Some Low-Risk Prostate Cancers Need Closer Scrutiny

Neil Osterweil

July 16, 2015

Clinicians can't safely assume that a man with newly diagnosed, clinically low-risk prostate cancer is an automatic candidate for active surveillance, results of a large cohort study imply.

Among more than 10,000 men diagnosed with clinically low-risk prostate cancer in 2010 and 2011, nearly half had tumor upgrades at the time of prostatectomy and nearly 1 in 10 had an increase in disease stage, report Paul L. Nguyen, MD, and colleagues from Harvard Medical School and affiliated hospitals in Boston, Massachusetts.

"When patients think of active surveillance, they might look at guidelines and think 'I have low-risk prostate cancer, and so I'm fine with active surveillance,' and that might be true for many patients, Dr Nguyen said in an interview with Medscape Medical News.

"But low-risk prostate cancers are not all the same, and what we identified here is a subset of low-risk patients who have a very significant risk of harboring more aggressive disease," he added.

Older men, those with higher prostate-specific antigen (PSA) levels, and those with a higher percentage of biopsy cores positive for prostate cancer were more likely to be upgraded or upstaged, the investigators reported in the August issue of the Journal of Urology.

The men in the study all had newly diagnosed clinically low-risk disease (cT1c/T2a, PSA level less than 10 ng/mL, and a Gleason score/sum of 3 + 3 = 6).

The men at relatively higher risk for an increase in grade or stage (upon prostatectomy) were older than 60 years, had more than 25% of biopsy cores positive for cancer, and/or had a PSA level greater than 5.0 ng/mL.

These men should be considered for further testing, such as advanced imaging, before being assigned to active surveillance, the authors write.

Active Interest

The terms are a bit fuzzy, but unlike "watchful waiting," which is largely based on observation of changes in a patient's symptoms, "active surveillance" is a management strategy based on regular monitoring with digital rectal exams, PSA, and ultrasonography. Active surveillance is widely accepted in Europe and appears to be gaining a solid foothold in the United States as well, as reported by Medscape Medical News.

Current criteria for active surveillance generally consider insignificant disease to be a Gleason score of 6 or less and organ-confined disease. However, previous studies have also shown that these measures are not foolproof: that is, Gleason scores and tumor stages determined by biopsy often differ from those determined after radical prostatectomy, the investigators note.

To see whether they could identify characteristics that might signal higher-risk subgroups among patients with clinically low-risk disease, the authors turned to the Surveillance, Epidemiology, and End Results (SEER) database. They identified 10,273 men for the final cohort.

They found that 44% of patients (4467) had disease upgraded at prostatectomy to a Gleason score of 7 to 10. Most of these patients (86.2%) had a Gleason pattern of 3 + 4 = 7, 10.6% had a pattern of 4 + 3 = 7, and 1.3% had Gleason scores of 8 to 10.

A total of 992 patients (9.7%) had their tumor stage increased at the time of prostatectomy, with 88.4% of this group restaged with T3a disease, 14.4% with T3b, 1.4% with T4, and 3% with N1.

There was also a subset of 5581 men in the study who had complete information available about the number of biopsy cores and percentage of positive cores.

In multivariate analyses of these men, the investigators found that factors significantly associated with upgrading were age older than 60 years (adjusted odds ratio [AOR], 1.39), PSA level greater than 5.0 ng/mL (AOR, 1.28), and more than 25% positive cores (AOR, 1.76)  (P < .001 for all). The same three factors were also all significantly associated with an increase in stage, with respective AORs of 1.42, 1.44, and 2.26 (P < .001 for all).

Among the 5581 men, 60% of those with PSA levels of 7.5 to 9.9 ng/mL and more than 2% positive cores were upgraded.

The findings suggest that patients with these specific risk factors might be good candidates for additional studies before being followed with active surveillance.

"It would not be prudent to perform advanced imaging on all low-risk patients.

However, our results propose clinical features that could justify further evaluation," the investigators write.

For example, a patient with PSA level of 7.6 to 10 ng/mL and more than 25% cores positive may have a 60% chance of harboring higher-grade disease, they say.

The authors caution, however, that the decision to choose active surveillance may also be influenced by a patient's comorbidities and life expectancy.

They also acknowledged that the study may have been biased by the inclusion of only patients selected for prostatectomy.

Shaky SEER Data

An even bigger concern, says a genitourinary oncologist who was not involved in the study, is that the study relied on PSA data from SEER. The SEER administrators recently acknowledged that the PSA values are unreliable because of a coding and reporting issue.

"It's a little suspect because of the PSA problems," said Matthew Cooperberg, MD, from the University of California San Francisco Medical Center.

It's a little suspect because of the PSA problems. Dr Matthew Cooperberg

He said that the study results are unlikely in the near future to influence clinical practice significantly, primarily because the advanced imaging studies required for further evaluation, such as MRI-guided biopsy, are highly dependent on dedicated and experienced radiologists specializing in prostate.

"I think the community standard for prostate MR is terrible, and really not worth the thousands of dollars that we spend per scan. The scans we receive from the community are often not interpretable or have been incorrectly interpreted," Dr Cooperberg said.

Daniel P. Petrylak, MD, a professor of oncology at the Yale Cancer Center in New Haven, Connecticut, who was not involved in the study, told Medscape Medical News that the findings indicate significant room for improvement.

"If half of these low-risk patients harbor Gleason 7 disease or pT3 disease, that tells us that we need better diagnostic tests," he said.

As clinicians become better at using and interpreting newer technologies, such as fusion MRI, which combines MRI and ultrasonography, "then we will be able to select out those patients who could truly benefit from expectant observation," he added.

The study was supported by Fitz's Cancer Warriors; David and Cynthia Chapin; the Prostate Cancer Foundation; Hugh Simons in honor of Frank and Anne Simons, Scott Forbes and Gina Ventre; and a grant from an anonymous family foundation. Dr Nguyen disclosed financial interest and/or other relationship with Medivation and Genome Dx. Dr Cooperberg and Dr Petrylak have disclosed no relevant financial relationships.

J Urol. 2015;194:343-349. Abstract


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