You are in: eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > HEAD AND NECK ONCOLOGY Radiation Therapy, General PrinciplesArticle Last Updated: May 1, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Gary J Schreiber, MD, Medical Director, Clinical Instructor Radiology, Department of Radiation Oncology, St Francis Hospital, Northwestern Medical School Gary J Schreiber is a member of the following medical societies: American Academy of Clinical Psychiatrists Editors: Daniel J Kelley, MD, Consulting Staff, Eastern Shore ENT & Allergy Associates; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Karen Hall Calhoun, MD, Chair, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Missouri; Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders; Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine Author and Editor Disclosure Synonyms and related keywords: radiation therapy, cancer treatment, radiation, radiotherapy, xerostomia, dry-eye syndrome, intensity modulated radiation therapy, IMRT, radiation-induced cell death, external beam therapy INTRODUCTIONSection 2 of 11
  Shortly after Roentgen discovered radiographs in 1895, their clinical usefulness as a means of cancer treatment was first appreciated. Since that time, radiation therapy has developed into a recognized medical specialty. The Curie family discovered radium in 1898. Alexander Graham Bell suggested its use in brachytherapy for direct implantation in malignant tumors. The lack of a precise method of measuring dosage limited the early use of radiation therapy. An early prescription typically called for an erythema dose as the standard unit of radiation. One of the limiting factors in early treatment was skin tolerance. This hurdle was overcome by Coutard's recognition of the usefulness of fractionation, ie, dividing the dose into several smaller increments rather than a single massive dose. At the same time, high-energy supervoltage was developed, and later, megavoltage-dedicated radiotherapy units were introduced. For excellent patient education resources, visit eMedicine's Imaging Center and Cancer Center. Also, see eMedicine's patient education article Understanding X-rays. BIOLOGIC BASIS OF RADIATION THERAPYSection 3 of 11
The exact mechanism of cell death due to radiation is still an area of active investigation. A large body of evidence supports double-stranded breaks of nuclear DNA as the most important cellular effect of radiation. This breakage leads to irreversible loss of the reproductive integrity of the cell and eventual cell death. Radiation damage can be directly ionizing; however, in clinical therapy, damage is most commonly indirectly ionizing via free-radical intermediaries formed from the radiolysis of cellular water. Radiation can also affect the processes of the cell cycle necessary for cell growth, cell senescence, and apoptosis (programmed cell death). Many of these processes are only now beginning to be elucidated and manipulated in order to make radiation therapy more effective. The therapeutic mechanism for radiation is based on the intrinsic ability of cells to repair damage and the ability of the radiation oncologist to take advantage of any geometric separation between the malignant and nonmalignant tissues. A logarithmic curve of survival versus dose characterizes cell survival after exposure. The curve forms an initial shoulder followed by a logarithmic decline in survival, which varies with the dose (see Image 2). Sublethal damage, which must be overcome with each fraction of radiation therapy, is thought to cause the initial shoulder. Repeated small doses of radiation are less damaging to a sensitive cell than a single fraction of equivalent total dose (see Image 3). Manipulation of the cellular environment can alter the shape of the survival curve. In addition to the intrinsic cellular radiosensitivity, cell survival is found to be related to oxygen tension, position of the cell in the mitotic cycle, and dose rate. These features are responsible for the 4 R's of radiobiology, namely, repair, redistribution, repopulating, and reoxygenation. Several models have been used to conceptualize radiation-induced cell death and to explain the cell survival curve. The cell survival curve can be interpreted to follow a linear-quadratic model, ie, the surviving fraction is equivalent to e(aD - bD2), where a = alpha and b = beta component, respectively (see Image 4). In the linear-quadratic model, 2 components of cell injury are present. The linear-alpha component is responsible for the initial shoulder on the cell survival curve and is caused by repairable damage to the target. The quadratic-beta component represents nonrepairable damage. The linear component is proportional to the dose, while the quadratic component is proportional to the dose squared. Acute reacting tissues and tumors have a relatively larger alpha component and a larger a:b ratio. Smaller a:b ratios characterize late responding tissues. This difference between the tumor and late responding tissues is useful in designing schemes, which use multiple daily fractions rather than the conventional once daily treatments. Values for a:b are as follows:
BASIC RADIATION PHYSICSSection 4 of 11
