RADIATION ONCOLOGY

An Introduction

by W.G. McMillan

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?

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.

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 = Planck’s constant

• using both equations• if is long, then v is small and E is small

Electromagnetic Spectrum

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.

Photon Interaction With Matter: Photoelectric Effect Z

First Radiograph: 1896

Photon Interaction With Matter: Compton Effect Independent of Z

Portal Image

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

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

Direct vs Indirect Action of Radiation on DNA

Human Chromosomes With and Without Radiation

Surviving Fraction of Cells Post Radiation

HeLa Cell Survival Curve Post Radiation

2 Phases of Cell Survival Curve Post Radiation

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.

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)

4 R’s of Radiobiology (Reoxygenation not shown)

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

OER and Different Radiation Types

Cell Cycle Considerations

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

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.

Normal Tissue Radiation Biology

• Casaret’s Classification of tissue radiosensitivity

• based on parenchymal cells

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.

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.

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.

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).

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)

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.

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

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

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

How is radiation delivered?

• external beam radiotherapy (teletherapy).– linear accelerators or radioactive isotope.

• brachytherapy– intracavitary or interstitial implants.

Immobilization

Simulation

Beam Shaping

Linear Accelerator

Cobalt Machine

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).

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

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.

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

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.

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

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