Ngcezu, Sonwarile Arthur. Student no 0200932R. MSc Thesis. Physics. Faculty of Science. 2006. Supervisor: Prof D van der Merwe. / Purpose: A retrospective study was conducted to calculate biological objective functions [Tumor control probability (TCP) for the prostate and normal tissue complication probability (NTCP), in particular for the rectum] for patients treated at Johannesburg hospital during the years 2002 – 2003 for prostate cancer and to correlate these values with observed clinical outcome. Ultimately these results were used to evaluate the effects of dose escalation on tumor control and rectal complications following radiotherapy using conformal external beam radiotherapy. Methods and materials: To calculate the TCP and the NTCP use was made of BIOPLAN, a PC-based software. This software allows the user to evaluate a treatment plan from the point of view of the biological response of the irradiated tissue, providing at the same time flexibility in the use of models (Poisson Statistics for TCP and Lyman-Kutcher-Burman for NTCP) and parameters. The clinical analysis was based on reports from on treatment review and follow-up visits made by the patients periodically after the treatment. PSA was used as a measure of biochemical failure and correlated with calculated TCP. Also, reported complications were compared to NTCP values calculated by BIOPLAN. The follow-up data were about 2 months to 2.5 years old. Results: Complications reported after therapy were all less than grade 3 (RTOG) for the patients, which means only mild complications were reported. No patient reported having necrosis, perforation or a fistula for all the prognostic groups. The calculated average NTCP (mild complications) was 36.3 ± 33.3 % and it was 3.9 ± 3.6 % for severe complications. The calculated TCP had an average of 84.3 ± 7.4 % and no biochemical failure was detected on the follow-ups. As the total dose was elevated through 70-Gy, 72-Gy, 76-Gy, and 86-Gy (2 Gy equivalent), the average TCP increased through 76.2 ± 3.8 %, 77.7 ± 2.6 %, 81.5 ± 4 % and 92.5 ± 2.5 %, respectively. The TCP therefore increased about 22 % by increasing prescribed doses from 70 Gy to 86 Gy. The relation between rectal overlap volume and the NTCP was not obvious (scattered). Conclusions The model predictions gave a reasonable reflection of the reported clinical outcome. A more comprehensive study requires derivation and use of accurate model parameters, and more mature follow-up data.

Ce travail de thèse est centré sur l'établissement de modèles prédictifs de toxicité radio-induite et sur l’étude de leur intérêt en cas de radiothérapie par modulation d’intensité. Six modèles NTCP ont été implémentés et leur paramètres identifiés pour la prédiction des toxicités rectale et vésicale tardives dans le cancer de la prostate. Leur capacité prédictive a été démontrée pour les deux organes. Par ailleurs, le modèle LKB a été utilisé pour la prédiction de l’œsophagite aiguë en cas de radiothérapie du cancer bronchique non à petites cellules. Ensuite, le bénéfice tiré de l’incorporation du paramètre de dose équivalent uniforme (EUD) pour la planification inverse de la radiothérapie par modulation d’intensité (IMRT) a été évalué. L’évaluation de cette approche a montré une baisse significative de la dose dans les parois vésicale et rectale. L’incorporation de plusieurs modèles biologiques dans le processus d’optimisation de l’IMRT a aussi été réalisée. Des fonctions objectif ont été établies pour les différents facteurs biologiques comme le NTCP, l’EUD et le TCP. Les résultats dosimétriques obtenus montrent la supériorité de l’optimisation basée sur des facteurs biologiques sur celle reposant uniquement sur des facteurs physiques. Enfin, les modèles NTCP classiques ont été améliorés en intégrant un paramètre radiobiologique supplémentaire, le rapport α/β. Ce rapport α/β a été identifié pour différents types de toxicité. Avec ce nouveau paramètre, les modèles NTCP peuvent finalement être étendus à des patients traités suivant différents fractionnements, les traitements hypofractionnés étant de plus en plus utilisés. / This thesis is focused on the predictive models of irradiation induced toxicities in intensity modulated radiotherapy. Six different NTCP models were implemented and their parameters were identified at predicting late rectal and bladder toxicities in prostate cancer. Their predictive skills have been demonstrated on both organs. Second, LKB model was used to predict the irradiation induced acute esophagitis after nun-small-cell lung cancer. Then, the benefit of using EUD in prostate cancer IMRT inverse planning was evaluated. The evaluation of the proposed approach proved that the use of EUD significantly decreased both the dose in the bladder and rectum walls. Then, the incorporation of different biological models in IMRT optimization process has been realized. Objective functions were established for different biological factors like NTCP, EUD and TCP. Obtained results show the superiority of the optimization based on biological factors over the optimization relying only on physical factors. Finally, classical NTCP models were corrected to deal with another radiobiological parameter, the α/β ratio. With this additional factor, NTCP models can be extended to predict toxicity for patients with different dose fractionation, these kinds of treatments being more and more clinically used.

