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The Use of Imaging in the Prediction and Assessment of Cancer Treatment Toxicity

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Hossein Jadvar
Hossein Jadvar
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Abstract and Figures

Multimodal imaging is commonly used in the management of patients with cancer. Imaging plays pivotal roles in the diagnosis, initial staging, treatment response assessment, restaging after treatment and the prognosis of many cancers. Indeed, it is difficult to imagine modern precision cancer care without the use of multimodal molecular imaging, which is advancing at a rapid pace with innovative developments in imaging sciences and an improved understanding of the complex biology of cancer. Cancer therapy often leads to undesirable toxicity, which can range from an asymptomatic subclinical state to severe end organ damage and even death. Imaging is helpful in the portrayal of the unwanted effects of cancer therapy and may assist with optimal clinical decision-making, clinical management, and overall improvements in the outcomes and quality of life for patients.
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diagnostics
Review
The Use of Imaging in the Prediction and Assessment
of Cancer Treatment Toxicity
Hossein Jadvar
Division of Nuclear Medicine, Department of Radiology, Keck School of Medicine,
University of Southern California, Los Angeles, CA 90033, USA; jadvar@med.usc.edu;
Tel.: +1-323-442-1107; Fax: +1-323-442-3253
Received: 9 May 2017; Accepted: 17 July 2017; Published: 20 July 2017
Abstract:
Multimodal imaging is commonly used in the management of patients with cancer.
Imaging plays pivotal roles in the diagnosis, initial staging, treatment response assessment, restaging
after treatment and the prognosis of many cancers. Indeed, it is difficult to imagine modern precision
cancer care without the use of multimodal molecular imaging, which is advancing at a rapid pace with
innovative developments in imaging sciences and an improved understanding of the complex biology
of cancer. Cancer therapy often leads to undesirable toxicity, which can range from an asymptomatic
subclinical state to severe end organ damage and even death. Imaging is helpful in the portrayal of
the unwanted effects of cancer therapy and may assist with optimal clinical decision-making, clinical
management, and overall improvements in the outcomes and quality of life for patients.
Keywords: toxicity; therapy; cancer; imaging
1. Introduction
Cancer treatment has evolved considerably, with significant improvements in various outcome
measures. Some malignancies may be amenable to cure, while some can be managed as a chronic
disease. These achievements are fundamentally based on the ever-growing advances in our
understanding of the complex biology and spatiotemporal heterogeneity of cancer. Innovations in
multimodal imaging have also provided unprecedented opportunities to contribute to this quest.
Imaging has become a major component of comprehensive cancer care and may be used for diagnosis,
staging, assessing treatment response, restaging after therapy, and prognosis.
Cancer treatments are varied and are evolving towards precision therapy based on the underlying
molecular profile of tumors. Most treatments are associated with at least some level of undesired
toxicity, which may be due to a direct effect on non-tumor tissue or the body’s reaction to the treatment’s
direct damage of tumor cells. Imaging can play a major role in the assessment of anticipated and,
occasionally, the unanticipated toxicity of cancer treatment. Treatment-induced toxicity is reported on
a grading scale from one to five [
1
]. Grade one toxicity denotes asymptomatic or mildly symptomatic
adverse events which may be observed on imaging and often do not lead to the need for intervention.
With an increasing grade score, the severity of toxicity increases; to the extent that grade five denotes
death. Typically, grade two toxicity (a moderately adverse event) may lead to an intervention, including
a decrease in drug doses or the use of steroids [
2
]. In this article, we briefly review the use of imaging
in the assessment of cancer treatment toxicity—organized by organ systems—providing a concise
guide to the published literature on this topic. A comprehensive glossary of imaging features for
various cancer treatment-related conditions is not the intention of this narrative review. The interested
reader may refer to the relevant specified references for such details.
Diagnostics 2017,7, 43; doi:10.3390/diagnostics7030043 www.mdpi.com/journal/diagnostics
Diagnostics 2017,7, 43 2 of 12
2. Neurological Toxicity
Cancer therapy-associated neurotoxicity can occur in patients regardless of the site and type of
tumor [
3
]. Perry et al. have reviewed the literature on cancer therapy-associated neuropathology [
4
].
Chemotherapy can occasionally lead to significant neurotoxicity; for example, platinum-based
drugs cause peripheral neuropathy by damaging sensory neurons within the dorsal root ganglia.
Predicting the occurrence and severity of neurotoxicity remains challenging [
5
]. The damage caused
by cancer therapy may have a variable onset (acute, delayed) and include direct cellular toxicity,
changes in cellular function, and other adaptations such as inflammation that can indirectly cause
injury [
6
]. Manifestations of neurotoxicity can be varied, including alterations in attention, cognitive
impairment, psychiatric events, diminished executive functions, cerebrovascular complications, diffuse
brain atrophy, and posterior reversible encephalopathy syndrome (PRES) [
7
]. PRES may be associated
with a variety of immunosuppressive therapies and other agents such as cisplatin, rituximab, and
bevacizumab. There may be multiple predisposing host risk factors that can contribute to the
development of neurotoxicity, including patient’s age, genetic background, and their predisposition
to idiosyncratic reactions [
4
]. The relevant biological factors may include polymorphisms in folate
metabolizing enzymes and apolipoprotein E, as well as those in blood-brain barrier transporter
genes [8].
Imaging is often used not only to assess the response to therapy and to differentiate between
radiation necrosis and residual or recurrent tumors but also to detect and characterize potential
chemotherapy-associated toxicity [
9
,
10
]. Moreover, a combination of pre, during and post-chemotherapy
imaging assessments of relevant biomarkers may facilitate the querying process of the underlying
mechanisms that are involved in therapy-induced neurotoxicity. The use and limitations of various
imaging modalities in the assessment of cancer treatment-related neurotoxicity have previously
been reviewed [
11
–
13
]. Generally, anatomically-based imaging modalities, particularly magnetic
resonance (MR) imaging, can be helpful in the assessment of inflammation, edema, atrophy, necrosis,
gliosis, hemorrhage, ischemia, etc. For example, Futterer et al. showed that MR diffusion abnormalities
might be seen in the corpus callosum of patients receiving bevacizumab therapy for malignant brain
tumors [
14
]. In PRES, there are often posterior brain subcortical white and gray matter lesions on
fluid-attenuated inversion recovery (FLAIR) and T2-weighted sequences [
10
]. There are relatively few
scintigraphic studies dedicated to the imaging assessment of therapy-associated neurotoxicity. However,
single photon computed tomography (SPECT) and positron emission tomography (PET) with relevant
radiotracers could assess perfusion and metabolism and various biomarkers—including conditions
such as cognition—which may become altered during cancer therapy.
3. Pulmonary Toxicity
The lung is a common site of cancer therapy-related acute and chronic toxicity caused by
radiotherapy and several anticancer drugs such as methotrexate, paclitaxel, docetaxel, and gemcitabine.
