Radiation Biology

Mr. Jose Santos, 69-year-old male was diagnosed to have nasopharyngeal carcinoma stage
III. He was advised a combination of chemotherapy and radiation using the AL Sarraf
Protocol. Mr. Santos has several questions in relation to his treatment.

1. How does radiation kill cells? What type of radiation modality is needed (external
vs internal radiation) and what equipment us used conventionally?
2. Patient was advised to have his blood checked. He was found to have anemia
with hemoglobin of 9g and was advised blood transfusion. Why do we advise
correction of anemia prior to the start of radiation therapy?
3. How is radiation therapy programmed? How many times a day over how many
weeks? Please tabulate the different fractionation schemes in terms of the total
dose given, how many times per day overall treatment time, acute and late
effects.
4. Why is radiation therapy given in fractionated courses rather than in one single
treatment? What is the radiobiologic basis for this? (4Rs)
5. What are the normal tissues that should be protected for patients undergoing
radiation to the nasopharynx? What is QUANTEC. Give the dose limits that
QUANTEC provides for the normal tissue protection of this patient.
6. On the fourth week of radiation therapy, patient requests to interrupt radiation
therapy because of the side effects of treatment. How will you advise our patient
and what is the radiologic phenomenon that strongly discourages treatment
breaks?
7. Use the linear quadratic equation to show the advantage of hyperfractionation
over convention fractionation in the treatment of patients with nasopharyngeal
cancer. Assuming α/β for tumor is 10 and for normal tissue is 3 and we are
planning a total of 35 sessions in 2 Gy fraction for conventional treatment.
1. Radiation Therapy and Equipment:

How Radiation Kills Cells:

Radiation damages the DNA of cells, preventing them from dividing and proliferating. It can
cause breaks in the DNA strands, leading to cell death.

Type of Radiation Modality:

• External Radiation: Uses a machine (linear accelerator) to deliver radiation from outside
the body.
• Internal Radiation (Brachytherapy): Involves placing a radioactive source directly inside
or very close to the target tissue.

Conventional Equipment:

• Linear Accelerator (LINAC): Generates high-energy X-rays or electrons for external beam
radiation.
• Gamma Knife: Precise radiosurgery for brain lesions.
• HDR (High Dose Rate) Brachytherapy Equipment: Used for internal radiation.

2. Correction of Anemia Prior to Radiation Therapy:

• Anemia reduces the oxygen-carrying capacity of blood.

• Adequate oxygenation is crucial for the radiosensitivity of tumors.
• Correcting anemia improves tissue oxygenation and enhances the effectiveness of
radiation therapy.

3. Radiation Therapy Program:

Programming:

• Simulation: Determines the treatment area and patient positioning.

• Treatment Planning: Determines the radiation dose and field arrangements.

Fractionation Schemes:

Fractionation Scheme Total Times per Overall Acute Late Effects

Dose Day Treatment Time Effects
Conventional (e.g., 2 60-70 1-2 5-7 weeks Common Late,
Gy) Gy moderate
Hyperfractionation 60-70 2 4-6 weeks Reduced Not well
Gy known
Hypofractionation 40-50 1-5 1-4 weeks More Late,
(SBRT) Gy acute uncertain
4. Fractionation in Radiation Therapy:

• Radiobiologic Basis (4Rs):

1. Repair: Allows normal tissues to repair sublethal damage between fractions.
2. Repopulation: Permits normal tissue recovery and repopulation.
3. Redistribution: Allows cells to progress through the cell cycle, making them more
sensitive to radiation.
4. Reoxygenation: Oxygen enhances the effectiveness of radiation, and
fractionation helps reoxygenate tissues.

5. Radiation Protection and QUANTEC:

Normal Tissues in Nasopharynx Radiation:

• Parotid glands
• Spinal cord
• Brainstem

QUANTEC (Quality Assurance in Radiation Oncology):

• Provides dose-volume constraints for critical structures to minimize radiation toxicity.

6. Advising Patient on Treatment Breaks:

Radiobiologic Phenomenon:

• Accelerated repopulation of tumor cells during treatment breaks.

Advice:

• Minimize treatment breaks to maintain treatment efficacy.

• Manage side effects with supportive care.

7. Linear Quadratic Equation for Hyperfractionation:

SF=e−(α⋅D+β⋅D^2)

Advantages of Hyperfractionation:

• With a higher number of smaller fractions, hyperfractionation can potentially reduce late
effects while maintaining tumor control.
• Calculate Survival Fraction (SF) for different fractionation schedules to compare their
radiobiological effectiveness.
Given:

• α/β for tumor = 10 Gy

• α/β for normal tissue = 3 Gy
• Total dose = 35 sessions * 2 Gy = 70 Gy

SFconventional=e−(10⋅70+3⋅70^2)

SFhyperfractionation=e−(10⋅35+3⋅35^2)

Compare the survival fractions to evaluate the relative effectiveness of hyperfractionation.

