New concepts re Active Surveillance for Prostate Cancer

Summary of April Meeting of IPCSG of San Diego

By Bill Lewis

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New concepts in the screening and conservative management (Active Surveillance) approaches for Prostate Cancer

Franklin Gaylis MD, FACS

Chief Scientific Officer, Genesis Healthcare Partners

Voluntary Clinical Professor, Department of Urology, UCSD

Background:  Prostate cancer is the second leading cause of cancer-related death.  Although the percentage of men diagnosed with prostate cancer in their lifetime has almost doubled from 9% to 17% since 1990, when the PSA test was widely adopted for screening, the percentage of men that actually die of prostate cancer is now only about 3%.  Due to PSA screening, there are 40% fewer deaths from prostate cancer than before.  Many of the men now diagnosed with prostate cancer each year have "low risk disease," and never would die of it, but still undergo active treatment that is unnecessary.  In May 2012, the U.S. Preventative ServicesTask Force recommended against PSA screening, due to frequent overdiagnosis and overtreatment.  The PIVOT (prostate intervention vs observation trial) suggested that "observation" was as effective as surgery, in July 2012.  But that applied only to low risk PCa, and there was a significant benefit for patients with high risk prostate cancer. 

The Task Force recommendations were widely adopted, resulting in a 50% decline in PSA screening, and in turn resulting in fewer diagnoses of low risk PCa (as is desirable, since such cancers normally don't need to be treated), but an increase in finding high risk PCa.  This suggests that men are not being biopsied as early in their disease progression, due to the reduced frequency of PSA screening, and Dr. Gaylis and colleagues published a letter in the New England Journal of Medicine in February 2016 pointing this out, and warning that doctors may now be missing the window of curability for many men -- as was common in the pre-PSA era. 

Just this month, the Task Force updated their recommendations to indicate that the decision whether or not to test for PSA must be "individualized" for men aged 55 - 69 years (including both men at average risk, as well as those who are at “increased risk,” such as African American men, and those with a family history of prostate cancer).  They still oppose testing of men aged 70 years and older, indicating their opinion that the benefits do not outweigh the harms.  A major factor in the Task Force revision of their guidelines is the fact that whereas in 2012, very few men went on active surveillance, now almost 40% do after diagnosis (thus avoiding the harms of overtreatment).  The American Urologic Association immediately issued a statement in favor of the revised guideline.  Supporting evidence for the value of screening comes from the European Randomized Study of Screening for Prostate Cancer, which issued the prediction that 3 men out of 1000 will avoid metastatic prostate cancer because of screening. 

Dr. Gaylis feels that men at "increased risk" (see above) should start PSA testing much earlier than age 55; as early as age 40.  And he also believes that the age 70 cutoff is artificially rigid, and that each man's situation should be considered individually.  The popular term is "shared decision making."  He has been doing this throughout his career, and notes that our support group helps men to be involved in the decision making.

Active surveillance can be considered to relate to "time of treatment," or "delayed treatment."  The careful follow-up recommended by Genesis Healthcare includes an annual digital rectal exam (because very aggressive cancer may not produce PSA; Dr. Gaylis found a half-inch tumor in the prostate of a man with a PSA of only 0.7), regular PSA testing (useful for the vast majority), genomic testing (such as Oncotype Dx, Prolaris, and Decipher), multiparametric MRI, and biopsies. 

About 33% of men on active surveillance will eventually require active treatment to prevent harm from the disease.  Only 3% of men with favorable-risk PCa who go through active surveillance (with active treatment if and when needed) will die of the cancer within 10 years.  The risk of dying from some other cause was 19 times higher than the risk of dying from PCa!  (Source:  J. Urol. Suppl., 2009,181:606 abstract 1682)

At Genesis Healthcare, for five years now, a "best practice" standard of care involving treatment both of "very low risk" men, as well as more liberal criteria for reasonable exceptions to the most strict criteria has been used and shared with other doctors and groups.  Their data was published, with their guidelines, in the “Gold Journal,” Urology, last year.  Now about 70% of their "low risk" patients go on active surveillance, and more than 85% of "very low risk" patients likewise.  The definition of “very low risk” is as follows:  Stage T1c disease (identified only by needle biopsy; not palpable by DRE nor visible by imaging); Gleason Score = 6 or less; PSA less than 10 ng/ml; three or fewer biopsy cores positive, and less than 50% cancer in any core; PSA “density” less than 0.15 ng/ml/gram (density = PSA score divided by the estimated weight of the whole prostate).  The more liberal criteria amount to the patient’s request to go on active surveillance, with the risk estimated as low and approved by the physician.

Genetic testing discussion:  Note that Genetics examines the function of a single gene, whereas "Genomics" examines groups of genes to identify their combined influence on an organism.  The Oncotype DX prostate cancer assay was discussed as an example of genomic testing.  It is suitable for newly-diagnosed men with very low, low, or low-intermediate risk PCa.  It helps to improve assignment of the degree of risk, particularly to identify patients who may need immediate treatment. 