Radiation therapy (RT) is often employed in the treatment of lung cancer. While treatment planning
is optimized to limit non-target radiation, some damage may occur along the path of the radiation
beam. Post-RT lung density changes on computed tomography (CT) and symptomatic radiation
pneumonitis have been found to be associated with RT techniques, total doses as low as 16–30 Gy, and
increasing age [
15
]. Farr et al. studied the potential use of perfusion SPECT in predicting the risk of
RT in combination with standard CT-based dose-volume parameters in patients with non-small-cell
lung cancer who were undergoing radiotherapy [
16
]. Perfusion SPECT could be used to improve
radiotherapy planning and reduce pulmonary radiotoxicity. Earlier studies with
99m
Tc-DTPA aerosol
inhalation planar lung scintigraphy had shown that there was a significantly shorter clearance time
in patients with chemotherapy-induced pulmonary damage compared with their pretreatment state
or to those who did not receive chemotherapy [
17
,
18
]. Petit et al. hypothesized that pretreatment
pulmonary inflammation renders the lung more susceptible to radiotoxicity [
19
]. In a retrospective
study of 101 patients with non-small-cell lung cancer who were treated with chemo-radiation
Diagnostics 2017,7, 43 3 of 12
therapy,
18
F-fluorodeoxyglucose (FDG) PET/CT was performed to assess the relationship between
radiation-induced lung injury and pretreatment increased lung density, on CT, and pretreatment
pulmonary FDG uptake, on PET. The risk of lung radiotoxicity was increased in those lung segments
that showed a high pretreatment pulmonary FDG uptake, suggesting that the risk of radiation injury
may be decreased if the areas of pulmonary hypermetabolism subtended by the radiation port can be
minimized [
20
]. MacManus and colleagues determined that for every one-level increase in a defined
visual scoring of lung FDG uptake, the risk of radiation pneumonitis increased by 40% [21].
In another investigation, FDG PET/CT was employed to evaluate late pulmonary toxicity which
was induced by rituximab-containing chemotherapy in patients with non-Hodgkin lymphoma [
22
].
Asymptomatic subpleural pulmonary interstitial abnormalities were noted on FDG PET/CT, with
mild to moderate hyper-metabolism at 1 to 3 months post treatment. The authors warned that this
pattern should not be mistaken for lymphoma recurrence. A similar observation has been reported in
a larger group of 460 patients with lymphoma who underwent chemotherapy and serial FDG PET/CT
scans [
23
]. Diffuse ground-glass opacities with peripheral-dominant pulmonary FDG uptake was noted
in asymptomatic patients. In patients exposed to cyclophosphamide, bleomycin, or everolimus, a range
of findings may be seen on CT, while diffuse high bilateral pulmonary FDG uptake may be present on
PET [
24
–
29
] (Figure 1). Other chemotherapy agents, such as gemcitabine, can also cause a diversity of
pulmonary toxicity ranging from mild dyspnea to severe pulmonary fibrosis and acute respiratory
distress syndrome [
30
]. The CT findings are nonspecific and typically demonstrate ground-glass
opacities with or without smoothly thickened septal lines (reticular) and, in the most severe cases,
a honeycomb fibrotic pattern with possible diffuse alveolar infiltrates [
31
]. Comprehensive reviews of
chest CT findings in pulmonary complications (e.g., bronchiolitis obliterans organizing pneumonia,
nonspecific interstitial pneumonia, eosinophilic pneumonia, obliterative bronchiolitis, diffuse alveolitis,
etc.) from cancer treatment have been published [32–34].
Diagnostics 2017, 7, 43 3 of 12
assess the relationship between radiation-induced lung injury and pretreatment increased lung
density, on CT, and pretreatment pulmonary FDG uptake, on PET. The risk of lung radiotoxicity was
increased in those lung segments that showed a high pretreatment pulmonary FDG uptake,
suggesting that the risk of radiation injury may be decreased if the areas of pulmonary
hypermetabolism subtended by the radiation port can be minimized [20]. MacManus and colleagues
determined that for every one-level increase in a defined visual scoring of lung FDG uptake, the risk
of radiation pneumonitis increased by 40% [21].
In another investigation, FDG PET/CT was employed to evaluate late pulmonary toxicity which
was induced by rituximab-containing chemotherapy in patients with non-Hodgkin lymphoma [22].
Asymptomatic subpleural pulmonary interstitial abnormalities were noted on FDG PET/CT, with
mild to moderate hyper-metabolism at 1 to 3 months post treatment. The authors warned that this
pattern should not be mistaken for lymphoma recurrence. A similar observation has been reported
in a larger group of 460 patients with lymphoma who underwent chemotherapy and serial FDG
PET/CT scans [23]. Diffuse ground-glass opacities with peripheral-dominant pulmonary FDG uptake
was noted in asymptomatic patients. In patients exposed to cyclophosphamide, bleomycin, or
everolimus, a range of findings may be seen on CT, while diffuse high bilateral pulmonary FDG
uptake may be present on PET [24–29] (Figure 1). Other chemotherapy agents, such as gemcitabine,
can also cause a diversity of pulmonary toxicity ranging from mild dyspnea to severe pulmonary
fibrosis and acute respiratory distress syndrome [30]. The CT findings are nonspecific and typically
demonstrate ground-glass opacities with or without smoothly thickened septal lines (reticular) and,
in the most severe cases, a honeycomb fibrotic pattern with possible diffuse alveolar infiltrates [31].
Comprehensive reviews of chest CT findings in pulmonary complications (e.g., bronchiolitis
obliterans organizing pneumonia, nonspecific interstitial pneumonia, eosinophilic pneumonia,
obliterative bronchiolitis, diffuse alveolitis, etc.) from cancer treatment have been published [32–34].
Figure 1. Pulmonary toxicity in a patient with chronic myelomonocytic leukemia treated with
etoposide. A computer tomography (CT) scan (left panel) shows diffuse ground glass and reticular
opacities in bilateral posterior pulmonary segments. A coronal 18F-fluorodeoxyglucose (FDG)
positron emission tomography (PET) scan (right panel) demonstrates bilateral diffuse pulmonary
uptake (Used with permission from [29]).
Figure 1.
Pulmonary toxicity in a patient with chronic myelomonocytic leukemia treated with etoposide.
A computer tomography (CT) scan (
left panel
) shows diffuse ground glass and reticular opacities in
bilateral posterior pulmonary segments. A coronal
18
F-fluorodeoxyglucose (FDG) positron emission
tomography (PET) scan (
right panel
) demonstrates bilateral diffuse pulmonary uptake (Used with
permission from [29]).
