Basic Principles

Radiation exposure may be natural (50%) or environmental (man-made) (50%). Radon gas accounts for the majority (37%) of natural radiation. The contribution of man-made radiation has dramatically increased to 50% from 15% in the mid-1980s. CT now is responsible for 24% of all radiation exposure and almost half of man-made radiation (see Fig. 699-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com ). Though it has been estimated that as high as 2% of all cancers in the USA may be attributable to radiation from CT studies, 75% of radiologists and emergency department physicians underestimate the radiation dose from CT. Some imaging procedures do not produce radiation (see Table 699-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com), and not all radiation-producing modalities expose a child to the same amount of radiation (see Table 699-2 on the Nelson Textbook of Pediatrics website at www.expertconsult.com ).

Figure 699-1 All exposure categories collective effective dose (percentage) 2006.

(From the National Council on Radiation Protection and Measurements: Medical radiation exposure of the U.S. population greatly increased since the early 1980s. www.ncrponline.org/Press_Rel/Rept_160_Press_Release.pdf. Accessed December 2, 2010.)

Table 699-1 IMAGING MODALITIES

Table 699-2 RADIATION DOSE BY IMAGING TEST*

^* Background radiation = 1 mrad/day or 300 mrad/year,

^† Scan explained as CT dose index (CTDI). First dose is with adult factors; second, shown in parentheses, is examination adjusted for children.

^‡ Expressed as effective dose. These are rough guidelines for dose given to a 5 yr old with normal renal function.

From Valentin J: Radiation dose to patients from radiopharmaceuticals. (Addendum 2 to ICRP Publication 53.) ICRP Publication 80. Approved by the Commission in September 1997. Ann ICRP 28:1, 1998.

Nuclear medicine and positron emission tomography examinations are described by the amount of radioactivity injected (millicuries or becquerels) or are converted to effective dose (millisieverts; see later). The units of absorbed dose, as defined by the International Commission of Radiation Units, are the rad, introduced in the 1960s, and the gray (Gy), introduced in 1985. The metric used in denoting biologic response is the rem (old unit) and the sievert (Sv) (Table 699-3). Equivalent dose and effective dose are measured in Sv and mSv. Not all radiation has the same effect on biologic tissue for a given dose. Beta rays are quite superficial; alpha particles and protons cause significantly more damage than gamma radiation (x-rays) for a given absorbed dose. Diagnostic imaging uses x-rays. Each dose has a modifier, for example, skin dose, whole body dose, organ dose, or effective dose. Effective dose considers specific tissues and their radiosensitivity.

Biologic Effects of Radiation

Biologic effects of radiation are divided into two types. Deterministic effects (determined by the dose) are characterized by a threshold dose: For example, cataracts occur with an acute exposure to > 200 rad or with long-term exposure to > 500 rad (Table 699-4). Deterministic effects never occur from the doses generally used in diagnostic radiation (<0.1 Gy, 1 rad), but newer invasive procedures (therapeutic interventional) have on rare occasions led to these effects. Stochastic (random) effects are of greater concern because they can occur at any dose; that is, there is no threshold, with the probability of an effect increasing with rising dose. These effects can be caused by any radiation striking vulnerable tissue (most importantly DNA, but cytoplasm also may be at risk) and causing irreversible damage. These effects lead to the linear nondose threshold (LNT) concept, which states that radiation damage increases with rising dose in a linear fashion. This concept stresses that no level of radiation exposure can be considered to be absolutely safe.

Table 699-4 DETERMINISTIC DOSE RATES

Modified from Hall EJ: Radiobiology for the radiologist, ed 5, Philadelphia, 2000, Lippincott Williams & Wilkins.

Radiation can cause carcinogenesis, genetic mutations, and cell death. The biologic effects of radiation result primarily from damage to DNA directly through interaction of fast recoil electrons caused by the absorption of x-rays (one third of the damage) or secondarily by the formation of free radicals. Because approximately 80% of the cell is water, most of the energy deposited in a cell results in production of aqueous free radicals. The reactions are rapid (10⁻¹⁸ to 10⁻³ seconds). A dose of 1 rad results in approximately 10³ ionizations per cell type. The biochemical and physiologic changes that follow take hours or days, whereas the induction of cancer takes many years.

The manifestations of DNA injury are variable. The cell containing the damaged DNA might die; cell death (apoptosis) is a mechanism for eliminating heavily damaged and potentially mutable cells. Damage to a base pair is the most prevalent and least significant effect. Breaks of a single strand of DNA usually have little biologic significance because each strand is repaired with use of the opposite strand as a template, but a mutation can result if misrepair occurs.

