The main purpose of this study was to evaluate medication use patterns (i.e., dose escalation, medication adherence, persistence, and switching) of rheumatoid arthritis (RA) patients on etanercept (ETN), infliximab (IFX) or adalimumab (ADA) and the associated healthcare utilization costs using Texas Medicaid data. Study participants were Medicaid beneficiaries (18-63 years) with an RA diagnosis (ICD-9-CM code 714.0x) who had no claim for a biologic agent in the 6-month pre-index period (July 1, 2003 - Dec 31, 2010). The index date was the first date when the patient had the first fill for any of the study TNF inhibitors (ETN, ADA or IFX) within the study identification period (Jan 1, 2004 – Aug 31, 2010). Data were extracted from July 1, 2003 to August 31, 2011. Prescription and medical claims were analyzed over an 18-month study period (i.e., 6-month pre-index and 12-month post-index periods). The primary study outcomes were adherence, persistence, dose escalation, switching and cost (i.e., total healthcare, RA-related and TNF inhibitor therapy cost). The study covariates were demographic factors (age, gender, race/ethnicity), pre-index use of other RA-related medications (pain, glucocorticoids and disease modifying antirheumatic drugs), total number of non-study RA-related medications used at index, pre-index RA and non-RA related visits, pre-index healthcare utilization cost and Charlson Comorbidity Index score. Conditional regression analyses, which accounts for matched samples, were used to address the study objectives. After propensity score matching, 822 patients (n=274/group) comprised the final sample. The mean age (±SD) was 48.9(±9.8) years, and the majority of the subjects were between 45 and 63 years (69.2%), Hispanic (53.7%) and female (88.0%). Compared to patients on ETN, the odds of having a dose escalation were ≈ 5 [Odds Ratio= 4.605 [95% CI= 1.605-12.677], p=0.0031] and ≈ 8 [Odds Ratio=7.520, [95% CI= 2.461-22.983], p=0.0004] times higher for IFX and ADA patients, respectively, while controlling for other variables in the model. Compared to ETN, patients on IFX (p=0.0171) were more adherent while adherence was comparable with patients on ADA (p=0.1144). Compared to patients on ETN, the odds of being adherent (MPR ≥ 80%) to IFX was ≈ 2 times higher [Odds Ratio= 2.437, [95% CI=1.592-3.731], p < 0.0001] while controlling for other variables in the model. Persistence to index TNF inhibitor therapy and likelihood to switch or discontinue index TNF inhibitor therapy were comparable among the 3 study groups. In addition, the duration of medication use (i.e., persistence) prior to switching or discontinuation of index therapy was comparable among the 3 study groups. Furthermore, for each of the cost variables (total healthcare, RA-related and TNF inhibitor therapy cost), costs incurred by patients on ETN were significantly lower (p < 0.01) than those incurred by ADA patients but significantly higher (p < 0.01) than those incurred by IFX patients. Finally, a positive and significant relationship (p < 0.0001) was found between RA-related healthcare cost, adherence and persistence to TNF inhibitor therapies. In conclusion, ETN was associated with lower rates of dose escalation compared to ADA or IFX. However, adherence was better and associated healthcare costs were lower with IFX. Clinicians should endeavor to work with each individual patient to identify patient-specific factors responsible for poor medication use behaviors with TNF-inhibitor therapies. Reducing the impact of these factors and improving adherence should be included as a major part of the treatment plan for each RA patient. RA patients need to be adequately educated on the importance of adhering and persisting to their TNF-inhibitor therapy as poor medication adherence/persistence negatively impacts the RA disease process. / text

No description available.

Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20997号 / 医博第4343号 / 新制||医||1027(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 平井 豊博, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Using a tailored dose distribution for personalized radiotherapy with the help of positron emission tomography (PET) might give an edge for successful tumour elimination. One of the main determinants for tumour radioresistance in several solid tumours has been investigated as hypoxia, including head and neck cancer (HNC). Using novel methods of converting radiotracer uptake into partial oxygen pressure distribution in the form of partial pressure maps, it is possible to delineate the hypoxic region of a target to further escalate the treatment dose there, aiming at an increase in tumour control. However, the registration between functional and structural images may have an impact on the effectiveness of dose escalation, and choosing the correct registration method could be imperative. In this master’s thesis, the impact of choosing rigid or deformable image registration between planning-CT and PET/CT images on the characterization of the hypoxic compartment, as well as on the treatment evaluation in terms of tumour control and normal tissue complication, was assessed. This was achieved by, using hypoxic patients of a cohort of 22 HNC patients, creating a separate plan for each registration method, for each patient, and comparing them quantitatively. The results showed that both methods would yield distinctly different dose distributions when planned using the same objectives and constraints in terms of dose level and shape. Furthermore, they both give a distribution of similar quality. However, using rigid registration together with the deformed PET did not render lower results overall in tumour control. Thus, no advantage could be seen in choosing deformable registration over rigid registration when aiming at tumour control.

