NCCN Guidelines: Updating Initial Risk Stratification and Staging Workup for Clinically Localized Evaluation of Prostate Cancer

The latest update to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology; Prostate Cancer, Version 2.2022, was issued on  November 30, 2021.  It followed only 2 months after the September 30 release of Version 1.1022,² which caused controversy by removing “preferred option” to describe active surveillance in patients with low-risk prostate cancer. (Version 2.2022 addressed these concerns by stating that active surveillance is preferred for most patients with low-risk prostate cancer and by providing detailed guidance on the principles of active guidance and observation.) There are challenges in keeping this guideline up to date, because there are so many “amazing” changes taking place in prostate cancer, according to NCCN Prostate Cancer Panel chaired by Edward Schaeffer, MD, PhD, Chair of Urology at Northwestern Memorial Hospital and Professor of Urology at Northwestern University, Chicago.³

In the section of the guideline that addresses initial risk stratification and staging workup for clinically localized disease (PROS-2), the biggest changes in Version 2.2022 from Version 1.2022 are in the utility of imaging, such as multiparametric magnetic resonance imaging (mpMRI), and the use of tumor multigene molecular testing in the very low-, low-, and intermediate-risk groups. 

Very Low Risk Group

Version 2.2022	Consider confirmatory mpMRI ± prostate biopsy if not performed prior to biopsy to establish candidacy for active surveillance. All patients should undergo a confirmatory prostate biopsy within 1-2 years of their diagnostic biopsy.
Version 1.2022	Consider confirmatory prostate biopsy ± mpMRI ± prostate biopsy if not performed prior to biopsy to establish candidacy for active surveillance.

 

Patients at very low risk meet all the following criteria: Stage cT1c; Gleason Grade Group (GGG) 1; PSA <10 ng/mL; <3 prostate biopsy fragments/cores positive, with ≤50% cancer in each fragment/core; and PSA density <0.15 ng/mL/g). Further additional evaluation should consider a follow-up mpMRI if not performed initially. All patients should undergo a confirmatory prostate biopsy within 1-2 years of the initial diagnostic biopsy. Thus, an initial confirmatory prostate biopsy was removed in favor of first obtaining an mpMRI, unless already obtained. 

Low Risk Group

Version 2.2022	Consider confirmatory mpMRI ± prostate biopsy and/or molecular tumor analysis if MRI not performed initially for those considering active surveillance. All patients should undergo a confirmatory prostate biopsy within 1-2 years of their diagnostic biopsy.
Version 1.2022	Consider confirmatory prostate biopsy ± mpMRI ± prostate biopsy if not performed prior to biopsy to establish candidacy for active surveillance.

 

Patients with low-risk prostate cancer, defined as Stage cT1-cT2a, GGG 1, PSA <10 ng/mL, but does not otherwise qualify for very low risk, can be potential candidates for active surveillance, similar to very low-risk prostate cancer, consideration of mpMRI is recommended, if it has not already been done, along with a confirmatory prostate biopsy. In addition, clinicians should consider tumor-based molecular assays.

Intermediate Risk Group

Version 2.2022	Favorable: Consider confirmatory mpMRI ± prostate biopsy and/or molecular tumor analysis if MRI not performed initially for those considering active surveillance. All patients should undergo a confirmatory prostate biopsy within 1-2 years of their diagnostic biopsy.
Version 1.2022	Favorable: Consider confirmatory prostate biopsy ± mpMRI ± prostate biopsy if not performed prior to biopsy to establish candidacy for active surveillance.

 

Patients with  intermediate-risk prostate cancer have no high or very high-risk group features and one more intermediate risk factors (IRFs) out of Stage  cT2b-cT2c, GGG 2 or 3, PSA 10-20 ng/mL. Favorable intermediate risk is defined as 1 IRF, GGG 1 or 2, <50% biopsy cores positive (e.g., <6 of 12 cores). Recommendations for additional evaluation in these patients are identical to those for the low-risk group.

Evidence for mpMRI and tumor multigene molecular testing

The role of mpMRI in the diagnosis of prostate cancer has become increasingly important in recent years, as reflected in the NCCN and other prostate cancer guidelines.⁴  mpMRI typically includes diffusion-weighted imaging (DWI) and/or dynamic contrast-enhanced (DCE) images in addition to the standard anatomical T2-weighted imaging. The quality mpMRI involves a 3 T magnet. It has a higher signal to noise ratio, allowing quality imaging within a short time and without the use of an endorectal coil (although the need for an endorectal coil remains controversial).

The NCCN guideline recommendations are based on evidence reviewed and voted on by the guideline panels. This evidence is eventually published  in the Discussion section of the guidelines. However, because the NCCN guideline on prostate cancer is updated so frequently, the Discussion section often lags behind the recommendations within the same  guideline. In Version 2.2022 (and Version 1.2021), for example, the Discussion section is dated November 17, 2020. Many of the recent updates related to the implementation of mpMRI have been based on its increased availability and ability to stage and characterize prostate cancer.

The evidence supporting the use of mpMRI in the initial evaluation of prostate cancer is based on studies showing that it aids in the detection of larger and/or poorly differentiated cancers (GGG 2).⁵ Furthermore, the incorporation of mpMRI into MRI-TRUS fusion-targeted prostate biopsy increased the rate of diagnosis of high-grade cancers with fewer biopsy cores needed and reduced the detection of low-grade and insignificant cancer.^5-7

In addition to identifying higher risk lesions, mpMRI aids in the detection of extracapsular extension (T staging), with high negative predictive values in low-risk men, which are important for assessing eligibility for active surveillance and for reaching decisions about nerve-sparing strategies at radical prostatectomy.⁸ mpMRI has been demonstrated as equivalent to computed tomography (CT)  imaging in the detection and staging of pelvic lymph nodes.^9-10 It’s superior (sensitivity and specificity) to bone scan and targeted x-rays in the detection of bone metastases.¹¹

The NCCN recommendation to use tumor molecular testing is based on the goal of achieving personalized or precision medicine. Molecular testing of a tumor offers the potential to evaluate the “biologic behavior” of a cancer, which would aid in clinical decision making, the guideline says.

