Two recent studies have demonstrated that combining radiotherapy with administration of zoledronic acid may provide pain relief while reducing the overall radiation dose required.7,8 In the first study, 139 patients with bone metastases from a variety of cancers received radiotherapy in a single dose of either 8Gy or 6Gy plus 4mg of zoledronic acid every 4 weeks for 18 to 30 weeks.7 The two radiation doses were equally effective at relieving pain in the supine and sitting positions, although the higher dose provided more pain relief in the standing position and delayed the onset of skeletal-related events (SREs). It was, however, associated with greater toxicity. In the second trial, 100 breast cancer patients with bone metastases were randomized to receive a radiotherapy dose of either 30Gy in 10 fractions or 15Gy in five fractions, along with 4mg of zoledronic acid every 28 days.8 There were no significant differences between groups in response to treatment, occurrence of SREs, or findings on MRI and bone scintigraphy, and patients in the low-dose arm reported greater satisfaction with treatment.
Recent guidelines from the American Society for Radiation Oncology reaffirm the central role of radiotherapy in palliation of bone metastases and find that various fractionation schemes are effective and safe for treatment or prevention of CIBP.9 The guideline authors also state that in patients with painful bone metastases, use of surgery, radionuclides, bisphosphonates, or kyphoplasty/vertebroplasty does not obviate the need for external-beam radiation therapy to achieve adequate pain relief; they recommend that prospective studies explore the use of radionuclides in patients with limited bone metastases and in combination with systemic agents.
Recent Developments in Radionuclide Treatment
Radionuclides are an important alternative to radiotherapy when painful bone metastases are present at multiple sites or when patients have already received high cumulative doses of radiation.10 Currently, two radionuclides are approved in the United States for palliation of pain: strontium 89 HCl and samarium-153 lexidronam. These agents have been studied primarily in patients with prostate cancer, and little is known about their efficacy in patients with breast cancer. Recently, a systematic review examined 19 trials of radionuclide therapy that included patients with breast cancer. Unfortunately, the results found that the available evidence is of poor quality, and no conclusions regarding efficacy in breast cancer patients could be drawn.10 Clearly, this will be an important area for future research.
Alpha-pharmaceuticals, which deliver short-range radiation to cancer cells with lower penetration of surrounding tissue than beta-emitting pharmaceuticals, may be an attractive option for treatment of patients with CIBP.11 Radium-223 chloride is a bone-targeted alpha-pharmaceutical that has been shown to improve survival in prostate cancer patients with bone metastases. A recent randomized, double-blind study investigated whether use of radium-223 relieves pain in a dose-dependent manner in patients with castration-resistant prostate cancer.11 A total of 100 patients received a single injection of radium-223 in a dose of 5, 25, 50, or 100 kBq/kg and were followed for 16 weeks; their pain was evaluated with a visual analog scale and a pain index.
A significant dose-dependent reduction in pain occurred at week 2, and by week 8, the proportion of patients with a favorable pain response ranged from 40% in the 5kBq/kg group to 71% in the 100kBq/kg group. More than half of patients in the highest-dose group had complete or marked pain response. Pain relief persisted 28 days in the 5kBq/kg group and 44 days in the 50kBq/kg and 100kBq/kg groups, a nonsignificant difference. Approximately half of patient reported one or more serious adverse events, but the occurrence of adverse events was not dose-related.