Radiobiology of Particle Therapy
CERN Summer School Student Lectures, 2014
Manjit Dosanjh, CERN [email protected] Cancer – a growing challenge
More than 3 million new cancer cases in Europe each year and 1.75 million associated deaths
Increase by 2030: 75% in developed countries and 90% in developing countries
Manjit Dosanjh, 2014 Cancer – a growing societal challenge
Over 3 million cancer cases in Europe each year
Surgery Radiotherapy Chemotherapy & others
X-ray, IMRT, Brachytherapy, Hormones; Immunotherapy; Cell therapy; Genetic treatments; Hadrontherapy Novel specific targets (genetics..) Local control Local control Limited Local control
Survival Quality of life Radiotherapy in the 21st century 3 "Cs" of Radiation
Cure (~ 50% cancer cases are cured) Conservative (non-invasive, few side effects) Cheap ( 5-10% of total cost of cancer on RT)
• There is no substitute for RT in the near future • The rate of patients treated with RT is increasing • More than 50% patients treated with RT
(J.P.Gérard) Manjit Dosanjh, 2014
The ideal treatment eliminate all tumour cells without affecting normal cells
ª Physics : ² 100% of the dose on target ² 0% dose in surrounding healthy tissues or critical organs ª Biology : ² differential effect ² kill 100% of cancer cells ² "protect" normal cells
Manjit Dosanjh, 2014 Single photon beam
80 50 30
Manjit Dosanjh, 2014 Two opposite photon beams
110 100 110
Manjit Dosanjh, 2014 Alternative – Particle Therapy
• 1946: Robert Wilson Protons can be used clinically
Robert Wilson
Manjit Dosanjh, 2014 Why hadron/particle therapy
Photons
Carbon Protons Depth in the body (mm) Tumours near critical organs Tumours in children Radio-resistant tumours
Manjit Dosanjh, 2014 Depth-Dose Curves of Photon vs. Ion Beams
Advantages of ion beams • Physical selectivity • High-LET effect • Reduced integral dose
Manjit Dosanjh, 2014 No treatment without detection!
Particle Detection Imaging
PET Scanner
Breast imaging (ClearPEM)
Manjit Dosanjh, 2014 Multimodality imaging: CT with PET
morphology metabolism
Manjit Dosanjh, 2014 Two sides of Radiation
Manjit Dosanjh, 2014 Radiation Sickness
System effected/ Syndrome Symptoms Dose
Nervous system Shock, severe 100 Gy CNS or Cerebrovascular nausea, Syndrome disorientation, seizures, coma G.I. system Nausea, vomiting, 10 Gy Gastrointestinal Syndrome diarrhea, dehydration Blood cells / bone marrow Chills, fatigue, 3-8 Gy Hematopoietic Syndrome hemorrhage, ulceration, infections, anemia Skin Burning/ infection, 10 Gy Erethema sloughing of skin, hair loss Ovaries/ Sterilit y 0.6-0.8 Gy Testes 2-6 Gy Manjit Dosanjh, 2014
Variation in Radiation Sensitivity Among Adult Human Organs
Approximate Tolerance Dose (TD) beyond which there is a high probability of delayed injury, e.g. 5% clinical injury within 5 years after exposure.
Manjit Dosanjh, 2014 2 1.8 1.6 1.4 1.2 Typical doses in mSv 1 0.8 0.6 0.4 0.2 0 Dental X-ray Chest X-ray Breast X-ray Spine X-ray Natural CT Scan - Head radia on per year
100 90 80 70 60 50 40 30 20 10 0 Airline Dose in PET CT Scan - CT Scan - PET+CT Cura ve RT 5 year Lowest crew flying full-body abdomen heart maximum annual polar route CT scan and pelvis limit rad. dose (annual) Workers increase Manjit Dosanjh, 2014 cancer Questions
• What is radiobiology? • Why do we need biology for radiotherapy? • What kinds of biology are important for radiotherapy? • How do you inves gate biological effects of par cle beams? • What do the data tell you? • Do we know everything we need to know?
Manjit Dosanjh, 2014 The Beginning …………….
