expert roundtables

Osseous Metastasis in Metastatic Castration-Resistant Prostate Cancer

by Peter R. Carroll, MD, MPH, Neal D. Shore, MD, FACS

Overview

Transition to metastatic disease in patients with prostate cancer is a seminal event in the treatment paradigm. Clinical data have shown that approximately one-third of men with M0 castration-resistant prostate cancer (CRPC) actually have metastatic disease. There have been several new and effective treatments for this stage of disease, recently approved, that are proven to extend life. Identifying metastatic disease earlier could enable earlier intervention with these new therapeutic options to potentially improve outcomes. Unfortunately, there are no clear-cut guidelines on the type and timing of imaging to identify metastatic disease. Top experts in the field discuss identification and treatment strategies for bone metastasis in metastatic CRPC (mCRPC).

Q:

What is the importance of osseous metastasis in mCRPC, and are bone metastases under-reported?

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

Bone is the primary site of metastases. One could say there is an importance to visceral metastases as well. You may select chemotherapy of one type, such as chemotherapy for those with visceral-predominant disease, for instance, whereas with bone disease, you may do something a bit differently. I think all metastases are under-reported, and over the next 2-3 years I think we’ll identify them much earlier in the course of disease.

“I think all metastases are under-reported, and over the next 2-3 years I think we’ll identify them much earlier in the course of disease.”

Peter R. Carroll, MD, MPH

I think that with these advanced imaging techniques – positron emission tomography (PET) imaging, choline, gallium, and sodium fluoride – what you will see is that we will identify both bone-specific metastases as well as visceral metastases with greater clarity. We will also be able to manage patients based on the volume of the disease as well as the sites and biology of the disease.

Again, the 2 places this occurs is before initial treatment. So we will identify the metastatic sites in those patients who by standard technology – computed tomography (CT) and bone scan – were thought not to have metastatic disease. For those patients who had treatment, who were thought to have localized disease and the prostate-specific antigen (PSA) rises, we will identify the site(s) of disease and its extent with greater clarity, whether it be in the bone or soft tissues or a combination.

Neal D. Shore, MD, FACS

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

Bone metastases are a sentinel event in the development. We’ve known for over 100 years that the bone microenvironment is a very trophic milieu for adenocarcinoma cells from prostate cancer. Stephen Paget demonstrated this very nicely. There are various chemokines and trophic molecules that make the bone particularly inviting for prostate cancer cells. If we are following patients appropriately and optimally, and one could look at the recommendations we had from the RADAR guidelines paper, we would capture the development of bone metastases as well as non-bone metastases fairly early on. We need to do a good job of querying our patients and their caregivers regarding any potential for symptoms of bone metastases, which certainly would include pain-related development, but often symptoms from bone are not just a binary phenomenon of pain/no pain. Symptoms from bone metastases can include worsening of movement and inability to do normal, enjoyable activities, from walking up and down stairs, getting in and out of the car, swinging a golf club or a tennis racket, or doing daily house chores such as mowing the yard or taking out the trash. Often this is because of discomfort or fatigue related to these bone metastases, without the outright acknowledgment of pain, which patients should be queried on. These are indeed, as studies and publications have shown, real symptoms related to bone metastasis. And it is here where certain antiresorptive therapies can be of benefit, such as the bisphosphonates, or denosumab, as well as other therapies that can be life prolonging and reduce the risk of skeletal-related events. Denosumab and bisphosphonate work on preventing skeletal-related events. Therapies such as radium-223, enzalutamide, and abiraterone not only prolong survival but can also reduce the risk of skeletal-related events.

“Therapies such as radium-223, enzalutamide, and abiraterone not only prolong survival but can also reduce the risk of skeletal-related events.”

Neal D. Shore, MD, FACS

Regarding bone metastasis, I have really worked harder – myself and my nurses, who work with patients with advanced prostate cancer – to ask them questions beyond whether they are having pain or not, as it relates to their daily activities, their sleep patterns, etc. We also ask their caregivers, which invariably are their spouses. Often the spouses will relate symptoms that the patient may be reluctant to mention. Sometimes patients are reluctant to talk about it for fear of not appearing strong, or maybe they are afraid that another therapy may be offered that might have associated adverse events for it, or maybe they just want to please the physician. There are a multitude of concerns that must be overcome so that we make sure patients get the right therapy at the right time.

I do think there may be a role for earlier use of some of these agents. The 6 therapies we have been discussing have all been approved in the CRPC state – that was the pathway for approval with US Food and Drug Administration (FDA) and European Medicines Agency (EMA), based on a survival endpoint. There is no doubt now, with evidence from STAMPEDE and CHAARTED, that giving taxane-based therapy in the high-volume, newly diagnosed androgen-sensitive metastatic state is of benefit. Potentially using enzalutamide, abiraterone in patients prior to developing CRPC – and for that matter sipuleucel-T and radium-223 for patients who have bone metastatic disease while androgen sensitive – these are just all unanswered questions where we don’t have enough evidence at the current time. But it surely is provocative to think that we could be impacting disease progression for these patients with these drugs that clearly have mechanisms of action that work in more advanced disease states.

“But it surely is provocative to think that we could be impacting disease progression for these patients with these drugs that clearly have mechanisms of action that work in more advanced disease states.”

Neal D. Shore, MD, FACS

References

Crawford ED, Petrylak DP, Shore N, et al. The role of therapeutic layering in optimizing treatment for patients with castration-resistant prostate cancer (RADAR II). Urology. March 13, 2017. pii: S0090-4295(16)31023-8. doi: 10.1016/j.urology.2016.12.033. [Epub ahead of print].

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.

Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1889;1:571-573.

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

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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