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Radiation in Medicine: A Need for Regulatory Reform 2 Clinical Applications of Ionizing Radiation This chapter provides an overview of the wide array of clinical applications of ionizing radiation. As is customary, applications are grouped here into diagnostic and therapeutic uses. These two categories are further divided by whether the ionizing radiation is administered through external or internal sources. Also of importance for understanding this area of medicine are the many different medical conditions for which these clinical applications are critical and the levels of exposure to radiation involved in each procedure. This last information is important because the known or perceived risks from these clinical applications are related directly to exposure levels. It is against these risks that government regulation is primarily aimed. Thus, this chapter also discusses the forms that government control takes over the various sources and uses of ionizing radiation. As will become apparent to the reader, the divisions of regulatory authority do not clearly correspond to the risks associated with the sources and applications. As an aid to the reader, Table 2.1 provides a chart of radiation sources and their applications. In addition, a preliminary section introduces some terminology about how levels of radiation are customarily denoted. The following two main sections of the chapter discuss in turn the diagnostic and the therapeutic applications of ionizing radiation. These sections are followed by the chapter's conclusion. MEASURES OF PATIENT EXPOSURE TO IONIZING RADIATION Initial systematic studies of patient exposure, beginning in the 1970s, used an index called "entrance skin exposure" in units of milliroentgen (mR). Since
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.1 Radiation in Medicine Applications Radiation Source Origin Diagnostic Therapeutic Ioninzing Radiationa Radioactive Materials Reactor-generated byproduct material Nuclear reactors Nuclear medicine (radiopharmaceuticalsb) Nuclear medicine (radiopharmaceuticalsb) Teletherapy (Sealed sources) Brachytherapy (sealed sources) Radium Naturally occurring Brachytherapy Accelerator-generated radionuclides Particle accelerators (linear accelerators, cyclotrons) Nuclear medicine (radiopharmaceuticals) Nuclear medicine (radiopharmaceuticals); Brachytherapy (sealed sources) Machine-Produced Radiationc X-radiation X-ray machines Radiography Fluoroscopy Computed tomography Dental x-rays External beam x-ray therapy
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Radiation in Medicine: A Need for Regulatory Reform High-energy particle radiation Particle accelerators (linear accelerators, cyclotrons) Electron, neutron, and positive ion therapy High-energy particle radiation Nuclear reactors Boron neutron capture therapy Nonionizing Radiationd Magnetic resonance imaging (MRI) machine MRI scan Ultrasound Ultrasound scan NOTE: Sources or machines indicated in bold are subject to NRC regulation. All others may be regulated at the state level. a Scope of Institute of Medicine study. b Also subject to regulation by the Center for Drug Evaluation and Research and/or the Center for Biologics Evaluation and Research of the Food and Drug Administration (FDA). c All devices are subject to regulation by the FDA's Center for Devices and Radiological Health. d Uses of nonionizing radiation are included here for illustrative purposes only; they are not within the scope of this study.
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Radiation in Medicine: A Need for Regulatory Reform that time, the metrics used in science and medicine have changed to internationally accepted units, and the relevant index in radiology is now ''entrance skin air kerma" (ESK) in units of milligray (mGy). An entrance skin exposure of 100 mR is equivalent to an ESK of 0.869 mGy; both measures quantify the intensity of x-rays in air at the patient's skin. To calculate a patient's radiation dose for a specific organ for a given ESK, radiologists must consider both the attenuation and the scattering of the x-ray within the patient. To help in this process, the Food and Drug Administration (FDA) of the Department of Health and Human Services and others have published tables and computer codes that give the dose to various organs per unit ESK for many different radiographic procedures. To estimate patient risk or to compare a nonuniform exposure to whole body exposure, the International Commission on Radiological Protection recommends that individual organ doses be converted to "effective dose equivalent" (EDE) in units of millisievert (mSv).1 EDE is the dose that, if delivered uniformly, would have the same biological effect as the actual (nonuniform) dose. It is calculated as the product of individual organ dose and an "organ weighting factor" given by the International Commission on Radiological Protection. Collective dose equivalent is the product of EDE and the number of persons receiving a radiation dose; it is expressed in units of person-sievert (person-Sv). Collective dose equivalent for diagnostic medical x-rays, for example, can be estimated as the product of the EDE per procedure and the total number of procedures. Collective dose equivalent is of interest in terms of broad population exposure to radiation overall and to radiation from various medical uses. If medical uses produced a very high exposure compared to the exposure levels encountered in ordinary daily activities, policymakers and others might have reason to direct relatively more attention to the regulation of medical uses of ionizing radiation. Conversely, if it is the case that common daily activities expose the general population to radiation levels significantly far in excess of those from medical applications, policymakers might have less reason or interest in such regulation. The discussions that follow present information on radiation exposure from various procedures in some depth, with the aim of providing the reader with a sense of the inherent risk (or lack of it) of various techniques that use ionizing radiation. These interventions are by no means the only source of exposure to radiation in this country, however. Normal background radiation from all natural sources (including radon) in the United States exposes each member of the population to an average EDE of about 3 mSv per year. 1 The earlier unit was millirem (mrem); 1 mSv = 100 mrem.