Radio waves Microwave Infrared Visible Ultraviolet X-Ray Gamma Ray
Energy, E 10 neV 10 μeV 1 meV 10 meV 1 eV 10 eV 100 eV 100 keV 1 MeV 1 GeV 1 TeV Source: ESA
X-rays – November 1895: – 1901: first physics Nobel prize
Wilhelm Röntgen Manjit Dosanjh, 2014 ………..of radiation biology
Henri Becquerel (1852-1908)
1896: Discovery of natural radioactivity
Thesis of Mme. Curie – 1904 1898: Discovery of α, β, γ in magnetic field radium
used immediately for “Brachytherapy”
Marie Curie Pierre Curie19 Manjit Dosanjh, 2014 (1867 – 1934) (1859 – 1906) First radiobiology experiment: Pierre Curie
The first radiobiology experiment. Pierre Curie using a radium tube to produce radia on ulcer on his arm. Hall fig. 1-2
Manjit Dosanjh, 2014 Early results…..
1896 -The first radia on therapy of a cancer pa ent (Victor DESPEIGNES, Lyon) 1896: First diagnos c use Kaiser, Vienna 1899 - The first successful radia on treatment of tumour -Thor Stenbeck, Stockholm 1900 – Pallia on of tumour 1902- radium used to treat pharyngeal carcinoma in Vienna 1904 - Pa ents in New York undergoing implanta on of radium tubes in the tumours 1904 - Chromosomal damage caused by radia on in embryos 1907-The first described fatal cases (11) of cancer 1910 - Hypothesis - Cancer arises from damage on the chromosomes (Muller) 1911 - The first specifica on of skin cancer (94 cases) - Herman Hesse 1911 - Report on radia on causes muta on in fruit fly Drosophila - Herman Muller
1917 – Observa ons of sterility among radiologists 1921 – The 100 th death among radiologists 1926 - Muller showed radia ons role in muta on and chromosomes are target 1928 – The Interna onal Commission on Radiological Protec on (ICRP) formed
Manjit Dosanjh, 2014
Direct and indirect action of radiation
Critical target for the biological effects of radiation: DNA Direct action: secondary e- resulting from absorption of e.g. an X-ray photon interacts with the DNA dominant process for radiations with high LET: neutrons, α-particles, heavy ions Indirect action: - secondary e interacts with another molecule, e.g. H2O, to generate OH• which produces the damage to the DNA dominant process for radiations with low LET: X-, γ-rays. 2 nm
H O e- H OH• p+ indirect
e- direct p+ Manjit Dosanjh, 2014 DNA damage
Manjit Dosanjh, 2014 Cell culture techniques and cell survival curves
Puck and Marcus promoted the study of radiation on individual cells…cell culture
S/S0 = colonies produced / cells plated * PE PE = plating efficiency (correction factor derived from control samples)
Manjit Dosanjh, 2014 Clonogenic cell survival 100
10-1
10-2
D10 dose Surviving fraction Surviving
10-3
10-4
0 2 4 6 8 10 12 14 16 18 Dose (Gy)
Manjit Dosanjh, 2014 Cell survival curves
• describe the relationship between the radiation dose and the proportion of cells that survive
• presented with the dose plotted on a linear scale and the surviving fraction on a logarithmic scale
1
0.1
Surviving fraction
0.01 0 100dose (cGy)200 300
Manjit Dosanjh, 2014 Cellular Survival Curves and Relative Biological Efectiveness
Dx ____ = RBE Di
Manjit Dosanjh, 2014 RBE and how does it vary
• Varies with type of radiation • Varies with type of cell/tissue • Varies with the biological effect under investigation • Varies with dose rate and fractionation • An increase in RBE in itself does not offer therapeutic advantage unless there is differential effect between normal and tumour tissues • OER (oxygen enrichment ratio) effects RBE • Effected by presence of other chemicals present
Manjit Dosanjh, 2014 Cell killing by diferent radiation types
Manjit Dosanjh, 2014 Ions vs x-rays, radiobiological advantages RBE = Dx/Dion (at same effect level)
1
RBE=1.62 x-rays RBE=3.97 C-266MeV/u
C-18MeV/u
0.1
Survival RBE=3.63 RBE=1.57
0.01 0 1 2 3 4 5 6 7 8 9 10 11 Dose (Gy)
