Targeted Radionuclide Therapy for Bone Metastasis

Abstract

Bone metastases markedly reduce the quality of life due to bone pain, pathologic fractures, loss of mobility, and hypercalcemia. A graded three-step approach, as recommended by the World Health Organization (WHO), is used to treat pain according to its severity. Nonsteroidal anti-inflammatory drugs are used in patients with mild to moderate pain. When pain persists or increases, a weak opioid such as codeine or hydrocodone is added. Higher doses or more potent opioids are used if the pain persists or becomes more severe. Bisphosphonates (BPs) are useful in the treatment of osteoporosis and metastatic disease by decreasing the resorption of the bone. BPs bind to bone mineral and directly interfere with the activation of osteoclasts. They are internalized by osteoclasts and inhibit specific biochemical and metabolic pathways in these cells; they also reduce skeletal complications and reduce the rate of development of new lesions and delay progression in bone metastases. External beam radiation therapy given as a single or multifractionated dose is an effective treatment and provides early relief, especially for localized bone pain due to bone metastasis. Therapy with bone-seeking radiopharmaceuticals is effective for reducing pain in patients with widespread, painful bone metastases from various malignancies particularly prostate cancer. A variety of radiopharmaceuticals have been used and tested, including many beta-emitting nuclides and alpha-emitting radium-223 (223Ra) dichloride. Each of these agents targets the bone by chemical bonding or adsorbing to the trabecular surface of the bone, the metal-chelated radiotracer to the trabecular surface, while 32P-sodium orthophosphate and 89Sr-chloride distribute more widely throughout the bone. 89Sr-chloride and 153Sm-EDTMP are two FDA-approved beta-emitting radiopharmaceuticals that have largely replaced 32P-sodium orthophosphate in the treatment of metastatic bone pain in the USA. More recently, alpha-emitting 223Ra-dichloride has been used in symptomatic castration-resistant prostate cancer (CRPC). The onset of pain relief commonly occurs within 7–21 days. Retreatment is possible after allowing for marrow recovery; however, multiple therapies require consideration of cumulative marrow toxicity.89Sr-chloride and 153Sm-EDTMP have been used extensively, primarily for the treatment of bone pain from breast and prostate cancer due to the presence of osteoblastic disease that enables high uptake of the agents. Radionuclide therapy may be used alone or in combination with chemotherapy or radiation therapy to enhance pain relief and delay onset of new pain; consideration needs to be directed to overlapping or cumulative toxicities especially in the marrow that may require supportive treatment. Patients most suitable for bone pain therapy are those with multiple sites of bone metastases confirmed by a bone scan showing focal sites of increased radiopharmaceutical uptake and those who have symptoms related to osseous disease that requires increased doses of pain medication or is refractory to pain medication. 223Ra is an alpha-emitting radionuclide that accumulates in the bone as it is analogous to calcium. The high linear energy transfer of alpha radiation leads to double-strand DNA breaks within the cells. While effective for pain palliation, it has also shown survival benefit in those with metastatic osseous disease from prostate cancer. However, it is currently approved for use only in symptomatic CRPC patients who have no other visceral diseases.KeywordsBone metastasisBone pain palliationRadium-223 dichlorideStrontium-89 chlorideSamarium-153 EDTMPPhosphorus-32Bone-targeted radionuclide therapyRadiopharmaceutical therapy for bone metastases