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Table of Contents
Intro
Acknowledgements
Author biographies
Bleddyn Jones
Joshua Moore
Glossary of the main terms and symbols used (some others are given in specific chapters)
Chapter Particle physics for biological interactions
1.1 Physical beam parameters, essential dosimetry and reference (or control) radiation requirements for RBE studies
1.1.1 Straggling and fragmentation
1.1.2 Separation of charged particles with increasing tissue depth
1.1.3 Particle accelerators
1.1.4 Proton range uncertainties
1.2 Physics interacting with biology
1.2.1 Relative biological effect
1.2.2 Choice of the control (or reference) radiation source
1.2.3 Can RBE reduce with the depth of the SOBP placement in the case of passively scattered but not pencil scanned beams?
References
Chapter The essential radiobiology background
2.1 Introduction
2.2 Background and models
2.2.1 The linear quadratic model
2.2.2 Model variants
2.2.3 Biological effective dose
2.2.4 Repopulation allowances
2.2.5 Biological effective dose and repopulation
2.2.6 BED expression of high-LET radiation
2.2.7 Dose rate, total fraction treatment time and incomplete repair between treatment fields
2.2.8 Closely spaced fractions
2.2.9 Hypoxia
2.2.10 Very low doses
2.2.11 Higher doses per fraction
2.3 The α/β ratio and its choice for modelling particle therapies
2.3.1 The α/β ratio
2.3.2 Applications of BED equations
2.3.3 Special considerations for particle therapy
2.4 The design of experiments for RBE determination and other purposes
References
Chapter Medical and surgical considerations that influence radiation tolerances, including interpretation of clinical trials
3.1 Introduction
3.2 Surgery
3.3 Cytotoxic chemotherapies
3.4 Age and other medical conditions.
3.5 Reductions in prescribed dose
3.6 Interpretation of the case histories and literature
3.7 Clinical trials
3.8 Ethical issues
3.9 Mixed end points
3.10 The importance of follow-up
3.11 Publication bias
References
Chapter Treatment planning and further medical perspectives
4.1 Introduction
4.1.1 Treatment-planning processes
4.1.2 The important interaction of RBE issues with the marginal target volumes
4.1.3 Comparative planning studies
4.1.4 Trade-off situations in comparative treatment planning
4.1.5 How to accommodate assumed errors in RBE
4.1.6 The product of LET and dose
4.1.7 Some final caveats and suggestions
References
Chapter Historical development of radiotherapy: what was learned from fast neutrons including their linkage with proton relative biological effect
5.1 Introduction
5.2 A brief synopsis
5.3 Neutron therapy
5.4 More recent developments based on neutron studies
5.5 Estimation of neutron RBE from neutron energy
5.6 Some important conclusions
Appendix A
Appendix B
References
Chapter Fractionation modelling
6.1 Introduction and background radiobiology
6.2 A brief history of fractionation
6.2.1 Radiobiology
6.2.2 A synopsis of clinical fractionation
6.3 Modelling of fractionation
6.3.1 LQ modelling of fractionation in high-LET radiations with inclusion of RBE
6.3.2 BED equations
6.3.3 Converting a specific low-LET BED fractionation to that for high LET, when the low-LET α/β ratio is known, but with no change in overall treatment time
6.3.4 Overall fractionation differences between low- and high-LET radiations
6.3.5 Boost doses
6.3.6 Converting a specific low-LET BED fractionation to that for high LET, when the low-LET α/β ratio is known, but with a change in overall treatment time.
6.3.7 Alternative approach for isoeffect calculations in the case of two high-LET schedules
6.3.8 Differences in exposure times
6.3.9 RBE and dose per fraction: clinical implications
6.3.10 Effects of regions of higher and lower dose per fraction relative to the prescribed dose for different fractionation patterns
6.3.11 Taking RBE uncertainty into account in fractionation
6.4 The use of the linear quadratic model with large fraction sizes
6.5 Optimisation of fractionation using calculus methods
6.6 Other contributions to fractionation
6.7 Summary
References
Chapter The scientific case for using a variable proton RBE rather than a constant RBE
7.1 Introduction
7.1.1 Arguments to preserve the status quo or avoid using RBE
7.1.2 Justification of a variable RBE
7.2 Discussion
7.2.1 Inclusion of flexible RBEs in treatment plans
References
Chapter A general RBE linear energy-efficiency model for protons and light ions
8.1 Introduction
8.2 The available experimental data and its important limitations
8.3 Description of the Z-specific model
8.3.1 The relationship between Z and LETU
8.3.2 Changes in the radiosensitivities with LET
8.3.3 Obtaining αH and βH values
8.3.4 An alternative method which does not use LETU but the slope of the radiosensitivity or measured RBE increments with increasing LET (up to the turnover point)
