By Sivi Bakthavachalam, MD
The field of radiation therapy has revolutionized the treatment of head and neck cancer over the past 15 years. With the introduction of newer technologies in radiation treatment more advanced stage tumors are being irradiated with fewer complications and side effects. The advent of intensity-modulated radiation therapy (IMRT) in head and neck oncology has allowed for effective and accurate tumor irradiation while sparing surrounding critical structures and tissue. This discussion will provide an explanation of the various types of radiation treatments used in otolaryngology, with a focus on IMRT, while first reviewing the basics of radiation physics, radiation biology, and the different fractionation schemes. Clinical principles of administering radiation and its specific indications will also be discussed.
The history of radiation in medicine began in 1895 when William Roentgen first discovered the x-ray beam. He pioneered the use of x-rays for diagnostic purposes. Also in the late 1800's, the first effect of radiation on humans was accidentally discovered. Becquerel was carrying a vial of radium in his vest pocket and it burned his skin when exposed to the sun. 1899 marked the first use of radiation to treat a malignant neoplasm. One-hundred treatments over the course of a nine month period were required to treat a woman's basal cell carcinoma on the nose in Stockholm, Sweden. In the 1900's radiation was being used as a form of cautery in surgery.
Radiation beams can be composed of photons, protons, neutrons, or electrons, with photons being the most common. A radiation beam can most commonly interact with matter in 3 different ways: photoelectric effect, Compton effect, and pair production. The photoelectric effect refers to a photon interacting with the absorbing matter's inner shell electrons. The degree of absorption is proportional to the matter's atomic number. This effect accounts for the different densities of anatomic structures giving rise to each structure's distinguishing characteristics on x-ray film. The Compton effect, which is the most common in radiotherapy, refers to a photon interacting with an outer shell electron with uniform tissue absorption. Finally, pair production refers to photons interacting in an electromagnetic field.
Radiation doses are often measured in Grays (Gy) or centi-grays (cGy). One "Gray" is equivalent to one joule absorbed per kilogram of tissue. Prior to the use of "Grays," "rads" were the most common unit of radiation employed. One-hundred rads equals one Gray. With radiation beams, the depth dose varies based on electron or photon beams. In photon beams the energy builds from the surface and then attenuates (surface-sparing). In electron beams the energy is highest at the surface and then attenuates (surface-affecting). Electron-beam radiotherapy is what's employed for treating skin lesions.
The goal of radiation therapy is to eliminate or provide local control of tumor growth at a prescribed dose while minimizing damage to surrounding healthy tissue. Radiation kills cells in one of two ways: 1) direct mechanism and 2) indirect mechanism. The direct mechanism refers to a radiation beam directly causing damage to the DNA strands in the cell nucleus. The indirect mechanism refers to the radiation targeting molecules in the cytoplasm, causing the formation of oxygen free radicals. These radicals then diffuse into the nucleus and damage the cell DNA. This latter mechanism is the most common. The ultimate consequence of radiation is loss of cellular function of cell reproduction. Well-oxygenated tissue is the most radiosensitive because the oxygen stabilizes free radicals allowing them to diffuse into the cell nucleus. Dose-survival curves depict the effects of varying doses of radiation on a cell population. At a very low dose the cell population does not change because of "sub-lethal repair." This refers to a cell population's ability to repair and repopulate under a low enough dose of radiation as to not affect the total cell population. This is called the "shoulder effect." Radiation survival curves depend on the inherent radiosensitivity of a cell, oxygen content, position in the cell cycle, and potential for tumor cell proliferation. The strategy involved in the field of radiation oncology is to exploit the differences between normal and abnormal tissue. Tissues that respond acutely to radiation are composed of actively dividing cells such as mucous membranes and tumor cells. The late effects of radiation are seen in muscle, nerve tissue, and bone. As a result acute effects of radiation include mucositis and xerostomia and late effects include osteoradionecrosis and fibrosis. A tumor's response to radiation is dependant on its ability to re-populate, repair, redistribute, and re-oxygenate (four R's).
Conventional radiation therapy consists of administering one large dose of radiation to a target. This method would obviously cause indiscriminate damage to healthy tissues without opportunity for sublethal repair. In order to circumvent this problem radiation is often administered in a fractionated scheme. Fractionation refers to the clinical manner in which radiation is given in divided daily doses. Smaller dosing prevents excessive damage to healthy tissue. Tumor cell growth increases exponentially during radiation treatment, therefore the shortest effective schedule is most desirable to prohibit opportunity for tumor cell proliferation. The most radiosensitive cells die first and then time off between fractions allows time for sublethal repair, re-oxygenation, and redistribution in the cell cycle to a point that is more radiosensitive.
