Prostate Cancer Surveillance: Biopsy Findings Appear Indispensable

by Nick Mulcahy | Medscape.com | 05.12.2010

Surveillance biopsy — and not prostate-specific antigen (PSA) kinetics — is the test that clinicians should rely on to determine which men with low-risk prostate cancer on active surveillance are progressing and in need of treatment.

This guidance is suggested in the conclusion of a study published online May 3 in the Journal of Clinical Oncology.

"We recommend careful follow-up with annual surveillance biopsy to trigger intervention within the window of curability," write the study authors, led by Ashley Ross, MD, from Johns Hopkins University School of Medicine in Baltimore, Maryland.

The investigators found that PSA kinetics — PSA velocity and PSA doubling time — did not "reliably predict adverse pathology."

Dr. Ross and colleagues "caution against relying on PSA kinetics" to determine progression and the need for treatment.

In the study of 290 men with low-risk prostate cancer who opted for active surveillance instead of treatment, twice-yearly PSA measurements and annual biopsy were performed. Treatment (prostatectomy or radiation) was recommended when biopsy progressed, which was defined as a Gleason score of 7 or higher, more than two positive cores, or more than 50% core involvement.

In the men who eventually underwent radical prostatectomy, PSA velocity (P = .79) and PSA doubling time (P = .87) were not associated with the presence of unfavorable surgical pathology. The average time that the men were followed was about three years.

The recent prominent inclusion of active surveillance in the National Comprehensive Cancer Network (NCCN) guidelines makes the study "a timely article," say Jared Whitson, MD, and Peter Carroll, MD, from the University of California San Francisco (UCSF), in an editorial that accompanies the study.

The NCCN guidelines indicate that cancer progression might have occurred if PSA doubling time is less than three years, note the editorialists.

However, the study suggests that PSA doubling time is not a reliable predictor of biopsy progression.

Drs. Whitson and Carroll say that the results of the study are "somewhat unexpected in light of the existing literature."

They note that three previous studies have shown a statistically significant association between PSA kinetics and biopsy progression. Only one previous study failed to show an association between PSA doubling time and biopsy progression.

The new study might not be reliable, suggest the editorialists.

"One must wonder the role sample size could have played in the lack of significant findings in this study," write Drs. Whitson and Carroll.

Nevertheless, both sets of experts believe that PSA kinetics are, in the words of the editorialists, "not sufficient to eliminate surveillance biopsies."

In other words, patients on active surveillance must undergo the annual invasive procedure regardless of PSA kinetics results.

Biopsy Findings Are Preliminary

The 290 men in the study met the Johns Hopkins' criteria for active surveillance: PSA density below 0.15 ng/mL per cm3; Gleason score of 6 or lower with no pattern of 4 or higher; two or fewer cores with cancer; and 50% or less involvement of any core by cancer. The criteria were met in the context of two or more serial PSA measurements after diagnosis from 1994 to 2008.

With a median follow-up of 2.9 years, 188 (65%) men remained on active surveillance and 102 (35%) developed biopsy progression, which was the trigger for curative intervention in the study.

PSA kinetics were not used as a trigger for intervention.

Despite their firm recommendation to use annual surveillance biopsy to trigger intervention, the study authors admit there is some uncertainty about this marker.

"Long-term data are not yet available to determine whether biopsy progression is a valid proxy for whether disease will cause harm," they write.

However, preliminary data from the study support the use of repeat biopsy results to guide management decisions, they add.

For example, in the study, 6.7% of patients who experienced progression on biopsy during surveillance had minimal disease in the prostatectomy specimen, compared with 27.3% of those who elected to undergo treatment without documented progression (P = .05).

"These preliminary data suggest that biopsy progression is correlated to disease progression among men in our active surveillance program," the authors point out.

The Current State of Knowledge

In their editorial, Drs. Whitson and Carroll review the state of knowledge in active surveillance for men with low-risk, early-stage prostate cancer.

Like the study authors, the editorialists say that PSA kinetics have not been proven accurate enough yet to eliminate the need for an annual biopsy.

But they also say that in various studies to date, pathologic outcomes seem favorable with active surveillance.

"Pathologic outcomes of candidates for active surveillance seem favorable overall, with risks of extracapsular extension ranging from 7% to 19% and seminal vesicle invasion ranging from 2% to 9%, mainly depending on the inclusion of patients with Gleason 7 disease," the editorialists write.

They note that another major finding in the field to date is that "between 14% and 35% of men on active surveillance will undergo curative treatment, again depending mainly on the inclusion of patients with Gleason 7 tumors." The mean follow-up is from 3 to 4.6 years in these studies, he added.

Thus, outcomes in active surveillance seem partly dependent on whether or not patients with more advanced, Gleason 7 disease are included in a study, suggest the editorialists.

Patients with Gleason 7 disease were not enrolled in the current study. And the NCCN only recommends active surveillance for men with scores of 6 or below. However, in a previous interview with Medscape Oncology, Dr. Carroll said that studies at his home institution, UCSF, have included men with higher scores.

Drs. Whitson and Carroll also ask a basic and compelling question: "Are the pathologic, biochemical, and survival outcomes in men who undergo treatment after an initial period of surveillance as favorable as those in men who are candidates for surveillance but who undergo immediate treatment?"

"So far, it seems so," they answer. However, they also suggest that more study is needed on this question.

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