How ‘low risk’ is low-risk prostate cancer?


As it becomes apparent that more prostate cancers are clinically insignificant than previously believed, the role of active surveillance in the management of men with low-risk prostate cancer merits expansion.

National Report-As it becomes apparent that more prostate cancers are clinically insignificant than previously believed, the role of active surveillance in the management of men with low-risk prostate cancer merits expansion.

Related - Clinicians say active surveillance is effective but rarely recommend it

Yet, a new study from the University of Texas MD Anderson Cancer Center in Houston reveals that the vast majority of men diagnosed with low-risk prostate cancer are receiving treatment. Further, 80% of the men with low-risk prostate cancer who were diagnosed by a urologist received treatment while only 20% were managed with active surveillance.

In the cohort of 12,068 men age 66 years and older (median age, 72 years) who were diagnosed with low-risk cancer, 70% of those 76 to 80 years old and more than half of those older than 80 years still received up-front treatment despite life expectancies of 10 years or less (JAMA Intern Med July 14, 2014 [Epub ahead of print]).

To reflect recent findings that active surveillance for such men is safe, the National Comprehensive Cancer Network (NCCN) has updated guidelines for initial therapy offered to men with prostate cancer to include more men as candidates for active surveillance.

Next: 'Underappreciated' reservoir of men

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‘Underappreciated’ reservoir of men

Three prostate cancer experts contacted by Urology Times agreed that the reservoir of men with clinically insignificant prostate cancer that does not warrant treatment is underappreciated.

“There has been a shift in medicine over the past 15 to 20 years, with many new tests geared toward finding cancer early, resulting in over-diagnosis and potentially overtreatment,” said Laurence Klotz, MD, chief of urology at Sunnybrook Health Sciences Centre and professor of surgery at the University of Toronto.

“I think there’s a consensus emerging that there’s an ideal group of patients based on several factors such as tumor volume, PSA density, cancer grade, and T-stage,” said Peter Carroll, MD, MPH, professor and chair of urology at the University of California, San Francisco.

“People now will acknowledge that well-evaluated men with one to two cores of low-grade prostate cancer with a PSA density of 0.15 or less appear to be very good candidates for active surveillance,” Dr. Carroll added.

Such criteria constitute low risk as defined by NCCN, which recommends active surveillance for men with a life expectancy less than 10 years, and consideration of active surveillance along with consideration of radiation therapy and surgery in men with longer life expectancies.

Strict criteria

Dr. Carroll’s group at UCSF has found that intermediate-term outcomes are acceptable among carefully selected low-risk patients at their institution who experience disease progression and are managed initially with active surveillance. The strict active surveillance criteria are stage ≤T2, PSA level ≤10.0 ng/mL, Gleason score 2-6 with no pattern 4 or 5, ≤33% diagnostic biopsy cores that are positive for cancer, and ≤50% cancer involvement in any single core (Eur Urol Sept. 9, 2013 [Epub ahead of print]). For this group, prostate cancer-specific survival was 100% and overall survival was 98% at a median of 60 months of follow-up.

Restricting surveillance to men who fulfill these criteria would mean that few men-perhaps 15% to 20% with prostate cancer-would be offered active surveillance, says Dr. Carroll. Use of newer technologies such as gene expression profiling and multiparametric magnetic resonance imaging (MRI) would increase the eligibility for active surveillance, perhaps by double or triple.

Prospective series of men managed with active surveillance have found a 15-year mortality in the range of 5%, says Dr. Klotz, and some of these series contained men with both low-risk and intermediate-risk disease. The likelihood of dying from other cancers over this time frame is about 10 times greater, he notes.

Although small-volume (redefined as <1.3 mL by the European Randomized Study of Screening of Prostate Cancer) Gleason 6 disease is considered a standard criterion for active surveillance, “there is less consensus with higher volume Gleason 6 disease in men who are young,” Dr. Klotz said.

These men have a higher risk of harboring higher-grade occult prostate cancer that has been missed. Selected patients with Gleason 3+4 disease on active surveillance have outcomes as good as those with Gleason 6, he added.


Next: SPCG-4 data support surveillance


Peter C. Albertsen, MD, points to the median 13-year follow-up (with the longest follow-up being 23 years) from the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4) to support active surveillance. In this study of men with disease identified clinically, long-term outcomes for those with low-grade disease were comparable with watchful waiting compared with surgery (although deaths from any cause in the overall cohort were fewer in the surgery group) (N Engl J Med 2014; 370:932-42). Men enrolled in the study had higher-grade cancers than those of contemporary U.S. cohorts, he notes, with a mean PSA level of 13.0 ng/mL.

