Small-scale dosimetry methods for normal tissues after radioembolization and peptide receptor radiotherapies; a focus on the liver parenchyma and the bone marrow

Sammanfattning: Radionuclide therapies are increasingly used in cancer treatments as they have been proven to be both effective and safe. As biodistributions and uptake vary widely between patients, a standardized approach is bound to leave a fraction of patients overtreated or undertreated. Dosimetry-based evidence suggests treatment regimens could be improved on a patient-specific basis as the absorbed dose limits for critical organs are not always reached. This thesis has investigated two radionuclide therapies with distinctly different targeting mechanisms and has aimed at investigating the absorbed dose distributions in tumor tissue and the parenchyma of the liver after radioembolization and the radiosensitive red marrow after peptide receptor radionuclide therapy (PRRT). In the first study, a patient with hepatocellular carcinoma underwent radioembolization prior to tumor resection with the aim of reducing the probability of tumor recurrence within the resection boundaries. Using SPECT images, autoradiography, and biopsies, the absorbed dose distribution was evaluated. The analysis revealed a low absorbed dose and a small coefficient of variation in the liver parenchyma. However, the distribution in the tumor showed high levels of heterogeneity, with the greatest accumulation of microspheres found in viable tumor tissue. The three consecutive studies (II-IV) focused on the absorbed dose to the red marrow after PRRT. Since terbium-161, a radionuclide with a considerable emission of low-energy electrons, may be better suited to treat disseminated disease than lutetium-177 and yttrium-90, the second study focused on using an existing model of the bone marrow to investigate potential implications of bone marrow irradiation from terbium-161. The results demonstrated a strong dependence on the source distribution for terbium-161 due to the short range of the low-energy electrons while simultaneously indicating an increased absorbed dose to the red marrow compared to lutetium-177. The third study investigated the presence of somatostatin receptor subtype 2 (SSTR2) on CD34+ stem and progenitor cells in the bone marrow. After the first treatment cycle with [177Lu]Lu-DOTATATE, four SPECT/CT images were acquired for 17 patients with neuroendocrine neoplasms. The T9-L5 vertebrae, hip bones, thoracic aorta, and subcutaneous adipose tissue, along with a single tumor, were delineated in each patient. A compartment model was used to separate the contribution from blood-based activity and demonstrated prolonged retention in the bone marrow cavities for all patients and skeletal sites. These results inspired the development of a small-scale dosimetry model of the bone marrow in the fourth study to investigate how CD34+ stem and progenitor cells are irradiated by uptake related to the expression of SSTR2. The model utilized previously described spatial distributions of CD34+ stem and progenitor cells to demonstrate an increased absorbed dose from terbium-161 compared to lutetium-177. In conclusion, our results help to explain the observed hematological toxicities after [177Lu]Lu-DOTATATE therapy by demonstrating a specific uptake in the radiosensitive bone marrow. As upcoming clinical trials with terbium-161 may result in a shift from lutetium-177 in somatostatin receptor-based radionuclide therapies, we used these findings to show that this can lead to increased irradiation of the red marrow.