1. RADIATION ONCOLOGY An Introduction by W.G. McMillan

2. Radiation What is it? How does it work? Why do it? How do we measure it? How do we deliver it? How is it different from getting an X-ray?

3. Physical Considerations Excitation an electron in an atom or molecule is raised to a higher energy level without being ejected Ionization an electron in an atom or molecule is given enough energy to be ejected. in living material, this releases enough energy locally to break biological bonds. C=C requires 4.9 eV and 1 ionization event provides ~ 33 eV.

4. Ionizing Radiation Electromagnetic waves of wavelength, frequency v, velocity c where v = c and c = 3 x 10 10 cm/sec  -rays: radioactive decay of unstable nucleus x-rays: produced by electrical device photons: packets of energy where E = hv where h = Planck’s constant using both equations if is long, then v is small and E is small

6. Electromagnetic Spectrum

7. Ionizing Radiation Particulate electrons: small negatively charged particles can be accelerated to almost the speed of light. protons: positively charged particles, mass ~ 2000 times greater than electron  particle: nucleus of helium atom = 2 protons + 2 neutrons ( ie decay of radium-226 to radon-222) heavy charged ions: nuclei of elements C, Ne, Argon, etc.

8. Photon Interaction With Matter: Photoelectric Effect  Z

9. First Radiograph: 1896

10. Photon Interaction With Matter: Compton Effect Independent of Z

11. Portal Image

12. Biological Considerations Radiation Interaction with biological materials Cell Survival Curves Repair of Radiation Damage Effect of oxygenation on radiation damage Cell cycle considerations Pharmacological modification of radiation effects

13. Radiation Interaction With DNA Indirect Interaction fast electron hits H 2 O  H 2 O + + e - ; H 2 O + + H 2 O  H 3 O + + OH - reactive species interact with DNA Direct Interaction photons (rarely) or particles (always) directly interact with DNA

14. Direct vs Indirect Action of Radiation on DNA

15. Human Chromosomes With and Without Radiation

16. Surviving Fraction of Cells Post Radiation

17. HeLa Cell Survival Curve Post Radiation

18. 2 Phases of Cell Survival Curve Post Radiation

20. Radiation Damage 3 types: Lethal: leads irrevocably to cell death Potentially lethal: radiation damage which can be modified by artificial post radiation conditions (ie balanced salt solution) to allow repair. Sublethal: in normal conditions, can be repaired in a few hours. Its repair is shown by increased survival when a dose of radiation is split into 2 fractions separated by a time interval.

21. Radiation Damage Repair Sublethal Damage Repair (SLD): mechanism is thought to be based on repair of multiple hit, not single hit damage. for multiple hit damage, if there is a time interval between radiation doses, then repair of the first hit can occur before the second hit occurs. size of the shoulder on the survival curve correlates with amount of sublethal damage repair. very little SLD repair when irradiated with large particles (no shoulder on curve)

24. 4 R’s of Radiobiology (Reoxygenation not shown)

25. Oxygen Effect on Radiation Damage OER (Oxygenation Enhancement Ratio): the ratio of the doses of radiation needed to achieve the same biological effect under hypoxic vs aerated conditions. thought to act at the level of free radicals (ie indirect effect on DNA).  -rays: at low doses, OER ~ 2. At high doses, ~ 3.5. densely ionizing particles (ie  particles), OER ~ 1. intermediate ionizing particles (ie neutrons), OER ~ 1.6

26. OER and Different Radiation Types

27. Cell Cycle Considerations

28. Pharmacologic Modification of Radiation Effect Radiosensitizers: many substances will sensitize cancer cells to radiation, but most also sensitize normal cells to the same degree. 2 types of substances show differential effect between tumours and normal tissues: –Halogenated Pyrimidines (BUdR, IUdR): substituted for thymidine in DNA, weakening it and making it more sensitive to x-rays and UV light. quickly cycling cells take up more than normal cells. –Hypoxic Cell Sensitizers: misonidazole, etanidazole

29. Pharmalogical Modification of Radiation Damage Radioprotectors: effective vs sparsely ionizing radiation ( x and  - rays). Work by scavenging free radicals. amifostine (WR2721) is carried by astronauts d-Con (WR1607) is more potent, but cardiotoxic. cystaphos (WR638) is carried by Russian infantry. Clinical trials: amifostine: RC trial in China in rectal cancer showed protection to skin, mucous membrane, bladder and pelvic structures.

30. Normal Tissue Radiation Biology Casaret’s Classification of tissue radiosensitivity based on parenchymal cells

33. Normal Tissue Adverse Effects Normal tissues do not all respond in the same way to radiation: early responding tissues (skin, mucosa, intestinal epithelium. late responding tissues (spinal cord) How do we influence normal tissue reaction? early responding tissue: fraction size, total dose and treatment time all affect early responding tissue. fraction size and total dose affect late responding tissue.

34. Fractionation Spares normal tissue by: repair of sublethal damage. repopulation of cells if overall time is long enough. May also spare tumour cells. Increases tumour damage by reoxygenation reassortment of cells into radiosensitive phases of cell cycle.

