Clinically relevant normal tissue responses to radiation Flashcards
Which of the following statements concerning the effects of radiation on the heart is TRUE?
A. Radiation associated valvular disease is rare in patients receiving ≥ 35 Gy to the heart.
B. Pericardial effusion is the most common Grade 3+ toxicity after definitive lung radiotherapy
C. An increased incidence of cardiovascular disease among Hodgkin’s disease survivors who received mediastinal radiotherapy has not been observed
D. The critical structure associated with the pathogenesis of radiation-induced heart disease appears to be the endothelial lining of blood vessels
E. An excess relative risk for myocardial infarction has been detected in the Japanese atomic bomb survivors, but only among those who received doses greater than 10 Gy
D
The critical target structure associated with the development of radiation-induced heart disease appears to be the endothelial lining of blood vessels, particularly arteries. Irradiation of endothelial cells is thought to induce early stimulation of a pro-inflammatory signaling cascade that enhances arteriosclerosis and microvascular dysfunction. Historically, radiation pericarditis represented a significant complication of large-volume radiation therapy to the breast or mediastinum to doses greater than 40 Gy. With current treatment methods, however, a much smaller heart volume is irradiated, so radiation pericarditis is now infrequently observed.
Radiotherapy-induced valvular disease may occur in greater than 80% of patients receiving ≥ 3 Gy to the heart (Answer Choice A).
Pericardial effusion is the most common cardiac Grade 1-2 toxicity after definitive lung radiotherapy, but the most common Grade 3+ cardiac toxicities are acute coronary syndrome, new congestive heart failure, and arrhythmia. (Answer Choice B).
Following mediastinal radiotherapy for treatment of Hodgkin’s Lymphoma, a statistically significant increase in the risk of fatal cardiovascular disease, primarily attributable to myocardial infarction, has been reported among patients surviving 10 years or more (Answer Choice C). Similarly, an increased risk of myocardial infarctions has also been reported after post-operative radiotherapy for breast cancer.
One of the most important recent findings among the survivors of the Japanese atomic bombings is that mortality from myocardial infarction is significantly increased more than 40 years after receiving acute doses as low as 1-2 Gy (Answer Choice E).
All of the following complications have been observed after high-dose irradiation of a short segment of bone, EXCEPT:
A. Osteoradionecrosis
B. Stress fractures
C. Growth retardation after irradiation of epiphyseal plates in children
D. Radiation-induced bone sarcomas
E. Bone marrow failure
E
Bone marrow failure is not a concern after localized irradiation because of the limited volume of bone marrow irradiated and compensation from the unirradiated marrow volume. Osteoradionecrosis and stress fractures, on the other hand, can be major problems (Answer Choices A-B). In children, growth retardation is a concern after irradiation of growth plates (Answer Choice C). Bone sarcoma is the most common secondary neoplasm following irradiation of bony structures (Answer Choice D).
Acute radiation esophagitis presents as dysphagia or a substernal burning sensation as early as 2 weeks after the start of conventionally fractionated radiation therapy. Medical management most often involves:
A. Angiotensin converting enzyme inhibitors
B. Gene therapy with manganese superoxide dismutase
C. Non-steroidal anti-inflammatory drugs
D. Pentoxifylline
E. Vitamin E
C
NSAIDs can help prevent esophagitis by decreasing inflammation. Although ACE-inhibitors have proven effective in the treatment of radiation nephropathy and pneumopathy, there are no data supporting their use in the treatment of radiation-induced esophagitis (Answer Choice A). Intra-esophageal administration of MnSOD-plasmid liposomes has been shown to protect the mouse esophagus from both single dose and fractionated irradiation. These studies have been recently been translated to a phase I clinical trial, but a benefit of this approach has not been proven in humans (Answer Choice B). Both pentoxifylline and vitamin E have been shown, in combination, to prevent as well as induce significant regression of radiation-induced fibrosis in breast cancer patients treated with radiotherapy.
One type of radiation-induced bone injury is mandibular osteoradionecrosis (MORN). Which of the following is NOT a risk factor for MORN?