Manjit Dosanjh, 2014 Chromatin Rejoining From Heavier Ion Damage is Slower
Manjit Dosanjh, 2014Goodwin et al. Tissue Dependence of RBE on Repair
Manjit Dosanjh, 2014 Radiobiological Damage
• Molecular • Subcellular • Cellular: Cell cycle effect, cell types • Tissue/organ • Whole multicellular organism • Population of multicellular organisms
Manjit Dosanjh, 2014 Major Events Which Follow Energy Absorption Major Events Which Follow Energy Absorption FromFrom Ionizing Ionizing RadiationRadiation
Genetic Heredity Damage Defects (germ cells)
Energy Biochemical Cellular Deposition Changes Damage
Cancer Induction Somatic Damage Developmental (other cells) Defects (Fetal)
Other Medical Effects Manjit Dosanjh, 2014 Efects on DNA Macromolecules
• Point mutation – Ionizing radiation that ruptures the chemical bond of a macromolecule severing one of the sugar-phosphate chain siderails of the DNA ladder (Single-strand break) – Gene mutations may result – These can occur with low-LET radiation – Repair enzymes can reverse this damage
Manjit Dosanjh, 2014 Manjit Dosanjh, 2014 Double Strand Breaks
• One or more breaks in each of the two sugar-phosphate chains • Not repaired as easily as single strand breaks • More common with high LET radiation
Manjit Dosanjh, 2014 Efects of Ionizing Radiation Upon Chromosomes
• If chromosomes are broken, two or more fragments are produced • Each fragment has a fractured extremity • These can join to another fractured extremity • These new formations are known as an aberration
Manjit Dosanjh, 2014 Track Structures of Proton vs. Carbon Ions
Linear Energy Transfer (LET) stands for the radiation energy deposited per unit length in tissue. • X-rays and proton beams are low-LET radiations • Heavy ion beams are high-LET radiation in Bragg peaks
Biological advantages: • High LET to provide significant differences in DNA damages • Suppression of radiation repair • Yet avoids some complications with higher-Z ions
Manjit Dosanjh, 2014 DNA X-rays Protons Carbon ions
Marx, Nature, 2014
Manjit Dosanjh, 2014 DNA damage and its consequences
repair misrepair cancer
DNA single strand break mutation
DNA double strand break chromosome aberration
repair no repair cell death
Manjit Dosanjh, 2014 Timing of damage efect
• Immediate/early effects: cell death, animal death • Short term: minutes, hours, weeks….. • Delayed effects: cancer induction, genetic effects • Long term/late effects: years , centuries • Bystander effect
Manjit Dosanjh, 2014 OER for high and low LET radia ons X-rays
OER varies with LET: X-rays=2.5 Neutrons=1.6 Alpha par cles=1.0 neutrons Alpha par cles
Manjit Dosanjh, 2014 Re-oxygenation in Radiotherapy
•Hypoxia confers resistance to X-rays/ gamma rays – also to chemotherapeu c drugs •Human tumours that do not respond to radiotherapy may not re-oxygenate •Op mal frac ona on regimen depends on reoxygena on
Manjit Dosanjh, 2014 Fractionation
• Increased survival when a dose is split into two or more frac ons separated by a me interval • There is a point at which an increase in the number of frac ons will no longer increase survival—plateau in the response
Manjit Dosanjh, 2014 Manjit Dosanjh, 2014 Cells spend most me in G0 phase—out of the cell cycle
Go= growth arrest G1= Gap 1 G2 + Gap 2 S = synthesis M = mitosis
Fate of different Chromosomes in each Phase of the cell cycle Experiments of Warren Sinclair: Survival curves during cell cycle
----- calculated for -hypoxic condi ons of -Mito c cells
Late S—least sens.
M>G2>G1>early S>late S for sensi vity Difference caused by cell cycle are similar to difference caused by Oxygen effect Manjit Dosanjh, 2014 Figure 8.4 The Biology of Cancer (© Garland Science 2007) Manjit Dosanjh, 2014 Regulation of the cell cycle
IR block
IR block
Cell cycle arrest can occur in response to DNA damage (e.g. IR) in order to allow for DNA repair.
