Radiobiology

Question 1

Why is radiotherapy for cancer patients a balance between benefits and risks?

Answer 1

The benefits of radiotherapy are that you can control the tumour (and even kill it). The potential risks are that radiotherapy is not specific to the tissue of the tumour, but also to normal healthy tissue. So the healthy tissue can be damaged and there could even be induction of secondary tumours.

Question 2

So what has to be taken into account in regard to the therapeutic window of radiotherapy?

Answer 2

The therapeutic window between:
- tumour control probability (cure)
- normal tissue complication probability (side effects).

Question 3

How can the therapeutic window between the benefits and the risks of radiotherapy be improved?

Answer 3

• By application of appropriate and accurate diagnostic tools to obtain detailed information to precisely define the treatment target volume.
• By using highly sophisticated technical equipment, high conformal, precision radiotherapy to selectively irradiate the tumour while sparing healthy tissues and organs.
• By taking advantage of the knowledge about biological processes which determine the effects of irradiation on tumour- and healthy cells and tissues.

Question 4

What are the hallmarks of radiobiology (the 6Rs)?

Answer 4

The 6Rs determine the treatment efficacy of radiotherapy in the clinic → complication rate (by normal tissue cell injury) and tumour control rate (by tumour cell kill).

These 6Rs can be modulated and consist of:
- Radiosensitivity
- Repair/recovery
- (Re)oxygenation
- Redistribution
- Repopulation
- Reactivation of the immune respons.

Question 5

What is the link between the hallmarks of cancer and the hallmarks of radiobiology?

Answer 5

Reactivation of the immune response

Question 6

What is the main effect of radiation on cells?

Answer 6

Induction of DNA damage

Question 7

Thus, the main effect of radiation on cells is the induction of DNA damage. There are two ways radiation can induce DNA damage, via:

• direct action
• indirect action

Describe these two types of DNA damage.

Answer 7

• Direct action → radiation induces base deletions and single and double strand breaks.
• Indirect action → radiation induces the ionization of water molecules, which produces free radicals and in turn this damages the DNA.

Question 8

What is the most important free radical that is responsible for inducing DNA damage via indirect action of radiation?

Answer 8

Reactive Oxygen Species (ROS)

Question 9

What happens when a DNA double strand break is not repaired?

Answer 9

The lesion is lethal to the cell.

Question 10

What determines whether DNA damage of a cell results in cell survival, malignant transformation or cell death?

Answer 10

• Cell survival → the amount and type of damage can be handled and a network of survival responses get activated.
• Malignant transformation → the damage is excessive and/or irreperable, which results in mutations and chromosomal aberrations.
• Cell death → damage is excessive and/or irreperable, leading to activation of apoptosis.

Question 11

What is another main effect of radiation on cells (after DNA damage has already occured)?

Answer 11

Late cell death

Question 12

What is the difference between early and late cell death? And what is mitotic catastrophe?

Answer 12

Some cell types (e.g. lymphocytes) show apoptotic or other types of cell death.
- Early cell death → cells that die before mitosis can occur.
- Most cell types die during mitosis after the first cell division → mitotic catastrophe.
- Cell death can still occur after some cell divisions, referred to as late cell death.

Question 13

What is meant with redistribution in regard to the 6R’s as a hallmark of radiobiology?

Answer 13

The return to the normal cell cycle distribution of the cell population as pre-irradiation.

Question 14

In regard to the cell cycle, what cell cycle phase of cells is the most sensitive to radiation?

Answer 14

Cells that enter the G2 and M phase of the cell cycle. Thus, cells that prepare for or initiate proliferation.

Question 15

What is meant with fractionated radiation?

Answer 15

The radiation therapy is delivered over the course of multiple days. Each treatment of radiation is called a dose fraction. It enables selective sparing of healthy cells.

Question 16

How does fractionated radiotherapy enable sparing of healthy tissue?

Answer 16

Fractionation exploits the difference between tumour- and normal tissue cells in their capacity to repair the DNA damage as a result of radiation.