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Radiation in Medicine: A Need for Regulatory Reform DIAGNOSTIC APPLICATIONS OF IONIZING RADIATION The diagnostic uses of ionizing radiation are classified below under two basic headings: radiology and nuclear medicine. In radiology, the radiation administered is external to the patient; in nuclear medicine, it is internal. The discussion of each of these two classes of applications addresses types of procedures, utilization, radiation doses, and radiation regulation and control. External Sources: Radiology Types of Procedures In the 100 years since the discovery of x-rays, diagnostic radiology has grown from a scientific curiosity to a pervasive and essential part of modern health care. Radiology originated with the use of ionizing radiation to diagnose human disease. The development of nonionizing technologies, such as ultrasound and magnetic resonance imaging (MRI), has led to the more generic term "medical imaging." Indeed, the fastest growing areas of radiology are these two nonionizing modalities. Nevertheless, x-ray imaging continues to comprise 80 to 90 percent of all imaging procedures. It is performed using three different imaging techniques: radiographic imaging, fluoroscopic imaging, and computed tomography (CT). The physical principle underlying x-ray imaging is the partial transmission of x-rays through the body. An external source produces x-rays, and this radiation interacts with tissues in the patient's body either through absorption or scattering. The degree of interaction depends on various factors (such as the energy of the x-rays and the density of tissues traversed). The three main imaging techniques rely on different mechanisms for detecting, viewing, or recording the x-rays emerging from the patient's body.2 In all cases, however, the essential interaction 2 In radiographic imaging, the x-rays emerging from the patient are detected by a cassette containing a sheet of film sandwiched between fluorescent intensifying screens. The resulting radiographic image may be thought of as a two-dimensional map of the differential attenuation of x-rays passing through the body. For fluoroscopic imaging, transmitted radiation is detected by an x-ray image intensifier. Radiologists may use a television pickup tube or a 35-millimeter (mm) cine camera to view the resultant image or, for very common procedures, observe the dynamic image on a closed-circuit television monitor. Selected still images may also be obtained. CT imaging relies on x-ray transmission confined to a narrow (1 to 10 mm) strip. Transmitted x-rays are detected by a scintillation or solid-state radiation detector. By rotating the x-ray source around the patient and taking thousands of transmission measurements at many different angles, a digital image can be reconstructed of a tomographic or cross-sectional "slice" of the patient without anatomical structures superimposed upon one another. In a typical procedure, 10 to 50 adjacent slices are obtained. CT images are much sharper than conventional film-screen images because scatter radiation is eliminated, comparatively high doses of radiation are used, and a narrow range of gray shades can be displayed.
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Radiation in Medicine: A Need for Regulatory Reform of x-rays with tissue produces an unwanted, but unavoidable, consequence, namely the deposit of some radiation dose in the patient. The vast majority of x-ray procedures are performed by radiographic imaging. These radiographic imaging procedures are in turn typically divided into what are considered "conventional" examinations, on the one hand, and "contrast studies," on the other. Conventional examinations. Most notable among the conventional examinations is chest radiography, the most common of all radiographic imaging procedures. It is widely available (even at bedside, using portable x-ray machines), low in cost, and conveniently repeated to assess clinical changes. It is a primary tool in the diagnosis of diseases of the lungs (particularly infectious disease and cancer); it provides information on midline anatomical structures and the cardiovascular system (e.g., for diagnosing congestive heart failure); and it is useful for monitoring the status of critically ill patients. At times, chest radiography has been used ineffectively and inappropriately (e.g., for certain screening or administratively required examinations or for routine hospital admission). To reduce unnecessary utilization, professional organizations have established standards for its performance. Chest radiography may undergo technological modification in the future, such as the use of digital image receptors, but it will likely remain the most prevalent imaging examination. Other conventional examinations include those of the extremities, spine, skull, abdomen, pelvis, and breast. Radiographic views of the extremities are the most efficient way to diagnose broken bones and injured joints, but radiographic imaging is now less common than before for several other parts of the body. For example, CT and MRI examinations have largely replaced radiographic imaging of the spine and skull for central nervous system evaluation, and body CT and ultrasound have somewhat reduced the use of conventional radiographic examinations of the abdomen and pelvis. Mammography is an example of a radiographic imaging procedure that now plays a critical role in the diagnosis of a major health problem in this nation. It has undergone dramatic improvement in image quality and reduction in patient dose, and the development of units dedicated exclusively to mammography has optimized the total radiographic system (from x-ray tube to film-screen cassette) for breast imaging. The consequences of these technological advances are significant. For example, in women older than 50 years of age, screening mammography is the best method for early detection of breast cancer. As part of a comprehensive program of screening, follow-up, and treatment, mammography can be expected to yield a 30 to 50 percent reduction in breast cancer mortality (Feig, 1995; Tabar et al., 1995).
