499 Objectives To perform individualised patient dosimetry for safe, efficacious radiopeptide treatment of metastatic neuroendocrine tumors. Methods Forty-three patients underwent radiopeptide treatment with 7.5GBq 177Lu-Octreotate with nephroprotective amino acid infusion. Serial gamma (113 keV (6.4%); 208 keV (11%)) whole-body (WB) planar scintigraphy and quantitative SPECT with low-dose CT attenuation correction was performed at 4h, 24h, 48h and 5d for each of four cycles of therapy, 8-12 weeks apart. Activities in critical normal organs (kidney, red marrow and liver) were calculated by applying ROIs to the SPECT/CT slices to obtain organ counts, then converting to activities using 177Lu phantom calibration factors. Effective doses (Gy) to critical organs were calculated using OLINDA. Serial WB ROI analysis of critical organs was compared with corresponding SPECT/CT dosimetry. Monte Carlo methodology utilising image data was developed to estimate therapeutic radiation absorbed doses to tumors. Hemopoietic, renal and hepatic function was monitored weekly for eight weeks after each cycle of 177Lu-Octreotate. Results Median effective dose per cycle of 177Lu-Octreotate therapy to red marrow was 0.20Gy (0.06-0.44Gy), kidney 4.52Gy (2.41-7.58Gy) and liver 4.96Gy (1.36-7.31Gy). No evidence of nephrotoxicity, myelosuppression or liver toxicity was seen. Conclusions Individualized dosimetry from quantitative analysis of SPECT/CT and WB gamma scintigraphy defined the effective dose to critical organs from 177Lu-Octreotate radiopeptide therapy. No toxicity to bone marrow, kidney or liver was seen.Tumor dosimetry is variable and requires Monte Carlo methodology.

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 &bgr;-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°C, demonstrated the release of less than 15% of the activity within three half-lives. The biodistribution of 188Re-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.

Medical Journal of AustraliaVolume 166, Issue 10 p. 518-519 Editorial The taxanes: miracles for breast cancer treatment or just more chemotherapy? Phillip G Claringbold, Phillip G Claringbold Head Department of Oncology, Fremantle Hospital, Fremantle, WASearch for more papers by this author Phillip G Claringbold, Phillip G Claringbold Head Department of Oncology, Fremantle Hospital, Fremantle, WASearch for more papers by this author First published: 01 May 1997 https://doi.org/10.5694/j.1326-5377.1997.tb123242.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume166, Issue10May 1997Pages 518-519 RelatedInformation

Liver metastases cause the majority of deaths from colorectal cancer and response to chemotherapy is poor. Intrahepatic arterial 90Y-microspheres may induce tumour regression but the β-radiation dose is variable and cannot be determined in patients. The 81 keV γ emission of holmium-166 (166Ho) was used to determine, by single photon emission computed tomographic (SPECT) imaging, the β-radiation absorbed dose to normal liver in pigs following intrahepatic arterial administration of 166Ho-microspheres. The SPECT system was calibrated with anthropomorphic liver phantoms containing known activity concentrations of 166Ho-chloride. The relationship of SPECT counts to phantom activity concentration was linear with a correlation coefficient of r = 0.996. The SPECT pattern of liver distribution following successive administrations of tracer activities of 166Ho-microspheres was similar. The ratio of initial to total SPECT estimates of mean activity concentration in regions of interest, from which anatomically matched biopsy samples were later obtained and counted in an ionization chamber, showed good correlation (r = 0.924). Prospective SPECT dosimetry performed on a tracer activity of 166Ho-microspheres predicted the total administered activity required to deliver a prescribed radiation absorbed dose of 25 Gy to the liver within an error of ± 8%. This study demonstrates the feasibility of prospective control of the absorbed radiation dose to the critical normal organ by SPECT dosimetry on a tracer dose of 166Ho-microspheres prior to administration of a therapy dose.

