A modest proposal? Relabel Gleason as a noncancer.

The pros and cons.

By Howard Wolinsky

Today, Drs. Scott Eggener, Matt Cooperberg, Alejandro Berlin, Gladell Paner, and Andrew Vickers entered the lion’s den with a modest proposal calling on the medical establishment to stop calling Gleason 6 prostate cancer.

I am joining them as a co-author/patient advocate diagnosed almost 12 years ago with very low-risk Gleason 6 who has spoken out on the need to rename this so-called “cancer” as noncancerous or precancerous. I speak for myself and TheActiveSurveillor.com, not any of the groups I participate in

We make our pitch in the Journal of Clinical Oncology in an article entitled “Low-Grade Prostate Cancer: Time to Stop Calling It Cancer.” The article is available here: https://ascopubs.org/doi/10.1200/JCO.22.00123

(Scott Eggener, MD.)

I have heard for years from experts like Eggener, my former urologist at the University of Chicago, saying Gleason 6 is never going to kill you and questioning whether Gleason 6 should be called cancer at all.

I once wrote a book on the future of pathology. I know the pathologist mindset very well. They are the most brilliant of all doctors. They also are sticklers for the rules.

(They tend to be introverted, too. Ask me to tell a joke about them.)

Gleason 6 looks like cancer to them. So cancer it is. I suspect that only 10-20% of pathologists could support renaming Gleason 6 as a noncancer or a precancer.

But they don’t deal with patients like urologists do in a long-term relationship in which the doctors observe the behavior of our prostates.

Urologists like Eggener see these “cancers” over time and have a sense of how they grow or don’t grow. I suspect that half of urologists favor renaming Gleason 6.

In December 2010, a urologist in the Chicago suburbs tried to rush me into an OR for a radical prostatectomy though I only had a single minimal core of “prostate cancer.”. Like most urologists then, he wasn’t a believer in active surveillance, close monitoring of the faux “cancers” with PSAs, biopsies, digital rectal exams, and MRIs.

I saw Eggener a few days later. He told me I was the “poster boy” for AS and predicted that I’d be the same in 10 years. He was right. That freakin’ cancer was seen only once in six biopsies and 20 PSAs and digital rectal exams, and two MRIs.

I switched doctors--I can explain why at another time. But Eggener and I stayed in touch, and he invited me to join the paper as a patient advocate (speaking for myself). (

I wrote about this issue a year ago in MedPageToday: https://www.medpagetoday.com/special-reports/apatientsjourney/90601)

In any case, I will share some quotes from the paper and then share comments from some of the top docs on the subject. This is a long article because I don’t want to edit what these doctors said. So take your time. You can read it in bits and pieces.

The C-word and Gleason 6 is a volatile issue. Change won’t come overnight. Docs are drawing lines in the sand.

I’d like you to share your opinion in the comments and answer the survey: “Should the cancer label be removed from Gleason 6?: https://www.surveymonkey.com/r/ZQHDQYK.

What does the paper say?

*Prostate-specific antigen (PSA) screening for prostate cancer (PCa) remains highly controversial, largely because it is unclear whether the primary benefits of reducing rates of metastases and cancer mortality are worth the risks of overdiagnosis, overtreatment, and potential treatment-related morbidity. 

*A major contributing factor to overdiagnosis and overtreatment of prostate cancer is the designation of a particular pattern of low-grade cellular changes in the prostate as cancer, Gleason 6, which, in our view, should not be called cancer.

*A simple terminology change for these lesions and removal of the cancer label would dramatically reduce overdiagnosis and overtreatment and markedly change the cost-benefit calculus of PSA screening.

*Although GS6 (Gleason Score 6) meets the pathologic criteria of a cancer (invasion of the stroma (supportive tissue)), without the simultaneous presence of higher-grade disease, it is effectively incapable of invading adjacent local structures or metastasizing. When a prostate is surgically removed and contains only GS6, there is essentially a 100% chance of remaining metastasis-free although the cancer has typically been present for years and often decades.

