Radiation Biology Flashcards
Linear Quadratic equation
S = exp^(-aD-BD^2)
S=surviving fraction
a = alpha, coefficient
of radiation sensitivity for linear component
B = beta. coefficient
of radiation sensitivity for quadratic component
D = dose delivered as single fraction
EQD2 equation
and describe the concept
EQD2 allows us to work out an equivalent total dose as if it was in 2Gy per fraction for treatments that were given either hyper- or hypo- fractionated. To be able to calculate if it has reached tolerance dose for noral tissues when adding 2 or more treatments.
EQD2 = D x (a/B + d) / (a/B + 2)
a/B = this is the ratio for tissue/tumour under consideration with the unit Gy
Define Biologically Effective Dose (BED) of a given schedule, including the formula for its calculation
i. BED is a measure of the true biological dose delivered calculated using the a/B ratio for the tissue/tumour. BED is mainly used for stereotactic RTx now
ii. BED = nd x(1+d/(a/B))
a/B ratio is for tissue/tumour, unit Gy
i. Outline the concept of forgotten dose and its clinical relevance to retreatment of spine
i. Forgotten dose is the concept that normal tissue may have some recovery of their tolerance dose following radiation exposure, such that a proportion of the radiation dose is “forgotten”
ii. For this woman, as it has been 2 years since her previous treatment her normal tissue tolerance is likely higher than it would be if she had just completed treatment.
ii. List the factors that need to be taken into account when considering re-treatment in general
i. OARs
i. - Initial radiation dose to OARs and calculating the EQD2 if was not treated in 2Gy fractions.
ii. - Initial radiation volume and coverage of OARs and how this relates to the planned re-irradiation ?degree of overlap.
ii. Concurrent treatments (chemotherapy or immunotherapy) delivered at the time of initial RT which could affect tolerance of OARs
iii. Time interval between the initial treatment and the planned retreatment, is there a potential for recovery of normal tissue tolerance
iv. Patient factors –
i. function of tissue/organ being retreated, i.e. is the underlying organ function good or does the patient have underlying medical conditions such as emphysema and needing to retreat lung
ii. Expected life span of patient or QOL if left untreated: are they at risk of developing late toxicities, or do the benefits of retreating outweigh late toxicity risks
iii. Patient age and ability to tolerate RTx
v. Alternative treatment options – consider if surgery or supportive care would be better options
Briefly discuss the re-treatment tolerance for late effects for spinal cord. Include in your answer any relevant clinical and laboratory data where appropriate.
Tolerance dose for spinal cord = 50Gy for 0.02% risk of meylopathy
Late effects for spinal cord is myelopathy which is permanent and Lhermitte’s sign which is usually reversible. Retreatment tolerance for spinal cord can be increased with a time interval. There has been lab studies on rats and Rhesus monkeys that looked at spinal cord myelopathy with retreatment.
In human studies it is estimated a 25% recovery in dose tolerance of the spinal cord has been suggested based on data that looked at a greater than 6 month period between two course of RT
Outline the proposed mechanisms of late radiation injury to the spinal cord.
Late damage includes two principal syndromes. The first, occurring from about 6 to 18 months, involves demyelination and necrosis of the white matter from parenchymal cell loss; the second is mostly a vasculopathy and has a latency of 1 to 4 years.
- Parenchymal cell loss
i. Occurs 6 months and over after radiation to spinal cord
ii. Diffuse or focal demyelination and extensive necrosis, probably as a consequence of injury and loss of oligodendrocytes by killing of glial progenitor cells (astrocytes) which cause gliosis and eventuall fibrosis of the cord - Vascular injury
i. Occurs 6 months to years after radiation
ii. Fibrin rich necrosis of white matter can occur and is thought to be caused by microvascular damage leading to increased capillary permeability and resultant slowing of blood flow to obliteration of vessels
iii. Probable mechanism is endothelial cell damage, leading to eventual obliteration of small vessels
Define and discuss the concept of a serial functional subunit. Include in your answer a brief description of ‘threshold dose’.
In serial FSUs the function of the entire organ depends on the function of each individual FSU.
Serial FSU organ such as spinal cord are not significantly affected by volume effect. Function of the organ is dependent on dose (threshold dose); with a hotspot capable of causing a ‘break’ in the series structure if it reaches over a certain threshold dose.
Serial FSU = must not exceed max DOSE
Parallel FSU = must not exceed max VOLUME
No organ is completely serial or parallel.
ii. Below are two cell survival curves for low and high α/β cell lines. (1) Identify the axes and curves labelled A-D
A. Surviving fraction
B. Dose in Gy
C. high a/B ratio cell line
D. low a/B ratio cell line
The dose-responsiveness relationship for late responding tissues (low alpha/beta) is more curved than for early-responding tissues (high alpha/beta) . In the linear-quadratic formulation, this translates into a larger a/B ratio for early effects than late effects.