Liver metastases cause the majority of deaths from colorectal cancer and response to chemotherapy is poor. Intrahepatic arterial Y-90-microspheres may induce tumour regression but the beta-radiation dose is variable and cannot be determined in patients. The 81 keV gamma emission of holmium-166 (Ho-166) was used to determine, by single photon emission computed tomographic (SPECT) imaging, the beta-radiation absorbed dose to normal liver in pigs following intrahepatic arterial administration of Ho-166-microspheres. The SPECT system was calibrated with anthropomorphic liver phantoms containing known activity concentrations of Ho-166-chloride. The relationship of SPECT counts to phantom activity concentration was linear with a correlation coefficient of r = 0.996. The SPECT pattern of liver distribution following successive administrations of tracer activities of Ho-166-microspheres was similar. The ratio of initial to total SPECT estimates of mean activity concentration in regions of interest, from which anatomically matched biopsy samples were later obtained and counted in an ionization chamber, showed good correlation (r = 0.924). Prospective SPECT dosimetry performed on a tracer activity of Ho-166-microspheres predicted the total administered activity required to deliver a prescribed radiation absorbed dose of 25 Gy to the liver within an error of +/- 8%. This study demonstrates the feasibility of prospective control of the absorbed radiation dose to the critical normal organ by SPECT dosimetry on a tracer dose of Ho-166-microspheres prior to administration of a therapy dose.

BACKGROUND:Total-body irradiation, followed by hematopoietic system rescue by bone marrow transplantation (BMT), has been found to improve the response of patients with multiple myeloma to treatment with melphalan. The problems of nonhematopoietic toxicity from whole-body irradiation might be circumvented by using a bone-seeking radiopharmaceutical, such as samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP), to ablate the bone marrow.PURPOSE:A mouse model system for multiple myeloma was used to evaluate the potential therapeutic efficacy of sequential therapy with 153Sm-EDTMP, melphalan, and BMT.METHODS:Female C57BL/KaLwRij mice were inoculated with 8 x 10(5) 5T33 murine myeloma cells. Treatment protocols were begun 3 or 10 days later, when the myeloma was either confined to bone marrow or disseminated in liver, spleen, and lymph nodes, simulating human multiple myeloma. 153Sm, a potent beta particle-emitting radioisotope of short half-life (46.7 hours), was linked to the bone-seeking chelate EDTMP. Animals in the first treatment group were each given 22.5 MBq 153Sm-EDTMP via the jugular vein (day 3 or 10), followed by 18.5 mg/kg melphalan (maximum tolerated dose) given intraperitoneally 5 days later (day 8 or 15) and syngeneic BMT another 2 days later (day 10 or 17). Survival in groups of six to 10 animals for each time series was compared with that in mice left untreated (control cohort), in mice treated with 153Sm-EDTMP alone (day 3 or 10), or in mice treated with melphalan alone (day 8 or 15). The hematopoietic systems of animals in the latter two treatment groups recovered full function, obviating the necessity of BMT. The end point was onset of paraparesis, at which time the animals were immediately killed by carbon dioxide asphyxiation.RESULTS:Median survival in untreated control animals was 23 days in those with localized disease and 24 days in those with disseminated myeloma. Treatment with 153Sm-EDTMP alone improved survival to a median of 29 days when commenced on day 3 and 30 days when begun on day 10. Melphalan treatment alone improved the median survival to 31 days for animals with localized myeloma and 34 days in animals with disseminated disease. Additional improvement in survival to a median of 42 days was achieved in animals treated 3 days after tumor inoculation with sequential 153Sm-EDTMP, melphalan, and BMT; median survival was 40 days using this regimen in animals with disseminated myeloma.CONCLUSIONS:Animals in all three treatment protocols survived longer than those left untreated after inoculation with myeloma cells (P < .001). Sequential treatment with 153Sm-EDTMP, melphalan, and BMT was significantly more effective than single-agent treatment (P < .01). No evidence of radiotoxicity was detected in nonhematopoietic organs.IMPLICATIONS:The survival advantage conferred by our sequential treatment protocol suggests its potential clinical usefulness in the treatment of multiple myeloma and other hematologic malignancies in humans.

