Radiopharmaceutical therapy (RPT) is one of the few viable alternatives to chemotherapy for patients with metastatic cancer. In non-Hodgkin's lymphoma (NHL), RPT has yielded durable remissions in treatment- refractory patients. RPT is the only treatment for neuroendocrine and metastatic thyroid cancer and is an emerging treatment for metastatic ovarian, prostate and other cancers. ClinTrials.gov lists 136 radionuclide therapy trials. RPT is administered like chemotherapy, by assuming that a maximum tolerated administered activity (AA) defined in a dose escalation trial applies to all patients. Such generic dosing has led to conservative treatment, yielding low toxicity at the expense of tumor control. With prior NIH support we have developed a patient-specific dosimetry (PSD) methodology and have shown it to be superior to generic treatment by enabling, for example, more aggressive yet safe therapy of diffuse lung metastases in thyroid cancer and a combined XRT/RPT treatment plan for osteogenic sarcoma, boosting tumor dose while keeping adjacent spinal cord dose below the MTD. The objectives of this competing renewal application are to further improve accuracy and to evaluate overall impact on RPT. Specifically: 1. We propose to develop a method to enable micro-scale dosimetry from macro-scale (imaging) data. Imaging-based PSD accuracy is limited by imaging resolution. In some cases, micro-scale absorbed dose (AD) distributions are key to understanding and thereby avoiding normal organ toxicity. 2. In evaluating impact, statistical uncertainty is important to interpreting results and guiding treatment. We will develop a method to calculate the uncertainty and confidence level of dosimetry results. 3. Accrual of a large number of dose-response studies, in a standardized manner, is needed to evaluate the impact of Aims 1 and 2, and PSD, generally, on improving tumor control with RPT. The software package, 3-D Radiobiological Dosimetry (3D-RD) developed with prior NIH support, and revised in Aims 1 and 2, will be used to perform PSD calculations for a large number of existing and prospective, in- house, and collaborating institution studies. Single-institution studies yield limited data;3D-RD analysis for collaborator studies leverages data from other sites and increases the patient population pool to yield a robust data set for dose-response studies. 4. 3D-RD includes radiobiological modeling for dose rate and dose non- uniformity. Parameters values for these models cannot currently be measured in individuals. Instead, literature values are used. Without standardization, different investigators/institutions will use different values making response comparisons across studies difficult. To support the standardization needed for the dose-response studies of aim 3 we will establish an on-line database of reference radiobiological parameter values. Such a database would be analogous to the ICRP reference man compilation of organ masses and compositions. RPT is a promising treatment for metastatic cancer. RPT is currently delivered according to a chemotherapy paradigm. Support for this proposal will help bring a rational, AD-based approach, to RPT delivery.

Public Health Relevance

Targeted radionuclide therapy is an emerging modality for cancer therapy that involves the delivery of radioactive atoms using carriers that preferentially bind to tumor cells. Such treatment is best implemented with patient-specific dosimetry calculations. Support of this proposal will develop the methodology and tools needed to improve radiopharmaceutical therapy by implementing a patient-specific, absorbed-dose-based approach to treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA116477-07S1
Application #
8519640
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Deye, James
Project Start
2005-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$23,286
Indirect Cost
$8,912
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Plyku, Donika; Mena, Esther; Rowe, Steven P et al. (2018) Combined model-based and patient-specific dosimetry for 18F-DCFPyL, a PSMA-targeted PET agent. Eur J Nucl Med Mol Imaging 45:989-998
Josefsson, Anders; Hobbs, Robert F; Ranka, Sagar et al. (2018) Comparative Dosimetry for 68Ga-DOTATATE: Impact of Using Updated ICRP Phantoms, S Values, and Tissue-Weighting Factors. J Nucl Med 59:1281-1288
Fisher, Darrell R; Fahey, Frederic H (2017) Appropriate Use of Effective Dose in Radiation Protection and Risk Assessment. Health Phys 113:102-109
Fahey, Frederic H; Goodkind, Alison B; Plyku, Donika et al. (2017) Dose Estimation in Pediatric Nuclear Medicine. Semin Nucl Med 47:118-125
Plyku, Donika; Hobbs, Robert F; Huang, Kevin et al. (2017) Recombinant Human Thyroid-Stimulating Hormone Versus Thyroid Hormone Withdrawal in 124I PET/CT-Based Dosimetry for 131I Therapy of Metastatic Differentiated Thyroid Cancer. J Nucl Med 58:1146-1154
Yoshida, Takahiro; Jin, Kideok; Song, Hong et al. (2016) Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer. Oncotarget 7:33306-15
O'Reilly, Shannon E; Plyku, Donika; Sgouros, George et al. (2016) A risk index for pediatric patients undergoing diagnostic imaging with (99m)Tc-dimercaptosuccinic acid that accounts for body habitus. Phys Med Biol 61:2319-32
Woliner-van der Weg, Wietske; Schoffelen, Rafke; Hobbs, Robert F et al. (2015) Tumor and red bone marrow dosimetry: comparison of methods for prospective treatment planning in pretargeted radioimmunotherapy. EJNMMI Phys 2:5
Banerjee, Sangeeta Ray; Foss, Catherine A; Pullambhatla, Mrudula et al. (2015) Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates. J Nucl Med 56:628-34
Plyku, Donika; Loeb, David M; Prideaux, Andrew R et al. (2015) Strengths and Weaknesses of a Planar Whole-Body Method of (153)Sm Dosimetry for Patients with Metastatic Osteosarcoma and Comparison with Three-Dimensional Dosimetry. Cancer Biother Radiopharm 30:369-79

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