ASTRO 2023 (16-25) Flashcards
XVI-1) An employee working in a nuclear power plant is accidentally exposed to
a total body -ray dose of 2 Gy. Ten days after the accident, you draw
blood and submit it for hematologic analysis. Which of the following
would you expect to see?
A. A decrease in hemoglobin concentration and platelet counts
B. A decrease in platelet count and an increase in lymphocyte count
C. A decrease in lymphocyte count, but no effect on hemoglobin
concentration
D. An increase in neutrophil count, but no effect on hemoglobin
concentration
E. No effect on lymphocytes, hemoglobin, neutrophils or platelets
XVI. Total Body Irradiation Answers & Explanations
XVI-1) C
Ten days after a total body dose of 2 Gy, one would expect lymphocyte and neutrophil counts to decrease, but hemoglobin concentration and platelet counts to remain normal. Platelets will not decrease until ~20 days after a 2 Gy exposure. Hemoglobin will not decrease unless much higher doses are received and a longer time period has elapsed.
XVI-2) A terrorist preparing a “dirty bomb” containing 210Po received a total body
dose equivalent of approximately 8 Sv resulting from an accidental
ingestion of this radioisotope. He did not seek medical attention and died
7 days later from acute radiation toxicity. Which of the following would
you expect to see at autopsy?
A. Complete bone marrow aplasia
B. Mitotic arrest of intestinal crypt cells
C. Cerebral edema
D. Microvasculitis
E. Brain necrosis
XVI-2) B
This individual will experience the GI syndrome and die before his bone marrow would become completely aplastic, although there probably would be some hypoplasia in the marrow, spleen, and lymph nodes. A characteristic feature observed in people who die from the GI syndrome is mitotic arrest in the intestinal crypt cells. The other listed changes (cerebral edema, microvasculitis, brain necrosis) would be expected with the cerebrovascular syndrome, which would not occur unless the total dose received was at least 3-4 fold higher than 8 Sv.
XVI-4) The death of a person 30-60 days following a total body radiation dose
close to the LD50 (no medical intervention) would likely be due to damage
to the:
A. Heart
B. Bone marrow
C. Central nervous system
D. Brain
E. Gastrointestinal system
XVI-4) B
The death of a person 30-60 days following a total body radiation dose close to the LD50 would be due to damage to the bone marrow, resulting in the gradual reduction in the level of peripheral blood elements. Infection due to loss of white blood cells and/or hemorrhage due to the loss of platelets are typically the cause(s) of death. Usually, death from ablation of the bone marrow would not be manifest until about a month or two after irradiation; this is a reflection of the normal turnover rates of the mature blood components, which would not be replaced in the absence of functioning bone marrow stem cells. Death from radiation damage to the heart, liver, or kidney would not occur within two months following irradiation. Death due to damage to the gastrointestinal system usually takes place within 5-16 days following irradiation and would not be likely with a dose near the LD50 since it requires higher doses to manifest.
XVI-3) Which of the following pairs of total body radiation effects and
approximate threshold dose is CORRECT?
A. Gastrointestinal syndrome – 2 Gy
B. LD50 (no medical intervention) – 3.5 Gy
C. LD50 (best current medical treatment) – 15 Gy
D. Cerebrovascular syndrome – 5 Gy
E. Hematopoietic syndrome – 0.2 Gy
XVI-3) B
Estimated human LD50 (dose to result in lethality in 50% of an irradiated population) is 7 Gy with the best medical intervention and 3.5 Gy without any medical intervention. The dose thresholds for the hematopoietic, gastrointestinal, and cerebrovascular syndromes are roughly 2 Gy, 8 Gy and 20 Gy, respectively.
Condition ;Threshold dose; Days until Death
Hematopoietic Syndrome; 2 Gy; 30-60 days
Gastrointestinal Syndrome; 8 Gy; 5-16 days
Cerebrovascular Syndrome; 20 Gy; Hours – 2 days
XVI – 5) Which of the following statements is correct? After total body irradiation,
the prodrome of the radiation syndrome:
A. Is not seen unless doses exceed 10 Gy
B. Occurs after the exposed person has recovered from the GI syndrome
C. Can be ameliorated through treatment with amifostine approximately
3-5 hours after the exposure
D. Includes GI symptoms such as anorexia, nausea, and vomiting that
occur within minutes to hours following exposure and lasting hours to
days, depending on the radiation dose
E. Is characterized by hematopoietic system damage, but no effects
related to the gastrointestinal system
XVI-5) D
The prodrome of the radiation syndrome is a spectrum of early symptoms that occur shortly after whole body irradiation, lasts for a limited amount of time, and varies in time of appearance, duration, and severity depending on the dose. GI symptoms such as anorexia, nausea, and vomiting occur when an individual is exposed to doses near the LD50; at higher doses, symptoms such as fever and hypotension are also seen. The radioprotector amifostine would not be expected to ameliorate these symptoms if given after irradiation.
XVI-6) Following a total body dose of 12 Gy in one fraction, an exposed
individual will not show the bone marrow syndrome because:
A. Higher doses than 12 Gy are needed to cause the bone marrow
syndrome
B. The individual will likely die within 5-16 days from the GI syndrome,
before overt symptoms of the bone marrow syndrome occur
C. This dose is not sufficiently high to cause any radiation syndrome
D. A bone marrow transplant will likely have been given and would mask
the symptoms of the bone marrow syndrome
E. At this dose the radiation syndrome prodrome will be so severe it will
overshadow the bone marrow syndrome
XVI-6) B
Following a total body dose of 12 Gy, an irradiated individual will likely die within 5-16 days from the GI syndrome. Thus, death will occur before the symptoms of the bone marrow syndrome are manifest, usually starting at about 20 days and resulting in death at 30-60 days. The bone marrow syndrome, resulting from damage to bone marrow stem cells, occurs after doses in the 2-8 Gy region.
XVI-7) For individuals accidentally exposed to radiation, a bone marrow
transplant is potentially useful when the radiation dose is within a narrow
range. That dose window is approximately:
A. 1-2 Gy
B. 3-4 Gy
C. 8-10 Gy
D. 15-20 Gy
E. Bone marrow transplants have no potential usefulness at any dose
XVI-7) C
Bone marrow transplants are only useful when the radiation dose to the exposed person is within about 8-10 Gy. At lower doses, an exposed person will likely survive with appropriate medical care. For doses above 10 Gy death from effects on the GI tract will occur even despite use of all effective currently available treatments.
XVI-8) Which of the following statements is FALSE regarding the symptoms that
make up the prodrome after total body irradiation:
A. After receiving 2 Gy, the majority of those affected experience nausea
and vomiting within 30 minutes
B. Serotonin-receptor antagonists are recommended in the management
of nausea and vomiting after total body irradiation
C. Time to onset of prodromal symptoms is inversely related to radiation
dose
D. Diarrhea is a prodromal symptom
E. The severity of prodromal symptoms is directly related to radiation
dose
XVI-8) A
After exposure to 2 Gy, 50% or less will experience nausea and vomiting. Typically, this occurs within 2-6 hours of exposure. The majority of those who receive greater than 10 Gy would be expected to show prodromal symptoms by about 30 minutes after exposure. Symptoms of the prodromal syndrome after a sublethal exposure to total body irradiation include fatigue, anorexia, nausea and vomiting. The onset of these symptoms are inversely proportional to the dose of the exposure. In individuals who receive a supralethal dose of total body irradiation, additional prodromal symptoms include fever, immediate diarrhea, apathy, headache and hypotension.
XVI-9) Which of the following is NOT recommended as part of routine
management of the gastrointestinal radiation syndrome after accidental
total body irradiation:
A. Antiemetics
B. Antibiotics
C. Antidiarrheals
D. Corticosteroids
E. Oral nutritional support
XVI-9) D
Systemic corticosteroids are not recommended in management of patients with gastroinstestinal syndrome from total body irradiation..Supportive care (including psychological support), symptomatic treatment (50HT3 antagonist antiemetics, etc.), and fluid/electrolyte replacement (PO and/or IV) should be the earliest goals of medical management.
XVI-10 With recent advances in supportive measures to manage acute radiation
exposure, what syndrome has been seen following exposure to 8-10 Gy
in modern nuclear reactor accidents?
A. Pulmonary
B. Renal
C. Endocrine
D. Musculoskeletal
E. Hepatic
XVI-10 A
Pulmonary syndrome has been found to occur in nuclear reactor workers who were exposed to 8-10 Gy and survived hematopoetic syndrome due to modern supportive care with isolation, IV hydration, transfusions, antibiotics and hematopoetic colony stimulating factors. These patients died at approximately 130 days after exposure due to pneumonitis.
XVII. Clinically Relevant Normal Tissue Responses to Radiation
XVII-1) 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 radiationinduced 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
XVII. Clinically Relevant Normal Tissue Responses to Radiation Answers &
Explanations
XVII-1) 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.
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.
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. 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
XVII-2) 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
XVII-2) 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. In children, growth retardation is a concern after irradiation of growth plates. Bone sarcoma is the most common secondary neoplasm following irradiation of bony structures.
XVII-3) 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
XVII-3) 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.
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. 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.
XVII-4) 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
XVII-4) 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).
XVII-5) 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
XVII-5) 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.
XVII-6) 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
XVII-6) 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
XVII-7) 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
XVII-7) 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.
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
.
The tolerance dose for the production of blindness is greater than that for cataract formation.
The latency period for the induction of a radiation-induced cataract decreases with increasing dose
XVII-8) 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
XVII-8) 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.
XVII-9) 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
XVII-9) 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.
XVII-10) 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.
XVII-10) 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. 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. 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.
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
XVII-11) 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 radiationinduced dermal ulcers; both result from ischemic necrosis due to the
loss of small blood vessels
XVII-11) 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.
XVII-12) 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
XVII-12) 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.
XVII-13) With respect to the morphologic changes associated with radiationinduced 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
XVII-13) 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.
XVII-14) 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
XVII-14) A
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 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
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
XVII-15) 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
XVII-15) D
There are typically no distinct pathognomonic characteristics of CNS injury that would unambiguously identify radiation as the causative agent.
XVII-16) Which of the following statements is CORRECT? Following acute
irradiation of the skin:
A. Epilation and the loss of sebaceous gland secretions follow similar
time courses
B. The first visible reaction is moist desquamation, typically observed
within 24 hours of irradiation
C. Epilation is only observed at doses much greater than those that cause
the main wave of erythema observed at about one week
D. Pigment changes are typically seen within days due to the high
proliferation rate of melanoblasts
E. It is usually possible to predict the extent of late reactions based on
the severity of early reactions
XVII-16) A
Following irradiation of the skin, the dose and time course for epilation and loss of sebaceous gland secretion are similar. Following skin irradiation, the first visible evidence of damage is a transient erythema that is observed within 24 hours following irradiation, whereas moist desquamation would only be observed after a few weeks. Epilation is observed at doses similar to those that cause the main wave of erythema that is typically manifested about one week following irradiation. Pigment changes typically appear long after irradiation due to the low proliferation rate of melanoblasts. It is usually not possible to predict the extent of late reactions based upon the severity of early reactions because early reactions result from killing of epidermal stem cells, whereas late reactions likely occur due to vascular damage in the dermis.
XVII-17) Which of the following conditions is NOT an expected manifestation of
radiation-induced heart disease?
A. Accelerated coronary atherosclerosis
B. Hypertrophic cardiomyopathy
C. Cardiac fibrosis
D. Pericarditis
E. Cardiac myocyte degeneration
XVII-17) B
Hypertrophic cardiomyopathy is not considered a common feature of radiation-induced heart disease. Accelerated coronary atherosclerosis, on the other hand, is an important source of morbidity and mortality after irradiation of intra- or peri-thoracic tumors. Cardiac myocyte degeneration and cardiac fibrosis (adverse cardiac remodeling) may contribute to post-radiation congestive heart failure. Fibrotic thickening of the pericardium and pericardial exudate may occur and could lead to constrictive pericarditis.
XVIII. Mechanisms of Normal Tissue Radiation Responses
XVIII-1) Which of the following cytokines is generally considered both antiinflammatory and immunosuppressive?
A. Interleukin 1
B. Interleukin 6
C. Interleukin 8
D. Interleukin 10
E. Tumor necrosis factor alpha (TNF⍺)
XVIII. Mechanisms of Normal Tissue Radiation Responses Answers &
Explanations
XVIII-1) D
IL-10 is produced by a variety of different cell types, particularly monocytes/macrophages and lymphocytes. It is a major anti inflammatory cytokine that inhibits the initiation and effector phases of cellular immune responses as well as a variety of inflammatory responses.
