academic institution, is primarily a community-based practice, Dr Lin told Medscape Medical News. It also has a higher percentage of black patients than the other eight study sites.

The cohort study involves 905 men with very-low-, low-, and intermediate-risk prostate cancer (according to National Comprehensive Cancer Network [NCCN] definitions) who were enrolled from 2008 to 2013.

Although median follow-up is only 28 months, there have been no prostate-cancer-specific deaths in the cohort, and only two men who transitioned to surgery were found to have positive lymph nodes.

 
It's very important to have this dataset.
 

"This is real-world active surveillance. It's very important to have this dataset," said Alexander Kutikov, MD, a urologist from the Fox Chase Cancer Center in Philadelphia, who was asked for comment and was not involved with the research. He pointed out that a majority of the Canary PASS sites are major academic cancer centers.

Dr Kutikov also explained that the "most robust datasets" in North America come from three pioneering centers: Sunnybrook in Toronto; the University of California, San Francisco; and Johns Hopkins in Baltimore.

But all three are single-center cohorts and their methods and personnel could yield anomalous, nonrepresentative results to some degree, he observed. A multicenter study is needed, said Dr Kutikov.

To date, much of the multicenter Canary PASS results are in line with prominent single-center data.

"We demonstrated that in a diverse clinical setting, active surveillance delays or avoids active treatment with a median time free from treatment of more than 5 years, consistent with results from single-center studies," Dr Lin and colleagues write in their study, published in the February issue of the Journal of Urology.

The study design dictates that men be followed with periodic biopsies, digital rectal exams, and prostate-specific antigen (PSA) testing, and be "reclassified" as needed on the basis of two measures: increased Gleason grade (primary or sum); and greater tumor volume (a ratio of positive to total number of cores; a ratio below 34% indicaties stability and a ratio of 34% or above indicates an increase).

Of the 905 participants, 216 (24%) underwent tumor grade and/or volume reclassification, which was the primary end point of the study.

The investigators prefer the term reclassification over progression because undersampling at the initial diagnosis can be the reason a more serious prostate cancer is not detected at first; they offer treatment (usually surgery) to men who are reclassified.

Notably, not everyone who was offered treatment jumped at the opportunity.

"Interestingly, a substantial proportion of patients who experience disease reclassification on active surveillance do not opt for primary treatment, while many without reclassification opt for curative treatment during a relatively short follow-up," the investigators report.

Of the 216 reclassified men, 83 remained on active surveillance or were considering treatment. Another 115 underwent curative treatment and 18 dropped out of PASS without confirmed treatment.

Of the 689 men who did not undergo disease reclassification, 560 remained on active surveillance, 55 opted for treatment, and 74 dropped out.

The dropout rate in the Canary PASS study appears to be higher than at least one of the pioneering centers (Sunnybrook). Only 2.5% of men in the Toronto cohort have been lost to follow-up, principal investigator Lawrence Klotz, MD, said in 2014.

In the Canary PASS study, the probability of a patient remaining on active surveillance 2 years after diagnosis was 88%, 5 years after diagnosis was 71%, and 10 years after diagnosis was 50%, according to Kaplan–Meier estimates.

Primary Takeaway Message

Overall, of the men who underwent surgery after a period of active surveillance, 34 (33%) were pathologically upgraded at prostatectomy and 14 (14%) were downgraded.

A total of 35 men (34%) had adverse pathologic features at surgery, including a primary Gleason pattern of 4 or 5, extraprostatic extension, seminal vesicle invasion, or lymph node metastasis.

"Importantly, there was no significant relationship between risk classification (very low, low, and intermediate) at diagnosis and adverse pathology at surgery," the investigators report. Surgery allows a definitive analysis of the prostate because the entire gland (and any other features around the gland) can be determined.

Specifically, the percentage of men who, after a period of being watched, had adverse pathology at surgery were similar in the three risk categories; 37% were classified as very low risk at diagnosis, 32% as low risk, and 40% as intermediate or high risk.

 
It didn't matter what your risk group was.
 

This finding was the biggest "takeaway" for Dr Kutikov. "NCCN risk stratification didn't really correlate with adverse pathology [at surgery]," he said. "It didn't matter what your risk group was."

The clinical factors associated with reclassification were "weak" or "modest," Dr Lin pointed out. "Clinical factors cannot adequately predict who will progress," he said. However, the study did show that PSA density, tumor volume, and body mass index "do seem to have a modest association with grade progression."

An increase in Gleason grade was the primary reason (87%) that men were reclassified in the study.

The Canary PASS data suggest that clinical characteristics alone, such as Gleason grade, stage, and biopsy characteristics, "are not sufficient to accurately distinguish indolent cancers from those that may be more aggressive," the investigators note.

A more biologically based assessment of risk at diagnosis, as well as during periodic re-evaluation, is needed, they say.

"It's up to us to find better markers," said Dr Lin.

This study is supported by the Canary Foundation, the National Cancer Institute at the Early Detection Research Network, and the Pacific Northwest Prostate Cancer SPORE. Dr Kutikov has disclosed no relevant financial relationships. Coauthor Ian Thompson Jr, from the University of Texas Health Sciences Center at San Antonio, reports having a financial interest and/or other relationship with MagForce and Exosome Diagnostics.

J Urol. 2016;95:313-320. Abstract

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