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Radiation in Medicine: A Need for Regulatory Reform Contrast studies. Contrast studies are a wide range of radiographic imaging studies in which the patient is administered an agent to improve contrast in the x-ray image. For example, patients ingest or are injected with compounds containing barium (oral) or iodine (oral and intravenous) or with low-density agents such as air. Contrast agents have been used in imaging of the alimentary tract (upper gastrointestinal (UGI) series and barium enema), the urinary tract (intravenous pyelogram), the gall bladder (oral cholecystogram), and the spinal cord (myelogram). The frequency of contrast studies decreased from 1970 to 1980, as competing techniques (e.g., endoscopy and colonscopy for alimentary tract evaluation, ultrasound and CT for body evaluation, and CT for central nervous system evaluation) became available. The advent of MRI in the 1980s accelerated this decrease. In general, the trend away from contrast studies can be attributed to various technological, medical, and economic factors, such as improved diagnostic accuracy, reduced risk of medical complications, and the changing content of various physician specialties. For instance, myelography is much less frequently performed because MRI yields superior images and requires no needle puncture of the spinal canal. As another example, although the double-contrast UGI series yields diagnostic results and clinical outcomes nearly identical to those of endoscopy at one-third the cost, endoscopy has largely supplanted the UGI series in many institutions, in part owing to the establishment of gastroenterology as a procedure-oriented subspecialty. Another form of contrast study is the "special"3 or intravascular procedure. Here, a catheter is introduced into an artery or vein and directed to an area of interest. Once in position, an iodinated contrast agent is injected into the catheter while many images (tens to hundreds) are rapidly obtained. In many instances, radiologists perform a subtraction study, in which an image with contrast agent present is subtracted from an identical image without contrast to yield an image of just the vascular anatomy. There are several variations of these special procedures. Cerebral angiography is performed to evaluate conditions such as vascular obstructive disease, 3 "Interventional procedures" seek to treat disease by anatomic manipulation or drug delivery, through a fluoroscopically guided intravascular catheter. Although interventional procedures are therapeutic applications rather than diagnostic, they are mentioned here because they evolved from special procedures. In percutaneous transluminal angioplasty, a small balloon-tipped catheter is used to open blocked arteries mechanically. The analogous procedure for the coronary arteries in the heart is called percutaneous transluminal coronary angioplasty. Other types of catheters, which use heat rather than expansion to open blockages, also are available. Intraluminal thrombolytic therapy uses selective catheterization to deliver clot-dissolving drugs directly to the site of vascular obstruction. Traumatic or congenital bleeding can be treated by embolotherapy, by introducing an artificial clot-forming material, such as surgical gelatin foam, into the specific site of the bleeding.
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.2 Relative Frequency and Absolute Utilization Rate of Radiological Procedures in 1980 Examination Relative Frequency (%) Rate per 1,000 Population Skull 2.6 20.8 Other head and neck 1.9 15.5 Cervical spine 2.8 22.6 Head CT 1.5 11.9 Body CT 0.3 2.7 Chest 35.3 283.2 Mammogram 0.7 5.8 Abdomen 1.9 15.0 Biliary 4.4 35.0 Thoracic spine 1.0 8.0 Lumbar spine 7.1 57.1 Full spine 0.8 6.2 Upper gastrointestinal 4.2 33.6 Barium enema 2.7 21.7 Pyelogram 2.3 18.6 Pelvis 2.6 20.8 Extremity 24.8 199.1 Special vascular procedure 0.6 4.4 Cardiac catheterization 0.3 2.2 Other 2.2 17.3 Total 100.0 801.5 SOURCE: Summaries presented in National Council on Radiation Protection Report 100 (NCRP), 1989. aneurysm, arteriovenous malformation, and brain tumor. Visceral and peripheral angiography studies are performed to evaluate obstructions and aneurysms in the vascular system. Cardiovascular procedures are done to measure heart functional capacity and to assess coronary artery obstruction. Utilization Rates The most recent detailed data about the rates of use of radiological diagnostic procedures date to work by the National Council of Radiation Protection (NCRP) for 1980 (NCRP, 1989), as presented in Table 2.2. As these data indicate, the chest x-ray examination is by far the most common procedure (accounting for over one-third of all procedures tabulated); it is followed by examinations of the extremities (about one-quarter) and of the spine (thoracic, lumbar and full, adding to about one-tenth).
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.3 Total Number (in thousands) of Imaging Procedures in U.S. Hospitals, 1970–1990 Procedure 1970 1980 1990 General radiology 81,700 133,132 179,063 Computed tomography (CT) 0 2,931 13,394 Ultrasound 200 5,177 11,815 Magnetic resonance imaging 0 0 1,874 Total 81,900 141,240 206,146 NOTE: General radiology includes all x-ray procedures except CT. SOURCES: Johnson and Abernathy, 1983; NCRP, 1989; Sunshine et al., 1991; Mettler et al., 1993. Although broad-based data are sparse at best, the total numbers of procedures and rates per 1,000 population have certainly increased in the intervening years. In addition, the relative distribution among types of procedures has undoubtedly changed in response to new imaging modalities and shifts in the settings in which radiological examinations are done. In 1980, approximately 80 to 85 percent of all radiological procedures were estimated to have been performed in hospitals (for both inpatients and outpatients), and the remaining 15 to 20 percent were done in physician offices or outpatient imaging centers. By 1990, approximately 25 to 35 percent of all imaging procedures were estimated to occur outside of hospitals (Sunshine et al., 1991). The trend towards nonhospital-based imaging has accelerated since 1990, as health care providers have reacted to market and reimbursement forces by moving imaging procedures outside the hospital setting. No studies have updated the distribution of procedures at the level of detail reflected in Table 2.2 Some more recent information on specific diagnostic modalities is available, however. The frequency of CT use has greatly increased, from about 2 percent of radiological procedures (excluding ultrasound and MRI) in 1980 to about 7 percent in 1990. The rates of some procedures, such as plain films of the skull or lumbar spine and contrast studies of the GI tract, have probably decreased. Over the years, several agencies, associations, and individuals have developed data on the total volume of imaging procedures. These include the FDA, the NCRP, and the American College of Radiology (ACR) (see Johnson and Abernathy, 1983; NCRP, 1989; Sunshine et al., 1991; Mettler et al., 1993). Since the compilation of the information presented in Table 2.2, less detailed surveys (which have not broken down rates for specific imaging procedures) have been published. Table 2.3 gives information for hospital-based procedures for 1970, 1980, and 1990. In this 20-year period, the total number of imaging procedures in hospitals rose by two and a half times, from just under 82 million