Breakage of both strands of DNA (the least common event) is more problematic. The end result seems to depend on the proximity of the break in each strand. If widely separated, repairs occur as with a single-strand break. If the breaks in the two strands are opposite each other (or separated by only a few base pairs), however, repair is more difficult without a template. This type of break is the mechanism of radiation-induced cell death, chromosomal damage, mutations, and carcinogenesis.

When DNA damage occurs, aberrations are produced in chromosomes, resulting in an unstable aberration (usually lethal to dividing cells) or stable aberration. Stable aberrations can result in failure of chromosomes to reunite (leading to deletions) or in abnormal rearrangement of chromosomes, such as reciprocal translocation or aneuploidy. Although it is logical to think that these abnormalities in chromosomes lead to mutations that can activate oncogenes or protooncogenes or cause mutations in tumor-suppressor genes (Chapter 486), few radiation-induced cancers show specific translocations such as would be associated with activation of specific oncogenes or known tumor-suppressor genes. An exception is the radiation induction of papillary thyroid carcinoma in children, which probably results from activation of the RET oncogene (Chapter 500).

Radiation carcinogenesis seems to be a progressive multistep process composed of three independent stages: morphologic changes, cellular immortality, and tumorigenicity. Radiation exposure induces cellular genomic instability. This instability is transmitted to a cell’s progeny, resulting in a continued elevation in the rate at which genetic changes arise in the subsequent generations of the irradiated cell (Fig. 699-2).

Figure 699-2 Schematic of radiation-induced mutagenesis. Open circles represent normal wild-type cells, whereas closed circles represent mutated cells. A, Most of the cells in an irradiated population retain the wild-type phenotype. B, Example of a cell directly mutated by radiation exposure; the mutation is transmitted to all of its progeny. C and D are examples of mutations arising as a result of radiation-induced genomic instability. The irradiated cell and its immediate progeny are wild type, but the frequency with which mutations arise among the more distant descendants of the irradiated cell is elevated.

(From Little JB: Ionizing radiation. In Kufe DW, Pollock RE, Weichselbaum RR, et al, editors: Holland-Frei cancer medicine, ed 6, Ontario, Canada, 2003, BC Decker.)

A longitudinal study of the lifetime risks of excess cancer mortality secondary to irradiation has been evaluated in atomic bomb survivors. More than 86,000 survivors have been followed for more than 50 yr since exposure. Individual radiation doses were estimated by considering the person’s location in relation to distance from the epicenter and individual shielding situations. Most of the exposure was direct gamma irradiation, with some neutron exposure. Age at exposure influences sensitivity to radiation-induced cancers (Fig. 699-3). Compared with the middle-aged adult, children are 10 times more sensitive to radiation-induced carcinogenesis, and the youngest neonate is more sensitive than the older child. Because of the higher risks associated with breast and thyroid cancer, girls are more sensitive than boys. It must be understood that cancer rates in this study are mortality figures. The incidence of cancer in this population is estimated to be two times greater than mortality.

Figure 699-3 Lifetime risk of excess cancer per Sievert (Sv) as a function of age at the time of exposure. Data from the atomic bomb survivors. The average risk for a population is about 5% per Sievert, but the risk varies considerably with age: children are much more sensitive than adults. At early ages, girls are more sensitive than boys.

(From Hall EJ: Introduction to session I: Helical CT and cancer risk, Pediatr Radiol 32:225–227, 2002.)

The doses used in diagnostic radiology for multislice CT scans overlap with low-dose induced cancer in atomic bomb survivors (Fig. 699-4). It has been estimated that the lifetime risk of cancer following head and abdominal CT scans in children is 1 : 1000. Therefore, since stochastic effects are random but increase with rising dose, it is mandatory that we use the lowest dose necessary to get diagnostic images. The advent of digital picture archiving communication systems (PACSs) utilizes post-processing algorithms and can make all the pictures good. This obviates the imager’s ability to know whether enough or too much radiation was given. It does not allow the imager to determine whether the patient received “as low as reasonably achievable” (ALARA) radiation dosing. It is for this reason that some radiation metric should appear on each image.

Figure 699-4 Relevant dose range for pediatric CT: 6-100 mSv (0.006-0.1 Sv). There is direct, statistically significant evidence for risk in the dose range from 0-0.1Sv.

(From Brenner DJ: Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative, Pediatr Radiol 32:228–231, 2002.)