One part of the Oncotype DX test evaluates the genes that affect the "health" of the interaction of the prostate cells with the surrounding stroma.  Stroma is the scaffold or supporting structure around the cells.  Proliferation genes are used to measure of how rapidly the cells turn over, or multiply.  (Note that the Prolaris test only looks at proliferation.)  Androgen signaling genes provide a measure of the cell's responsiveness to testosterone.  And cellular organization is the fourth group of genes evaluated.  All four groups of genes, 12 genes in all, are compared with 5 reference genes that serve to account for varying RNA quality and quantity in the test sample.  The assay provides an overall "Genomic Prostate Score" on a scale of 100, with higher scores representing more aggressive cancer. 

A study at UCSF showed, that whereas 10% of a group of 288 men were thought to be very low risk using the strict guidelines like Genesis Healthcare uses, after considering the Oncotype DX score, it was found that 26% of the men could be treated as very low risk.  As might be expected, given the uncertainties of biopsy results, some individual men found their GP Score raised their predicted risk, while others found the opposite.  Dr. Gaylis emphasized that these tests provide "additional information" that can be a valuable part of the overall assessment of risk and treatment options for each man.

Dynamic contrast enhanced (DCE) MRI detects the greater blood flow (more blood vessels) in prostate tumors as compared with healthy tissue.  Along with two other parameters measured using MRI, a "PI-RADS" (Prostate Imaging Reporting and Data System) score is generated, on a scale of 1 to 5, with 5 being "highly suspicious of malignancy."

Fusion biopsies (combining prior MRI data with real-time ultrasound to guide the needles during the biopsy procedure) are now gaining acceptance, because they reportedly detect cancer two to three times as often as standard (i.e., "systematic" but blind, often referred to as random) biopsies, and are especially effective in finding cancer when the MRI images show a high level of suspicion.  This new approach provides progress toward targeted, "pinpoint" biopsies.

A study published last year showed that only 5-11% of men on active surveillance after being diagnosed at age 66 or older during the years 2001-2009, received follow-up testing that met the strict guidelines of the prominent PCa research groups at Johns Hopkins and at Sunnybrook (Toronto, Canada), respectively.  Hopefully, our group members are followed more closely!

At Genesis Healthcare, in collaboration with UCSD, three specific measures of the quality of active surveillance activities now are:  adoption (currently, 70% of qualified candidates go on active surveillance), adherence (follow-up PSA testing; DRE annually; and "confirmatory biopsy" within 18 months), and patient satisfaction at their first consultation.

Questions/discussion:  Comments on drugs used for patients on active surveillance, such as Metformin, a statin, and Proscar?  There is provocative info in the literature that says that statins help prevent growth of prostate cancer.  Some doctors are using these drugs.  Xtandi is being used in a trial at Genesis Healthcare, with patients on active surveillance.  Also Casodex is being used by some.  There is no data available yet that proves the benefits of any of these scientifically.

Are there oncologists at Genesis Healthcare?  They have radiation oncologists, but there are “political problems” with adding medical oncologists, so they don't have any.

A comment on economics: In the USA, we have an 18% inflation rate for medical expenses, and those expenses currently total 18% of GDP.  That’s about twice the rate in other 1st world countries. The Task Force did a little good, trying to recommend against unnecessary expenses, but their recommendations also had some bad effects.  The AUA (American Urologic Association) only recommends based on "scientific data," so they offer no recommendations for many issues.

Value of estradiol (an estrogen)?  Estrogen slows prostate cancer, but can cause strokes.

Differences of other genomic tests compared to the Decipher test?  Prolaris predicts 10-year survival, and is based only on “proliferation promoting” gene activity.  The GenomeDX “Decipher” test is useful to predict if radiation would benefit a man who has adverse pathology (disease outside of the prostate and/or PSA rising after prior treatment).  All are RNA based test.  The microarray technology of the Decipher test looks at thousands of genes (others only look at hundreds), but shallowly (low, med, high); it is especially good at predicting recurrence after prostatectomy.

Dr. Gaylis is not in favor of MRI before biopsy, but wants 12-core first, then later a fusion biopsy and (for low risk patients) genomic testing to confirm the original biopsy findings.

A major factor in the Task Force revision of their guidelines is the fact that whereas in 2012, very few men went on active surveillance, now almost 40% do after diagnosis (thus avoiding the harms of overtreatment).

TURP effect on future treatment, for men on active surveillance?  Depends on how aggressive the surgery was.  A new technique is to vaporize the tissue, which he thinks may reduce introduction of cells into the bloodstream.  He has tried green and red light laser, but didn't like them.  Now there is a technology using steam.  Another new technology is the PlasmaButton from ACMI, which coagulates the tissue, and seems worthwhile.