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.4 Estimated Total Number of All Medical Imaging Procedures, 1970–1990 Year No. of Procedures Total U.S. Population Rate per 1,000 population 1970 136,000,000 204,000,000 670 1980 181,000,000 226,000,000 800 1990 294,000,000 249,000,000 1,180 NOTE: Procedures include nonionizing technologies (ultrasound and magnetic resonance imaging). SOURCES: Johnson and Abernathy, 1983; NCRP, 1989; Sunshine et al., 1991; Mettler et al., 1993. procedures to more than 206 million, with a steep growth rate in the use of CT, ultrasound, and MRI. The upward trend in the overall use of diagnostic radiology procedures, including both those provided in hospitals and those provided in nonhospital settings such as physician offices and freestanding centers, is slightly smaller in percentage terms but dramatic nonetheless. Data in Table 2.4 indicate that the total number of procedures more than doubled, from 136 million to 294 million, between 1970 and 1990, resulting in rates per 1,000 persons of 670 and 1,180, respectively. While the total utilization rate of all imaging procedures per 1,000 population grew 48 percent from 1980 to 1990, rates of procedures that expose patients to ionizing radiation rose only about 28 percent. The 1990 figures cited here are based on fairly crude estimates, but they are the best available at this time. No work has been published in recent years to assess the impact of managed care or other cost-containment strategies on the use of diagnostic radiology services. It should be emphasized that the charge to the committee was to assess the Nuclear Regulatory Commission's (NRC's) Medical Use Program and problems related to misadministrations. Consequently, the committee did not examine the overuse of radiation in medicine, which is probably best addressed by professional training and patient advocacy. Radiation Doses Radiation dose and the immediate or short-term adverse consequences of diagnostic radiology procedures are of concern to the health care professions, the public, and regulators. Radiation dose depends on numerous factors, including the size of the patient, the radiation sensitivity of the image receptor, the energy of the x-ray beam, the radiation exposure rate, and the total time the x-ray tube is energized. Because exposure of both individual patients and populations is of concern, measurements are taken for both person-specific exposure (e.g., ESK and EDE, see above) and collective dose equivalent.
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.5 Typical Entrance Skin Air Kerma (ESK) per Procedure and Typical Effective Dose Equivalent (EDE) for Several Common Procedures Procedure/View Average ESK per Imagea Average EDE per Procedureb EDE Level as % of Background Radiation Chest 0.08(8) 3 AP 0.23(27) LAT 0.70(80) Skull 0.22(22) 7 AP 4.17(480) LAT 2.46(283) Cervical spine 0.20(20) 7 AP 2.26(260) LAT 1.48(170) Lumbar spine 1.27(127) 42 AP 7.68(884) LAT 27.8(3,200) Abdomen 0.56(56) 19 AP 5.76(663) LAT 18.25(2,100) Upper gastrointestinal 1.08 36 Fluoro (rate per minute) 17.38(2,000) Spot film 7.35(846) Head computed tomography 1.11 37 10-mm slice 44(5,063) Mammogram 0.06(6) 2 Craniocaudal 1.28(128)c Extremities 0.01 0.3 Hand/foot 0.09(10) NOTE: A given procedure usually consists of two or more films. AP = Anterior/posterior. LAT = Lateral view. SOURCES: NCRP, 1989; Suleiman et al., 1991; et al., 1992. a In units of milligray (mGy); figures in parentheses are the equivalent "entrance skin exposure" measure in units of milliroentgen (mR). b In units of millisievert (mSv); figures in parentheses are the equivalent in millirem (mrem). c Mean glandular dose. Patient-specific radiation dose. Table 2.5 provides, for several common imaging procedures, comparative information related to some of these factors: the average ESK per image, the average EDE per procedure (which can include multiple images), and the level of EDE from the procedure, expressed as a percentage of background radiation.
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.11 Estimated Number of New Cancer Cases by Site in 1995 Site No. of New Cases No. Treated with Radiationa % of Total Treated with Radiation Oral cavity Lip 2,550 800 0.2 Tongue 5,550 1,700 0.3 Mouth 11,000 3,300 0.6 Pharynx 9,100 2,700 0.5 Digestive organs Esophagus 12,100 6,000 1.2 Stomach 22,800 0 0 Small intestine 4,600 0 0 Large intestine 100,000 10,000 1.9 Rectum 38,200 19,100 3.7 Liver and biliary 18,500 900 0.2 Pancreas 24,000 19,200 3.7 Other digestive 2,800 300 0.1 Respiratory system Larynx 11,600 4,000 0.8 Lung 169,900 136,000 26.4 Other respiratory 4,800 2,400 0.5 Bone 2,070 200 <0.1 Connective tissue 6,000 1,800 0.4 Melanoma of skin 34,100 3,400 0.7 Breast 183,400 128,400 24.9 Genital organs Cervix uteri 15,800 4,700 0.9 Corpus uteri 32,800 24,600 4.8 Ovary 26,600 2,700 0.5 Other, female 5,700 2,900 0.6 Prostate 244,000 73,200 14.2 Testis 7,100 2,100 0.4 Other, male 1,100 300 0.1 Urinary organs 79,300 11,900 2.3 Eye 1,870 200 <0.1 Brain or central nervous system 17,200 14,600 2.8 Endocrine glands 15,380 1,500 0.3 Leukemia 25,700 300 0.1 Other blood or lymph Hodgkin's disease 7,800 3,900 0.8
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Radiation in Medicine: A Need for Regulatory Reform Non-Hodgkin's lymphoma 50,900 17,800 3.5 Multiple myeloma 12,500 4,500 1.9 All other and unspecified 45,230 4,500 0.9 Total 1,252,050 509,900 100.0 a Data are rough estimates of how many new cases may receive radiation therapy. Although the number of estimated new cases is fairly reliable, the distribution of therapy cases is more difficult to predict, owing to its dependence on practice patterns. SOURCE: American Cancer Society (see Wingo et al., 1995). treated with radiation therapies. The actual frequency distribution by site is quite variable, because it depends on local patterns of care, the initiation of new treatment protocols, and the retirement of old ones. Patterns of Care Studies. The ACR, through the Patterns of Care Studies (POCS), has conducted periodic surveys of the status of radiation oncology in the United States. The relatively small number of centers and physicians involved in the specialty of radiation oncology (and the field's exclusive focus on cancer) facilitate in-depth surveys of the patterns of care in clinical radiation therapy. The POCS measure the size and composition of the radiation oncology care delivery system in the United States and document both the process of care and patient outcomes. Over time, the POCS also contribute information leading to changes in process and improvements in outcomes. The POCS data are valuable in placing radiation oncology in perspective among the cancer treatment modalities. Based as they are on statistically valid samples of the total spectrum of practice in the United States, the numbers can be relied upon to demonstrate what is experienced in the community in terms of tumor response, survival, and complications. Some of these outcomes data are presented later in this section. Table 2.12 summarizes the results of those surveys that tracked facilities and work load, showing data for selected years between 1975 and 1990. Between 1975 and 1990, for example, the total number of facilities increased by just under 300 while treatment machines rose by more than 1,000. In the same period, the number of new patients rose by nearly 180,000 persons (or about 12,000 a year on average). Much of the growth in machines and new patients in this period occurred between 1986 and 1990, and most of this can be attributed to the expansion of freestanding (nonhospital-based) radiation oncology centers. In 1986, approximately 20 percent of facilities were freestanding, whereas just four years later the figure had increased to 27 percent.