The other cytokines (IL-1, IL-6, IL-8, and TNF⍺) are all considered pro inflammatory. There is considerable overlap between the activities of TNF⍺ and IL-1. TNF⍺ is secreted mainly by activated monocytes/macrophages and has profound pro-inflammatory effects. It also stimulates the secretion of many other cytokines, including IL-1, IL- 6, and IL-8.
IL-1 is also a key mediator of host response to infection and inflammation. The main cellular sources of IL-1 are cells of the monocyte and macrophage lineage. Similar to TNF⍺, IL-1 induces several secondary cytokines, including IL-6 and IL-8. Upon stimulation by IL-1 and/or TNF⍺, IL-6 and IL-8 are produced by a large number of different cell types, including monocytes, fibroblasts, endothelial cells and epithelial cells.
XVIII-2) Studies with laboratory animals have shown that all of the following
interventions can reduce lethality after total body irradiation, EXCEPT:
A. Fluid and electrolyte therapy
B. Inhibitors of poly(ADP-ribose) polymerase (PARP)
C. Antibiotics
D. Probiotics
E. Blood product administration
XVIII-2) B
The radiation dose-dependent lethality and reduction in gut crypt cell survival is significantly potentiated, not reduced, in PARP-deficient mice and in mice treated with a PARP inhibitor. Treatment with fluids, electrolytes, antibiotics, and blood products is part of the standard supportive care after exposure to total body irradiation. Manipulation of the gut ecosystem through administration of probiotics has been demonstrated to prevent radiation-induced enteritis in animals.
XVIII-3) With regard to the retreatment tolerance of previously-irradiated normal
tissues, which of the following statements is FALSE?
A. The lung is capable of long-term recovery after doses that are below
the tolerance dose for radiation pneumonitis
B. Re-irradiation of the mucosa does not produce a more severe acute
reaction compared to mucosa that has not been previously irradiated
C. The spinal cord is capable of moderate long-term recovery after
irradiation
D. Re-irradiation tolerance of the kidney increases with increasing time
interval between treatments, indicating continuous repair of subthreshold damage
E. The onset of late bladder damage occurs much earlier in animals that
were re-irradiated following a low sub-tolerance initial radiation dose,
as opposed to being treated to tolerance in a single course of therapy
XVIII-3) D
In the kidney, the tolerance to retreatment decreases with time, indicating a continuous progression of renal injury in the interval between treatments. Experimental studies in mice given initial radiation doses approximately 30-50% of the biologically effective tolerance dose (BEDt) showed that the lungs could be re-irradiated with doses equivalent to the BEDt provided a sufficient time interval between the first and second treatments had elapsed. Re-irradiation tolerance for acute damage in rapidly dividing mucosal tissues is commonly observed. Rodent and monkey data indicate that, contrary to popular belief, the spinal cord is capable of considerable recovery from the injury caused by an initial radiation treatment and can subsequently be retreated with at least a partial tolerance dose. In the bladder, the latency period before expression of injury is shorter in animals that were re-irradiated, as opposed to being treated to tolerance in a single course of therapy, even after low, sub tolerance initial radiation doses.
XVIII-4) Which of the following statements concerning radiation-induced late
effects is TRUE?
A. Most late effects develop primarily as a direct result of endothelial cell
killing
B. Most late effects are due to the loss of parenchymal cell clonogens
C. Radiation-induced late effects produce unique pathological responses
D. The development of late effects shares many elements in common
with both acute and chronic wound-healing responses in normal
tissues
E. Once present, late effects are irreversible
XVIII-4) D
Despite the recent surge in interest in radiation-induced late effects, the precise mechanisms responsible for their development and progression remain unclear. Historically, late effects were considered to be a consequence of the radiation-induced killing of either parenchymal or vascular target cell populations, and as such, were thought to be inevitable, progressive, and untreatable. More recent findings suggest that this hypothesis is overly simplistic. Radiation-induced late effects are now viewed as the result of dynamic interactions between multiple cell types within the tissue. The parenchymal cells are no longer viewed as passive bystanders, merely dying as they attempt to divide, but rather are thought to be active participants in an orchestrated, yet limited, response to injury. In general, irradiating late-responding normal tissues leads to an acute inflammatory response followed by an aberrant chronic inflammatory/wound healing response in which vascular and parenchymal cell dysfunction and cell loss, associated with chronic overproduction of particular cytokines and growth factors, result in fibrosis and/or necrosis, depending on the particular organ involved. This new paradigm promises novel approaches to the mitigation of radiation induced normal tissue complications, including the possibility that late effects might be reduced by the application of therapies directed at altering steps in the cascade of events leading to the clinical expression of the injury. There are no pathognomonic features characteristic of irradiated late-responding normal tissues.
XVIII-5) With regard to the latency period for the expression of radiation-induced
normal tissue injury, which of the following statements is CORRECT?
A. The latency period for early-responding tissues decreases markedly
with increasing radiation dose
B. Shortening the overall treatment time by accelerating radiotherapy
substantially reduces the latency period for early-responding tissues
C. Shortening the overall treatment by accelerating radiotherapy tends to
increase the latency period for late-responding tissues
D. The higher the total radiation dose, the shorter the latency period for
many late-responding tissues
E. The latency period for early-responding tissues depends on the rate of
vascular endothelial cell turnover
XVIII-5) D
Early-responding tissues exhibit radiation-induced injury during or shortly after a course of radiotherapy. Late reactions are manifested months or years following the completion of radiotherapy. The classical model of radiation-induced normal tissue injury hypothesizes that normal tissue injury involves the loss of specific target cell clonogens. In early responding tissues such as the skin and oral mucosa, clonogenic cell turnover is rapid, as is clonogenic cell death. Thus, the latency period, i.e., the period before the expression of radiation-induced injury, is short. This latency period is fixed in early-responding tissues, since it depends on the time it takes for cells to move from the stem cell compartment through the transit compartment, and finally to the terminally-differentiated, non dividing parenchymal cell that is lost through normal wear and tear.
In contrast, target cell turnover is slow or non-existent in late-responding tissues and therefore the latency period is long. Shortening the overall treatment time may cause greater cell depletion and increase the severity of early reactions since the time available for cell repopulation would be limited under these circumstances. This might result in more pronounced “consequential” late effects; however, the latent period for these late effects would, if anything, decrease, rather than increase.
According to classical theory, the decrease in the latency period with dose for late effects was thought to be due to the enhanced cell killing resulting from the use of higher doses. It is now recognized that this cell killing likely plays only a limited role in the development of most late responses. In contrast, it is thought that when irradiation of a tissue may give rise to a late radiation reaction, there is initially an acute inflammatory response followed by an aberrant chronic inflammatory/wound healing response. Vascular and parenchymal cell dysfunction and cell loss then occur which are accompanied by a chronic overproduction of particular cytokines and growth factors, ultimately resulting in the manifestation of radiation toxicity. Thus, it is now thought that the process ultimately leading to the development of late radiation effects actually begins relatively quickly after irradiation. Presumably, the speed and/or intensity of this process is somewhat dose dependent such that the length of time necessary before a late effect is observed clinically decreases with increasing dose. There is no relationship between the latency period for early-responding tissues and endothelial cell turnover; if anything, the latter has been considered a target cell for injuries in late-responding tissues.
XVIII-6) For normal tissues such as spinal cord, a small dosimetric hotspot could
be disastrous in terms of increasing the likelihood for a serious late
complication. However, a small volume receiving a high dose during lung
irradiation may not lead to any late sequelae. The best explanation for this
observation is that:
A. The spinal cord has a large functional reserve, but the lung does not
B. Target cells in the lung are better able to repair radiation damage than
their counterparts in the spinal cord
C. Surviving clonogens in the lung can repopulate rapidly, whereas those
in the spinal cord cannot
D. Migration of cells from outside the irradiated volume helps to
augment lung function, but this process does not occur in the spinal
cord
E. The putative functional subunits in the lung are arranged in parallel,
whereas those in the spinal cord are arranged in series
XVIII-6) E
The reason a large dose to a small length of the spinal cord may cause severe radiation injury, such as myelopathy, is that the inactivation of even a single functional subunit (FSU) can disrupt the function of the entire organ for tissues whose FSUs are arranged in a serial fashion. In contrast, a high dose to a small volume of the lung may have little impact because the remainder of the lung will continue to function normally because its FSUs are arranged in parallel.
XVIII-7) Radiation effects in the nervous system typically arise as a consequence
of damage to:
A. Axons
B. Neurons
C. Oligodendrocytes and glial cells
D. The perikaryon
E. Dendrites
XVIII-7) C
The effects of radiation on the nervous system arise primarily as a consequence of damage to oligodendrocytes and glial cells. Although radiation likely does cause some damage to neurons as well, this alone does not seem to manifest itself as a frank nervous system injury.
XVIII-8) Which of the following statements is TRUE concerning irradiation of the
salivary glands?
A. Serous acinar cells die only by mitotic catastrophe after irradiation
B. The serous acinar cells of the parotid and submaxillary glands are
considered the target cells for radiation-induced salivary gland
damage
C. Salivary dysfunction is a late radiation effect rarely observed earlier
than six months following treatment
D. Mucous cells are more radiosensitive than serous cells
E. Dose fractionation results in significant sparing of serous cells
XVIII-8) B
The serous acinar cells of the parotid and submaxillary glands are considered to be the targets for radiation-induced salivary gland damage. Serous acinar cells typically die by apoptosis and not mitotic catastrophe following irradiation. Salivary dysfunction is an early radiation response that often begins while radiotherapy is still ongoing. Mucous cells are more radioresistant than serous cells. Fractionation results in relatively little sparing from radiation-induced killing of serous cells, as is typical for cells with a pro-apoptotic tendency.
XVIII-9) Which statement concerning transforming growth factor beta 1 (TGF-β1)
and basic fibroblast growth factor (bFGF/FGF2) is TRUE?
A. The pro-fibrotic activities and role in radiation-induced fibrosis of
TGF-β1 are mediated by SMAD3
B. Stimulation of TGF-1 synthesis should improve the therapeutic ratio
C. bFGF has been shown to sensitize endothelial cells to radiationinduced apoptosis
D. The serum concentration of TGF-1 always decreases following lung
irradiation
E. TGF-β1 promotes the radiation-induced inflammatory response
XVIII-9) A
Transforming growth factor beta 1 (TGF-β1) plays a central role in radiation-induced fibrosis as it causes epithelial to mesenchymal cell trans-differentiation and promotes the influx of fibroblasts as well as the production of extracellular matrix. TGF-β1 activates SMAD proteins, including SMAD3, which modulates the transcription of target genes with pro-fibrotic activities. It is thought that stimulation of TGF-1 synthesis causes fibrosis and would therefore decrease the therapeutic ratio.Basic fibroblast growth factor (bFGF/FGF2) has been shown to protect (not sensitize) endothelial cells from radiation-induced apoptosis. In addition, TGF-β1 has anti-inflammatory activity. The clinical interpretation of serum TGF-1 levels during thoracic irradiation is complex; on the one hand, levels are elevated in patients who develop radiation pneumonitis while, on the other hand, lung tumors may self generate TGF-1 causing levels to fall during treatment).
XVIII-10) Regarding radiation fibrosis, which of the following statements is TRUE?
A. Fibrosis occurs in only a select few tissues and organs
B. The severity of late fibrosis can be predicted based on radiotherapy
treatment parameters and is not tissue-dependent
C. Radiation fibrosis is typically inhomogenous; some affected areas
could be densely collagenous whereas others may have only a few
fibrous bands, despite both areas having received the same dose
D. Irradiated bone marrow commonly develops regions of fibrosis
E. Increases in collagen deposition are associated with down-regulation
of fibrogenic cytokines.
XVIII-10) C
Fibrosis is one of the most common late radiation effects and can be noted in a majority of irradiated tissues and organs. Although the appearance of fibrosis is both time- and dose-dependent, its extent and severity can vary not only within a single organ, but also across different individuals. Bone marrow is one of the few tissues where fibrosis is rarely seen; in general, fibrosis only appears within the marrow if a tumor or inflammatory lesion was present prior to irradiation. Bone marrow is usually replaced by adipose tissue. Much of the regulation of collagen deposition is mediated through the action of fibrogenic cytokine families and is characterized by the upregulation of such cytokines as TGF-1.
XVIII-11) The cells thought to be responsible for radiation-induced cognitive
dysfunction reside in:
A. Medulla oblongata
B. Cerebral cortex
C. Substantia nigra
D. Hippocampus
E. Hypothalamus
XVIII-11) D
Radiation-induced cognitive impairment is marked by decreased verbal memory, spatial memory, attention, and novel problem-solving ability. The incidence and severity of radiation-induced cognitive impairment increases over time. The hippocampus houses neuronal stem cells and is one of only two areas where neurogenesis continues after birth. The hippocampus plays an important role in learning and memory consolidation.
