Radium 223: Counseling Patients With mCRPC

Jorge A. Garcia, MD, FACP: We’ll talk a little about what else we would tell our patient if we were to select radium 223 dichloride as the treatment choice for that particular moment in time, specifically for this patient. My discussion usually goes according to why I’m picking or selecting radium 223 dichloride. I obviously educate the patient about what options we have. It’s very hard to talk to patients and tell them you have 20 options, so I usually tell what I describe as the buckets of treatment, and I explain to the patient that the goal is to actually get exposed to all treatments that have a chance to be life-prolonging, meaning that have led to survival improvement. Then I explain to the patient why I would pick radium 223 dichloride in that particular case.

As I said earlier, it’s very important to actually explain to the patient that this agent works mechanistically in a different manner, again through the bone microenvironment. I know the mechanism of action is not specifically known. We do know it’s an alpha emitter, so it’s an alpha particle. It’s like a radionucleotide-based therapy, but these particles are big, they’re thick, and they have short penetrance. Basically what they do is they go to areas where there has been bone remodeling, and they compete in that space. They rerepair that vicious circle of osteoblast, osteoclast, and so on.

It is also important to remember that alpha emitters do have and do impact DNA. They actually break DNA, the double-strand DNA, contrary to the beta emitters where the single-strand DNA breaks. I also tell the patients about survival improvement. I talk to the patients about why fixating on the PSA [prostate-specific antigen] during the next 4 to 6 months of radium 223 dichloride may not be the most important feature of our follow-up. As I said earlier, I like to actually tell the patients that although in the ALSYMPCA trial scans were not mandated, I like to continue getting the scans. Although I can be criticized for saying bone scans and CT [computed tomography] scans, the reality of it is we don’t know what the impact of alpha emitters is. I just do it, to be honest with you, because I don’t want to lose a patient who is progressing rapidly without any symptoms, without any drastic PSA changes. Specifically we’re looking for visceral changes.

I tell my patients that it’s very important for them to know that the treatment roughly is going to be 4 to 6 months. In my personal practice, most patients can get 4 to 6 cycles of therapy. In fact, the median number of trials given in ALSYMPCA was 6, and the expanded access was between 4 and 6. I tell the patients that I’m going to be the quarterback of their chair, that I’m going to be using either radiation oncology or the nuclear medicine team to actually give the radium 223 dichloride, which is a pretty straightforward approach. In this case, you go to nuclear medicine, you get an IV [intravenous] push over 5 minutes of the infusion. But it’s very important for us to work cohesively as a team because I like to pay attention to blood counts obviously every month.

Every time the patient is coming to get radium 223 dichloride, I check the hemoglobin, the platelets, white blood cells, and neutrophils. But more important than that is also to recognize the fact that there are other things outside PSA that one can pay attention to. Alkaline phosphatase, which is either made in the liver or made in the bone, is a very good marker for bone disease when you see it elevated. Traditionally, 80% of men with prostate cancer will develop bone metastases, and a significant proportion of those patients will have an elevated alkaline phosphatase, which means they have active disease in the bones.

If you were to have a patient such as that, you could in fact pay attention to their alkaline phosphatase changes during the time where you’re treating them with radium 223 dichloride. This is because I would bet that if you look at the data and clinically speaking, almost half of patients who have wide response to radium 223 dichloride will have declines in their alkaline phosphatase levels if they had it elevated from the beginning. In fact, if you look at the correlation between alkaline phosphatase decline and PSA declines, at least I published that when I was a fellow in San Francisco, you can see that there is a natural parallel association between the decline of alkaline phosphatase and the declines in PSA. Sometimes you see also the opposite: when alkaline phosphatase is rising, your PSA is also rising.

In ALSYMPCA, approximately 30% of patients or so have alkaline phosphatase declines, so I think it’s a good way to also help navigate the lack of PSA reductions. If you have a patient who feels better, who is not having symptomatic progression, whose scans are stable but their PSA is creeping up a little, you can ensure the patient that they’re not symptomatic and their scans are stable. Yes, your PSA is going up a little, but look at your alkaline phosphatase. Your alkaline phosphatase is the opposite; it’s coming down. The fact that it’s coming down would represent, at least in my opinion, treatment effect.

It’s also important to recognize that having a baseline hemoglobin of a less than 10 or 10.5 g/dL will be important before you start radium 223 dichloride. You pay attention to it and every subsequent infusion, but it’s not a mandatory test that you have to actually do on a subsequent basis. It’s important for us clinically to do it so you’re not seeing the patient developing anemia, especially if the patient has been heavily pretreated in the past. The incidence of thrombocytopenia and/or neutropenia, as I said to you about the ALSYMPCA data, was around 1% to 2% in the chemotherapy-naїve patient population. I like to do it again because I don’t want to actually have any issues with thrombocytopenia or neutropenia in those patients. It’s a low likelihood, but it’s still something I like to pay attention to.

