1. External Beam Radiotherapy (EBRT) - The Basic Concept

1. Simulation - The patient is immobilized (a thermoplastic mask is used for the head and neck), reference points are marked with lasers/x-ray markers, and a planning CT scan is taken.
2. Treatment Planning - The radiation oncologist outlines the tumor and nearby critical structures (spinal cord, salivary glands, optic nerves, brainstem) on the CT images. Three target volumes are defined:
   • GTV (Gross Tumor Volume) - the visible/palpable tumor
   • CTV (Clinical Target Volume) - GTV plus areas at risk of microscopic spread (e.g., draining lymphatics)
   • PTV (Planning Target Volume) - CTV plus a margin to account for daily setup variation and patient motion
3. Verification - Before treatment starts, imaging (portal films, orthogonal x-rays) confirms the patient is positioned exactly as planned.
4. Dose Delivery - Delivered via a linear accelerator (LINAC), which produces a beam shaped by jaws or a multileaf collimator (MLC) - a device with many metal leaves that block or shape the beam (this replaced older lead blocks).
5. Quality Assurance - Ongoing checks that the machine and plan are performing accurately.

A linear accelerator (LINAC) - the machine that delivers external beam RT (Cummings Otolaryngology, Fig. 75.5)

2. 3D Conformal Radiotherapy (3D-CRT)

• Uses 3D CT-based planning so the radiation oncologist can see the tumor and organs at risk in three dimensions, not just on a flat x-ray.
• Multiple beams are shaped (using the MLC) to conform to the 3D shape of the tumor from each beam angle, sparing more normal tissue than old 2D techniques.
• Classic technique for laryngeal cancer: opposed lateral fields matched to an anterior low-neck field (the "three-field technique"), using a "half-beam" setup to avoid overlapping the spinal cord.
• Limitation: beam intensity across each field is still relatively uniform ("static" fields) - it cannot create the complex, non-uniform dose "sculpting" that IMRT can.

3. Intensity-Modulated Radiotherapy (IMRT)

• Head and neck anatomy is crowded with critical structures (parotid/salivary glands, spinal cord, brainstem, optic nerves, esophagus) sitting very close to the tumor - IMRT's ability to "bend" dose around these structures is especially valuable here.
• Uses inverse treatment planning: the planner specifies desired doses to tumor and dose limits to organs at risk, and computer software works backward to calculate the beam pattern.
• Allows a simultaneous integrated boost (SIB) - delivering a higher dose to gross tumor and a lower dose to at-risk nodal areas in the same treatment session, rather than sequential fields.
• Major benefit: parotid gland sparing, which reduces xerostomia (dry mouth) - proven in the landmark PARSPORT trial, which showed IMRT significantly reduced xerostomia compared to conventional RT in pharyngeal cancers.
• Drawback: takes considerably more planning time/expertise than 3D-CRT, and poor planning has been linked to local treatment failures.
• A newer variant, Volumetric Modulated Arc Therapy (VMAT), delivers IMRT-style modulation while the machine rotates continuously around the patient - cutting treatment time from ~20-25 minutes (standard IMRT) to just 3-5 minutes, with even better organ-at-risk sparing and theoretically lower risk of secondary cancers.

IMRT plan: color-coded isodose lines (66 Gy, 54 Gy, 35 Gy) show how dose is sculpted to the tumor while falling off toward normal tissue.

4. Image-Guided Radiotherapy (IGRT)

• Because IMRT plans have very steep dose gradients (high dose right next to low dose), even small daily positioning errors can cause the tumor to be underdosed or a critical organ to be overdosed.
• IGRT solves this by taking imaging (e.g., cone-beam CT, portal imaging) immediately before or during each treatment session to verify and, if needed, adjust the patient's position/target location in real time - rather than relying only on the initial simulation setup.
• In the textbook's own words regarding early glottic cancer outcomes: better results with modern techniques come from combining accurate dose delivery with "image-guided verification for accurate daily reproducibility and dosimetry."
• The combination is often referred to as IG-IMRT, considered a current standard of care in many centers for HNC, since it lets clinicians exploit IMRT's tight conformality safely.

