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 #
5R01CA116477-08
Application #
8484359
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
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$370,920
Indirect Cost
$141,957
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Hobbs, Robert F; Howell, Roger W; Song, Hong et al. (2014) Redefining relative biological effectiveness in the context of the EQDX formalism: implications for alpha-particle emitter therapy. Radiat Res 181:90-8
Sgouros, George; Hobbs, Robert F (2014) Dosimetry for radiopharmaceutical therapy. Semin Nucl Med 44:172-8
Sgouros, George; Goldenberg, David M (2014) Radiopharmaceutical therapy in the era of precision medicine. Eur J Cancer 50:2360-3
Hobbs, R F; Jentzen, W; Bockisch, A et al. (2013) Monte Carlo-based 3-dimensional dosimetry of salivary glands in radioiodine treatment of differentiated thyroid cancer estimated using 124I PET. Q J Nucl Med Mol Imaging 57:79-91
Cheng, Lishui; Hobbs, Robert F; Segars, Paul W et al. (2013) Improved dose-volume histogram estimates for radiopharmaceutical therapy by optimizing quantitative SPECT reconstruction parameters. Phys Med Biol 58:3631-47
Hobbs, Robert F; Song, Hong; Watchman, Christopher J et al. (2012) A bone marrow toxicity model for ²²³Ra alpha-emitter radiopharmaceutical therapy. Phys Med Biol 57:3207-22
Senthamizhchelvan, Srinivasan; Hobbs, Robert F; Song, Hong et al. (2012) Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma. J Nucl Med 53:215-24
Sgouros, George; Hobbs, Robert F; Atkins, Francis B et al. (2011) Three-dimensional radiobiological dosimetry (3D-RD) with 124I PET for 131I therapy of thyroid cancer. Eur J Nucl Med Mol Imaging 38 Suppl 1:S41-7
Senthamizhchelvan, Srinivasan; Bravo, Paco E; Lodge, Martin A et al. (2011) Radiation dosimetry of 82Rb in humans under pharmacologic stress. J Nucl Med 52:485-91
Hobbs, Robert F; McNutt, Todd; Baechler, Sebastien et al. (2011) A treatment planning method for sequentially combining radiopharmaceutical therapy and external radiation therapy. Int J Radiat Oncol Biol Phys 80:1256-62

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