Increased biologic vulnerability to radiation is seen in the fetus exposed in utero through maternal radiation. The Oxford Childhood Cancer Study, comparing the frequency of radiation exposure in utero among children dying from childhood malignancy with that among those dying of other causes, found that in utero radiation exposure was associated with a 92% excess risk of dying from leukemia before age 10 yr and a 180% excess risk of dying from other malignant diseases. A follow-up conducted 40 yr later still found a 228% increased relative risk of cancer associated with radiation in utero.

The fetus and infant are most vulnerable to radiation-induced cancer because (1) they are growing rapidly, with many cells undergoing mitotic activity, (2) radiation-induced tumors (except leukemia) take a long time to develop and children have a longer lifetime, and (3) the cumulative effect of radiation is lifelong.

Most childhood tumors occur sporadically, but 10-15% of cases have a strong familial association. Familial tumors have specific chromosomal deletions in common. In some of these tumors (retinoblastoma), the two-hit hypothesis by Knudson is apparent (Chapter 485). It is not coincidental that individuals with many of the congenital diseases are at risk for the development of tumors after irradiation. Diseases that are associated with sensitivity to radiation are listed in Table 699-5.

Decreasing Unnecessary Diagnostic Radiation in Children While Still Obtaining Diagnostic Images—Our Responsibility

Selecting the correct examination is the responsibility of the ordering physician and may involve consultation with the pediatric radiologist. Organizations such as the American College of Radiology have evidence-based imaging guidelines. As an example, evidence-based medicine has shown little yield from an imaging work-up (including CT) of a child with a single nonfebrile seizure without other neurologic abnormalities. This is especially true if there is no antecedent history of abnormal behavior or of personality or developmental change. CT does not detect as many abnormalities as MRI, but CT involves radiation. MRI detects the subtle changes of congenital or acquired anomalies much more easily. Therefore, it is appropriate, except in an emergency situation, to obtain MRI within a reasonable time frame instead of performing two tests (CT followed by an MRI).

It has been estimated that 30% of CT examinations are redundant, can be replaced by another, non–radiation-producing modality, or, in fact, are performed without evidence-based indications. To correct this situation, a dialogue between the ordering physician and pediatric radiologist is crucial. Working together, they can obtain indicated examinations with the most appropriate modality, lowest dose, and diagnostic images.

Radiation Therapy—Acute and Late Effects

Radiation therapy uses high doses to kill malignant cells. The sensitivity of normal cells is quite close to that of malignant cells, and to achieve significant cure rates, radiation oncologists must accept a given percentage of serious complications (5-10%). Radiation causes tissue loss plus injury to the underlying vasculature. The vascular change may be progressive, leading to arteriocapillary fibrosis and irreparable injury, in turn leading to further tissue loss.

The acute effects of therapy (occurring less than 3 mo after therapy begins) are usually related to the area of the body being irradiated (except fatigue, which can begin during this time period). These acute effects include radiation-caused pneumonitis, dermatitis, mucositis and esophagitis, cerebral edema, and swelling of the organ irradiated. There may be changes in bowel movement patterns. Of these, one of the most severe acute reactions is pneumonitis. It can be manifest within 24 hours of irradiation when there is an exudation of proteinaceous material into the alveoli and intraalveolar edema. Most often, however, radiation pneumonitis begins 2-6 mo after the beginning of radiation with a clinical presentation of fever, cough, congestion, and pruritic pain.

The late effects of therapy (beginning > 3 months after therapy) are numerous (Table 699-6).

Table 699-6 LATE EFFECTS OF RADIATION THERAPY IN CHILDREN TREATED FOR CANCER

* With intrathecal chemotherapy (methotrexate).

Derived from Halperin EC, Constine LS, Tarbell NJ, et al, editors: Pediatric radiation oncology, ed 3, Philadelphia, 1999, Lippincott Williams & Wilkins.

Annually, childhood cancer affects 70-160 per million children between the ages of 0 and 14 yr. Because of earlier diagnosis and improved therapy, more than 79% of children who were diagnosed from 1995-2001 with cancer are long-term survivors. Approximately 1 : 570 young adults is a long-term survivor of cancer, and up to 25% have a complication related to their therapy.

Second cancers account for 6-10% of all cancers in children or adults. Among children in the Childhood Cancer Survivor Study, there is a cumulative incidence of second neoplasms of 3.2% at 20 years from original diagnosis. Primary malignancies with the highest cumulative incidence of a second neoplasm in the order of frequency are: Hodgkin’s disease (7.6), soft-tissue sarcoma (4.0), bone (3.3), leukemia (2.1), central nervous system (CNS) (2.1), and non-Hodgkin (1.9). This reflects an overall standard incidence rate (SIR) of 6.38% (Fig. 699-5). The most prevalent second tumors are bone, breast, thyroid, and CNS (Fig. 699-6).