*Reclassification of GS6 would immediately lead to markedly fewer diagnoses of PCa; fewer men receiving radiation, surgery, and other treatments; fewer men experiencing treatment-related side effects; lower patient and family anxiety; and substantial reductions in financial burden to individuals and the health care system. No matter how much time a physician may spend downplaying the significance of a GS6 diagnosis or emphasizing the phrase low-risk, the words “you have cancer” have a potent psychological effect on most men and their families. 

*Other cancers, including Gleason 2-5, have had the cancer diagnosis removed. 

* Renaming GS6 is important for public health A sensible path forward requires input from many stakeholders, including pathologists, urologists, radiation oncologists, patients, and partners. The exact relabeling is not pertinent except for it not including cancer, as most people understandably associate the word with an aggressive and possibly lethal malady. Regardless of what tempering terms might be used, if the disease label includes cancer, it affects mental health, modulates decisions and behavior, and increases tolerance for treatment-derived toxicities. 

Other experts speak out

I wrote notes to the leaders in prostate cancer and asked what they thought about our modest proposal. I’ll run their responses verbatim.

Ming Zhou, MD, PhD, Pathologist-in-chief, Tufts Medical Center, Boston.

(Ming Zhou, MD, PhD)

Zhou is a preeminent pathologist. Last year, I invited him to debate Eggener at the AnCan Virtual Support Group for AS. The question was, “Is Gleason 6 cancer?”

Zhou was “pro.” Eggener was “con.” 

We asked the audience where they stood before the debate. The majority favored leaving the cancer tag on Gleason 6. However, after the debate, the majority favored renaming Gleason 6.

(Here’s the video: https://ancan.org/webinar-is-gleason-6-really-prostate-cancer-a-debate/)

Then, something remarkable happened. Zhou switched teams and supported renaming Gleason 6.

Here’s what he told me in response to the paper.

Zhou:

Gleason score 6 (Grade Group 1) prostate cancer meets the pathological criteria for cancer and some of them share molecular features with high-grade prostate cancer. However, it is time for pathologists to seriously consider renaming it as a lesion that will not invoke a strong response typically associated with a cancer diagnosis for the purpose of best management of these patients. 

I had a debate with Dr. Scott Eggener 8 months ago on this topic. His argument and the evidence he cited were persuasive and helped clear many of my questions and concerns. 

One of my biggest concerns is patients with Gleason score 6 (Grade Group 1) cancer detected in prostate biopsy, if no longer diagnosed as cancer, may not be followed up appropriately and may miss the window of optimal treatment. However, pathology is not the only factor that determines how these patients will be managed. They will be risk-stratified based on biochemical and molecular markers and imaging.

 I believe these tests will be able to identify patients at risk for high-grade cancer. 

My 2nd concern is the medicolegal one. Will pathologists be liable if a high-grade cancer is detected after a Gleason score 6 “noncancer” is rendered? But this will be analogous to an “ASAP’ diagnosed followed by a cancer diagnosis. 

The key is good communication between pathologists and clinicians and patients regarding the implications of a Gleason score 6 “noncancer” diagnosis. 

My final concern is how this change may impact patients who are already affected by health-care disparity in many parts of this country and the world. As patients with Gleason score 6 “noncancer” are followed with new biochemical and molecular markers and imaging studies, patients with poor resources are certainly disadvantaged from access to these new diagnostic tests. it is important to make sure this change will not further exacerbate this issue.