The importance of sparing the hippocampus was demonstrated in the phase III NRG-CC001 trial of whole-brain radiotherapy plus memantine, with or with hippocampal avoidance. Patients were randomly assigned to memantine plus whole-brain radiotherapy (30 Gy in 10 fractions) vs memantine plus hippocampal-avoidant whole-brain radiotherapy (30 Gy in 10 fractions). Hippocampal-avoidant whole-brain radiotherapy plus memantine reduced the risk of cognitive function failure by 26% (P = .033).
XIX. Therapeutic Ratio
XIX-1) For tumors exhibiting central hypoxia, what strategy is most likely to
improve the therapeutic ratio of treatment?
A. Stimulation of repair in hypoxic tumor cells
B. Inhibition of reoxygenation in tumor cells
C. Use of a systemic radioprotector drug that reaches both tumor and
normal cells
D. Inhibition of DNA repair in tumor and normal cells
E. Use of a systemic radioprotector drug that preferentially accumulates
in normal tissues
XIX. Therapeutic Ratio Answers & Explanations
XIX-1) E
Normal tissues are typically well-oxygenated, but some tumors may contain a fraction of radioresistant hypoxic cells. Larger tumors are more likely to harbor hypoxic regions. In order for a radioprotector to be efficacious and improve the therapeutic ratio, it must have a preferential effect on normal tissues either through increased selectivity for normal tissues or decreased selectivity for tumor cells. Amifostine is the prototypical radioprotector with Phase III data and meta-analyses demonstrating reduction in mucositis and xerostomia without affecting progression-free survival or overall survival. The disadvantages of amifostine include the need for IV infusion, moderate rates of nausea/vomiting, and risk of hypotension.
Answers A and B describe strategies that would protect tumor cells. Answer C describes radioprotection of both normal tissues and tumor, which is next expected to change the therapeutic ratio. Answer D describes inhibition of DNA repair in both normal and tumour cells and would be expected to sensitize both populations but not change the therapeutic ratio.
XIX-2) All of the following could affect the slope of a tumor control probability
(TCP) curve, EXCEPT:
A. Tumor size
B. Tumor oxygenation
C. Intrinsic tumor cell radiosensitivity
D. Volume of normal tissue in the radiation field
E. Histopathological tumor type and grade
XIX-2) D
The slope of a tumor control probability (TCP) curve is determined byfactors that introduce heterogeneity into the population of tumors under study. Tumor heterogeneity can be caused by variations in tumor size, oxygenation, tumor cell radiosensitivity, or histological type and grade of the tumor. While it may be important for toxicity and therefore for the therapeutic ratio, the volume of normal tissue in the radiation field does not affect the tumor control probability.
XIX-3) A new agent that can alter blood flow is being assessed for its potential
clinical usefulness in combination with radiation therapy. Which of the
following effects on blood flow would be expected to result in therapeutic
gain and thus lead to a potentially useful agent in the clinic?A.
Unchanged in normal tissues and increased in tumors
B. Increased in normal tissues but decreased in tumors
C. Decreased in normal tissues and in tumors
D. Unchanged in normal tissue but decreased in tumors
E. Increased in normal tissues and unchanged in tumors
XIX-3) A
In order for there to be a therapeutic gain, the differential between the radiation response of tumor and normal tissue must be increased. Since blood flow is typically not compromised in normal tissues. However, since many tumors contain hypoxic cells, increasing blood flow to the tumor could result in radiosensitization. In contrast, decreasing blood flow to tumors would not be expected to be advantageous, since it could cause increased hypoxia and thus radiation resistance.
XIX-4) Which of the following statements is CORRECT? Normal tissue
regeneration/repopulation:
A. Occurs in acutely responding normal tissues during the course of a
standard course of radiotherapy
B. Interferes with reoxygenation
C. Is the reason that prolonging overall treatment time spares late
responding normal tissues
D. Occurs at the same rate after irradiation in acutely and late responding
tissues
E. Is the reason why accelerated fractionation protocols increase
reactions in late responding normal tissues
XIX-4) A
Regeneration/repopulation can occur in early responding tissues such as skin during the course of a standard course of radiotherapy, increasing the tolerance of these tissues to radiation. The apparent slower kinetics of late responding tissues suggests that no repopulation occurs in these tissues compared to acutely responding issues. If repopulation were to take place, then this would reduce, not increase, late effects, irrespective of the fractionation schedule. Repopulation/regeneration plays no role in reoxygenation.
XIX-5) A prostate cancer patient is planned to go through a moderately
hypofractionated IMRT treatment. Your clinic’s standard for planning has
been to use 10 mm margins in every dimension except 7 mm posteriorly
without daily image guidance. Which of the following strategies would
NOT improve the therapeutic ratio of the treatment?
A. The addition of a hydrogel spacer between the rectum and prostate
B. The use of daily cone-beam CT for image guidance
C. The use of smaller PTV margins (i.e., 5 mm except 3 mm posteriorly)
without daily cone-beam CT
D. The use of daily cone-beam CT plus smaller margins
E. The use of implanted gold fiducials and intrafraction stereoscopic xray monitoring and targeting adjustment
XIX-5) C
All of the proposed interventions would improve the therapeutic ratio except the use of smaller PTV margins without image guidance. Image guidance increases the fidelity of setup and reduces the risk of geometric miss, particularly in the setting of variability in bladder and rectal filling. The use of reduced PTV margins can improve the therapeutic ratio by limiting the volume of normal tissue treated, but only if the dose to tumour is not compromised. The margins proposed in answer C would not be sufficient to cover tumor without image guidance. Lastly, hydrogel spacers have been shown to displace the rectum posteriorly and reduce GI toxicity.
XIX-6) Hypofractionation is being used to definitively treat many different
malignancies including breast and prostate cancer. Which of the following
is TRUE about its use in prostate cancer?
A. Treatment of the whole prostate using the same total dose but higher
dose per fraction allows safe dose escalation while sparing normal
tissues
B. Treatment of the whole prostate to the same biologically effective
dose (BED) to tumor but higher dose per fraction allows shorter
treatment time and little to no change in the therapeutic ratio
C. Treatment of the whole prostate to the same BED to tumor but higher
dose per fraction allows a shorter treatment time and selective sparing
of the adjacent normal tissues
D. The BED to normal tissues is significantly higher with
hypofractionated regimens and therefore stereotactic methods must be
used to treat the prostate
XIX-6) B
The goal of hypofractionation is to provide more convenient (shorter) treatments to patients while maintaining or improving the therapeutic ratio. Hypofractionation for low- and intermediate-risk prostate cancer typically involves treatment of the prostate cancer to an EQD2 of 74-78 Gy (assuming α/β of 1-3 for tumor). The most thoroughly tested regimens include 70 Gy in 28 fractions (RTOG 0415) and 60 Gy in 20 fractions (UK CHHIP and PROFIT). In general, these regimens were tested for non-inferiority against roughly biologically equivalent conventional regimens (73.8 Gy/41 fractions for RTOG 0415, 74 Gy/37 fractions for UK CHHIP, and 78 Gy/39 fractions for PROFIT. A major concern about hypofractionation was the possibility of significantly increased acute and late toxicity not predicted by linear quadratic modeling. The above trials have demonstrated this not to be the case, so long as appropriate dose constraints are achieved. There is some evidence, however, of a small increase in acute GI toxicity across trials.
Answer A is incorrect, as maintaining the same total dose (e.g., 78 Gy) while hypofractionating (e.g., 20 fractions) would increase the BED to both tumor and normal tissues. While this would improve the likelihood of tumor control, it also would move rightward along the normal tissue probability curve with a disproportionate increase in NTCP, thereby decreasing the therapeutic ratio.
Answer C is incorrect, as hypofractionation regimens maintaining an equivalent BED compared to an effective conventional regimen are not expected to significantly spare normal tissues (although the BED to normal tissues may be marginally less depending on the alpha/beta used for tumor).
Answer D is incorrect, as the BED to normal tissues for the regimens mentioned above is not significantly different from conventional regimens. As a result, both predicted toxicity and measured toxicity are not significantly different. Daily image guidance was not mandatory on UK CHHIP (~30% treated with it) but was required on PROFIT and RTOG 0415; none of these trials used real-time tracking methods. However, daily image guidance is typically preferred, especially if treating according to the respective protocol.
XIX-7) Your clinic has a fancy new treatment planning system that uses
radiobiologic tumor control probability (TCP) and normal tissue
complication probability modeling (NTCP) to help select the best
treatment plan. Your dosimetrist has come up with 4 plans to review.
Based on the TCP/NTCP curves below, which of the following plans
would you choose?
XIX-7) D
Tumor control probability (TCP)/Normal tissue complication probability modeling (NTCP) curves are a convenient way to assess the therapeutic ratio of a treatment as it relates to the prescribed dose. The probability of either tumor control or tissue complication is typically sigmoidal. The therapeutic ratio can be estimated by the widest vertical separation of the TCP and NTCP curves. The ideal treatment plan (i.e., a high therapeutic ratio) demonstrates a high likelihood (e.g., >90%) of tumor control while maintaining TCP as low as possible. The example in A is the worst case scenario, in which normal tissue toxicity is nearly certain at doses that would provide meaningful tumor control. Such is sometimes the case in situations where reirradiation is being considered.
Examples B and C show suboptimal scenarios in which NTCP is still highly likely if trying to achieve curative doses. Of the depicted curves, example D demonstrates the highest therapeutic ratio.
XX. Time, Dose, Fractionation
XX-1) Which of the following total doses, given as daily 1.5 Gy fractions, is
approximately equivalent to a conventional schedule of 30 fractions of 2
Gy for late normal tissue reactions? Assume the / ratio is equal to 3 Gy.
A. 53 Gy
B. 60 Gy
C. 67 Gy
D. 75 Gy
E. 81 Gy
XX. Time, Dose, Fractionation Answers & Explanations
XX-1) C
XX-2) Assuming no difference in overall treatment time, which of the following
statements is CORRECT concerning isoeffect curves?
A. Tissues with a greater repair capacity have steeper isoeffect curves.
B. Increased proliferation of the critical cell population during the course
of radiotherapy will decrease the slope of the isoeffect curve.
C. Tissues with steep isoeffect curves have high / ratios.
D. Isoeffect curves for tumor control will be steeper if significant
reoxygenation occurs between dose fractions.
XX-2) A
An isoeffect curve describes the relationship between total dose for a given level of tissue effect and the different fractionation parameters (overall time, dose per fraction, number of fractions, etc). Isoeffect curves are often plotted with the log of the total dose on the y-axis and the log of the fraction size (from high to low) on the x-axis. Tissues with a greater repair capacity will show greater sparing with increasing fractionation (smaller fraction sizes) and therefore will have steeper isoeffect curves. Increased proliferation will cause an increase in the slope of an isoeffect curve because it would take a higher total dose to kill the larger number of cells produced during the course of treatment (Answer Choice B).
Tissues with steep isoeffect curves have low, not high, / ratios.
Reoxygenation decreases the slope of the isoeffect curve because it decreases the number of radioresistant hypoxic cells and hence reduces the total dose required to control the tumor, everything else being equal.
XX-3) A total dose of 70 Gy delivered in 2 Gy fractions is used to treat a
particular tumor. Assume that the tumor is characterized by an / ratio
of 2 Gy and a Tpot of 30 days. For the dose-limiting normal tissue, the /
ratio is 4 Gy. Which one of the following treatment schedules would most
likely yield the highest therapeutic ratio?
A. Standard fractionation
B. Accelerated treatment
C. Split-course treatment
D. Hyperfractionation
E. Hypofractionation
XX-3) E
In principle, a hypofractionated protocol would yield the highest therapeutic ratio because if treating with either standard or small fraction sizes (i.e., hyperfractionation) there would be greater sparing of this tumour (/ ratio = 2 Gy) than for the critical dose-limiting normal tissue (/ ratio = 4 Gy). There would not be much point to using accelerated treatment since this is a relatively slow-growing tumor (Tpot = 30 days), nor would split course treatment be indicated since, again, the /ß ratio suggests greater recovery in the tumor versus the normal tissue.