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.12 Number of Radiation Oncology Facilities, Number of Treatment Machines, and Patient Loads, 1975-1990 1975 1980 1986 1990 Facilities 1,047 1,083 1,144 1,321 Treatment machines Linear accelerator/betatron 407 801 1,294 1,893 Cobalt 970 825 671 504 Total 1,377 1,626 1,965 2,397 New patients 312,548 377,837 444,558 492,120 Per 1,000 population 1.49 1.67 1.85 1.98 Per facility 299 349 389 373 Per machine 227 233 226 205 SOURCE: ACR Patterns of Care Study, Owen et al., 1992. The POCS data reported here reflect the level of clinical activity for new patients only. If an average of 20 to 25 treatments per patient is assumed, in 1990 the estimated number of patient-treatments for this group would range between 9.8 million and 12.3 million. Clearly, however, radiation oncology has a considerably greater work load than that. The total number of patients seen per year is the sum of new patients and ''old" patients (previous patients returning for additional treatment). Depending on practice patterns, these prior patients may account for 30 to 50 percent of total patient load. By using the same 20-to-25 treatments per patient assumption, in 1990 the total number of patient-treatments could be estimated to range between 12.7 million and 18.4 million. One influential result of the sequential POCS is the availability of outcomes data based on a properly balanced sample of the total practice in the United States. These data show overall survival, disease-free survival, recurrence rates, and complications. Taken as a whole, the data illustrate remarkably high survival rates and comfortably low complication rates. Rates, of course, strongly relate to variables such as tumor type, disease stage, and patient age. Advances in radiation oncology continue to improve a patient's opportunity for long-term survival. For stage I and II cancers of the tongue and floor of the mouth, recurrence rates at the original cancer site have been reduced from 41 percent (when treated with external beam alone) to 26 percent (when treated with interstitial brachytherapy). For women with carcinoma of the cervix, the four-year survival rate increased from 62 to 73 percent; 15 years after the 1973 study, 51 percent of patients with stage I carcinomas are still alive. Not only survival is at issue; radiation therapy of prostate cancer maintains potency in patients at the same rate as state-of-the-art nerve-sparing prostatectomy.
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Radiation in Medicine: A Need for Regulatory Reform The POCS have also increased knowledge of dose effectiveness. Stage B prostate cancer shows greatest sensitivity to doses between 60 and 70 Gy, with no advantage seen in higher doses. The higher risks associated with doses over 70 Gy, however, may be acceptable to patients with stage C prostate cancer. Collective Dose Few recent estimates of collective dose to the U.S. population from radiation therapy have been performed. Although such a calculation could be done, it would be of questionable validity and usefulness, for several reasons. Organ weighting factors used to define EDEs are derived for healthy populations exposed to comparatively low (less than a few grays) radiation levels; they do not take into account the effects of fractionated high-level exposure or implications of a population of cancer patients. Thus, collective dose from radiation therapy should not be used to estimate rates of radiation-induced cancer among the patient population that already has cancer. The incidence of secondary neoplasms following radiation therapy has been extensively reported in the literature. Various types of radiation-induced cancer have been observed to arise both in the treatment area and at distant sites that were irradiated by scattered and leaking radiation. The issue of secondary tumors can be significant in treatment decisions for patients with curable tumors and otherwise long life expectancies. For instance, elevated incidence of in-field sarcoma has been observed 10 years following radiotherapy for breast cancer. Elevated rates of cancer have also been observed in children receiving cranial irradiation for leukemia and in young adults treated for Hodgkin's disease and seminoma. Of course, some chemotherapeutic agents also increase the risk of later malignancy, so choices among therapeutic options are often difficult. Radiation Regulation and Control Regulation and control of external beam radiation therapy is analogous to that of diagnostic radiology and nuclear medicine. In NRC states, the federal government regulates cobalt teletherapy (because Co-60 is reactor produced), and the state regulates all other external beam therapy. In Agreement States, the state regulates all external beam therapy. Typical state laws specify radiation shielding design levels for facility construction, required interlocks, area radiation monitors, warning labels, and access control. Some states may specify qualifications, training, and licensure of equipment operators and (rarely) radiological physicists, as well as content and frequency of accelerator calibrations. The level of oversight varies considerably from state to state, with some states providing inspection by state radiologic health personnel and others simply registering the existence of the facility.