Manjit Dosanjh, 2014 P53-guardian of the genome…..Lane,92
Contributions to Pre-Clinical Theoretical Modeling • Software for Cell Inactivation Modeling & Statistics (Albright) • Neyman Distributions and their importance to particle effects (Albright, Tobias) • Lethal-Potentially-Lethal Model of Cell Inactivation (Curtis) • Design for Study of Radioactive Beams (Chatterjee, Tobias) • Design for Particle Radiography (Tobias, Fabrikant) • Spiral Filter Design for Spread-Out Bragg Peaks (Tobias) • Design for Particle Beam Wobbling (Tobias) • Repair-Misrepair Model of Cell Inactivation (Tobias) • Design for Particle Beam Raster Scanning (Tobias)
Manjit Dosanjh, 2014 Simplified view of some of the cellular pathways involved in response IR
Connell, P. P. et al. Cancer Res 2009;69:383-392
Copyright ©2009 American Association for Cancer Research Manjit Dosanjh, 2014
Basic radiobiology of high-LET damage & repair--which genes/proteins are important ?
• Bcl-2 is an anti-apoptotic protein that is frequently overexpressed in 30-50% of tumors, and overexpression is associated with radioresistance Brahme 2004 Manjit Dosanjh, 2014 Int J Radiat Oncol Biol Phys, V 58, pp 603-616 4Rs of Radiobiology Relevant to Clinical Dose Fractionation • Repair - spares late responding normal tissue preferentially • Reassortment/Redistribution of cells in the cell cycle – increases acute effects – no influence on late effects – increases damage to tumor • Repopulation/Regeneration – spares acute responding normal tissue preferentially – no influence on late effects, – danger of tumor repopulation • Reoxygenation – no influence on normal tissue responses – increases tumor damage
Manjit Dosanjh, 2014 Department of Radiation Oncology
Holthusen-Curve: Dose-Response-Relationship
10 Tumor Control 0 80
60 Adverse Effects
40 Therapeutic Window Probability [%] Probability 20 Cure w/o Side Effects
10 20 30 40 50 60 70 80 90 10 „Optimal Dose“ [Gy] After: Holthusen, H. und Braun, R. ( 1933 ) : 0 Grundlagen und Praxis der Röntgenstrahldosierung, Thieme Verlag, Leipzig Ultimate Goal: Heavy Ions & Therapeutic Gain
• Overcoming tumour radioresistance • Enhancing tumour cell killing • Protecting normal cells
Hadrontherapy vs x-radiotherapy
• Tumours close to critical organs • Tumours in children • Radio-resistant tumours
Photons and Electrons vs. Hadrons • Physical dose high near surface • Dose highest at Bragg Peak • DNA damage easily repaired • DNA damage not repaired • Biological effect lower • Biological effect high • Need presence of oxygen • Do not need oxygen • Effect not localised • Effect is localised Charged Particle Therapy – 2014
• Goal now is to evaluate “best” clinical implementation for each of two charged particle modalities (proton or carbon) for maximizing dose to the tumor, while sparing surrounding normal tissue. Other intermediate ions (helium, lithium, boron) are also under consideration. • Criteria for comparison • New physical dose gold standard: IMRT/IGRT • New understanding of biological models • New understanding of treatment planning models • New molecular tools to probe mechanisms of action
Manjit Dosanjh, 2014 https://cds.cern.ch/record/1611721 References
• cern.ch/crystalclear • cern.ch/enlight • cern.ch/medipix • cern.ch/twiki/bin/view/AXIALPET • cern.ch/medaustron • cern.ch/fluka/heart/rh.html • www.fluka.org/fluka.php • cern.ch/wwwasd/geant • cern.ch/wwwasd/geant/tutorial/tutstart.html Acknowledgements
• ENLIGHT community (cern.ch/enlight) • ULICE (cern.ch/ulice) • ENVISION (cern.ch/envision) • PARTNER (cern.ch/partner) • ENTERVISION (cern.ch/partner)
• CERN KNOWLEDGE TRANSFER (cern.ch/knowledgetransfer)