Η παρούσα διπλωματική εργασία αποτελεί μία βιβλιογραφική μελέτη επάνω στην υποκλασματοποιημένη ακτινοθεραπεία του γλοιοβλαστώματος. Το πολύμορφο γλοιοβλάστωμα είναι ο πιο επιθετικός τύπος πρωτοπαθούς εγκεφαλικού όγκου με δυσμενείς προγνωστικούς δείκτες. Η θεραπεία του γλοιοβλαστώματος έχει προβληματίσει καθώς τα αποτελέσματα από τις διάφορες θεραπευτικές προσεγγίσεις είναι απογοητευτικά. Στο πρώτο μέρος της εργασίας έχουν δοθεί στοιχεία για την παθοφυσιολογία της νόσου και έχει γίνει ανάλυση της επίδρασης της ακτινοβολίας πρώτα στην οργανική ύλη και στην συνέχεια στο γλοιοβλάστωμα. Αμέσως μετά, εξετάστηκε, ο ρόλος της ακτινοθεραπείας κάνοντας εκτενή αναφορά στις βασικές της αρχές και στις τεχνολογικές εξελίξεις των ακτινοθεραπευτικών τεχνικών σε σχέση με το γλοιοβλάστωμα. Έγινε αναφορά σε κάθε μια χωριστά και παρουσιάζονται τα πλεονεκτήματα και τα μειονεκτήματα όλων των τεχνικών στο γλοιοβλάστωμα. Ακολούθως, η εργασία αυτή εστίασε την προσοχή της στην υποκλασματοποίηση της ακτινοθεραπείας, περιγράφοντας τον ορισμό της και παρουσιάζοντας τις διαστάσεις της. Στο τέλος του πρώτου μέρους αφιερώθηκε ένα μικρό κομμάτι στις γονιδιακές θεραπείες, καθώς δεν είναι λίγοι οι ερευνητές που αναζητούν ευθύνες σε συγκεκριμένα γονίδια και ελπίζουν να ανοίξει ο δρόμος σε νέες γονιδιακές θεραπευτικές προσεγγίσεις στο γλοιοβλάστωμα. Στο δεύτερο μέρος της εργασίας έγινε αναλυτική αναφορά στις μελέτες που έχουν γίνει σχετικά με την υποκλασματοποιημένη ακτινοθεραπεία του γλοιοβλαστώματος και παρατέθηκαν τα σημαντικότερα συμπεράσματα ολόκληρης της βιβλιογραφικής ανασκόπησης στο θέμα. Ένας συγκεντρωτικός πίνακας με επιλεγμένα στοιχεία όλων των μελετών ολοκλήρωσε τη διπλωματική εργασία αυτή. / The present dissertation is a literature study on the hypofractionated radiotherapy of glioblastoma. Glioblastoma multiform is the most aggressive type of primary brain tumour with unfavourable prognostic indicators. Treatment of glioblastoma has puzzled since the results of the different therapeutic approaches are disappointing. In the first part, information was given concerning the pathophysiology of the disease and an analysis have been made on the effect of radiation in the first organic material and then in glioblastoma. Then, the role of radiotherapy was examined, with extensive reference to basic principles and technological developments in radiotherapeutic techniques compared to glioblastoma. A reference was made to each single technique and then all advantages and disadvantages on glioblastoma were presented. Thereafter, the dissertation focuses its attention on subfractionation of radiotherapy, describing its definition and showing its dimensions. At the end of the first part a small chapter was devoted in gene therapies, as there are a few researchers looking into specific genes and hope to open the road to new gene therapeutic approaches in glioblastomas. The second part was a detailed report to studies that have been made on hypofractionated radiotherapy of glioblastoma and the most important conclusions of the literature review on the subject have been cited. Finally, a summary table of selected data of all studies concludes this dissertation.

A partir de um melhor entendimento sobre a radiossensibilidade do câncer de próstata, com a redefinição de parâmetros radiobiológicos, atualmente os esquemas hipofracionados de próstata tornaram-se um dos principais desafios da radioterapia moderna. Associado a este conhecimento, o emprego de técnicas precisas de radioterapia possibilitaram a entrega de maiores doses por fração, com manutenção da toxicidade e melhor controle de qualidade dos planos de tratamento. Pretendemos avaliar a implementação da radioterapia tridimensional computadorizada (3D-CRT) ou intensidade modulada do feixe (IMRT) utilizando o regime de hipofracionamento moderado (70 Gy em 28 frações) em pacientes com neoplasia localizada da próstata na rotina do departamento de radioterapia do Hospital das Clínicas da FMRP-USP. Avaliação da viabilidade técnica e do impacto financeiro na utilização da radioterapia hipofracionada na instituição. / Evaluate the implementation of computerized three-dimensional radiation therapy (3D-CRT) or intensity modulated beam (IMRT) using moderate hypofractionation schedule (70 Gy in 28 fractions) in patients with localized prostate cancer (no metastasis lymph node or distant metastasis) in routine of department of radiotherapy of the Hospital of FMRP-USP. Assessment of technical feasibility and financial impact on the use of hypofractionated radiotherapy in the institution.