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1. Historical Background

• 1920s: Ionizing radiation first used for head and neck cancer, via external beam or interstitial rods (radium implants).
• Henri Coutard popularized protracted radiotherapy, which for a time partially displaced surgery as primary treatment for H&N cancer.
• Early era (orthovoltage generators, radium implants) caused severe skin damage, poor cure rates, and many complications.
• 1950s: The modern era began with the linear accelerator and telecobalt units, producing supervoltage radiation - far less skin toxicity.
• 1970s: Postoperative (adjuvant) radiotherapy became standard, shown to improve cure rates over surgery or RT alone.
• Late 1980s-1990s: 3D image-guided targeting, multileaf collimators, 3D-CRT, and finally IMRT emerged - progressively improving tumor dose conformality while sparing normal tissue.
• Today, RT alone or combined with cisplatin-based chemotherapy remains a mainstay of treatment for many head and neck cancers worldwide.

2. Radiobiology - How Radiation Kills Tumor Cells

• DNA is the critical target. Radiation is called "ionizing" because it must ionize atoms to cause damage.
• Direct effect: radiation is absorbed directly by DNA, ionizing its atoms (relatively rare).
• Indirect effect (more common): radiation ionizes surrounding water molecules, generating free radicals (hydroxyl radicals, peroxide, hydrated electrons) that then damage DNA.
• Both mechanisms cause strand breaks in DNA. Single-strand breaks are easily repaired using the opposite strand as template. Double-strand breaks are the most important lesion - these cause mutation or, more importantly, cell killing.
• Other mechanisms of cell death: apoptosis, cell-cycle arrest, and mitotic death/catastrophe.

• Radiation triggers arrest, usually at the G1 and G2 checkpoints.
• Normal cells and cancer cells retaining functional p53 arrest in G1 (p53-mediated).
• Cells with p53 loss/mutation cannot arrest in G1 but can still arrest in G2; when they re-enter the cycle, some fail cytokinesis (forming multinucleated giant cells) or undergo mitotic catastrophe.

• States that rapidly proliferating cells are more radiosensitive than slowly proliferating ones.
• This is only partly true - many slowly proliferating normal tissues (e.g., kidney) are highly radiosensitive but express injury late. Similarly, some rapidly dividing tumors (e.g., glioblastoma) can be quite radioresistant.
• Tumor regression depends on more than direct cell death - also on stromal content, rate of cell death, and clearance of inactivated cells.

• Plotting surviving fraction (log scale) against dose (linear scale) produces a curve with an initial shoulder region (repairable damage) followed by a straight-line portion at higher doses.
• The clinically most influential model is the linear-quadratic (LQ) model, describing cell killing as having both a linear (αD) and a quadratic (βD²) dependence on dose - this underlies modern fractionation calculations (the α/β ratio).

Direct vs indirect radiation-DNA interaction (Cummings Otolaryngology, Fig. 75.6)

3. Fractionation - Why Radiation Is Given in Multiple Small Doses

• Conventional fractionation: ~2 Gy/day, once daily, 5 days/week, to a total of 60-70 Gy.
• Hyperfractionation: Multiple smaller fractions per day (e.g., 1.1-1.2 Gy/fraction, twice daily) to a higher total dose (74-80 Gy) over the same overall treatment time. Rationale: late-responding normal tissues are more sensitive to fraction size than tumors are, so shrinking fraction size allows a higher cumulative dose without increasing late morbidity. Trials showed improved locoregional control (8-20% absolute benefit) and in some cases improved overall survival, at the cost of somewhat greater acute toxicity.
• Accelerated fractionation: Larger daily doses given to shorten overall treatment time, aiming to overcome tumor repopulation during therapy (a documented cause of treatment failure with prolonged treatment courses). Results across trials have been inconsistent for survival benefit, and added mucosal toxicity is a concern.