Question 17

Describe what you can see in this picture.

Answer 17

• Tissue/organ specific sigmoid shaped curve. The green curve is relative radiosensitive tissue compared to a radioresistant tissue.
• This conclusion can be made based on the threshold dose. The green curve has a lower threshold dose that correlates with a higher probability of tissue injury, whereas the yellow curve has a higher threshold dose with lower chances of tissue injury.

Question 18

What organ is the least sensitive to radiation therapy and can thus receive a high(er) dose of radiation? And what organ is the most sensitive to radiation therapy?

Note: this question is not important for the exam

Answer 18

• Least sensitive → brain (can receive up to 60 Gy)
• Most sensitive → testes (can receive less than 10 Gy)

Question 19

What can be concluded based on this picture?

Answer 19

That multiple fractionated radiotherapy widens the therapeutic window between the tumour control probability and normal tissue complication probability.

Question 20

What can be concluded based on this picture?

Answer 20

That there is a time scale of the effects of radiation exposure to biological systems. For example, enzymatic reactions due to radiation exposure occurs quite early, whereas carcinogenesis can occur at a very late stage after radiation exposure.

Question 21

Why is it neccessary to increase the radiation dose by 3 times in order to kill hypoxic (tumour) cells compared to well oxygenated (tumour) cells?

Answer 21

Because in the presence of oxygen, oxygen fixates the damage of radiation (think of the indirect action of radiation on DNA damage). Thus, in the abscence of oxygen, the DNA damage is less permanent, which means that radiation works less well.
In summary, hypoxic tumours are radioresistant because the lack of oxygen results in less fixation of DNA damage.

Question 22

If hypoxic tumours are radioresistant, what can be done to make these tumours more radiosensitive?

Answer 22

Reoxygenate the hypoxic tumour inbetween irradiation fractions, causing the hypoxic tumour cells to be sensitized.

Question 23

Why is it sometimes necessary to increase the radiation dose with time?

Answer 23

Because for some tumours, the repopulation rate increases over time. Therefore, the radiation dose also needs to be increased over time.

Question 24

Explain why the overall treatment time (OTT) should be limited for rapid repopulating tumours.

Answer 24

If the OTT is prolonged for these kind of tumours, an extra radiation dose of X Gy per day is required to compensate for the loss of tumour control due to the accelerated tumour cell repopulation.

Question 25

What is radiation-induced immune activation?

Answer 25

Radiation carries the potential to initiate the adaptive and innate immune system, resulting in systemic anti-tumorigenic effects inside and outside of the irradiation field. It results in:
- the activation and maturation of dendritic cells → via lymphatic vessels → dendritic cells activate CD8+ lymphocytes → through blood vessels the lymphocytes cause a local cytotoxic effect in the tumour and a initiate an immunogenic systemic response.

Question 26

What is the definition of abscopal effect?

Answer 26

The response of a tumour or metastasis outside the scope of the treated volume.

Question 27

What is a specific focus of research in regard to radiotherapy?

Answer 27

The use of radiotherapy to activate the immune system.

Question 28

Describe the 6Rs of radiobiology in brief.

Answer 28

• Radiosensitivity → intrinsic and acquired radioresistance of cancer (stem) cells / the heterogenic cancer cell population.
• Repair → mechanisms of sublethal damage repair, involving homologous recombination (HR) and non-homologous end joining (NHEJ).
• Redistribution → of cells in the cell cycle affects their radioresistance. Cells in the late-S phase are more resistant and cells in the G2/M-phase are more sensitive to radiation.
• Repopulation → Cancer Stem Cells not eradicated by irradiation are involved in the accelerated repopulation of the tumour.
• Reoxygenation → cells in hypoxic niches within the tumor are more radioresistant. Reoxygenation between radiation fractions is important to increase tumor cell killing.
• Reactivation of the immune response → local irradiation induces systemic immune activation to attack distant tumour cells.