New clinical practice guidelines for the management of prostate cancer from the National Comprehensive Cancer Network expand the number of patients who may be considered for active surveillance to those with favorable intermediate-risk prostate cancer.
New clinical practice guidelines for the management of prostate cancer from the National Comprehensive Cancer Network (NCCN) expand the number of patients who may be considered for active surveillance to those with favorable intermediate-risk prostate cancer.
In Version 2.2016 of the NCCN prostate cancer clinical guideline, active surveillance may now be considered for patients with favorable intermediate-risk prostate cancer, defined as predominant Gleason grade 3 (ie, Gleason score 3+4=7), <50% positive biopsy cores, and no more than one NCCN intermediate risk factor.
The NCCN guideline panel recommends consideration of active surveillance based on consideration of the patient’s prostate cancer risk profile, age, and health, citing concern about potential over-treatment “related to the increased frequency of diagnosis of prostate cancer from widespread use of PSA for early detection or screening.”
Dr. MohlerThe panel for the 2016 prostate cancer guideline is composed of 30 radiation oncologists, medical oncologists, and urologists. The guideline is updated as critical new information becomes available. “It’s truly a multidimensional guideline and they are also incredibly current because they are published at least annually,” said James Mohler, MD, who chaired the NCCN guidelines panel, serving in this capacity for 10 years.
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The panel assigns levels to recommendations based on the strength of the data and the agreement among panel members, assigning level 1 when high-level evidence exists and unanimity is achieved, followed by 2A, 2B, and 3. “Most of the recommendations are level 1 or 2A, meaning that there’s excellent evidence and there’s either unanimity or near so,” said Dr. Mohler, associate director and senior vice president for translational research and chair of the department of urology, Roswell Park Cancer Institute, Buffalo, NY.
A consensus was reached for the 2016 guideline that insignificant prostate cancer, especially cancers detected early using serum prostate-specific antigen (PSA) testing, poses little threat to men with life expectancy <20 years, and these men should therefore be eligible for active surveillance.
The 2009 NCCN prostate cancer guideline was the first to recommend active surveillance as the only management strategy for men with low-risk prostate cancer and a life expectancy <10 years.
“In 2009, we also split out very low-risk prostate cancer using the Epstein criteria, and said that the only recommendation there should be active surveillance when your life expectancy is less than 20 years,” Dr. Mohler said. “The 2016 guideline, I believe is the first guideline anywhere to say that active surveillance is an option for men who have intermediate-risk prostate cancer, but we’ve divided the intermediate-risk category into favorable and unfavorable.”
The distinction between favorable and unfavorable intermediate-risk disease was a topic of lengthy discussion among panel members, he said, and in the end, the guideline panel chose to use the definition of favorable intermediate risk established by Zumsteg et al (Eur Urol 2013; 64:895-902). They derived their classification scheme using a group of prostate cancer patients treated with external beam radiation therapy, in whom prostate cancer-specific mortality was assessed.
In such favorable intermediate-risk patients, demonstration of disease progression through surveillance would allow for conversion to potentially curative treatment, Dr. Mohler said.
A more restrictive definition of favorable intermediate risk than the one favored by the NCCN guideline panel would still make active surveillance an appropriate choice in young, healthy men, who could be converted to potentially curative treatment if disease progression is demonstrated through active surveillance. Many urologists use a more stringent definition, he said. They consider favorable intermediate risk to include men who would be low risk except for a single core of Gleason grade 3+4=7.
Dr. GomellaMoving beyond Gleason grade to stratify intermediate-risk patients for consideration of active surveillance is favored by Leonard Gomella, MD, chairman of the department of urology, Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, who was not involved with the 2016 NCCN guideline. Introduction of a Gleason pattern 4 into the mix of patients for whom active surveillance can be considered has made urologists “a little bit nervous,” he said. “We need more differentiation than just Gleason score.”
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Because the definition for favorable intermediate risk in the new guideline is inferred from studies of radiation therapy, he said that further validation of this definition would solidify consideration of active surveillance in this group as a recommendation.
Further sub-classification of the intermediate-risk group can be accomplished by more liberal use of genomic biomarkers or imaging markers, Dr. Gomella believes.
“Not all favorable intermediate-risk patients act as if they’re favorable, and not all unfavorable intermediate-risk patients act as we think they’re going to act. I believe this is where approaches such as genomic testing and possibly new imaging studies-whether diffusion-weighted MRI or new PET scan radiotracers-are going to help us further define this,” he said.
Tissue-based molecular assays are incorporated in the 2016 guideline, which states that such assays provide prognostic information independent of NCCN risk groups and can improve decision-making in newly diagnosed men considering active surveillance. The three assays that have received positive reviews in the post-biopsy setting by the Molecular Diagnostic Services Program, and are covered by the Centers for Medicare & Medicaid Services, are Decipher (GenomeDx Biosciences), Oncotype DX (Genomic Health, Inc.), and Prolaris (Myriad Genetics, Inc.).
Nevertheless, Dr. Gomella believes that the use of genomic testing for active surveillance is understated in the 2016 guideline, as its mention is omitted from the subsection entitled “Principles of Active Surveillance and Observation.” Instead, readers are referred to a discussion of genomic testing and tissue biomarkers for risk stratification purposes.
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Dr. Gomella is a believer in the concept of active surveillance but did sound one cautionary note about its practice. In a country such as Sweden, often cited as a model for this approach where active surveillance is applied more frequently than it is in the United States, prostate cancer as a cause of death is nearly twice as common.
For patients with very low-risk, low-risk, or favorable intermediate-risk prostate cancer, the choice of initial therapy should consider expected patient survival:
Patients with clinically localized prostate cancers who are candidates for definitive treatment and choose active surveillance should have regular follow-up. Follow-up should be more rigorous in younger men than in older men.
Active surveillance involves actively monitoring the course of disease with the expectation to intervene with potentially curative therapy if the cancer progresses.
About one-third of men chosen for active surveillance will require treatment, although treatment delays do not seem to impact cure rate.
The latest 2016 NCCN update that allows men with “favorable” intermediate-risk prostate cancer to consider active surveillance as an option may benefit some men who fall into this category, according to Leonard Gomella, MD, of Kimmel Cancer Center. The traditional criterion for active surveillance excluded Gleason pattern 4 cancer in the biopsy.
Dr. Gomella describes the following case in which the NCCN update was consulted.
“A very healthy 57-year-old asymptomatic patient with mild lower urinary tract symptoms who presented with a rising PSA level over 3 years (from 1.2 to 3.3 ng/dL) and a normal prostate exam was recently evaluated in our Genitourinary Multidisciplinary Clinic. Biopsy demonstrated three of 12 biopsy cores with prostate cancer: 10% Gleason 3+3, 15% Gleason 3+3, and 15% Gleason 3+4. Further characterization with genomic testing was recommended but the patient was not interested.
“The patient was interested in active surveillance. We discussed active treatment as an option with surgery or radiation, and the surveillance protocol that would be followed: follow-up magnetic resonance imaging-guided fusion biopsy in 1 year, with periodic PSA testing with biopsies thereafter during longitudinal follow-up. Although he does not meet the <10-year life expectancy criterion for consideration of active surveillance and did have some pattern 4 cancer, we agreed to this approach, with all parties recognizing that at some point in the future he may require definitive therapy.
“The 2016 NCCN guidelines do provide some guidance in patients with higher Gleason pattern characteristics.”
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