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1 Author(s): Theodore Lawrence, M.D., Ph.D., 2011

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1 1 Author(s): Theodore Lawrence, M.D., Ph.D., 2011
License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution – Share Alike 3.0 License: We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers. 1 1 1 1

2 Citation Key for more information see: http://open. umich
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3 Introduction to Radiation Oncology Pre-clinical
Ted Lawrence, MD, PhD Department of Radiation Oncology University of Michigan Winter 2009

4 Overview Radiation Oncology depends on the fields of radiation physics, radiation biology and medicine The understanding and application of each is enhanced by a knowledge of the other In these lectures, we will review how radiation interacts with tissue physically and biologically, and then focus on how to apply these concepts to treat patients

5 What is a radiation oncologist?
An oncologist A specialist and a generalist (all parts of the body) A person expert in applications of radiation Uses radiation in a clinic and in an operating room Directs therapists (who place patients on the machines), dosimetrists (who do dose calculations), and physicists A member of a multidisciplinary team A teacher

6 Electromagnetic Spectrum
100 102 104 106 108 1010 1012 1014 1016 1018 1020 1022 1024 radio microwave infrared frequency near-infrared visible ultraviolet x-rays therapy rays cosmic rays wavelength Source Undetermined

7 Kinds of radiation - Photons
Gamma rays and x-rays Penetrates deeply, so that the dose to the skin is less than the deep dose (“skin sparing”) Depth of penetration moderately dependent on the energy of the beam. This is the main form of radiation used because it permits us to treat deep tumors without skin damage.

8 Kinds of radiation - Electrons
Electrons interact directly with tissues, so that the dose to the skin tends to be high compared to deeper tissues Depth of penetration is strongly dependent on the energy of the beam This type of radiation is used to treat skin cancers, or other cancers that are relatively close to the surface of the body (< 6 cm)

9 Kinds of radiation - Charged particles
Charged particles (protons and carbon nuclei) have better depth dose characteristics than photons and electrons Depth of penetration is strongly dependent on the energy of the beam Can go deeper than electrons with more skin sparing Carbon nuclei can kill hypoxic cells as effectively as well oxygenated cells However- MUCH (at least 20x) more expensive

10 Source Undetermined

11 How radiation is produced-teletherapy
Teletherapy – radiation delivered by a machine Cobalt (rarely used in the modern era) Radioactive material (activated in a cyclotron) and placed in the head of a machine Linear accelerator Electrons are accelerated and made very energetic Can be used directly Can be directed at a metal target to produces high energy photons (x-rays)

12 Brachytherapy-basics
The placement of radioactive sources into or next to the tumor Depends on the “inverse square” rule of radiation The intensity of the radiation depends on the square of the distance from the source (2x the distance, decrease the intensity by 4x)

13 Brachytherapy-concepts
Advantage: can permit much more radiation to be given to the tumor compared to the normal tissue Disadvantage: harder to make the dose uniform to the tumor Placement can be permanent or temporary (minutes to days)

14 Source Undetermined

15 Results of Treatment Source Undetermined

16 Prostate brachytherapy
Source Undetermined

17 High dose rate brachy (HDR) Example – Ring and Tandem
Source Undetermined Source Undetermined Used to treat cervical and endometrical cancer Source Undetermined

18 Interaction of radiation with cells
Electrons can interact directly (direct effect) Electrons can produce free radicals (particularly OH•, O•, and H202) which then interact

19 INDIRECT ACTION DIRECT ACTION OH photon e p photon e p H20 NEGATIVE
20Å Source Undetermined

20 Effects at the cellular level
Free radicals exist for microseconds to milliseconds after the radiation Biological effects occur over hours, days, and years Molecular and cellular targets of radiation DNA Cell membrane

21 Source Undetermined

22 Source Undetermined

23 Cell survival curve Source Undetermined

24 Effects of radiation on DNA
Single and double strand breaks Single strand breaks are well repaired, because there is an intact (correct) template in the other strand Repair occurs during next 6 hours

25 Sublethal damage repair
Repeated fraction curve Surviving fraction Dose (Gy) Single dose curve T. Lawrence

26 Fluorodeoxyuridine inhibits SLDR
Source Undetermined

27 Results of DNA damage The double strand break appears to be the lethal lesion- cell must “guess” what to put back in place One double strand break can kill a cell Can lead to mutations and second cancers (≈ 1/ patients)

28 Mechanisms of cell death after DNA damage-mitosis
During mitosis, chromosomes become condensed , align, and move to the two daughter cells Cells with chromosomal damage cannot perform mitosis properly and die in the attempt This explains why it can take months to years for tumors to shrink

29 Effect of Irradiation ± BrdUrd on Chromosomes 1 and 4
Source Undetermined

30 Mechanisms of cell death after DNA damage- Apoptosis
Programmed cell death DNA damage can cause some cells to activate a death pathway Often happens during a phase of the cell cycle other than mitosis Mechanism for cell death of lymphocytes (lymphomas) and spermatocytes (seminoma)

31 Control Cells Apoptotic Cells
Apoptosis Control Cells Apoptotic Cells Source Undetermined

32 DNA fragmentation Source Undetermined

33 Effects of radiation on the cell membrane
The cell membrane is the origin of many “life” (growth factor receptor) and “death” (apoptotic) signals Radiation can activate or suppress the former and activate the latter