A. Presence of teeth
B. Pre-existing dental disease
C. Use of fluorinated water
D. Tooth extraction after radiotherapy
E. Use of large doses per fraction during treatment
C
Use of fluorinated water as a part of normal dental hygiene would, if anything, help prevent dental caries and reduce the risk of MORN. MORN is most commonly precipitated by post-radiotherapy tooth extraction secondary to poor dentition. Early studies from the 1960s and 1970s at MD Anderson Cancer Center showed that patients with teeth were at a significantly greater risk of MORN than patients without teeth. However, current treatment practices do not require the removal of all teeth prior to radiotherapy, but rather, recommend careful dental care. Radiation tolerance of the mandible is also affected by pre-irradiation dental disease, fraction size and gender (males more susceptible).
Which of the following types of blood cells is most radioresistant?
A. Granulocyte/monocyte colony forming cells (GM-CFC)
B. Spleen-colony forming units (CFU-S)
C. Macrophages
D. Unprimed T-helper cells
E. B-cells
C
Macrophages are among the most radioresistant cells in the body and are capable of surviving large doses of radiation. GM-CFC and CFU-S, which are progenitor cells, are radiosensitive, as are unprimed T-cells and B-cells.
What portion of the gastrointestinal tract generally exhibits the greatest acute radiation-induced injury for a given dose?
A. Stomach
B. Oropharynx
C. Small intestine
D. Large intestine
E. Esophagus
C
In both animal studies and real-world accidental exposures (e.g., the Chernobyl disaster) to whole-body radiation, the small intestine has typically shown the most sensitivity among components of the gastrointestinal tract. At a histologic level, the small intestine experiences significant denudation due to loss of radiosensitive crypt cells; this ultimately
Which of the following statements concerning radiation-induced damage to the eye is TRUE?
A. The threshold radiation dose for cataract formation is approximately 10 Gy
B. It is often possible to distinguish between a radiation-induced cataract and an age-induced cataract
C. The neutron RBE for cataract formation is about 5 for low total doses
D. The tolerance dose for the development of blindness is lower than the tolerance dose for cataract formation
E. The length of the latency period for cataract formation is independent of radiation dose
B
It is often possible to distinguish a radiation-induced cataract from an age-related cataract as a radiation-induced cataract usually begins at the posterior portion of the lens and an age-related cataract more commonly appears in the anterior portion of the lens.
The threshold dose for cataract formation is now known to be well below 10 Gy (Answer Choice A). Several recent studies, which included early lens opacities as well as cataracts that interfere with vision, have longer follow-up times than that presented in previous research as well as greater statistical power. This work suggests a low threshold (<1 Gy) for cataract development and is statistically consistent with no threshold for cataract induction.
The low-dose neutron RBE for cataract formation is greater than 20 (Answer Choice C).
The tolerance dose for the production of blindness is greater than that for cataract formation (Answer Choice D).
The latency period for the induction of a radiation-induced cataract decreases with increasing dose (Answer Choice E).
Which of the following statements is TRUE concerning radiation effects on the bone marrow?
A. The absolute lymphocyte count rate of decrease over 2 days may estimate the severity of total body irradiation induced injury.
B. Following total body irradiation, thrombocytopenia is typically observed before neutropenia
C. Lymphocyte counts do not decrease until several weeks after total body irradiation
D. Individuals suffering from bone marrow syndrome usually die of severe anemia
E. There is no late effect pathology associated with bone marrow irradiation
A
Following total body irradiation, neutropenia is observed prior to thrombocytopenia. For even modest doses, a decrease in lymphocyte count can be detected within 1-2 days following total body irradiation. Serial blood counts over this period can be useful in assessing dose and guiding treatment after accidental exposure. The Andrews lymphocyte nomogram can be used to estimate the severity of injury following total body irradiation. Individuals suffering from bone marrow syndrome usually die of infection and/or hemorrhage. Survivors of total bone marrow irradiation demonstrate a late loss of bone marrow architecture characterized by tissue replacement with lipid cells.
Which of the following statements is TRUE concerning the effects of radiation on the gonads?
