Cancer therapies 3 - radiotherapy

What are the different forms of radiotherapy?

• Brachytherapy —> direct application

  • Pleisiotherapy (e.g. strontium 90 wand)

  • Implantation —> iridium wires

  • Systemic admin

• Teletherapy (most common) —> external beam

  • Orthovoltage source

  • Linear accelerator (most common)

  • Cobalt 60

How is teletherapy used therapeutically?

• Radiation prod by linear accelerators or by natural radioactive decay

• Electromagnetic radiation

  • X rays

  • Gamma rays

  • Electrons

• Particle beam therapy —> heavy particles (not commonly used)

How does high energy electromagnetic radiation work?

• Low linear energy transfer —> x-ray, gamma rays

  • Lose energy slowly as they pass through tissues

  • Deep penetration (but consider effect on deep structures)

• Indirectly ionising

  • Absoprtion by Compton effect

  • Interaction of photon with water molecules importnat

What is the Compton effect?

• The maximum dose is not absorbed at the surface —> build up below surface, attenuated deeper

  • bigger field = bigger dose because more scatter

What should you do if you want to treat something superficial with radiotherapy?

Counteract the Compton effect —> bolus = tissue-like material allows build up dose to occur @ surface of skin rather than deeper

What is the critical target for therapeutic radiation? How is this target damaged?

DNA —> damage caused by ionisation of water molecules

• Free radicals generated

• DNA damaged by these free radicals

What makes damage by radiotherapy permanent?

Oxygen (damage rapidly reversible unless fixed by this) —> in hypoxic cells DNA is rapidly repaired

• Requires 2.5-3x as much radiation to kill hypoxic cell cf to euoxic cell

How does oxygen inhibit the repair of free radical induced damage?

• Forms irreversible peroxides w/ the injured biomolecules

• Makes radiation damage permanent

What does cell death by radiation occur due to?

• Induction of apoptosis

• Permanent cell cycle arrest

• Mitotic catastrophe

Damage often not expressed until cell tries to divide

What is this?

Linac machine

• Isocentric mounting —> couch, collimator and gantry rotate around a fixed point

  • minimises damage to surrounding healthy tissue

Label this Linac machine

1. Electron gun

2. Accelerating wave-guide (travelling / standing wave)

3. Magnetron

4. RF wave-guide

5. Photon target

6. Photon jaws

7. Flattening filter

How do you shape the beam of a radiotherapy machine?

• With the jaws

  • Like an xray —> rectangular field

• Shaping to the tumour using a multileaf collimator & margins

What can we do to incr tumour dose while sparing surrounding tissue?

Use multiple beams (fields)

maximise dose tumour gets but minimise dose surrounding tissue gets

What are electrons useful for?

• Directly ionising & high linear energy transfer

  • Very light cf to the nuclei of target tissue—> lose a lot of their energy in a single interaction.

• Can treat superficial tumours

What are the 4 Rs of response to radiotherapy?

• Repair

• Repopulation

• Redistribution/ reassortment

• Reoxygenation

What happens during repair after radiotherapy?

Repair of sublethal or potentially lethal damage to cells after exposure —> occurs rapidly

What is fractionation?

• Fractionation is the practice of giving multiple small frequent doses instead of one big one over set period of days / wks

  • Between txs —> cells can REPAIR sublethal damage esp in healthy tissue

  • Normal tissue & tumour tissue can REPOPULATE from cells that are in resting phases/cycle arrest

How does repopulation occur as a response to radiotherapy?

• Seen in rapidly dividing tissues

• Cells are recruited from G₀

• Protects rapidly dividing normal tissues

• Rapidly dividing tumours also repopulate effectively

How does redistribution / reassortment occur as a response to radiotherapy?

• Cells are more sensitive to radiation in some phases of the cell cycle than others (late G2 & M)

  • Cells may become synchronised in the post tx period

  • Synchrony is soon lost

  • Timescale over which redistribution occurs is variable & poorly defined

• Slowly dividing tissues may be more radioresistant as fewer cells in sensitive phases

How does reoxygenation occur as a response to radiotherapy?

• Important factor

• Many solid tumours have poor blood supply

  • Sinusoidal vessels, poorly formed microvasculature

• Areas of hypoxia/necrosis

• Reoxygenation may occur after therapy

  • Euoxic cell death

  • Changes in tumour vascularity

What is the aim of fractionation

• Achieve better tumour cell kill for any given level of normal tissue toxicity

  • reduce normal tissue toxicity

    • REPAIR

    • REPOPULATION

  • achieve better tumour cell kill

    • REOXYGENATION

    • REDISTRIBUTION

What are the different ways you can you use fractionation?

