Radium-223 vs EBRT for Multiple Painful Bone Metastases: The Data Favor Radium-223

Over 90% of patients with metastatic prostate cancer have bone metastases, and the vast majority of these patients develop bone pain from the metastases during the course of the disease.[1] All such patients should be treated with zoledronic acid and/or denosumab.[2] The disease course of prostate cancer can often be very protracted, with survival ranging from several years to decades. During that time, the bone marrow often becomes infiltrated by the cancer, leading to anemia and thrombocytopenia. Patients commonly need red cell transfusions during the terminal phases of the disease. Moreover, at least two chemotherapy agents that can suppress bone marrow function-docetaxel and cabazitaxel-should be used to extend life and improve quality of life.[3]

Within this context, the judicious use of marrow-damaging external beam radiotherapy (EBRT) is mandated, since the marrow within the radiated field does not regenerate, leading to progressive anemia and thrombocytopenia. In addition, as Dr. Roach notes, radiopharmaceuticals, especially radium-223, also have a role in the management of patients with painful metastatic bone disease.[4] In the pivotal Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial, in which the average patient received 6 monthly doses of radium-223 and in which EBRT was equally available to both groups, the median overall survival was 14.9 months in the radium-223 group and 11.3 months in the placebo group. Moreover, radium-223 significantly prolonged time to first skeletal-related event compared with placebo (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.52 to 0.83; P < .001; median, 15.6 months vs 9.8 months). Finally, radium-223 reduced the need for the use of EBRT for bone pain (HR = 0.67; 95% CI, 0.53–0.85). Taken together, these data suggest that patients treated with radium-223 will live longer, have fewer skeletal-related events, and need less EBRT. Therefore, when painful bone metastases develop after chemotherapy with docetaxel or cabazitaxel, radium-223-not EBRT-is the preferred method of pain control. Of course, bisphosphonates or denosumab should be continued whenever possible. Stereotactic radiosurgery should be considered for some lesions in order to preserve marrow function.

There are some patients in whom chemotherapy is not an option (the very elderly, those who are debilitated, and those with organ dysfunction), and there are others who refuse chemotherapy. For these patients I use radium-223 first for pain control. ALSYMPCA permitted the simultaneous use of EBRT. Therefore, if a patient has a dominant painful lesion, it would be appropriate to radiate and then add systemic radium, provided that the patient does not have progressive liver metastases.

So what are the downsides of the use of radium-223?

1. Cumulative bone marrow damage is a well-recognized toxicity of radiopharmaceuticals.[5] In ALSYMPCA, anemia was similar in both the treated and placebo groups (31%). Blood transfusions were required for 137/614 (22%) and 69/307 (22%) of radium-223 and placebo patients, respectively. Thrombocytopenia (12% vs 6%) and neutropenia (5% vs 1%) were more common in the radium-223 group. There was some evidence of cumulative thrombocytopenia and anemia caused by radium-223, but this was confounded by the use of prior docetaxel and by a high volume of bone disease in some patients. Therefore, the ALSYMPCA investigators performed a regression analysis for the prediction of grade 2–4 hematologic adverse events. Prior docetaxel compared with no prior docetaxel was associated with a greater risk of anemia (HR = 1.41; P = .01), neutropenia (HR = 2.73; P = .03), and thrombocytopenia (HR = 2.47; P < .01). Treatment with radium-223 was associated with a greater risk of neutropenia (HR = 3.95; P = .02) and thrombocytopenia (HR = 2.14; P = .01). Higher baseline alkaline phosphatase level (≥ 220 U/L) and greater extent of disease (≥ 6 metastases/superscan) were more strongly associated with an increased risk of anemia (HR = 2.78; P < .0001 and HR = 4.35; P < .0001) than with an increased risk of thrombocytopenia (HR = 1.74; P = .02 and HR = 3.58; P = .03).[4] Taken together, these data do suggest that care should be taken in the use of radium-223 if patients have had prior docetaxel and/or have a high burden of disease. In such patients, EBRT with a restricted field is probably preferred. There are only limited data on the use of chemotherapy after radium-223. Sartor et al reviewed the clinical courses of the 93 patients in the ALSYMPCA trial who received chemotherapy (predominantly docetaxel) after radium-223 and compared these with the clinical courses of the 43 patients who received chemotherapy after placebo. The benefit of radium-223 was maintained and there was no sign of cumulative bone marrow suppression, although only 8 and 6 patients, respectively, had available data at 12 months after the start of chemotherapy.[6]

2. Cost and availability factors, as noted by Dr. Roach, favor EBRT. Radium cannot be given during chemotherapy and is contraindicated in patients with visceral (liver) metastases. Furthermore, the drug needs to be approved by third-party payers and ordered in advance of use. Thus, careful timing of the use of radium-223 is mandatory.

3. The long-term toxicity of radium remains a concern. However, at a median follow-up of 1.5 years from the end of radium-223 treatment, there were no secondary hematological malignancies.[7]

In conclusion, in order to achieve maximum survival of patients with metastatic castration-resistant prostate cancer, the judicious use of all available effective agents and modalities is required. Both EBRT and radium-223 are effective at relieving pain, but both may decrease bone marrow function. Since radium-223 has a documented survival advantage compared with the standard of care, which includes as-needed EBRT, the data favor radium-223 over EBRT for painful bone metastases.

Financial Disclosure:The author serves as a consultant to Bayer HealthCare and Algeta ASA, and his practice has received research funding from both companies.

References:

1. Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003;21:1232-7.

2. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48:3082-92.

3. Hurwitz M, Petrylak DP. Sequencing of agents for castration-resistant prostate cancer. Oncology (Williston Park). 2013;27:1144-9, 1154-8.

4. Parker C, Nilsson S, Heinrich D, et al; for the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-23.

5. Sartor O, Bruland O. Stromal targeted therapies in prostate and renal cancer: new concepts and knowledge. Clin Genitourin Cancer. 2011;9:1-2.

6. Sartor O, Coleman RE, Nilsson S, et al. Safety of cytotoxic chemotherapy following radium 223 dichloride therapy in the phase 3 ALSYMPCA study in patients with castration resistant prostate cancer (CRPC) with bone metastases. Ann Oncol. 2012;23(suppl 9):308. Abstr 936P.

7. Nilsson S, Vogelzang NJ, Sartor O, et al. 1.5-year post-treatment follow-up of radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase 3 ALSYMPCA study. J Clin Oncol. 2014;32(suppl 4):abstr 9.