Access Type

Open Access Dissertation

Date of Award

January 2024

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Medical Physics

First Advisor

Otto Muzik

Second Advisor

Yuni K. Dewaraja

Abstract

Radiopharmaceutical therapies (RPTs) have their roots in the initial discoveries of radiation and radiotherapy at the turn of the 20th century, but recent interest in the 177Lu- based RPTs 177Lu-DOTATATE and 177Lu-PSMA-617 have highlighted the need to investigate patient-specific, dosimetry-guided approaches to planning these therapies. These RPTs are currently administered in “one-size-fits-all” regimens of fixed activity injections and current dosimetry methodologies often have large uncertainties and are reliant upon reference values that do not necessarily apply to all patients. In this work, several ways to make patient-specific dosimetry in 177Lu-DOTATATE and 177Lu-PSMA- 617 RPTs more accurate or more accessible are addressed.In the first study, information available prior to the start of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) including quantitative 68Ga-DOTATATE PET/CT imaging and biomarkers from patient’s medical records was used to predict the absorbed dose (AD) delivered to the kidneys following the first cycle of therapy. Kidney AD was able to be predicted with a mean absolute percent error (MAPE) of 18% with a relatively simple regression model of renal uptake on 68Ga-DOTATATE PET/CT. The second study quantified the impact of different SPECT/CT imaging schedules on the time-integrated activity (TIA) used for dosimetry in 177Lu-DOTATAE PRRT via patient data and clinically realistic simulations. TIA estimates with 2 and 3 SPECT/CT time points were within 5%, on average, of the reference 4 time point SPECT/CT TIA if imaging time points were not too close together or too early (all <48 h). Single time point TIA estimates had performance comparable to multi-time point imaging at optimal time points, but systematically underestimate the absorbed dose with large variability if not imaged near the optimal time points. The third study saw the development of a novel dosimetry method for quantifying bone marrow AD in patients treated with 177Lu-PSMA-617 radioligand therapy for metastatic castrate resistant prostate cancer. The novel method incorporated information on patient-specific tumor and marrow distributions by leveraging information from 68Ga- PSMA-11 PET/CT and 99mTc-sulfur colloid SPECT/CT imaging studies, respectively. This informed a micro-scale model of the complex spongiosa structure which was coupled with a MC dosimetry code to apportion AD directly to the active marrow and treating the dose distinctly from the other components of the marrow space. This novel methodology was compared with existing dosimetry methodologies. AD values with the novel methodology were lower than other image-based dosimetry methods and more in agreement with accepted dose limits for bone marrow toxicity. The results additionally indicate that blood- based dosimetry, which is commonly applied to 177Lu-PSMA-617 RLT, is not adequate for predicting hematological toxicity and image-based dosimetry studies are necessary for accurately quantifying absorbed dose to the bone marrow, particularly in patients with a substantial metastatic burden in the bone. The results of these studies all support different aspects of improving the RPT dosimetric workflow and move the field toward patient-specific, dosimetry guided therapy.

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