A. Older women are more sensitive to radiation-induced sterility than younger women
B. An acute dose of 3 Gy can both destroy the gametogenic epithelium and eliminate the production of sex hormones in adult men
C. Spermatids and spermatozoa are quite radiosensitive whereas spermatogonia are relatively radioresistant
D. A minimum waiting period of 5 years is recommended for both men and women before attempting procreation following radiotherapy, in order to reduce the risk of radiation-induced genetic effects
E. If sterility in the male is not produced within the first month after the start of radiotherapy, it is unlikely to ever occur
A
Older women are more sensitive to the induction of radiation-induced sterility than younger women, presumably due to the diminished number of oocytes compared with that seen in younger women. A dose of 3 Gy can destroy the gametogenic epithelium but would not eliminate the production of sex hormones in adult men. Spermatids and spermatozoa are more radioresistant than spermatogonia. Based on animal data, a minimum waiting period of 3-6 months is recommended for both men and women before attempting procreation following radiotherapy in order to reduce the risk of radiation-induced genetic effects. A modest radiation dose is unlikely to kill many of the more mature members of the spermatogenic series, although it could be lethal to most of the spermatogonial stem cells. Thus, even if there is no significant drop in sperm count within the first 30 days after the start of irradiation, this does not preclude the possibility that sterility could occur about a month or two later. This is a reflection of the turnover time (approximately 70 days) required for a spermatogonia stem cell to develop into a mature spermatozoa.
With respect to radiation-induced toxicity in the lung, which of the following statements is FALSE?
A. The likelihood of the injury is dependent on the volume irradiated
B. Radiation pneumonitis is a characteristic late effect of lung radiotherapy that occurs 6-12 months after treatment completion.
C. The dose response curve for lung injury following whole lung irradiation is steep regardless of the dose per fraction used
D. Lung toxicity is enhanced when radiation is combined with carboplatin-paclitaxel.
E. Several cell types are involved in the development of pulmonary late effects, including the type II pneumocyte, fibroblasts, the alveolar macrophage and vascular endothelial cells.
B
Radiation pneumonitis is a characteristic late effect of lung radiotherapy that occurs approximately 2-3 months after treatment completion.
In patients receiving concurrent chemoradiation therapy for non-small cell lung cancer, the risk of fatal pneumonitis for V20 = 20-29.9% is 1%, V20 = 30-39.9% is 2.9%, and V20 ≥ 40% is 3.5%. The volume of lung irradiated has been shown to be a particularly critical factor with respect to the degree of pulmonary toxicity observed (Answer Choice A). Many radiation oncologists are using the V20 or V30, the dose received by 20-30% of the lung, as a defining limiting factor.
Regarding lung tolerance dose, as expected, large single doses to the entire lung induce steep dose responses, with incidences of radiation pneumonitis being reported at ~5% following 8.2 Gy, but rising to 50% following 9.3 Gy (Answer Choice C). With increasing fractionation, higher total doses can be tolerated, yet the dose response curves remain steep, with a reported 5% incidence following a dose of 26.5 Gy, rising to a 50% probability when the total dose is increased to 30 Gy, the latter frequently being observed in the pediatric population.
Tolerance doses are affected significantly by a broad range of chemotherapeutic agents, which have been shown to act synergistically or independently to enhance toxicity (Answer Choice D).
Laboratory animal models have identified multiple cell types that appear to play critical roles in the development of radiation-induced late effects in the lung (Answer Choice E).
The oral mucosa and skin present with many similar pathological features during their progression toward radiation toxicity. Which of the following statements regarding the overlapping pathologies observed in these tissues is FALSE?
A. Oral mucositis is a result of the death and consequent desquamation of the epithelial layers, and is therefore an analogous event to the radiodermatitis (dry/moist desquamation) seen as an early response in irradiated skin
B. Erythema secondary to vasodilation is observed in skin following doses greater than about 2 Gy, similar to the case for mucositis
C. Radiation effects in both oral mucosa and skin are dependent on total dose, fraction size, and volume irradiated
D. Possible late effects in both skin and oral mucosa include ulceration and fibrosis
E. The development of dental caries following oral radiotherapy is similar mechanistically to the infections that accompany radiation-induced dermal ulcers; both result from ischemic necrosis due to the loss of small blood vessels
E
The oral mucosal response to irradiation is indeed similar to that seen in skin. However, the formation of dental caries is a direct consequence of the killing of saliva-secreting acini cells in the salivary glands, ultimately leading to xerostomia. This results in the loss of saliva’s normal antibacterial action and acidification of the mouth. This is in contrast to the infections observed in irradiated skin which are a downstream consequence of damage to small blood vessels.
With respect to radiation-induced heart disease (RIHD), which one of the following statements is FALSE?