8.3.5 The RBE at any specified dose per fraction
8.4 The graphical results
8.4.1 Radiosensitivity data
8.4.2 Fits to experimental RBE data sets
8.4.3 Applications of the model to clinical radiobiology
8.5 Further investigations: properties of LETU
8.6 Conclusions and what remains to be done
References
Chapter Inclusion of the energy-efficiency LET and RBE model in proton therapy
9.1 Introduction
9.2 RBE uncertainties.
9.3 Description of the quantitative model
9.4 RBE graphical examples
9.5 Some comparisons with experimental data sets
9.6 Two clinical examples where PBT could be sub-optimal
9.6.1 Prostate cancer
9.6.2 Paediatric cancers and other radiosensitive tumours such as lymphomas
9.7 Prediction of tumour response from the RBE increment
9.8 Intensification of dose rates
9.9 Concluding discussion
References
Chapter Proton therapy risk assessment using small increments in RBE in the central nervous system and estimation of remission times
10.1 Introduction
10.2 Methods
10.3 Results
10.3.1 Remission duration considerations
10.4 Discussion
10.5 Conclusions
References
Chapter Radiobiological interpretation of the finding of RBE changes within similar SOBPs placed at superficial and deep locations in passively scattered beams but not in scanned pencil beams
11.1 Introduction
11.2 Methods
11.2.1 Linear quadratic model base equations
11.2.2 The modelling method
11.3 Results
11.4 Discussion
11.5 Conclusions
References
Chapter Particle therapy dose-time compensations in unintended interruptions and re-treatments
12.1 Introduction
12.2 Unintended treatment interruptions
12.2.1 Background
12.2.2 Treatment delays
12.2.3 Calculations for compensation of treatment interruptions
12.2.4 Calculations using a variable RBE value
12.2.5 Comparison of the two methods
12.2.6 Summary for unintended treatment gap corrections
12.3 Re-treatments
12.3.1 Background
References
Chapter Errors of Bragg peak positioning and their radio-biological correction
13.1 Introduction
13.1.1 Further abbreviations and definitions
13.1.2 Background considerations
13.1.3 Brief description of methods
13.2 Model description
13.2.1 Biological effective dose equations.
13.2.2 Assessment of BED changes after an error
13.2.3 Worked examples of errors and their correction
13.2.4 The potential impact of erroneous fractions on tumour control
13.3 Conclusions
References
Chapter What remains to be done: including FLASH dose rates and conclusions
14.1 Introduction
14.2 Dose escalation where circumstances permit
14.3 Simultaneous 'sensitisation' effects by new therapies
14.4 Sensitivity analysis of the energy-efficiency model
14.5 What could be achieved in a single international laboratory dedicated to high-LET radiobiology
14.5.1 Simulated experiments
14.5.2 Uniqueness of LETU for each ion species
14.5.3 Priority in radiobiological experiments
14.6 Some untested situations
14.7 Conclusions
References.
Acknowledgements
Author biographies
Bleddyn Jones
Joshua Moore
Glossary of the main terms and symbols used (some others are given in specific chapters)
Chapter Particle physics for biological interactions
1.1 Physical beam parameters, essential dosimetry and reference (or control) radiation requirements for RBE studies
1.1.1 Straggling and fragmentation
1.1.2 Separation of charged particles with increasing tissue depth
1.1.3 Particle accelerators
1.1.4 Proton range uncertainties
1.2 Physics interacting with biology
1.2.1 Relative biological effect
1.2.2 Choice of the control (or reference) radiation source
1.2.3 Can RBE reduce with the depth of the SOBP placement in the case of passively scattered but not pencil scanned beams?
References
Chapter The essential radiobiology background
2.1 Introduction
2.2 Background and models
2.2.1 The linear quadratic model
2.2.2 Model variants
2.2.3 Biological effective dose
2.2.4 Repopulation allowances
2.2.5 Biological effective dose and repopulation
2.2.6 BED expression of high-LET radiation
2.2.7 Dose rate, total fraction treatment time and incomplete repair between treatment fields
2.2.8 Closely spaced fractions
2.2.9 Hypoxia
2.2.10 Very low doses
2.2.11 Higher doses per fraction
2.3 The α/β ratio and its choice for modelling particle therapies
2.3.1 The α/β ratio
2.3.2 Applications of BED equations
2.3.3 Special considerations for particle therapy
2.4 The design of experiments for RBE determination and other purposes
References
Chapter Medical and surgical considerations that influence radiation tolerances, including interpretation of clinical trials
