In this blog PCRI presents an interview from our contributing partner, Prostatepedia. 

Prostatepedia spoke with Dr. E. David Crawford at length about bone metastases in prostate cancer. Here is the interview:

When do bone metastases normally occur in prostate cancer? In newly diagnosed men or in men whose cancers have come back after treatment?

Dr. E. David Crawford: It has been known for decades that prostate cancer has a predilection to spread predominantly to bone. This distinguishes prostate cancer from most other cancers, although some cancers do spread to bone.  Not only do you have the risk of prostate cancer spreading to bone when it progresses, but one of the more common treatments that we  use, hormonal therapy, has a pronounced effect on bone and can cause bone thinning, osteoporosis, and the risk of developing fractures. This propensity of prostate cancer to spread to bone brings to mind English surgeon Stephen Paget’s “seed and soil” theory. Paget’s theory was that the seed, which is prostate cancer itself, preferentially goes to bone because the soil there is ripe for prostate cancer to grow. 

Does hormonal therapy make bone more susceptible to cancer spread?

Dr. Crawford: That is a great question and one that is in the back of many people’s minds. I think that you can alter the soil so the seed  doesn’t implant, but that remains to be proven. The only trial that really addressed that question was a clinical trial with Xgeva. They gave Xgeva to men with nonmetastatic castrate-resistant prostate cancer and a rapid PSA doubling time to see if they could delay the cancer from spreading to bone. In fact, Xgeva did delay the spread to bone by four to six months. The FDA didn’t approve the agent because there was a 4% increased risk of osteonecrosis of the jaw and because of cost, among other issues. That was too bad because it would have been a benchmark to have a drug for nonmetastatic castrate-resistant disease. We don’t have anything approved in that arena  right now.

I just finished the IMAAGEN study with Janssen Biotech looking at Zytiga in men with nonmetastatic prostate cancer in biochemical failure—i.e. their PSAs had started to rise. It looks like Zytiga does delay progression to bone metastases and improve survival rates, though it is important to keep in mind that our trial was not a large randomized trial, but a large Phase II trial. But the interesting thing about the trial is that in about 40% of men whom we thought didn’t have metastatic disease, we found bone metastases upon scanning. Those are bone metastases that might have been missed. We presented that paper  at the annual meeting of the American Urological Association  this year and won one of the “Best of Posters” distinctions. I was excited about that.

How and when are bone metastases usually detected? 

Dr. Crawford: There are two buckets of patients.  In the first bucket are patients who have bone metastases at initial diagnosis. In the second bucket are prostate cancer patients who had hormone therapy with radiation or for rising PSAs and are now refractory, or as we call them right now, castrate-resistant. They now have non-metastatic castrate-resistant prostate cancer and have developed bone metastases. We now have a variety of new drugs for men with castrate-resistant metastatic prostate cancer. 

Bone disease is a seminal event.  Our ability to detect bone metastases is somewhat limited. You’ve got to have a lot of bone destruction, 30 to 40%, before we can see something on a standard bone scan. 

For that second bucket of patients, the non-metastatic castrate-resistant prostate cancer, when to scan for bone metastases is under discussion. Two years ago we convened a group  of experts called The RADAR Group.  We discussed that bone metastases in castrate-resistant metastatic disease is a seminal event for instituting many of the newly approved drugs. Most of these men don’t have any symptoms, so how do you know what to look for? The RADAR Group came up with an algorithm to help determine the best time to scan.

When to scan is important, because we want to detect metastatic disease at a time when we can institute newer drugs like Zytiga, Xofigo, Xtandi, Jevtana, and Provenge.
Why? Let’s use Provenge as an example. If you use Provenge earlier in disease progression, when men have a lower PSA (such as 22 ng/dl with metastatic disease), men actually lived 13 months longer. This is true with a lot of the other drugs we use: with Xofigo, Zytiga, and Xtandi. Men with lesser disease do better. 

How do you treat bone metastases?

First, we have drugs we use with hormone therapy to prevent osteoporosis: drugs like Xgeva, Fosamax, and Zometa. These drugs do two things. First, they prevent osteoporosis, because most of them paralyze the osteoclast so it doesn’t chew up the bone. Second, these drugs can help prevent skeletal-related events, such as fractures, the need  for surgery and radiation, etc., in patients who have bone metastases. 

There are three really nice studies on Xgeva. One study looked at Xgeva’s ability to prevent cancer treatment-induced bone loss. The study showed that Xgeva prevented osteoporosis. In another study, which I spoke about earlier, Xgeva prevented bone metastases from occurring in people who didn’t already have them and were castrate-resistant. 

The bisphosphonate Zometa decreases skeletal-related events in men who already have bone metastases and are on hormone therapy or who are castrate resistant. That is significant. These skeletal-related events can cause morbidity, spinal cord compression, and other significant events. A third trial with Xgeva prevented skeletal- related events, and was better  
than Zometa.

What about the radiopharmaceuticals?