Diagnostics 2017,7, 43 4 of 12
4. Cardiac Toxicity
The cardiovascular system is often affected by various cancer drug therapies (e.g., anthracyclines,
monoclonal antibodies, fluoropyrimidines, taxanes, alkylating agents, vinka alkaloids, and angiogenesis
inhibitors) [
35
–
37
]. Cardiac toxicity can become chronic, with significant irreversible morbidity and even
mortality [
38
–
40
]. The diagnostic imaging techniques that can be used to assess cardiac toxicity include
echocardiography, scintigraphy, CT, and MRI [
41
–
44
]. However, the early prediction of cardiac injury
remains challenging; easier prediction would be desirable in order to accordingly adapt chemotherapy
for optimal clinical management. The majority of optimal imaging modalities and measurement
parameters are unsettled [
45
]. The measurement of left ventricular ejection fraction (LVEF) with either
echocardiography or multiple-gated acquisition (MUGA) radionuclide angiography is currently the
most common approach used [
46
,
47
]. Cancer treatment-related cardiotoxicity is defined as a >5%
reduction in LVEF to <55% with heart failure symptoms, or a >10% reduction to <55% in asymptomatic
patients [
48
]. However, both echocardiography and MUGA scintigraphy are relatively insensitive to
early cardiac injury and small changes in LVEF. Aiken et al. reviewed the specific case for the use
of MUGA scintigraphy in the assessment of doxorubicin-induced cardiotoxicity [
49
]. With regards
to a radiation-induced decline in myocardial perfusion, Zellars and colleagues, using SPECT, have
shown that an active breathing coordinator (which enables radiation-delivery when the chest wall is
farther from the heart and, hence, less cardiac radiation exposure) does not prevent radiation-induced
cardiac hypo-perfusion defects [
50
]. More recently, Italian researchers have investigated whether
serial FDG PET/CT predicts doxorubicin cardiotoxicity [
51
]. This combined preclinical mice and
retrospective clinical human (in patients with Hodgkin’s lymphoma (HD) treated with an adriamycin,
bleomycin, vinblastine, and dacarbazine (ABVD) regimen) study showed that there were doxorubicin
dose-dependent increases in left ventricular glucose consumption (LV-MRGlu), particularly in the
presence of low baseline LV FDG uptake. The authors concluded that low myocardial FDG uptake
prior to the initiation of doxorubicin chemotherapy in HD patients might predict the development of
chemotherapy-induced cardiotoxicity (Figure 2).
Diagnostics 2017, 7, 43 4 of 12
4. Cardiac Toxicity
The cardiovascular system is often affected by various cancer drug therapies (e.g.,
anthracyclines, monoclonal antibodies, fluoropyrimidines, taxanes, alkylating agents, vinka
alkaloids, and angiogenesis inhibitors) [35–37]. Cardiac toxicity can become chronic, with significant
irreversible morbidity and even mortality [38–40]. The diagnostic imaging techniques that can be
used to assess cardiac toxicity include echocardiography, scintigraphy, CT, and MRI [41–44].
However, the early prediction of cardiac injury remains challenging; easier prediction would be
desirable in order to accordingly adapt chemotherapy for optimal clinical management. The majority
of optimal imaging modalities and measurement parameters are unsettled [45]. The measurement of
left ventricular ejection fraction (LVEF) with either echocardiography or multiple-gated acquisition
(MUGA) radionuclide angiography is currently the most common approach used [46,47]. Cancer
treatment-related cardiotoxicity is defined as a >5% reduction in LVEF to <55% with heart failure
symptoms, or a >10% reduction to <55% in asymptomatic patients [48]. However, both
echocardiography and MUGA scintigraphy are relatively insensitive to early cardiac injury and small
changes in LVEF. Aiken et al. reviewed the specific case for the use of MUGA scintigraphy in the
assessment of doxorubicin-induced cardiotoxicity [49]. With regards to a radiation-induced decline
in myocardial perfusion, Zellars and colleagues, using SPECT, have shown that an active breathing
coordinator (which enables radiation-delivery when the chest wall is farther from the heart and,
hence, less cardiac radiation exposure) does not prevent radiation-induced cardiac hypo-perfusion
defects [50]. More recently, Italian researchers have investigated whether serial FDG PET/CT predicts
doxorubicin cardiotoxicity [51]. This combined preclinical mice and retrospective clinical human (in
patients with Hodgkin’s lymphoma (HD) treated with an adriamycin, bleomycin, vinblastine, and
dacarbazine (ABVD) regimen) study showed that there were doxorubicin dose-dependent increases
in left ventricular glucose consumption (LV-MRGlu), particularly in the presence of low baseline LV
FDG uptake. The authors concluded that low myocardial FDG uptake prior to the initiation of
doxorubicin chemotherapy in HD patients might predict the development of chemotherapy-induced
cardiotoxicity (Figure 2).
Figure 2. Myocardial FDG uptake significantly increases in HD patients with late treatment-related
cardiac abnormalities, defined as electrocardiographic or echocardiographic abnormalities (left
panel) compared to those patients without late therapy-induced cardiotoxicity (right panel). FDG
PET/CT scans: the baseline at staging (PET1); a negative interim scan during chemotherapy (PET2), a
negative scan after the completion of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD)
chemotherapy at 4–6 weeks post-therapy (PET3) and a negative six-month follow-up scan (PET4)
(Used with permission from [51]).
Cardiac MRI is ideal in characterizing myocardial tissue and assessing chamber ventricular
volume and function [52,53]. It has the advantages of lacking ionizing radiation and a high soft tissue
contrast but has limitations with regards to its access, availability, and cost. The interested reader is
referred to an excellent systematic review by Thavendiranathan and colleagues on the use of cardiac
Figure 2.
Myocardial FDG uptake significantly increases in HD patients with late treatment-related
cardiac abnormalities, defined as electrocardiographic or echocardiographic abnormalities (
left panel
)
compared to those patients without late therapy-induced cardiotoxicity (
right panel
). FDG PET/CT
scans: the baseline at staging (PET1); a negative interim scan during chemotherapy (PET2), a negative
scan after the completion of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy
at 4–6 weeks post-therapy (PET3) and a negative six-month follow-up scan (PET4) (Used with permission
from [51]).
Cardiac MRI is ideal in characterizing myocardial tissue and assessing chamber ventricular
volume and function [
52
,
53
]. It has the advantages of lacking ionizing radiation and a high soft tissue
contrast but has limitations with regards to its access, availability, and cost. The interested reader is
referred to an excellent systematic review by Thavendiranathan and colleagues on the use of cardiac
Diagnostics 2017,7, 43 5 of 12
MRI in the assessment of cancer treatment-related toxicity, with specific sections focusing on the
detection of early cardiac injury, the identification of short-term cardiotoxicity (<1 year of treatment),
the detection of the late effect of therapy (>1 year after treatment), and the monitoring of the response
to cardioprotective therapy [
54
]. This systematic review revealed that MRI evidence of myocardial
inflammation and edema may portray the earliest signs of cancer treatment-related cardiotoxicity
and the potential ensuing ventricular dysfunction. The authors suggest further investigations to
decipher whether the higher cost of cardiac MRI can be adequately balanced by the ability to identify
a higher-risk group who can benefit from preemptive targeted cardiac therapy, leading to a reduction
in cardiac morbidity and a favorable cost-benefit ratio.
Konski et al. retrospectively evaluated 102 patients with esophageal cancer who were treated with
chemo-radiotherapy and developed symptomatic cardiotoxicity [
55
]. Changes in FDG myocardial
uptake as measured by standardized uptake value (SUV) did not correlate with cardiac toxicity.
However, it must be noted that the determination of a potential relation in myocardial metabolism
and a chemo-radiotherapy effect may be challenging, as normal myocardial FDG uptake is quite
variable even with prolonged fasting preparation, while isolating physiologic metabolic variability
from systemic drug-induced metabolic changes can be difficult [
56
]. Moreover, hyper-metabolism
around the heart may reflect chemotherapy-induced pericarditis [57].