3.1 Introduction
3.2 Surgery
3.3 Cytotoxic chemotherapies
3.4 Age and other medical conditions.
3.5 Reductions in prescribed dose
3.6 Interpretation of the case histories and literature
3.7 Clinical trials
3.8 Ethical issues
3.9 Mixed end points
3.10 The importance of follow-up
3.11 Publication bias
References
Chapter Treatment planning and further medical perspectives
4.1 Introduction
4.1.1 Treatment-planning processes
4.1.2 The important interaction of RBE issues with the marginal target volumes
4.1.3 Comparative planning studies
4.1.4 Trade-off situations in comparative treatment planning
4.1.5 How to accommodate assumed errors in RBE
4.1.6 The product of LET and dose
4.1.7 Some final caveats and suggestions
References
Chapter Historical development of radiotherapy: what was learned from fast neutrons including their linkage with proton relative biological effect
5.1 Introduction
5.2 A brief synopsis
5.3 Neutron therapy
5.4 More recent developments based on neutron studies
5.5 Estimation of neutron RBE from neutron energy
5.6 Some important conclusions
Appendix A
Appendix B
References
Chapter Fractionation modelling
6.1 Introduction and background radiobiology
6.2 A brief history of fractionation
6.2.1 Radiobiology
6.2.2 A synopsis of clinical fractionation
6.3 Modelling of fractionation
6.3.1 LQ modelling of fractionation in high-LET radiations with inclusion of RBE
6.3.2 BED equations
6.3.3 Converting a specific low-LET BED fractionation to that for high LET, when the low-LET α/β ratio is known, but with no change in overall treatment time
6.3.4 Overall fractionation differences between low- and high-LET radiations
6.3.5 Boost doses
6.3.6 Converting a specific low-LET BED fractionation to that for high LET, when the low-LET α/β ratio is known, but with a change in overall treatment time.
6.3.7 Alternative approach for isoeffect calculations in the case of two high-LET schedules
6.3.8 Differences in exposure times
6.3.9 RBE and dose per fraction: clinical implications
6.3.10 Effects of regions of higher and lower dose per fraction relative to the prescribed dose for different fractionation patterns
6.3.11 Taking RBE uncertainty into account in fractionation
6.4 The use of the linear quadratic model with large fraction sizes
6.5 Optimisation of fractionation using calculus methods
6.6 Other contributions to fractionation
6.7 Summary
References
Chapter The scientific case for using a variable proton RBE rather than a constant RBE
7.1 Introduction
7.1.1 Arguments to preserve the status quo or avoid using RBE
7.1.2 Justification of a variable RBE
7.2 Discussion
7.2.1 Inclusion of flexible RBEs in treatment plans
References
Chapter A general RBE linear energy-efficiency model for protons and light ions
8.1 Introduction
8.2 The available experimental data and its important limitations
8.3 Description of the Z-specific model
8.3.1 The relationship between Z and LETU
8.3.2 Changes in the radiosensitivities with LET
8.3.3 Obtaining αH and βH values
8.3.4 An alternative method which does not use LETU but the slope of the radiosensitivity or measured RBE increments with increasing LET (up to the turnover point)
8.3.5 The RBE at any specified dose per fraction
8.4 The graphical results
8.4.1 Radiosensitivity data
8.4.2 Fits to experimental RBE data sets
8.4.3 Applications of the model to clinical radiobiology
8.5 Further investigations: properties of LETU
8.6 Conclusions and what remains to be done
References
Chapter Inclusion of the energy-efficiency LET and RBE model in proton therapy
9.1 Introduction
9.2 RBE uncertainties.
9.3 Description of the quantitative model
9.4 RBE graphical examples
9.5 Some comparisons with experimental data sets
9.6 Two clinical examples where PBT could be sub-optimal
9.6.1 Prostate cancer
9.6.2 Paediatric cancers and other radiosensitive tumours such as lymphomas
9.7 Prediction of tumour response from the RBE increment
9.8 Intensification of dose rates
9.9 Concluding discussion
References
Chapter Proton therapy risk assessment using small increments in RBE in the central nervous system and estimation of remission times
10.1 Introduction
10.2 Methods
10.3 Results
10.3.1 Remission duration considerations
10.4 Discussion
10.5 Conclusions
References
Chapter Radiobiological interpretation of the finding of RBE changes within similar SOBPs placed at superficial and deep locations in passively scattered beams but not in scanned pencil beams
11.1 Introduction
11.2 Methods
11.2.1 Linear quadratic model base equations
11.2.2 The modelling method
11.3 Results
11.4 Discussion
11.5 Conclusions
References
Chapter Particle therapy dose-time compensations in unintended interruptions and re-treatments
12.1 Introduction
12.2 Unintended treatment interruptions
12.2.1 Background
12.2.2 Treatment delays
12.2.3 Calculations for compensation of treatment interruptions
12.2.4 Calculations using a variable RBE value
12.2.5 Comparison of the two methods
12.2.6 Summary for unintended treatment gap corrections
12.3 Re-treatments
12.3.1 Background
References
Chapter Errors of Bragg peak positioning and their radio-biological correction
13.1 Introduction
13.1.1 Further abbreviations and definitions
13.1.2 Background considerations
13.1.3 Brief description of methods
13.2 Model description
13.2.1 Biological effective dose equations.
13.2.2 Assessment of BED changes after an error
13.2.3 Worked examples of errors and their correction
13.2.4 The potential impact of erroneous fractions on tumour control
13.3 Conclusions
References
Chapter What remains to be done: including FLASH dose rates and conclusions
14.1 Introduction
14.2 Dose escalation where circumstances permit
14.3 Simultaneous 'sensitisation' effects by new therapies
14.4 Sensitivity analysis of the energy-efficiency model
14.5 What could be achieved in a single international laboratory dedicated to high-LET radiobiology
14.5.1 Simulated experiments
14.5.2 Uniqueness of LETU for each ion species
14.5.3 Priority in radiobiological experiments
14.6 Some untested situations
14.7 Conclusions
References.