expert roundtables

Defining Oligometastatic Disease and Treatment Implications

by Peter R. Carroll, MD, MPH, E. David Crawford, MD, Leonard Gomella, MD, and Neal D. Shore, MD, FACS

Overview

In the treatment of prostate cancer, there is little consensus on the criteria to define oligometastatic prostate cancer (OPC). This is in part due to a lack of good data to quantify its frequency, and few guidelines exist for treating OPC. As such, a definitive treatment strategy for OPC currently remains uncertain. Top experts in the field discuss the evolving definition of oligometastatic disease as well as the imaging and treatment implications.

Peter R. Carroll, MD, MPH

Ken and Donna Derr – Chevron Distinguished Professor
Taube Family Distinguished Professor in Urology
Department of Urology
UCSF - Helen Diller Comprehensive Cancer Center
University of California, San Francisco
San Francisco, CA

I might just lead with a few general comments regarding the reality of prostate cancer in 2017. I believe the negative public pressure on prostate-specific antigen (PSA) screening will be tempered, but it will not go away. I do think that screening does decrease prostate cancer-specific mortality, but it is fair to say that it does so at the expense of over-detection. The field is moving very rapidly to try to limit the detection of low-risk disease, especially in those patients who have no disease, but an elevated PSA. As a consequence, fewer biopsies will be done, and biopsy schemes will be planned in a way to maximize the detection of high-risk disease and minimize the detection of low-risk disease. Active surveillance, although increasingly seen as a safe alternative, will be challenged by focal forms of treatment, I think to the detriment of men with low-risk disease.

"Active surveillance, although increasingly seen as a safe alternative, will be challenged by focal forms of treatment, I think to the detriment of men with low-risk disease.”

Peter R. Carroll, MD

I think increasingly relevant to this discussion is that prostate cancer is seen as a spectrum of disease, and we will be moving relatively rapidly to what most people would characterize as precision oncology. Precision oncology is treating the right patients at the right time with the right sequence of therapies. And this is all going to result in improved survival.

“Precision oncology is treating the right patients at the right time with the right sequence of therapies.”

Peter R. Carroll, MD
Q:

How do you define oligometastatic disease, and how has this definition evolved over the years?

Peter R. Carroll, MD, MPH

Ken and Donna Derr – Chevron Distinguished Professor
Taube Family Distinguished Professor in Urology
Department of Urology
UCSF - Helen Diller Comprehensive Cancer Center
University of California, San Francisco
San Francisco, CA

I think that the operational definition of oligometastatic disease is going to change as we use new forms of imaging. Some people will say 2 to 3 sites of metastases; others will say as many as 5 sites. But these are rather arbitrary definitions, and I think with new imaging technology and new forms of treatment, this operational definition will change. But in general right now it is between 3 and 5, based on bone scan and positron emission tomography (PET) scan. But as we are getting into new forms of therapy, that number may change. And it may also be defined based on biology, where the metastases are, their size, and whether or not they are symptomatic. So, I think we will evolve into a more global definition – it won’t simply be a number; it’ll be replaced by phenotype and biology.

“Some people will say 2 to 3 sites of metastases; others will say as many as 5 sites. But these are rather arbitrary definitions, and I think with new imaging technology and new forms of treatment, this operational definition will change. But in general right now it is between 3 and 5, based on bone scan and PET scan.”

Peter R. Carroll, MD

Oligometastatic_Definition

Neal D. Shore, MD, FACS

Medical Director and CPI Carolina Urologic Research Center Managing Partner, Atlantic Urology Clinics
Myrtle Beach, SC

Oligometastatic disease is a very controversial, yet important, disease state diagnosis in 2017. One can think of 2 discrete buckets of patients: The first bucket would be patients who are newly diagnosed, presenting with disease outside of the prostate. We have typically defined patients as having high-volume vs low-volume disease. The oligometastatic category would be the low-volume patients, and most would use the definitions that were used by the CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials, suggesting that oligometastatic disease or low-volume disease for newly diagnosed patients would be <4 metastatic lesions and no visceral metastases, as well as the presence of soft tissue-only disease, specifically lymph node involvement. There is a second bucket of oligometastatic disease that can develop in patients who have had the primary treated – in other words, the prostate was removed and/or irradiated – successfully – and then the patient develops a relapse of disease with 1 to 3 lesions that are demonstrable radiographically. So, that’s another bucket of patients who have oligometastatic disease.


Oligometastatic_OPC

Heretofore, both buckets of patients have been treated with systemic therapy, traditionally with androgen-deprivation therapy (ADT). To date, the CHAARTED trial, using a combination of ADT with 6 cycles of taxane-based therapy, demonstrated significant improvement in overall survival in patients with high-volume disease. There is still controversy as to whether or not patients with low-volume disease would benefit.

Leonard Gomella, MD

Chairman, Department of Urology
Bernard W. Godwin, Jr. Professor of Prostate Cancer
Sidney Kimmel Medical College
Sidney Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, PA

This is becoming a new concept in the management of a lot of cancers, including prostate cancer. Right now for prostate cancer, oligometastatic disease is probably 3 or fewer lesions, based on several important studies that have been performed over the last couple of years, looking at tumor volume. Other studies have used 5 or fewer lesions as defining oligometastatic disease, but I think some of the best data support the use of 3 or fewer lesions, outside of the primary. This definition uses our current standard imaging techniques, essentially your standard computed tomography (CT) scan with and without contrast, or magnetic resonance imaging (MRI), and a standard technetium-99m (Tc-99m) bone scan – that’s the current way we are defining oligometastatic disease. It doesn’t matter where the site is in the definition of oligometastatic disease – it could be up in the humerus, the upper abdomen, or nodes. The definition almost, in my opinion, sort of excludes visceral metastases in that if a patient has something in his liver, even if it is one big lesion, I don’t think that is considered oligometastatic using the most current definitions.