The guideline lists six available tissue-based tests for prostate cancer risk stratification/prognosis. For initial clinical assessment and staging evaluation in men with low or favorable intermediate disease and life expectancy of 10 years or longer, the guideline panel  recommends the use of the Decipher Prostate (Veracyte), Oncotype DX Genomic Prostate Score (Exact Sciences), Prolaris (Myriad Genetics), or ProMark (Metamark Genetics) assays. Patients with unfavorable intermediate or high-risk disease and life expectancy of 10 or more years may consider the Decipher Prostate or Prolaris assays.

The  guideline panel notes that a number of retrospective case cohort series have demonstrated the ability of these tests to provide prognostic information independent of NCCN or Cancer of the Prostate Risk Assessment (CAPRA) risk groups. This includes likelihood of death with conservative management, likelihood of biochemical recurrence or adverse pathological features after radical prostatectomy, or likelihood of developing biochemical recurrence or metastases of  external beam radiation therapy (EBRT).

Among the studies that examined how tumor molecular assays impact treatment, a prospective study of almost 4000 patients newly diagnosed with localized prostate cancer indicated that use of one of three tissue-based gene expression classifiers was more frequent in patients with low-risk disease and that use of these assays significantly increased the likelihood of active surveillance.¹² . One out of 9 patients with favorable-risk prostate cancer who underwent genomic testing opted for active surveillance.

The guideline notes that more comparative effectiveness research is needed to provide additional evidence about the utility of these tests for better risk stratification of men with prostate cancer.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology. 

References 

1. Schaeffer EM, Srinivas S, Antonarakis ES, et al. National Comprehensive Cancer Network Clinical Practice Guidelines (NCCN Guidelines). Prostate cancer. Version 2.2022. November 30, 2021. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459 Accessed December 29, 2021.
2. Schaeffer EM, Srinivas S, Antonarakis ES, et al. National Comprehensive Cancer Network Clinical Practice Guidelines (NCCN Guidelines). Prostate cancer. Version 1.2022. September 10, 2021.
3. Goodman A. NCCN guidelines for prostate cancer: panel clarifies role of active surveillance for low-risk prostate cancer. ASCO Post. December 25, 2021. https://ascopost.com/issues/december-25-2021/nccn-guidelines-for-prostate-cancer-panel-clarifies-role-of-active-surveillance-for-low-risk-prostate-cancer/ Accessed December 29, 2021.
4. Mason BR, Eastham JA, Davis BJ. Current status of MRI and PET in the NCCN guidelines for prostate cancer. J Natl Compr Canc Netw. 2019;17(5):506-513. DOI: 6004/jnccn.2019.7306
5. Turkbey B, Mani H, Shah V, et al. Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging-based molds. J Urol. 2011;186(5):1818-1824. DOI: 1016/j.juro.2011.07.013
6. Siddiqui MM, Rais-Bahrami S, Truong H, et al. Magnetic resonance imaging/ultrasound fusion biopsy significantly upgrades prostate cancer versus systemic 12-core transrectal ultrasound biopsy. Eur Urol. 2013;64(5):713-719. DOI: 1016/j.eururo.2013.05.059
7. Rastinehad AR, Turkbey B, Salami SS, et al. Improving detection of clinically significant prostate cancer: magnetic resonance imaging/transrectal ultrasound fusion guided prostate biopsy. J Urol. 2013;19(6)1:1749-1754. DOI: 1016/j.juro.2013.12.007
8. Wysock JS, Rosenkrantz AB, Huang WC, et al. A prospective, blinded comparison of magnetic resonance (MR) imaging –ultrasound fusion and visual estimation in the performance of MR-targeted prostate biopsy: the PROFUS trial. Eur Urol. 2014;66(2):343-351. DOI: https://doi.org/10.1016/j.eururo.2013.10.048
9. Somford DM, Hamoen EH, Fütterer JJ, et al. The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate, and high risk prostate cancer. J Urol. 2013;190(5):1728-1734. DOI: 1016/j.juro.2013.05.021
10. Pasoglou V, Larbi A, Collette L, et al. One-step TNM staging of high-risk prostate cancer using magnetic resonance imaging (MRI): toward an upfront simplified “all-in-one” imaging approach? 2014;74(5):469-477. DOI: 10.1002/pros.22764
11. Heck MM, Souvatzoglou M, Retz M, et al. Prospective comparison of computed tomography, diffusion-weighted magnetic resonance imaging and [¹¹C] choline positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer patients. Eur J Nucl Med Mol Imaging. 2014;41(4):694-701. DOI: 1007/s00259-013-2634-1
12. Lecouvet FE, EI Mouedden J, Collette L, et al. Can whole-body magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer? Euro Urol. 2012;62(1):68-75. DOI: 1016/j.eururo.2012.02.020
13. Hu JC, Tosoian JJ, Qi J, et al. Clinical utility of gene expression classifiers in men with newly diagnosed prostate cancer. JCO Precis Oncol. 2018;2:1-15. DOI: 1200/po.18.00163