L’hépatite B est une maladie infectieuse grave et extrêmement contagieuse. Malgré l’existence d’un vaccin efficace plus de 240 millions de personnes souffrent d’une infection hépatique chronique et plus de 780 000 personnes meurent chaque année des conséquences aiguës ou chroniques de l’hépatite B. Les traitements actuels qui consistent en l’utilisation d’interféron et/ou d’inhibiteurs de la réplication virale sont encore insuffisants. De nouvelles thérapeutiques ciblant l’entrée virale sont en développement, notamment le Myrcludex B qui inhibe l’infection en empêchant l’entrée virale. Cependant, les mécanismes d’entrée du VHB dans l’hépatocyte sont encore mal connus. Récemment, l’identification du NTCP comme récepteur spécifique du VHB a permis de mieux comprendre le mécanisme d’attachement de ce virus. Ce récepteur constitue une nouvelle cible pour des antiviraux. C’est aussi un transporteur de sels biliaires fortement régulé par les cytokines pro-inflammatoires. Les objectifs de ce travail étaient : (i) d’étudier la fusion du VHB, étape cruciale de l’entrée d’un virus enveloppé, en établissant un modèle artificiel de fusion entre des particules virales purifiées et des liposomes, et (ii) d’étudier l’effet de l’interleukine 6 sur l’entrée virale. Nous n’avons pas pu mettre en évidence de fusion entre les particules virales et des liposomes suggérant l’incapacité de ce virus à fusionner avec une bicouche lipidique néanmoins il reste possible que des conditions particulières liées aux spécificités du VHB soient requises. Nos résultats ont également montré que l’interleukine 6 inhibait l’entrée virale en diminuant l’expression de NTCP. / Hepatitis B is a severe and extremely contagious infectious disease. Despite an effective vaccine more than 240 million people are suffering from chronic infection and over 780 000 persons die each year from the consequences of acute and chronic hepatitis B. Current treatments consisting in the use of interferon and/or viral replication inhibitors are insufficient. New therapeutics targeting viral entry are in progress, such as Myrcludex B that has been shown to inhibit HBV infection by preventing HBV entry. However, the mechanism of HBV entry into hepatocytes is still poorly understood. Recently, the identification of NTCP as a specific HBV receptor allowed us to better understand the attachment of this virus. This receptor is now a target for antiviral molecules. It is also a carrier for bile salts known to be strongly regulated by pro inflammatory cytokines. The aims of our thesis were: (i) to study HBV entry by establishing an artificial model of fusion between purified viral particles and liposomes, and (ii) to study the interleukin 6 effect on viral entry. Our results with fusion assays suggest an absence of fusion in the entry process of this virus. However, fusion could require peculiar conditions related to HBV specificities. Our results also demonstrated that interleukin 6 inhibits virus entry by down-regulating NTCP expression.