"This definition uses our current standard imaging techniques, essentially your standard CT scan with and without contrast, or MRI, and a standard Tc-99m bone scan – that’s the current way we are defining oligometastatic disease.”

Leonard G. Gomella, MD, FACS

E. David Crawford, MD

Professor of Urology
University of California, San Diego
Former, Distinguished Endowed Professor of Surgery, Urology, and Radiation Oncology
Head, Section of Urologic Oncology
University of Colorado Anschutz Medical Campus
Aurora, CO

Absolutely. I agree. And this whole concept of oligometastatic disease is not entirely new. We’ve known from other cancers that management of the primary with limited metastases improves the outcome. I was first exposed to this when I moved to Denver in the late 1980s and inherited a bunch of patients who had been treated by an “older urologist.” Back then, the interventions included things like bilateral orchiectomy and estrogens because we didn’t really have luteinizing hormone-releasing hormone (LHRH) agonists; they were just sort of beginning to enter practice at that time. Doctors would radiate, with 1 or 2 metastases in the spine. I’d be incredulous, wondering what the heck they were doing, radiating metastases in the face of metastatic disease. But you know what? I’d inherit these patients and I’d follow them for several years, and many of them would live for 10 plus years, and after a while I began to see that these guys were really onto something. And as Dr Gomella just defined, that was really oligometastatic disease – 2, 3, 4 metastases – and they were being aggressive in treating those and the primary.

As we go forward, there is a lot of interest in treating the primary and evidence of the primary serving as a repository for further metastases and further development of more aggressive disease. In dealing with patients with metastatic disease, when you treat them with hormone therapy, we know that in the bulk of patients, the primary will sort of dwindle away. When you do a rectal exam of patients dying of metastatic disease, you often don’t really feel anything – but in perhaps one-third of the patients, you do – so maybe they’d benefit. So, there is all this interest right now in doing radical prostatectomies and things like that for the primary. I think what we have done in treating the primary for a very long time is to use “not too aggressive” techniques, with things like cryotherapy and radiation therapy. There is an androgen release that occurs with these techniques, and there is an interest in that right now. So, this whole thing about oligometastatic disease has been around for a while, but it is only recently that we really defined it and thought about some of the things you can do to deal with it.

We actually dealt with this in one of our early Southwest Oncology Group (SWOG) trials on combined androgen blockade: we used the classifications of minimal disease and severe disease. Minimal disease is sort of what we are talking about with oligometastatic disease – people with minimal axial skeletal involvement vs more severe disease that would include lymph nodes, liver, and things like that. We used to count lesions on bone scans, try to quantify them and then associate that with survival rates. It sort of worked, and then it didn’t work, and then PSA came into play. Despite the vagueness and differing definitions, oligometastatic sort of implies, in my opinion, that you have disease that is not too severe and that we could apply some sort of ablative techniques or other treatments to the lesions as well as the primary.

Q:

How do newer imaging techniques factor into the evaluation of oligometastatic disease?

Peter R. Carroll, MD, MPH

Ken and Donna Derr – Chevron Distinguished Professor
Taube Family Distinguished Professor in Urology
Department of Urology
UCSF - Helen Diller Comprehensive Cancer Center
University of California, San Francisco
San Francisco, CA

That is an area that is moving relatively quickly. We have been doing the gallium positron emission tomography (PET) imaging now for probably 1-2 years, scanning hundreds of people. In my opinion, novel forms of PET imaging will replace the standard imaging. Obviously, we’ll have to get the view of the US Food and Drug Administration (FDA) on this, but it is clear in my mind that there is value. Now, we need to do the right trials to demonstrate that there is value – randomized trials of PET imaging before surgery or radiation, to see influences on outcomes and biochemical-free survival – but I think there is great enthusiasm for these imaging techniques. In my opinion, and I have been doing this for a while, this new imaging has really changed my sense of what prostate cancer is.

Neal D. Shore, MD, FACS

Medical Director and CPI Carolina Urologic Research Center Managing Partner, Atlantic Urology Clinics
Myrtle Beach, SC

How we define metastatic disease with our imaging techniques is a very important question. Historically, we have relied in the last 3 decades on Tc-99m bone scan imaging, and I think that is still the case in the overwhelming majority of clinical sites throughout the world. That said, I agree there is a rapidly evolving use of different molecular tracers and PET scanning. Over the years, we started with fluorodeoxyglucose (FDG)-PET, carbon-11 acetate (C-11 acetate), C-11 choline radiotracers, and sodium fluoride PET scanning, and all of these have demonstrated some improved accuracy in detecting either soft tissue or bone lesions, depending upon their targeted focus. Most recently, there has been tremendous interest in gallium prostate-specific membrane antigen (PSMA) scanning, as well as a new test known as the FACBC (anti-1-amino-3-[18F]-fluorocyclobutane-1-carboxylic acid) or AXUMIN (fluciclovine F 18) test that was recently approved in the United States by the FDA, manufactured by a company known as Blue Earth Diagnostics. There are multiple companies that have gallium PSMA scanning. Additional radiographic testing that can be very sensitive, with improved specificity, and thus more accurate in picking up smaller lesions, in both bone and soft tissue, is whole-body MRI. One of the challenges regarding these newer tests is both accessibility as well as affordability throughout the global community.

Oligometastatic_Evolution

References

James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.

Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737-746. 

US Food and Drug Administration. FDA approves new diagnostic imaging agent to detect recurrent prostate cancer. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503920.htm. Accessed August 3, 2017.

Yu EY, Li H, Higano CS, et al. SWOG S0925: a randomized phase II study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2015;33(14):1601-1608.

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