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Radiation in Medicine: A Need for Regulatory Reform The regulation of cobalt teletherapy is unique: 10 CFR Part 35 sets out detailed requirements for obtaining a license to possess and operate a cobalt teletherapy unit. Because the regulations of Agreement States must comply with NRC regulations, Part 35 essentially regulates all cobalt teletherapy treatments in the United States. The NRC requires that physicians who are authorized users of Co-60 teletherapy machines be board certified or meet several hundred hours of training requirements. A "teletherapy physicist" must be named on the license and meet similar qualifications. Personnel operating the unit must receive annual instruction in radiation protection and emergency procedures. The QM section of Part 35.32 defines the required components of a valid physician prescription. It also requires a system of double checks for dosimetry calculations; documented institutional validation of computerized treatment planning software; and identification, prior to each treatment, of the patient by two independent methods. If it is discovered that a patient's delivered total dose varies by more than 20 percent (greater or less) from the prescribed dose, the NRC Operations Center in Washington, D.C., must be notified within one calendar day of discovery of the "misadministration" and the event is thoroughly investigated. In addition, the patient and the patient's referring physician must be notified within 24 hours. All NRC-required records, such as dosimetry equipment calibrations, annual and monthly teletherapy calibrations, personnel training, documentation of required checks in patient charts, and investigations of misadministrations, must be available for unannounced on-site NRC inspection. The FDA regulates equipment design and construction. Because linear accelerators and radiation therapy treatment planning systems are Class III medical devices, their safety and manufacture is controlled by the FDA. Problems with the operation of such equipment, particularly those resulting in an adverse patient outcome, must be reported subject to the Safe Medical Device Act, as amended in 1991. Internal Sources: Brachytherapy Overview Malignant neoplasms also may be treated by radiation sources placed within the body. Brachytherapy is the placement of sealed sources of radionuclides (called seeds) either in body cavities (intracavitary brachytherapy) or directly into body tissues (interstitial brachytherapy). Chief among the advantages of brachytherapy compared to other methods is that the highest radiation dose is delivered where it is most needed. Historically, brachytherapy developed before teletherapy, well before optimal sources of external beam radiation were available.
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.13 Some Properties of Radionuclides Commonly Used for Brachytherapy Element Isotope Half-Life Source Forms Implant Type Gold Au-198 2.7 days Seeds Permanent Palladium Pd-103 17 days Seeds Permanent Iodine I-125 60 days Seeds Permanent Iridium Ir-192 74 days Seeds, wire Temporary Cesium Cs-137 30 years Tubes, needles Temporary Strontium Sr-90 29 years Plaque Temporary NOTE: Radionuclides are listed in approximate order of prevalence of use. The original method of brachytherapy is now sometimes called "low dose rate" (LDR) brachytherapy. The radioactivity of sources available at the time of brachytherapy's development was such that, to give a tumor-killing dose, sources had to be left in place for days. Because of the low activity, these sources could be handled manually. LDR therapy typically involves tumor dose rates of from 0.3 to 0.6 Gy per hour. In the past 20 years, techniques have been developed to manufacture high-activity sources that provide dose rates of 1 to 2 Gy per minute. With "high dose rate" (HDR) brachytherapy, a treatment can be completed in a matter of minutes. The high activity of these sources precludes their manual handling. To handle these HDR sources, intracavitary brachytherapy employs applicators (metal or plastic devices inserted into a body cavity) into which the sealed radioactive sources are later inserted, or "afterloaded," by a computerized robotic device. This approach avoids having radioactive sources in the operating room while others are present. For interstitial brachytherapy, sources are either inserted directly into tissues or are afterloaded into hollow needles or plastic catheters that pierce the tumor. In some cases, seeds are implanted directly into tissues and left permanently. For radiation safety and radiobiological considerations, permanent implants are feasible only with nuclides having a fairly short half-life. In the early days of brachytherapy, radium-226 (Ra-226) was the only radionuclide available. After World War II, reactor-produced nuclides became available and the use of Ra-226 gradually declined. The radionuclides commonly applied in brachytherapy in the United States today are listed in Table 2.13 in approximate order of prevalence of use. Cesium-137 (Cs-137) is used almost exclusively for LDR intracavitary brachytherapy. Iridium-192 (Ir-192) is used both for LDR interstitial implants and as a single high-strength source for HDR treatments. Iodine-125 (I-125) seeds have been used extensively for permanent interstitial implants at a wide variety of sites, particularly the prostate. Recently, palladium-103 (Pd-103) has been developed for use in permanent implants, because its shorter half-life delivers
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Radiation in Medicine: A Need for Regulatory Reform the total tumor dose over a shorter period of time. Gold-198 (Au-198) seeds also are used for permanent implants requiring rapid delivery of the total dose. Strontium-90 (Sr-90) plaques are used to irradiate very superficial lesions, and use of a strontium applicator is confined almost entirely to the treatment of pterygium, a proliferative disorder of the eye. Types of Procedures Brachytherapy is used alone or in conjunction with external beam radiation therapy to treat a wide variety of malignant neoplasms. Perhaps the most prevalent is the use of LDR and HDR intracavitary brachytherapy for treatment of gynecological malignancies. It is most often used as a local boost following wide-field pelvic teletherapy. The brachytherapy boost is delivered in one or more fractions, each of which requires insertion of applicators into the uterus and vagina. Depending on the overall boost dose and the number of fractions, each implant may deliver from 6 to 20 Gy. LDR treatments last a few days, whereas HDR treatments last a few minutes. Because of the high dose