Thulani Nyathi, Student no: 0413256X, MSc thesis, Physics, Faculty of science. 2006. Supervisor: Prof D van der Merwe. / This study aims to calculate tumour control probabilities (TCP) and normal tissue complication probabilities (NTCP) using radiobiological models and correlate these probabilities with clinically observed treatment outcome from follow-up records. These radiobiological calculations were applied retrospectively to thirty-nine paediatric patients who were treated with radiation at Johannesburg Hospital during the period January 1990 to December 2000 and had histologically proven rhabdomyosarcoma. Computer software, BIOPLAN, was used to calculate the TCP and NTCP arising from the dose distribution calculated by the treatment planning system and characterized by dosevolume histograms (DVHs). There was a weak correlation between the calculated TCP and the observed 5-year overall survival status. Furthermore, potential prognostic factors for survival were examined. Statistical analysis was performed using the Cox proportional hazards regression model. The 5-year overall survival rate was 55 %. The findings of this study are a yardstick against which more aggressive radiotherapy fractionation regimes can be compared.

The chief aim in developing radiation treatment plans is to maximise tumour cell kill while minimising the killing of normal cells. The acceptance by a radiation oncologist of a radiation therapy treatment plan devised by the radiation therapist, at present is largely based on the oncologists' previous clinical experience with reference to established patterns of treatment and their clinical interpretation of the dose volume histogram. Some versions of radiotherapy planning computer software now incorporate a function that permits biologically based predictions about the probability of tumour control (TCP) and/or normal tissue complications (NTCP). The biological models used for these probabilities are founded upon statistical and mathematical principles as well as radiobiology concepts. TCP and NTCP potentially offer the capability of being able to better optimise treatments for an individual patient's tumour and normal anatomy. There have been few attempts in the past to correlate NTCPs to actual treatment complications, and the reported complications have generally not shown any significant correlation. Thus determining whether either or both NTCPs and TCPs could be correlated with the observed clinical outcomes of prostate radiotherapy is the central topic of this thesis. In this research, TCPs and NTCPs were prospectively calculated for prostate cancer patients receiving radiation therapy, and subsequently assessed against the clinical results of the delivered treatments. This research was conducted using two different types of NTCP models, which were correlated against observed treatment-induced complications in the rectum and bladder. The two NTCP models were also compared to determine their relative efficacy in predicting the recorded toxicities. As part of this research the refinement of some of the published bladder parameters required for NTCP calculations was undertaken to provide a better fit between predicted and observed complication rates for the bladder wall which was used in this research. TCPs were also calculated for each patient using the best available estimate of the radiosensitivity of the prostate gland from recent research. The TCP/NTCP data was analysed to determine if any correlations existed between the calculated probabilities and the observed clinical data. The results of the analyses showed that a correlation between the NTCP and a limited number of toxicities did occur. Additionally the NTCP predictions were compared to existing parameters and methods for radiotherapy plan evaluation - most notably DVHs. It is shown that NTCPs can provide superior discriminatory power when utilised for prospective plan evaluation. While the TCP could not be correlated with clinical outcomes due to insufficient follow-up data, it is shown that there was a correlation between the TCP and the treatment technique used.

京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第20592号 / 生博第380号 / 新制||生||50(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 藤田 尚志, 教授 朝長 啓造, 教授 豊島 文子 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Prostate cancer is the most common malignancy afflicting Canadian men in 2011. Physicians use digital rectal exams (DRE), blood tests for prostate specific antigen (PSA) and transrectal ultrasound (TRUS)-guided biopsies for the initial diagnosis of prostate cancer. None of these tests detail the spatial extent of prostate cancer - information critical for using new therapies that can target cancerous prostate. With an MRI technique called proton magnetic resonance spectroscopic imaging (1H-MRSI), biochemical analysis of the entire prostate can be done without the need for biopsy, providing detailed information beyond the non-specific changes in hardness felt by an experienced urologist in a DRE, the presence of PSA in blood, or the “blind-guidance” of TRUS-guided biopsy. A hindrance to acquiring high quality 1H-MRSI data comes from signal originating from fatty tissue surrounding prostate that tends to mask or distort signal from within the prostate, thus reducing the overall clinical usefulness of 1H-MRSI data. This thesis has three major areas of focus: 1) The development of an optimized 1H-MRSI technique, called conformal voxel magnetic resonance spectroscopy (CV-MRS), to deal the with removal of unwanted lipid contaminating artifacts at short and long echo times. 2) An in vivo human study to test the CV-MRS technique, including healthy volunteers and cancer patients scheduled for radical prostatectomy or radiation therapy. 3) A study to determine the efficacy of using the 1H-MRSI data for optimized radiation treatment planning using modern delivery techniques like intensity modulated radiation treatment. Data collected from the study using the optimized CV-MRS method show significantly reduced lipid contamination resulting in high quality spectra throughout the prostate. Combining the CV-MRS technique with spectral-spatial excitation further reduced lipid contamination and opened up the possibility of detecting metabolites with short T2 relaxation times. Results from the in vivo study were verified with post-histopathological data. Lastly, 1H-MRSI data was incorporated into the radiation treatment planning software and used to asses tumour control by escalating the radiation to prostate lesions that were identified by 1H-MRSI. In summary, this thesis demonstrates the clinical feasibility of using advanced spectroscopic imaging techniques for improved diagnosis and treatment of prostate cancer.

