VOL 1 CHAPTER 5 - Radiotherapy Principles, Fractionation & Radiosensitizers in Head and Neck Cancer

Описание: SCOTT BROWN OTORHINOLARYNGOLOGY / ENT
VOL 1 CHAPTER 5

Radiotherapy employs ionizing radiation, typically high-energy photons, to treat malignancies by inducing cellular damage. This process works primarily through the generation of free radicals from water molecules, which cause DNA strand breaks, leading to cell cycle arrest, repair, or apoptosis. A fundamental concept in radiobiology is the distinction between "acute-reacting" tissues (rapidly dividing cells like bone marrow, mucosa, and squamous cell carcinomas) and "late-reacting" tissues (slowly dividing cells like bone and nerve). While acute effects manifest quickly, late effects appear months or years later and are often irreversible because these tissues lack the capacity for rapid repopulation.
The differential response of these tissues underpins the science of fractionation. Late-reacting tissues possess a greater capacity to repair sublethal DNA damage, a characteristic represented by the "shoulder" on a cell survival curve and described mathematically by a low α/β ratio in the linear-quadratic equation,. Consequently, these tissues are highly sensitive to large fraction sizes. "Hyperfractionation" exploits this by delivering smaller individual doses (sparing late-reacting tissues) to allow for a higher total dose that increases tumor kill,. Conversely, "accelerated" radiotherapy shortens the overall treatment time to counter the rapid proliferation of tumor clonogens, though this strategy is often limited by severe acute reactions in normal tissues.
A significant barrier to effective radiotherapy is tumor hypoxia, as oxygen is required to fix radiation-induced DNA damage. Cells in necrotic, oxygen-deprived tumor centers are relatively radioresistant. Various strategies have been employed to overcome this, such as hyperbaric oxygen and blood transfusions, but these have largely failed to improve outcomes. Chemical radiosensitizers, particularly nitroimidazoles, act as oxygen mimetics to sensitize hypoxic cells. However, with the exception of nimorazole, which showed benefit in a Danish trial for pharyngeal and laryngeal cancers, these agents are not widely used due to a lack of consistent clinical evidence. Bioreductive drugs, such as mitomycin C and tirapazamine, which become cytotoxic only in hypoxic environments, have also been investigated, but Phase III trials have generally been disappointing,.
Currently, the most clinically successful method for enhancing radiotherapy is concurrent chemotherapy. Meta-analyses confirm that combining cisplatin with radiotherapy yields better results than radiotherapy alone, making it the standard of care. Neo-adjuvant chemotherapy (administered prior to radiation) has been effective for organ preservation, such as in laryngeal cancer, but has not demonstrated a survival advantage over surgery or concurrent chemoradiotherapy.
Recent advances focus on molecularly targeted therapies. Overexpression of the Epidermal Growth Factor Receptor (EGFR) is common in head and neck cancers and correlates with a poor prognosis. Cetuximab, a monoclonal antibody that binds to EGFR, has been shown to improve locoregional control and survival when combined with radiotherapy, with less toxicity than cisplatin. However, cisplatin remains the gold standard for patients who can tolerate it. Finally, immunotherapy, specifically anti-PD1 monoclonal antibodies, is emerging as a promising avenue, particularly for recurrent disease, with ongoing research into its application in the curative setting alongside radiotherapy.