'Reassuring' Data on Active Surveillance in Prostate Cancer

Alexander M. Castellino, PhD

September 07, 2015

A new study of active surveillance (AS) for prostate cancer in men with very-low-risk and low-risk prostate cancer from the Johns Hopkins Hospital, Baltimore, offers reassurance, say the authors.

"Our study should reassure men that carefully selected patients enrolled in active surveillance programs for their low-risk prostate cancers are not likely to be harmed by their disease," said senior author H. Ballentine Carter, MD, in a Johns Hopkins press release.

The study was published online August 31 in the Journal of Clinical Oncology.

The study involved 1298 men enrolled in the AS program between 1995 and 2014, and the median follow-up for all patients was 5 years (range, 0.01 - 18 years). The results show that 47 men died from causes other than prostate cancer, two men died as a result of prostate cancer, and three men developed metastatic disease, the researchers report.

With a hazard ratio of 24:1 for nonprostate-cancer to prostate-cancer mortality or metastases, these men are 24 times more likely to die from other causes, the researchers point out.

"The natural progression of prostate cancer occurs over a long period of time, some 20 years, and most men with low-risk prostate cancer will die of another cause," Dr Carter commented.

AS is a management approach in prostate cancer that addresses the issue of men being overtreated.

"There is a careful balance, which is sometimes difficult to find, between doing no harm without treatment and overtreating men, but our data should help," Dr Carter said.

"The data are similar to data from other studies and support AS for most men with low-risk prostate cancer," Anthony V. D'Amico, MD, from the Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, told Medscape Medical News.

According to Dr D'Amico, the operative word is most. "One cannot draw this conclusion for all patients with low-risk prostate cancer," he said.

Dr D'Amico authored an accompanying editorial. In it, he proposes that the focus should move toward defining a validated risk-assessment scheme based on cancer and patient factors.

Study Details

In the Johns Hopkins study, men at low risk and very low risk for prostate cancer were offered AS as a management strategy since January 1995. Criteria used to enroll men included clinical disease stage, prostate-specific antigen (PSA) density, PSA, and Gleason score.

As part of AS, patients underwent PSA measurement and digital rectal examination every 6 months, and had an annual 12- to 14-core biopsy.

Curative intervention was recommended when disease was upstaged based on biopsy findings.

Of 1298 men in the study, 88.4% were white, median age was 66 (range, 41 - 92 years), and 71% (n = 926) were diagnosed with very-low-risk disease and 29% (n = 372) with low-risk disease.

At 10 years, the overall survival rate was 93.0%, the cancer-specific survival rate was 99.9%, and the metastasis-free survival rate was 99.4%.

The corresponding rates at 15 years were 69.0%, 99.9%, and 99.4%.

After a median of 2 years, following the annual biopsy, disease was reclassified in 467 (36%) men; of these, 361 underwent treatment. In addition, 109 men elected to be treated in the absence of biopsy reclassification.

Study Limitations Discussed

In his editorial, Dr D'Amico observed that the data from the study are not applicable to all men with low-risk prostate cancer.

"Not all men are represented in this study," he told Medscape Medical News. In particular, men older than 70 years and black men are under-represented, he pointed out.

It is well known that black men with prostate cancer are a high-risk group and have high-grade disease, he added. As an example, he cited a 2013 study, which reported that being black is an independent predictor of adverse pathological features (J Clin Oncol. 2013;31:2991-2997).

According to the findings, black men with very-low-risk prostate cancer and who met criteria for AS, but chose to undergo surgery, were 2.2 times more likely to be upgraded and 3.2 times more likely to have adverse pathology at radical prostatectomy, including extracapsular extension and/or positive margins, Dr D'Amico explained.

Another limitation to the study reported by Dr Carter and colleagues is the relatively short follow-up, Dr D'Amico commented. The median follow-up of 5 years makes the study observations preliminary, with longer-term follow-up needed for making more definite conclusions about young men or healthy older men with much longer life expectancies, he said.

"With longer follow-up, the data may change, but they're unlikely to change dramatically, because men in this age group tend to die of other causes," Dr Carter stated in the press release.

However, Dr D'Amico notes that "because the median follow-up time was only 5 years and because PC has a long natural history, the 15-year rates for freedom from metastasis and PC death of greater than 99% overestimate the actual rates that would be observed when all men in the study have been observed for 15 years."

Biopsy Method in Active Surveillance

Another issue is the biopsy method that was used in the AS program.

Dr D'Amico pointed to a recent report (JAMA. 2015;313:390-397), which concluded that the biopsy method used in AS may be inadequate for all patients. "In all studies based on 12-core needle biopsies, there is a substantial possibility of missing occult high-grade prostate cancer," Dr D'Amico told Medscape Medical News.

He notes in his editorial that the standard procedure using [transrectal ultrasound-guided prostate needle biopsy] is associated with a sampling error that ranges between 41% and 48% and poses a dilemma whether AS is appropriate for healthy older or black men.

"Using targeted biopsies with multiparametric magnetic imaging resonance [mpMRI] may be a way for detecting occult disease, especially in high-risk populations who may be candidates for AS," he said.

In the Hopkins press release, Dr Carter also noted that currently "doctors no longer require annual biopsies among the lowest-risk groups, and when they do perform a biopsy, they use MRI-guided technology and will often ask pathologists to check biopsy tissue levels of proteins made by the PTEN gene, a biomarker for prostate cancer aggressiveness."

The Future of Active Surveillance in Low-risk Prostate Cancer

According to Dr D'Amico, patient factors such as race and comorbidity should also be taken into consideration when offering AS in order to personalize the approach.

"The authors provided helpful information about patient- and cancer-related parameters associated with upgrading to Gleason score 7 or greater at surveillance biopsy," Dr D'Amico states in the editorial.

"However, information about patient factors, including comorbidity, ethnicity, and family history, should also be considered in decisions about when to use AS and in which patients AS will not often lead to missing occult high-grade prostate cancer that can progress to metastasis during their remaining life expectancy," he added.

Dr D'Amico indicated that a risk-group-based assessment scheme should be the focus in the future.

"I offer the suggestion that our attention should shift away from establishing that long-term rates of metastasis and death as a result of prostate cancer are low for a population of men diagnosed with favorable-risk prostate cancer who are observed on an AS protocol or who are randomly assigned to AS versus intervention [in a clinical study]," Dr D'Amico writes in his editorial.

"Rather, we should focus on defining a validated risk-assessment scheme that is based on a panel of cancer and patient factors capable of determining whether an individual man of a given age, health, and ethnicity, and with specific tumor characteristics, family history, and perhaps mpMRI imaging characteristics, is best served by being observed on a AS protocol," he concludes.

Drs Carter and D'Amico have disclosed no relevant financial relationships. Several of the study authors report financial relationships with industry.

J Clin Oncol. Published online August 31, 2015. Abstract, Editorial

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