The a/ratio is the dose at which the linear (a) and the quadratic (B) components of cell killing are equal, that is, aD=BD^2 or D = a/B
Define the term α/β value and describe how it can be found from a cell survival curve. (1)
The ratio of the parameters alpha and B in the linear quadratic model; used to quantify the fractionation sensitivity of tissues.
From a cell survival curve the a/B can be found when the components of alpha cell killing are equal to B components of cell killing.
iii. List four potential limitations of the Linear Quadratic model in clinical practice. (2)
i. At very low doses per fraction<1Gy, the LQ model could underestimate the biological effect of a given dose, due to the low-dose hyper-radiosensitivity phenomenon.
ii. At very high doses per fraction >8Gy, the LQ model underestimates the biological effect due to factors such as vascular and stromal damage not being taken into account.
iii. The LQ model does not include a time factor and assumes sufficient time between fractions for repair of sublethal damage
iv. It does not take into account tissue /tumour repopulation over time
v. It has not been validated with concurrent chemotherapy
i. What is sublethal damage repair?
i. SLD repair is the operational term for the increase in cell survival that is observed if a given radiation dose is split into two fractions separated by a time interval.
ii. Using a labelled diagram, outline the key differences in cell survival curves for a single fraction vs. multiple fraction course of radiation therapy. (2)
The concept of an “effective” survival curve for a multi fraction regimen is illustrated. If the radiation dose is delivered in a series of equal fractions separated by time interval sufficiently
long for the repair of sublethal damage to be complete between fractions, the shoulder of the curve is repeated many times. The effective dose-survival curve is an exponential function of dose, that is a straight line from the origin through a point on the single-dose survival curve corresponding to the daily dose fraction (e.g. 2Gy).
The dose resulting in one decade of cell killing (D10) is related to the D0 by the expression D10=2.3xD0
D0 of the effective survival curve (i.e. the reciprocal of the slope), defined to be the dose required to reduce the fraction of surviving cells to 37%, has a value close to 3Gy for cells of human origin
D10 is the dose required to kill 90% of the population.
iii. Describe the mechanism of acute skin reaction including how moist desquamation develops. (3)
Skin is an example of a H-type tissue from Michalowski’s classification (hierarchical)
H-type tissues have 3 groups of cells present: Stem cells, Maturing/partly differentiated and functional cells.
The skin is composed of the outer layer, the epidermis, which is the site of early radiation reactions, and the deeper layer, the dermis, which is the site of late radiation reactions
The epidermis is derived from a basal layer of actively proliferating cells, which is covered by several layers of nondividing differentiating cells to the surface, at which the most superficial keratinized cells are desquamated. It takes about 14 days from the time a newly formed cell leaves the basal layer to the time it is desquamated from the surface. The target cells for radiation damage are the dividing stem cells in the basal layer.
Early erythema develops in the second to third week of a fractionated regimen, similar to sunburn, which is caused by vasodilation, oedema, and loss of plasma constituents from capillaries. Reactions resulting from stem cell death take longer to develop and cause desquamation from depletion of the basal cell population.
At lower doses, islets of skin may regrow from surviving stem cells; at higher doses, at which there are no surviving stem cells within the area treated, moist desquamation is complete, and healing must occur by migration of cells from outside the treated area.
iv. Briefly describe consequential late effects and how they differ from late toxicities of radiation therapy. Give a clinical example. (2)
If intensive fractionation protocols deplete the stem cell population below levels needed for tissue restoration, an early reaction in a rapidly proliferating tissue may persist as a chronic injury. This has been termed a consequential late effect, that is, a late effect consequent to, or evolving out of, a persistent severe early effect. The earlier damage is most often attributable to an overlying acutely responding epithelial surface—for example, fibrosis or necrosis of skin consequent to desquamation and acute ulceration.
Name the structures labelled A to I in the diagram of an animal cell below:
(3)
Name the DNA-repair pathway that is involved during / immediately after DNA replication pertaining to incorrectly paired nucleotides. (1)
Microsatellite Instability (MSI) is caused by mutations in the genes responsible for the above pathway. Name at least one affected gene and name the associated syndrome. (1)
Proofreading / Mismatch repair. Proofreading, which corrects errors during DNA replication. Mismatch repair, which fixes mispaired bases right after DNA replication
Lynch syndrome caused by mutation in the DNA mismatch repair gene
Define the term “doubling dose”.
Doubling dose is the dose required to double the incidence of spontaneous anomalies within a population.
Esitmated doubling dose fir humans is about 2 Sv from atomic bomb data.
Discuss the potential effects of significant ionising radiation exposure on the human embryo and foetus.
Preimplantation
0-9 days (1st week)
* All or nothing response, either survives or dosesn’t after IR exposure
* Radiation causes embryonic death above 0.1Gy
Embryonic stage / organogenesis
10days – 6 weeks
* Theshold dose of 0.1Gy
* Radiation causes major structural abnormalities at this stage as it is organoogenesis
* Can also cause Severe intrauterine growth restriction from cellular depletion
* Microcephaly
Early Foetal stage
6 weeks – ?end of 2nd trimester (26 weeks) * Mental retardation, most severe if exposed between 8-15 weeks. Result from failure of cells to migrate from proliferative zones.
