Abstract
Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy.
Highlights
Cancer in patients often has two disease components: loco-regional and disseminated
The primary tumor and immediate microscopic spread in the surrounding tissue is referred to as loco-regional disease, whereas disseminated disease can typically be metastatic in nature or disease that has spread to remote sites through the lymphatic system
The mean absorbed tumor dose for 177Lu-prostate-specific membrane antigen (PSMA)-617 was 4.0 Gy/MBq, which corresponded to an absolute dose of ~5 Gy and ~10 Gy when injecting 1.25 MBq or 2.5 MBq 177Lu-PSMA-617, respectively
Summary
Cancer in patients often has two disease components: loco-regional and disseminated. The primary tumor and immediate microscopic spread in the surrounding tissue is referred to as loco-regional disease, whereas disseminated disease can typically be metastatic in nature or disease that has spread to remote sites through the lymphatic system. On the other hand, targeted radionuclide therapy (TRT) is a systemic treatment approach primarily for disseminated disease that makes use of intravenously-applied radioconjugates, which accumulate selectively in cancer tissue due to specific targeting of tumor cell-associated receptors or antigens. This concept is routinely applied in clinics with, for example, somatostatin receptor-targeted peptides (such as LutatheraTM, 177Lu-DOTATATE, and somatostatin analog [2]) for the treatment of neuroendocrine tumors, as well as with antibodies to target CD20 (e.g., ZevalinTM and 90Y-Ibritumomab tiuxetan [3]) for the treatment of Non-Hodgkin’s lymphoma. Off-target accumulation of radioconjugates may, cause a risk of damage to radiosensitive healthy tissue such as the bone marrow and the kidneys, which present the dose-limiting factors in TRT [5,6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
