Risk Stratification Emphasized in Newest NCCN Prostate Cancer Guidelines

September 2018 Vol 9, No 9

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

The NCCN guidelines move toward consensus with other guidelines, most notably the US Preventive Services Task Force, in that shared decision-making with respect to screening men 45 to 75 years of age is recommended, said Peter R. Carroll, MD, MPH, at the NCCN 23rd Annual Conference. The paradigms of prostate cancer detection are changing to ones in which low-risk disease is not detected and surveillance is offered to those with lower-risk disease, he said. This sentiment was echoed by James L. Mohler, MD, associate director for translational research, Roswell Park Comprehensive Cancer Center, Buffalo, NY, who presented an update to management approaches to prostate cancer.

An alternative to biopsy in patients with an elevated PSA level is the use of serum- or urine-based biomarkers that increase 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 [ie, a higher-grade tumor]," said Dr Carroll, professor and chair, Department of Urology, University of California, San Francisco. These tests miss few high-risk cancers but decrease the biopsy rate by 30% to 40%, he said.

"The other big marker right now is multiparametric MRI," said Dr Carroll. Using multiparametric MRI or biomarkers misses only about 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, as there is no mortality benefit from treating these cancers, he said. Active surveillance is based on the rationale that the initial assessment is reasonably accurate and that monitoring identifies subclinical 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," said Dr Carroll.

Several studies show no harm in treatment delay up to 2 years. "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 men with low-risk disease to determine who may be harboring higher-risk cancers are Oncotype Dx Genomic Prostate Score, Prolaris, Decipher genomic classifier, and ProMark.

Risk Stratification
The cost of treatment for castration-resistant disease to add 2 years of survival is about $1.3 million, so the financial burden is substantial, said Dr Mohler, in explaining part of the rationale for the treatment guidance in the updated guidelines.

"What's really new this year is our emphasis on risk stratification and the proper staging workup," which has been condensed into 1 table in the NCCN guidelines, he said. Each risk group is assigned its own page with recommendations for initial therapy. Recommendations for molecular testing and germline testing are included in the table. "What we're trying to do is develop a more personalized medicine" for men with prostate cancer, said Dr Mohler.

For the first time in NCCN prostate cancer guidelines, risk stratification by family history is also emphasized, "and for the first time we finally know what a strong family history is," he said. A brother or father or multiple family members diagnosed with prostate cancer before age 60 years constitutes a strong family history. "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," he said.

Estimating life expectancy is important for molecular testing and treatment decisions, especially in low-risk groups. An estimation is possible by using life insurance or Social Security Administration life expectancy tables and adjusting them for individual patients based on whether one believes that the patient is in the healthiest quartile or unhealthiest quartile.

Molecular Assays
Molecular assays performed on prostate biopsy or radical prostatectomy specimens provide prognostic information independent of NCCN risk groups, including predicting the likelihood of death with conservative management, the likelihood of biochemical progression after radical prostatectomy or external beam therapy, and the likelihood of developing 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 a positive test should be referred for genetic counseling. The results have treatment implications in that men with a positive genomic test may be considered for earlier use of platinum chemotherapy or referral for clinical trials in which PARP inhibitors are being tested.

DNA analysis for microsatellite instability (MSI) and immunohistochemistry for mismatch repair deficiency (dMMR) should also be considered. If either is found, the patient should be referred to a genetic counselor to assess for the possibility of Lynch syndrome and potential use of pembrolizumab once androgen deprivation therapy (ADT) fails.

Intermittent Rather Than Continuous ADT
In castration-naive patients, complete androgen blockade "does not work," he said. Intermittent ADT appears to be as good as continuous ADT on the end point of overall survival, with a significant quality-of-life benefit. Intermittent ADT can be personalized based on the PSA response, Mohler indicated. A PSA that falls to <0.2 ng/mL signals an outstanding response to ADT and a patient who will do well off ADT for a prolonged period.

For younger and healthier men with metastatic castration-naive prostate cancer, survival is improved with the addition of docetaxel to ADT. Abiraterone 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-naive disease," Dr Mohler said.

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

Castration-Resistant Nonmetastatic Disease: Apalutamide Added as Option
For patients with nonmetastatic castration-resistant prostate cancer, apalutamide was added as an option in the guidelines based on the results from the SPARTAN trial, which showed a 2-year benefit in metastasis-free survival with apalutamide compared with placebo in men with a PSA doubling time ≤10 months, at a cost of an increase in pathologic fracture to 11.7% from 6.5% in the placebo group. Whether the delay in the development of metastatic disease will translate to an improvement in overall survival will require longer follow-up. With an array of options for the treatment of bone metastases and the expense of apalutamide, "you might want to reserve your apalutamide for that time, when you do develop that metastasis," he said.

All treatment strategies for castration-resistant prostate cancer exceed $100,000 per life-year saved, noted Dr Mohler. From the patient perspective and a health economist's perspective, therefore, "we need to do better at how to use these," he said. 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," he said.

This is something we should be thinking about." DNA repair mutation analysis may identify patients eligible for enrollment into a clinical trial of a PARP inhibitor.

More Subsequent Options for Metastatic Disease
Subsequent systemic therapy for M1 castration-resistant prostate cancer has become more complicated. For 2018, the NCCN panel differentiated visceral versus skeletal metastases for the purpose of selecting therapy.

For patients without visceral metastases, first options include abiraterone with prednisone, docetaxel, and enzalutamide; radium 223 for symptomatic bone metastases; referral to a clinical trial; and other secondary hormone therapy. For patients with visceral metastases, the guidelines recommend consideration of biopsy and choosing subsequent therapy based on histologic evidence of either small cell carcinoma or adenocarcinoma, and then treat per the guidelines.

Last modified: October 7, 2018

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