X-Rays and gamma ray photons are part of the electromagnetic spectrum. The dual nature of electromagnetic radiation is used to explain its wave and particulate behavior. A photon is a packet of energy that can be characterized by the equation E = hv, where h is Planck's constant (6.62 X 10-34 J-sec) and v is the frequency of the photon. Frequency is equivalent to the quotient of the speed of light (3 X 108 m/sec) divided by the wavelength. Thus, high-energy radiations have a short wavelength and high frequency. The interaction of a photon beam with matter results in the attenuation of the beam. Five major types of interactions typically occur, namely, coherent scattering, photoelectric effect, Compton scattering, pair production, and photodisintegration. The particular type of interaction is related to photon energy. In radiation therapy, the photoelectric effect, Compton effect, and pair production are of interest, with the Compton effect being the predominant interaction. Photoelectric effect involves the interaction of the photon with the tightly bound inner electrons and is proportional to the cube power of the absorbing matter's atomic number. This interaction is responsible for the different radiographic densities seen on diagnostic radiographs. Compton effect involves interaction with outer electrons that are bound more loosely. This effect is related to electron density and, therefore, results in much more uniform tissue absorption than lower energy photons. In radiation therapy, Compton effect predominates; therefore, the contrast observed on therapy port films is inferior to diagnostic radiographs (see Image 5). Pair production involves interaction of the photon with the atomic nuclear electromagnetic field. This interaction becomes significant at high energies (>10 MeV) and is proportional to the atomic number of the absorbing matter. Radioactive isotopes occur naturally and can be generated artificially. Becquerel recognized radioactivity in 1896 and is honored by having the unit of activity named after him. The activity of a radioisotope decays over time. Its energy spectrum, decay spectrum, and half-life characterize the isotope. A particular isotope may decay via the production of alpha particles or beta particles (positive or negative charge), through electron capture, internal conversion, or a combination of these reactions. Likewise, a nuclear transformation occurs when a chemical reaction takes place following a nuclear reaction and results in the generation of a new species. Physical Characteristics of Commonly Used Isotopes
Radiation dose or exposure is measured in units of absorbed radiation per unit of tissue. The Gray (Gy) represents 1 J/kg of tissue. Older literature uses the rad, which is equivalent to 0.01 Gy. The exposure and dose rate of radiation decrease according to an inverse square law, such that the exposure decreases by 4 when the distance increases by 2. External beam therapy is commonly delivered via a medical linear accelerator or Cobalt-60 unit. The introduction of these megavoltage units ushered in the modern age of radiation therapy. These units deposit the maximum dose beneath the surface; therefore, external beam therapy is considered skin sparing. Photons traverse the entire tissue thickness but deposit less dose as the depth increases. Many modern linear accelerators are also capable of producing electrons, which can be used for treatment situations where the limited depth penetration of these particles is useful, such as in cases where the contralateral parotid gland must be spared (see Image 6). TREATMENT PLANNINGSection 5 of 11
The process of treatment planning calls for an integration of the physical findings and diagnostic imaging information with knowledge of the pertinent anatomy, pathology, and natural history of the particular tumor type. The radiation oncologist and other members of the multidisciplinary team must decide if radiation will play a role in the treatment of the patient. Once the decision is made, consideration must be given to whether the radiation is prescribed as definitive, palliative, or adjuvant therapy, and if it will be integrated with surgery and chemotherapy. The radiation oncologist may recommend additional studies in the workup of the patient or may choose to coordinate the patient's care. A detailed knowledge of the various modalities of radiation therapy in the physician's armamentarium together with their individual physical characteristics and unique toxicities is essential. Contemporary treatment-planning computers allow for the incorporation of 3-dimensional anatomic data to be used for planning of radiation fields. Using beam's-eye-view technology, the field of radiation can be planned so that the physician is assured that the radiation field adequately covers the target and spares or minimizes the dose to the nontarget healthy tissues (see diagram in Image 1). Complex beam arrangements can be used with the knowledge that a geometric miss can be avoided. An entire lexicon of treatment-planning terminology has been created as a result. The physician uses the clinical and radiographic findings to determine the gross tumor volume (GTV). Next, the clinical tumor volume (CTV) is defined to include microscopic extension of the disease. The planning treatment volume (PTV) allows for day-to-day variation. In order to minimize any variation in patient positioning, meticulous immobilization is essential. Thermoplastic masks and other similar positioning devices frequently are used in the treatment of head and neck cancer. FRACTIONATIONSection 6 of 11
