☢️Radiobiology Unit 14 – Radiotherapy: Biological Basis & Applications

Fundamentals of Radiobiology

• Radiobiology studies the effects of ionizing radiation on living organisms and biological systems
• Ionizing radiation includes high-energy electromagnetic waves (X-rays, gamma rays) and particulate radiation (electrons, protons, neutrons, alpha particles)
  • These types of radiation have sufficient energy to ionize atoms or molecules by removing electrons from their orbits
• Radiation interacts with matter through various processes, such as photoelectric effect, Compton scattering, and pair production
• Linear energy transfer (LET) measures the amount of energy deposited per unit length along the path of ionizing radiation
  • High LET radiation (alpha particles, neutrons) causes more dense ionization events and greater biological damage compared to low LET radiation (X-rays, gamma rays)
• Relative biological effectiveness (RBE) compares the biological effects of different types of radiation at the same absorbed dose
  • RBE is influenced by factors such as LET, dose rate, and biological endpoint
• Absorbed dose is the amount of energy deposited per unit mass of tissue, measured in gray (Gy) or rad (1 Gy = 100 rad)
• Equivalent dose accounts for the varying biological effects of different types of radiation by multiplying the absorbed dose by a radiation weighting factor, measured in sievert (Sv) or rem (1 Sv = 100 rem)

Radiation Effects on Cells and Tissues

• Radiation induces damage to cellular components, primarily through direct ionization of DNA and indirect effects mediated by free radicals
• Direct effects involve the direct interaction of radiation with critical targets in the cell, such as DNA, leading to strand breaks, base damage, and cross-linking
• Indirect effects occur when radiation interacts with water molecules, generating reactive oxygen species (ROS) that can damage cellular components
• DNA double-strand breaks (DSBs) are the most critical type of damage, as they can lead to cell death, mutations, or chromosomal aberrations if not repaired correctly
• Cells have various DNA repair mechanisms to detect and repair radiation-induced damage, such as non-homologous end joining (NHEJ) and homologous recombination (HR)
• The cell cycle plays a crucial role in determining radiosensitivity, with cells in the G2 and M phases being the most sensitive to radiation
• Radiation can induce cell death through different mechanisms, including apoptosis, necrosis, and mitotic catastrophe
  • Apoptosis is a programmed cell death pathway triggered by irreparable DNA damage or other cellular stresses
• Tissues with rapidly dividing cells (intestinal epithelium, bone marrow) are more radiosensitive compared to those with slower turnover rates (nervous system, muscle)

Types of Radiotherapy

• External beam radiotherapy (EBRT) delivers radiation from an external source, such as a linear accelerator, to the target tumor
  • EBRT techniques include 3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and stereotactic radiotherapy (SRS/SBRT)
• Brachytherapy involves the placement of radioactive sources directly inside or near the tumor, allowing for high doses to be delivered to the target while sparing surrounding normal tissues
  • Brachytherapy can be administered through intracavitary (within a body cavity), interstitial (within the tissue), or surface (on the skin) approaches
• Systemic radiotherapy uses radioactive substances that are administered orally or intravenously, targeting cancer cells throughout the body
  • Examples include radioactive iodine (I-131) for thyroid cancer and radium-223 for bone metastases
• Particle therapy employs charged particles, such as protons or carbon ions, which have unique physical properties that allow for more precise dose delivery and reduced exposure to normal tissues
• Intraoperative radiotherapy (IORT) delivers a single high dose of radiation directly to the tumor bed during surgery, potentially reducing the need for post-operative EBRT
• Radioisotope therapy involves the use of radiolabeled molecules that selectively target and deliver radiation to cancer cells expressing specific receptors or antigens
  • Examples include radioimmunotherapy (RIT) and peptide receptor radionuclide therapy (PRRT)

Treatment Planning and Delivery

• Radiotherapy treatment planning involves the use of imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), to delineate the target tumor and normal tissues
• Contouring is the process of outlining the gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV) on the imaging datasets
  • GTV represents the visible tumor, CTV includes the GTV plus a margin for microscopic disease, and PTV adds a margin to account for uncertainties in patient positioning and organ motion
• Dose prescription specifies the total dose to be delivered to the target, as well as the dose per fraction and overall treatment duration
  • Conventional fractionation delivers 1.8-2 Gy per fraction, 5 days a week, over several weeks
  • Hypofractionation uses larger doses per fraction (>2 Gy) over a shorter overall treatment time
• Treatment planning systems (TPS) optimize the radiation beam arrangement, shapes, and intensities to achieve the desired dose distribution while minimizing exposure to normal tissues
• Image-guided radiotherapy (IGRT) employs imaging techniques, such as cone-beam CT or ultrasound, to verify patient positioning and target localization before and during treatment delivery
• Adaptive radiotherapy (ART) involves modifying the treatment plan based on changes in tumor size, shape, or position during the course of radiotherapy, ensuring optimal dose delivery
• Quality assurance (QA) procedures are essential to ensure the accuracy, precision, and safety of radiotherapy treatment planning and delivery