Ms Leony Santos has T3N0 stage 3 rectal cancer concurrent chemo with radiotherapy

1. Explain the molecular basis of carcinogenesis.

2. How do radiosensitizers help in killing tumor cells? Give at least three examples of
radiosensitizer drugs.

3. Our patient was advised to undergo RT daily 5 days a week for 5 weeks. She asks why
she cannot be treated once a week instead. What is the radiologic basis of fractionation?

4. Give the possible fractionation schemes for our patient. Give the number of fractions,
overall time, and the fractions per day.

5. The prevalent equipment that we are using in our radiation facility for external beam
radiation are the LINAC and Co-60 teletherapy unit. What are the other alternative
modalities that may be used? Why are LINACS and Co-60 still the most preserved
machines?

6. How does ionizing radiation kill cells? Explain at the molecular level.

7. What complications may happen when the small intestines, bladder, and intestines are
irradiated with the treatment? TD5/5 and clinical end point.

8. Ms. Santos reports to her rad oncologist that she missed her period for a month and
might be pregnant. If she is, what are the possible complications to the embryo (fetus) if
radiation is given at this time?
1. Molecular Basis of Carcinogenesis:

• Initiation: DNA damage occurs due to exposure to carcinogens, leading to genetic

mutations.
• Promotion: Altered cells undergo clonal expansion and exhibit abnormal growth.
• Progression: Further genetic alterations result in malignant transformation and the
development of cancer.

2. Radiosensitizers in Killing Tumor Cells:

• Definition: Radiosensitizers enhance the sensitivity of tumor cells to radiation, increasing

the effectiveness of radiotherapy.
• Examples:
1. Cisplatin: Enhances DNA damage.
2. Fluorouracil (5-FU): Inhibits DNA synthesis.
3. Gemcitabine: Interferes with DNA replication.

3. Radiologic Basis of Fractionation:

• Tumor Response: Fractionation exploits the difference in repair capacity between normal
and tumor tissues.
• Normal Tissue: Allows repair of sublethal damage between fractions, reducing toxicity.
• Tumor Cells: Less efficient repair, leading to cumulative lethal damage.

4. Possible Fractionation Schemes:

• Conventional Fractionation:
o Number of Fractions: 25
o Fractions per Day: 1
o Overall Time: 5 weeks
• Hyperfractionation:
o Number of Fractions: 40
o Fractions per Day: 2
o Overall Time: 4 weeks

5. Radiation Equipment and Alternatives:

• LINAC (Linear Accelerator):

o Versatility, precision, and ability to deliver various energy beams.
• Co-60 Teletherapy Unit:
o Cobalt-60 gamma rays for external beam radiation.

Alternative Modalities:

1. CyberKnife (Stereotactic Radiosurgery): Precise, high-dose radiation.

 2. Tomotherapy: Combines imaging and radiation delivery in a single machine.

Reasons for LINAC and Co-60 Preservation:

• Proven technology with a long track record.

• Cost-effectiveness and reliability.
• Adequate for most clinical scenarios.

6. Ionizing Radiation and Cell Kill (Molecular Level):

• Direct Effect: Ionization of atoms in critical molecules (e.g., DNA) causing immediate
damage.
• Indirect Effect: Generation of free radicals that damage cellular components, particularly
DNA.

7. Complications of Irradiating Small Intestines, Bladder, and Rectum:

• Small Intestines: Acute radiation enteritis, chronic fibrosis.

o TD5/5 (Tolerance Dose): 45 Gy in 25 fractions.
• Bladder: Cystitis, fibrosis.
o TD5/5: 60 Gy in 30 fractions.
• Rectum: Proctitis, fibrosis.
o TD5/5: 60 Gy in 30 fractions.

8. Radiation and Pregnancy Complications:

• Possible Complications:
1. Congenital abnormalities.
2. Mental retardation.
3. Increased risk of childhood cancers.
• Risk Mitigation:
1. Minimize fetal exposure during treatment planning.
2. Consideration of alternative treatments.
3. Detailed discussion with the patient regarding risks and benefits.
Radiation Biology

1. What is the mechanism of action of radiation therapy? What is the main target?
Illustrate the events following the interaction of photons with the DNA.
2. The prescription of her external beam radiation therapy is 5000cGy over 5 weeks.
What is the basis for a fractionated regimen over a single treatment? (Clue: 4 Rs
of radiobiology)
3. Which of the types of radiation sources (X-ray, gamma-ray, proton beam, neutron
beam alpha particles) are commonly used in the clinics and why?
4. Ms. J.R. underwent blood tests which showed that her hemoglobin was low and
was advised to have a blood transfusion so that her radiotherapy would be more
effective. Explain the basis for this.
5. Our patient as prescribed by the radiation oncologist will receive once a day
treatment 5 days a week for 6 weeks. What are the other fractionation schemes?
Tabulate the 3 main regimens. Tabulate according to the number of fractions per
day, total overall treatment time, acute side effects, dose per fraction and late
side effects.
6. It was also found out that Ms. J.R. is 3 months pregnant. What would be the
anticipated complications for the fetus depending on the age of gestation?
7. Dose prescription to the target tumor volume as well as organs at risk needs to be
carefully defined for each treatment regimen. What is our reference for risk
complication assessment based on TD 5/5 or volumetric considerations? What
would be the organs at risk for treatment in the pelvis?
8. What is the radioprotector that has been shown to be developed in the clinical
setting? What is the mechanism of action?
9. The radiation oncologist discussed at length with our patient to follow the
scheduled treatment and avoid interruptions. The phenomenon behind this is the
concept of "accelerated fractionation". Explain.
10. What is the principle that supports the efficacy of low dose rate brachytherapy?
What is sublethal damage and repair and what makes this possible?
11. Why is oxygen important in radiotherapy?
12. Part of the radiotherapy regimen is brachytherapy. How is this done? What
radioisotopes are used? The gold standard is the low dose rate brachytherapy
system which works on the principle of inverse dose rate effect. Please explain
this principle.
1. Mechanism of Action of Radiation Therapy:

