Chapter 15

Question 1

Define therapeutic ratio in terms of RT treatment. How can the therapeutic ratio be altered to benefit the patient (2 ways)

Answer 1

TR = dose of a therapeutic agent required to produce a given level of damage to a critical normal tissue DIVIDED by the dose of the agent required to produce a defined level of anti-tumor effect

Improved by either

1. increasing the effective RT dose delivered to tumor relative to that given to normal tissue (better positioning, smaller tx field, SRS)
2. increase the biologic response of the tumor relative to that of the surrounding normal tissue (give RT sensitizer)

Question 2

What are the acute and chronic sides seen in irradiated lung tissue?

Answer 2

Acute - pneumonitis

Chronic - fibrosis leading to VQ mismatch

Question 3

Explain the TD5/5

Answer 3

Its the total dose to normal tissue at which no more than 5% of the pop will get severe complications w/in 5y of RT treatment

Question 4

Describe conformational RT.

Major advantage?

Answer 4

Uses 3D treatment planning and uses a series of specific radiation beams from different angles to maximize tumor dose while minimizing normal tissue radiation

Question 5

Define GTV and PTV

Answer 5

GTV - gross tumor volume - the extent of the tumor as defined by CT or MRI imaging

PTV - planning target volume - accounts for microscopic disease just beyond the detectable edge of the tumor as well as for body or organ movement. It is the slightly larger area that will be irradiated to ensure that the entire tumor is treated at the max dose

Question 6

Briefly describe IMRT and at least one drawback

Answer 6

Intensity modulated RT - uses computerized algorithm to design optimal beam orientations and intensities. Uses special collimators that move during RT. Results in decreased normal tissue RT while maximizing delivery to tumor.

Downside - increased volumes of normal tissue are exposed to low doses of RT which can lead RT induced malignancies. Too soon to know if big problem.

Question 7

How does radioimmunotherapy work?

Answer 7

Conjugation of radionucleotides to specific antibodies or agents that bind receptors on cancer cells allowing targeting of the radionucleotide to the cancer cells. Optimal radionucleotide would emit alpha particles which would penetrate to a radius of 1-3 cells away from where its absorbed

Indium 111

Question 8

List 3 ways that HIGH LET RT leads to improve therapeutic ratio

Answer 8

1. most energy is deposited at the end of their track (Bragg peak). Give improved depth dose distribution in deep seated tumors.
2. hypoxic cells are protected to a lesser extent than when low LET RT used, dt reduced oxygen enhancement ratio
3. HIGH LET RT results in less variation in radiosensitivity w/ phases of cell cycle
4. less ability to repair damage from HIGH LET RT

Question 9

Tumors grow from stem cells which have unlimited proliferative capacity. To achieve tumor control, all stem cells much be killed. The dose reqd to control a tumor depends on only two things:

Answer 9

RT sensitivity of stem cells and the # of stem cells

Question 10

The terms ___ and ___ have been used to describe, respectively, tumors that regress rapidly or slowly after RT treatment. The rate of regression (does OR does not) correlate w/ the ability to cure a tumor w/ tolerable doses of RT?

Answer 10

radiosensitive
radioresistent
does not

Question 11

Oxygen must be present in the cell at the time of RT (or w/in milliseconds of dosing) to enhance to biological effect of RT. Why does this occur?

Answer 11

Oxygen can interact w/ radicals formed by radiation resulting in products which cause damage to DNA that is more difficult for the cell to repair. Cells radiated in the presence of air are 3 times more sensitive to RT than severely hypoxic cells.

Question 12

Define oxygen enhancement ratio

Answer 12

The ratio of doses required to give the same biological effect in the absence or presence of oxygen

Question 13

Genes upregulated by hypoxia contain a hypoxia response element (HRE) in their promoter region that is responsive to the transcription factor ___. This TF is increased in low oxygen environs and in tumors. It is ubiquitinated in the presence of ____. Hypoxia for a long period of time will lead to death by apoptosis unless there is a mutation in the gene ___ which can lead to resistance of hypoxia induced apoptosis.

Answer 13

HIF-1
Von Hippel Lindau
P53

Question 14

Define/describe reoxygenation.

Answer 14

Even if only a small fraction of tumor cells are hypoxic, after a dose of RT the percentage of cells that are hypoxic increases. With time, some surviving hypoxic cells may gain access to o2 and be more sensitive at a future dose. Reoxygenation therefore can result in a substantial increase in the sensitivity of tumors during fractionated treatment.

