Bone Versus Visceral Metastases in mCRPC

Daniel J. George, MD:For patients with advanced stage prostate cancer who go on to have recurrence and ultimately develop metastatic disease, typically in the castrate-resistant setting, the vast majority will develop osseous metastatic disease—probably 80% to 90%. What’s interesting is that there’s probably a group of patients, as high as 50%, for which osseous metastatic disease is their first presentation of metastasis. The group of patients who start with osseous metastatic disease are more likely to develop more osseous metastatic disease in the future. This is really important. In my mind, that disease becomes the new primary disease. Their primary tumor may have been removed or radiated. That’s not the source of further spread; it’s the bone.

The new bone lesions, or that new site or primary disease is going to be what causes the progression in bone to other lesions as well as extra osseous spread of disease, eventually. What’s concerning is that those patients can ultimately develop visceral disease, not just lymph node disease.

There’s a group of patients who first develop metastatic disease in lymph nodes, sometimes only in lymph nodes, who have a very good prognosis. But there is this larger group of patients who develop osseous metastatic disease, particularly as a first presentation, for which I’m concerned will be the driver of their morbidity and mortality.

Visceral metastases are really concerning to us because this is a disease that historically doesn’t start in those settings, except in the cases of variant histologies. Neuroendocrine cancers or anaplastic prostate cancers, those that make very little to no PSA [prostate specific antigen]—sometimes those patients will present more frequently with visceral metastatic disease.

Small, subtle lung nodules are a form of visceral metastatic disease that don’t carry a worse prognosis than bone metastasis. So, even within visceral disease, I’ll kind of subdivide those. It’s really the liver and other visceral organs that we’re most concerned about as being a source of early mortality associated with visceral disease, but that’s a small percentage of patients. That’s probably just 5% to 10% of patients. The majority of our patients with metastatic disease are going to present in the bone either initially or subsequently. It’s really that bone burden that drives the morbidity and, ultimately, the mortality of this disease in the majority of these patients.

Back to this case; this was a patient who had, as I described, an accelerated course of disease—from localized disease to bone metastasis. It’s not coincidental that the symptoms for this patient really coincided with the development and progression of bone metastases. When I see symptoms in patients, and they can be subtle, like, in this case, some lower back pain that might be mild and managed with non-narcotic analgesics, or fatigue, or other kinds of generalizable symptoms like weight loss or loss of appetite, I start thinking more about bone metastatic burden. Rarely will those patients have visceral disease as their primary site of metastasis. Most of the time we’re seeing those patients present with increasing progressive bone metastasis.

Pain is traditionally associated with that, but that’s not the only symptom. In fact, it’s probably not the most common symptom. Some of these other symptoms, to me, are really indicators of that osseous metastatic burden. When I see that, I think about inflammation. Those are all consequences associated with inflammation, either locally or systemically. Inflammatory prostate cancer is ultimately what we need to treat. Treating it both within the bone and systemically is really critical.

It’s an exciting time right now, in terms of imaging for prostate cancer. We’ve been stuck with bone scans for 60 years and CT [computed tomography] scans, probably, for 30 or 40 years. We haven’t really made a lot of progress in the imaging of this disease, and it’s problematic because, at the end of the day, what we are really measuring is an indirect measure of the cancer or an incomplete measure, when it comes to soft tissue disease of the cancer. And so, we’re really sort of left in the dark with what’s happening at the molecular and biologic levels of this disease.

Right now, we’re at the early stages with these newer molecular PET [positron-emission tomography] images, with either Axumin, PSMA [prostate-specific membrane antigen] PET, choline PET, or FDG [fluorodeoxyglucose] PET. I think we’re going to see more and more of these approaches in the future. This is not the end of this era. I think it’s just the beginning. It’s going to really help us do, I think, 2 things. It’s going to help us begin to start to subcharacterize these prostate cancers, not by their sites of disease but by their biology. And so, rather than thinking of lymph node-only, it may be PSMA-only, where all of the disease sites are PSMA-positive versus one that might be mixed or one that might be relatively low.

The other piece that’s going to help us is understanding the impact, in terms of therapy. This can guide our treatment approaches. Not just initially for a PSMA-positive tumor, but also in terms of disease progression; what does that disease progression look like? Is there a different marker that’s evolving in that setting? And so, as we develop more and more of these tools, it’s going to be helpful for us to be more precise in our therapeutics. It’s also going to make things a bit more clear, in terms of the mechanisms and selection of resistance that’s developing in this setting.

Transcript edited for clarity.

mCRPC Treated With Radium-223 Therapy

January 2015

H&P:

• A 71-year old gentleman presented with urinary incontinence
• Past medical history: HBP controlled with lisinopril
• On digital rectal examination prostate was enlarged
• Patient was asymptomatic

Imaging:

• Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland with a Gleason score 9 [4+5] with 9 of 12 cores positive
  • PSA, 10.2 ng/mL
• CT scan was negative for metastases
• He was started on a 3-month depot injection of leuprolide 22.5 mg and treated with 7800 cGy IMRT

April 2016

• Patient returned for 3-month injection; his PSA level increased to 47 ng/mL
  • CT/Bone scans were negative for metastases
• He was started on enzalutamide
  • PSA, 12 ng/mL

October 2016

• 6 months later the patient complained of severe fatigue and lower back pain
  • Imaging with CT and bone scan showed multiple metastases of the spine and pelvis
  • PSA levels increased to 76 ng/mL
  • ALP, 268 U/I
• Radium-223 therapy was initiated in addition to continuing enzalutamide
• After 3 infusions of radium-223
  • PSA declined to 31 ng/mL
  • ALP decreased to 80 U/l
  • CT scan showed no new bone metastases
  • Fatigue decreased, and patient’s physical activity increased