34 Effects of RT depend on biology
Genetics Oxygen status Hypoxic cells (in tumors) are resistant Cell cycle S phase resistant, M is sensitive Chemical modifiers (protectors/sensitizers)

35 Effect of radiation depends on physics
Kind of radiation (High LET vs Low LET) How fast radiation is given (1 Gy/min causes more effects than 1 Gy/hr) How many fractions 30 Gy in 3 Gy fractions causes more effects than 30 Gy in 2 Gy fractions The total time 60 Gy in 2 Gy fractions given 6 times a week causes more effects than 60 Gy in 2 Gy fractions given 5 times a week How much tissue is irradiated (normal tissue)

36 Effects at the tumor/organ level
The 4 R’s Fractionation Hyperfractionation Accelerated fractionation Radiation modifying drugs Parallel and serial organs Therapeutic index Why does radiation cure cancers?

37 4 “R’s” of Radiation Biology
Repopulation - tumor cells can grow back during a course of radiation Accelerated repopulation Reoxygenation- tumor O2 increases as cells die Redistribution - cell cycle distribution changes Repair - cells can repair damage between fractions

38 Hyperfractionation Standard: 1.8 to 2 Gy per day
Hyperfractionation: two treatments per day Each treatment is with less dose than standard ( Gy) Overall treatment time about the same as standard Rapidly proliferating cancers (head and neck) Normal cells repair damage of many fractions better than tumor Clinical result: for same anti-tumor effect, less late toxicity

39 Accelerated fractionation
Standard: 1.8 to 2 Gy per day Accelerated fractionation Giving 2 treatments a day (same as hyperfractionation) Each treatment is about the same dose as standard This means more dose per day than standard Overall treatment time is shorter than standard Goal: prevent tumor from growing during treatment (accelerated repopulation)

40 Chemical modifiers Radiation protectors Radiation sensitizers
Hypoxic cell sensitizers Chemotherapeutic agents Molecularly targeted therapies Radiation protectors Scavenge free radicals Prevent cytokine induced damage (anti-inflammatory)

41 Normal Tissues: Parallel and Serial Organs
Parallel organ Damage to small fraction has no clinical toxicity Clinical toxicity occurs when pass a threshold for fraction of the organ injured Examples: lung and liver Serial organ Damage to a small fraction produces toxicity Examples: esophagus and spinal cord

42 Serial Circuit T. Lawrence

43 Serial Circuit: Interruption
T. Lawrence

44 Parallel Circuit T. Lawrence

45 Parallel Circuit: No Interruption
T. Lawrence

46 Effect of radiation on normal organs
Organs vary in radiation tolerance Kidney - 20 Gy in daily 2 Gy fractions Liver - 30 Gy Spinal cord - 46 Gy Parenchyma of the organ Vasculature leading to the organ

47 Therapeutic index Definition: selectivity of radiation for killing the cancer compared to the normal cells The therapeutic index for a single radiation treatment is small How can we increase the therapeutic index? Multiple fractions (1.230 = 36) Drugs that selectively sensitize tumor cells Drugs that selectively protect normal cells

48 Fractionation versus single fraction
Small tumors not abutting critical structures can be treated with a single fraction Usually Gy Concept is ablation Metastases to brain, lung, and liver Larger tumors or tumors that contain normal tissues Concept is therapeutic index: treatment causes at least slightly more tumor kill than normal tissue damage By giving treatments of 1.8 to 2 Gy each, this effect is multiplied

49 Why does radiation fail?
Tumor size Can’t give enough radiation to kill every tumor stem cell without intolerable damage to normal tissue [fractionation; tumor sensitization; normal tissue protection] Genetic radiation resistance [tumor sensitization] Tumor physiology Hypoxic cells are relatively resistant to radiation, and may reside in the center of tumors [fractionation; tumor sensitization] Rapidity of tumor cell growth [accelerated fractionation; tumor sensitization]

50 Why does radiation cure cancers?
Normal cells migrate back into irradiated field Cancer cells may not repair DNA damage correctly Cancer cells often have disordered cell cycle checkpoints May attempt to replicate DNA before it is properly repaired Greater dependence of tumor on new vasculature, which may be more sensitive to radiation Probably not due to initial damage from radiation For same dose of radiation, cancer cells and normal cells have same number of DNA double strand breaks

51 Summary Radiation affects tissues through the generation of free radicals Cell death is caused chiefly by DNA double strand breaks The effects of radiation can be modified by Physical factors (fraction size, total time, total dose, dose rate, and radiation type) Volume of organ irradiated Tumor genetics Tumor physiology (the 4 R’s) Chemical modifiers

52 Additional Source Information for more information see: http://open
Slide 6: Source Undetermined Slide 10: Source Undetermined Slide 14: Source Undetermined Slide 15: Source Undetermined Slide 16: Source Undetermined Slide 17: Sources Undetermined Slide 19: Theodore Lawrence Slide 21: Source Undetermined Slide 22: Source Undetermined Slide 23: Source Undetermined Slide 25: Theodore Lawrence Slide 26: Source Undetermined Slide 29: Source Undetermined Slide 31: Source Undetermined Slide 32: Source Undetermined Slide 42: Theodore Lawrence Slide 43: Theodore Lawrence Slide 44: Theodore Lawrence Slide 45: Theodore Lawrence

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