Figure 699-5 Second malignancies among the Childhood Cancer Survivor Study cohort. CNS, central nervous system; NBL, neuroblastoma; ST, soft-tissue.

(Robison LL: Treatment-associated subsequent neoplasms among long-term survivors of childhood cancer: the experience of the Childhood Cancer Survivor Study, Pediatr Radiol 39[Suppl 1]:S32–S37, 2009.)

Figure 699-6 Standardized incidence ratio by type of second malignancy. CNS, central nervous system.

(Robison LL: Treatment-associated subsequent neoplasms among long-term survivors of childhood cancer: the experience of the Childhood Cancer Survivor Study, Pediatr Radiol 39[Suppl 1]:S32–S37, 2009.)

Table 699-7 relates second cancers to primary cancer and latency period. Almost 70% of the second neoplasms are in the field of the original irradiation. Radiation therapy increases the risk of second cancers in a dose-dependent manner for nongenetic neoplasms.

The exact complications depend on the location of the treatment field. In children, because of the location of many childhood tumors, the normal brain is commonly in the treatment field. Standard irradiation of the brain in children results in cortical atrophy in more than half of patients who receive 2000-6000 rads; 26% have white matter changes (leukoencephalopathy), and 8% have calcifications. The younger the child is at the time of irradiation, the greater is the atrophy. Some patients also demonstrate mineralizing microangiopathy. Radiation-induced changes of the brain are potentiated by methotrexate administered before, during, or after radiation therapy.

Cerebral necrosis is a serious complication of radiation-induced vascular disease. It usually is diagnosed 1-5 yr after irradiation but can occur up to a decade later. Brain necrosis may manifest as headache, increased intracranial pressure, seizures, sensory deficits, and psychotic changes.

Spinal cord irradiation may result in radiation myelitis, which may be either transient or permanent. Acute transient myelitis often appears 2-4 mo after irradiation. Patients with myelitis usually present with Lhermitte’s sign, a sensation of little electrical shocks in the arms and legs occurring with neck flexion or other movements that stretch the spinal cord. Reversal of transient myelopathy usually occurs between 8 and 40 wk and does not necessarily progress to delayed necrosis.

Delayed myelopathy occurs after a mean latent period of 20 mo but can occur earlier if the total dose or the dose per fraction is high. It usually manifests as discontinuous deterioration and is irreversible. In the cervical and thoracic regions, sensory dissociation develops, followed by spastic and then flaccid paresis. In the lumbar cord, flaccid paresis is dominant. The mortality for high thoracic and cervical lesions reaches 70%, death being due to pneumonia and urinary tract infections.

Central nervous system irradiation may also affect growth by compromising function of the pituitary–hypothalamic axis and leading to diminishing growth hormone production and release. Non–growth hormone trophins may also be affected by CNS irradiation, leading to gonadotrophin deficiency or precocious puberty. Central hypothyroidism can also develop. CNS irradiation also compromises bone mineral deposition both locally (in the radiation field) and systemically.

Irradiation also has other effects specific to children (see Table 699-6). Scoliosis and hypoplasia of bones may occur if fractionated treatment schemes exceed 4,000 rad. Fractionated doses higher than 2,500 rad can result in slipped capital femoral epiphyses. An increase in the incidence of benign osteochondromas also has been reported after childhood irradiation. Chest wall irradiation of girls (besides causing breast cancer) may impair breast development and/or cause fibrosis and atrophy of breast tissue.

Whole-Body Irradiation

Internal Contamination

External Contamination

The presence of external radioactive contamination on a patient’s skin is not an immediate medical emergency. Management involves removing and controlling the spread of radioactive materials. If a patient has suspected surface contamination and no physical injuries, decontamination can be performed relatively easily. If substantial physical trauma or other life-threatening injuries are combined with external contamination, surface decontamination should proceed only after the patient has been stabilized physiologically. In many accident situations, essential medical care is delayed inappropriately by hospital emergency staff because of fear of radiation or spread of contamination in the hospital. After a radiation accident, triaging of patients is critical and is based on exposure and symptoms (Fig. 699-7).

Figure 699-7 Management of radiation sickness at different levels of medical care, depending on the appearance of early symptoms and the estimated radiation dose to the whole body.

(From Turai I, Veress K, Günalp B, et al: Medical response to radiation incidents and radionuclear threats, BMJ 328:568–572, 2004.)