“I would argue that men who are seeking active surveillance in 2014 are men who have even more localized and more low-grade disease than men participating in the SPCG-4 study,” said Dr. Albertsen, professor of surgery, division of urology, University of Connecticut Health Center, Farmington. “They would probably do even better than the men in the SPCG-4.”

Indeed, the typical patient diagnosed with prostate cancer today is asymptomatic with low-volume disease confined to the prostate and a low PSA level, says Dr. Carroll. Rarely are men presenting with advanced or metastatic prostate cancer.

No consensus on approach to AS

The optimal method to approach active surveillance has not been established. The frequency of repeat biopsies and other follow-up tests is not standard. At UCSF, low-risk prostate cancer patients undergo biopsy 12 to 24 months after their diagnostic biopsy. Serum PSA level is measured every 3 to 4 months and Doppler ultrasound is performed approximately every 6 months. The interval between evaluations may be extended depending on these findings and the time on active surveillance.

Long-term monitoring “is driven in part by how compulsive clinicians are and how afraid they are of missing a cancer progression,” said Dr. Albertsen. Insisting on an annual biopsy “might be overkill,” he said, especially the longer out that the patient is on active surveillance. After the first repeat biopsy at about 12 months, biopsies every 2 years or 3 years would be reasonable.

“Most people are beginning to agree that a multiparametric MRI image belongs, at least at the start of active surveillance, if not further downstream,” according to Dr. Albertsen. Consensus is lacking over what constitutes a negative MRI, however. As long as the MRI fails to show obvious tumor, it’s probably safe to continue active surveillance, he said.

At Sunnybrook, an MRI is not done routinely in men with prostate cancer but is reserved for the one-third of men with adverse PSA kinetics or another red flag or cause for concern, Dr. Klotz says. Despite this limited use of MRI, outcomes at his institution are “favorable.” In the Sunnybrook active surveillance study, started more than 15 years ago, the observed actuarial prostate cancer mortality rate at 10 years was about 3%.

Genomic classifiers may eventually be used in active surveillance but have yet to prove their worth for this indication. “Many of us were disappointed in the predictive power of the urine marker PCA3,” Dr. Albertsen said.


Next: Management consistent with risk


Management consistent with risk

Even with low-risk prostate cancer, patients must accept a slight tolerance for risk to choose active surveillance. “I always start the conversation with the threat posed by the disease,” said Dr. Albertsen. The natural history of low-grade, low-volume prostate cancer is such that progression to advanced disease may not occur or may take 20 years or longer. The window to cure the disease is therefore long, and this concept should be presented to patients.

Nevertheless, for years, the mantra of the American Cancer Society had been that early diagnosis and early treatment of cancer offers the best chance for cure, without differentiating between low-risk and more aggressive forms of the disease. The idea that emergent treatment may therefore not be needed may be alien to a patient, representing a psychological barrier to active surveillance, Dr. Albertsen believes. Personal experience with cancer (ie, a relative or close friend dying of prostate cancer) and the health care delivery system may also color patients’ perceptions of active surveillance for low-risk disease.

Dr. Carroll agrees that for too long, detection of cancer meant treatment of cancer, without the admission that prostate cancer represents a spectrum of disease.

“For most patients, a cancer diagnosis portends a very uncertain future,” he said. “With screening and re-screening, we often identify occult disease that may not be placing patients at risk, and we need to get that information out to patients before they undergo screening and biopsy.”

Early detection strategies are still warranted, he says, but should be followed by careful risk assessment and selection of treatment based on risk.

Under current payment models, a financial incentive to recommend treatment may also exist, presenting another barrier to offering active surveillance to appropriate patients. In the MD Anderson study, physician characteristics were more important than patient age or extent of disease in predicting whether patients with low-risk prostate cancer received active surveillance or treatment up-front, with urologists and those who more often treat aggressive prostate cancer more likely to treat the patient.

But active surveillance is “here to stay,” said Dr. Carroll, “and the more we understand it and offer it, the better things will be for patients and our specialty. I worry we will lose our position as the primary purveyors of prostate cancer care if we don’t become more broad minded. Recognizing prostate cancer represents a full spectrum of risk, our response to it should be totally consistent with risk.”UT

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