Conventional fractionation in the United States is considered to be 1.8-2 Gy per day, administered 5 days each week for 5-7 weeks, depending on the particular clinical situation. The alteration of this scheme has been evaluated for a variety of reasons, including time constraints, staff constraints, machine availability, and patient convenience. A variety of methods have been used to correlate different dose-fractionation schemes. These methods are rooted in an understanding of the dose-response curves and the association (or lack thereof) between acute reaction and long-term sequelae of treatment. Strandquist produced the first clinical isoeffect curve. He calculated the relationship between time, dose, cure, and skin reactions in the treatment of skin cancers. Later, Ellis recognized that the time factor was actually dependent on both the overall treatment time and the number of fractions. He devised the nominal standard dose (NSD) formula, ie, D = NSD X N0.24 X T0.11, where D = dose, N = number of fractions, and T = overall time. These formulas have been used in an attempt to adjust for the alterations in the standard fractionation schemes. Most contemporary isoeffect formulas make use of the linear-quadratic model as a basis for dose adjustments, ie, D1/D2 = (a/b + d2) / (a/b + d1), where D is the total dose and d is the dose per fraction. This formula assumes a complete repair of sublethal damage between the fractions. The major deficiency with these formulas is the lack of precision in determining a/b for the various tissue types, tumor types, and individual variations. One of the early attempts at altered fractionation was the use of split-course therapy. The attempt was to attain comparable or better levels of tumor control by allowing reoxygenation with reduced acute toxicity. A 2- to 3-week rest from the treatment was often used. However, this rest period resulted in poorer long-term control because repopulation and accelerated repopulation dominated. Other fractionation schemes include hyperfractionation, hypofractionation, and accelerated fractionation. In hyperfractionated regimens, the goal is to deliver higher tumor doses while maintaining a level of long-term tissue damage that is clinically acceptable. The daily dose is unchanged or slightly increased while the dose per fraction is decreased, and the overall treatment time remains constant. The a/b for the tumor must be greater than that of the dose-limiting tissue. An additional rationale for hyperfractionation is to allow radiosensitization through redistribution. With a greater number of fractions, the likelihood is greater that the tumor will be in a sensitive phase of the cell cycle at some time during the treatment. This strategy invariably results in more intense acute reactions when compared to conventional treatment. In the accelerated fractionation schemes, the dose per fraction is unchanged while the daily dose is increased, and the total time for the treatment is reduced. Three basic variations are possible. Continuous hyperfractionated accelerated radiation therapy (CHART) is an intense schedule of treatment, where multiple daily fractions are administered within an abbreviated period of time. An intense acute reaction develops in most patients. This reaction usually limits the total dose. In a concomitant boost technique, the first fraction of the day is administered in a larger volume, while the second fraction is targeted to a reduced-boost field of treatment. The boost may be administered early in the course of therapy or toward the end of treatment. This regimen is based upon the recognition that the treatment can induce an accelerated repopulation of the tumor cells so that reduction of the overall treatment time results in improved control. Clinical trials are in progress with the goal of evaluating these various altered fractionation patterns and comparing them to conventional treatment. Results from the recently completed randomized trial, RTOG-9003, supports the benefit of altered fractionation over conventional treatment for head and neck cancer. So far the benefit seems to be in local regional control. Further follow-up is necessary to determine if there is an overall survival benefit as well. ACUTE EFFECTSSection 7 of 11
Radiation effects on the normal tissues are divided into acute and chronic effects. Acute effects occur during the course of therapy and during the posttherapy period (approximately 2-3 weeks after the completion of a course of irradiation). Chronic effects can manifest anytime thereafter, from weeks to years after the treatment. Patients are usually most bothered by the acute effects, but physicians are at least equally concerned about the chronic effects. The acute effects can be quite uncomfortable but generally resolve. The chronic effects can be devastating, permanent, and progressive. Much of the effort that goes into the treatment planning regards minimizing the normal tissue effects of treatment. The tissues that divide rapidly (eg, mucous membranes) respond acutely to radiation and are responsible for much of the acute morbidity of the