Lithium formate EPR dosimetry : Properties and applications in radiotherapy

Each year 10 000 Norwegian cancer patients are treated with radiation. According to the World Health Organization (WHO), more than half of all cancer patients should be offered radiation therapy during their period of illness. The precise radiation targeting of cancer cells with sufficient radiation dose, so that the cancer cells stop dividing while adverse effects are acceptable, is crucial for the outcome of radiation therapy. In this dissertation for the degree of Philosophiae doctor, Einar Waldeland has studied a method for measuring radiations doses, namely electron paramagnetic resonance (EPR) dosimetry. The radiation sensitive material employed is lithium formate monohydrate, which is a relatively new material for this application. To date, this method is not routinely used in Norway and to a limited extent elsewhere. The thesis covers some basic properties of this new dosimetry system and concludes with the feasibility of the method for high precision dosimetry of patient treatments. The work also compares this method with the most established EPR dosimetry system, alanine EPR dosimetry. 6 individual peer-reviewed papers are included in the thesis. They show basic qualitative properties of the EPR signal from lithium formate irradiated with neutrons, protons, nitrogen ions, electrons and photons, and how these properties may be utilized for dose measurements. The two first works outline how the signal may be used to characterize the radiation type used, when this is not known by the observer. The third work describes properties of the method when extremely high doses are used, such as industrial sterilization of food. The next two papers include correction factors necessary for standardized high precision dose measurements for radiation therapy of patients. The last work demonstrates the use of lithium formate EPR dosimetry in a realistic treatment of a humanlike phantom

Stereotactic Body Radiation Therapy Is Effective and Safe in Patients with Early-Stage Non-Small Cell Lung Cancer with Low Performance Status and Severe Comorbidity

Background: The purpose of this study was to assess stereotactic body radiation therapy (SBRT) results and toxicity for stage I non-small cell lung cancer patients with low performance status and severe comorbidity. Patients and Methods: From September 2008 to April 2010, 36 patients with 38 lesions were treated with hypofractionated SBRT. All except one were medically inoperable, had low performance status and/or severe cardiovascular and/or cardiopulmonary comorbidity. The patients were immobilized in an Elekta stereotactic body frame to improve setup accuracy, and four-dimensional CT scans were used for target delineation. Fractions of 15 Gy were prescribed to cover the planning target volume, giving a total dose of 45 Gy, with 1 fraction every second day. Cone beam CT was applied at each fraction to correct for setup errors. The patients were followed with toxicity evaluation and radiographic follow-up. Results: Median follow-up time was 13.8 months (0–21 months). The local tumor control after 12 months was 100%. Four patients developed regional relapse about 12 months after SBRT. The 1-year disease-free survival was 83%. The median tumor shrinkage at 1 year was 22 mm. Three patients experienced systemic relapse after 13 months. One patient developed grade 3 chest pain toxicity and 16 patients reported temporary grade 1 chest pain toxicity. Two patients reported temporary increased dyspnea. No patient experienced a reduction of the performance status after SBRT. Conclusion: SBRT is an effective and safe treatment modality for elderly patients with early-stage non-small cell lung cancer, having low performance status and severe comorbidity. It is possible to achieve high local control rates with good tolerance

In silico investigations of intratumoral heterogeneous interstitial fluid pressure

