Thirty-five patients with disseminated skeletal metastases from a variety of tumor types underwent clinical trial of samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) on a day-patient basis. Individual beta radiation dosimetry was based on pharmacokinetic studies of a 20 mCi tracer dose of 153Sm-EDTMP. The retained skeletal activity varied unpredictably from 40% to 95% of the administered dose, but in all patients greater than 98% of the nonosseous activity was cleared in the urine within 6 hours. Prospective calculation of radiation dosimetry in each patient permitted an accurate dosage schedule based upon total red marrow exposure, starting at 100 cGy and escalating to 280 cGy to define the dose-limiting myelotoxicity. Pain was relieved in 22 of 34 evaluable patients (65%) for periods ranging from 4 to 35 weeks, following a single administration of 153Sm-EDTMP. Recurrence of pain responded to retreatment with 153Sm-EDTMP in five of nine patients. The dose-limiting toxicity was myelosuppression manifested particularly by delayed thrombocytopenia. Platelet counts less than 100 x 10(9)/L occurred in 42% of courses when bone marrow radiation absorbed dose exceeded 200 cGy. Myelosuppression was transient and platelet counts had recovered to pretreatment levels within 10 weeks of treatment. 153Sm-EDTMP is effective for the amelioration of pain due to disseminated skeletal metastases particularly with carcinoma of breast or prostate where 83% of patients experienced pain relief. In 15 of the 34 evaluable patients there was evidence of stabilization or regression of skeletal metastases on radiographs and follow-up technetium-99m methylene diphosphonate (99mTc-MDP) bone scans.
153Sm-EDTMP (ethylenediaminetetramethylene phosphonate), prepared from a kit, was administered to 28 patients in a clinical trial of therapy for painful skeletal metastases unresponsive to all conventional treatment. The 103 keV gamma emission of 153Sm was utilized for prospective individual estimation of beta radiation absorbed dose to red marrow to minimize myelotoxicity and provide optimum internal radiotherapy to skeletal metastases in each patient. Pain relief occurred within 14 days of administration of 153Sm-EDTMP in 15 of 19 patients (79%) who could be evaluated at 6 weeks, when clinical response was maximal. Duration of response ranged from 4 to 35 weeks. Recurrence of pain responded to retreatment with 153Sm-EDTMP in five of eight cases. No dose-response relationship was apparent for pain relief but reversible myelotoxicity was frequently observed at radiation absorbed doses to bone marrow greater than or equal to 270 cGy. Dosimetry calculation was based on pharmacokinetic studies of a tracer administration of 153Sm-EDTMP in each patient. Assumptions inherent in this prospective method of predicting dose to bone marrow were validated experimentally. Biodistribution studies in rats demonstrated rapid skeletal uptake and long term retention of 153Sm-EDTMP in bone over 5 days. Urinary clearance accounted for 40% of injected dose, and less than 1.0% of administered activity was retained in non osseous tissue. Microdensitometry of autoradiographs of sheep vertebra and femur confirmed surface uptake of 153Sm-EDTMP in cortical bone and demonstrated relatively high trabecular bone activity which is the major component of radiation absorbed dose to bone marrow. Haematological studies in rabbits showed 153Sm-EDTMP-induced myelotoxicity to be transient and no histopathological abnormalities were demonstrable with doses ten times greater than those administered to patients.
A lyophilized kit formulation for the efficient labelling of lipiodol with generator-produced rhenium-188 is described. The preliminary preparation of the lipophilic complex bis-(diethyldithiocarbamato)nitrido rhenium-188 (188ReN-DEDC) was carried out using a two-vial kit containing S-methyl-N-methyl-dithiocarbazate, SnCl2 and sodium oxalate in the first vial, and diethyldithiocarbamate and a carbonate buffer in the second vial. After mixing of the reaction solution with lipiodol, the complex 188ReN-DEDC was quantitatively extracted and retained by this hydrophobic substance, thus allowing the stable incorporation of the beta-emitting radionuclide. The radiochemical purity of the complex 188ReN-DEDC was 97+/-2%. The activity extracted into the lipiodol phase was 96+/-3% of the initial activity, indicating that the complex 188ReN-DEDC was almost quantitatively removed from the aqueous reaction solution. In vitro stability studies in human plasma, at 37 degrees C, demonstrated the release of less than 15% of the activity within three half-lives. The biodistribution of Re-lipiodol in non-tumour-bearing Wistar rats at 6, 24, 48 and 72 h after intraportal venous injection showed one-third of total activity in the liver at 6 h, declining to 2% retention at 72 h. Bowel uptake at 6 and 24 h declined to low levels at 48 and 72 h. Renal activity peaked at 1.7%, diminishing to 0.6% over 48 h. Rat whole body gamma imaging showed gut activity in addition to hepatic uptake at 6 and 24 h, but only liver was evident from 48 to 72 h. Kidneys were not demonstrable at any imaging time point. In nine patients, activity was localized in the tumours immediately following intrahepatic arterial injection. Computed tomography/single-photon emission computed tomography (CT/SPECT) imaging at 1 and 24 h confirmed the retention of 188Re-lipiodol in the hepatoma, with minimal gut uptake and no lung activity over 24 h. These patients were subsequently treated with activities of 2.5-5 GBq of 188Re-lipiodol fractions without adverse effects. Six patients followed for up to 2 years in the pilot study achieved stable disease and there was objective partial response in one patient. Repeated treatments were performed on two to three occasions in three patients without evident toxicity. An additional patient given 6 GBq of 188Re-lipiodol demonstrated myelosuppression, which recovered with granulocyte colony-stimulating factor (GCSF) and platelet support. It is concluded that 188Re-lipiodol, prepared using our novel kit formulation, is stable in vivo and provides safe and effective therapy of unresectable hepatocellular carcinoma when given via the hepatic artery, either alone or in combination with transarterial chemoembolization.
In order to increase the availability and affordability of radioimmunotherapy of refractory or relapsed non-Hodgkins lymphoma, we developed and evaluated radioiodinated rituximab in an ongoing physician-sponsored Phase II Clinical Trial. The chimeric 1gG(1) anti CD 20 monoclonal antibody rituximab was radiolabeled with iodine-131 using a modified Chloramine T method with high radiochemical purity (98% +/- 0.82) and preservation of immunoreactivity. All patients received therapeutic loading doses of unlabeled rituximab (375 mg/m(2)) immediately prior to administration of tracer (200 MBq (131)I) or therapy (1.7-4.3 GBq (131)I) activities of (131)I-rituximab to provide additive immunotherapy and enhance tumor uptake of the radiolabeled antibody. Objective response rate (ORR) was 71% in 35 patients with a median follow-up of 14 months (range 4-28 months). Complete remission (CR) was achieved in 54% of patients, with median duration 20 months. Toxicity evaluation included an additional 7 patients followed for at least 3 months. Tracer dosimetry studies were performed in each patient and the whole body radiation absorbed dose was limited to a mean prescribed dose (MPD) of 0.75 Gy. Myelosuppression was reversible and in only 2 of 42 patients was grade IV hematological toxicity observed. No hemopoietic support was required in any patient. There was no instance of hemorrhage or infection in this group of patients in each of whom individual prospective dosimetry was performed prior to (131)I rituximab radioimmunotherapy for relapsed or refractory non-Hodgkins lymphoma.
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