Principles of Radiotherapy

XRT, local tumour control

____ is one of the two most effective treatments for cancer aside from surgical resection. It has replaced surgery for the long-term control of many tumours where it often gives reasonable probability of ________ with good cosmetic result.

Palliation

Reducing the violence of a disease or easing the symptoms without curing the underlying disease

Adjuvant

An additional therapy designed to help reach the clinical objective goal

Therapeutic index and metastasis

What are the biggest problems for cancer therapy?

Surgery, radiotherapy, 50

_______ is the treatment with the largest contribution to cancer cures (49-50%), followed by ________ (~40%). ~___% of all cancer patients will receive XRT at some time in their illness.

Therapeutic index, damage to surrounding normal tissue and consequent risk of complications

____ is the most important factor in curative XRT— the dose that can be delivered to a tumour is limited by _________.

sigmoidal

Dose-response curves are typically ________.

the larger the dose that can be safely administered

The further apart the % tumour control probability and % normal tissue complication probability curves are…

limit of tolerance of the dose-limiting organ at risk (OAR), tumour control probability, normal tissue complication probability, maximising TCP for an acceptable level of NTCP

XRT treatments are designed on the basis of ________ for that tumour location. Optimization of XRT treatment plans involves computation of ________ and _______, and the therapeutic index depends on ________.

as the volume of an organ irradiated by a high dose increases the probability of NTCP and tolerance dose increases

The volume effect in XRT explains that…

dosimetric factors, many overlapping beams were used with the overlapping dose hitting the tumour

Therapeutic index in curative XRT derives largely from ________. For several decades, to obtain the maximum dose to a tumour while minimising dose to surrounding tissues _________.

linear accelerator (LINAC), delivers high energy x-rays or electrons

The primary device used in hospitals for external beam radiotherapy (XRT) is a ________ that ________.

Gross tumour volume (GTV)

Total tumour volume that includes all areas visible on imaging

Clinical target volume (CTV)

GTV plus volumes with expected subclinical spread

Planning target volume (PTV)

CTV plus patient specific margins for tumour motion or deformation

Treatment volume (TV)

Volume of tissue receiving the prescribed dose

Irradiated volume (IV)

Volume of tissue exposed to significant doses regarding to normal tissue tolerance

immobilisation and imaging > tumour and organ segmentation > image verification > dosimetry planning > radiotherapy treatment

Steps of creating a radiation treatment plan:

dose fractionation, counteract tumour repopulation while allowing healthy tissues to recover

A second major contribution to TI derives from _________ primarily to _________

loss of clonogenic potential, loss of clonogenic potential of normal stem cells

Cancer control (i.e. TCP) in XRT depends primarily on _________. The effect of radiation on normal tissues (i.e. NTCP) is also mediated in part by ________.

clonogenic survival curve, all forms of early cell death and prolonged growth inhibition

In 1956, the effects of radiation on HeLa cervical cancer cells were first described using a _________. The “gold-standard” version integrates ___________.

predict cell survival and determine fractionation schedules

The linear-quadratic formula is used to…

SF = e^-(aD + bD²) where SF = surviving fraction, a = linear component representing single-hit cell killing, b = quadratic component representing repairable cell killing, and D = dose per fraction (Gy)

The linear-quadratic formula is:

surviving fraction (i.e. cells that retain clonogenic potential) after a given dose (log scale), radiation dose (linear scale), a/b ratio, a and b contributions to cell killing are equal

In a clonogenic survival curve, ________ (y) is graphed versus ________ (x). The important parameter for XRT planning is ______ which is the dose where _________.

damage that can not be repaired, damage that can be repaired

In the linear-quadratic formula, a represents ______ while b represents _______.

be avoided by fractionation, time-dependent

In the LQ equation b is important because it represents the component of cell killing caused by damage that can ___________, i.e. the impact of b-type damage is _______.

increase in cell survival observed when a total dose of radiation is split into smaller fractions separated over time

Split-dose recovery refers to…

bendy survival curve, high split dose recovery capacity

Larger values of b (i.e. low a/b ratio) indicate _______ and ________.

flatter survival curve, little split dose recovery capacity

Larger values of a (i.e. high a/b ratio) indicate ______ and _____.

high total dose that needs to be administered, repair capacity

The more fractions that are administered, the _________. The “shoulder” of the fraction is a function of _______ which is what determines the slope of the total dose required.

there is full repair of surviving cells between fractions and there is no proliferation of tumour cells

Important assumptions for fractionation include:

normal tissues are spared because of repair of sublethal damage between fractions and increased damage to the tumour because of reoxygenation and reassortment of cells into radiosensitive phases of the cell cycle

Fractionation works because…

repair, reassortment, repopulation, and reoxygenation

The 4 Rs of radiobiology are:

all cells repair radiation damage but with different efficiencies, normal tissues to repair all repairable damage prior to giving another fraction

Repair in radiobiology refers to the fact that __________. It is essential to…

cells have different radiation sensitivities in different phases of the cell cycle, mitosis, late S phase