XX-4) Which of the following fractionation schedules would likely produce the
highest incidence of late normal tissue toxicity? (Assume / = 2 Gy for
the critical normal tissue injury)
A. 20 Gy in 4 fractions over 1 week
B. 24 Gy in 6 fractions over 2 weeks
C. 45 Gy in 15 fractions over 3 weeks
D. 50 Gy in 25 fractions over 5 weeks
E. 60 Gy in 60 fractions over 6 weeks
XX-4) C
Since the focus of this question concerns late effects, the overall treatment time (a maximum of 6 weeks) should not be an important determinant of outcome. The BEDs calculated for each of the different fractionation schedules are 70, 72, 113, 100 and 90 Gy2, respectively. The protocol of 45 Gy delivered in 15 fractions results in the greatest value for BED and, therefore, should be the most likely to produce late normal tissue complications. This illustrates the point that both fraction size and total dose play important roles in determining the probability of late effects.
XX-5) A standard treatment protocol for a particular type of cancer is 60 Gy
delivered in once-daily 2 Gy fractions. If the fraction size is decreased to
1.3 Gy in an attempt to reduce the incidence of late effects, approximately
what total dose should be delivered to maintain the same level of tumor
control? (Assume an equal effect per fraction, no repopulation, and an /
ratio for the tumor of 10 Gy.)
A. 64 Gy
B. 68 Gy
C. 72 Gy
D. 76 Gy
E. 80 Gy
XX-5) A
XX-6) Which of the following statements is correct? One goal of
hyperfractionation is to:
A. Decrease toxicity to early-responding tissues
B. Deliver the total radiation dose in a shorter overall time
C. Reduce the number of fractions used
D. Prevent tumor cell repopulation
E. Decrease the incidence of late effects while maintaining or improving
tumor control
XX-6) E
One goal of hyperfractionation is to improve the therapeutic ratio by decreasing the incidence of late reactions, while maintaining or improving tumor control. Therapeutic gain can be achieved only if the late responding normal tissue has a lower / ratio than that of the tumor.
Hyperfractionation would be likely to have no effect on early-responding tissues or may slightly increase toxicity; it would not decrease these toxicities
For hyperfractionation, the larger number of smaller-sized dose fractions is typically delivered over about the same overall treatment time as conventional therapy, meaning that there would be no change in the potential of surviving tumor clonogens to repopulate
XX-7) Which of the following statements is TRUE concerning experimental
support for the hypothesis that late-responding tissues have lower /
ratios than early-responding tissues?
A. High LET radiations exhibit RBEs that are greater for early effects
than for late effects
B. The use of hyperfractionation results in an increased severity of late
effects if the dose is titrated to produce equal early effects
C. Isoeffect curves are steeper for late effects than for early effects
D. When a treatment plan is changed from many small doses to a few
large fractions and the total dose is titrated to produce equal early
effects, late effects tend to be less severe
E. The isoeffect curve for skin acute effects is steep, indicating a high
sensitivity to fractionation
XX-7) C
Isoeffect curves are steeper for late effects than for early effects, meaning that late-responding tissues are more sensitive to changes in dose per fraction than early-responding tissues (and tumors).
RBEs for high LET forms of radiation are greater for late effects compared to early effects when hyperfractionation is used Hyperfractionation would reduce the severity of late effects if the total dose was titrated to maintain the same level of early effects m. When a treatment plan is changed from many small doses to a few large fractions and the total dose is titrated to produce equal early effects, late effects would be more severe.
The isoeffect curve for skin acute effects is shallow, indicating a lower sensitivity to fractionation; in other words, fractionation does not greatly alter the severity of acute dermatitis.
XX-8) A clinician changes from the usual fractionation schedule of 1.8 Gy given
once per day to an accelerated treatment using 1.6 Gy fractions delivered
twice per day. In order to avoid the possibility of reduced normal tissue
tolerance due to incomplete repair, what should be the minimum interfraction interval for the accelerated schedule?
A. 0.5-1 hour
B. 1-2 hours
C. 2-3 hours
D. 3-6 hours
E. 6-8 hours
XX-8) E
Results from clinical trials of hyperfractionation and accelerated fractionation employing more than one fraction per day have shown worse late complications when the time between fractions was less than 6 hours. This finding has been attributed to incomplete repair, because sublethal damage recovery is generally slower in late-responding tissues. It has since been suggested that even an inter-fraction interval of 6 hours may not be sufficient for those normal tissues with the slowest repair rates and that a longer time between fractions may be necessary to avoid a reduction in tolerance dose.
XX-9) A conventional treatment for a particular type of tumor is 25 fractions of
2 Gy delivered once per day. A hyperfractionated regimen is proposed
that would consist of 1.2 Gy fractions delivered twice per day. What
would be the approximate therapeutic gain in changing from the standard
to hyperfractionated schedule if both were designed to produce the same
probability of late complications? (Assume that there is no tumor cell
repopulation during treatment, full repair of sublethal damage occurs, the
tumor has an / ratio of 10 Gy and the normal tissue has an / ratio of
2 Gy.)
A. 0.8
B. 1.0
C. 1.2
D. 1.4
E. 1.6
XX-9) C
The BEDs for the standard protocol are 60 Gy10 and 100 Gy2, respectively, for the tumor and late-responding normal tissue, as determined from the equation:
𝐵𝐸𝐷= 𝑛𝑑 ( 1 + 𝑑/(alpha/𝛽)
Assuming the BED of 100 Gy2 for the normal tissue is maintained for the hyperfractionated protocol, this would correspond to a total dose of 1.2 Gy per fraction multiplied by 52 fractions, or 62.4 Gy. Putting these values into the BED equation for the tumor, the BED would increase from 60 Gy10 for the standard treatment, to 70 Gy10 for the hyperfractionated
Treatment. The therapeutic index (TI), BEDtumor-hyperfractionated/BEDtumor
standard divided by BEDnormal-hyperfractionated /BEDnormal-standard,
equals 70 Gy10/60 Gy10/100 Gy2/100 Gy2 = 1.2.
XX-10) All of the following processes could be involved in the increased efficacy
and safety of conventionally fractionated radiation in the clinic compared
to single or hypofractionated treatment, EXCEPT:
A. Sublethal damage repair in normal tissues between fractions
B. Reoxygenation in tumors
C. Redistribution/reassortment of cells in tumors
D. Repopulation of critical cell populations in normal tissues
E. Potentially lethal damage repair in tumors
XX-10) E
Sublethal damage repair (SLDR) and repopulation in normal tissues treated with fractionated radiation therapy may contribute to reduced toxicity associated with treatment. Reoxygenation in tumors and possible redistribution of proliferating tumor cells into more sensitive phases of the cell cycle may contribute to increased efficacy of dose fractionation, at least in theory. Potentially lethal damage repair in tumors would not contribute to the efficacy of dose fractionation as this would enhance the survival of tumor cells.
XX-11) Data suggests that treatment breaks are detrimental to tumor control in
head and neck cancer. The radiobiological basis of this phenomenon is:
A. Redistribution
B. Reoxygenation
C. Repair
D. Repopulation
E. Radiosensitization
XX-11) D
Accelerated repopulation is triggered several weeks after the initiation of a course of radiation therapy. A dose increase of approximately 0.6 Gy per day is needed to compensate for this repopulation. Hence, any interruptions in treatment, once it has begun, can compromise tumour control due to accelerated repopulation.
XX-12) Continuous hyperfractionated accelerated radiation therapy (CHART)
involved all of these EXCEPT:
A. Short overall treatment time of 12 consecutive days
B. Three fractions of radiation per day
C. Total dose of 50 – 54 Gy
D. Low dose per fraction (1.4 – 1.5 Gy)
E. Concurrent chemotherapy
XX-12) E
The CHART protocol was performed in the 1990s in the UK for the treatment of head and neck squamous cancers and non-small cell lung cancer. It involved 36 fractions over 12 consecutive days with three fractions delivered daily. Each fraction was between 1.4 – 1.5 Gy with a total dose of 50 – 54 Gy. The strategy was based on the thought that low dose/fraction would minimize late effects and a short treatment time would maximize tumor control. There was no concurrent chemotherapy given.
Long-term results showed no differences in disease outcomes for head and neck cancer patients, but there was an improvement in late morbidity with CHART compared to conventional fractionation. For NSCLC, there was an improvement in local progression and overall survival. Despite these promising results, CHART has had limited adoption due to the resource intensive nature of the treatment as well as the more widespread use of concurrent chemotherapy.
XX-13) Data has suggested that overall treatment time is crucial for which of the
following tumors:
A. Head and neck cancer
B. Endometrial cancer
C. Melanoma
D. Breast cancer
E. Basal cell carcinoma
XX-13) A
Data has shown that local tumor control is decreased by about 1.4% for each day that treatment is prolonged for head and neck cancer and 0.5% for uterine cervix cancer. There is no data suggesting a similar effect in melanoma, breast, or basal cell cancer.
XX-14) Considering our current knowledge of typical alpha/beta values and basic
radiobiological concepts, which of the following organ sites would be
most likely to gain therapeutic benefit with hypofractionation?
A. Prostate
B. Head and Neck
C. Breast
D. Bladder
E. Brain
XX-14) A
Because of the low alpha/beta ratio of prostate cancer cells, a hypofractionated protocol would not result in greater normal tissue damage than tumor kill. In the case of other tumors, the higher alpha/beta ratio of the tumor than that of critical dose-limiting normal tissue would result in hypofractionation causing greater recovery in the tumor versus the normal tissue.
XXI-1) Which of the following equations would be most appropriate to use when
calculating the BED for treatment involving a permanent radioactive
implant?
XXI. Brachytherapy Answers & Explanations
XXI-1) E
An equation that takes into account the complete decay of the brachytherapy source is most appropriate for calculation of the BED for a permanent radioactive implant. Choice A is the correct equation to use for standard external beam therapy when the dose is delivered typically over a 1-2 minute period or for high dose-rate brachytherapy.
Choice B takes into account repopulation during the course of radiotherapy and should be used to compare fractionated protocols of different durations.
Choice C is used for treatment with closely-spaced, multiple fractions per day when incomplete repair may be an issue.
Choice D is used to calculate the BED for a brachytherapy treatment at a constant, low-dose rate.
XXI-2) Which of the following radiobiological processes contributes to the
inverse dose-rate effect?
A. Repair of sublethal damage
B. Accumulation of cells in S phase
C. Proliferation
D. Repair of potentially lethal damage
E. Redistribution
XXI-2) E
Decreasing the dose rate over the range from 1 Gy/min to 0.01 Gy min generally results in an increase in the surviving fraction following irradiation with a fixed dose of radiation due to repair of sublethal damage (SLDR). The inverse dose-rate effect is the observation that, as the dose rate declines further over a critical range, cellular survival decreases as the same fixed dose is delivered. This effect relates to reassortment/redistribution of cells into the radiosensitive phase of the cell cycle by progressing through the DNA damage-induced G2 block. It would not be anticipated that SLDR, the accumulation of cells in S phase, proliferation, or repair of potentially lethal damage (PLDR) would cause an inverse dose-rate effect, since each of these processes would increase cell survival.
XXI-3) All of the following are used for brachytherapy implants EXCEPT:
A. Cesium-137
B. Iridium-192
C. Iodine-125
D. Iodine-131
E. Gold-198
XXI-3) D
Cesium-137, Iridium-192, Iodine-125, and Gold-198 are all available for brachytherapy implants. Iodine-131 is an unsealed isotope that is administered systemically for diagnostic or therapeutic purposes.
XXI-4) Which of the following has a half-life of 30 years?
A. Cesium-137
B. Iridium-192
C. Iodine-125
D. Iodine-131
E. Gold-198
XXI-4) A
Cesium-137 has a half-life of 30 years. Iridium-192 has a half-life of 74.2 days. Iodine-125 has a half-life of 60.2 days. Iodine-131 has a half-life of 8.0 days. Gold-198 has a half-life of 2.7 days.
XXI-5) Iridium-192 is characterized by the following EXCEPT:
A. It is the most widely used radionuclide for brachytherapy procedures
in the US.
B. It has a small source size.
C. It is used for permanent implants.
D. The lower photon energy makes radiation protection easier than
radium or cesium.
E. It is available for use with computer-controlled remote afterloaders.
XXI-5) C
Iridium-192 is the most widely used radionuclide in part because of its convenience, its small size, its low photon energy simplifying radiation protection, and its ability to be used in remote afterloaders. It is used for temporary implants and is not used for permanent implants.
XXI-6) The principal reason for choosing brachytherapy rather than external beam
radiation is:
A. Brachytherapy is associated with lower risk of exposure to hospital staff.
B. Implant of a brachytherapy source within the tumor provides a distinct
geometrical advantage for sparing the surrounding normal tissues.
C. Brachytherapy from a single dwell position provides a uniform dose
within the implanted tissue.
D. The dose rates that can be achieved with brachytherapy are more cytotoxic
compared to that with external beam in all tumor types.