A partir de um melhor entendimento sobre a radiossensibilidade do câncer de próstata, com a redefinição de parâmetros radiobiológicos, atualmente os esquemas hipofracionados de próstata tornaram-se um dos principais desafios da radioterapia moderna. Associado a este conhecimento, o emprego de técnicas precisas de radioterapia possibilitaram a entrega de maiores doses por fração, com manutenção da toxicidade e melhor controle de qualidade dos planos de tratamento. Pretendemos avaliar a implementação da radioterapia tridimensional computadorizada (3D-CRT) ou intensidade modulada do feixe (IMRT) utilizando o regime de hipofracionamento moderado (70 Gy em 28 frações) em pacientes com neoplasia localizada da próstata na rotina do departamento de radioterapia do Hospital das Clínicas da FMRP-USP. Avaliação da viabilidade técnica e do impacto financeiro na utilização da radioterapia hipofracionada na instituição. / Evaluate the implementation of computerized three-dimensional radiation therapy (3D-CRT) or intensity modulated beam (IMRT) using moderate hypofractionation schedule (70 Gy in 28 fractions) in patients with localized prostate cancer (no metastasis lymph node or distant metastasis) in routine of department of radiotherapy of the Hospital of FMRP-USP. Assessment of technical feasibility and financial impact on the use of hypofractionated radiotherapy in the institution.

Hypofractionated conformal stereotactic radiotherapy (HCSRT) has been used for the treatment of AVMs at the Umeå University Hospital since 1986. From this year and onwards an increasing number of patients with single or oligo brain metastases have also been treated using this technique. In paper I we have retrospectively evaluated our treatment results of AVMs in terms of obliteration and complications. The rates of obliteration and complications seem to be comparable with SRS even if the AVM volumes in our series were larger than in most series with SRS. In paper II we have retrospectively evaluated the results in terms of local control, survival and complications in two groups of patients with single or oligo brain metastases. One group was treated with HCSRT alone and the other group was treated with whole brain radiotherapy in combination with a stereotactic boost. Controversy still exists concerning the benefit of additional use of WBRT in combination with stereotactic irradiation. The survival times were equal in the two groups and no significant difference in local control was observed. The omission of WBRT seems to carry a higher risk for development new brain metastases distant from the irradiated area. In paper III we report the treatment results in a subgroup of AVMs treated with a combination of embolisation and HCSRT. We also focus on the reduction of vascular density within the nidus of an AVM and propose a method to digitally compare images and more objectively assess a reduction in vascular density following embolisation. Obliteration rates seem comparable with other series using a combination of SRS and embolisation even if our rate of complications was higher than what is usually reported. Using luminescence as measure of vascular density all AVMs seemed to be less dense after embolisation. Treatment accuracy in terms of reproducibility of the isocenter in consecutive treatment sessions is crucial in fractionated radiotherapy. In paper IV we have radiologically evaluated the reproducibility of the isocenter in successive treatment sessions using the non invasive relocatable Fixster frame. There was a high degree of reproducibility and only small errors that most likely is of no clinical importance. A reliable dose plan is equally important as a tool to predict the dose delivered inside and outside the target volume. In paper V we have evaluated the reliability of treatment plans in HCSRT for targets of different geometry and size. A liquid ion chamber and gel dosimeter was used for assessment of dose distribution and absorbed dose. The doseplanning system proved to be accurate in predicting the absorbed dose and dose distribution for the different targets.