The 5T33 multiple myeloma is one of a series of transplantable murine myelomas arising spontaneously in C57BL/KaLwRij mice. This study describes the establishment and characterisation of the 5T33 murine myeloma in vitro as a cultured cell line in terms of its morphology, growth rate, expression of paraprotein (IgG2b) and tumorigenicity in syngeneic animals. The 5T33 cell line has been in continuous culture for over 10 months and has achieved more than passage 34. In culture, 5T33 myeloma grows as single cells or in small clusters of loosely adherent cells on an adherent stromal cell layer. Maximum doubling time is approximately 25 h, and over 90% of the cells express cytoplasmic IgG2b paraprotein. The cultured 5T33 myeloma cells are highly tumorigenic in C57BL/KaLwRij mice with as few as 500 cells inducing paralysis and death as early as day 36 post-tumour inoculation. Kinetics of tumour development and detection of IgG2b paraprotein are dose dependent. Two weeks following intravenous inoculation of 5 x 10(5) cultured 5T33 myeloma cells, tumour cells were readily identified in the bone marrow. By 3 weeks post-tumour inoculation, 5T33 myeloma cells were found in various tissues throughout the animal. Studies are now underway to determine the sensitivity of this cell line to various therapeutic modalities.

Chemoradiotherapy with melphalan and 153Sm-ethylenediaminetetramethylene phosphonate (EDTMP) was used to ablate bone marrow in WAG rats which were subsequently rescued by marrow transplantation. Internal irradiation of bone marrow with high doses of up to 3.5 GBq kg-1 153Sm-EDTMP alone produced profound, but self-limiting, myelosuppression and all animals recovered spontaneously. Melphalan alone in doses of 9.5 mg kg-1 also caused transient myelosuppression without mortality. However, the combination of 9.5 mg kg-1 melphalan and 555 MBq kg-1 153Sm-EDTMP caused marrow ablation and death in 80% of animals. The mortality of this chemoradiotherapy regimen was reduced to 7% by sequential administration of 153Sm-EDTMP on day 0 and melphalan on day 5 followed by marrow transfusion of 7.5 x 10(7) cells on day 6. These results were comparable to those obtained following bone marrow transplantation 24 h after lethal total body external beam irradiation. In the inbred WAG rat experimental model the sequential chemoradiotherapeutic regimen of internal irradiation with 153Sm-EDTMP followed by chemotherapy with melphalan was demonstrated to ablate bone marrow effectively whilst preserving the capacity for recovery following marrow transplantation.

A phase II study of 153Sm ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) palliative treatment was conducted on 23 patients with painful disseminated skeletal metastases. The administered activity of 153Sm-EDTMP was determined by prospective dosimetry and the radiation absorbed dose to bone marrow was fixed at 2 Gy. Symptomatic relief of bone pain was experienced by 14 of 23 evaluable patients (61%) with a median duration of 8 weeks (range 0-40). Toxicity was limited to myelosuppression with median nadir counts of leucocytes 3.3 x 10(9)/1 (range 1.0-7.5) and platelets 133 x 10(9)/1 (range 24-176) occurring at 2 weeks and 4 weeks, respectively. Retreatment with 153Sm-EDTMP was studied in 15 patients, including in 4 of the 23 patients treated with a single dose. The retreatment median radiation absorbed dose to red marrow was 1.9 Gy given at a median of 9 weeks (range 6-38) after initial treatment. Good control of pain was obtained in 13 of these patients (87%). Both the median duration of pain control (24 weeks) and survival (9 months) in the retreated group were substantially greater than for patients treated with a single dose, where duration was 8 weeks and survival 4 months. Additional toxicity in the retreated patients was confined to anaemia which required blood transfusion in 9 of the 15 patients (60%).

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.