In summary, while the current, relatively simple imaging methods for determining gross left
ventricular function changes (as reflected by LVEF) have been helpful in clinical decision-making,
additional investigations into the multimodal imaging assessment of the earliest signs of
treatment-induced myocardial damage may provide opportunities for adaptive treatments that
optimize therapy efficacy while minimizing adverse cardiac events in a cost-effective manner for
the large cohort of cancer patients who receive cardio-toxic treatments.
5. Hepatic and Gastrointestinal Tract Toxicity
The liver, as the main physiological detoxifying organ, is another common site of cancer treatment
toxicity [
58
,
59
]. A number of anticancer agents, such as 5-fluorouraci, leucovorin, bevacizumab,
and pazopanib, may lead to hepatic steatosis. Hepatic steatosis is detected on unenhanced CT as
diffuse fatty change, with a decline in hepatic attenuation by 10–25 Hounsfield Units (HU) below
that in the spleen [
60
]. While simple hepatic steatosis may remain asymptomatic, an evolution to
and development of steatohepatitis may lead to a decline in hepatic function and regeneration [
31
].
Radiation therapy to nearby organs may also result in hepatic injury [61] (Figure 3).
Selective intra-arterial delivery of chemotherapy or radioactive microsphere therapy has been
shown to be safe and effective in a number of clinical settings, including unresectable hepatocellular
carcinoma, unresectable or recurrent cholangiocarcinoma, and liver dominant metastases from
colorectal cancer, breast cancer, renal cell carcinoma, pancreatic cancer, melanoma, and neuroendocrine
tumors [
62
,
63
]. The therapy procedure is preceded by angiographic mapping, which includes
99m
Tc-MAA hepatic perfusion delineation, pulmonary shunt calculation and coil embolization of
aberrant or collateral vessels as needed to limit the exposure of and toxicity to non-tumor tissues from
the therapy agent [
64
]. The interested reader is referred to comprehensive reviews of the side effects
of intra-arterial radio-embolization [
65
]. Radiotoxicity is related to the radiation-induced toxicity
(inflammation, ulceration, necrosis, abscess, and stricture) of the unintended exposed organs or tissues
(e.g., stomach, duodenum, gallbladder, normal liver, pancreas, etc.). Atassi and colleagues provide an
excellent review of the multimodality imaging findings for the recognition of potential complications
and the assessment of the therapy response to radio-embolization [66].
Radiation therapy for lung cancer may result in esophageal injury. Symptomatic esophagitis
may be predicted with the level of FDG uptake in the esophagus [
67
,
68
]. Similarly, the rest of the
gastrointestinal tract may be affected, with signs such as gastritis, enteritis, colitis, pneumatosis
intestinalis, bowel ischemia, infarction, hemorrhage and perforation [
69
–
73
]. Torrisi and colleagues
provide an excellent review of the typical morphological changes, which may be seen on CT, associated
Diagnostics 2017,7, 43 6 of 12
with these conditions [
31
]. Scintigraphy may also be helpful for the evaluation of gastrointestinal
bleeding and abdominal infection. Given that, on PET with FDG, the bowel shows variable uptake,
which may also be affected by some medications (e.g., higher bowel FDG uptake with metformin
therapy for diabetes mellitus), the assessment of enteric complications solely based on metabolic
information may have limited use. However, indicators on the accompanied CT may be helpful
(e.g., mesenteric fat strand lines adjacent to the bowel, fluid collections, bowel wall thickening, etc.).
For example, intense small or large bowel FDG uptake with the aforementioned secondary abnormal
signs on CT hints at enterocolitis. Chemotherapy is often associated with neutropenia, which may lead
to neutropenic enterocolitis [74].
Diagnostics 2017, 7, 43 6 of 12
variable uptake, which may also be affected by some medications (e.g., higher bowel FDG uptake
with metformin therapy for diabetes mellitus), the assessment of enteric complications solely based
on metabolic information may have limited use. However, indicators on the accompanied CT may
be helpful (e.g., mesenteric fat strand lines adjacent to the bowel, fluid collections, bowel wall
thickening, etc.). For example, intense small or large bowel FDG uptake with the aforementioned
secondary abnormal signs on CT hints at enterocolitis. Chemotherapy is often associated with
neutropenia, which may lead to neutropenic enterocolitis [74].
Figure 3. Hepatic radiation injury in a patient who underwent radiotherapy for distal esophageal
cancer. The coronal maximum projection image (FDG PET image) shows residual esophageal tumor
hypermetabolism (SUVmax = 3.4) (black arrow) and hypermetabolic areas (SUVmax = 3.5) in liver
segments I, II, and III (white arrow). (Used with permission from [61]). SUV, standardized uptake
value.
6. Urinary System Toxicity
Renal toxicity is a relatively common toxicity caused by chemotherapy (e.g., cisplatin,
methotrexate) [75]. The typical signs include diminished renal function with a rising serum creatinine
level, a decreased urine output, blood electrolyte or other metabolite derangements and the potential
development of nephrotic syndrome. Multimodality imaging (e.g., ultrasonography, CT, MRI,
scintigraphy) can be helpful for the assessment of renal changes in morphology and function that
may have resulted from therapy-induced injury. Clearly, in patients with renal toxicity from systemic
therapy, the iodinated contrast agents for CT studies or the gadolinium-based agents for MRI studies
may only be used with caution, or not at all, in order to avoid compounding the harm to the kidneys.
Good hydration is helpful in renal protection. In certain treatments, renal protection may be archived
with the preemptive use of appropriate agents. Radiation nephropathy has been described in some
patients who undergo peptide receptor radionuclide therapy (PRRT). The radiolabeled somatostatin
analogs localize in proximal tubular cells. Methods that can interfere with the reabsorption pathway
may aid in renal protection. Rolleman et al. provide a summary of the potential mechanisms for renal
injury and the methods for renal protection in PRRT [76]. These methods include an infusion of amino
acids (e.g., a mixture of lysine and arginine) to reduce renal reabsorption, other experimental
approaches, such as the design and development of new peptides with a higher affinity and
specificity for somatostatin receptors, and the use of radio-protective drugs. In the case of
Figure 3.
Hepatic radiation injury in a patient who underwent radiotherapy for distal esophageal
cancer. The coronal maximum projection image (FDG PET image) shows residual esophageal tumor
hypermetabolism (SUVmax = 3.4) (black arrow) and hypermetabolic areas (SUVmax = 3.5) in liver
segments I, II, and III (white arrow). (Used with permission from [
61
]). SUV, standardized uptake value.
6. Urinary System Toxicity
Renal toxicity is a relatively common toxicity caused by chemotherapy (e.g., cisplatin,
methotrexate) [
75
]. The typical signs include diminished renal function with a rising serum creatinine
level, a decreased urine output, blood electrolyte or other metabolite derangements and the potential
development of nephrotic syndrome. Multimodality imaging (e.g., ultrasonography, CT, MRI,
scintigraphy) can be helpful for the assessment of renal changes in morphology and function that
may have resulted from therapy-induced injury. Clearly, in patients with renal toxicity from systemic
therapy, the iodinated contrast agents for CT studies or the gadolinium-based agents for MRI studies
may only be used with caution, or not at all, in order to avoid compounding the harm to the kidneys.
