New Prostate Cancer Guidelines Support Use of Molecular-Based Prognostic Tests

Eric Klein, MD

Molecular-based tests that predict prostate cancer’s aggressiveness are reliable enough to gain a stronger, though still qualified, endorsement in the National Comprehensive Cancer Network’s newly updated treatment guidelines.

The NCCN’s increased support of the assays’ clinical use for risk stratification in localized disease should boost physicians’ and patients’ confidence in choosing active surveillance rather than immediate treatment based on the tests’ results, says Eric Klein, MD, Chairman of Cleveland Clinic’s Glickman Urological & Kidney Institute.

“These new tools are readily available now and can be easily used to help make the right decision for each patient,” Dr. Klein says.

Active surveillance — careful monitoring after initial biopsy, with selective intervention based on apparent progression — is a safe and acceptable option in appropriate early-stage patients, but it is not used as often as is indicated.

Prostate cancer is the most common malignancy in men, with an estimated 180,890 new cases expected to be diagnosed in the United States in 2016. A 2015 JAMA Internal Medicine study using the National Cancer Data Base found that as much as 40 percent of men with prostate cancer were clinically eligible for active surveillance, but no more than 12 percent actually were managed that way. Increased use of active surveillance would help reduce the problem of overtreatment of prostate cancer and its concomitant expense and morbidity.

“There’s plenty of room for putting more men on surveillance,” Dr. Klein says. “In 2016, our goal should be to treat only those patients who have potentially lethal cancers, and to carefully monitor the rest. These biomarker tests are useful for individual risk assessment and selecting the right treatment for the right patient at the right time.”

Assessing tumors’ biologic potential

Urologists have access to a growing number of the molecular risk-profiling tests, which were developed in recent years to address concerns about tumor heterogeneity in prostate biopsy tissue sampling. The prognostic assays provide information on the biologic potential of an individual patient’s tumor, including the likelihood of death with conservative management, likelihood of biochemical recurrence after surgery or radiotherapy, and likelihood of metastasis after surgery or salvage radiotherapy.

The previous NCCN guidelines said men with clinically localized prostate cancer “could consider” using one of the molecular predictive assays to better quantify risk of progression or mortality. Reviewers involved in updating the guidelines for 2016 recommended that the advisory contain more information about the tests, including guidance about their use, validation and risks.

The updated NCCN guidelines provide an overview of the six clinically available biomarker tests, listing the patient populations in which each test has been studied, the test’s reported outcomes, supporting references, and coverage recommendations from the company advising the Centers for Medicare & Medicaid Services about reimbursement.

Researchers at Cleveland Clinic’s Glickman Urological & Kidney Institute working in conjunction with Genomic Health Inc. helped develop Oncotype DX Prostate, one of the six prostate cancer molecular prognostic tests in clinical use. The Urological & Kidney Institute’s researchers also helped validate two other tests, Decipher and ProMark.

The updated NCCN guidelines note that only limited prostate cancer-specific survival data are available for men who’ve received the tests, and whether their use improves long-term patient outcomes is unclear. Head-to-head comparisons of the six tests haven’t been conducted, and prospective randomized clinical trials to assess their clinical utility are unlikely, due to the lengthy study period needed to produce meaningful results.

Still, the updated guidelines say men with clinically localized disease “may consider” using any of the six tests, which “provide prognostic information independent of NCCN risk groups.”

Cleveland Clinic an ‘early adopter’

“I think an even stronger supportive statement could have been made, but I’m a believer and I recognize that not everyone is there yet,” says Dr. Klein. “At Cleveland Clinic we were early adopters of the gene-signature tests, in part because of our development and validation studies. We’ve thought about this for a long time and have helped bring the tests to fruition. Their use as an option is incorporated into the care paths that guide our prostate cancer patients’ management.

“Development of these biomarker tests was in part to help understand the biology of prostate cancer, but more importantly to change behavior,” Dr. Klein says. “Prior to their development, there was a lot of resistance to active surveillance because of the uncertainty about a tumor’s biologic potential. A number of studies in the literature now show that physicians who use the tests actually put more men on active surveillance, and that’s the desired goal.

“I’ve used the tests in several ways,” he says. “One way is to convince patients that surveillance is safe. Another is to convince me that surveillance is safe for a particular patient. A third way is to convince me or the patient that treatment is appropriate and worth the side effects, based on the biology of their tumor.”

Expanding active surveillance

Until now, physicians typically have considered active surveillance an option only for patients with low- and very-low-risk prostate cancer. However, NCCN reviewers questioned whether the heterogeneity that is known to exist within risk groups justified broadening active surveillance eligibility to include some intermediate-risk patients with favorable prognoses — and if so, how to define “favorable.”

After reviewing research detailing outcomes of intermediate-risk men on active surveillance, an NCCN expert panel determined that extending active surveillance consideration to men with favorable intermediate-risk cancer is appropriate, though physicians should use caution and closely monitor patients for tumor progression. The panel defined favorable as predominant Gleason grade 3 (Gleason score 3+4=7); percentage of predictive biopsy cores less than 50, and no more than one NCCN intermediate-risk factor.

“That’s significant change,” Dr. Klein says. “At present, virtually 100 percent of urologists who see any grade 7 cancer are going to treat it. Changing that behavior will go slowly, but the accumulated evidence suggests that certain patients with favorable intermediate-risk disease are surveillance candidates, and that message is starting to get out.”

Earlier docetaxel use

The updated NCCN guidelines contain two other significant changes: recommending the option of upfront use of the antimitotic drug docetaxel in men undergoing external beam radiation therapy and androgen-deprivation therapy for high-risk or very-high-risk localized prostate cancer, and also using upfront docetaxel in men with low-volume metastatic castration-naïve disease.

Although research about the survival benefit from earlier docetaxel use is not definitive, particularly for men with low-volume metastatic disease, the NCCN panel decided the evidence “is compelling enough … not to deny patients the opportunity for this potentially beneficial approach.”

The case for upfront docetaxel in patients with high-volume disease “is really convincing,” Dr. Klein says, citing outcomes from the ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED), in which Cleveland Clinic participated. “And in younger patients with low-volume metastatic disease, initial docetaxel is probably also the right thing to do,” he says. “They have the most life expectancy to gain by using an aggressive treatment approach at initial diagnosis.”