Redistribution in radiobiology is important because ________. The highest radiation sensitivity is in ________ and the most radioresistant phase is ________.

ability of radiation to kill cells is oxygen dependent, a few days after the first dose

Reoxygenation in radiobiology is important because ____________ and reoxygenation of the tumour typically occurs ________.

ratio of hypoxic to aerobic doses needed to achieve the same biological effect, OER = Dhypoxia/Dnormoxia

The oxygen enhancement ratio refers to _________ and the formula is ________.

ability of oxygen to make damage done by a free radical permanent because of formation of a peroxide that changes DNA composition

The oxygen fixation hypothesis refers to…

hypoxic

Tumour cells in ______ regions are more resistant to radiotherapy.

that were hypoxic at the time of irradiation become oxygenated by the time the next fraction is delivered

Reoxygenation itself refers to the process by which tumour cells…

hypoxic, their oxygen and nutrient supplies improve, increased radiosensitivity

Cells that survive the first dose of XRT tend to be _____, but after irradiation _______ leading to _______.

predictive of poor clinical response, FDG-PET, measures glucose metabolism using radiolabelled glucose which selectively binds hypoxic areas

Despite reoxygenation, hypoxia is ___________. To determine hypoxia ______ can be used, which ________.

treat in the shortest time possible, accelerated fractionation

To address repopulation of fast-growing tumours, it is critical to _______. Thus, ________ was investigated and it leads to better response in rapidly proliferating tumours (little difference for slow growing tumours).

total dose, dose per fraction, time between fractions, and total treatment time

Optimisation of a fractionation schedule depends on individual circumstances and includes the following parameters:

Early effects

Injury manifests within days to weeks post-XRT; generally heal over time and/or are manageable

Late effects

Injury manifests months to years post-XRT; may improve but never completely resolve and can be debilitating or life threatening

Iso-effect dose

The total dose of radiation required to achieve a given level of biological damage

late effects, early effects, smaller the fraction

Fractionation tends to spare _______ but not ______. The __________ the more sparing for tissues with low a/b.

repair, repopulation, increase the iso-effect dose

Of the 4 Rs, _____ and _____ tend to make the tissue more tolerant to a second dose of radiation, i.e. they _______ when radiation treatment is fractionated.

redistribution, reoxygenation, reduce the required total dose for an iso-effect

Of the 4 Rs, _______ and ______ tend to make the tissue more sensitive to a second dose of radiation, i.e. they ________.

redistribution, repopulation

Of the 4 Rs, _____ and _____ are only important for rapidly proliferating cell populations.

low a/b, rapid increase, decreasing dose per fraction

Late-responding tissues typically have _____, indicating high capacity for repair/split-dose recovery. There is ______ of tolerance dose with ________.

high a/b, less rapid increase, decreasing dose per fraction

Early-responding tissues typically have ________. There is _______ in tolerance with _________.

early, little repair and thus little change in iso-effect dose with fractionation

Tumours typically respond like ___-responding tissues, i.e. they show…

radiosensitivity, range of radiosensitivity across tumour types

The tentative 5th R is ________ as there is a…

surviving fraction at 2 Gy (SF2)

Clinical radioresponsiveness was demonstrated by determining in vitro parameters such as ________. This is predictive for some tumour sites, but not others.

Tumour size, number of clonogenic cells, larger tumours are more difficult to cure because they have more clonogenic cells

_____ is important for TCP. The dose of XRT required to control a tumour depends on ______, therefore ___________.

a sealed radiation source is placed inside or next to the area requiring treatment

Brachytherapy is a form of radiotherapy where…

cervix, prostate, breast, and skin

Brachytherapy is mostly used for cancers of the…

low dose radiation from implanted seeds that stay for several months and high dose radiation from an inserted source that is removed after about 30 minutes

There are two types of brachytherapy for the prostate:

dose delivery and dose distribution

The main reasons for choosing interstitial or intracavitary radiotherapy over external beam treatment relate to…

placing the source in the tumour resulting in high doses to a localised area that rapidly drops off at the edge of the target, thus sparing surrounding healthy tissue

Brachytherapy takes advantage of the volume effect by…

4D radiation dose delivery leading to better dose distribution, using fewer high-dose fractions due to 4D delivery, individualisation beyond contouring, and use of radiation modulating drugs like sensitizers

Major advances have and will come in 4 areas of XRT:

multileaf collimators, shape the beam, complicated tumour shapes

Tomotherapy involves computer-controlled beam delivery using _________ to _______, which allows complex treatment plans to be developed and implemented for ________.

Hypofractionation

Use of fewer higher-dose fractions in a shorter overall treatment time

administration of unsealed targeted radionuclides, short range beta or electron emission, radioimmunotherapy, radiolabeled neoantigen-specific antibodies

Radioisotope therapy is _________ using _______ to achieve a clinically important outcome for a patient with cancer. An example includes _________ where there is delivery of radiation to the tumour via ________.