Targeted Therapy for Bone Metastasis

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 WHO, is used to treat pain according to its severity. Usually 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 are useful in the treatment of osteoporosis and metastatic disease by decreasing the resorption of bone. They bind to bone mineral and directly interfere with the activation of osteoclasts. Bisphosphonates are internalized in the osteoclasts and inhibit specific biochemical and metabolic pathways in these cells. Bisphosphonates reduce skeletal complications and reduce the rate of development of new lesions and delay progression in bone metastases. External beam radiation therapy is effective for localized bone pain due to bone metastasis. It provides rapid pain relief that can start as early as 48 h after the commencement of therapy. Radiation destroys viable tumor cells and enables osteoblastic repair of damaged bone. Radiotherapy may be given as a single dose or multifractionated dose. There is preferential use of the multifractionated dose method in USA. Therapy with bone-seeking radiopharmaceuticals is efficacious to reduce pain in patients with widespread painful bone metastases. Beta-emitting nuclide phosphorus-32 (32P) sodium phosphate or orthophosphate, strontium-89 (89Sr) chloride, and samarium-153 ethylene diamine tetramethylene phosphonic acid (153Sm-EDTMP) have been approved for clinical use in the USA. All agents have advantages and side effects. Moreover, the sources of radiation within bone differ with the radiopharmaceutical used. The metallic chelated radiotracers tend to chemically absorb to the trabecular surface, whereas 32P-sodium orthophosphate and 89Sr-chloride distribute more widely throughout bone. 89Sr-chloride is one of the two FDA-approved radiopharmaceuticals that has largely replaced 32P-sodium orthophosphate in the treatment of metastatic bone pain. The onset of pain relief commonly occurs within 7–21 days, and mean duration of relief is about 2–6 months. Retreatment can be given after 90 days, although multiple ­therapies may lead to greater marrow toxicity. 89Sr-chloride has been extensively used, mainly in the treatment of bone pain from breast and prostate cancer. Radionuclide therapy can be administered in association with chemotherapy. The combination may enhance pain relief and delay the onset of new painful metastases. 153Sm-EDTMP is a stable complex that selectively accumulates in skeletal tissue. Bone metastasis may contain 3–5 times more 153Sm-EDTMP than healthy bone tissue. The low energy of the beta particle reduces the radiation burden to bone marrow. Hematological side effects are generally mild. Pain relief is generally noted within 5–10 days and can last up to 4 months. Repeated dosing of 153Sm-EDTMP is feasible if pain returns or increases. Patients referred for bone pain therapy have multiple painful bone metastases confirmed by a bone scan which shows multiple focal sites of increased radiopharmaceutical uptake and who is experiencing worsening of bone pain, in spite of narcotic pain medication. In patients with established bone metastases, hormonal or chemotherapy can palliate symptoms, but rarely produces durable control. Recent data offer a compelling rationale to combine chemotherapy with bone-seeking radiopharmaceuticals for prolonging survival and enhance quality of life.