Towards patient selection for cranial proton beam therapy – Assessment of current patient-individual treatment decision strategies

Proton beam therapy shows dosimetric advantages in terms of sparing healthy tissue compared to conventional photon radiotherapy. Those patients who are supposed to experience the greatest reduction in side effects should preferably be treated with proton beam therapy. One option for this patient selection is the model-based approach. Its feasibility in patients with intracranial tumours is investigated in this thesis. First, normal tissue complication probability models for early and late side effects were developed and validated in external cohorts based on data of patients treated with proton beam therapy. Acute erythema as well as acute and late alopecia were associated with high-dose parameters of the skin. Late mild hearing loss was related to the mean dose of the ipsilateral cochlea. Second, neurocognitive function as a relevant side effect for brain tumour patients was investigated in detail using subjective and objective measures. It remained largely stable during recurrence-free follow-up until two years after proton beam therapy. Finally, potential toxicity differences were evaluated based on an individual proton and photon treatment plan comparison as well as on models predicting various side effects. Although proton beam therapy was able to achieve a high relative reduction of dose exposure in contralateral organs at risk, the associated reduction of side effect probabilities was less pronounced. Using a model-based selection procedure, the majority of the examined patients would have been eligible for proton beam therapy, mainly due to the predictions of a model on neurocognitive function.:1. Introduction 2. Theoretical background 2.1 Treatment strategies for tumours in the brain and skull base 2.1.1 Gliomas 2.1.2 Meningiomas 2.1.3 Pituitary adenomas 2.1.4 Tumours of the skull base 2.1.5 Role of proton beam therapy 2.2 Radiotherapy with photons and protons 2.2.1 Biological effect of radiation 2.2.2 Basic physical principles of radiotherapy 2.2.3 Field formation in radiotherapy 2.2.4 Target definition and delineation of organs at risk 2.2.5 Treatment plan assessment 2.3 Patient outcome 2.3.1 Scoring of side effects 2.3.2 Patient-reported outcome measures – Quality of life 2.3.3 Measures of neurocognitive function 2.4 Normal tissue complication probability models 2.4.1 Types of NTCP models 2.4.2 Endpoint definition and parameter fitting 2.4.3 Assessment of model performance 2.4.4 Model validation 2.5 Model-based approach for patient selection for proton beam therapy 2.5.1 Limits of randomised controlled trials 2.5.2 Principles of the model-based approach 3. Investigated patient cohorts 4. Modelling of side effects following cranial proton beam therapy 4.1 Experimental design for modelling early and late side effects 4.2 Modelling of early side effects 4.2.1 Results 4.2.2 Discussion 4.3 Modelling of late side effects 4.3.1 Results 4.3.2 Discussion 4.4 Interobserver variability of alopecia and erythema assessment 4.4.1 Patient cohort and experimental design 4.4.2 Results 4.4.3 Discussion 4.5 Summary 5. Assessing the neurocognitive function following cranial proton beam therapy 5.1 Patient cohort and experimental design 5.2 Results 5.2.1 Performance at baseline 5.2.2 Correlation between subjective and objective measures 5.2.3 Time-dependent score analyses 5.3 Discussion and conclusion 5.4 Summary 6. Treatment plan and NTCP comparison for patients with intracranial tumours 6.1 Motivation 6.2 Treatment plan comparison of cranial proton and photon radiotherapy 6.2.1 Patient cohort and experimental design 6.2.2 Results 6.2.3 Discussion 6.3 Application of NTCP models 6.3.1 Patient cohort and experimental design 6.3.2 Results 6.3.3 Discussion 6.4 Summary 7. Conclusion and further perspectives 8. Zusammenfassung 9. Summar

Technologies for Delivery of Proton and Ion Beams for Radiotherapy

Recent developments for the delivery of proton and ion beam therapy have been significant, and a number of technological solutions now exist for the creation and utilisation of these particles for the treatment of cancer. In this paper we review the historical development of particle accelerators used for external beam radiotherapy and discuss the more recent progress towards more capable and cost-effective sources of particles.Comment: 53 pages, 13 figures. Submitted to International Journal of Modern Physics

Towards Laser Driven Hadron Cancer Radiotherapy: A Review of Progress

It has been known for about sixty years that proton and heavy ion therapy is a very powerful radiation procedure for treating tumours. It has an innate ability to irradiate tumours with greater doses and spatial selectivity compared with electron and photon therapy and hence is a tissue sparing procedure. For more than twenty years powerful lasers have generated high energy beams of protons and heavy ions and hence it has been frequently speculated that lasers could be used as an alternative to RF accelerators to produce the particle beams necessary for cancer therapy. The present paper reviews the progress made towards laser driven hadron cancer therapy and what has still to be accomplished to realise its inherent enormous potential.Comment: 40 pages, 24 figure

Towards 3D printed multifunctional immobilization for proton therapy: initial materials characterization