Todd M. Morgan, M.D. is a urological surgeon and Chief of Urologic Oncology at Michigan Medicine. Morgan last became a hero to the AS community when he stood up--almost alone--against a plan by the major guideline group, National Comprehensive Cancer Network, to put AS on a par with surgery and radiation. NCCN reversed itself. (https://www.medpagetoday.com/urology/prostatecancer/95949)

(Todd Morgan, MD)

Morgan:

This is an extremely well-written and well-reasoned commentary that is critically important for the field. I hope it serves as a tipping point. The article covers the critical points in favor of a nomenclature change as well as the key counter-arguments. While Gleason 6 disease may meet the current histologic criteria for being dubbed a “cancer,” the article makes a convincing case that the ends justify the means here – changing the name would undoubtedly lead to improved health outcomes, which is our main responsibility as physicians. If we look at the big picture rather than focusing in at 100X, I think it’s clear how much a simple change in terminology would positively impact patient care.

Peter Carroll, MD, MPH, Ken and Donna Derr – Chevron Distinguished Professor, Taube Family Distinguished Professor in Urology, Department of Urology, UCSF – Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

Carroll certainly is a hero to the AS community. He pioneered AS. But he is no fan of a name change for Gleason 6 because he feels it’s a minor point to bigger issues in the cancer world.

(Peter Carroll, MD)

Carroll:

I have been a very strong advocate for AS and started the program at UCSF and enrolled the overwhelming majority of patients and lead the most research with regard to this issue. I very much appreciate you sending this to me in advance of publication. I have not heard from Matt in advance. I think you miss broad issues with regard cancer care in general, this issue of over-detection extends weIl beyond prostate cancer and I think society needs a reset and measured approach to cancer in general (renaming prostate cancer is simply not enough).

Next up is Brian Helfand, MD, PhD, my current urologist, who is also a strong supporter of AS. We have disagreed before, but he usually has come along to my side. Maybe this time, too?

Brian Helfand, MD, PhD, Division Chief, Urology at NorthShore University HealthSystem; Clinical Associate Professor, University of Chicago.

(Brian Helfand, MD, PhD)

I can’t say I agree with your manuscript. You have been dealing with academic urologists where this is a no-brain situation. However, most of America will think that you can ignore [Gleason 6] because it’s not cancer. This has already been shown in watchful waiting [a different management approach], which failed many men.

William Catalona, MD, is Professor of Urology at Northwestern University’s Feinberg School of Medicine and the Principal Investigator on the Northwestern-based prostate SPORE since 2013.

Catalona is the dean of prostate cancer surgery. He trained doctors like Eggener and Helfand.

Back in 2011, he told me I ought to have a radical prostatectomy. Pronto. We were just chatting. In 2010, my 10th year on AS, he told me he had made a mistake in my case, but no others. He alludes to that in his comment below and his long-time relationship with Eggener.

(William Catalona, MD)

Catalona:

You are correct that I disagree with the authors. The main issue is the substantial biopsy sampling error rate – at least 50% of patients selecting AS are reclassified as having higher grade disease within 5-10 years. And more than two-thirds for those who have 4 or more biopsy cores containing cancer (Matt Cooperberg is a co-author on our recent SPORE project paper reporting that patients with > 4 cores of GG1 disease behave more like high-risk patients than like low-risk patients in terms of converting from AS to active treatment) convert to active treatment. 

As it is, it is difficult enough to maintain surveillance, as ~80% discontinue surveillance biopsies after undergoing a few (and MRI or genomic classifiers are not an adequate substitute). No doubt, this issue would be compounded if the patients did not think they actually had “cancer.”

Another important fact is that the molecular genetics of GG1 cancer are dissimilar from normal prostate tissue and the demonstration that patients can die of their GG1 focus further supports this concern. I suspect the “Dean” of prostate cancer pathology – Jonathan Epstein at Johns Hopkins - may agree with me on this point, and he is someone you should ask, if you want to write a balanced report. 

(Note: Epstein declined to comment on the JCO paper. He is writing a rebuttal to the journal article. But next up will be another prominent pathologist. If you read my MedPageToday.com article, you can hear his opinion. Nyet to change. But he is hugely supportive of AS.)