A. Individuals 20-65 years of age have a lower risk for the development of radiation-induced coronary artery disease compared with other age groups
B. The parietal pericardium may be damaged by radiation therapy, with the injury typically presenting as an increased thickness of the fibrous layer
C. The risk of pericarditis increases with increasing dose per fraction
D. The majority of cardiac complications observed are consistent with the hypothesis that the most radiosensitive cells are the cardiomyocytes
E. Cardiac effects are described as “delayed”, and typically appear months to years after radiotherapy
D
Vascular endothelial cells are the most radiosensitive cells in the heart, with direct radiation damage to this population leading to protein leakage, fibrin deposition and the up-regulation of such cytokines as transforming growth factor beta 1 (TGF-1). Many other cell types within the heart contribute to the development of radiation-induced heart disease (RIHD), but of them all, the cardiac myocyte, a fixed post-mitotic cell, is the most radioresistant. A number of large clinical trials, particularly those performed in Hodgkin’s disease patients, have indicated that the populations most at risk for RIHD are young females and the elderly, and that the important factors governing tissue tolerance are total dose, fraction size, and volume irradiated. Typically, late effects in the heart occur months to years after treatment completion. One structure that may be affected by radiation therapy is the parietal pericardium, with an associated fibrous thickening due to collagen replacing the external adipose layer.
With respect to the morphologic changes associated with radiation-induced liver disease (RILD), notably veno-occlusive disease (VOD), all of the following may be observed, EXCEPT:
A. Heavy congestion in the sinusoids
B. Atrophy of the liver plates
C. Fiber-filled lumen of the sublobular veins
D. Apoptotic Kupffer cells filled with hematoxylin
E. Subacute morphological changes
D
The Kupffer cells, hepatic-specific phagocytes, often increase in size during the progression of veno-occlusive disease (VOD) and can contain large amounts of hemosiderin, a pigment that is a breakdown product of hemoglobin derived from phagocytized erythrocytes that have leaked from damaged vasculature. Hematoxylin is a nuclear stain widely used in histology that would not be expected to be found in the liver. Although the VOD lesion presents at about 90 days post-irradiation and is technically a late effect, nonetheless it is typically defined clinically and morphologically as a “subacute” effect. The morphologic hallmark of VOD is the presence of lesions with severely congested sinusoids in the central zones of the lobules, and an accompanying atrophy of the central portion of the liver plates. The lumens of the central and sublobular veins are filled with a dense network of reticulin fibers that frequently contain trapped red cells.
Which of the following statements regarding radiation-related inflammatory effects is FALSE?
A. Following radiation injury, the extent of neutrophil infiltration into the irradiated volume is positively correlated with the severity of the late complication
B. A distinct inflammatory phase is a major component of many acute tissue reactions
C. In both experimental animals and humans, late infiltrations of activated macrophages have been noted in irradiated tissues such as lung and oral mucosa
D. Total body irradiation to doses of 1 Gy or more can lead to abnormalities in T cell immunity
D
Although transient neutrophil infiltration is a recognized early step in the normal wound healing process, it appears to play little or no part in the development of radiation-induced late effects.
Radiation has both direct and indirect effects on various components of the inflammatory system (Answer Choice B). Indirectly, radiation exposure can be considered pro-inflammatory, with an “-itis” being a commonly observed early radiation response in many tissues and organs, e.g. lung (pneumonitis), skin (radiodermatitis) and the alimentary tract (mucositis). In many of these tissues, the inflammation is mediated by activated macrophages that recognize the chronic dysregulation characteristic of irradiated tissues during the development of late effects (Answer Choice C). However, radiation’s direct effects on inflammatory cells are more anti-inflammatory in nature. For example, it has been recognized both in the Japanese A-bomb survivors and in the Chernobyl cleanup workers that total body irradiation (TBI) doses of 1 Gy and above can lead to abnormal T cell immunity, possibly due to altered T cell differentiation and increased cell killing (Answer Choice D).
Which of the following statements concerning irradiation of the CNS is FALSE?
A. Selective damage to gray matter would preclude radiation as the cause of injury
B. Demyelination and white matter necrosis are common manifestations of radiation-induced injury to the CNS
C. Oligodendrocytes and vascular endothelial cells are considered to be the principal target cells for radiation-induced damage to the CNS
D. Most forms of radiation injury to the CNS are characterized by distinct pathognomonic characteristics specific to radiation-induced damage
E. Cognitive deficits are a late effect seen in both children and adults
D
There are typically no distinct pathognomonic characteristics of CNS injury that would unambiguously identify radiation as the causative agent.