Good hydration is helpful in renal protection. In certain treatments, renal protection may be archived
with the preemptive use of appropriate agents. Radiation nephropathy has been described in some
patients who undergo peptide receptor radionuclide therapy (PRRT). The radiolabeled somatostatin
analogs localize in proximal tubular cells. Methods that can interfere with the reabsorption pathway
may aid in renal protection. Rolleman et al. provide a summary of the potential mechanisms for
renal injury and the methods for renal protection in PRRT [
76
]. These methods include an infusion of
amino acids (e.g., a mixture of lysine and arginine) to reduce renal reabsorption, other experimental
Diagnostics 2017,7, 43 7 of 12
approaches, such as the design and development of new peptides with a higher affinity and specificity
for somatostatin receptors, and the use of radio-protective drugs. In the case of radiolabeled prostate
specific membrane antigen (PSMA) targeted therapy in patients with metastatic castrate-resistant
prostate cancer, the application of PSMA inhibitors such as 2-(phosphonomethyl)pentanedioic acid
(PMPA) has been found to reduce off-target radiation to the kidneys [
77
]. The bladder may also be
affected by chemotherapy (e.g., cyclophosphamide) toxicity, typically in form of cystitis, which may
become hemorrhagic. Cross-sectional imaging findings are generally not specific, but may display
diffuse, nodular, or combination diffuse-nodular bladder wall thickening.
7. Hematopoietic Toxicity
Bone marrow toxicity is a common occurrence after chemo-radiation therapy. Imaging-based
prediction of the extent and severity of marrow suppression can be helpful in assessing and managing
potential acute and late hematological toxicity. Metabolic imaging with PET is useful in assessing
the effect of treatment on bone marrow and provides a possible platform for predicting marrow
response after treatment [
78
–
80
]. A Tibetan mini-pig animal model study showed that FDG PET may
be helpful in assessing absorbed radiation doses to the bone marrow and predicting the survival
outcome [
81
]. McGuire et al. correlated the change in the uptake of the cellular proliferation PET
biomarker,
18
F-fluorothymidine (FLT), in the bone marrow of patients undergoing chemo-radiation
therapy for pelvic cancer [
82
]. Radiation doses of 4 Gy after 1–2 weeks of therapy caused about a
50% decrease in FLT uptake, which was reflective of the decline in normal proliferating marrow cells.
Interestingly, FLT uptake in marrow which was exposed to >35 Gy radiation was about 19% greater at
1 month after therapy than at 1 year after therapy, suggestive of chronic therapy-induced bone marrow
suppression. In the case of PRRT for neuroendocrine tumors, it has been shown that hematological
toxicity is not related to splenic radiation [83].
8. Skin Toxicity
Cancer treatments may lead to cutaneous toxicity. Kumar et al. describes a case report of patients
with metastatic non-small-cell lung cancer undergoing erlotinib (a reversible epidermal growth factor
receptor kinase inhibitor) who developed skin toxicity in the form of pustular skin nodules that
demonstrated hyper-metabolism on FDG PET/CT [
84
] (Figure 4). Most skin nodules typically appear
during the first week of treatment and disappear after the discontinuation of erlotinib, which can be
useful in a differential diagnosis from skin metastases. Another case report showed similar findings
for cutaneous nodular hyper-metabolism with FDG PET/CT in a patient with erythema nodosum-like
panniculitis and in a patient with advanced melanoma treated with dabrafenib (a BRAF inhibitor) and
trametinib (a MEK inhibitor) [85].
Figure 4.
Cutaneous toxicity in a patient with metastatic lung cancer treated with erlotinib. A fused
sagittal FDG PET-CT image of the skull shows multiple focal areas of FDG uptake in the scalp (
left panel
)
that corresponded to pustular nodules, as seen on the photograph (
right panel
). (Used with permission
from [84]).
Diagnostics 2017,7, 43 8 of 12
9. Conclusions
The treatment of cancer leads to an unwanted toxicity. The extent and severity of the adverse
events may limit the type, dosing amount, and the number of therapy cycles, and occasionally may
lead to the termination of treatment. Understanding the underlying mechanisms that are involved
with various cancer therapy regimens can help in optimizing the effectiveness of the treatment while
reducing any unwanted side effects. While some treatment toxicities may be asymptomatic, others
may lead to irreversible end organ damage or even death. Imaging can play an important role in the
care of cancer patients, not only for the assessment of the state of tumors and their response to therapy,
but also in order to decipher the radiographic and scintigraphic signs of treatment toxicity.
Acknowledgments:
This work was supported in part by the National Institutes of Health grants R01-CA111613,
R21-CA142426, R21-EB017568, and P30-CA014089.
Author Contributions: Hossein Jadvar was the sole contributor to this review article.
Conflicts of Interest: The author declares no conflict of interest.
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... Hence, for cases of ovarian cancer there is a crucial need for tools that can assist medical professionals to plan their therapeutic procedure in order to achieve optimal results. One of the widely used means in cancer treatment planning is medical imaging, which can provide information for planning surgical operations, systemic therapy and radiotherapy [4][5][6]. ...
The emerging role of PET/CT scanning in the treatment planning of ovarian cancer: A mini-review
Article
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  • Jun 2024
Given the many obstacles faced during the treatment of ovarian cancer, usually due to diagnosis at advanced stages, it is crucial to use different means to plan the therapeutic procedure in order to achieve optimal results. Positron emission tomography–computed tomography (PET/CT) is a recent hybrid method of medical imaging that can provide various information on the anatomic and biochemical status of a tumor, as well as possible metastases and hence provide better insights to clinicians for the therapeutic procedure. To this end, the present mini-review explores the role of PET/CT scanning in planning surgical procedures, systemic anticancer therapy and radiotherapy and summarizes the current status of studies that examine the use of PET/CT in the personalized therapy of ovarian cancer. Nonetheless, more clinical and observational studies are required to further verify the use of PET/CT in planning therapeutic procedures for patients with ovarian tumors.
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... This highlights the importance of discovering and validating biomarkers that are both sensitive to treatment effects and predict outcomes following combination cancer therapies [2], enabling patient risk stratification for individualized treatment techniques. Risk stratification studies have focused on early detection and cancerous nodules classification [3][4][5], histologic subtype classification [6], prognosis after radiation therapy or surgery [7], prediction of lung toxicity after radiation therapy [8,9], and prediction of response to chemoradiation or immunotherapy [10][11][12], utilizing a variety of survival prediction modeling [10][11][12][13][14][15][16][17][18][19][20]. ...
