Sketches of some important historical figures in the development of radiation oncology

Roentgen

Becquerel

Curie

Ewing

Peters

Rutherford

The origins of clinical radiation therapy

A definition of radiation oncology

The planning and conduct of a course of radiation therapy

6 questions!

What is the indication for radiation therapy?

What is the goal of radiation therapy?

What is the treatment volume?

What is the treatment technique?

• Teletherapy
• Brachytherapy
  • Interstitial brachytherapy: placement of radioactive sources directly into tissue (eg, breast cancer, soft tissue sarcoma)
  • Intracavitary brachytherapy: placement of radioactive sources in a body cavity (eg, within the nasopharynx, or against/through the cervical os)
  • Mold therapy: placement of radioactive sources on the skin surfaces (eg, back of the hand)

What is the treatment dose and fractionation?

Dose rate matters, such as in TBI for BM transplantation and in brachytherapy.

What is the radiation tolerance of surrounding normal tissues?

External beam radiation treatment planning

Treatment volume

• Gross tumor volume (GTV)
  • Demonstrable tumor, includes enlarged regional lymph nodes.
• Clinical target volume (CTV)
  • GTV + subclinical disease (ie, volumes of tissues with suspected tumor)
• Planning target volume (PTV)
  • CTV + margins for geometric uncertainties.

Uncertainties

Mechanical uncertainties

• Field-size setting
• Rotational setting
• Cross hairs
• Isocenter
• Light-beam congruence
• Alignment systems
• Couch top
• Beam-shaping blocks or collimators

Patient-related uncertainties

• Target delineation
• Organ motion
• Skin marks
• Repositioning
• Patient motion

Immobilization

Respiratory-dampened, respiratory-gated, and respiration-synchronized radiotherapy

DNA damage by ionizing radiation

Relevance of radiobiologic concepts in clinical radiation therapy

Radiation and cancer biology’s contributions to the clinical practice of radiation oncology

Empiricism versus research-based radiation oncology

Physic versus biology

Effects of irradiation on cells

The most common radicals are produced from the radiolysis of cellular water.
eg, .OH, Eaq, H., H2O2

Radiation-induced cell death

• Necrotic cell death
• Apoptosis

Modifiers of radiation response

Several approaches have been used to enhance the therapeutic ratio in radiation therapy

• Physical modifiers of low-LET radiations
• High-LET radiations
• Hyperbaric oxygen or tourniquet techniques
• Hypoxic sensitizers
• Perfluorocarbons
• Cytotoxic agents
• Epidermal growth factor receptor (EGFR)
  • Radiotherapy increases the expression of EGFR in cancer cells. Blockade of EGFR signaling can sensitize cells to radiation.
• Radioprotectors
• Hyperthermia

Radiosensitivity and Radiocurability

• Fractionation
  • Multiple exposures could hit the cells in a radiosensitive phase (e.g., mitosis)
• 4 explanations associated with radiosensitivities of tumors
  • Hypoxia
  • Proportion of clonogenic cells
  • Inherent radiosensitivity of tumor cells
  • Repair of radiation damage

Probability of tumor control

• 45-50Gy
  • Subclinical disease in SCC of the URT or for adenoca. of the breast.
• 60-65Gy, in 6-7 weeks
  • Microscopic evidence of tumor, such as at the surgical margin
• 65 to 76 to 80Gy, 2 Gy/day using 5 fractions weekly.
  • Clinically palpable head and neck tumors

Normal tissue effects

The radiation dose necessary to produce a particular sequelae increases as the irradiated fraction of volume of the organ decreases -> conventional dose-volume histograms (DVHs), normal tissue complication probability (NTCP) models

In regard to multiple functional subunits (FSUs),
serially structured organs – damage to one portion -> entire organ dysfunctional. eg, GI tract or nervous tissue
parallel structure – it isn’t

The minimal TD – TD_5/5: no more than a 5% severe complication rate within 5 years after treatment.

Quantitation of treatment toxicity

Therapeutic ratio (Gain)

Therapeutic gain factor (TGF) = % tumor control / % complications

Impact of local tumor control on survival

Dose-time factors

The advantages of dose fractionation

• Reduction in the number of hypoxic cells
• Reduction in the absolute number of clonogenic tumor cells
• Blood vessels compressed by a growing cancer are decompressed
• Radiation-induced redistribution of cells – rapidly proliferating cells move into the moresensitive phases
• Reduced acute normal tissue toxicity (but not chronic toxicity)

Optimal overall times depend primarily on the doubling time of the tumor cells and intrinsic radiosensitivity, ?.

Low ?/? ratio means fast proliferation -> short overall treatment

For median potential doubling times of 5 days and intermediate radiosensitivity, overall times of 2.5 to 4 weeks would be optimal.

Altered fractionation

Minimum of 6 hours of interfraction interval should be allowed for maximum repair of normal tissues.

Accelerated repopulation

Isoeffect graphs

It took a higher dose in the two-fraction schedule to produce the same reaction as with the single-fraction schedule.

Linear-Quadratic equation (?/? ratio)

log_eS=\alpha D+\beta D^2

where ? and ? are parameters describing the cell’s radiosensitivity, and D is the dose to which it is exposed.

The overall effect of many small fractions – to amplify the dominance of the ? component.
? is reparable component

Low ?/?: early reaction?
High ?/?: late reaction?

BED = \frac{InS}{\alpha}

BED = biologically equivalent dose
d=fractionation, nd=total dose
Tpot=effective doubling time of tumor cells

BED = nd[1+\frac{d}{\alpha/\beta}]-\frac{0.693}{\alpha Tpot}

Brachytherapy and the radiobiologic dose rate effect

• Interstitial BT
• Intracavitary BT
• Mold BT

Low-dose rate (LDR) brachytherapy & High-dose rate (HDR) brachytherapy

• Acute HDR: worst cell survival
• Low dose rate: better cell survival
• Lower dose rate: cell survival got worse – b/c cells are redistributed into a more sensitive phase (G2) of the cell cycle.
• Below critical dose rate: best cell survival – b/c

Dose rate effect is most dramatic between 1cGy/minute and 1 Gy/minute.

At ultra-high doses and instantaneous dose rate (i.e., 10 Gy pulsed in nanoseconds), the rapid deposition of energy consumes oxygen too quickly for diffusion to maintain an adequate level of oxygenation.

Paterson’s isoeffect dose curve

The Target Theory of Radiobiology and How It Has Shaped Our Understanding of the Cell Survival Curve

Principle of target theory is that inactivation of the target inside a cell or a bacteria or a virus results in its death.

• Single-hit/single-target model: radiation-induced cell death
• Multiple-hit/multiple-target model: some cells might not die unless multiple targets are inactivated.
• Multiple hit/single-target model: stubborn single target that required repetitive assaults to be inactivated.

Probability of survival – P(X) = S

P(X)=S=[1-(1-e^{-D/D_0})^{n}]^{m}

n=2 (diploid), m=1 (single target)

Importance of treatment planning in radiation therapy

Three-Dimensional Treatment Planning