* Threshold dose 0.1Gy
* IQ decrease of 25 points per Gy
* Eye, skeletal and genital abnormalities
Late foetal stage ?third trimester
27 weeks – 40 weeks
* Microcephaly, most marked in 3rd trimester
* Cancer following irradiation in utero
* Increases risk of childhood cancer by 40% above spontaneous level
* Excess absolute risk is 6% per Gy
Define the term “doubling dose”.
What is the estimated doubling dose for humans according to The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)?
Doubling dose is the dose required to double the incidence of spontaneous anomalies within a population.
Esitmated doubling dose for humans is about 2 Sv of absorbed radiation dose from atomic bomb data.
Regarding combinations of radiation therapy and systemic therapies:
- Define spatial co-operation and give one clinical example
Define spatial co-operation. (1)
i. Spatial co-operation refers to when the targets of radiation and chemotherapy are located at different anatomical sites, each modality acts independently of the other.
ii. Give one clinical example. (1)
i. Radiation used to treat primary site, and chemotherapy used for micrometastatic disease. Eg. Breast cancer
ii. Seclusion sites: brain, testes – where chemotherapy is the primary modality, and radiation is used for those sanctuary sites with inadequate chemotherapy penetration, such as PCI for small cell lung cancer. Or RT to testes and chemo for systemic treatment in testicular treatment
List classes of immunotherapy agents and give an example of an individual target in each
- Checkpoint Inhibitors:
* Example: Pembrolizumab (Keytruda)
* Target: Programmed Death 1 (PD-1) receptor - Checkpoint Ligands:
* Example: Atezolizumab (Tecentriq)
* Target: Programmed Death Ligand 1 (PD-L1) - CAR-T Cell Therapy:
* Example: Kymriah (tisagenlecleucel)
* Target: CD19 (Chimeric Antigen Receptor-T Cell Therapy targeting CD19) - Cytokines:
* Example: Interferon-alpha (various brand names)
* Target: Various immune cells, including interferon receptors - Oncolytic Viruses:
* Example: Talimogene laherparepvec (T-VEC or Imlygic)
* Target: Replication in cancer cells, leading to cell lysis and immune activation - Monoclonal Antibodies:
* Example: Rituximab (Rituxan)
* Target: CD20 antigen on B cells in certain types of lymphoma and leukemia
* Example: Trastuzumab (Herceptin)
* Target: Human Epidermal Growth Factor Receptor 2 (HER2) in HER2-positive breast cancer
* Example: Bevacizumab (Avastin)
* Target: Vascular Endothelial Growth Factor (VEGF) to inhibit angiogenesis in various cancers - Immune Checkpoint Ligand Blockers:
* Example: Nivolumab (Opdivo)
* Target: Programmed Death 1 (PD-1) receptor
* Example: Ipilimumab (Yervoy)
* Target: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) - Vaccines:
* Example: Sipuleucel-T (Provenge)
* Target: Prostatic Acid Phosphatase (PAP) in metastatic prostate cancer
Describe the four main steps in the ‘abscopal’ effect. For each step, outline a key activity that takes place.
The ‘abscopal effect’ is a phenomenon in cancer treatment where localized radiation therapy not only affects the targeted tumor but also triggers an immune response that leads to the regression of non-irradiated tumors in distant parts of the body. This effect occurs due to the release of tumor-specific antigens and damage-associated molecular patterns (DAMPs) from the irradiated tumor, which activate the immune system to attack tumors outside the radiation field. The four main steps in the abscopal effect are as follows:
- Local Tumor Irradiation:
Key Activity: The primary step involves delivering radiation therapy to the localized tumor. The radiation causes DNA damage and cell death in the targeted tumor cells.
2.Release of Tumor Antigens and DAMPs:
Key Activity: As a result of radiation-induced cell death, the irradiated tumor releases tumor-specific antigens and damage-associated molecular patterns (DAMPs). DAMPs are endogenous molecules released from dying cells that signal tissue damage to the immune system.
- Antigen Presentation and Immune Activation:
Key Activity: Dendritic cells, which are specialized antigen-presenting cells, take up the released tumor antigens and present them to T cells. This process activates tumor-specific cytotoxic T cells, a type of immune cell capable of recognizing and attacking cancer cells. - Systemic Immune Response:
Key Activity: The activated cytotoxic T cells, along with other immune cells, enter the bloodstream and travel to distant sites in the body. These T cells recognize and attack cancer cells in non-irradiated tumors located far away from the original irradiated tumor. This systemic immune response is responsible for the regression of the non-irradiated tumors, resulting in the abscopal effect.
The abscopal effect is an essential mechanism in immunogenic cell death induced by radiation therapy. It highlights the potential of radiation therapy to not only directly kill tumor cells but also engage the immune system to target cancer cells throughout the body. While the abscopal effect is an exciting concept, it may not occur in all cases, and ongoing research is focused on understanding the factors that influence its occurrence and ways to enhance its effectiveness in cancer treatment.