Multitask Learning Radiomics on Longitudinal Imaging to Predict Survival Outcomes following Risk-Adaptive Chemoradiation for Non-Small Cell Lung Cancer
Article
Full-text available
  • Feb 2022
Simple Summary Personalized cancer treatment strategies, including risk-adaptive chemoradiation therapy based on medical imaging, seek to improve outcomes of patients with unresectable and locally advanced non-small cell lung cancer. Refining patient risk stratification relies on outcome prediction modeling based in part on information from different imaging modalities and imaging time points during and after treatment. Using prospectively collected longitudinal data from FDG-PET, CT, and perfusion SPECT images of patients enrolled on a clinical trial, our aim was to evaluate the utility of a multitask machine learning radiomics framework for survival outcome prediction. We found that multitask learning of FDG-PET radiomics on pretreatment and mid-treatment images achieved higher survival prediction concordance compared with single-task learning of other modalities and clinical benchmark models. Our multitask learning radiomics framework can be applied to other longitudinal imaging datasets, and, once validated, can strengthen clinical decision support for personalized and adaptive treatment courses. Abstract Medical imaging provides quantitative and spatial information to evaluate treatment response in the management of patients with non-small cell lung cancer (NSCLC). High throughput extraction of radiomic features on these images can potentially phenotype tumors non-invasively and support risk stratification based on survival outcome prediction. The prognostic value of radiomics from different imaging modalities and time points prior to and during chemoradiation therapy of NSCLC, relative to conventional imaging biomarker or delta radiomics models, remains uncharacterized. We investigated the utility of multitask learning of multi-time point radiomic features, as opposed to single-task learning, for improving survival outcome prediction relative to conventional clinical imaging feature model benchmarks. Survival outcomes were prospectively collected for 45 patients with unresectable NSCLC enrolled on the FLARE-RT phase II trial of risk-adaptive chemoradiation and optional consolidation PD-L1 checkpoint blockade (NCT02773238). FDG-PET, CT, and perfusion SPECT imaging pretreatment and week 3 mid-treatment was performed and 110 IBSI-compliant pyradiomics shape-/intensity-/texture-based features from the metabolic tumor volume were extracted. Outcome modeling consisted of a fused Laplacian sparse group LASSO with component-wise gradient boosting survival regression in a multitask learning framework. Testing performance under stratified 10-fold cross-validation was evaluated for multitask learning radiomics of different imaging modalities and time points. Multitask learning models were benchmarked against conventional clinical imaging and delta radiomics models and evaluated with the concordance index (c-index) and index of prediction accuracy (IPA). FDG-PET radiomics had higher prognostic value for overall survival in test folds (c-index 0.71 [0.67, 0.75]) than CT radiomics (c-index 0.64 [0.60, 0.71]) or perfusion SPECT radiomics (c-index 0.60 [0.57, 0.63]). Multitask learning of pre-/mid-treatment FDG-PET radiomics (c-index 0.71 [0.67, 0.75]) outperformed benchmark clinical imaging (c-index 0.65 [0.59, 0.71]) and FDG-PET delta radiomics (c-index 0.52 [0.48, 0.58]) models. Similarly, the IPA for multitask learning FDG-PET radiomics (30%) was higher than clinical imaging (26%) and delta radiomics (15%) models. Radiomics models performed consistently under different voxel resampling conditions. Multitask learning radiomics for outcome modeling provides a clinical decision support platform that leverages longitudinal imaging information. This framework can reveal the relative importance of different imaging modalities and time points when designing risk-adaptive cancer treatment strategies.
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... This phenomenon is attributable to both secondary malignancies and late cardiotoxicity [2][3][4] and can considerably impair life expectancy in younger patients. Moreover, the occurrence of cardiac injury can decisively affect both overall performance status as well as quality of life, particularly in elderly subjects, in patients with cardiovascular comorbidities, or in those in which additional thoracic irradiation is indicated [4][5][6][7]. In these regards, dose-dependent anthracycline-induced cardiomyopathy is one of the most acknowledged and well-studied clinical models of cardiovascular toxicity by chemotherapy. ...
A Score-Based Approach to 18F-FDG PET Images as a Tool to Describe Metabolic Predictors of Myocardial Doxorubicin Susceptibility
Article
Full-text available
  • Oct 2017
Purpose: To verify the capability of (18)F-fluorodeoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) to identify patients at higher risk of developing doxorubicin (DXR)-induced cardiotoxicity, using a score-based image approach. Methods: 36 patients underwent FDG-PET/CT. These patients had shown full remission after DXR-based chemotherapy for Hodgkin's disease (DXR dose: 40-50 mg/m² per cycle), and were retrospectively enrolled. Inclusion criteria implied the presence of both pre- and post-chemotherapy clinical evaluation encompassing electrocardiogram (ECG) and echocardiography. Myocardial metabolism at pre-therapy PET was evaluated according to both standardized uptake value (SUV)- and score-based approaches. The capability of the score-based image assessment to predict the occurrence of cardiac toxicity with respect to SUV measurement was then evaluated. Results: In contrast to the SUV-based approach, the five-point scale method does not linearly stratify the risk of the subsequent development of cardiotoxicity. However, converting the five-points scale to a dichotomic evaluation (low vs. high myocardial metabolism), FDG-PET/CT showed high diagnostic accuracy in the prediction of cardiac toxicity (specificity = 100% and sensitivity = 83.3%). In patients showing high myocardial uptake at baseline, in which the score-based method is not able to definitively exclude the occurrence of cardiac toxicity, myocardial SUV mean quantification is able to further stratify the risk between low and intermediate risk classes. Conclusions: the score-based approach to FDG-PET/CT images is a feasible method for predicting DXR-induced cardiotoxicity. This method might improve the inter-reader and inter-scanner variability, thus allowing the evaluation of FDG-PET/CT images in a multicentral setting.
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Imaging of Colorectal Liver Metastasis
Article
  • Oct 2021
Colorectal cancer (CRC) is one of the most common cancers in the world. The most important determinant of survival and prognosis is the stage and presence of metastasis. The liver is the most common location for CRC metastasis. The only curative treatment for CRC liver metastasis (CRLM) is resection; however, many patients are ineligible for surgical resection of CRLM. Locoregional treatments such as ablation and intra-arterial therapy are also available for patients with CRLM. Assessment of response after chemotherapy is challenging due to anatomical and functional changes. Antiangiogenic agents such as bevacizumab that are used in the treatment of CRLM may show atypical patterns of response on imaging. It is vital to distinguish patterns of response in addition to toxicities to various treatments. Imaging plays a critical role in evaluating the characteristics of CRLM and the approach to treatment. CT is the modality of choice in the diagnosis and management of CRLM. MRI is best used for indeterminate lesions and to assess response to intra-arterial therapy. PET-CT is often utilized to detect extrahepatic metastasis. State-of-the-art imaging is critical to characterize patterns of response to various treatments. We herein review the imaging characteristics of CRLM with an emphasis on imaging changes following the most common CRLM treatments.