Mechanism:

• Interaction with DNA: Ionizing radiation damages the DNA within the targeted cells.
• Direct and Indirect Effects: Direct ionization of DNA molecules and indirect damage
through the generation of free radicals.
• DNA Breaks: Single-strand and double-strand breaks in the DNA helix.

Main Target:

• DNA in Tumor Cells: The primary target is the DNA of rapidly dividing tumor cells.

Illustration:

1. Photon Interaction: High-energy photons (X-rays or gamma rays) interact with atoms in
the tissue.
2. Ionization Events: Ionization of atoms occurs, leading to the formation of free radicals.
3. Free Radical Formation: Free radicals cause damage to cellular components, particularly
DNA.
4. DNA Strand Breaks: Single-strand and double-strand breaks in the DNA structure.
5. Cellular Response: Cells attempt to repair damage, but unrepaired damage may lead to
cell death or delayed effects.

2. Basis for Fractionated Regimen:

Clue: 4 Rs of Radiobiology:

1. Repair: Allows normal tissues to recover between fractions.

2. Repopulation: Permits recovery of rapidly dividing normal cells.
3. Redistribution: Allows cells to progress through the cell cycle, making them more
sensitive to radiation.
4. Reoxygenation: Oxygen enhances the effectiveness of radiation, and fractionation helps
reoxygenate tissues.

Basis for Fractionation:

• Fractionation minimizes damage to normal tissues while allowing for the redistribution
and repair of sublethal damage in both normal and tumor cells.

3. Types of Radiation Sources in Clinics:

Commonly Used:
 • X-rays: Generated by linear accelerators (LINAC).
• Gamma-rays: Emitted by Co-60 teletherapy units.

Reasons for Use:

• Penetrating ability to reach deep-seated tumors.

• Controlled and focused delivery.

4. Hemoglobin and Blood Transfusion:

• Basis: Low hemoglobin levels reduce oxygen-carrying capacity.

• Importance: Adequate oxygenation enhances radiosensitivity, making radiotherapy more
effective.

5. Fractionation Schemes:

Regimen Fractions/Day Total Acute Side Dose per Late Side

Treatment Effects Fraction Effects
Time
Once a day (5 1 6 weeks Common Standard Late,
days/week) moderate
Hyperfractionation 2 4-6 weeks Reduced Reduced Not well
known
Hypofractionation 1-5 1-4 weeks More acute Higher Late,
(SBRT) uncertain

6. Complications for a Pregnant Patient:

• First Trimester (Weeks 1-12): Risk of malformation.

• Second Trimester (Weeks 13-26): Possible intellectual and developmental effects.
• Third Trimester (Weeks 27-40): Low risk, but potential for growth restriction.

7. Risk Complication Assessment and Organs at Risk in Pelvis:

• Reference: TD 5/5 (Tolerance Dose at 5% Risk of Complication).

• Organs at Risk in Pelvis: Bladder, rectum, small bowel.

8. Radioprotector in Clinical Setting:

• Amifostine: Acts as a free radical scavenger, protecting normal tissues during radiation.

9. Accelerated Fractionation:

• Explanation: Intensive schedule with shorter overall treatment time.

• Purpose: Mitigate tumor repopulation, potentially improving local control.

10. Low Dose Rate Brachytherapy:

 • Principle: Continuous delivery of radiation at a low rate over an extended period.
• Sublethal Damage and Repair: Radiation is given at a rate that allows normal tissue repair
between doses.

11. Importance of Oxygen in Radiotherapy:

• Oxygen Enhances Radiosensitivity: Oxygenated tissues are more sensitive to radiation.

• Radiobiological Oxygen Effect: Oxygen facilitates the formation of free radicals,
increasing damage to DNA.

12. Brachytherapy Procedure and Radioisotopes:

• Procedure: Radioactive sources placed directly into or near the tumor.

• Radioisotopes: Ir-192, I-125, Cs-137, etc.

Inverse Dose Rate Effect:

• Principle: Higher doses per fraction in low dose rate brachytherapy result in greater cell
killing effectiveness compared to high dose rate.