Question 15

Name/describe 2 ways to measure oxygen in tumors

Answer 15

1. Polarographic oxgen electrodes.
   Measure microregional pO2, in multiple locations. Invasive, require putting probes into tissue in vivo. Also cant distinguish bt viable and non-viable tissue.
2. Studies of intrinsic markers of hypoxia such as HIF1a, GLUT1 in tissue blocks. Cant measure in vivo
3. PET imaging

Question 16

Name 2 radiation sensitizers that have improved outcome w RT in hypoxic cells

Answer 16

Mizonidazole

Hyperbaric oxygen

Question 17

There are acute and late responses of tissues to RT. These are generally seen in 2 distinct groups of cells w/ certain characteristics. Describe characteristics of cell types that display acute vs late responses. Give examples of each and avg time frame in which these different effects are seen.

Answer 17

ACUTE: bm and gi - rapid renewal where cell division is critical to maintain organ function. w/in 3m

LATE: organs w/ infrequent cell division (liver, kidney, nerves). Cell death is slow since they don’t normally enter the cell cycle. Often its damage to the supporting cells (connective tissue and vasculature) that leads to progressive impairment in circulation to the organ). >3m. Usually the limiting factor in dosing patient.

Question 18

Describe the side effects of RT (using technical RT terminology) to skin

Answer 18

Early erythema - from mast cell degranulation
Dry desquamation - following steps depend on rate of cell loss and proliferation of basal cells of epithelium
Moist dequamation
Ulceration

Question 19

Describe the different RT reactions seen in lung. State wHEN they are noted.

Answer 19

Pneumonitis seen 2-6m post RT

Fibrosis seen >1y post RT

Question 20

What is max tolerated RT dose to whole body?

Answer 20

BT 2 and 8 Gy = severe BM toxicity.

May be saved w/ BMT.

Question 21

Draw a curve demonstrating the therapeutic ratio for RT. Include a curve for normal tissue and for tumor tissue.

Answer 21

TR is favorable if tumor control curve is displaced left of curve for normal tissue damage - the greater the displacement the more radio curable the tumor. If the curves were close together or if the tumor control was to the right of tissue dmg, a high level of complications would have to be accepted for minimal tumor control (unfavorable TR).

15.19 p 310

Question 22

Misonidazole is in the drug family of nitroimidazoles. What does it do and how does it do this? What is the major negative side effect of this drug?

Answer 22

Radiation sensitizer which sensitizes hypoxic cells in vitro in a dose dependent fashion w/o effecting well-oxygenated cells (normal cells).

Causes dose dependent peripheral neuropathy.

Question 23

Amifostine is used in RT for what? What is the key to amifostine helping w/ tumor control?

Answer 23

Its a radioprotective agent. Scavenges RT produced radicals. This will occur both in tumor cells and in normal cells. The key is having a medication that is preferentially taken up into normal cells. Works as a sulfhydryl containing compound. Selective uptake is believed to be dt poor penetration from tumor blood vessels.

Question 24

5Rs

Answer 24

Radiosensitivity
Repair 
Reoxygenation
Repopulation 
Redistribution

Question 25

The shoulder on a survival curve after a single radiation dose is indicative of what?

Answer 25

The capacity of the cells to accumulate and repair RT damage

Question 26

If fractionation of RT is spread out over too long a pd of time, which R can lead to increased tumor survival or progression?
This effect is generally seen over what pd of time?

Answer 26

Repopulation - after some time the tissues can respond by increasing the rate of cell proliferation leading to faster growth than kill.
Usually w/in 3-4 weeks, this is not significant, however beyond that, there is a substantial increase in the total dose required as tx duration is lengthened.

Question 27

Describe the alpha/beta ratio, draw 2 curves one w/ high a/b ratio and one w/ low a/b ratio.
What tissues tend to have high and low ratio?

Answer 27

Alpha - initial slope
Beta - secondary slope (larger beta, curvier survival curve)

LARGE a/b ratio - steep curve w/ little curvature (small shoulder)

• less repair capacity and shallow isoeffect curve
• early responding tissue in 8-12Gy range
• Tumors have values equal/greater than early responding tissues

SMALL a/b ratio - shallow curve w/ greater curvature - large shoulder

• consistent w/ greater repair capacity and steep isoeffect curve
• late responding tissues a/b in 2-4 Gy range

Question 28

What is hyperfractionation?

Answer 28

tx multiple times per day to give lower doses per fration w/o increasing total tx time (making it take more weeks which would lead to repop probs).
Reduces late effects w/o sacrificing tumor control. But may slightly increase early effects.