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Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational (18)F-FDG PET/CT Observation
Article
Full-text available
  • Jun 2017
The present translational study aimed to verify whether serial (18)F-fluoro-deoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT), predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated with intravenous administration of saline (n = 5), doxorubicin 5 mg/Kg (n = 5) or doxorubicin 7.5 mg/Kg (n = 5) and submitted to dynamic microPET scan to estimate left ventricular glucose consumption (LV-MRGlu) before and after chemotherapy. Thereafter, we retrospectively identified 69 patients successfully treated with Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) regimen for Hodgkin's Disease (HD) and submitted to four consecutive FDG-PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean standardized uptake value (LV-SUV). All patients were subsequently interviewed by telephone (median follow-up: 30 months); 36 of them accepted to undergo electrocardiogram and transthoracic echocardiography. Results: In mice LV-MRGlu was 17.9±4.4 nMol x min-1 x g-1 at baseline. doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9±9 nMol x min-1 x g-1, p<0.05 vs. controls) and in the high-dose subgroup (37.2±7.8 nMol x min-1 x g-1, p<0.01 vs. controls; p<0.05 vs. standard-dose). In HD patients LV-SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New onset cardiac abnormalities appeared in 11/36 (31%) patients. In these subjects, pre-therapy LV-SUV was markedly lower with respect to the remaining ones (1.53±0.9 vs 3.34±2.54, respectively, p<0.01. Multivariate analysis confirmed the predictive value of baseline LV-SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV-MRGlu, particularly in presence of low baseline FDG uptake. These results imply that low myocardial FDG uptake prior to the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity suggesting that prospective clinical trials are warranted to test this hypothesis.
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Erythema Nodosum–Like Panniculitis as a False-Positive 18F-FDG PET/CT in Advanced Melanoma Treated With Dabrafenib and Trametinib
Article
Full-text available
  • Oct 2016
We present a 35-year-old woman with left axillary mass. Histopathological analysis revealed metastatic infiltration for BRAF-mutant melanoma. F-FDG PET/CT showed bilateral axillary lymphadenopathy as well as bone and subcutaneous metastases. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) combined therapy was started with a complete metabolic response established by 2 consecutive PET/CT scans. A follow-up PET/CT showed FDG uptake in several subcutaneous nodules in both distal legs, suggesting metastases. Painless cutaneous lesions were observed on physical examination, and biopsy revealed erythema nodosum-like panniculitis.
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18F-Fluorodeoxyglucose Positron Emission Tomography Can Quantify and Predict Esophageal Injury During Radiation Therapy
Article
Full-text available
  • Jul 2016
Purpose: We sought to investigate the ability of mid-treatment (18)F-fluorodeoxyglucose positron emission tomography (PET) studies to objectively and spatially quantify esophageal injury in vivo from radiation therapy for non-small cell lung cancer. Methods and materials: This retrospective study was approved by the local institutional review board, with written informed consent obtained before enrollment. We normalized (18)F-fluorodeoxyglucose PET uptake to each patient's low-irradiated region (<5 Gy) of the esophagus, as a radiation response measure. Spatially localized metrics of normalized uptake (normalized standard uptake value [nSUV]) were derived for 79 patients undergoing concurrent chemoradiation therapy for non-small cell lung cancer. We used nSUV metrics to classify esophagitis grade at the time of the PET study, as well as maximum severity by treatment completion, according to National Cancer Institute Common Terminology Criteria for Adverse Events, using multivariate least absolute shrinkage and selection operator (LASSO) logistic regression and repeated 3-fold cross validation (training, validation, and test folds). This 3-fold cross-validation LASSO model procedure was used to predict toxicity progression from 43 asymptomatic patients during the PET study. Dose-volume metrics were also tested in both the multivariate classification and the symptom progression prediction analyses. Classification performance was quantified with the area under the curve (AUC) from receiver operating characteristic analysis on the test set from the 3-fold analyses. Results: Statistical analysis showed increasing nSUV is related to esophagitis severity. Axial-averaged maximum nSUV for 1 esophageal slice and esophageal length with at least 40% of axial-averaged nSUV both had AUCs of 0.85 for classifying grade 2 or higher esophagitis at the time of the PET study and AUCs of 0.91 and 0.92, respectively, for maximum grade 2 or higher by treatment completion. Symptom progression was predicted with an AUC of 0.75. Dose metrics performed poorly at classifying esophagitis (AUC of 0.52, grade 2 or higher mid treatment) or predicting symptom progression (AUC of 0.67). Conclusions: Normalized uptake can objectively, locally, and noninvasively quantify esophagitis during radiation therapy and predict eventual symptoms from asymptomatic patients. Normalized uptake may provide patient-specific dose-response information not discernible from dose.
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Dose to specific subregions of pelvic bone marrow defined with FDG-PET as a predictor of hematologic nadirs during concomitant chemoradiation in anal cancer patients
Article
Full-text available
  • Jun 2016
  • MED ONCOL
To test the hypothesis that irradiated volume of specific subregions of pelvic active bone marrow as detected by 18FDG-PET may be a predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation, we analyzed 44 patients submitted to IMRT and concurrent chemotherapy. Several bony structures were defined: pelvic and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. Active BM was characterized employing 18FDG-PET and characterized in all subregions as the volume having standard uptake values (SUVs) higher than SUVmean. All other regions were defined as inactive BM. On dose–volume histograms, dosimetric parameters were taken. Endpoints included white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin (Hb) and platelet (Plt) nadirs. Generalized linear modeling was used to find correlations between dosimetric variables and blood cells nadirs. WBC nadir was significantly correlated with LSBM mean dose (β = −1.852; 95 % CI −3.205/−0.500; p = 0.009), V10 (β = −2.153; 95 % CI −4.263/−0.721; p = 0.002), V20 (β = −2.081; 95 % CI −4.880/−0.112; p = 0.003), V30 (β = −1.971; 95 % CI −4.748/−0.090; p = 0.023) and IBM V10 (β = −0.073; 95 % CI −0.106/−0.023; p = 0.016). ANC nadir found to be significantly associated with LSBM V10 (β = −1.878; 95 % CI −4.799/−0.643; p = 0.025), V20 (β = −1.765; 95 % CI −4.050/−0.613; p = 0.030) and IBM V10 (β = −0.039; 95 % CI −0.066/−0.010; p = 0.027). Borderline significance was found for correlation between Plt nadir and LSBM V30 (β = −0.056; 95 % CI −2.748/−0.187; p = 0.060), V40 (β = −0.059; 95 % CI −3.112/−0.150; p = 0.060) and IBM V30 (β = −0.028; 95 % CI −0.074/−0.023; p = 0.056). No inactive BM subsites were found to be correlated with any blood cell nadir. 18FDG-PET is able to define active bone marrow within pelvic osseous structures. LSBM is the strongest predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation.