Purpose: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.) The need for further validation of novel PET tracers before their implementation in dose escalation schema and 3.) The lack of concrete pre-clinical data supporting the use of PET images for guidance of selective sub-volume dose escalations. Methods and materials: In order to compare multiple PET images the confounding effects of mispositioning and anatomical change between imaging sessions needed to be alleviated. To mitigate the effects of these sources of error, deformable image registration was employed. A deformable registration algorithm was selected and the registration error was evaluated via the introduction of external fiducials to the tumor. Once a method for image registration was established, a procedure for validating the use of novel PET tracers with FDG was developed. Nude mice were used to perform in-vivo comparisons of the spatial distributions of two PET tracers, FDG and FLT. The spatial distributions were also compared across two separate tumor lines to determine the effects of tumor morphology on spatial distribution. Finally, the research establishes a method for acquiring pre-clinical data supporting the use of PET for image-guidance in selective dose escalation. Nude mice were imaged using only FDG PET/CT and the resulting images were used to plan PET-guided dose escalations to a 5 mm sub-volume within the tumor that contained the highest PET tracer uptake. These plans were then delivered using the Small Animal Radiation Research Platform (SARRP) and the efficacy of the PET-guided plans was observed. Results and Conclusions: The analysis of deformable registration algorithms revealed that the BRAINSFit B-spline deformable registration algorithm available in SLICER3D was capable of registering small animal PET/CT data sets in less than 5 minutes with an average registration error of .3 mm. The methods used in chapter 3 allowed for the comparison of the spatial distributions of multiple PET tracers imaged at different times. A comparison of FDG and FLT showed that both are positively correlated but that tumor morphology does significantly affect the correlation between the two tracers. An overlap analysis of the high intensity PET regions of FDG and FLT showed that FLT offers additional spatial information to that seen with FDG. In chapter 4 the SARRP allowed for the delivery of planned PET-guided selective dose escalations to a pre-clinical tumor model. This will facilitate future research validating the use of PET for clinical selective dose escalation.

No description available.

Computed tomography urography (CTU) is today the imaging method used to investigate patients with suspected urinary tract malignancy, replacing the old imaging method intravenous pyelography (IVP) about a decade ago. The downside of this shift was that the effective radiation dose to the examined patient was eight times higher for CTU compared to IVP. Based on four different studies, the present thesis focused on efforts to reduce the CTU radiation dose.   In study I, the number of cysts and solid lesions in the separate scan phases was evaluated in 57 patients undergoing four-phase CTU 1997-98. The number of scans was reduced from four to three when the nephrographic scan was abolished following study I. Study II registered the diameter of renal cell carcinoma (RCC) and the presenting symptoms in the total number of patients (n=232) diagnosed with RCC between 1997 and 2003. The results from study II showed that the critical size for RCCs to cause macroscopic hematuria was ≥ 4 cm. Study III was a dose-escalation study aimed to decide the minimal possible tube load in the unenhanced and excretory phase scans if the low dose images are reviewed together with normal dose corticomedullary phase images. Study III showed that it is possible to reduce the mean effective dose in three phase CTU from 16.2 mSv to 9.4 mSv with a combined low and normal dose CTU protocol. Study IV investigated the changes in the CTU protocol between 1997 and 2008, and the development of the effective radiation dose. Study IV clarified how the CTU protocol has changed between 1997 and 2008 and as a result the mean effective radiation dose to patients undergoing CTU in 2008 is only 39% of the effective dose in 1997.   In conclusion, the findings from the studies included in this thesis have contributed to a reduced radiation dose to patients undergoing CTU. The mean effective dose from CTU is at present only three times higher compared to that from the IVP.

