Targeting the Skeleton and Cancer in Bone Samarium treatment of osteosarcoma, osteoblastic bone metastases, and neoplastic disease in the bone marrow

the effectiveness of an intervention against cancer cells compared to normal tissue. Although chemotherapy and radiation are common and effective treatment modalities for skeletal neoplasia (1), bone-seeking radioisotopes offer a new opportunity to provide additional benefit via specific targeting of the skeleton and/or bone-forming lesions (e.g. osteoblastic metastases in the skeleton, marrow, or osteoblastic osteosarcoma). Principles of effective targeted therapy of skeletal neoplasia with a bone-seeking radiopharmaceutical, samarium will be reviewed in the context of our recent and extensive experience using high-dose samarium at Mayo Clinic. The skeleton, osteoblastic metastases, and osteoblastic osteosarcoma lesions usually have medium, modestly avid, and very high uptake of bone-seeking phosphonates. Both 99mTcMDP (used for routine bone scans) and 153Sm-EDTMP, Quadramet (Berlex)a therapeutic beta-emitting radioisotope that also emits a gamma photon to permit imaging and dosimetrylocalize to the skeleton, osteoblastic metastases, and osteosarcomas with very high tumor (bone)/blood and tumor (bone)/muscle ratios (2-5) . The bone scan is qualitatively predictive of uptake and radiation dose that can be delivered. The high therapeutic index of radiation delivered by 153Sm-EDTMP into bone-forming cancer lesions was initially demonstrated in canine osteosarcoma (6). Many of the dogs in this early series had durable clinical responses using standard doses of 153Sm-EDTMP. Subsequent studies in Oslo have also shown clinical effectiveness of 153SmEDTMP in canine osteosarcoma (7). The therapeutic targeting of osteoblastic skeletal metastases by 153Sm-EDTMP has been detailed in phase I/II clinical trials (8-15) as well as randomized clinical trials (16). The promise of targeted radiotherapy of human osteosarcoma using 153Sm-EDTMP was shown for the first time by extremely impressive palliation in a 35 year man with recurrent, relapsed osteosarcoma involving the spine and associated hemiparesis (17). Pain at the L1 recurrence site in this man markedly improved; neurologic deficit (paresis) resolved for months after administration of the bone-seeking radioisotope. 153Sm-EDTMP (Samarium 153Sm lexidronam; Quadramet) was FDA approved for treatment of bone metastases in 1997. Uptake, localization, and retention of 153Sm-EDTMP into bone and bone-forming lesions has been studied (2, 3, 18) (19-23). Rapid blood and non-osseous tissue clearance is seen after samarium administration (3). 153Sm-EDTMP remains tightly bound after Targeting the Skeleton and Cancer in Bone Samarium treatment of osteosarcoma, osteoblastic bone metastases, and neoplastic disease in the bone marrow