A concern from patients, especially male patients who are married, grandfathers, or fathers, there is always a connotation of radionucleotide-based therapy or radiopharmaceuticals. There is the thought that, “Am I going to be radioactive when I get home after I start my treatment?” The reality of it is, for radium 223 dichloride, if you look at the biodistribution—and I’m certainly not an expert in that data, at least in the biology of that data—you can see that within 4 hours, almost 95 if not greater than that of the material has been already been out of the system. It usually passes through feces. By the next day it’s pretty much gone or out of our body because it concentrates really in the bone.

There is some element of GI [gastrointestinal] adverse effects specifically sometimes stopping the stools. I really haven’t seen that in my practice, and I use quite a bit of radium 223 dichloride not only in the trial but also after FDA registration. I haven’t seen that. I think the most common cause, at least in my practice, of why people actually stop radium 223 dichloride is because they progress. This is for a small percentage of patients perhaps because they have some issues with low counts. I personally like to use radium 223 dichloride earlier rather than later.

But again, it needs the right patient phenotype, someone who’s not rapidly progressing. If you have someone who’s really crippled by pain because of prostate cancer in the bones, it is very hard for you—at least in my practice—to suggest to use radium 223 dichloride because time to pain control may not be a week. When it’s with docetaxel with cytotoxic therapy, you can control pain quite drastically and quite rapidly in a week, within the first week of therapy if the therapy is working. It may be better for those patients to concentrate weekly in controlling the disease, controlling the symptoms. Once you’re done with chemotherapy you can decide what to do with radium 223 dichloride. Certainly, in the context of those symptomatic patients, especially if you need rapid pain control, I prefer to start on cytotoxic-based chemotherapy.

There are patients who may have isolated bone progression, meaning that you may be able to actually use palliative radiation therapy to control bone pain. If you look at ALSYMPCA, radiation therapy was not excluded. Prior radiation therapy for pain control was not excluded in the trial. In fact, it was part what was allowed as best supportive care. I don’t do that, and I’ll explain why in a second. If you have someone who has isolated pain progression, you could actually consider giving that patient—or working with your radiation oncologists to give that patient—a little bit of radiation therapy for palliative purposes, and then move on to radium 223 dichloride. That would be perfectly reasonable because radiation therapy was allowed within that ALSYMPCA data.

I would argue that for those patients who may have still some degree of bone pain, if you feel they’re not symptomatically progressing on radium 223 dichloride, you could actually consider giving them radiation therapy while they are on radium 223 dichloride. I don’t tend to do that that much. I want to make sure that if I’m going to do radiation quickly, I’ll do it before I start treatment. If you need radiation therapy for palliative intent during therapy, to me that’s an element of progression unless I was preceding your treatment. If someone is on oral therapy, chemotherapy, radium, or sipuleucel-T and progressing symptomatically and in need of palliation radiation therapy, to me that’s an element of progression because that’s how I define progressive disease in a castration-resistant setting.

Lastly, for that point of counseling the patient, you can tell the patient there is no need for the patient to actually be concerned about that. Patients can go back and take care of their grandchildren. There are some universal precautions that we actually counsel the patients with. We have a team of people who will sit with the patient, educate the patient—they think of things that we do for this class of agents as to what to do, what not to do. But they’re not beta emitters, so in that context I don’t think that’s going to be a big issue for treatment selection, and certainly there is some reluctance from the patient to receive this treatment.

Transcript edited for clarity.

Case:A 69-Year-Old Man with Advanced Castrate Resistant Prostate Cancer

Initial presentation

• A 69-year-old man presented with intermittent back discomfort and loss of appetite
• PMH: hyperlipidemia controlled on a statin, no known family history of cancer
• PE: DRE revealed asymmetric, boggy prostate; otherwise unremarkable

Clinical Workup

• Biopsy with TRUS showed adenocarcinoma of prostate
  • Stage T2N0M0
  • Grade group 4
• Germline genetic testing: MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2 and CHEK2
• Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement
• Bone scan was negative
• PSA 24.9 ng/mL

Treatment and Follow-Up

• EBRT + ADT was started
• Follow up at 6 months, PSA 11.2 ng/mL
• At 12 months PSA 18.6 ng/mL
  • Patient reported increasing back discomfort and difficulty walking
  • Bone scan at that time showed multiple vertebral lesions at L3/L4
• Treatment with radium-223 dichloride was initiate
  • 6 infusions were completed, treatment was well tolerated