3% of Surveillance Cohort Has Metastatic Prostate Cancer

Fran Lowry

April 19, 2016

Data from North America's premiere active surveillance center continue to clarify which men with prostate cancer are optimal candidates for this emerging management approach — and which men are not.

In their latest publication, researchers from the Sunnybrook Health Sciences Center in Toronto indicate that conservative management of men with elements of Gleason pattern 4 prostate cancer could be putting them at risk for eventual metastasis.

In a cohort of 980 men followed with active surveillance for a median of 6.3 years (range, 0.2 to 20.2 years), 30 patients (3.1%) developed metastasis, senior author Laurence Klotz, MD, and colleagues report in their study, published in the May issue of the Journal of Urology.

"Active surveillance has some uncertainties, such as lack of a standardized protocol and uniform criteria for eligibility," the authors write.

Last year, the Toronto group reported results on prostate-cancer-specific survival in the same surveillance cohort (J Clin Oncol. 2015;33:272-277). There were 15 deaths from prostate cancer, and a cumulative hazard ratio (HR) for nonprostate to prostate cancer mortality of 9.2 to 1.

Dr Laurence Klotz

"We took an inclusive approach to active surveillance, and more than 20% of our cohort was at intermediate risk. We now have 30 patients who have developed metastases, which is far more than any other active surveillance series," Dr Klotz told Medscape Medical News.

He cited two reasons this cohort has a relatively high number of patients who developed metastatic disease.

"One is that it is a more mature cohort with a lot of patients who have been followed for more than 15 years, and the second is that we took an inclusive approach, and we are now able to look back to see if we could predict who would get metastasis," Dr Klotz said.

The team found that the presence of any Gleason pattern 4 disease at baseline conferred a fourfold greater risk for progression to metastatic disease, even though patients were treated when testing revealed a worsening of disease.

Active surveillance for Gleason 7 can carry significantly greater risk.

"The message is that active surveillance for Gleason 7 can carry significantly greater risk, even selecting out those patients who you think are the most favorable," Dr Klotz said.

Of the 980 men analyzed in this single-center prospective study, which began in 1995, 211 (21.5%) were classified as intermediate risk. Median age was 70 years, median prostate-specific antigen (PSA) level was 6.2 ng/mL, and median time to metastasis was 8.9 years.

Metastases developed in bone in 18 patients (60%) and in lymph nodes in 13 patients (43%).

Independent predictors of metastases were a PSA doubling time of less than 3 years (HR, 3.7; 95% confidence interval [CI], 1.4 - 9.4; P = .0006), a Gleason score of 7 (HR, 3.0; 95% CI, 1.2 - 7.3; P = .0018), and three or more positive cores (HR, 2.7; 95% CI, 1.1 - 6.8; P = .0028).

Although the intermediate-risk group was at higher risk for metastasis, men with a Gleason score of 6 and a PSA level above 10 ng/mL were not at increased risk for metastasis. Metastasis developed in only two patients with a Gleason score of 6, and neither had surgical pathology grading, Dr Klotz reported.

Members of the Sunnybrook team have been learning as they go along, he explained.

"Our cohort is all pre-MRI. Most of these patients were diagnosed more than 10 to 15 years ago, when we didn't really know how to do surveillance as well as we do now," he said.

The study suggests important caveats, even though it is just a single-center experience, he added.

Some Gleason 7 Exceptions

"Patients with intermediate risk are certainly candidates for surveillance, particularly if they are older, but need to understand that the risk is a little higher. Most patients with Gleason 7 managed with surveillance did fine, but the risk, instead of being close to zero, is more like 15% to 20% at 15 years," Dr Klotz said.

The second important lesson is that all patients need a "decent" MRI, he said.

"If the MRI shows a large target, then they should have a biopsy. If it shows large-volume Gleason 7, then they are not good candidates for active surveillance," he explained.

But some Gleason 7 patients are strong candidates for active surveillance, he clarified.

"There is a special group of patients whose Gleason 7 had less than 10% pattern 4. I think those patients are probably not much different than Gleason 3-plus," he stated.

"In general, for men with Gleason 7, active surveillance is an option, but caution is warranted. They should have an MRI. Those with large-volume disease are not good candidates, but those with small-volume disease, especially if there is less than 10% Gleason 4, are excellent candidates for active surveillance," Dr Klotz summarized.

Counterpoint: Active Surveillance May Be Ill-Advised

The risk for metastasis is probably underestimated in this study, Michael Koch, MD, from the Indiana University School of Medicine in Indianapolis, writes in an editorial comment on the study.

They may be overly optimistic about the safety.

"While the authors have highlighted the risk factors for developing metastases in patients treated with AS, they may be overly optimistic about the safety of this management strategy, particularly in patients with Gleason 7 disease," he explains.

Because median follow-up was only 6.3 years, "the number of patients with Gleason 7 disease in whom metastases develop will grow even further. As of now, AS would appear to be ill-advised in this group of patients," Dr Koch notes.

In another editorial comment, Joel Nelson, MD, from University of Pittsburgh Medical Center, points out that "with no systematic protocol to detect metastatic disease in the current study, the reported rate of 3% is a best-case scenario. It is likely that many more men have metastatic disease, and although it may be asymptomatic, it is still incurable."

The task now "is to avoid misclassification of disease as indolent when it is not and detect progression before it is too late," he writes.

"The main point about this study is that the criteria to start active surveillance in this cohort are more liberal than in other cohorts. They are including men who have Gleason 3 + 4 cancers, and that would be a group of men in whom, I think, there should be some pause," Dr Nelson told Medscape Medical News.

"When this study started, it wasn't clear what the natural progression of the disease was going to be. Gleason 3 + 3 cancers are extremely indolent, and those are men who should be watched, but Dr Klotz and his colleagues included some men who had Gleason pattern 7 disease. Whether that is going to be done in other active surveillance cohorts going forward is unclear, but this would all give us some reason to be careful because there is a rate of metastatic disease," he said.

Dr Klotz, Dr Koch, and Dr Nelson have disclosed no relevant financial relationships.

J Urol. 2016;195:1409-1414. Abstract


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