treatment. Two major theories are used to explain late injury. One theory attributes chronic injury to the damage of the microvasculature, while the other attributes injury to stem cell depletion. The mucous membranes of the oral cavity and the oropharynx respond early to fractionated radiation. Erythema is often evident after 1 week of treatment at conventional doses. This condition progresses over the next few weeks through various stages of mucositis, ranging from small patches to confluent or even ulcerated areas. Mucositis represents caking of the dead epithelial cells, fibrin, and inflammatory cells. Consider superimposed infection with yeast species or bacteria when patients report oral or throat pain during treatment. Healing begins while the patient is still undergoing treatment but may continue for several weeks after the radiation is completed. Loss of taste is a common acute effect of treatment. Taste loss begins early and progresses rapidly during the second 2 weeks of treatment. Patients may report diminished acuity, odd sensation, or complete absence of taste. Xerostomia is often present and exacerbates this loss of taste. This condition is often accompanied by a loss of appetite and weight loss. Recovery of taste is a slow and, frequently, an incomplete process. The major salivary glands (ie, parotid and submandibular glands) are responsible for nearly 80% of salivary production. The parotid glands primarily consist of serous acini, while the submandibular glands produce mucinous and serous secretions. The minor salivary glands, which are distributed throughout the oral mucosa, produce mostly mucinous secretions. Radiation affects the saliva volume and production and also alters the composition of the saliva. Decreased salivary pH and decreased volume are significant contributors to the altered oral mucosal flora and predispose patients to caries. Salivary production decreases rapidly with treatment, declining by nearly 50% after a week of treatment. Patients frequently describe thickened, tenacious, ropy saliva, which may make speech difficult in addition to affecting swallowing and taste. High-energy radiographs are skin sparing. Skin reactions, which were at one time dose limiting, are rarely a problem when high-energy radiographs are used. While erythema is common after several weeks of radiation, severe skin reactions, such as those observed in the orthovoltage era, are uncommon. When a need for skin irradiation exists (eg, skin involvement by the tumor or skin as the target in the treatment of basal cell cancers), the technique is adjusted so that a brisk skin reaction is produced. The use of less-penetrating orthovoltage radiographs, treatment with electrons, or the addition of tissue-equivalent bolus material placed over the radiation field can circumvent skin sparing. Even with megavoltage treatment, skin tanning and dry desquamation can occur. The addition of certain chemotherapeutic drugs can enhance skin and other effects. Radiation can induce melanin production, which is often first observed in the skin follicles because these skin invaginations receive a slightly higher dose as the beam enters tangentially to the surface. Skin sensitivity is increased because of the treatment. In situations where the skin is denuded, known as moist desquamation, the area must be kept clean to avoid superinfection. Re-epithelization moves centrally from the field edges and is generally completed within 3 weeks prior to the completion of treatment. Sweat glands and sebaceous glands may cease functioning, but the in-field hair loss usually is temporary. Regrowth is evident within a few weeks after cessation of therapy. LATE EFFECTSSection 8 of 11
The late effects of radiation can be a source of ongoing morbidity from a course of radiation therapy. Just as with the acute effects, the chronic effects are related to site, dose, volume, and time. Other therapies, such as surgery and chemotherapy, can increase the probability and severity of radiation-related morbidity. High doses of radiation to the neck can result in fibrosis. This condition is especially true in the postoperative setting where the neck may develop a woody texture and have limited movement. Likewise, the masticatory muscles may develop fibrosis, which can result in trismus. Instruct patients to begin stretching exercises of their jaw muscles as soon as possible after surgery. Obstruction of the cutaneous lymphatics results in lymphedema, which may be associated with episodes of intermittent erysipelas. Delayed wound healing can be a consequence of high-dose preoperative radiation. Telangiectasis may appear some time after the treatment in the areas that were treated without skin-sparing techniques such as with electrons, tangential irradiation, and deliberate addition of bolus material. The loss of salivary function is usually complete after modest doses of radiation to the parotid glands. The basal flow rates correlate with the response to radiation therapy. With 40-60 Gy, fewer than 20% of patients have a measurable salivary flow. For patients receiving fewer than 30 Gy, some function may return after 6-12 months. However, at dose levels exceeding 50 Gy, xerostomia usually is irreversible. Dry mouth is probably the most common problem for patients who receive