General attrition rates in drug development pipeline have been recognized as a necessity to shift gears towards new methodologies that allow earlier and correct decisions, and the optimal use of all information accrued throughout the process. The quantitative science of pharmacometrics using pharmacokinetic-pharmacodynamic models was identified as one of the strategies core to this renaissance. Coupled with Optimal Design (OD), they constitute together an attractive toolkit to usher more rapidly and successfully new agents to marketing approval. The general aim of this thesis was to investigate how the use of novel pharmacometric methodologies can improve the design and analysis of clinical trials within drug development. The implementation of a Monte-Carlo Mapped power method permitted to rapidly generate multiple hypotheses and to adequately compute the corresponding sample size within 1% of the time usually necessary in more traditional model-based power assessment. Allowing statistical inference across all data available and the integration of mechanistic interpretation of the models, the performance of this new methodology in proof-of-concept and dose-finding trials highlighted the possibility to reduce drastically the number of healthy volunteers and patients exposed to experimental drugs. This thesis furthermore addressed the benefits of OD in planning trials with bio analytical limits and toxicity constraints, through the development of novel optimality criteria that foremost pinpoint information and safety aspects. The use of these methodologies showed better estimation properties and robustness for the ensuing data analysis and reduced the number of patients exposed to severe toxicity by 7-fold.  Finally, predictive tools for maximum tolerated dose selection in Phase I oncology trials were explored for a combination therapy characterized by main dose-limiting hematological toxicity. In this example, Bayesian and model-based approaches provided the incentive to a paradigm change away from the traditional rule-based “3+3” design algorithm. Throughout this thesis several examples have shown the possibility of streamlining clinical trials with more model-based design and analysis supports. Ultimately, efficient use of the data can elevate the probability of a successful trial and increase paramount ethical conduct.

The clinical introduction of proton therapy requires an extensive analysis of its benefits compared to conventional radiotherapy and a detailed analysis of possible uncertainties which might have serious consequences for patient treatment. In the first part of the presented thesis, the expected toxicities were evaluated for a treatment of head and neck cancer patients using a biologically adapted dose escalation schedule with photon and proton therapy. The feasibility of the dose escalation schedule could be demonstrated for both photon and proton therapy, since only a small increase in toxicity risk occurred for most toxicities. However, the expected toxicity risks were in most cases smaller with proton therapy. Furthermore, a higher benefit was found for patients with primary tumour locations in the upper head and neck area, who thus might be preferably referred to proton therapy. In the second part of this thesis, an extensive analysis of the impact of tumour motion in lung cancer treatment with active-scanning proton therapy was conducted. It could be shown, that dose degradations were small for tumour motion amplitudes below 5 mm. Parameters like the target volume concept, the optimisation approach, changes in the motion pattern and application sequence times had additional impact on the dose degradation. However, their magnitude was patient specific. Since not all parameters can be assessed before treatment, e.g. the motion pattern during treatment, prospective estimations should be supplemented by retrospective analyses. / Die Einführung der Protonentherapie in die klinische Praxis erfordert umfassende Analysen ihrer Vor- und Nachteile im Vergleich zur konventionellen Photonentherapie sowie detaillierte Untersuchungen der Auswirkungen von Unsicherheiten in der Therapieapplikation. Im ersten Teil der vorliegenden Arbeit wurden die zu erwartenden Nebenwirkungen bei der Behandlung von Patienten mit Kopf-Hals-Tumoren mit einem biologisch-adaptierten Fraktionierungsschema inklusive Dosiseskalation mit Photonen- und Protonentherapie evaluiert. Dabei konnte gezeigt werden, dass die Dosiseskalation sowohl mit Photonen- als auch Protonentherapie angewandt werden kann, da die Wahrscheinlichkeit für das Auftreten von Nebenwirkungen in den meisten Fällen kaum erhöht wurde. Weiterhin wurden die Nebenwirkungswahrscheinlichkeiten mit der Protonentherapie im Vergleich zur Photonentherapie reduziert. Dies war vor allem für Patienten mit Tumoren im oberen Kopf-Hals-Bereich der Fall. Diese könnten daher bevorzugt zur Protonentherapie überwiesen werden. Darüber hinaus wurde im zweiten Teil der Arbeit eine umfassende Analyse des Einflusses der Tumorbewegung auf die Dosisverteilung bei Behandlung von Lungentumoren mit aktiver Protonenstrahlformierung durchgeführt. Dabei zeigte sich, dass Dosisdegradierungen bei Bewegungsamplituden unter 5mm gering sind. Parameter wie das Zielvolumenkonzept, Veränderungen des Bewegungsmusters oder der Applikationszeiten nehmen zusätzlich Einfluss auf die Dosisdegradierung, allerdings in unterschiedlichem Maß für individuelle Patienten. Da nicht alle Parameter vor Behandlung bekannt sein können, sollten prospektive Dosisabschätzungen durch retrospektive Analysen ergänzt werden.