Updated NCCN Prostate Cancer Guideline Emphasizes Risk Stratification

Wayne Kuznar

May 2018, Vol 8, No 5 - NCCN Guideline Updates


The updated prostate cancer guideline issued by the National Comprehensive Cancer Network (NCCN) continues to support early detection efforts in well-informed, healthy men, but acknowledges that the optimal screening of high-risk patients is not completely known. The guideline also supports the use of active surveillance in men who have low-risk prostate cancer.

The NCCN guideline moves toward consensus with other prostate cancer guidelines, most notably those of the US Preventive Services Task Force, in that shared decision-making with respect to screening men aged 45 to 75 years is recommended, said Peter R. Carroll, MD, MPH, Program Leader, Prostate Cancer Program, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, at the 2018 NCCN annual conference.

New Perspective on Low-Risk Disease

The paradigms of prostate cancer detection are changing so that detection of low-risk disease is not followed, and surveillance rather than treatment is offered to those with lower-risk disease, Dr Carroll said. This sentiment was echoed by the chair of the NCCN Prostate Cancer Guideline Committee, James L. Mohler, MD, Associate Director, Translational Research, Roswell Park Comprehensive Cancer Center, Buffalo, NY, who discussed management approaches in prostate cancer.

An alternative to performing biopsies in patients with elevated prostate-specific antigen (PSA) levels is the use of serum- or urine-based biomarkers that increase the specificity of screening.

“What they’re doing is determining which men with an elevated PSA are harboring clinically significant disease, defined by an elevated Gleason score,” said Dr Carroll. These tests miss few high-risk cancers, but decrease the biopsy rate by 30% to 40%, he added.

“The other big marker right now is multiparametric MRI” (magnetic resonance imaging), Dr Carroll told attendees. Using multiparametric MRI or biomarkers misses only approximately 1% to 2% of high-risk tumors, and even fewer if both tests are used, while avoiding unnecessary biopsies and detecting fewer lower-­risk cancers.

Active surveillance should be considered for men with low- or very low-risk tumors, because there is no survival benefit from treating these cancers, Dr Carroll said. Active surveillance is based on the rationale that the initial assessment is reasonably accurate, and that monitoring identifies subclinical disease progression at a time when initial treatment options are still available and curative.

“In my opinion, very few men with low-risk disease should ever be treated,” Dr Carroll posited. Several studies have shown that there is no harm in delaying treatment by up to 2 years, he noted.

“We have this window of opportunity to follow patients carefully and select those who actually need to be treated from among the majority who do not,” said Dr Mohler.

Gene or protein signature tools that may be helpful in determining which men with low-risk disease are harboring higher-risk cancers include Oncotype DX Genomic Prostate Score, Prolaris, Decipher genomic classifier, and ProMark.

Risk Stratification

The cost of treatment for castration-resistant disease that adds 2 years of survival is approximately $1.3 million, so the financial burden is substantial, said Dr Mohler, explaining part of the rationale for the treatment guidance in the updated NCCN guideline.

“What’s really new this year is our emphasis on risk stratification and the proper staging workup,” which has been condensed into a table in the NCCN guideline, he added.

“What we’re trying to do is develop a more personalized medicine” for men with prostate cancer, Dr Mohler told attendees.

For the first time, the NCCN prostate cancer guideline includes risk stratification by family history, “and for the first time we finally know what a strong family history is,” he said. A brother or a father or multiple family members diagnosed with prostate cancer before age 60 years constitutes a strong family history of the disease.

“Now we’re learning more about the need to identify DNA repair gene abnormalities and also to search for Lynch syndrome, which is something that most urologists probably weren’t familiar with until recently,” Dr Mohler said.

Estimating life expectancy is important for molecular testing and treatment decisions, especially in low-risk populations. This can be done with life insurance or Social Security Administration life-expectancy tables, and adjusting them for individual patients depending on whether the patient is in the healthiest or unhealthiest quartile.