E. A precise brachytherapy implant delivers similar dose rate to both normal
tissues and the tumor.
XXI-6) B
The principal reason for choosing brachytherapy rather than external beam radiation is that a brachytherapy implant within the tumor provides a distinct geometrical advantage for sparing the surrounding normal tissues. Brachytherapy is associated with higher risk of exposure to hospital staff. There is a steep dose rate gradient around an implanted radioactive source that results in a variation in the dose and associated cell killing.
Dose rates associated with brachytherapy are equal to or less than external beam radiation and would not be more cytotoxic.
The cell killing is highest immediately adjacent to the source, within the tumor. This has the advantage in a well-placed implant of lower dose rate to the normal tissues that are at a greater physical distance from the sources.
XXI-7) Brachytherapy:
A. Allows for a low dose rate treatment minimizing toxicities to
surrounding normal tissues.
B. Is used predominantly for retinal tumors.
C. Requires the use of antibodies for targeting the radionuclide to the
tumor.
D. Can be used to treat larger tumors than can be treated with external
beam irradiation.
E. Can be activated with microwave radiation.
XXI-7) A
One major advantage of brachytherapy is that it is able to treat the tumour and reduce toxicities to normal tissues because of the dose-rate effect. It is used predominantly for prostate and cervical carcinomas. While antibodies CAN be used for targeting, more often the brachytherapy is delivered as a seed therapy or interstitial implant. Brachytherapy is not activated in general, and microwave would not do it in any case.
XXII. Radiobiological Aspects of Alternative Dose Delivery Systems
XXII-1) Which of the following statements about carbon ion therapy is FALSE?
A. For a given dose to the tumor in the Bragg peak, carbon ions produce
better sparing of normal tissues in the entrance region of the beam than
either protons or photons
B. Carbon ions have a high RBE in the Bragg peak region
C. There is reduced scattering in both the lateral and longitudinal
directions for carbon ions compared to protons
D. There is a greater variation in radiosensitivity between oxygenated
and hypoxic tumor cells using carbon ions compared with photons
E. PET verification can be used for carbon ion treatment
XXII. Radiobiological aspects of alternative dose delivery systems Answers
& Explanations
XXII-1) D
Carbon ions represent a high LET form of radiation and, as such, displayless dependence upon oxygen for cell killing (and therefore have a lowerOER). Hence, there should be fewer hypoxic tumor cells surviving carbonion therapy than following treatments using either X-rays or protons.Basic research with light ions established that carbon ions suitable forradiotherapy (~400 MeV/amu) have superior depth-dose profiles from theentrance region of the beam up through the Bragg peak.
Two centers, one at the HIMAC in Chiba, Japan, and the other at the HITin Heidelberg, Germany, have been treating with carbon ions using agantry for over a decade and a number of other centers have come onlinesince then. Carbon ions show an increased RBE for both cells irradiatedin vitro and tissues exposed in vivo. The exact RBE depends on the energyof the beam and the characteristics of the cells at risk.
An additional advantage of treatment with carbon ions is the reduction inlateral and longitudinal scatter.
It is possible to verify the carbon ion treatment plan using PET since asmall fraction of the ions undergo nuclear fragmentation when a beam ofcarbon ions penetrates a thick absorber. Often, one or two neutrons are stripped, converting the stable 12C to the positron emitting isotopes 11Cand 10C. These isotopes travel with almost the same velocity as the mainbeam and stop in nearly the same location. They have short half-lives andas the emitted positron combines with an electron in an annihilationreaction, two 0.51 MeV photons are produced that can be detected by aPET scanner. As a consequence, the high dose treatment volume can be visualized
XXII-2) Which of the following statements concerning intensity-modulated
radiation therapy (IMRT) is CORRECT?
A. IMRT employs significantly higher energy photon beams than
unmodulated radiation dose-delivery techniques.
B. IMRT results in fewer radiation therapy-induced second cancers in the
pediatric population as compared to adults.
C. IMRT is most conformal if used in the conventional 1.8-2.0
Gy/fraction format
D. IMRT allows for higher doses to acutely responding normal tissues
while decreasing dose to late responding normal tissues.
E. The whole-body patient dose is increased with IMRT, compared to
treatment plans involving unmodulated beams due to leakage from the
head and scatter from the collimator.
XXII-2) E
The whole-body patient dose is higher with intensity modulated radiation therapy (IMRT) technique because, in addition to leakage from the head, there is scatter from the collimator. IMRT usually employs a linear accelerator at mega-voltage energies, which are similar to or lower than energies used to deliver treatment doses with an unmodulated field.
The higher risk of IMRT radiotherapy-induced second cancers in pediatric patients than in adult patients is a direct consequence of the smaller size of the body of a child compared with an adult. As originally discussed by Hall (2006), radiogenic organs are closer to the treatment site in a child and thus receive larger radiation doses than when a comparable treatment is delivered to an adult.
IMRT is most conformal if all target volumes are treated simultaneously using different fraction sizes. This permits graded dose levels to the gross tumor with embedded normal tissues and tissues at risk for tumor spread (normal tissues surrounding the gross tumor and lymph nodes). Such a treatment strategy is called the simultaneous integrated boost (SIB). The SIB strategy uses the same plan for the entire course of treatment to deliver prescribed doses to treated volumes.
The effect of modified fractionation on acute and late toxicity of normal tissue is taken into account during treatment planning. The SIB-IMRT fraction sizes are estimated using an isoeffect relationship based on the linear-quadratic (LQ) equation using the values of LQ model parameters (such as α/β ratios and tumor doubling time) for the isodose calculations for various tissues components in the treatment volume.
XXII-3) Which one of the following statements concerning radiolabeled
immunoglobin therapy is FALSE?
A. One disadvantage associated with the use of 90Y-labeled antibodies is
that the relatively low energy (<100keV) and short range of the -
particles emitted limit the so-called “crossfire effect.”
B. Both ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar)
target CD20.
C. Radiation safety is an important issue regarding the use of 131I-labeled
compounds because this isotope emits -rays that may pass through
the patient.
D. The dose-limiting organ associated with the use of tositumomab
(Bexxar) is the bone marrow.
E. The dose-limiting organ associated the use of tositumomab (Bexxar)
is the thyroid gland
XXII-3) A
90Y emits -particles with a relatively high energy (0.9 MeV) and long range that can penetrate several millimeters into the tissue. Thus, there is a significant crossfire effect, i.e., cells adjacent to those that have taken up the radioisotope are also irradiated. Radioimmunotherapy (RIT) involves treatment with a targeted radiopharmaceutical that combines a tumor-selective monoclonal antibody conjugated to a radionuclide, typically a medium-range - emitter. Two radiopharmaceuticals have been approved by the FDA for the management of relapsed and refractory CD20-positive low-grade B cell non-Hodgkin’s lymphoma (NHL): 90Y-ibritumomab tiuxetan (Zevalin) and 131I-tositumomab (Bexxar; Answer Choice B). Both drugs are composed of a murine antibody selective for the CD20 surface antigen found on over 95% of NHL B-cells (in addition to all normal mature B cells).
90Y is a pure -emitter with a short effective half-life; therefore, very little of the radioactivity produced by Zevalin escapes the patient, minimizing the radiation safety hazard. However, a surrogate imaging isotope, such as 111In, must be incorporated into the Zevalin framework to allow positional localization. Bexxar incorporates 131I, which is a medium energy, mixed-spectrum - and -emitter with a emission at 364 keV that can be detected using a gamma camera. Because of the penetrating - rays of 131I and eight-day half-life, more rigorous radiation safety precautions must be used with Bexxar.
Hematologic toxicity is the major dose-limiting toxicity for RIT. Thyroid uptake of 131I is not uncommon but is not dose limiting. To prevent thyroid uptake of 131I, oral iodine is given a day before Bexxar administration and continued for 14 days after the therapeutic dose.
XXII-4) Which of the following 5Rs of radiobiology likely has a negative impact
on severely hypofractionated schedules (1-5 fractions) used in stereotactic
body radiotherapy?
A. Radiosensitivity
B. Repair/recovery
C. Redistribution/reassortment
D. Repopulation
E. Reoxygenation
XXII-4) E
Most human tumors except for very small ones have radioresistant hypoxic cells. The negative influence of hypoxic cells against local tumour control is greater in hypo-fractionated radiotherapy compared to conventional therapy. SBRT treatments are usually completed within <1 to 2 weeks and re-oxygenation during the course of SBRT therapy is very limited to negligible. Laboratory and clinical data suggest an intra fraction interval of at least 3 days to increase possibility for re oxygenation of tumor cells between fractions.
XXII-5) Which of the following are TRUE about particle therapy?
A. Protons have a Bragg peak and are considered high LET radiation
B. C-ions have no Bragg peak and are considered high LET radiation
C. Boron-neutron capture therapy delivers high LET radiation to the
tumor
D. Si-ions have a Bragg peak and are considered low LET radiation.
E. Photons are considered as low LET radiation and do have a Bragg
peak associated with them.
XXII-5) C.
BNCT uses neutrons to activate Boron-containing compounds to release alpha particles in the tumor. These alpha particles are high LET. Protons have a Bragg peak but are considered to be low LET radiation with an RBE of near 1.1. C-ions have a Bragg peak and are considered high LET radiation. Si-ions have a Bragg peak and deliver high LET radiation. Photons are low LET but have no Bragg peak associated with them.
XXIII-1) Which of the following is a small molecule tyrosine kinase inhibitor?
A. Trastuzumab
B. Erlotinib
C. Bevacizumab
D. Sirolimus
E. Cetuximab
XXIII. Chemotherapeutic Agents and Radiation Therapy Answers &
Explanations
XXIII-1) B
Erlotinib (Tarceva) is a small molecule inhibitor of the epidermal growth factor (tyrosine kinase) receptor (EGFR). It reversibly binds to the ATP binding site of the receptor, which prohibits the formation of phosphotyrosine residues and subsequent downstream signaling cascades. Trastuzumab (Herceptin) is a monoclonal antibody against the Her2/neu
receptor. It binds to domain IV of the extracellular segment of the Her2/neu receptor, leading to arrest during the G1 phase of the cell cycle and decreased proliferation, downregulation of Akt, and suppression of angiogenesis.
Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that blocks angiogenesis via the inhibition of the vascular endothelial growth factor (VEGF)-A ligand.
Sirolimus (Rapamycin) binds to the FKBP12 complex and inhibits mTOR (FRAP1), a downstream target of the PI(3)K/AKT pro-survival signaling pathway that is activated by radiation exposure.
Cetuximab is a chimeric (mouse/human) monoclonal antibody against EGFR
XXIII-2) Which of the following statements is TRUE concerning bortezomib?
Bortezomib is:
A. An agent that stimulates ubiquitin-mediated degradation of IB
B. FDA-approved for use in the treatment of renal cell carcinoma
C. A drug that specifically targets EGFR signaling pathways
D. A proteasome inhibitor
E. A monoclonal antibody
XXIII-2) D
Bortezomib (Velcade) is a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell myeloma (Answer Choices D and B). In normal cells, the proteasome facilitates the degradation of abnormal or misfolded proteins or those tagged via ubiquitylation. Bortezomib acts by inhibiting the activity of the 26S proteasome and, therefore, the degradation of proteins. NF-B is not directly targeted by proteasome inhibitors, however, proteasome inhibitors indirectly promote NF-B being kept in its inactive form by blocking the ubiquitin-mediated degradation of its repressor, IB EGFR signaling pathways are not a target for bortezomib. Bortezomib is an N-protected dipeptide, not a monoclonal antibodyb med
XXIII-3) Which of the following best describes the mechanism of action of the
chemotherapeutic agent, irinotecan?
A. Inhibits ribonucleotide reductase
B. Stimulates thymidylate synthase
C. Interferes with the action of topoisomerase I
D. Generates DNA crosslinks
E. Inhibits DNA synthesis through depletion of nucleotides
XXIII-3) C
Irinotecan (Camptosar) is an inhibitor of the topoisomerase I enzyme. Its active metabolite, CPT-11, is a camptothecin analog that specifically inhibits DNA replication and transcription. Gemcitabine inhibits the ribonucleotide reductase enzyme. 5-Fluorouracil (5-FU) stimulates thymidylate synthase. Cisplatin is an example of an exogenous agent that causes formation of a covalent linkage (crosslink) between nucleotides of DNA. Other choices can include carmustine and mitomycin C.
Methotexate is an example of an antimetabolite that exerts its antifolate effects by competitively inhibiting dihydrofolate reductase (DHFR) with much higher affinity than folate, thus reducing tetrahydrofolate synthesis which is necessary for amino acid and nucleic acid synthesis.
