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 radiaon per year 100 90 80 70 60 50 40 30 20 10 0 Airline Dose in PET CT Scan - CT Scan - PET+CT Curave 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 radiaon ulcer on his arm. Hall fig. 1-2 Manjit Dosanjh, 2014 Early results….. 1896 -The first radiaon therapy of a cancer paent (Victor DESPEIGNES, Lyon) 1896: First diagnos=c use Kaiser, Vienna 1899 - The first successful radiaon treatment of tumour -Thor Stenbeck, Stockholm 1900 – Palliaon of tumour 1902- radium used to treat pharyngeal carcinoma in Vienna 1904 - Paents in New York undergoing implantaon of radium tubes in the tumours 1904 - Chromosomal damage caused by radiaon in embryos 1907-The first described fatal cases (11) of cancer 1910 - Hypothesis - Cancer arises from damage on the chromosomes (Muller) 1911 - The first specificaon of skin cancer (94 cases) - Herman Hesse 1911 - Report on radiaon causes mutaon in fruit fly Drosophila - Herman Muller 1917 – Observaons of sterility among radiologists 1921 – The 100 th death among radiologists 1926 - Muller showed radiaons role in mutaon and chromosomes are target 1928 – The Internaonal 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,