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Using FLT PET to quantify and reduce hematologic toxicity due to chemoradiation therapy for pelvic cancer patients
Article
Full-text available
  • Apr 2016
Purpose: The purpose of the present prospective clinical trial was to determine the efficacy of [(18)F]fluorothymidine (FLT)-identified active bone marrow sparing for pelvic cancer patients by correlating the FLT uptake change during and after chemoradiation therapy with hematologic toxicity. Methods and materials: Simulation FLT positron emission tomography (PET) images were used to spare pelvic bone marrow using intensity modulated radiation therapy (IMRT BMS) for 32 patients with pelvic cancer. FLT PET scans taken during chemoradiation therapy after 1 and 2 weeks and 30 days and 1 year after completion of chemoradiation therapy were used to evaluate the acute and chronic dose response of pelvic bone marrow. Complete blood counts were recorded at each imaging point to correlate the FLT uptake change with systemic hematologic toxicity. Results: IMRT BMS plans significantly reduced the dose to the pelvic regions identified with FLT uptake compared with control IMRT plans (P<.001, paired t test). Radiation doses of 4 Gy caused an ∼50% decrease in FLT uptake in the pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT-identified bone marrow exposed to ≥4 Gy after 1 week developed grade 2 leukopenia sooner than subjects with less marrow exposed to ≥4 Gy (P<.05, Cox regression analysis). Apparent bone marrow recovery at 30 days after therapy was not maintained 1 year after chemotherapy. The FLT uptake in the pelvic bone marrow regions that received >35 Gy was 18.8% ± 1.8% greater at 30 days after therapy than at 1 year after therapy. The white blood cell, platelet, lymphocyte, and neutrophil counts at 1 year after therapy were all lower than the pretherapy levels (P<.05, paired t test). Conclusions: IMRT BMS plans reduced the dose to FLT-identified pelvic bone marrow for pelvic cancer patients. However, reducing hematologic toxicity is challenging owing to the acute radiation sensitivity (∼4 Gy) and chronic suppression of activity in bone marrow receiving radiation doses >35 Gy, as measured by the FLT uptake change correlated with the complete blood cell counts.
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Targeted Radionuclide Therapy: An Evolution Toward Precision Cancer Treatment
Article
  • May 2017
Objective: This article reviews recent developments in targeted radionuclide therapy (TRT) approaches directed to malignant liver lesions, bone metastases, neuroendocrine tumors, and castrate-resistant metastatic prostate cancer and discusses challenges and opportunities in this field. Conclusion: TRT has been employed since the first radioiodine thyroid treatment almost 75 years ago. Progress in the understanding of the complex underlying biology of cancer and advances in radiochemistry science, multimodal imaging techniques including the concept of "see and treat" within the framework of theranostics, and universal traction with the notion of precision medicine have all contributed to a resurgence of TRT.
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Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience
Article
  • Mar 2002
PURPOSE: This study sought to estimate cardiac dysfunction (CD) risk for patients receiving trastuzumab; to characterize observed CD by severity, treatment, and clinical outcome; to assess effects of baseline clinical risk factors on CD; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD. PATIENTS AND METHODS: A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed. Predefined criteria were used for the diagnosis, and the New York Heart Association functional classification system was used to document CD severity. Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset. RESULTS: Patients treated with trastuzumab were found to be at an increased risk for CD. The incidence was greatest in patients receiving concomitant trastuzumab and anthracycline plus cyclophosphamide (27%). The risk was substantially lower in patients receiving paclitaxel and trastuzumab (13%) or trastuzumab alone (3% to 7%); however, most of these patients had received prior anthracycline therapy. CD was noted in 8% of patients receiving anthracycline plus cyclophosphamide and 1% receiving paclitaxel alone. Most trastuzumab-treated patients developing CD were symptomatic (75%), and most improved with standard treatment for congestive heart failure (79%). CONCLUSION: Trastuzumab is associated with an increased risk of CD, which is greatest in patients receiving concurrent anthracyclines. In most patients with metastatic breast cancer, the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab.
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Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis
Article
  • Dec 2016
Background: The cardiovascular risk of angiogenesis inhibitors is not well-quantified. We hypothesized that, compared to direct vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF antibodies or decoy receptors), small molecule agents have higher risk due to their less specific mechanism. Methods: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for phase III randomised controlled trials comparing angiogenesis inhibitor-based therapy to other systemic therapy. Outcomes evaluated were hypertension, severe hypertension, cardiac dysfunction, congestive heart failure, cardiac ischemia, arterial thromboembolism, venous thromboembolism, and fatal cardiovascular events. Data were pooled using Mantel-Haenszel random effects method to generate odds ratios (OR). Results: We identified 77 studies meeting inclusion criteria. Compared to routine care, angiogenesis inhibitors were associated with a higher risk of hypertension (OR 5.28 [4.53-6.15], number needed to harm [NNH] 6), severe hypertension (OR 5.59 [4.67-6.69], NNH 17), cardiac ischemia (OR 2.83 [1.72-4.65], NNH 85) and cardiac dysfunction (OR 1.35 [1.06-1.70], NNH 139). VEGF inhibitors were associated with an increased risk of arterial thromboembolism (OR 1.52 [1.17-1.98], NNH 141). No significant interaction was observed between the two drug subgroups for any outcomes. We identified no significant increase in the risk of the other outcomes evaluated. Conclusion: Angiogenesis inhibitors increase the risk of hypertension, arterial thromboembolism, cardiac ischemia and cardiac dysfunction. There was no significant difference in cardiovascular risk between direct VEGF inhibitors and small molecule agents.
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Central Nervous System Complications of Oncologic Therapy
Article
  • Jun 2016
  • HEMATOL ONCOL CLIN N
Traditional and newer agents used to treat cancer can cause significant toxicity to the central nervous system. MRI of the brain and spine is the imaging modality of choice for patients with cancer who develop neurologic symptoms. It is important to be aware of the agents that can cause neurotoxicity and their associated imaging findings so that patients are properly diagnosed and treated. In some instances conventional MRI may not be able to differentiate posttreatment effects from disease progression. In these instances advanced imaging techniques may be helpful, although further research is still needed.
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Intra-Arterial Radionuclide Therapies for Liver Tumors
Article
  • Jul 2016
Intra-arterial radionuclide therapies serve essentially as internal radiation treatment options for both primary and metastatic liver tumors, which imply delivering implantable radioactive microspheres into branches of hepatic arteries that feed liver tumors to provide a high dose of targeted radiation to tumor tissue, while sparing the healthy liver tissue from hazardous effects of radiation. The principle of this therapeutic option depends on the unique preferential arterial supply of malignant liver tumors in contrast with mostly portal venous supply of normal hepatocytes as well as excess amount of arterial neovascularization in the tumor bed. Therefore, intra-arterial radionuclide therapy can provide very high radiation exposure to tumor tissue, which is impossible to reach with external radiation therapy due to serious side effects and moreover, radiation can be targeted to tumor tissue selectively with less side effects. Yttrium-90 (Y-90), a high-energetic beta emitter is the most preferred radionuclide, which is used to label microspheres. Two types of Y-90 microspheres are commercially available that are made of resin and glass. Many studies in the literature have demonstrated that Y-90 microsphere therapy is an efficient and safe locoregional therapeutic option for unresectable primary and metastatic liver tumors such as hepatocellular carcinoma and liver metastases from colorectal cancer and breast cancer as well as neuroendocrine tumors. Furthermore, limited number of studies has reported its use in some relatively uncommon metastatic liver tumors from melanoma, pancreatic, renal, and lung cancer. Besides Y-90 microspheres, Iodine-131 lipiodol, Rhenium-188 lipiodol, Rhenium-188 microspheres, Holmium-166 chitosan, and Holmium-166 microspheres have been introduced as alternative radiopharmaceuticals for intra-arterial therapy for liver tumors.
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