RADIATION ONCOLOGY

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RADIATION ONCOLOGY

• An Introduction
• by W.G. McMillan

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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?

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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.
• CC requires 4.9 eV and 1 ionization event
  provides 33 eV.

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Ionizing Radiation

• Electromagnetic
• waves of wavelength ?, frequency v, velocity c
• where ? v c and c 3 x 1010 cm/sec
• ?-rays radioactive decay of unstable nucleus
• x-rays produced by electrical device
• photons packets of energy
• where E hv where h Plancks constant
• using both equations
• if ? is long, then v is small and E is small

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Electromagnetic Spectrum
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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.

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Photon Interaction With Matter Photoelectric
Effect ? Z
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First Radiograph 1896
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Photon Interaction With Matter Compton Effect
Independent of Z
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Portal Image
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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

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Radiation Interaction With DNA

• Indirect Interaction
• fast electron hits H2O ? H2O e- H2O H2O ?
  H3O OH-
• reactive species interact with DNA
• Direct Interaction
• photons (rarely) or particles (always) directly
  interact with DNA

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Direct vs Indirect Action of Radiation on DNA
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Human Chromosomes With and Without Radiation
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Surviving Fraction of Cells Post Radiation
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HeLa Cell Survival Curve Post Radiation
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2 Phases of Cell Survival Curve Post Radiation
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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.

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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)

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4 Rs of Radiobiology (Reoxygenation not shown)
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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

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OER and Different Radiation Types
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Cell Cycle Considerations
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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

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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.

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Normal Tissue Radiation Biology

• Casarets Classification of tissue
  radiosensitivity
• based on parenchymal cells

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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.

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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.

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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
  gt 6 hours between fractions.

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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 dont change.
• in practice, not achievable since early effects
  become limiting. (remember, early effects depend
  on fraction size and overall time).

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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)

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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.

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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

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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

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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

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How is radiation delivered?

• external beam radiotherapy (teletherapy).
• linear accelerators or radioactive isotope.
• brachytherapy
• intracavitary or interstitial implants.

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Immobilization
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Simulation
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Beam Shaping
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Linear Accelerator
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Cobalt Machine
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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?/dm where d? is mean
  energy imparted to a material of mass dm. Unit is
  Gy (1 Gy 1 Joule / kg).

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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

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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 gt 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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CT Planning
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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

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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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CT Plan
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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

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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