36. Hyperfractionation Aims to further separate early and late effects: overall time is about the same, but number of fractions is doubled, dose per fraction is decreased and total dose is increased. Intent is to reduce late effects while getting the same or better tumour control with the same or slightly increased early effects time interval between fractions must be long enough to ensure that repair of sublethal damage is complete before the 2nd dose is given. Usually > 6 hours between fractions.

37. Accelerated Fractionation same total dose, ~ same number of fractions, but given twice daily. Therefore, overall time is ~ half. intent is to reduce repopulation in rapidly proliferating tumours, with little or no late effects since number of fractions and dose per fraction don’t change. in practice, not achievable since early effects become limiting. (remember, early effects depend on fraction size and overall time).

38. Chemotherapy Most anticancer drugs work by affecting DNA synthesis or function. Most chemotherapy agents are in 3 main groups: alkylating agents: substitute alkyl groups for H antibiotics: inhibit DNA and RNA synthesis antimetabolites: analogues of normal cell metabolites kill by 1st order kinetics (ie a given dose of drug kills a constant fraction of cells, so best chance of cancer control is when tumour is small)

39. Radiation and Chemotherapy Oxygen effect more complex than for radiation. some drugs more toxic to hypoxic cells, some to aerated cells and some show no difference. drug resistance is a huge problem: decreased drug accumulation (molecular pumps) elevated levels of glutathione. increase in DNA repair radiation resistance and chemotherapy resistance may develop together, but are rarely caused by one another.

40. Radiation and Chemotherapy often used together. idea of “spatial cooperation”: radiation is likely to be effective against a localized primary tumour, but it is ineffective against disseminated disease. Chemotherapy can cope with micrometastases, but not a large primary tumour (ie rectal cancer). Chemotherapy may be the primary treatment modality, and radiation is used to treat “sanctuary” sites ( ie small cell lung cancer). combination of toxicities can be limiting

41. Radiation and Surgery radiation often used as adjuvant to surgery: breast colorectal lung radiation is frequently used in the neoadjuvant setting, to make an unresectable tumour resectable: colorectal head and neck both can be used in the palliative setting: bone mets brain mets

43. Radiation and Surgery Multiple issues when combining two modalities: timing (ie colorectal cancer) fibrosis (ie breast cancer) functional result (ie anal canal cancer) cosmesis (ie breast or head and neck cancer) wound healing (any) pathology (ie colorectal cancer) radiation dose limitation (ie bone mets) delay in radiation treatment or surgery

45. How is radiation delivered? external beam radiotherapy (teletherapy). –linear accelerators or radioactive isotope. brachytherapy –intracavitary or interstitial implants.

49. Immobilization

50. Simulation

51. Beam Shaping

52. Linear Accelerator

53. Cobalt Machine

54. How do we measure it? before high energy, used SED (skin erythema dose). 1928, unit of radiation exposure used was the Roentgen (R). now we use absorbed dose = d  /d m where d  is mean energy imparted to a material of mass d m. Unit is Gy (1 Gy = 1 Joule / kg).

55. Case 1: 59 yr old female, postmenopausal Presented with lump in left breast, found in shower. Mammogram showed stellate lesion lumpectomy and AND pathology: 2.5 cm Grade 2 infiltrating duct carcinoma, 1 margin positive, 0/10 nodes positive, no lymphovascular invasion, ER/PR positive referred back for re-resection: no residual disease

56. Case 1 continued... referred to medical oncologist and put on TAM referred to radiation oncologist and offered radical radiation to breast: risk of local recurrence without it is > 30 % radiation decreases local recurrence to 6-7 %. Lumpectomy + radiation = mastectomy. 4250 cGy / 16 fractions / 3 weeks + 1 day can start 8-12 weeks after surgery radiation planning session daily in the building for ~ 1 hr.

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60. Case 1 continued... Acute toxicity: fatigue skin changes: erythema, moist and dry desquamation Chronic toxicity: skin: hyperpigmentation, telangiectasia, sun sensitivity breast parenchyma: firm texture, “radiation breast” (erythema, swelling, tenderness  rare mastectomy) rib brittleness pulmonary fibrosis cardiac events

61. Case 2: 68 yr old male Presented with 6 months of rectal bleeding and 2 months of diminished calibre stool. DRE showed barely palpable lesion, fixed. Colonoscopy showed lesion at 11 cm. Bx adenoca CXR -, CT abd/pelvis -, CEA  at 12. Referred for neoadjuvant chemoradiation: to make it resectable!!! 5FU for 1 cycle, then combined with radiation: 4500 cGy / 25 fractions / 5 weeks to pelvis.

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67. Case 2 continued... 4 weeks after completing neoadjuvant therapy, lesion was decreased and mobile. CT showed smaller lesion. LAR at 7 weeks pathology: 3 cm moderately differentiated adenocarcinoma, margins -, 0/10 lymph nodes +, no lymphovascular invasion

71. References Slides 5, 27, 42, 44, 48-53, from “Radiation Oncology”, Kasey Etreni MRT(T), Radiation Therapist, Northwestern Ontario Regional Cancer Centre, http://rope.nworcc.on.ca/What.pdf slides 6, 8-10, 14-19, 22-24, 26, 31, 32, 35, from “Radiobiology for the Radiologist”, Fourth Edition, Eric J. Hall, 1994 slides 11, 57-59, 62-66, from Chris deFrancesco, Radiation Therapist, Juravinski Cancer Centre