Study: Surveillance Is for Middle-Risk Prostate Cancer Too

Grade Migration in the Spotlight

Nick Mulcahy

February 19, 2015

Even more men with prostate cancer could be managed with active surveillance, a new study suggests.

At present, active surveillance is largely limited to men with low-risk disease, but it might also be suitable for those with "favorable" intermediate-risk prostate cancer, assert the study investigators, led by Ann Radlow, MD, from the Harvard Radiation Oncology Program in Boston.

Favorable intermediate risk was defined as a Gleason score of 3+4 or less, the percentage of positive biopsy cores below 50%, and no more than one National Comprehensive Cancer Network (NCCN) determinant of intermediate-risk prostate cancer (such as a prostate-specific antigen level from 10 to 20 ng/mL).

"Our results provide evidence to support active surveillance as an initial approach for men with favorable intermediate-risk prostate cancer," Dr Radlow and her colleagues write in their study, published online February 19 in JAMA Oncology.

However, the study did not actually follow men managed with active surveillance.

Instead, in the observational prospective cohort study, 3972 men with low-risk prostate cancer were compared with 1608 men with favorable intermediate-risk prostate cancer. All were treated with brachytherapy at the Prostate Cancer Foundation in Chicago from 1997 to 2013.

The average age of the men was 68 years.

The team found that the risk for prostate-cancer-specific mortality, which was the primary end point, was not significantly different between the two groups.

At a median follow-up of 7.7 years, 605 men had died, but only 34 died of prostate cancer (12 in the favorable intermediate-risk group and 22 in the low-risk group).

In fact, the risk for prostate-cancer-specific mortality was not significantly higher in the favorable intermediate-risk group than in the low-risk group (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 0.76 - 3.53; = .21).

This lack of significance between the groups also held true for all-cause mortality.

The "clinical significance" of the findings is that men with favorable intermediate-risk disease had outcomes similar to those with low-risk disease, and therefore might be "candidates for active surveillance," the investigators assert.

An urologist not involved with the study waved a yellow flag of caution about the idea.

In these patients, active surveillance is "risky" and should only be undertaken with "extreme caution," writes Fred Saad, MD, from the University of Montreal in Quebec, Canada, in an accompanying commentary.

Dr Saad reports that he has used active surveillance for "most" of his low-risk patients "for many years," but believes clinicians should be "extremely selective" in offering it to intermediate-risk patients.

"There is starting to be a realization that these patients are at higher risk of worse outcomes," Dr. Saad told Medscape Medical News.

 
The duration of follow-up in the study...is short.
 

He also says that "the duration of follow-up in the study...is short in terms of prostate cancer timelines."

Furthermore, Dr Saad emphasizes that the study is one of outcomes in patients who were treated, rather than observed. There is no guarantee that mortality outcomes would have been similar in intermediate-risk and low-risk patients followed with observation alone, he argues.

Dr Radlow and her colleagues concede that point, and say longer follow-up is needed. But they return to their mortality data to strengthen their conclusion.

The 8-year adjusted estimate for prostate-cancer-specific mortality was "low" for men with favorable intermediate-risk disease and low-risk disease (0.48% [95% CI, 0.23% - 0.93%] vs 0.33% [95% CI, 0.19% - 0.56%]), they report. The "clinical significance" of this "small" 0.15% absolute difference is questionable, they explain. In other words, there just is not much practical difference in mortality between the two groups.

The Influence of Grade Migration

This study is the first to directly compare mortality in men with favorable intermediate-risk and low-risk prostate cancer treated with high-dose radiotherapy such as brachytherapy, the investigators note.

Much of the value of this study, despite its shortcomings, needs to be understood in the context of evolving clinical circumstances, they say.

In general, active surveillance is currently only considered appropriate for patients with low-risk disease and a life expectancy of at least 10 years, in accordance with NCCN guidelines.

But there has been "grade migration" in the assessment of prostate cancer since the 2005 meeting of the International Society of Urologic Pathology. The consensus conference proceedings resulted in more prostate cancer being assessed with a Gleason score of 3+4 (intermediate risk) rather than 3+3 (low risk). "The reporting of secondary pattern Gleason grade 4 became more prevalent" after this influential meeting, Dr Radlow and colleagues report.

Clinicians need to recognize and acknowledge this "current era" of grade migration, which makes the differentiation of favorable and unfavorable intermediate risk very important, they suggest.

Dr Saad more or less agrees with these points.

 
There has been a certain degree of grade migration.
 

"It is true that in the past 10 years, there has been a certain degree of grade migration, where Gleason grade 3 cancers are sometimes reclassified to grade 4. This may suggest that historical studies showing very low progression of grade 3 cancers might in fact have included favorable-looking grade 4 disease by today's standards," he writes.

The investigators point out that the definition of favorable intermediate risk they used comes from an influential study (Eur Urol. 2013;64:895-902).

This difference between favorable and unfavorable intermediate risk could have other clinical implications, they say.

Favorable intermediate-risk patients might not benefit from androgen-deprivation therapy (ADT) in addition to radiation therapy, they suggest, citing that influential study.

Also, unfavorable intermediate-risk patients appear to require ADT to reduce their risk for prostate-cancer-specific mortality, they say, citing another study (Int J Radiat Oncol Biol Phys. 2013;85:693-699).

This matter of differentiating risk also colors previous clinical trial results, the investigators contend.

"It is important to note that men with intermediate-risk prostate cancer enrolled in prospective active surveillance studies could have had either favorable or unfavorable intermediate-risk disease," they write.

JAMA Oncol. Published online February 19, 2015. Abstract, Commentary

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