title: Gemcitabine radiosensitization after high-dose samarium for osteoblastic osteosarcoma.
abstract: Osteoblastic metastases and osteosarcoma can avidly concentrate bone-seeking radiopharmaceuticals. We sought to increase effectiveness of high-dose (153)Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP, Quadramet) on osteosarcomas using a radiosensitizer, gemcitabine. Fourteen patients with osteoblastic lesions were treated with 30 mCi/kg 153Sm-EDTMP. Gemcitabine was administered 1 day after samarium infusion. Residual total body radioactivity was within the safe range of <3.6 mCi on day +14 (1.1 +/- 0.4 mCi; range, 0.67-1.8 mCi). All patients received autologous stem cell reinfusion 2 weeks after 153Sm to correct expected grade 4 hematopoietic toxicity. Peripheral blood progenitor cells were infused in 11 patients; three patients had marrow infused. Blood count recovery was uneventful after peripheral blood progenitor cells in 11 of 11 patients. Toxicity from a single infusion of gemcitabine (1,500 mg/m2) in combination with 153Sm-EDTMP was minimal (pancytopenia). However, toxicity from a daily gemcitabine regimen (250 mg/m2/d x 4-5 days) was excessive (grade 3 mucositis) in one of two patients. There were no reported episodes of hemorrhagic cystitis (hematuria) or nephrotoxicity. At the 6- to 8-week follow-up, there were six partial remissions, two mixed responses, and six patients with progressive disease. In the 12 patients followed >1 year, there have been no durable responses. Thus, although high-dose 153Sm-EDTMP + gemcitabine has moderate palliative activity (improved pain; radiologic responses) in this poor-risk population, additional measures of local and systemic control are required for durable control of relapsed osteosarcoma with osteoblastic lesions. The strategy of radioactive drug binding to a target followed by a radiosensitizer may provide synergy and improved response rate.
authors.affiliation: Pediatrics Unit, M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. pmanders@mdanderson.org
authors.forename: Peter M
authors.initials: PM
authors.lastname: Anderson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wiseman
authors.forename: Linda
authors.initials: L
authors.lastname: Erlandson
authors.forename: Vilmarie
authors.initials: V
authors.lastname: Rodriguez
authors.forename: Barbara
authors.initials: B
authors.lastname: Trotz
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Dubansky
authors.forename: Karen
authors.initials: K
authors.lastname: Albritton
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D018952:Antigens, CD34 / Q000096:biosynthesis; D001859:Bone Neoplasms / Q000473:pathology*; D001842:Bone and Bones / Q000378:metabolism; D003131:Combined Modality Therapy / Q000379:methods*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D012516:Osteosarcoma / Q000473:pathology* / Q000628:therapy*; D010146:Pain / Q000188:drug therapy; D049268:Positron-Emission Tomography; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000494:pharmacology; D012074:Remission Induction; D012493:Samarium / Q000737:chemistry; D012509:Sarcoma / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D018712:Analgesics, Non-Narcotic; D018952:Antigens, CD34; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D003841:Deoxycytidine; D012493:Samarium; C061972:samarium Sm-153 lexidronam; D000469:Alkaline Phosphatase; D000093542:Gemcitabine