Darbo tikslas. Atsitiktinės atrankos perspektyviniame klinkiniame tyrime nustatyti ir palyginti lokalaus priešinės liaukos vėžio įprastai frakcionuoto (CFRT) ir hipofrakcionuoto (HFRT) išorinio trimačio konforminio spindulinio gydymo sukeliamas ūmines spindulines reakcijas, gydymo efektyvumą, bei lėtines spindulines reakcijas. Tyrimo medžiaga ir metodai. CFRT taikyta 44 pacientams, švitinta prostata ir sėklinių pūslelių pagrindas 37 frakcijos po 2,0 Gy iki suminės 74 Gy dozės. HFRT taikyta 47 pacientams, toks pat taikinys švitintas 13 frakcijų po 3,0 Gy ir 4 frakcijos po 4,5 Gy iki suminės 57 Gy dozės. Pacientai stebėti mažiausiai 2 metus. Rezultatai. Ūminių 2 laipsnio šlapimo pūslės spindulinių reakcijų buvo statistiškai reikšmingai mažiau HFRT pacientų grupėje. Visų tiesiosios žarnos ūminių spindulinių reakcijų trukmė buvo mažesnė HFRT grupėje . Lėtinių šlapimo pūslės ir tiesiosios žarnos spindulinių reakcijų dažnumas pacientų grupėse nesiskyrė. Biocheminio atsako į gydymą dydis ir greitis pacientų grupėse per 2 metų stebėjimo laiką nesiskyrė. Išvados. Taikytas hipofrakcionuotas išorinis lokalaus prostatos vėžio spindulinis gydymas yra saugus, tačiau atokiam šio gydymo metodo efektyvumui nustatyti reikalingas ilgesnis pacientų stebėjimo laikas. / The aim of the study. To investigate and compare toxicity and efficacy of conventionally fractionated (CFRT) vs. hypofractionated (HFRT) three dimensional conformal external beam radiotherapy for localized prostate carcinoma within prospective randomized study. Matherial and Methods. Forty-four patients in the CFRT treatment arm were irradiated with 74 Gy in 37 fractions (2 Gy per fraction), and 47 in the HFRT arm were treated with 57 Gy, given in 13 fractions of 3 Gy plus 4 fractions of 4.5 Gy. The clinical target volume includes the prostate and a base of seminal vesicles. A minimum follow-up was 2 years. Results. The only grade 2 genitourinary acute toxicity proportion was significantly lower in the HFRT arm. The median duration of overall gastrointestinal acute toxicity was significantly shorter with HFRT. There were no statistically significant differences in the late toxicity rates, biochemical tumor response rates and time to the response between study arms during 2 year follow-up. Conclusions. The investigated hypofractionated 3DCRT for localized prostate carcinoma found to be safe, but extended follow-up is needed to justify the efficacy of our fractionation schedule in the long term.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21653号 / 医博第4459号 / 新制||医||1035(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 富樫 かおり, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Tumours are characterised by unorganised vasculature, which often results in hypoxic regions. Hypoxia is a common cause for photon radiotherapy (RT) treatment failure, as hypoxic cells require up to 2-3 times higher doses compared to well-oxygenated cells for the same effect in terms of cell kill. The increase in dose that would be required to treat the tumours of cancer patients is limited by the radiation sensitivity of surrounding normal tissues. Using carbon ions instead of photons, the radiation dose can be conformed to the tumour to a much higher degree, resulting in an improved sparing of normal tissues. In addition, carbon ions have a much higher radiobiological effectiveness near the end of their range, which is positioned in the tumour. Also, the radiation modes of action leading to cell death when carbon ions interact with living tissues, are less sensitive to the oxygen status compared with the action modes of photons. The focus of this thesis lies in the development of models for the computation of the cell surviving fraction and tumour control probability (TCP) in hypoxic tumours after photon and carbon ion RT. The impact of fractionation was evaluated with regard to possible spatial changes in oxygenation, both for stereotactic body RT and for carbon ion RT. The feasibility of a method to determine and deliver the optimal photon dose for achieving a high TCP according to spatial variations in radiation sensitivity was evaluated in a treatment planning study. The radiobiological models were finally used for the theoretical quantification of the gain in using carbon ions instead of photons. The results show that there are great possibilities to increase the number of positive outcomes of radiation treatment of tumours if the key influential factors are taken into account, such as level and distribution of hypoxia, radiation quality and choice of fractionation schedule. / <p>At the time of the doctoral defence the following papers were unpublished and had a status as follows; Paper 3: Manuscript; Paper 4: Epubl ahead of print; Paper 5: Manuscript</p>

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.

The use of stereotactic body radiation therapy employing few large fractions of radiation dose for the treatment of non-small cell lung cancer has been proven very successful, high values of tumour control probability (TCP) being clinically achieved. In spite of the success of the fractionation schedules currently used, there is a tendency towards reducing the number of fractions for economical and practical reasons, and also for maximizing the comfort of the patients. It is therefore the main aim of this thesis to investigate the impact of a severely reduced number of fractions on the tumour control probability for tumours that contain hypoxic areas. The impact on TCP of other factors such as hypoxic fraction, distribution of the oxygen partial pressure and location of the hypoxic volume within the tumour were also investigated. The effect of tumour motion due to breathing was included and evaluated using Cone Beam Computed Tomography (CBCT) data from patients imaged with internal markers in the liver and pancreas. The results clearly showed that in the presence of hypoxia, TCP is seriously compromised if there is not enough time for reoxygenation between fractions. A reduction in the number of fractions of just one fraction may require an increase of several Gy per fraction to obtain a similar TCP. The diaphragmatic tumour motion range showed little influence on TCP provided that the PTV encompassed all tumour positions. The dose delivered to the PTV margin was found not to be the only factor that is significant for local control, the average dose correlated better with TCP. The agreement of the results of this work with clinical results also serve as a strong indicator that inter-fraction reoxygenation is an important process in real-life patients treated with stereotactic body radiotherapy.