Clinical Applications

• Radiotherapy is a key component of cancer management, used alone or in combination with surgery, chemotherapy, or targeted therapies
• Curative radiotherapy aims to eradicate the tumor and achieve long-term disease control, often in combination with other modalities
  • Examples include radical radiotherapy for prostate cancer, chemoradiotherapy for head and neck cancers, and trimodality therapy (chemoradiotherapy plus surgery) for locally advanced lung cancer
• Palliative radiotherapy is used to alleviate symptoms and improve quality of life in patients with advanced or metastatic disease
  • Common indications include bone metastases, brain metastases, and symptomatic local disease (bleeding, obstruction, pain)
• Neoadjuvant radiotherapy is administered before surgery to reduce tumor size, improve resectability, and decrease the risk of local recurrence
  • Examples include rectal cancer and soft tissue sarcomas
• Adjuvant radiotherapy is given after surgery to eliminate residual microscopic disease and reduce the risk of local recurrence
  • Examples include breast cancer (post-lumpectomy), brain tumors (post-resection), and sarcomas (post-wide excision)
• Radiotherapy is also used in non-malignant conditions, such as benign tumors (meningiomas, acoustic neuromas), arteriovenous malformations (AVMs), and inflammatory disorders (heterotopic ossification, Graves' ophthalmopathy)
• Stereotactic radiosurgery (SRS) delivers high doses of radiation in a single or few fractions to small, well-defined targets, such as brain metastases, acoustic neuromas, and trigeminal neuralgia
• Total body irradiation (TBI) is used as part of the conditioning regimen before hematopoietic stem cell transplantation in hematological malignancies

Side Effects and Management

• Radiotherapy side effects can be classified as acute (occurring during or shortly after treatment) or late (developing months to years after treatment)
• Acute side effects are usually self-limiting and resolve within a few weeks after treatment completion
  • Examples include skin reactions (erythema, desquamation), mucositis, fatigue, and hematological toxicity (neutropenia, thrombocytopenia)
• Late side effects may be persistent or progressive and can significantly impact quality of life
  • Examples include fibrosis, necrosis, second malignancies, and organ-specific dysfunction (xerostomia, pneumonitis, cardiac toxicity)
• Side effect severity is graded using standardized criteria, such as the Common Terminology Criteria for Adverse Events (CTCAE)
• Management of side effects involves a multidisciplinary approach, including supportive care, symptom control, and rehabilitation
  • Skin care measures, such as moisturizers and gentle cleansing, can help manage radiation dermatitis
  • Oral care protocols, including topical anesthetics and antimicrobial agents, are used to prevent and treat mucositis
• Radioprotectors are compounds administered before or during radiotherapy to reduce normal tissue toxicity, such as amifostine for xerostomia prevention in head and neck cancer patients
• Radiosensitizers are agents that enhance the effects of radiation on tumor cells, such as cisplatin or cetuximab in combination with radiotherapy for head and neck cancers
• Long-term follow-up and surveillance are essential to monitor for late side effects and provide timely interventions

Emerging Technologies and Techniques

• Proton therapy is an advanced form of particle therapy that allows for more precise dose delivery, reducing exposure to normal tissues and potentially improving outcomes
  • Protons have a unique depth-dose profile characterized by the Bragg peak, depositing most of their energy at a specific depth determined by their initial energy
• Heavy ion therapy, such as carbon ion radiotherapy, offers even greater biological effectiveness and potential advantages over proton therapy, particularly for radioresistant tumors
• Flash radiotherapy delivers ultra-high dose rates (>40 Gy/s) in a single or few fractions, potentially exploiting the differential response between normal tissues and tumors
  • Preclinical studies suggest that flash radiotherapy may reduce normal tissue toxicity while maintaining tumor control
• Radiomics involves the extraction of quantitative features from medical images (CT, MRI, PET) to develop predictive or prognostic models for personalized treatment planning and response assessment
• Artificial intelligence (AI) and machine learning (ML) are being increasingly applied in radiotherapy, from autosegmentation of target volumes to treatment planning optimization and quality assurance
• Theranostics combines diagnostic imaging and targeted radionuclide therapy, using the same molecular target for both purposes
  • Examples include PSMA-targeted imaging and therapy for prostate cancer and DOTATATE for neuroendocrine tumors
• Spatially fractionated radiotherapy (SFRT) delivers inhomogeneous dose distributions, with high doses to small subvolumes of the tumor while sparing adjacent normal tissues
  • SFRT techniques include grid therapy and lattice radiotherapy
• Radiotherapy combined with immunotherapy has shown synergistic effects, potentially enhancing systemic antitumor immune responses and improving outcomes
  • Abscopal effect refers to the regression of distant, non-irradiated tumors following local radiotherapy, mediated by systemic immune activation

Ethical Considerations and Patient Care

• Informed consent is a fundamental principle in radiotherapy, ensuring that patients understand the potential benefits, risks, and alternatives before agreeing to treatment
• Shared decision-making involves the collaboration between healthcare providers and patients in making treatment decisions that align with the patient's values, preferences, and goals
• Balancing the benefits and risks of radiotherapy is essential, considering factors such as tumor control probability, normal tissue complication probability, and quality of life
• Palliative radiotherapy raises unique ethical considerations, focusing on symptom relief and quality of life rather than curative intent
  • Goals of care discussions are crucial to align treatment decisions with the patient's wishes and priorities
• Equitable access to radiotherapy is a global challenge, with disparities in availability and affordability across different regions and populations
• Multidisciplinary care is essential in radiotherapy, involving close collaboration among radiation oncologists, medical physicists, radiation therapists, nurses, and other healthcare professionals
• Psychosocial support is an integral part of comprehensive cancer care, addressing the emotional, social, and spiritual needs of patients and their families
• Survivorship care focuses on the long-term health and well-being of cancer survivors, including the management of late effects, surveillance for recurrence or second malignancies, and promotion of healthy behaviors
• Advances in radiotherapy technology and techniques raise ethical questions related to resource allocation, cost-effectiveness, and prioritization of research and implementation
• Continuous quality improvement and patient safety initiatives are essential to ensure the delivery of high-quality, safe, and effective radiotherapy care