Dr. Crawford: It all started with radioactive phosphorous when I was a resident. Radioactive phosphorous worked, but wiped out the bone marrow  and so men were at risk of developing severe bone marrow depression. Then along came strontium-89 and samarium. These two drugs are beta emitters, which are small radioactive particles. One of them has been shown to reduce pain, but has never been shown to improve survival rates. Both strontium-89 and samarium were used in a few studies over the years, but not to the same degree as radioactive phosphorous. We used them anyway, because we didn’t really have any other agent to use in men with bone metastases. 

Now we have an agent that actually helps keep people alive: radium-223, or Xofigo. Radium-223 emits an alpha particle, which is hundreds of  times larger than a beta particle.  
For comparison, if a beta particle is the size of a BB, the alpha particle is the size of a Ping-Pong ball. The alpha particle carries more  punch and causes double-stranded DNA breaks and cell kill, but it doesn’t penetrate the bone marrow a lot, so you don’t get neutropenia and thrombocytopenia and the like that you do get with strontium-89 and samarium. 

Xofigo works. In the study in which Dr. Sartor and his group participated, the drug worked unbelievably well. When I got a call about four years  ago right before Christmas saying that they were stopping the trial, I said, “That’s too bad; I’m really sorry  to hear that,” because I thought it was over. But the medical director  said, “No, we’re stopping it early,  because there is a survival benefit.”  That was a shock: a radiopharmaceutical that improves survival rates? Xofigo worked. 
In the beginning, we had pegged radiopharmaceuticals like strontium-89 and samarium for people who were circling the drain and failing everything. Xofigo is a real step forward.
I think Xofigo ought to be used earlier in disease progression. We shouldn’t wait until somebody is writhing in pain or is opioid-dependent before using Xofigo. We have evidence that Xofigo prevents skeletal-related events. It improves survival rates and outcomes. It’s easy to administer. You don’t have to interrupt any of your other therapy to use it. 

Are there any risks to some of the medications used for bone metastases? I’ve heard about osteonecrosis of the jaw.

Dr. Crawford: Osteonecrosis of the jaw usually occurs with bisphosphonate use in 1 to 2%  
of people on chemotherapy and with more advanced disease. Before you go on a bisphosphonate, you need  to get a good dental evaluation and you need to maintain good dental hygiene practices during treatment.  The truth is, when you have advanced cancer you don’t have a lot of choices. A little osteonecrosis of the jaw is certainly not a good thing, but sometimes it beats the alternative. 

Osteonecrosis of the jaw is what killed that study on Xgeva’s ability to delay bone metastases in men with castrate-resistant nonmetastatic cancer and rising PSAs. They found around 4% of relatively asymptomatic men had osteonecrosis of the jaw. The FDA figured the osteonecrosis of the jaw wasn’t worth the benefit of a few months’ delay of metastatic disease. I’m not sure patients would make that same choice. Would you take a 4% increased risk of having osteonecrosis of the jaw in exchange for delaying bone metastases four to six months? I think most people would have said yes, but they didn’t ask patients.

How expensive are these medications?

Dr. Crawford: That is a real issue and we’re seeing a lot of pushback right now. All these new agents—Provenge, Zytiga, Xofigo, Xtandi, Taxotere, and Jevtana—are expensive.
Some of the agents, like Provenge, are very expensive to produce. Others are not expensive to make. 

Is there anything else you think patients concerned about developing bone metastases, or those who have already developed them, should know?

Dr. Crawford: I think bone is an extremely important target in prostate cancer and bone health  is very important for aging men.  Most men on hormone therapy or those who have prostate cancer should be on  both vitamin D and Calcium. Men should also consider doing weight-bearing exercises.

Men on hormone therapy need to consider going on a bisphosphonate, or at the very least get a bone mineral density evaluation before you start on hormonal therapy and a second six months to a year after treatment has started. An oral bisphosphonate may be enough, though oral bisphosphonates can cause esophageal problems. (If you lie down, it can cause reflux, so you may need to stand up for a couple  of hours after taking it.)

It is also important to monitor your bone. Men with metastatic lesions in the femur and humerus need to be watched very carefully so  they don’t get a pathologic or osteoporotic fracture. 
There is pretty good evidence that some of the more active bisphosphonates like Zometa or Xgeva should be used in men who have bone metastases and are on hormone therapy or chemotherapy. You can argue about should the dose be monthly or every three months. Most of the studies have been done with the one-month option. 





For more interviews with prostate cancer experts from Prostatepedia, click here. 

Prostatepedia, a division of Rivanna Health Publications, has a single mission: to help leading prostate cancer researchers explain their work and its implications to prostate cancer patients, activists, and health care providers. Formerly known as Prostate Forum, Prostatepedia, their monthly periodical, features informal conversations with leading experts.

E. David Crawford is the distinguished Professor of Surgery, Urology, and Radiation Oncology, and head of the Section of Urologic Oncology at the University of Colorado Anschutz Medical Campus.