Purpose: 3D printing technology is investigated for the purpose of patient immobilization during proton therapy. It potentially enables a merge of patient immobilization, bolus range shifting, and other functions into one single patient-speci c structure. In this rst step, a set of 3D printed materials is characterized in detail, in terms of structural and radiological properties, elemental composition, directional dependence, and structural changes induced by radiation damage. These data will serve as inputs for the design of 3D printed immobilization structure prototypes. Methods: Using four di erent 3D printing techniques, in total eight materials were subjected to testing. Samples with a nominal dimension of 20×20×80 mm3 were 3D printed. The geometrical printing accuracy of each test sample was measured with a dial gage. To assess the mechanical response of the samples, standardized compression tests were performed to determine the Young’s modulus. To investigate the e ect of radiation on the mechanical response, the mechanical tests were performed both prior and after the administration of clinically relevant dose levels (70 Gy), multiplied with a safety factor of 1.4. Dual energy computed tomography (DECT) methods were used to calculate the relative electron density to water ρe, the e ective atomic number Ze , and the proton stopping power ratio (SPR) to water SPR. In order to validate the DECT based calculation of radiological properties, beam measurements were performed on the 3D printed samples as well. Photon irradiations were performed to measure the photon linear attenuation coe cients, while proton irradiations were performed to measure the proton range shift of the samples. The direc- tional dependence of these properties was investigated by performing the irradiations for di erent orientations of the samples. Results: The printed test objects showed reduced geometric printing accuracy for 2 materials (deviation > 0.25 mm). Compression tests yielded Young’s moduli ranging from 0.6 to 2940 MPa. No deterioration in the mechanical response was observed after exposure of the samples to 100 Gy in a therapeutic MV photon beam. The DECT-based characterization yielded Ze ranging from 5.91 to 10.43. The SPR and ρe both ranged from 0.6 to 1.22. The measured photon attenuation coe cients at clinical energies scaled linearly with ρe. Good agreement was seen between the DECT estimated SPR and the measured range shift, except for the higher Ze . As opposed to the photon attenuation, the proton range shifting appeared to be printing orientation dependent for certain materials. Conclusions: In this study, the rst step toward 3D printed, multifunctional immobilization was performed, by going through a candidate clinical work ow for the rst time: from the material printing to DECT characterization with a veri cation through beam measurements. Besides a proof of concept for beam modi cation, the mechanical response of printed materials was also investigated to assess their capabilities for positioning functionality. For the studied set of printing techniques and materials, a wide variety of mechanical and radiological properties can be selected from for the intended purpose. Moreover the elaborated hybrid DECT methods aid in performing in-house quality assurance of 3D printed components, as these methods enable the estimation of the radiological properties relevant for use in radiation therapy

MRI-only based radiotherapy treatment planning for the rat brain on a Small Animal Radiation Research Platform (SARRP)

Computed tomography (CT) is the standard imaging modality in radiation therapy treatment planning (RTP). However, magnetic resonance (MR) imaging provides superior soft tissue contrast, increasing the precision of target volume selection. We present MR-only based RTP for a rat brain on a small animal radiation research platform (SARRP) using probabilistic voxel classification with multiple MR sequences. Six rat heads were imaged, each with one CT and five MR sequences. The MR sequences were: T1-weighted, T2-weighted, zero-echo time (ZTE), and two ultra-short echo time sequences with 20 mu s (UTE1) and 2 ms (UTE2) echo times. CT data were manually segmented into air, soft tissue, and bone to obtain the RTP reference. Bias field corrected MR images were automatically segmented into the same tissue classes using a fuzzy c-means segmentation algorithm with multiple images as input. Similarities between segmented CT and automatic segmented MR (ASMR) images were evaluated using Dice coefficient. Three ASMR images with high similarity index were used for further RTP. Three beam arrangements were investigated. Dose distributions were compared by analysing dose volume histograms. The highest Dice coefficients were obtained for the ZTE-UTE2 combination and for the T1-UTE1-T2 combination when ZTE was unavailable. Both combinations, along with UTE1-UTE2, often used to generate ASMR images, were used for further RTP. Using 1 beam, MR based RTP underestimated the dose to be delivered to the target (range: 1.4%-7.6%). When more complex beam configurations were used, the calculated dose using the ZTE-UTE2 combination was the most accurate, with 0.7% deviation from CT, compared to 0.8% for T1-UTE1-T2 and 1.7% for UTE1-UTE2. The presented MR-only based workflow for RTP on a SARRP enables both accurate organ delineation and dose calculations using multiple MR sequences. This method can be useful in longitudinal studies where CT's cumulative radiation dose might contribute to the total dose

Hypofractionated SBRT versus conventionally fractionated EBRT for prostate cancer: comparison of PSA slope and nadir.