Recent preclinical studies have shown that interstitial fluid pressure (IFP) within tumors can be heterogeneous Andersen et al. (2019). In that study tumors of two xenograft models, respectively, HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma, were investigated. Significant heterogeneity in IFP was reported and it was proposed that this was associated with division of tissue into compartments separated by thick connective tissue bands for the HL-16 tumors and with dense collagen-rich extracellular matrix for the Panc-1 tumors. The purpose of the current work is to explore these experimental observations by using in silico generated tumor models. We consider a mathematical multiphase model which accounts for tumor cells, fibroblasts and interstitial fluid. The model has been trained to comply with experimental in vitro results reported in Shieh et al. (2011) which has identified autologous chemotaxis, ECM remodeling, and cell-fibroblast interaction as drivers for invasive tumor cell behavior. The in silico model is informed with parameters that characterize the leaky intratumoral vascular network, the peritumoral lymphatics which collect the fluid, and the density of ECM as represented through the hydraulic conductivity of the interstitial space. Heterogeneous distribution of solid stress may result in heterogeneous compression of blood vessels and, thus, heterogeneous vascular density inside the tumor. To mimic this we expose the in silico tumor to an intratumoral vasculature whose net effect of density of blood vesssels and vessel wall conductivity is varied through a 2D Gaussian variogram constrained such that the resulting IFPs lie within the range as reported from the preclinical study. The in silico cervical carcinoma model illustrates that sparse ECM was associated with uniform intratumoral IFP in spite of heterogeneous microvascular network, whereas compartment structures resulted in more heterogeneous IFP. Similarly, the in silico pancreatic model shows that heterogeneity in the microvascular network combined with dense ECM structure prevents IFP to even out and gives rise to heterogeneous IFP. The computer model illustrates how a heterogeneous invasive front might form where groups of tumor cells detach from the primary tumor and form isolated islands, a behavior which is natural to associate with metastatic propensity. However, unlike experimental studies, the current version of the in silico model does not show an association between metastatic propensity and elevated IFP.publishedVersio

ESR-dosimetri ved nøytron- og ionebestråling av litium format

Litium format monohydrat (Lifo) er i denne oppgaven undersøkt som dosimetermateriale i ESR- (Elektron Spinn Resonans) dosimetri, med vekt på responsen ved nøytron- og ionebestråling. Lifo er tidligere vist å være et lovende ESR-dosimetermateriale fordi det er 5-6 ganger mer sensitivt enn alanin (det mest brukte ESR-dosimetret) og gir presise dosemålinger for lave doser. Til bestråling er det brukt elektroner, protoner, nøytroner og nitrogenioner. Det er foretatt sammenligninger mellom Lifo-dosimetre bestrålt med disse strålekvalitetene og 60Co γ-bestrålte Lifo-dosimetre. Dosimeterresponsen er i denne oppgaven vist å være uavhengig av de brukte elektronenergier. Dette er bekreftet av Monte Carlo-simuleringer, og en samlet elektron-energirespons for eksperimentelle og Monte Carlo-simulerte data ble funnet til å være 0.99±0.02. Samtidig er endringer i dosimeterresponsen ved høy-LET sammenlignet med lav-LETbestråling observert; i form av at doseresponsen (dosimeteravlesning per dose) ble redusert og ESR-linjebreddene økte. For bestråling med nitrogenioner ble det for eksempel funnet en reduksjon i doserespons på rundt 30% og en linjebreddeøkning på rundt 5% sammenlignet med γ-bestråling. Metningseksperimenter bekreftet de observerte endringene i responsen og indikerte endringer i de mikroskopiske materialegenskaper til partikkelbestrålte dosimetre. Dette var for eksempel reduksjon i T2-relaksasjonstid i høy-LET-bestrålte Lifo-dosimetre sammenlignet med γ-bestrålte Lifo-dosimetre. På bakgrunn av resultatene er det anslått at det i nitrogenbestrålte Lifo-dosimetre forekommer rundt 30% flere rekombinasjoner enn i protonbestrålte Lifo-dosimetre. Videre er det bekreftet at det er betydelig større lokal radikaltetthet i nitrogenbestrålte Lifodosimetre sammenlignet med protonbestrålte Lifo-dosimetre. Det er også vist at Lifo kan brukes som LET indikator for ukjente strålekvaliteter; enten ved å måle linjebredder, ved å beregne forholdet mellom peak-to-peak-verdien (PP-verdien) tilhørende målinger ved to forskjellige mikrobølgeeffekter eller ved å utføre en fullstendig metningsanalyse. Endringene i dosimeterrespons må tas i betraktning ved ESR-dosimetri med Lifo. Resultatene i denne oppgaven viser at egenskaper ved ESR-spekteret fra bestrålt Lifo, som linjebredden, kan brukes til å korrigere målingene for å finne riktig dose, noe som er viktig når en stor andel rekombinasjoner forekommer ved ionebestråling. Som dosimetersystem har ESR/Lifo mange fordelaktige egenskaper som det er vel verdt å fortsette kartleggingen av