XXIII-4) Sorafenib is FDA approved for use in the treatment of which cancer?
A. Hepatocellular carcinoma
B. Thyroid cancer
C. Pancreatic cancer
D. Non-small cell lung cancer
E. Kidney cancer
XXIII-4) C
Sorafenib is a targeted agent that has been approved by the FDA for use in patients with advanced renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine resistant advanced thyroid carcinoma. Sorafenib is a small molecule multi-kinase inhibitor that targets RAF1, KIT, FLT3, VEGFR (KDR) and PDGFR. RAF1 is a component of the RAS signaling cascade, a pathway that is often overactive in cancer, including renal cell carcinoma. Sorafenib also inhibits other kinases, including ones involved in tumor angiogenesis.
XXIII-5) Which of the following molecularly-targeted agents is an epidermal
growth factor receptor inhibitor?
A. Bevacizumab
B. Nivolumab
C. Imatinib
D. Cetuximab
E. Rituximab
XXIII-5) D
All the choices are examples of targeted agents, but of those listed, only cetuximab specifically targets the epidermal growth factor receptor (EGFR), a member of an important family of transmembrane signaling proteins.
EGFR signaling regulates normal cell growth and differentiation as well as tumorigenesis and disease progression in malignant tissues. EGFR isover-expressed in most solid tumors (breast, lung, colorectal cancers), and high levels of expression are positively correlated with aggressive tumour growth, reduced survival, and radioresistance. Because tumor cells depend on continued stimulation by growth factors, inhibition of the EGFR pathway is a therapeutic strategy in several tumor types.
Bevacizumab (Avastin) targets VEGF ligand and inhibits angiogenesis.
Nivolumab (Opdivo) is a human IgG4 monoclonal antibody that binds to the programmed death (PD)-1 receptor and blocks its interaction with its ligands, PD-L1 and PD-L2.
Imatinib (Gleevec) is an inhibitor of a small family of tyrosine kinases, including BCR-ABL, KIT and PDGFR; specifically, imatinib blocks the ATP-binding site of the p210 tyrosine kinase domain of the BCR-ABL fusion protein in chronic myeloid leukemia.
Rituximab is a monoclonal antibody against CD20, which has a direct anti-tumor effect in CD20-positive lymphomas by inducing apoptosis and cell lysis.
XXIII-6) Which of the following pairs of drug and description is CORRECT?
A. Glutathione – hypoxic cell cytotoxin
B. Nimorazole – most abundant cell sulfhydryl
C. Tirapazamine – radioprotector
D. Amifostine – bioreductive drug
E. Gefitinib – small molecule tyrosine kinase inhibitor
XXIII-6) E
Gefitinib is a small molecule tyrosine kinase inhibitor approved in the US for use in non-small cell lung cancer (NSCLC) harboring deletion of EGFR exon 19 or mutation of EGFR exon 21 (L858R). Glutathione is a cellular sulfhydryl compound that acts as an antioxidant. Nimorazole is a hypoxic cell radiosensitizer, while sufhydryls are considered radioprotectors. Tirapazamine is a hypoxic cell cytotoxin and therefore a radiosensitizer. Amifostine is a radioprotector that acts by detoxifying reactive metabolites of platinum and alkylating agents, and also scavenges free radicals.
XXIII-7) Which of the following pairs of a chemotherapeutic agent and its potential
target is CORRECT?
A. Etoposide – topoisomerase II
B. Topotecan – microtubules
C. Bevacizumab – EGFR
D. Sunitinib – histone deacetylase
E. 5-fluorouracil – glutathione
XXIII-7) A
Etoposide targets topoisomerase II. Topoisomerases are enzymes that participate in the overwinding or underwinding of DNA. Topoisomerase I catalyzes the transient breaking and rejoining of a single strand of DNA which lets the broken strand rotate around the intact strand, whereas Topoisomerase II cuts both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. Topoisomerase I inhibitors include irinotecan and topotecan; Topoisomerase II inhibitors include etoposide (VP-16), doxorubicin, daunorubicin, and mitoxantrone. Topotecan targets topoisomerase I. Bevacizumab targets the VEGF ligand. Sunitinib is a tyrosine kinase inhibitor with multiple targets including EGFR, FLT3, VEGFR and KIT. 5-fluorouracil targets thymidylate synthase.
XXIII-8) Which of the following statements is CORRECT? Multi-drug resistance:
A. Generally leads to cross-resistance to radiation
B. Is often induced by pre-exposure to ionizing radiation
C. Can be caused by either an increase in p-glycoprotein or other proteins
that increase drug efflux
D. Generally results in relatively small changes in sensitivity of cells or
tumors to chemotherapy agents
E. Is a transient response to intensive treatment and usually resolves
within 4-6 weeks
XXIII-8) C
Multi-drug resistance develops relatively frequently in cells and tumors exposed to chemotherapeutic agents. The primary mechanism by which this occurs is an increase in levels of p-glycoprotein or a different protein that non-specifically effluxes xenobiologics from cells. These multidrug resistant cells rapidly and efficiently efflux foreign molecules and thus maintain low, non-toxic intracellular drug levels even in the presence of high extracellular drug concentrations that would normally be lethal. Induction of multi-drug resistance by one drug can lead to resistance to a broad spectrum of related and unrelated drugs, which kill cells by different mechanisms.Cells or tumors that have become multi-drug resistant through this mechanism do not become radioresistant, as radiation cannot be effluxed
Radiation exposure does not cause multi-drug resistance.
The differences in the sensitivity of multi-drug resistant and non-resistant cells can be very large, often producing differences of several orders of magnitude in survival for a given drug dose.
Multidrug resistance represents a permanent change in the cell phenotype and is not transient.
Other changes in tumor cells can also increase resistance to multiple drugs. For example, increased glutathione levels would increase resistance to a spectrum of drugs with a mechanism of action involving formation of radicals. Similarly, an increase in the activity of a DNA repair pathway could lead to the improved repair of drug damage and increased survival. Resistance from these mechanisms is not nearly as dramatic as the drug resistance induced by the efflux proteins described above, but is important to radiotherapy because the changes can also cause small increases in radioresistance.
XXIII-9) Which of the following pairs of chemotherapy drugs and the dependence
of their toxicity on oxygenation status is INCORRECT?
A. Bleomycin – more toxic under aerated conditions
B. Tirapazamine – more toxic under hypoxic conditions
C. 5-Fluorouracil – no difference in toxicity between aerated and hypoxic
conditions
D. Mitomycin C – more toxic under aerated conditions
E. Misonidazole – more toxic under hypoxic conditions
XXIII-9) D
The bioreductive properties of mitomycin C make it more toxic to many cells under hypoxic conditions. Bleomycin induces DNA breaks and is dependent on the presence of oxygen. Tirapazamine is activated to a toxic radical only at a very low levels of oxygen, such as in human tumors. Tirapazamine has been shown to produce hydroxyl or benzotriazinyl radicals to damage DNA. Misonidazole is a hypoxic radiosensitizer.
XXIII-10) Which of the following statements concerning photodynamic therapy is
INCORRECT? Photodynamic therapy:
A. Reduces tumor burden via direct tumor cell killing rather than
indirectly via damage to tumor vasculature
B. Is generally used to treat either superficial tumors or those that can be
accessed with fiberoptic probes
C. Involves the use of a drug activated by visible light
D. Is toxic through the formation of singlet oxygen
E. Is maximally effective in aerobic tissues
XXIII-10) A
Photodynamic therapy (PDT) requires a photosensitizer, oxygen, and visible light to produce the cytoxic highly reactive singlet oxygen radical, which ultimately achieves tumor cell killing indirectly via damage to the tumor vasculature. Although direct tumor cell killing may occur, particularly when there is a long drug-light exposure that allows free diffusion of the photosensitizer into tumor tissue, in most instances, the main photosensitizing effect occurs while the drug is confined to the tumor vasculature and results in damage to these endothelial cells, which leads to the indirect killing of tumor cells as a result of the vascular damage.
PDT has been used to treat both superficial tumors as well as more deep seated tumors that can be accessed endoscopically and exposed to light using fiberoptic probes. Because oxygen is required for the PDT reaction, PDT is ineffective in hypoxic conditions.
XXIII-11) Cisplatin has all the following properties EXCEPT:
A. It inhibits DNA synthesis more than RNA or protein synthesis
B. It is cell-cycle non-specific
C. It is similar in efficacy to its isomer, trans-platinum
D. It causes both inter-strand and intra-strand crosslinking
E. It is used as a radiosensitizer with concurrent radiation therapy
XXIII-11) C
Cisplatin is a chemotherapeutic agent that causes DNA synthesis inhibition by causing both interstrand and intrastrand crosslinking. It is cell-cycle non-specific. It is used as a radiosensitizer with concurrent radiation therapy It is much more effective than its isomer, trans-platinum.
XXIII-12) Which of the following is associated with cardiac toxicity?
A. Doxorubicin
B. Cisplatin
C. Bleomycin
D. Methotrexate
E. Docetaxel
XXIII-12) A
Doxorubicin (Adriamycin) is associated with dose-related cardiomyopathy. Cumulative lifetime doses greater than 450 mg/m2 are associated with increased risk of heart failure similar to dilated cardiomyopathy. The mechanism behind cardiac toxicity is unclear, but appears to be associated with oxidative stress and is quite distinct from its antineoplastic actions.
Cisplatin has been linked to ototoxicity and renal toxicity.
Bleomycin is associated with an increased risk of pulmonary toxicity
Methotrexate is associated with mucositis and gastrointestinal toxicity
Docetaxel and other microtubule poisons are associated with peripheral neuropathy
XXIII-13) Which of the following effects is associated with improved survival in
patients treated with radiation therapy and cetuximab for head and neck
cancer:
A. Hair loss
B. Erythema
C. Acneiform rash
D. Desquamation
E. Pruritis
XXIII-13) C
Data suggests that patients treated with definitive radiation and cetuximab who develop a Grade 2 or greater acneiform rash experience have increased overall survival compared to patients who develop either no rash or grade 1 rash (HR 0.49).
XXIII-14) Which of the following targeted agents is an immune checkpoint
inhibitor?
A. Bevacizumab
B. Ipilimumab
C. Imatinib
D. Cetuximab
E. Crizotinib
XXIII-14) B
Ipilimumab is an antibody against the immune checkpoint molecule CTLA-4. Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A) ligand
Imantinib is a small molecular inhibitor of receptor tyrosine kinases. It is most selective for BCR-ABL, but also targets c-kit and PDGF-R.
Cetuximab is a monoclonal antibody against EGFR.
Crizotinib is a small molecular inhibitor of ALK and ROS1 kinases.
XXIII-15) Which of the following pairs of a targeted agent and its potential target is
CORRECT?
A. Crizotinib – anaplastic lymphoma kinase (ALK)
B. Imantinib – programmed cell death 1 (PD-1)
C. Cetuximab – ABL kinase
D. Sunitinib – Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
E. Sorafenib – CD20
XXIII-15) A
Crizotinib is a small molecular inhibitor of ALK and ROS1 kinases; it is FDA approved from non-small cell lung carcinomas bearing the EML4- ALK fusion gene. Imatinib is a small molecular inhibitor of receptor tyrosine kinases. It is most selective for BCR-ABL, but also targets c-kit and PDGF-R.
Cetuximab is a monoclonal antibody against EGFR. Sunitinib and sorafenib are “dirty” multi-targeted receptor tyrosine kinase inhibitors.
Inhibitors of programmed cell death 1 (PD-1) receptor include pembrolizumab and nivolumab. Inhibitors of programmed death ligand 1 (PD-L1) include atezolizumab, durvalamab, and avelumab. Ipilimumab is an example of a Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) inhibitor. Ipilimumab functions by disinhibiting the native ability of T cells to recognize and destroy cancer cells. Rituximab is an example of a CD20 inhibitor
XXIII-16) Which of the following is an example of synthetic lethality?
A. Retroviral overexpression of p53 in tumor cells to induce apoptosis
B. Infusion of chimeric antigen receptor-expressing T cells to induce an
anti-tumor immune response
C. The use of taxane-containing nanoparticles to take advantage of leaky
tumor vasculature and cause improved tumor cell kill while limiting
normal tissue toxicity
D. The use of poly-ADP ribose polymerase inhibitors to abrogate repair
of DNA damage in BRCA1/2-mutant tumors and thus promote lethal
DNA damage
E. The infusion of liposomal siRNA targeting K-ras in pancreatic cancers
XXIII-16) D
Synthetic lethality is the situation whereby a defect in one of a pair of genes has little to no effect on cell survival, while defects in both genes results in death. A clinically relevant example of this is the use of poly ADP ribose polymerase (PARP) inhibitors such as olaparib in BRCA1/2 mutated breast cancers. Because BRCA1/2-mutated cancers have defective homologous recombination repair (HRR), they depend on error prone alternative DNA repair pathways for genome maintenance and survival. PARP binds to single-strand DNA breaks to initiate non homologous repair. Inhibition of PARP by compounds such as olaparib interrupt this process, promote stalled replication forks, and result in double strand breaks. BRCA1/2-wild type cells with intact HRR do not depend on this pathway and are therefore not sensitive to PARP inhibition.