BackgroundPatients with early stage prostate cancer have a variety of curative radiotherapy options, including conventionally-fractionated external beam radiotherapy (CF-EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Although results of CF-EBRT are well known, the use of SBRT for prostate cancer is a more recent development, and long-term follow-up is not yet available. However, rapid post-treatment PSA decline and low PSA nadir have been linked to improved clinical outcomes. The purpose of this study was to compare the PSA kinetics between CF-EBRT and SBRT in newly diagnosed localized prostate cancer.Materials/methods75 patients with low to low-intermediate risk prostate cancer (T1-T2; GS 3 + 3, PSA < 20 or 3 + 4, PSA < 15) treated without hormones with CF-EBRT (>70.2 Gy, <76 Gy) to the prostate only, were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997-2012). Patients were excluded if they failed therapy by the Phoenix definition or had less than 1 year of follow-up or <3 PSAs. 43 patients who were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. PSA nadir and rate of change in PSA over time (slope) were calculated from the completion of RT to 1, 2 and 3 years post-RT.ResultsThe median PSA nadir and slope for CF-EBRT was 1.00, 0.72 and 0.60 ng/ml and -0.09, -0.04, -0.02 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadirs and slopes were 0.70, 0.40, 0.24 ng and -0.09, -0.06, -0.05 ng/ml/month, respectively. The PSA slope for SBRT was greater than CF-EBRT (p < 0.05) at 2 and 3 years following RT, although similar during the first year. Similarly, PSA nadir was significantly lower for SBRT when compared to EBRT for years 2 and 3 (p < 0.005).ConclusionPatients treated with SBRT experienced a lower PSA nadir and greater rate of decline in PSA 2 and 3 years following completion of RT than with CF-EBRT, consistent with delivery of a higher bioequivalent dose. Although follow-up for SBRT is limited, the improved PSA kinetics over CF-EBRT are promising for improved biochemical control

Radiation therapy for primary carcinoma of the extrahepatic biliary system. An analysis of 63 cases.

From 1976 to 1988, 63 patients received radiation therapy for primary cancers of the extrahepatic biliary system (eight gallbladder and 55 extrahepatic biliary duct). Twelve patients underwent orthotopic liver transplantation. Chemotherapy was administered to 13 patients. Three patients underwent intraluminal brachytherapy alone (range, 28 to 55 Gy). Sixty patients received megavoltage external-beam radiation therapy (range, 5.4 to 61.6 Gy; median, 45 Gy), of whom nine received additional intraluminal brachytherapy (range, 14 to 45 Gy; median, 30 Gy). The median survival of all patients was 7 months. Sixty patients died, all within 39 months of radiation therapy. One patient is alive 11 months after irradiation without surgical resection, and two are alive 50 months after liver transplantation and irradiation. Symptomatic duodenal ulcers developed after radiation therapy in seven patients but were not significantly related to any clinical variable tested. Extrahepatic biliary duct cancers, the absence of metastases, increasing calendar year of treatment, and liver transplantation with postoperative radiation therapy were factors significantly associated with improved survival

Intensity modulated radiation therapy and arc therapy: validation and evolution as applied to tumours of the head and neck, abdominal and pelvic regions

Intensiteitsgemoduleerde radiotherapie (IMRT) laat een betere controle over de dosisdistributie (DD) toe dan meer conventionele bestralingstechnieken. Zo is het met IMRT mogelijk om concave DDs te bereiken en om de risico-organen conformeel uit te sparen. IMRT werd in het UZG klinisch toegepast voor een hele waaier van tumorlocalisaties. De toepassing van IMRT voor de bestraling van hoofd- en halstumoren (HHT) vormt het onderwerp van het eerste deel van deze thesis. De planningsstrategie voor herbestralingen en bestraling van HHT, uitgaande van de keel en de mondholte wordt beschreven, evenals de eerste klinische resultaten hiervan. IMRT voor tumoren van de neus(bij)holten leidt tot minstens even goede lokale controle (LC) en overleving als conventionele bestralingstechnieken, en dit zonder stralingsgeïnduceerde blindheid. IMRT leidt dus tot een gunstiger toxiciteitprofiel maar heeft nog geen bewijs kunnen leveren van een gunstig effect op LC of overleving. De meeste hervallen van HHT worden gezien in het gebied dat tot een hoge dosis bestraald werd, wat erop wijst dat deze “hoge dosis” niet volstaat om alle clonogene tumorcellen uit te schakelen. We startten een studie op, om de mogelijkheid van dosisescalatie op geleide van biologische beeldvorming uit te testen. Naast de toepassing en klinische validatie van IMRT bestond het werk in het kader van deze thesis ook uit de ontwikkeling en het klinisch opstarten van intensiteitgemoduleerde arc therapie (IMAT). IMAT is een rotationele vorm van IMRT (d.w.z. de gantry draait rond tijdens de bestraling), waarbij de modulatie van de intensiteit bereikt wordt door overlappende arcs. IMAT heeft enkele duidelijke voordelen ten opzichte van IMRT in bepaalde situaties. Als het doelvolume concaaf rond een risico-orgaan ligt met een grote diameter, biedt IMAT eigenlijk een oneindig aantal bundelrichtingen aan. Een planningsstrategie voor IMAT werd ontwikkeld, en type-oplossingen voor totaal abdominale bestraling en rectumbestraling werden onderzocht en klinisch toegepast