• Larger fraction sizes

  • Greater normal tissue damage

  • Especially late responding tissues

• Smaller fraction sizes

  • Ideal for most tumours

  • More txs required for the same anti-tumour effect

What are the limiations of fractionation for animals?

• Requirement for general anaesthesia

• Cost

• Owner reluctance

  • Inconvenience

  • Frequent visits

  • Long hospitalisation

What is response to radiotherapy affected by?

• Tumour growth characteristics

• Tumour size

• Inherent sensitivity

• Tumour type

• Tumour site

• Patient species

How does volume impact the sensitivity of a tumour to radiation?

• Smaller tumours are more sensitive to radiation

• More rapidly dividing, higher growth fraction, more cells in sensitive phases

• Less likely to contain large numbers of hypoxic cells

• Easy to dose accurately & evenly

What is radiotherpy sensitivity dependent on?

Tumour type & site, patient spp.

What tumour type is more sensitive

Carcinomas or sarcomas?

Carcinomas more sensitive than sarcomas

List the highly radiosensitive tumours?

• Lymphoma

• Transmissible venereal tumour

• Gingival basal cell carcinoma (acanthomatous ameloblastoma)

List the moderately radiosensitive tumours?

• Oral SCC (dogs)

• Oral malignant melanoma (dogs)

• Nasal tumours

• Perianal adenocarcinoma

• MCTs

• Rhinarial SCC (cats)

• Thyroid carcinomas

• Brain tumours

List some tumours that are poorly radiosensitive

• Fibrosarcomas

• Haemangiopericytomas

• Oral SCC (cats)

• Osteosarcomas

• Rhinarial SCC

  • in dogs

Why do we get side effects as a result of radiation therapy?

• Due to undesirable effects on normal tissues

• Only tissues in the irradiated area (field) will be affected

  • remember exit beam location too

• Radiation damage is not usually apparent until cells try to divide

• Can be acute or late

  • Rapidly dividing cells express response in days to weeks

  • Slowly dividing tissues may not show effects of radiation for months or years

• Can be carcinogenic due to DNA damage & mutagenesis

• In what tissues do we see acute side effects of radiation therapy?

• How long do they last?

• Affect rapidly dividing tissues:

  • Skin 

  • Mucous membranes

  • Erythema/desquamation

• Develop during or soon after tx

• Resolve within a few weeks of cessation of therapy 

• Worse if tx course is compressed

• In what tissues do we see late side effects of radiation therapy?

• When do they start?

• What can occur?

• Affect slowly dividing tissues (e.g. cartilage / bone / brain)

• Develop many weeks, months or even years after treatment

• Damage to tissues & their microvasculature

  • Potentially very serious —> ischaemic necrosis of brain or bone tissue

  • Many inconsequential / less serious late effects —> alopecia, skin fibrosis etc.

  • Reduced healing capacity

Radiation is carcinogenic (due to DNA damage) however it tends to be years before malignancy develops in dogs.

• How can we avoid this?

• Avoid irradiating young patients

• Avoid irradiation caused by inadequate surgery or poor surgical planning

What needs to be considered when selecting whether radiotherapy is the best choice of tx?

• Is tx given w/ palliative / curative intent

• Would combined therapy be better than radiation alone?

• What will be effect on adjacent structures? (consider margins)

• Consider tumour of head, neck, extremities

• Concurrent dx

• Costs

• Which protocol?

  • daily or M-W-F

  • weekly

When is radiotherapy indicated for the majority of solid tumours?

• For most solid tumours complete excision = tx of choice

• Radiotherapy may be appropriate where complete excision cannot be achieved

How can radiotherapy be used as an adjunct to surgery?

• Post-op:

  • after radical surgical debulking (gross to microscopic dx)

  • remaining tumour has high growth fraction and should be well oxygenated

• Intra-op:

  • possible —> single large dose of radiotherapy to unresectable, otherwise inaccessible  tumours at the time of surgery

  • rarely done

• Pre-op (neoadjunctive):

  • reduces tumour burden

    • eliminates small numbers of tumour cells at the periphery of the lesion

    • ? reduced risk of tumour cell dissemination at surgery

  • Can have a negative impact on wound healing

  • Used occasionally for OSA and ST sarcoma

What are the outcomes of radiotherapy?

• The effects of radiation on tumour growth are not instantaneous

• Residual mass may be left esp mesenchymal tumours

• Analgesia may be achieved within hrs

  • V. valuable

  • Powerful for majority of patients

What are the key indications for radiotherapy?

Brain & nasal tumours

Before commencing radiotherapy, what is it important to do?

Ensure you know exactly where the tumour was:

• Take or draw a picture

• Take measurements

• Consider referral ideally prior to any (surgical) tx