Ce travail de thèse est centré sur l'établissement de modèles prédictifs de toxicité radio-induite et sur l'étude de leur intérêt en cas de radiothérapie par modulation d'intensité. Six modèles NTCP ont été implémentés et leur paramètres identifiés pour la prédiction des toxicités rectale et vésicale tardives dans le cancer de la prostate. Leur capacité prédictive a été démontrée pour les deux organes. Par ailleurs, le modèle LKB a été utilisé pour la prédiction de l'œsophagite aiguë en cas de radiothérapie du cancer bronchique non à petites cellules. Ensuite, le bénéfice tiré de l'incorporation du paramètre de dose équivalent uniforme (EUD) pour la planification inverse de la radiothérapie par modulation d'intensité (IMRT) a été évalué. L'évaluation de cette approche a montré une baisse significative de la dose dans les parois vésicale et rectale. L'incorporation de plusieurs modèles biologiques dans le processus d'optimisation de l'IMRT a aussi été réalisée. Des fonctions objectif ont été établies pour les différents facteurs biologiques comme le NTCP, l'EUD et le TCP. Les résultats dosimétriques obtenus montrent la supériorité de l'optimisation basée sur des facteurs biologiques sur celle reposant uniquement sur des facteurs physiques. Enfin, les modèles NTCP classiques ont été améliorés en intégrant un paramètre radiobiologique supplémentaire, le rapport α/β. Ce rapport α/β a été identifié pour différents types de toxicité. Avec ce nouveau paramètre, les modèles NTCP peuvent finalement être étendus à des patients traités suivant différents fractionnements, les traitements hypofractionnés étant de plus en plus utilisés.

Prostate cancer is the most common malignancy afflicting Canadian men in 2011. Physicians use digital rectal exams (DRE), blood tests for prostate specific antigen (PSA) and transrectal ultrasound (TRUS)-guided biopsies for the initial diagnosis of prostate cancer. None of these tests detail the spatial extent of prostate cancer - information critical for using new therapies that can target cancerous prostate. With an MRI technique called proton magnetic resonance spectroscopic imaging (1H-MRSI), biochemical analysis of the entire prostate can be done without the need for biopsy, providing detailed information beyond the non-specific changes in hardness felt by an experienced urologist in a DRE, the presence of PSA in blood, or the “blind-guidance” of TRUS-guided biopsy. A hindrance to acquiring high quality 1H-MRSI data comes from signal originating from fatty tissue surrounding prostate that tends to mask or distort signal from within the prostate, thus reducing the overall clinical usefulness of 1H-MRSI data. This thesis has three major areas of focus: 1) The development of an optimized 1H-MRSI technique, called conformal voxel magnetic resonance spectroscopy (CV-MRS), to deal the with removal of unwanted lipid contaminating artifacts at short and long echo times. 2) An in vivo human study to test the CV-MRS technique, including healthy volunteers and cancer patients scheduled for radical prostatectomy or radiation therapy. 3) A study to determine the efficacy of using the 1H-MRSI data for optimized radiation treatment planning using modern delivery techniques like intensity modulated radiation treatment. Data collected from the study using the optimized CV-MRS method show significantly reduced lipid contamination resulting in high quality spectra throughout the prostate. Combining the CV-MRS technique with spectral-spatial excitation further reduced lipid contamination and opened up the possibility of detecting metabolites with short T2 relaxation times. Results from the in vivo study were verified with post-histopathological data. Lastly, 1H-MRSI data was incorporated into the radiation treatment planning software and used to asses tumour control by escalating the radiation to prostate lesions that were identified by 1H-MRSI. In summary, this thesis demonstrates the clinical feasibility of using advanced spectroscopic imaging techniques for improved diagnosis and treatment of prostate cancer.