4. Treatment Techniques (Brief Recap)

• External Beam RT (EBRT): delivered via linear accelerator; workflow = simulation → planning (GTV/CTV/PTV delineation) → verification → delivery → quality assurance.
• 3D-CRT: CT-based 3D planning with shaped, largely uniform beams.
• IMRT/VMAT: intensity-modulated, inverse-planned beams for superior sparing of parotids, spinal cord, brainstem; VMAT delivers this via continuous gantry rotation, cutting treatment time dramatically.
• IGRT: imaging (e.g., cone-beam CT) immediately before/during treatment to verify positioning given IMRT's steep dose gradients.
• Brachytherapy: sealed radioactive sources placed directly into/near tumor (e.g., base of tongue) for rapid dose fall-off; can be low-dose-rate (catheter-based) or remote afterloading.

5. Indications - When Is RT Used?

• Definitive (curative) RT: primary treatment for early-stage disease (e.g., T1-T2 glottic cancer) where organ preservation and cure rates rival surgery, often with fewer functional deficits.
• Postoperative/Adjuvant RT (PORT): given after surgical resection when high-risk features are present - involved/positive margins, perineural invasion, bone/cartilage invasion, advanced T-stage (T3/T4), or advanced nodal disease (N2/N3), extracapsular extension. Landmark EORTC and RTOG trials showed that adding concurrent cisplatin chemotherapy to PORT further improves progression-free and overall survival in high-risk patients (particularly those with extracapsular extension or positive margins), at the cost of increased acute mucosal toxicity.
• Concurrent Chemoradiation (CRT): standard of care for many locoregionally advanced, unresectable, or organ-preservation cases (e.g., advanced laryngeal cancer, where CRT allows larynx preservation instead of total laryngectomy).
• Palliative RT: for symptom control (pain, bleeding, obstruction) in incurable or metastatic disease, using shorter/hypofractionated courses.

6. Complications of Radiotherapy

• Skin reactions: erythema, desquamation - IMRT can worsen skin reaction due to multiple beam angles; avoiding bolus effect (no ointments/creams over the field) helps.
• Mucositis: radiation kills basal stem cells in mucosa, causing painful denuding of epithelium; begins 2-3 weeks into treatment; incidence higher with concurrent chemoradiation (up to 64% in some series). Managed with oral hygiene, dietary modification, topical anesthetics.
• Acute xerostomia: significant salivary loss begins around 10 Gy to salivary glands.

• Chronic xerostomia: doses >26 Gy can cause permanent salivary gland dysfunction; managed by sparing at least one parotid (and submandibular glands) during planning, and using saliva substitutes. Amifostine reduced acute xerostomia from 78% to 51% and chronic xerostomia at 12 months from 57% to 34% in a landmark trial, but has significant side effects/cost and is not widely used; benefit is less clear with concurrent chemoradiation.
• Hypothyroidism: occurs in 30-40% after RT to the neck; requires periodic thyroid function testing.
• Laryngeal edema/necrosis: mild-moderate edema in 15-25% of glottic cancer patients post-RT; severe edema/necrosis is rarer (<5%).
• Osteoradionecrosis (ORN) of the jaw: a severe late complication, occurring in 5-10% of patients after conventional RT (mandible most affected due to its unilateral blood supply vs. bilateral maxillary supply). Risk factors include tooth extraction in irradiated fields and hyperfractionated regimens (23% vs. 9% incidence vs conventional in one study). Prevention includes pre-RT dental assessment/extraction of nonrestorable teeth, minimizing high-dose mandibular volume, and good oral hygiene. Management ranges from conservative debridement/antibiotics to radical resection with microvascular reconstruction in severe cases. Hyperbaric oxygen (HBO) has theoretical benefit but a randomized trial showed no clear advantage over placebo.

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