In October 2021, the National Comprehensive Cancer Network (NCCN) prostate caycer panel modified its guidelines (NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines®]) for low-risk prostate cancer to remove the word “preferred option” for active surveillance, giving equal weight to active surveillance, radiation therapy, and surgery as initial options for the management of low-risk cancer. This prompted an outcry of surprise, confusion, and in some instances anger from many prostate cancer oncologists on Twitter and the Internet, which led to further clarification from the NCCN panel on its reasoning and restoration of the word “preferred” for active surveillance. The panel provided new tables and explanatory footnotes, which allow for a better understanding of what prompted the change in the first place.
Laurence Klotz, MD, FRCSC
“When the word ‘preferred’ for active surveillance was removed from version 1.2022, it reminded me of what Elizabeth Taylor’s sixth husband said: ‘I know what to do, but I just don’t know how to make it exciting,’” said Laurence Klotz, MD, FRCSC, Professor of Surgery at the University of Toronto. “I would describe the situation as ‘a tempest in a teapot’,” he noted, now that the wording has been restored and the new information made available in footnotes and a table.
Thoughts From the Panel Chair
“The outcry on Twitter and the confusion and concern among some smart people about the change of a single word provided us with an opportunity to provide better information,” said NCCN prostate cancer panel chair Edward Schaeffer, MD, PhD, Chair of Urology at Northwestern Memorial Hospital and Professor of Urology at Northwestern University. “The panel spent a substantial amount of time to change the principles. The ‘meat’ of the changes is in prose, which comprises three or four pages that define what surveillance means, expectations for a person on active surveillance, who is a candidate, and how to decide when active surveillance is no longer an option.”
“Based on subsequent discussions, the revision [version 2.2022] is a complete reboot and rethinking of what the principles of active surveillance should look like. The discussion was the easy part, but the heavy lifting was to rethink the guidelines approach to active surveillance, because frankly changing one word was not the root cause of the issue,” Dr. Schaeffer stated.
Based on subsequent discussions, the revision [version 2.2022] is a complete reboot and rethinking of what the principles of active surveillance should look like.— Edward Schaeffer, MD, PhD
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Dr. Schaeffer and all the experts interviewed for this article agreed that the category of low-risk prostate cancer comprises a heterogeneous group of patients. Although they are a minority of patients, some within the category of “low risk” fall at the higher end of the spectrum, where treatment such as radiation therapy or surgery should be considered; they include men with a higher disease burden, BRCA-positive prostate cancer, a family history of prostate cancer, high anxiety levels about foregoing treatment, and younger age with any of these factors.
“Emerging data suggest that not all low-risk prostate cancers are the same, based on information on genetics and genomics,” stated Dr. Schaeffer.
The decision to opt for active surveillance for patients categorized as “low risk” is individualized and should be made in discussion with the patient and tailored to individual risk factors and concerns, experts agree.
The committee met and discussed heterogeneity within the low-risk category, and that’s how the word “preferred” was removed, according to Dr. Schaeffer. “This update was nuanced, and the reality is that most active surveillance studies included men at the lower end of low risk. Not all men with low-risk prostate cancer are candidates for active surveillance. The new update [version 2.2022] provides a lot of granularity as to which men should have active surveillance,” he added.
“We needed to do a better job in providing clear guidance for the community, and we did. There are so many amazing changes in the prostate cancer space that are reflected in the guidelines. It can be difficult to keep them updated. For example, this year, there are 10 pages of changes. One of them was to take out pronouns and refer to all people as patients,” Dr. Schaeffer explained.
“We made changes in version 1.2022 that I thought were appropriate, but we didn’t do a good enough job in explaining those changes. Now our document reflects why we made the changes we did,” Dr. Schaeffer said.
Experts who were not on the NCCN panel discussed the different processes involved in developing the American Urological Association (AUA) Clinical Practice Guidelines vs the NCCN Guidelines. The AUA Guidelines were last updated 7 years ago and involve more formal deliberations and steps. They are considered by many not to be as fluid or responsive in “real time” to changes in the prostate cancer landscape.
Ashley E. Ross, MD, PhD
As opposed to other guidelines, including the AUA Guidelines, “the NCCN Guidelines provide rapid updating and are more fluid. Because of the process, the discussion section lags behind the recommendation. The discussion in version 2.2022 shows that the panel reacted to the need for more explanation. Footnote V provides important information about the heterogeneity of low risk. The discussion is still in progress,” said urologist Ashley E. Ross, MD, PhD, Associate Professor at the Northwestern University Feinberg School of Medicine, Chicago.
Reacting to the initial step of removing the word “preferred” for active surveillance, Tomasz M. Beer, MD, FACP, Deputy Director of the Oregon Health & Science University (OHSU) Knight Cancer Center, commented: “This was a disappointment, and it felt like a step backward, weakening the case for active surveillance. It was still recommended and encouraged in the text. Active surveillance is an important approach that reduces overtreatment. It wasn’t a 180° turn; it was a small subtle change, but I couldn’t figure out why it was made. It felt a bit mysterious.”
Dr. Beer continued: “I would encourage the panel to spell out more clearly why a change was made.” (Dr. Beer was interviewed before the panel provided further supportive evidence.)
Active surveillance is an important approach that reduces overtreatment.— Tomasz M. Beer, MD, FACP
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“The NCCN panel went back and provided more clarity. Active surveillance is preferred for most patients, but low-risk prostate cancer is heterogeneous, and certain factors are associated with disease progression. The table provided looks at large surveillance studies and shows the knowledge gaps. Most of the studies had a selection bias, a ‘blind spot’ if you will, because men who were very close to being at very low risk were included. This information allows a more nuanced discussion with patients about markers of risk,” Dr. Ross said.
Patient Advocate Perspective
Charles Ryan, MD, President and Chief Executive Officer of the Prostate Cancer Foundation and a faculty member at the University of Minnesota, was pleased to see that the NCCN panel reacted to the outcry in the prostate cancer community about the removal of the word “preferred” for active surveillance.
“The issue around the treatment of early-stage prostate cancer is complicated and decisions need to be made in a risk-adapted fashion based on biologic factors,” Dr. Ryan explained. “Inclusion of the word ‘preferred’ is recognition that not all men require treatment. In fact, many men may experience clinical benefit through an approach that involves active surveillance, with serial testing, imaging, and sometimes biopsies.”
Charles Ryan, MD
“At first, we were alarmed because we couldn’t trace why the word was removed. This led to a discussion among the experts on the panel. It is important that the guidelines reflect what the panel thinks based on available evidence. I was frankly comforted by version 2.2022 to see the “preferred” status was restored for active surveillance. This continues to highlight the importance of risk-adapted therapy and the opportunity for many men to participate in active surveillance Dr. Ryan stated.
DISCLOSURE: Dr. Klotz, Dr. Schaeffer, and Dr. Ryan reported no conflicts of interest. Dr. Ross reported financial relationships with Astellas, Bayer, Blue Earth, Lantheus, Myovant Sciences, Pfizer, Janssen, and Veracyte. Dr. Beer has received institutional grants from Alliance Foundation Trials, Astellas Pharma, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Endocyte, Freenome, Grail, Harpoon Therapeutics, Janssen Research and Development, Medivation, Sotio, Theraclone Sciences/OncoResponse, and Zenith Epigenetics; has received personal fees from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squib, Clovis Oncology, Constellation, GlaxoSmithKline, Grail, Janssen, Merck & Co, Myovant Sciences, Novartis, Pfizer, Sanofi, and Tolero; and has stock ownership in Arvinas and Salarius Pharmaceuticals.