XXIV. Radiosensitizers, Radioprotectors and Bioreductive Drugs
XXIV-1) Which of the following statements concerning hypoxic cell sensitizers and
bioreductive drugs is TRUE?
A. One possible reason that clinical trials of hypoxic cell radiosensitizers
yielded disappointing results is the dose limitation imposed by severe
neurological toxicity that often developed in patients receiving higher
doses of the drugs
B. Bioreductive drugs are synthesized in a pro-drug form that, upon
administration, are oxidized and thereby activated to a cytotoxic
intermediate
C. Bioreductive drugs are more toxic to aerobic cells than to hypoxic
ones
D. Clinical trials of nimorazole have yielded results indicating a
significant improvement in both local control and overall survival in
patients with head and neck cancer treated with this drug and
radiotherapy
E. Hypoxic cell radiosensitizers are most effective in combination with
hyperfractionated radiotherapy
XXIV. Radiosensitizers, Radioprotectors and Bioreductive Drugs Answers
& Explanations
XXIV-1) D
Meta analysis has shown that when combined with radiotherapy, nimorazole significantly improves both local control and overall survival in select subsets of patients with head and neck cancer. One reason that clinical trials of hypoxic cell sensitizers may have yielded disappointing results was because of the dose-limiting peripheral neuropathy; this cumulative toxicity severely limited the total dose of sensitizers that could be given over a course of radiotherapy.
Bioreductive drugs are compounds that are metabolically-reduced under hypoxic conditions to yield cytotoxic species
Because the bioreduction occurs preferentially under hypoxic conditions, these drugs are selectively toxic to hypoxic cells and not aerobic ones.
In laboratory studies, hypoxic cell radiosensitizers are most effective when given in high doses and with large radiation doses; their effectiveness in model tumor systems decreases with increasing fractionation. One would expect from these laboratory studies that radiosensitizers would be more effective in combination with hypofractionated radiotherapy regimens or radiosurgery, rather than with standard radiotherapy regimens or hyperfractionated regimens.
XXIV-2) The enzyme inhibited by 5-fluorouracil that is most closely associated
with both its cytotoxic and radiosensitizing effects is:
A. Dihydrofolate reductase
B. Thymidylate synthase
C. RAD50
D. Tyrosine kinase
E. Ligase IV
XXIV-2) B
Thymidylate synthase is the enzyme inhibited by 5-fluorouracil, leading to the inhibition of DNA synthesis as well as the synthesis of both ribosomal and messenger RNA. This accounts for the drug’s cytotoxic and radiosensitizing effects.
XXIV-3) Radiosensitization produced by gemcitabine is associated with the
inhibition of which of the following enzymes?
A. Topoisomerase I
B. DNA-PKcs (PRKDC)
C. DNA polymerase
D. Ribonucleotide reductase
E. Sphingomyelinase
XXIV-3) D
In its active metabolite form, gemcitabine inhibits ribonucleotide reductase, which likely accounts for its action as a radiosensitizer. The inhibition of this enzyme affects DNA synthesis by preventing the de novo biosynthesis of deoxyribonucleoside triphosphate precursors.
XXIV-4) Sulfhydryl radioprotectors reduce radiation-induced toxicity by:
A. Preventing the formation of free radicals
B. Scavenging free radicals
C. Stimulating host immune responses
D. Inhibiting ion pair formation
E. Increasing intracellular oxygen
XXIV-4) B
Sulfhydryl radioprotectors reduce radiation toxicity by scavenging free radicals. Amifostine, the only FDA approved radioprotector, is a prodrug that is hydrolysed in vivo by alkaline phosphatase to the active sulfhydryl compound, WR-1065.
XXIV-5) Which of the following statements concerning amifostine is TRUE?
A. Amifostine is most effective when administered orally
B. Amifostine’s dose-limiting toxicity is peripheral neuropathy
C. Amifostine does not readily cross the blood-brain barrier
D. Maximum radioprotection against acute toxicities is achieved when
amifostine is administered after irradiation
E. Amifostine does not require metabolic activation for its activity as a
radioprotector
XXIV-5) C
Amifostine does not readily cross the blood brain barrier and therefore affords little radioprotection to tissues in the CNS. Amifostine must be administered intravenously for maximal efficacy.
Hypotension, nausea/vomiting, fatigue, and fever/rash are the main toxicities associated with amifostine.
Amifostine should be administered 15-30 minutes before radiotherapy, not after.
It is a pro-drug that is metabolized by alkaline phosphatase to the free thiol metabolite that acts as the direct radioprotective agent.
XXIV-6) One proposed mechanism through which cisplatin acts as a radiosensitizer
is by:
A. Inhibiting the production of dTMP
B. Interfering with DNA repair
C. Inhibiting the proteasome
D. Blocking growth factor receptors
E. Deacetylating histones
XXIV-6) B
Cisplatin binds to DNA to create adducts, leading to intrastrand and, at a lower frequency, interstrand cross-links. One mechanism that has been proposed to account for the radiosensitizing effect of cisplatin is through the inhibition of DNA double-strand break repair.
XXIV-7) Temozolomide improves survival in patients with glioblastoma that
receive radiation therapy, particularly if the tumor demonstrates:
A. epigenetic silencing of O6-methylguanine-DNA methyltransferase
(MGMT)
B. epigenetic silencing of microRNA expression
C. epigenetic silencing of PTEN
D. expression of the mutant receptor EGFRvIII
E. expression or amplification of Her2/neu
XXIV-7) A
Methylation of the promoter for MGMT (O6 -methylguanine-DNA methyltransferase) via an epigenetic mechanism (not via a gene mutation) decreases expression of this DNA repair gene. When tumor cells do express MGMT they are able to repair the alkylation of DNA caused by temozolomide. Therefore, patients with MGMT-expressing glioblastomas derive little benefit from concurrent temozolomide and radiation therapy. In contrast, when MGMT is silenced, temozolomide is able to achieve significant DNA damage via alkylation, which ultimately increases its radiosensitivity.
XXIV-8) Rapamycin, everolimus and temsirolimus may act as a radiosensitizers by
inhibiting:
A. K-ras
B. mTOR
C. MAPK
D. p38
E. EGFR
XXV-8) B
Rapamycin, everolimus and temsirolimus are all inhibitors of the mTOR (mammalian target of rapamycin) protein. mTOR functions downstream of PI(3)K to promote cell survival. Inhibition of mTOR blocks these pro survival pathways.
XXIV-9) Wee1 inhibitors have been tested as radiosensitizers because they:
A. Interfere with the G2/M checkpoint
B. Block phosphorylation of MAPK-related proteins
C. Suppress NHEJ repair
D. Are selectively toxic in hypoxic tumor cells
E. Inhibit the proteosome
XXIV-9) A
Ionizing radiation induces a G2/M checkpoint arrest, thereby allowing sufficient time for the repair of double strand breaks (DSBs) before the initiation of mitosis, since cell division in the presence of an unrepaired DSB could lead to mitotic catastrophe. Blockade of this checkpoint via inhibition of Wee1, which typically enforces it, would lead to significant radiosensitization. The Wee1 inhibitor, MK1775, has been tested in diffuse intrinsic pontine glioma (DIPG) and glioblastoma as a radiosensitizer
XXIV-10) What is the function of the LAG-3 molecule?
A. LAG-3 is a tyrosine kinase receptor located on the cell surface.
B. Acetylation of histones.
C. A negative regulator of the immune system.
D. Regulates p53 function.
E. Suppress NHEJ repair
XXIV-10) C
LAG-3 (Lymphocyte-activation gene 3, CD223) is a cell surface molecule present on T cells and other various immune system cells. LAG3’s main ligand is MHC class II. LAG-3’s physiological function appears to be as an immune checkpoint receptor (i.e. negatively regulation of T cell proliferation and activation) in a similar fashion to CTLA-4 and PD-1 Ongoing trials suggest that LAG-3 and PD-1 synergistically regulate T cell function in such a way as to allow an anti-tumoral immune response to be blunted effectively by inhibiting both pathways.
XXIV-11) Which of the following about alectinib is FALSE?
A. It is an anaplastic lymphoma kinase (ALK) inhibitor and is FDA
approved for the treatment of anaplastic lymphoma and ALK-fusion
gene positive non-small cell lung cancer (NSCLC).
B. Alectinib improves disease-free survival in first-line treatment of
ALK fusion-positive NSCLC compared to the 1st-generation ALKinhibitor crizotinib.
C. Alectinib has lower rates of Grade 3+ toxicity compared to crizotinib.
D. Alectinib has improved efficacy for brain metastases compared to
crizotinib.
E. Alectinib is more effective when combined with gefitinib
XXIV 11) A
Alectinib received full FDA approval in 2017 for the treatment of ALK fusion positive NSCLC [not anaplastic lymphoma] after the J-ALEX and ALEX trials showed improved PFS compared to crizotinib.
In both trials, alectinib had a lower rate of Grade 3+ adverse effects compared to crizotinib. The most common side effects with either drug are GI upset, transaminitis, and anemia.
In the ALEX trial, 122 patients had brain metastases at baseline, of whom 46 had received prior radiation therapy. Time to CNS progression was longer with alectinib compared to crizotinib in both patients with brain metastases at baseline as well as those without brain metastases at baseline
XXIV-12) Which of the following metastatic cancers is predicted to have the
LOWEST response rate from checkpoint blockade?
A. Melanoma
B. Lynch syndrome-associated endometrial cancer
C. Non-small cell lung cancer
D. Microsatellite-stable colorectal cancer
E. Human papilloma virus induced head and neck squamous cell
carcinoma
XXIV 12) D
The somatic mutation load of cancers is thought to be a major determinant of response to immune checkpoint blockade through the generation of neoantigens targetable by the immune system. Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are essentially synonymous for the purposes of mutagenicity, as the former leads to the latter. MMR deficiency is seen in 10-20% of patients with sporadic colorectal cancer and approximately 20% of sporadic endometrioid endometrial adenocarcinomas. MMR deficiency is also the hallmark of Lynch syndrome, which predisposes patients to these tumors as well as others. Although MSI is not a hallmark of melanoma and NSCLC, these diseases are typically associated with high mutational burden attributed to the instigating mutagenicity of ultraviolet light and tobacco exposure, respectively. Tumor mutational burden has been associated with response to anti-PD1 in these diseases.
XXIV-13) Which of the following is FALSE regarding superoxide dismutase (SOD)
mimetics?
A. The chemical structure of a SOD mimetic contains a redox active
metal ion that is oxidized in the presence of superoxide (O2
●-
)
B. Their mechanism of action involves converting superoxide (O2
●-
) into
hydrogen peroxide (H2O2)
C. Their ability to protect against radiation- and chemotherapy-related
oral mucositis in head and neck cancer is currently being evaluated in
clinical trials
D. An SOD mimetic has yet to be identified that protects against radiation
toxicity in normal tissues without also protecting tumor tissue
E. Their mechanism of action involves inhibition of catalase enzymatic
activity
XXIV 13) D
One SOD mimetic, GC4419, that is currently in clinical trials is able toselectively protect normal cells from radiation- and chemotherapy-related toxicity without protecting tumor cells.
Superoxide dismutase (SOD) mimetics contain a redox active metal ionas part of their chemical structure.
In the presence of superoxide (O2 ●- ), the redox active metal ion is oxidized(loses an electron) and the superoxide is reduced to hydrogen peroxide.
SOD mimetics have been evaluated in phase 1 and 2 clinical trials regarding their ability to protect against radiation- and chemotherapy induced oral mucositis; a phase 3 clinical trial is currently underway
XXIV-14) Which of the following compounds CANNOT be used to protect
mammalian cells from radiation damage?
A. WR-2721
B. WR-638
C. Taxanes
D. Cysteine
E. Amifostine
XXIV-14) C
Taxanes bind to microtubules and adversely affect their function by enhancing and preventing disassembly. Taxanes act as mitotic inhibitors by blocking cells in the G2/M phase of the cell cycle and, if the concentration is sufficient, killing them in this phase.
