京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18452号 / 医博第3907号 / 新制||医||1004(附属図書館) / 31330 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 武田 俊一, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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A well-established method for treating lung cancer is curative-intent radiation therapy (RT). The most significant challenge for RT is to accurately target the lesion volume while avoiding the irradiation of surrounding healthy tissue. Currently at the Juravinski Cancer Centre (JCC), treatment plans for lung cancer patients are completed using fluorodeoxyglucose positron emission tomography (FDG-PET) and four-dimensional computed tomography (4DCT) images. There is no clear protocol, however, to compensate for respiratory motion in PET images and it is not known how lesion volumes generated from PET reflect the true volume. This project evaluated methods to optimize the use of PET images in the radiation treatment planning workflow and quantify the effects of respiratory motion. First, a 4D XCAT digital phantom was used to quantify respiratory motion and its effects on lesion displacement. A CTN physical phantom and 3D-printed irregularly shaped lesion were imaged to determine the accuracy of the PET EDGE automated segmentation algorithm (ASA). Lastly, rigid and deformable image registration techniques were used to propagate the diagnostic PET scan of the irregular lesion to the 4D planning CT. PET EDGE was used to generate target volumes which were then compared to internal target volumes (ITVs) generated from manual contouring of the 4DCT image alone. We found that lesion displacement due to respiratory motion can be adequately modeled using a moving platform set to oscillate 1 cm and 2 cm for normal and deep breathing, respectively. Optimal target delineation was found when diagnostic PET was propagated to the planning CT using rigid image registration for lesions that experienced 1 cm of oscillatory motion during imaging. In contrast, PET EDGE would overestimate volumes in static cases and underestimate volumes in instances of 2 cm dynamic motion meant to simulate deep breathing. / Thesis / Master of Science (MSc)

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23766号 / 医博第4812号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 鈴木 実, 教授 中本 裕士, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Meta-analysis is a set of statistical procedures used to aggregate results from independent studies. These techniques are widely used in clinical research to get the overall picture from a series of trials addressing the same question. We used Bayesian hierarchical models to evaluate effect of the addition of chemotherapy to radiotherapy treatment in patients with newly diagnosed locally advanced squamous cell or undifferentiated nasopharyngeal cancer. We also performed subgroup analysis to determine the best timing and regimen of chemotherapy. It is demonstrated that the Bayesian model does not only efficiently incorporate all sources of variability, but is also robust under different likelihood functions. The results based on Bayesian hierarchical models assuming a non-informative prior are similar to those from classical random effects models. A significant effect was observed in favour of patients who received radiochemotherapy versus those who received radiotherapy alone. The analysis revealed that neoadjustant chemotherapy is the best timing for treatment. / Thesis / Master of Science (MS)

Telomerase is expressed in the majority (>85%) of tumours but not in differentiated normal tissue. This enzyme catalyses the elongation of telomeres – a process critical for continued cell proliferation. Telomerase is a potential novel target for molecularly-targeted radiotherapy (mRT), due to its nuclear localization and expression profile. The radiolabelling of telomerase inhibitors may accelerate and enhance the cytotoxicity of such molecules, as a result of irradiation of the DNA. An oligonucleotide targeting telomerase RNA (hTR), shown to inhibit enzyme activity in vitro, was selected for study. Complementary and non-targeting control oligonucleotides were conjugated to a metal chelator (DTPA) to allow radiolabelling with indium-111. The radioiodination of MST-312, BIBR-1532 and flavonoid-derived small molecule inhibitors of telomerase was also pursued. The inhibitory activity of the candidate molecules was analysed using the telomeric repeat amplification protocol (TRAP). The internalization of inhibitors was assessed by gamma-counting following cell lysis. The clonogenic assay was employed to measure the effect of modified inhibitors on cell survival. Small molecule telomerase inhibitors were modified for labelling with iodine-123, which led to a modest decrease in inhibitory potency, compared to the parent molecules. Radiolabelled small molecules exhibited poor stability and internalization into cancer cells, so were unsuitable for mRT. Modified oligonucleotides potently inhibited telomerase activity, whereas a non-targeting oligonucleotide exhibited no inhibitory activity. Indium-111 radiolabelled oligonucleotides decreased the clonogenic survival of telomerase-positive breast cancer cells but not telomerase-negative cells, in a sequence-specific manner. Accordingly, complementary radiolabelled oligonucleotides were found to induce the DNA damage marker γH2AX. Oligonucleotides localized to nuclear Cajal bodies, the sites of telomerase assembly, in a proportion of cancer cells. Telomerase inhibitors of different classes were radiolabelled with Auger electron-emitting radionuclides, and delivered to cells. Radiolabelled oligonucleotides targeting telomerase significantly reduced the clonogenicity of cancer cells in vitro. This study represents a novel approach for the mRT of telomerase-positive cancers.