Orientador: Marco Antônio Rodrigues Fernandes / Resumo: O sucesso da radioterapia está intimamente ligado à razão terapêutica que representa o quociente entre a quantidade de tecido tumoral irradiado e o volume de tecido sadio atingido. A Probabilidade de Complicação em Tecidos Normais (NTCP) e a Probabilidade de Controle do Tumor (TCP) são parâmetros fornecidos por Sistemas de Planejamentos de Tratamentos (TPS) computadorizados, usados na rotina da radioterapia que auxiliam na interpretação da qualidade do tratamento. Neste trabalho são analisados os planejamentos de radioterapia de 03 pacientes portadores de câncer de próstata. Os planejamentos dos tratamentos foram realizados no TPS XiO, simulando as técnicas de radioterapia por intensidade modulada de feixe (IMRT) e radioterapia tridimensional conformada (3D-CRT). A dose de radiação preconizada para o volume de tratamento planejado (PTV) foi de 7.600 cGy, as simulações foram realizadas para um arranjo de 6 campos de radiação com feixes de raios X de megavoltagem e energia de 10 MV. Os volumes prostáticos variaram entre 107 cm3 e 143 cm3. A dose de cobertura D98% do PTV variou de 6.940 cGy a 7.570 cGy com IMRT e de 6.410 cGy a 7.250 cGy com 3D-CRT. Os valores obtidos para o TCP ficaram entre 73,5% a 81,1% com IMRT e entre 70,6% a 75,9% com 3D-CRT. Considerando os valores de NTCP para o reto e a bexiga, os maiores valores encontrados foram 6,9% para o reto e 6,1% para a bexiga, ambos planejados com a técnica de 3D-CRT. Para os casos analisados, os resultados mostram que a técnic... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The success of radiotherapy is closely related to the therapeutic ratio which represents the ratio of the amount of irradiated tumor tissue to the volume of healthy tissue achieved. Normal Tissue Complication Probability (NTCP) and Tumor Control Probability (TCP) are parameters provided by computerized treatment planning systems (TPS), used in radiotherapy routine and also allow the interpretation of treatment quality. The aim of this work is analyze the planning of 03 cases of patients submitted to prostate cancer radiotherapy. The treatment plans were performed in TPS XiO, simulating the techniques of beam intensity modulated radiotherapy (IMRT) and tree-dimensional conformal radiation therapy (3D-CRT). The recommended radiation dose for the planned treatment volume (PTV) was 7600 cGy, the simulations were performed for an arrangement of 6 radiation fields with megavoltage X-ray beams and 10 MV energy. Prostatic volumes ranged from 107cm3 to 143cm3 . The D98% PTV coverage dose ranged from 6,940 cGy to 7,570 cGy with IMRT and from 6,410 cGy to 7,250 cGy with 3D-CRT. The values obtained for TCP were between 73.5% to 81.1% with IMRT and between 70.6% to 75.9% with 3D-CRT. Considering the NTCP values for the rectum and bladder, the highest values found were 6.9% for the rectum and 6.1% for the bladder, both planned using the 3D-CRT technique. For the analyzed cases, the results show that the IMRT technique presents better NTCP and TCP values than the 3D-CRT technique. These par... (Complete abstract click electronic access below) / Mestre