Fractionation schedules are broadly divided between standard fractionation and altered fractionation. Standard fractionation refers to the administration of 70 Gy of total radiation, 35 fractions, 2 Gy/fraction for 5 days out of the week. Altered fractionation schedules include hyperfractionation and accelerated fractionation. Hyperfractionation involves a greater number of smaller fractions of radiation and a greater overall dose in the same overall treatment time. A typical hyperfractionation schedule consists of 81.6 Gy total dose, 1.2 Gy/fraction, 68 fractions, 5 days/week. With smaller fractions, hyperfractionation prevents late damage to tissues because the late effects of radiation are determined by dose/fraction, not on the total dose. Conversely hyperfractionation has a higher rate of acute tissue damage. With divided doses, hyperfractionation allows time for normal tissue repair (4-6 hours) between dosing. Accelerated fractionation administers radiation in an overall shortened period of time while keeping approximately the same total dosing, fraction size, and number of fractions as standard fractionation. This schedule does not allow time for tumor to proliferate, but increases the amount of acute damage to healthy tissue. Three types exist: Types A, B, and C. Type A is intense continuous radiation with no weekend breaks (7 d/week) three times/day. It provides better local control than the standard schedule without an increase in survival. Type B is a split course scheme which allows for a two week break in the radiation dosing. The disadvantage is that tumor re-population can occur during this time. Type C is concomitant boost accelerated radiation where there is accelerated treatment only during the last phase of treatment. Studies have shown that accelerated fractionation schemes provide better local control than standard therapy but there is no increase in overall survival.
The main types of radiotherapy in otolaryngology include external beam, 3D conformal beam, intensity-modulated radiation therapy (IMRT), interstitial brachytherapy, and stereotactic radiation. External beam radiation refers to administering a uniform dose of radiation to a two dimensional area of the body with little control over the irradiation of surrounding tissues. 3D conformal therapy still involves a uniform dose in a 3D plane, but allows surrounding areas to be blocked out. IMRT is currently the most commonly used form of radiation in head and neck oncology. The radiation beams are administered as a gradient of energy with the target tissue getting the highest dosing while sparing surrounding tissue.
When planning the radiation therapy for a patient, one can administer it as beam first (forward planning) or dose first (inverse planning). Forward planning refers to designating the desired total dose of radiation to a specific target while avoiding surrounding structures and then administering the dose. This works best for regular shaped targets. Inverse planning refers to outlining the surrounding structures first and designating the safest dose to administer and allowing the computer to determine the dosing for the target tissue. This is best for irregularly shaped tumors and forms the basis for IMRT.
Intensity-modulated radiation therapy (IMRT) delivers multiple conformal beams of radiation whose intensity is optimized to deliver the high doses of radiation to certain target volumes and lower doses to surrounding tissue. Each beam of radiation carries multiple intensities in and around the target. This technology was the first to deliver radiation in a gradient fashion. The planning for IMRT begins with a CT Scan simulation. The radiation oncologist then spends the most amount of time contouring around the targets. This involves carefully outlining the structures that need to be spared of the higher doses of radiation (i.e. parotid gland, spinal cord). Contouring involves defining clinical tumor volumes (CTV), gross tumor volumes (GTV), and planned tumor volumes (PTV). The gross tumor volume is the size of the actual tumor as seen on CT Scan. The clinical tumor volume is the gross volume plus extra volume accounting for subclinical microscopic disease. The planned tumor volume additionally accounts for organ motion and setup variability. (PTV>CTV>GTV) Contouring normal structures involves outlining the parotid glands, spinal cord, brainstem, optic chiasm and great vessels. Each structure has a maximal radiation dose that in can absorb before causing radiation damage. For example, studies have indicated that the parotid gland can not absorb more than 26 Gy before it's function is irreversibly impaired. The radiation sparing structures are appropriately outlined, a min/max dose is assigned for each structure and the computer generates the dosing distribution to each area from the parameters set. Disadvantages of IMRT include the requirement for patient immobilization during the procedure. Patients need to be still for thirty minutes which is often difficult. Also, the ability to outline tumor volumes is limited by the CT/MRI capabilities.