WR-2721, also known as Amifostine or Ethyol, is the only FDA-approved radioprotective drug used for the prevention of xerostomia in head and neck cancer patients treated with radiation.
WR-638, also known as Cystaphos, has been proposed as a radioprotector
Cysteine as well as cysteamine are radioprotective sulfhydryl (SH) compounds but unfortunately associated with debilitating toxicity.
XXIV – 15) Superoxide is a reactive oxygen species involved in the biologic cascade
resulting in radiation induced severe oral mucositis. Which of the
following is INCORRECT about superoxide dismutase and superoxide
dismutase mimetics?
A. The active site of superoxide dismutase or superoxide dismutase
mimetics contains a redox active metal ion
B. Superoxide dismutases involve both the reduction and reoxidation of
the redox active metal
C. Two different superoxide dismutase isoforms have been identified in
mammals: SOD1 and SOD2
D. Avasopasem is a superoxide dismutase mimetic that reduced the
incidence of cisplatin and radiation induced severe oral mucositis in a
phase 2b clinical trial
E. Superoxide dismutases reduce the free radical to hydrogen peroxide,
which is subsequently converted to water by a catalase.
XXIV-15) C
Superoxide dismutase and superoxide dismutase mimetics catalyze the conversion of superoxide to hydrogen peroxide. Superoxide dismutase has redox active metals (Mn, Cu, Zn) at its active site. Three superoxide dismutases have been identified in mammals: Cu/Zn SOD, MnSOD, and ECSOD. The redox active metal reacts with superoxide forming molecular oxygen and the reduced redox active metal. The reduced redox active metal reacts with a second superoxide molecule forming hydrogen peroxide and re-oxidizing the redox active metal (see Figure 2 of PMID: 21473702). In a phase 2b clinical trial, Avasopasem reduced the incidence of severe oral mucositis in head and neck cancer patients receive cisplatin and ionizing radiation (PMID: 31618127)
XXV. Hyperthermia
XXV-1) Which of the following statements concerning the Arrhenius analysis of
mammalian cell killing by heat is TRUE?
A. An Arrhenius curve plots the log of the slope (1/D0) of heat survival
curves as a function of temperature
B. The break point in the Arrhenius plot is defined as the temperature at
which the slope of the plot significantly increases.
C. The Arrhenius relationship has been used to define the temperature
dependence of mechanisms of cell killing
D. The results of these analysis suggested the nuclear matrix may be a
target of heat-induced cell killing
E. The break point in the Arrhenius plot is different between rodent and
human cancer cells.
XXV. Hyperthermia Answers & Explanations
XXV-1) C
A linear Arrhenius plot is used for first order rate kinetics of a chemical reaction. Although cell killing is not a likely a simple chemical reaction, the plot for cell killing is useful for theorizing the mechanism of cell killing by heat. The Arrhenius plot demonstrates the temperature at which the mechanisms underlying cell killing changes, potentially reflecting different targets for cytotoxicity above the break point (43o C)
The Arrhenius analysis plots survival data of cell cultures exposed to increasing temperatures. The X-axis plots 1/D0, where D0 represents the time at a given temperature required to reduce the fraction of surviving cells to 37% of the initial population. The Y-axis plots 1/T, where T is the absolute temperature.
The slope of the Arrhenius plot suggests the activation energy of the chemical process involved in the cell killing. At some point (1/T), corresponding to approximately 43o , there is a significant and abrupt decrease in the slope.
The results of these analysis suggested that the target for heat cell killing may be a protein. The break point in the Arrhenius plot occurs at a temperature of approximately 43o C, and is the same across mammalian cells.
XXV-2) Hyperthermia combined with radiation may be effective in cancer therapy
because:
A. Tumor cells are intrinsically more sensitive to heat than normal cells
B. Hyperthermia can restore aeration to hypoxic tumor cells by
increasing blood flow, thereby increasing radiosensitivity.
C. Heat increases the number of ionizations produced by a given dose of
radiation
D. Hyperthermia induces radiosensitization by potentiating radiation
damage to DNA.
E. Heat can produce maximum radiosensitization even if delivered
several days after irradiation
XXV-2) B
Tumor cells are more likely to be hypoxic and demonstrate a low pH compared to normal cells, which can contribute to their relative radioresistance. Hyperthermia can increase the radiosensitivity of tumour cells by increasing blood flow, leading to increased aeration and radiosensitivity.
Tumor cells are not intrinsically more sensitive to heat than normal cells but are often found in a low pH environment which makes them more sensitive.
Heat does not affect the number of ionizations produced by a given dose of radiation
Hyperthermia induces radiosensitization by targeting proteins (likely repair proteins), not DNA.
If hyperthermia is adminsitered a long time following radiation there is decreased heat-induced radiosensitization because the majority of radiation-induced DNA damage has already been repaired
XXV-3) Which of the following statements concerning hyperthermia is TRUE?
A. Heat-induced radiosensitization occurs because heat directly damages
DNA
B. Following exposure to hyperthermic conditions, heat shock proteins
(HSPs) bind to and activate the heat shock transcription factor (HSF1).
C. Hyperthermia leads to the activation of HSF1, which subsequently
binds to HSE and increases expression of HSPs.
D. Hyperthermia increases expression of HSPs, which bind to the HSE,
leading to increased expression of HSF1.
E. Heat-induced radiosensitization occurs secondary to HSP-mediated
aggregation of nuclear proteins.
XXV-3) C
At normal body temperature, heat shock proteins (HSPs), such as Hsp90 or Hsp70, are bound to heat shock transcription factor (HSF1), thereby keeping it in its inactive state. Following exposure to higher temperatures, HSPs dissociate from HSF1 in order to stabilize degenerated proteins. HSF1 is then activated and translocates into the nucleus to bind to Heat Shock Element (HSE), the promoter for HSPs, leading to enhanced transcription of the HSP gene.
HSPs are molecular chaperones that bind to non-native or (partially) unfolded proteins and assist in their correct assembly by preventing their non-productive aggregation. An additional major mechanism for heat induced radiosensitization is inhibition of the re-polymerization step in the repair of radiation-induced base damage. Heat therefore does not cause DNA damage directly.
Hyperthermia leads to HSPs dissociating from HSF1, thereby leading to its activation.
Hyperthermia leads to HSP dissociation from HSF1, which is then activated and binds to the HSE, leading to increased expression of HSPs.
Heat-induced cell death may additionally occur by prompt apoptosis or by delayed death secondary to mitotic failure. In addition, apoptosis resistant cells may die a necrotic death or die due to permanent cell cycle arrest following a heat treatment.
XXV-4) Which of the following statements concerning thermotolerance is TRUE?
A. Thermotolerance is a heritable resistance to heat-induced cell killing
B. A brief exposure to a temperature above 43C results in resistance to
a subsequent additional heat treatment delivered immediately after the
43C treatment, but at a lower temperature
C. Thermotolerance develops during the heating of tissues at
temperatures higher than 43C
D. Thermotolerance limits the clinical utility of hyperthermia
E. Thermotolerance results in decreased likelihood of subsequent
thermotolerance.
XXV-4) E
An initial brief high temperature treatment followed by heating at a lower hyperthermic temperature is called Step-down heating. Step-down heating results in greater sensitivity to a subsequent heat treatment at a lower temperature due to inhibition of the development of
thermotolerance following the initial 43o C treatment.
Once the protein damage is removed by HSPs after heat treatment, the HSPs rebind HSF1, thereby decreasing the level of HSPs in an autoregulatory loop and restoring normal heat sensitivity.
Thermotolerance is an acquired transient resistance to heat that is not heritable by the progeny of the treated cells. Thermotolerance develops during the heating of tissues at temperatures lower than 43C.
The onset and decay of thermotolerance correlates with the appearance and disappearance of heat shock proteins, and is not related to the repair of DNA damage.
XXV -5) Concerning the effects of heat on cells, which of the following statements
is FALSE?
A. Cells of low pHe (extracellular pH) or low pHi (intracellular pH) are
sensitive to heat.
B. Cycling cells are more sensitive to heat than non-cycling cells.
C. Both chronic and acutely hypoxic cells have similar sensitivity to heat.
D. Initial shoulder of hyperthermic survival curve suggests the repair of
sublethal damage.
E. Hyperthermia does not affect the repair of radiation-induced DNA
damage
XXV-5) D
Due to the difference in the mode of action, it is important not to draw conclusions for heat based on the interpretation of radiation dose-response curves. The amount of energy involved in cell inactivation is a thousand times greater for heat than for x-rays.
Hypoxic cells are sensitive to heat due to their likely low pH. In this respect there are no apparent differences between chronic and acute hypoxia
By its effect on proteins, hyperthermia can alter repair of radiation damage
XXV-6) Blood perfusion through normal and tumor tissues can be modified by
heating. Which of the following statements is FALSE?
A. For both tumors and normal tissues, all functional capillaries are open
and used to capacity.
B. Normal tissues have a relatively high ambient blood flow, which
increases in response to thermal stress.
C. Tumor tissues have unresponsive neo-vasculature to heat and are
incapable of augmenting blood flow.
D. Hyperthermia can induce compression and occlusion of tumor blood
vessels.
E. Tumors get hotter than surrounding normal tissues because of
ineffective dissipation of heat.
XXV-6) A
Tumor vasculature often lacks normal vascular structure. As a result of poor oxygen delivery by tumor neo-vasculature, tumor capillaries with functioning vasomotor control generally are open and used to capacity. In normal tissues, however, vasomotor activity is related to demand. When demands for oxygen delivery and homeothermy are normal many capillaries in normal tissue are closed.
XXV-7) Hyperthermia and radiotherapy perform complementary actions in
achieving tumor cell killing. Which of the following statements is
FALSE?
A. Hyperthermia causes protein damage while radiotherapy causes DNA
double strand breaks in cells
B. Hyperthermia preferentially kills cells in S phase and radiotherapy
cells in G2/M phases of the cell cycle
C. Hyperthermia causes damage preferentially in hypoxic regions, while
radiotherapy primary affects aerobic regions of tumors
D. Hyperthermia above 43o
C inhibits repair of radiotherapy-induced
damage
E. Long-duration mild hyperthermia (42o
C) cannot inhibit the repair of
sublethal radiation damage because of the low temperature
XXV-7) E
Hyperthermia and radiation have different mechanisms of cell killing where heat affects proteins and radiation causes strand breakage in DNA. Cells are most resistant to radiation in S phase while most sensitive to heat in S phase. Studies have shown that hyperthermia at lower temperatures (42C) can have Thermal Enhancement Ratios above 1.0 (thus increasing radiation damage) and this increases with higher temperatures.
XXIII-17) Panitumumab is now FDA-approved for the management of k-ras wildtype metastatic colorectal cancer that has progressed through primary
chemotherapy. In regards to mechanism of action, panitumumab is most
similar to which of the following agents?
A. Rituximab
B. Cetuximab
C. Bevacizumab
D. Infliximab
E. Sunitinib
XXIII-17) B Panitumumab is a humanized IgG2 monoclonal antibody to the epidermal
growth factor receptor (EGFR). Cetuximab is a chimeric IgG1 antibody
also targeting the EGFR and is used in the treatment of metastatic k-ras
wild-type colorectal cancers as well as in head and neck cancers.
In contrast, Rituximab targets CD20 (primarily in B-cell lymphomas;
Answer Choice A).
Bevacizumab targets the VEGF-A ligand (Answer Choice C).
Infliximab is a monoclonal antibody against tumor necrosis factor (TNF)-
α and is used in the treatment of autoimmune disorders such as rheumatoid
arthritis and psoriasis (Answer Choice D).
Sunitinib is a multi-tyrosine kinase receptor inhibitor (Answer Choice E).
XXIII-18) Yttrium-90, a beta-emitting radioisotope, is used in the management of
several malignant conditions. It can be medically used in all the following
forms EXCEPT:
A. Bound to an anti-CD20 antibody in the treatment of certain types of
non-Hodgkin lymphoma.
B. Bound to resin microspheres in the treatment of hepatic metastases
from colorectal cancer.
C. Bound to glass microspheres in the treatment of hepatocellular
carcinoma.
D. Bound to metal needles in the local treatment of primary breast
adenocarcinoma.
XXIII-18) D Ibritumomab tiuxetan is an anti-CD20 antibody tagged with yttrium-90
(Y90) used for the systemic radioisotope based-treatment of widespread
B-cell lymphomas (Answer Choice A).
Y90 containing resin microspheres are FDA-approved for the treatment
of hepatic metastases from colorectal cancer (Answer Choice B).
Y90 containing glass microspheres are approved for the treatment of
primary hepatocellular carcinomas (Answer Choice C).