rate, the consequences of a mispositioned or lost source are much more severe for HDR treatments. Selected prostate cancers can be treated by a permanent interstitial implant. This technique involves implantation of 50 or more I-125 or Pd-103 seeds into the prostate. Because the procedure is done by transperineal needle insertion under ultrasonic visualization, open pelvic surgery is not required. A tumor dose of from 100 to 200 Gy (depending on the size of the gland and the activity implanted) is delivered as the radionuclide totally decays. Early clinical results in well-selected cases are similar to external beam radiation therapy and prostatectomy. Iridium-192 seeds, spaced 1 centimeter apart inside nylon ribbons that can be after loaded into nylon catheters, are used to treat many sites. For example, interstitial implantation in the breast may be used to provide a localized boost dose in breast-conserving therapy. A single catheter, inserted into a partially obstructed bronchus, esophagus, or bile duct, may be used to relieve obstruction. Boost treatment of primary head and neck cancers, particularly of the tongue and floor of the mouth, may be accomplished by iridium seed implantation. A typical treatment involves surgical placement of 5 to 10 catheters inserted through the tumor. Each catheter is loaded with a length of ribbon to provide an appropriate number of seeds for the size of the tumor in the plane of the catheter. A boost dose of 10 to 20 Gy is then delivered in one to two days. Radiation Regulation and Control Radiation regulation and control of nuclides used for brachytherapy is similar to that for diagnostic nuclear medicine. Because a majority of nuclides are
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Radiation in Medicine: A Need for Regulatory Reform reactor produced, the regulatory environment is primarily determined by the NRC, with Agreement States following suit. However, accelerator-produced nuclides are regulated by state law. The Department of Transportation sets packaging and labeling requirements for transport of therapeutic radionuclides. The QM requirements of 10 CFR Part 35, as discussed above with regard to cobalt teletherapy, apply also to brachytherapy (and to therapeutic unsealed radionuclides, discussed below). No treatment may be delivered without a written directive from a physician named on the authorized user list of the facility license; the patient's identity must be confirmed by two independent means before administration; each administration must be carried out in accordance with the directive; and any unintended deviation (misadministration) from the written directive should be identified and reported to the NRC and to the patient, and corrective action should be taken. The equipment and procedures for HDR remote after loading brachytherapy have been the subject of much regulatory interest. Several incidents of inadvertent patient overdose have been documented, one contributing to the death of a patient, as described in Chapter 1. The NRC recently has published a 60-page collection of current regulations, standards, and guidelines that apply to remote after loading brachytherapy (NRC, 1994). This document integrates statutory requirements of the NRC and FDA with standards and recommendations from international and national organizations such as the ACR, NCRP, American Association of Physicists in Medicine, American National Standards Institute, International Atomic Energy Agency, and National Institute of Standards and Technology. Internal Unsealed Sources: Therapeutic Nuclear Medicine Overview In contrast to the smaller amount of radioactivity utilized in diagnostic nuclear medicine, larger amounts of radioactivity are intentionally chosen for use in therapeutic nuclear medicine. Therapy in nuclear medicine involves oral, intravenous, or intracavitary delivery of radionuclides in liquid form (sometimes called "unsealed" radionuclides). The radionuclide is chosen with the aim of ensuring that subsequent physiological redistribution will concentrate the radioactivity in the target tissue and, at the same time, reduce the radioactivity in surrounding normal tissues. Radionuclides suitable for use in therapeutic nuclear medicine must either localize in their elemental form (such as iodine uptake in the thyroid gland) or be bound to an appropriate pharmaceutical or antibody. A list of common nuclides used for therapeutic nuclear medicine is shown in Table 2.14.
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Radiation in Medicine: A Need for Regulatory Reform TABLE 2.14 Radionuclides Commonly Used for Therapeutic Nuclear Medicine Element Isotope Half-Life (days) Chemical/Biological Form Gold Au-198 2.7 Colloid Iodine I-131 8.0 Sodium iodine, meta-iodobenzylguanidine, monoclonal antibodies Phosphorus P-32 14.3 Phosphate, colloid Strontium Sr-89 52.7 Strontium chloride Following therapeutic nuclear medicine interventions, some radiopharmaceuticals cause the patient's urine, sweat, saliva, and blood to contain a high level of radioactivity. In many instances, patients must be hospitalized for several days to prevent contamination of the public. Types of Procedures and Number of Treatments Iodine-131 (I-131) is the most commonly used therapeutic radiopharmaceutical, especially for treatment of hyperthyroidism and primary and metastatic thyroid cancer. The NRC has estimated annual use of I-131 for thyroid ablation at 50,000 administrations per year and for thyroid cancer at 10,000 administrations per year. Intravenously administered radioiodine in the form of meta-iodobenzylguanidine is used to treat neuroblastoma metastases. Monoclonal antibodies frequently are labeled with I-131 for use in radioimmunotherapy. Recent clinical trials of this modality have shown greatest promise for treatment of neoplasms of the circulatory system, particularly B-cell lymphoma. Radioimmunotherapy of solid tumors is more problematic, both in terms of getting sufficient dose to the tumor and in accurately calculating tumor dose. Other nuclides are less frequently used to treat a wide range of conditions. Intravenous phosphorus-32 (P-32) is effective in the treatment of myeloproliferative disease, particularly polycythemia vera. Pain from cancer metastases to the bone can be eased with intravenous strontium-89 (Sr-89) chloride. Intracavitary therapy employs P-32 or Au-198 colloid to suppress malignant effusions and dysprosium-165 (Dy-165) macroaggregates for radiation synoviorthesis in rheumatoid arthritis. In all of these applications, patient management is closely coordinated to benefit appropriately from the contributions of surgical, medical, radiation, and nuclear medical specialists.
