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Cure of human ovarian carcinoma solid xenografts by fractionated [211At] alpha-radioimmunotherapy: Influence of tumor absorbed dose and effect on long-term survival

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  1. Early Postoperative 18F-FET PET/MRI for Pediatric Brain and Spinal Cord Tumors

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  2. Predictive value of PET response combined with baseline metabolic tumor volume in peripheral T-cell lymphoma patients

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  3. Reproducibility of MR-based Attenuation Maps in PET/MRI and the Impact on PET Quantification in Lung Cancer

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  1. Extraction of 211At from nitric acid solutions into various organic solvents for use as an α-source for radiation chemistry studies

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  2. Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates

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  3. Absorbed Doses and Risk Estimates of (211)At-MX35 F(ab')2 in Intraperitoneal Therapy of Ovarian Cancer Patients

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  4. N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide, a molecule for radiohalogenation of proteins and peptides

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  5. Shelf-life of ɛ-lysyl-3-(trimethylstannyl)benzamide immunoconjugates, precursors for 211At labeling of antibodies

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  • Tom A Bäck
  • Nicolas Chouin
  • Sture Lindegren
  • Helena Kahu
  • Holger Jensen
  • Per Albertsson
  • Stig Palm
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The goal of this study was to investigate if targeted alpha therapy (TAT) could be used to successfully treat also macro tumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous (i.v.) fractionated regimen of alpha-radioimmunotherapy (α-RIT) in a subcutaneous (s.c.) tumor model in mice. We aimed at evaluating the absorbed dose levels required for tumor eradication and to monitor tumor growth, as well as the long-term survival after treatment.

METHODS: Mice bearing s.c.-tumors (50 mm3, NIH:OVCAR-3) were i.v.-injected repeatedly (1 to 3 injections, 7-10 days apart allowing bone-marrow recovery) with (211)At-MX35-F(ab')2 at different activities (close to acute myelotoxicity). Mean absorbed dose to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 days and survival for 1 year after treatment. Toxicity analysis included body weight, WBC and hematocrit.

RESULTS: Effects on tumor growth following fractionated α-RIT with (211)At-MX35-F(ab')2 was strong and dose-dependent. Complete remission (TFF=100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high and long-term toxicity effects (up to 60 weeks) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 weeks. Toxicity was also seen by reduced body weight. WBC-analysis after α-RIT indicated bone marrow recovery for the low activity groups, while for high activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 weeks after therapy). The main external indication of poor health was dehydration.

CONCLUSION: Having observed complete eradication of solid tumor xenografts, we conclude that TAT regimens could stretch beyond the realm of micrometastatic disease and be eradicative also for macro tumors. Our observations indicated that at least 10 Gy is required. This was in good agreement with the calculated TCP. Considering a RBE of 5, this dose level seemed reasonable. However, complete remission was achieved first at activity levels close-to lethal and was accompanied with biological effects that reduced the long-term survival.

Original languageEnglish
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume58
Issue number4
Pages (from-to)598-604
ISSN0161-5505
DOIs
Publication statusPublished - 2017

ID: 49714576