Interstitial brachytherapy is most commonly employed in oral cavity and oropharyngeal cancers. This treatment involves the placement of implants in tumor beds that are surrounded by critical structures. It's use is indicated for tumors <40 mm without bone involvement and can be used after primary external beam as a boost.
Due to the high rate of tumor recurrence following post-op XRT, intraoperative radiotherapy (IORT) attempts to minimize this failure rate by delivering a high dose of radiation directly to the exposed tumor bed during the time of surgery. IORT allows for a decreased dose of post-op external beam XRT.
Amifostine is the only FDA-approved tissue radioprotectent against xerostomia, a common complication of radiation therapy. It is a thiol-containing free radical scavenger that has an affinity for healthy tissues (i.e. salivary glands). Amifostine was originally developed by the armed forces to protect personnel against nuclear fallout. It is currently approved for use in post-op XRT and can either by administered intravenously or subcutaneously.
Stereotactic radiotherapy permits precise beams of high energy radiotherapy to be delivered through narrow beams. A stereotactic head frame is placed and a CT, MRI, or PET scan is performed and the patient is irradiated. It is most commonly used for acoustic neuromas, meningiomas, or paragangliomas. The gamma knife is commonly employed for acoustic neuromas but is also very expensive. Fractionated stereotactic therapy is used for patients with tumors <2 mm, serviceable hearing, and no vertigo.
Pre-operative radiation can be administered in a low dose with surgery shortly thereafter to avoid the late tissue effects of radiation. The disadvantage is that operating in irradiated tissue can be difficult and one must limit the radiation dose to avoid complications. Advantages to pre-op radiation are that the tissue is more radiosensitive pre-op due to a greater blood supply. The tumor can be converted to a more resectable state as well.
Indications for post-op XRT are perineural invasion, positive surgical margins or within 2 mm, +LNs, LN > 3 cm, lymphovascular spread, extracapsular spread, bone and soft tissue invasion. Advantages of post-op XRT are it permits for an easier surgical resection with non-irradiated tissue, allows for accurate surgical staging, and allows for adequate healing after surgery. Disadvantages of post-op xrt are that higher doses are often necessary because the tissue is often hypoxic and larger fields are often required. When treating head and neck cancer, the options include surgery, radiation, chemotherapy, chemo/xrt, and surgery with xrt. Selection of treatment depends on tumor size, site, histology, depth of invasion, stage, prior treatment, need for reconstruction, impact on QOL, and patient preference. Early stage carcinoma is commonly treated with single modality therapy (surgery or radiation) and advanced stage carcinoma is treated with multi-modality therapy (surgery + xrt or chemo/xrt). Indications for surgical extirpation must account for patient health status, tumor respectability, and post-op organ function. When the loco-regional control is similar for either surgery or chemo/xrt, one must choose the therapy with the least functional compromise/toxicity.
Complications of radiation therapy include mucositis, cutaneous reactions, xerostomia, soft tissue fibrosis ("woody" neck), dysphagia, dysgeusia, and osteoradionecrosis. Mucositis presents early on following radiation and can lead to tender, erythematous, swollen mucous membranes. Patients are more susceptible to viral and fungal infections and treatment consists of good dental hygiene and oral or topical anesthetics.
Radiation-induced xerostomia is the most common and often most debilitating complication of radiation therapy. DNA of salivary gland cells are destroyed resulting in decreased function of salivary glands. The parotid gland loses its function first even though the submandibular gland is responsible for most of the salivary flow and there is a rapid decrease is salivary function after just two weeks of radiation therapy. Effects of xerostomia include dental caries, dysphagia, dysgeusia, and dysarthria. Treatment consists of oral hydration, amifostine, use of parotid-sparing radiation techniques (IMRT), submandibular gland transfer, and cholinergic agents such as pilocarpine.
Osteoradionecrosis (ORN) is a late effect of radiation and is due to non-vital bone in an irradiated field. The reparative capacity of bone is unable to overcome the insult of radiation. Radiation leads to inflammation, thrombosis, hypovascularity, fibrosis, and fewer osteoblasts and fibroblasts. Typically greater than 60 Gy of radiation are required to cause ORN. Symptoms and signs include pain, trismus, oro-cutaneous fistula, pathologic fracture, or exposed bone. Treatment consists of hyperbaric oxygen (30-40 treatments), sequestrectomy of devitalized bone, use of bone graft for delayed reconstruction, or microvascular free tissue transfer for one-staged repair.
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