The purpose of this thesis is to validate the Monte Carlo algorithm for electron radiotherapy in the Eclipse™ treatment planning system (TPS), and to compare the accuracy of the Electron Monte Carlo algorithm (eMC) to the Pencil Beam algorithm (PB) in Eclipse™. Dose distributions from GafChromic™ EBT3 film measurements were compared to dose distributions from eMC and PB treatment plans. Measurements were obtained with 6MeV, 9MeV, and 12MeV electron beams at various depths. A 1 cm thick solid water template with holes for bone-like and lung-like plugs was used to create assorted configurations and heterogeneities. Dose distributions from eMC plans agreed better with the film measurements based on gamma analysis. Gamma values for eMC were between 83%-99%, whereas gamma values for PB treatment plans were as low as 38.66%. Our results show that using the eMC algorithm will improve dose accuracy in regions with heterogeneities and should be considered over PB. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2014. / FAU Electronic Theses and Dissertations Collection

Radiotherapy cures many cancers, but the optimum total doses and fractionations used to treat different cancer types remain uncertain. While conventional fractionation (≈2 Gy per fraction) is common in many countries, UK practice has been highly variable. This thesis compared different curative-intent radiotherapy dose-fractionations used in non-small cell lung and breast cancer. These two cancers together make up over a quarter of UK cancer incidence and mortality, and radiotherapy can increase cure rates of both cancers. Two studies were conducted: (A) A meta-analysis of randomised radiotherapy trials in non-small cell lung cancer and (B) A cohort study of non-small cell lung and breast cancer radiotherapy in the Thames Valley. For the meta-analysis, a systematic search was conducted. Eligible studies were randomised comparisons of two or more radiotherapy regimens. Median survival ratios were calculated for each comparison and pooled. 3,795 patients in 25 randomised comparisons of radiotherapy dose were studied. When radiotherapy was given alone, the higher dose within-trial resulted in increased survival (median survival ratio 1.13, 95% confidence interval 1.04-1.22). When radiotherapy was given with concurrent chemotherapy, the higher dose within-trial resulted in decreased survival (median survival ratio 0.83, 95% confidence interval 0.71-0.97). For the cohort study, multiple Public Health England data sources were combined to obtain information on radiotherapy, patient characteristics, and outcomes. Multivariable Cox regressions were conducted separately by cancer site. 324 non-small cell lung, 8,879 invasive breast, and 477 ductal carcinoma in situ patients were studied. In analyses of both non-small cell lung and invasive breast cancer, increasing radiotherapy dose was associated with improved survival in some treatment centres, while in other centres the opposite was true. These opposite trends by treatment centre were unlikely to be explained by chance, and they suggest that differences in patient selection were driving results. There were insufficient events among ductal carcinoma in situ patients to assess associations. Findings from the meta-analysis support consideration of further radiotherapy dose escalation trials, making use of modern methods to reduce toxicity. Findings from the cohort study suggest that it is not possible to use observational studies to examine causal effects of radiotherapy dose-fractionation. This thesis therefore shows the continued importance of conducting sufficiently large randomised trials to ascertain optimal dose-fractionation in radiotherapy.

In this project we introduced a spatial frequency-based objective function for optimization of dose distributions used in spatially fractionated radiotherapy (also known as grid therapy). Several studies indicate that tissues can tolerate larger mean doses of radiation if the dose is delivered heterogeneously or to a partial volume of the organ. The objective function rewards heterogeneous dose distributions in the collaterally irradiated healthy tissues and is based on the concept of a maximum stem-cell migration distance. The stem-cell depletion hypothesis stipulates that damaged tissues can be repopulated by nearby surviving stem-cells within a critical volume outlined by the maximum migration distance. Proton grid therapy dose distributions were calculated to study the viability of our spatial frequency-based objective function. These were computed analytically with a proton pencil beam dose kernel. A multi-slit collimator placed flush against the surface of a water phantom defined the entrance fluence. The collimator geometry was described by two free parameters: the slit width and the number of slits within a specified field width. Organs at risk (OARs) and a planning target volume (PTV) were defined. Two dose constraints were set on the PTV and objective function values were computed for the OARs. The objective function measures the high-frequency content of a masked dose distribution, where the distinction between low- and high frequencies was made based on a characteristic distance. Out of the feasible solutions, the irradiation geometry that produced the maximum objective function value was selected as the optimal solution. With the spatial frequency-based objective function we were able to find, by brute-force search, unique optimal solutions to the constrained optimization problem. The optimal solutions were found on the boundary of the solution space. The objective function can be applied directly to arbitrarily shaped regions of interest and to dose distributions produced by multiple field angles. The next step is to implement the objective function in an optimization environment of a commercial treatment planning system (TPS).