14.1 Radiotherapy modalities and dose fractionation

Radiotherapy modalities and dose fractionation are key aspects of cancer treatment. External beam radiotherapy and brachytherapy offer different approaches to delivering radiation, each with unique advantages for specific tumor types and locations.

Dose fractionation exploits biological differences between tumor and normal cells. By understanding the "4 Rs" of radiobiology and using models like the linear-quadratic equation, oncologists can optimize treatment schedules to maximize tumor control while minimizing side effects.

External Beam vs Brachytherapy

Delivery Methods and Applications

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• External beam radiotherapy (EBRT) delivers radiation from outside the body using linear accelerators or other radiation-producing machines
• Brachytherapy involves placing radioactive sources directly in or near the tumor
• EBRT treats larger areas and deeper-seated tumors
• Brachytherapy typically used for more localized treatments and delivers higher doses to smaller volumes
• Common EBRT techniques include 3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT)
• Brachytherapy classified as temporary (removable sources) or permanent (seeds left in place)
• Brachytherapy also categorized as low-dose-rate (LDR) or high-dose-rate (HDR) based on dose delivery rate

Treatment Planning and Delivery

• EBRT requires careful patient positioning and immobilization for accurate dose delivery (thermoplastic masks, vacuum cushions)
• Brachytherapy often involves surgical procedures for source placement (catheters, applicators)
• Image-guidance plays a crucial role in both EBRT and brachytherapy for precise target localization and treatment delivery
  • EBRT uses on-board imaging systems (cone-beam CT, MV/kV imaging)
  • Brachytherapy employs ultrasound, CT, or MRI for applicator placement and dose planning
• EBRT planning utilizes complex algorithms to optimize dose distribution (inverse planning, Monte Carlo simulations)
• Brachytherapy planning focuses on source positioning and dwell times to achieve desired dose coverage

Rationale for Dose Fractionation

Biological Principles

• Dose fractionation in radiotherapy exploits the differential response to radiation between tumor cells and normal tissues
• Maximizes tumor control while minimizing normal tissue toxicity
• The "4 Rs" of radiobiology form the biological basis for fractionation
  • Repair allows normal tissues to recover between fractions
  • Repopulation of surviving cells occurs during treatment course
  • Redistribution of tumor cells into more radiosensitive cell cycle phases
  • Reoxygenation of hypoxic tumor regions increases radiosensitivity
• Normal tissues generally have a greater capacity to repair sublethal damage between fractions compared to tumor cells
• Fractionation allows for redistribution of surviving tumor cells into more radiosensitive phases of the cell cycle (G2/M phase)
• Reoxygenation of hypoxic tumor regions occurs between fractions, increasing radiosensitivity of previously resistant hypoxic cells

Quantitative Models and Applications

• Linear-quadratic model quantifies and compares biological effects of different fractionation schedules
• Uses α/β ratio to characterize tissue-specific radiation sensitivity
• Standard fractionation typically delivers 1.8-2 Gy per fraction, 5 days a week
• Biologically effective dose (BED) calculation helps compare different fractionation schemes
  • $BED = nd(1 + d/(α/β))$
  • n number of fractions, d dose per fraction, α/β tissue-specific ratio
• Equivalent dose in 2 Gy fractions (EQD2) allows for standardized comparison
  • $EQD2 = D × (d + α/β) / (2 + α/β)$
  • D total dose, d dose per fraction, α/β tissue-specific ratio

Biological Basis of Hypofractionation vs Hyperfractionation

Hypofractionation Principles

• Hypofractionation delivers larger doses per fraction over a shorter overall treatment time
• Exploits lower α/β ratio of certain tumors compared to surrounding normal tissues
• Potentially improves therapeutic ratio for tumors with low α/β ratios (prostate cancer, α/β ≈ 1.5 Gy)
• Capitalizes on greater sensitivity of low α/β tumors to larger fraction sizes
• Reduces overall treatment time, potentially mitigating accelerated repopulation in fast-growing tumors
• Examples of hypofractionated regimens
  • Stereotactic body radiotherapy (SBRT) for early-stage lung cancer (54 Gy in 3 fractions)
  • Moderate hypofractionation for prostate cancer (60 Gy in 20 fractions)

Hyperfractionation Principles

• Hyperfractionation uses smaller doses per fraction delivered multiple times per day
• Takes advantage of faster repair kinetics of normal tissues compared to tumors
• Aims to reduce late normal tissue toxicity while maintaining or improving tumor control
• Particularly beneficial for rapidly proliferating tumors with high α/β ratios (head and neck cancers, α/β ≈ 10 Gy)
• Allows for dose escalation without significantly increasing late effects
• Examples of hyperfractionated regimens
  • Head and neck cancer treatment (81.6 Gy in 68 fractions, 1.2 Gy twice daily)
  • Limited-stage small cell lung cancer (45 Gy in 30 fractions, 1.5 Gy twice daily)

Comparative Analysis

• α/β ratio derived from linear-quadratic model key factor in determining appropriateness of altered fractionation schedules
• Both approaches consider time factor in radiobiology
• Hypofractionation potentially reduces impact of accelerated repopulation in fast-growing tumors
• Hyperfractionation exploits differential repair rates between tumors and normal tissues
• Choice between hypo- and hyperfractionation depends on tumor type, location, and surrounding normal tissue constraints
• Clinical trials comparing altered fractionation to standard fractionation crucial for establishing optimal treatment protocols

Advantages and Limitations of Stereotactic Radiotherapy

Advantages and Clinical Applications

• Stereotactic radiotherapy (SRT) delivers highly conformal, high-dose radiation to small target volumes with extreme precision
• Often administered in single or few fractions (1-5 treatments)
• Ability to treat inoperable tumors (brain metastases, early-stage lung cancer)
• Reduced overall treatment time improves patient convenience and resource utilization
• Potentially improved local control rates for certain tumor types
• Achieves higher biological effective dose (BED) compared to conventional fractionation
• Potentially overcomes radioresistance in some tumors due to high fractional doses
• Applications include
  • Intracranial SRT (acoustic neuromas, pituitary adenomas)
  • Stereotactic body radiotherapy (SBRT) for lung, liver, and spine lesions

Limitations and Considerations

• Risk of severe toxicity if normal tissues inadvertently irradiated due to high doses per fraction
• Effectiveness highly dependent on accurate target delineation and patient immobilization
• Requires advanced imaging and motion management techniques
  • 4D-CT for respiratory motion assessment
  • Real-time tumor tracking systems
• May be less effective for larger tumors or those with significant microscopic spread
• Typically treats smaller volumes with limited margins, risking geographical miss
• Long-term effects and optimal fractionation schemes still under investigation
• Necessitates careful patient selection and rigorous follow-up
• Technical challenges
  • Requires specialized equipment (Gamma Knife, CyberKnife, linear accelerators with stereotactic capabilities)
  • Demands high level of quality assurance and expertise from treatment team