therapeutic doses of radiation. Numerous approaches have been tried to address this problem. Pilocarpine 5 mg tid has been shown to stimulate residual salivary function. Some patients use artificial saliva substitutes, but most patients find them inadequate. Many patients must carry bottles of water to provide some relief. The US Food and Drug Administration (FDA) has recently approved the use of IV Amifostine (Ethyol) as a radioprotectant agent. Administered as a daily dose, Amifostine is to be used in the prevention of radiation-induced xerostomia in the postoperative setting. Concern about tumor protection appears to be unwarranted. Adverse effects, such as nausea and hypotension, the need for daily injections, and cost concerns may limit its wide acceptance. SQ administration, while not a labeled use, seems to be equally effective and associated with less toxicity. Intensity modulated radiation therapy (IMRT) is an increasingly available, novel approach to preventing xerostomia. At the time of treatment planning, the radiation oncologist uses an inverse-planning algorithm that allows selective avoidance of critical normal tissues without compromising the tumor doses. Other potential uses for IMRT include the ability to administer biologically higher doses to target tissues and biologically lower doses to nontarget tissues and thus increase the therapeutic ratio. Several planning systems and systems of delivery are currently available or are in the testing phases. The initial reports are encouraging. As a consequence of oral pain and altered diet during treatment and xerostomia following treatment, the oral flora and pH can be altered significantly. Without meticulous dental care during and after radiation therapy, patients are prone to accelerated caries and decay. Oral and gingival tissue may atrophy following radiation, which results in a thin pale layer with evidence of telangiectatic vessels. Ulceration and bone exposure can occur. If serious injury to the underlying bone occurs, osteoradionecrosis may follow. Fortunately, this complication is uncommon. When it does occur, management of the condition may be difficult. While patience is important, some cases require intervention, which includes the use of antibiotics, hyperbaric oxygen treatment, and resection. Radiation to the spinal cord may result in a self-limited transverse myelitis, known as Lhermitte syndrome. The patient notes an electric shocklike sensation that is most notable with neck flexion. Rarely does this condition progress to a true transverse myelitis with associated Brown-Séquard syndrome. The dose to the spinal cord must be limited so as to avoid this devastating complication. A course of treatment often affects the thyroid gland either directly or secondarily via the hypothalamic-pituitary axis. Chemical hypothyroidism is often the only manifestation of an endocrinopathy and is treated readily with supplemental thyroid preparation. Other endocrinopathies are uncommon. Other structures that must be considered during the treatment planning are the visual apparatus, the auditory apparatus, and the apex of the lungs. Exceeding the tolerance of the lacrimal gland can result in dry-eye syndrome. The lens is highly sensitive to radiation. Direct irradiation of the lens with the most commonly used therapeutic doses results in cataract formation. Tolerance of the retina and optic nerve must also be respected during the treatment planning to avoid visual loss. Radiation to the auditory apparatus may result in serous otitis or possible sensorineural hearing loss at high doses of irradiation. Radiation-induced cancers are fortunately quite uncommon following therapeutic doses of radiation. A much greater risk of second malignancy is due to the same etiologic and genetic mechanisms that are responsible for the primary tumor. SYSTEMIC AGENTSSection 9 of 11
Chemotherapy can enhance the effects of radiation therapy. Numerous agents have ben used either sequentially or concurrently with radiation. Most studies indicate that the best results can be obtained with concurrent radiation and platinum-based chemotherapy. The concurrent use of chemotherapy also intensifies the acute toxicities of treatment, and patients often require nutritional support during therapy. Recent encouraging data are being used to define a role for induction chemotherapy followed by concurrrent chemoradiotherapy. Other agents that are used in head and neck cancer include fluorouracil, paclitaxel (Taxol), docetaxel (Taxotere), and hydroxyurea. Biological agents are being studied that may reduce some of the toxicities of combined chemotherapy and radiation or enhance the effect of radiation therapy. Keratinocyte growth factor (KGF) has been found useful in reducing mucosal toxicity in patients undergoing total body irradiation and may be useful in other applications as well. Targeted therapies that act to interrupt signal transduction pathways are also being studied. Dramatic results with the epidermal growth factor receptor (EGFR) antibody cetuximab has resulted in recent FDA approval of this agent for use in head and neck cancers. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Radiation Therapy, General Principles excerpt Article Last Updated: May 1, 2007 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