Knowing Scott Eggener, I am not surprised that he continues to seek the role of drum major for beating this drum. But I would be concerned that calling GG1 something other than cancer could usher in another decade or so of the Dark Ages of early prostate cancer detection that ultimately would be reflected in another increase in the prostate cancer mortality rates that we experienced with the 2010-2018 USPSTF debacle from which we are now just beginning to recover (the Task Force should upgrade their recommendation from “C” to “B” based on the current evidence, but it is unlikely they will.

Happily, you continue to remain in the 50% lucky cohort that have an indolent tumor. But I have seen many who were not so fortunate. Sound clinical judgment, coupled with careful follow-up and application of high-quality effective treatment when indicated would be “a far better thing.”

Massimo Loda, M.D.

Loda is David D. Thompson Professor Weill Cornell Medical College, and Chairman of Pathology and Laboratory MedicineWeill Cornell Medicine, Pathologist-in-Chief, New York-Presbyterian-Weill Cornell Medical Center

Loda:

Just to be clear, I’m totally against this unscientific concept.

BIOLOGY. First, it does not make any biological sense. In ALL organ systems, glands that have invaded through a basement membrane to infiltrate stroma are cancerous: they now have access to lymphatics and blood vessels and therefore the potential to metastasize. 

They also have the ability to invade: Gleason 6 is not infrequently locally invasive with extraprostatic extension. It has been reported that a Gleason 6 tumor [metastasized], demonstrating that morphology alone (Gleason 6) does not mean that something has no malignant potential.  Fig 1 [In the Eggener report] shows a mixture of in situ cancers (SIL, DCIS) with invasive cancers with low malignant potential (e.g. PUNLMP) in which “cancer labels” were removed: apples and oranges since the former are in situ cancers, the latter indolent: two different concepts. Other cancers do not metastasize and yet are still called cancer (e.g. basal cell carcinoma of the skin). 

TISSUE ANALYSIS. The threshold for cancer vs not cancer cannot be when there is Gleason pattern 4 present. First, the interobserver variability for Gleason grading is relatively low. More importantly, one could only say Gleason 6 is not cancer (which is not true) if there is ABSOLUTELY no Gleason pattern 4 present, which is something that can NEVER be proven because we don’t look at every single cell in the tissue, even in a radical prostatectomy. 

How does one know on a biopsy (which represents less than one-three thousand of the overall gland in a tumor that is inherently multifocal and heterogenous), that an invasive Gleason 6 is not part of something more ominous? How would these authors propose calling for instance a left apex biopsy showing Gleason pattern 6 when the left mid biopsy has a Gleason grade 7? Would one still say that the left apex biopsy isn’t cancer? It seems even more confusing to call something cancer when a GS7 is around but not when you don’t see/detect the GS7 which could be there. I could go on.

CLINICAL BEHAVIOR. This is the reason for the misunderstanding. Other neoplasms are also called cancer and are not definitively treated. It seems to me that one of the biggest reasons clinicians want to remove the “cancer” label from Gleason 6 is because it is confusing for patients and difficult to explain to them why the lesion doesn’t need to be treated or the patient should go on active surveillance. To me, this is unscientific.

How a cancer is treated will differ based on aggressiveness and the organ of origin, but just because patients have a hard time understanding this concept does not mean we should change our definition of cancer from a biological standpoint. Instead of advocating multidisciplinary diagnostic consortia to decide on how to name an invasive tumor (should we do the same with surgical procedures?) that only pathologists are capable of interpreting, we need to do better when it comes to patient education and changing patients’ preconceived notions that all cancer is inherently deadly and needs to be treated.

I’m confident Dr. Epstein will tear this manuscript apart.

****

We shall see. What do you think? Answer the survey above.

---

Finally… We have more than 300 registrants from 14 countries to the webinar, "Your Voice in the Future of Active Surveillance” on Friday April 22 at 11 am Eastern/5 pm CET.

Why not join us live? Or just register to get a link to the video?

Register  here: https://bit.ly/3ueT9bc