R-223 is cleared through the bowel, so there can be some gastrointestinal toxicity, including diarrhea, nausea and constipation. Overall, it’s pretty well tolerated.

R-223 causes mild myelosuppression in many men that is usually Grade 1 in severity. Severe toxicity is uncommon but may be observed in men with a high burden of disease and limited bone marrow reserve. We do have to monitor patients blood counts monthly. I have not commonly observed myelosuppression in my patients.

I would counsel patients about the risk of myelosuppression with the chemotherapy that is administered in combination with R-223, but I wouldn’t do much more counseling. I have observed little myelosuppression with R-223, unless patients are also receiving chemotherapy.

In patients to whom I’ve administered treatment in the fourth-line setting, I observed minor toxicity. I have administered it to only a few patients, so it’s a little early to comment. But I have 1 patient who had Grade 2 thrombocytopenia and 1 who had Grade 3 thrombocytopenia. I believe it was caused by R-223 and not the disease because the patients recovered.

We need to make sure that patients have good bone marrow reserve, although we know that it does not effect the bone marrow as much as traditional radioisotopes. However, it can be a problem for some patients. We have had to discontinue R-223 in a couple of patients due to bone marrow suppression. I don’t know if it affects future bone marrow tolerance to chemotherapy. Some patients have diarrhea with it, but patients have not had to discontinue treatment because of it.

I counsel patients that they could experience mild or moderate diarrhea related to the infusion. I tell them not to expect the PSA to decline, although the rate of rise might slow down. I also warn patients that they may have a pain flare early on and advise them how to manage it, usually with ibuprofen.

R-223 fared well in trials in terms of toxicity. The major problem was occasional thrombocytopenia. But it didn’t cause much neutropenia. In my patients, I have observed 1 case of myelosuppression. But it’s difficult to tell in these circumstances because patients can have myelosuppression simply from marrow involvement. I have not had patients with declines in their white cell counts, and I have observed only occasional problems with thrombocytopenia.

Clinical trials suggest it doesn’t cause impaired future bone marrow tolerance to chemotherapy, but I don’t believe we know yet. I believe we need more data.

I generally tell patients R-223 is well tolerated. Some patients experience mild bone pain after receiving it. Occasionally patients may have diarrhea. I counsel patients about the potential for bone marrow problems, but I have not encountered that. I haven’t observed significant myelosuppression in the patients whom I’ve selected for treatment. But some patients with heavily pretreated disease have had their bone marrows wiped out. I don't know if R-223 impairs future bone marrow tolerance to chemotherapy.

Myelosuppression, especially anemia, is a concern in some patients. I have observed that patients on R-223 develop anemia with time. So you must watch out for that. The ALSYMPCA trial demonstrated that although patients don’t develop neutropenic fever at a high rate, there does seem to be a lower nadir on the neutrophils after chemotherapy. However, it is not significant enough to be called neutropenic fever. The data from ALSYMPCA don’t show that R-223 impairs future bone marrow tolerance to chemotherapy.

Patients may experience fatigue, and there may be a flare in pain and constipation. Research has shown that with R-223 almost all the side effects, including pain, are better on R-223 compared to placebo.

R-223 can, on rare occasions, cause myelosuppression, but it’s not a myelosuppressive drug. In the ALSYMPCA trial, Grade 3 to 5 thrombocytopenia was around 7% and Grade 3 or 4 neutropenia was 3%. So it can cause some myelosuppression. However, it’s not clinically relevant during the course of treatment for the vast majority of patients. Rarely, R-223 can cause diarrhea, low platelet counts and nausea.

R-223 is well tolerated. There is a low-grade incidence of diarrhea in the minority of patients, which is easily managed with over-the-counter products and hydration, in my experience. The second issue would be myelosuppression, especially in the postchemotherapy group, but to a limited degree. We are careful to monitor platelet levels and white and red blood cell counts, although the likelihood of seeing that type of suppression is low.

R-223 causes Grade 3 or 4 myelosuppression in about 1% of the patients prior to chemotherapy and about 2% to 3% of patients after chemotherapy. We have seen only Grade 1/2 myelosuppression in our patients.

I don’t believe that R-223 impairs future bone marrow tolerance to chemotherapy. If you evaluate the ALSYMPCA data, there was a balance between the number of patients who were on the treatment arm and the control arm who went on to receive chemotherapy, and no significant differences in myelosuppressive adverse events were reported.