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Radiation in Medicine: A Need for Regulatory Reform Radiation Regulation and Control The same regulatory apparatus that applies to radiation used in brachytherapy applies to radiation used for therapeutic nuclear medicine. For the latter, regulations address the fact that with unsealed source administration, the patient becomes a source of radiation and radioactive contamination. Regulations allow patient excreta to be exempt from treatment as radioactive waste. Hence, disposal of I-131-contaminated urine down the sanitary sewer system is allowed. Contaminated hospital items, such as eating utensils and sheets, must be decontaminated, usually by decay in storage, or disposed of as low-level radioactive waste. The patient may not be released until either the activity remaining in the patient falls below defined limits or the exposure rate 1 meter from the patient dips below 0.05 mSv/hr. Personnel working with large quantities of I-131 sodium chloride are closely monitored for exposure and thyroid uptake. CHAPTER SUMMARY Diagnostic and therapeutic clinical applications of ionizing radiation range from the simplicity of taking a chest x-ray to the complexity of treating a brain tumor. Each of these procedures benefits patients. Differing clinical applications involve varying risks to patients, but the level of risk has much to do with the process and little to do with the source of radiation. Whether a teletherapy machine contains a radionuclide produced by an NRC-regulated reactor, or by a hospital-owned accelerator, is of small import when calculating risk. Yet, as hinted at in this chapter's radiation regulation and control sections, regulation in the field is split along this less important distinction between sources. Not only is this fractured regulatory system illogical, it is also costly. This is explored in more depth in the next chapter, "Regulation and Radiation Medicine." REFERENCES ACR (American College of Radiology). Proceedings of the ACR/FDA Workshop in Fluoroscopy. Reston, VA: American College of Radiology, 1992. Adelstein and Manning. Isotopes for Medicine and the Life Sciences . Washington, DC: National Academy Press, 1995 Cagnon, C.H., Benedict, S.H., Mankovich, N.J., Bushberg, J.T., Siebert, J.A., and Whiting, J.S. Exposure Rates in High-Level-Control Fluoroscopy for Image Enhancement. Radiology 178:643-646, 1991. Conway B.J., McCrohan, J.L., Antonsen, R.G., Rueter, F.G., Slayton, R.J., and Suleiman, O.H. Average Radiation Dose in Standard CT Examinations of the Head: Results of the 1990 NEXT Survey. Radiology 184:135-140, 1992. Conway, B.J., Suleiman, O.H., Rueter, F.G., Antonsen, R.G., and Slayton, R.J. National Survey of Mammographic Facilities in 1985, 1988, and 1992. Radiology 191:323-330, 1994.
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Radiation in Medicine: A Need for Regulatory Reform Edwards, M. Clinical Applications of Ionizing Radiation. Paper commissioned by the Institute of Medicine Committee for Review and Evaluation of the Nuclear Regulatory Commission Medical Use Program. June 15, 1995 . Feig, S.A. Estimation of Currently Attainable Benefit from Mammographic Screening of Women Aged 40-49 Years. Cancer 75(10):2412-2419, 1995. Johnson, J.L., and Abernathy, D.L. Diagnostic Imaging Procedure Volume in the United States. Radiology 146:851-853, 1983. Mettler, F.A., Briggs, J.E., Carchman, R., Altobelli, K.K., Hart, B.L., and Kelsey, C.A. Use of Radiology in U.S. General Short-Term Hospitals: 1980-1990. Radiology 189:377-380, 1993. Mettler, F.A., Christie, J.H., Williams, A.G., Moseley, R.D., and Kelsey, C.A. Population Characteristics and Absorbed Dose to the Population From Nuclear Medicine: United States-1982. Health Physics 50:619-628, 1986. NCRP (National Council on Radiation Protection and Measurements). Report 100: Exposure of the U.S. Population from Diagnostic Radiation . Bethesda, MD: National Council on Radiation Protection and Measurements, 1989. NRC (U.S. Nuclear Regulatory Commission). Quality Management in Remote After loading Brachytherapy. NUREG/CR-6276. Washington, DC: Nuclear Regulatory Commission, 1994. Rueter, F.G., Conway, B.J., McCrohan, J.L., Slayton, R.J., and Suleiman, O.H. Radiography of the Lumbosacral Spine: Characteristics of Examinations Performed in Hospitals and Other Facilities. Radiology 185:43-46, 1992. Steele, G.D., Osteen, R.T., Winchester, D.P., Murphy, G.P., and Menck, H.R. Clinical Highlights from the National Cancer Data Base: 1994. CA 44:71-80, 1994. Suleiman, O.H., Anderson, J., Jones B, Rao, G.U.V. and Rosenstein. Tissue Doses in the Upper Gastrointestinal Fluoroscopy Examination Radiology 178:653-658, 1991. Sunshine, J.H., Mabry, M.R., and Bansal, S. The Volume and Cost of Radiological Services in the United States in 1990. American Journal of Roentgenology 157:609-613, 1991. Tabar, L., Fagerberg, G., Chen, H-H., Duffy, S.W., Smart, C.R., Gad, A., and Smith, R.A. Efficacy of Breast Cancer Screening by Age: New Results from the Swedish Two-County Trial. Cancer 75(10):2507-2517, 1995. Wingo, P.A., Tong, T., and Bolden, S. Cancer Statistics, 1995. CA 45:8-30, 1995
Representative terms from entire chapter: