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