Molecular Testing

Molecular assays performed on prostate biopsy or radical prostatectomy specimens provide prognostic information independent of NCCN risk groups, including predicting the likelihoods of death with conservative management, biochemical progression after radical prostatectomy or external beam therapy, and metastasis after radical prostatectomy or salvage radiotherapy.

As with low-risk disease, molecular and germline testing should also be considered in more advanced disease, “But it’s a little more complicated here,” Dr Mohler said. “We should test for germline or somatic mutations in the DNA homologous recombination genes in all men with high-risk cancer, very high-risk, regional, and especially metastatic disease.”

Men with positive test results should be referred for genetic counseling. The results have treatment implications in that men with positive genomic tests may be considered for earlier use of platinum chemotherapy or a referral for clinical trials with poly (ADP-ribose) polymerse (PARP) inhibitors.

DNA analysis for microsatellite instability (MSI) and immunohistochemistry for mismatch repair–deficiency (dMMR) should also be considered. If either MSI or dMMR is found, the patient should be referred to a genetic counselor to assess the possibility of Lynch syndrome and the potential use of pembrolizumab (Keytruda) if the patient does not respond to androgen-deprivation therapy (ADT).

Intermittent or Continuous ADT?

In patients with castration-naïve prostate cancer, complete androgen blockade “does not work,” Dr Mohler said. Intermittent ADT is as good as continuous ADT in terms of overall survival (OS), with a significant quality-of-life benefit. Intermittent ADT can be personalized based on the PSA response, Dr Mohler said. A PSA level <0.2 ng/mL signals an outstanding response to ADT and a patient who will do well without ADT for a prolonged period.

For younger and healthier men with metastatic, castration-naïve prostate cancer, survival is improved with the addition of docetaxel (Taxotere) to ADT. Abiraterone (Zytiga) is a less toxic alternative to chemotherapy, with a similar effect on survival.

“This has produced a change in the NCCN guideline, where we make more options available for castration-naïve disease,” Dr Mohler said.

“If the patient is asymptomatic, I always use intermittent ADT. I discuss a possible decrease in OS, but the trade-off is improved quality of life during off cycles,” he added. Continuous ADT can be considered for men with symptomatic, castration-naïve disease, unless the PSA response is outstanding, in which case intermittent ADT is preferred.

Apalutamide for Castration-Resistant Nonmetastatic Disease

For patients with nonmetastatic, castration-resistant prostate cancer (CRPC), the recently approved apalutamide (Erleada) was added as the newest treatment option in the guideline based on results from the SPARTAN trial, which showed a 2-year benefit in metastasis-free survival with apalutamide versus placebo in men with a PSA doubling time ≤10 months, at a cost of an increase in pathologic fracture (11.7% vs 6.5%, respectively). Whether the delay in the development of metastatic disease will translate to an improvement in OS remains to be seen. With an array of treatment options for bone metastases and the expense of apalutamide, “You might want to reserve your apalutamide for that time, when you do develop that metastasis,” Dr Mohler said.

All treatment strategies for CRPC exceed $100,000 per life-year saved, he noted. Therefore, from the perspectives of patients and health economists, “We need to do better at how to use these,” Dr Mohler continued.

A molecular assay that identifies high MSI or dMMR in a symptomatic patient can indicate eligibility for pembrolizumab instead of chemotherapy in later lines of treatment.

“We don’t know that yet; I’m just saying it’s possible. This is something we should be thinking about,” Dr Mohler said. A DNA repair mutation analysis may identify patients eligible for enrollment in a clinical trial of a PARP inhibitor.

More Options for Metastatic Disease

Subsequent systemic therapy for metastatic CRPC has become more complicated. In 2018, the NCCN panel differentiated visceral metastases from skeletal metastases for the purpose of selecting therapy.

For patients without visceral ­metastases, first options include abiraterone with prednisone, doce­taxel, enzalutamide (Xtandi), and radium-­223 (Xofigo) for symptomatic bone metastases; referral to a clinical trial; and secondary hormone therapy.

For patients with visceral metastases, the guideline recommends consideration of a biopsy, choosing subsequent therapy based on histologic evidence of small-cell carcinoma or adenocarcinoma, and then treating the patient according to the guideline.