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REVIEWS AND COMMENTARY

CT Findings of Chemotherapy-
induced Toxicity: What Radiologists
Need to Know about the Clinical

n REVIEW
and Radiologic Manifestations of
Chemotherapy Toxicity1
Jean M. Torrisi, MD
Cancer chemotherapy has evolved from cytotoxic agents
Lawrence H. Schwartz, MD
and now includes several new agents that target specific
Marc J. Gollub, MD molecules responsible for the regulation of cell growth,
Michelle S. Ginsberg, MD nutrient supply, and differentiation. These molecularly
George J. Bosl, MD targeted therapies have a different mechanism of action
Hedvig Hricak, MD, PhD, Dr hc than do classic cytotoxic agents, which predominantly at-
tack rapidly proliferating cells. Not surprisingly, therefore,
the toxicity of targeted and cytotoxic agents may differ
in both clinical and radiologic presentation. Many of the
Online CME toxicities of targeted therapies are not cumulative or dose
See www.rsna.org/education/ry_cme.html dependent, some are asymptomatic, and others may first
manifest radiologically. It is imperative that radiologists be
Learning Objectives aware of these toxicities and that they learn to recognize
After reading this article and taking the test, the reader
the relevant findings so that they can provide a complete
will be able to:
differential diagnosis and thus play an important role in
n Understand the classification of the newer agents and
be able to identify molecularly targeted agents and patient care.
their associated toxicities.
n Review the clinical manifestations of the toxicities q
RSNA, 2011
to help distinguish new-onset toxicity from disease
progression.
n Recognize some of the most common toxicities and Supplemental material: http://radiology.rsna.org/lookup
understand their management. /suppl/doi:10.1148/radiol.10092129/-/DC1
Accreditation and Designation Statement
The RSNA is accredited by the Accreditation Council for
Continuing Medical Education (ACCME) to provide con-
tinuing medical education for physicians. The RSNA
designates this education activity for a maximum of 1.0
AMA PRA Category 1 Credit ™. Physicians should
only claim credit commensurate with the extent of their
participation in the activity.
Disclosure Statement
The ACCME requires that the RSNA, as an accredited
provider of CME, obtain signed disclosure statements
from authors, editors, and reviewers for this case. For
this educational activity, L.H.S. disclosed relationships
with AstraZeneca and Novartis; the other authors and
the editor indicated that they have no relevant relation-
ships to disclose; one reviewer disclosed a relationship
with Novartis.

1
From the Departments of Radiology (J.M.T., L.H.S., M.J.G.,
M.S.G., H.H.) and Medicine (G.J.B.), Memorial Sloan-
Kettering Cancer Center, 1275 York Ave, Room C-278, New
York, NY 10065. Received November 16, 2009; revision
requested January 13, 2010; revision received March 2;
accepted March 9; final version accepted March 13; final
review by H.H. August 27. Address correspondence to
J.M.T. (e-mail: torrisij@mskcc.org).

q
RSNA, 2011

Radiology: Volume 258: Number 1—January 2011 n radiology.rsna.org 41

REVIEW: CT Findings of Chemotherapy-induced Toxicity
C
lassic chemotherapy agents inhibit
cell division and target rapidly
proliferating cells. In contrast, the
newer molecular targeted therapies are
directed at specific molecules respon-
sible for regulating cell activities, and the
onset and presentation of their toxicities
may therefore differ. Understanding
the mechanisms of action of the newer
molecular agents may aid recognition
of their associated toxicities, though
the mechanisms of the toxicities are
not completely understood. Several of
the monoclonal antibodies and tyrosine
kinase inhibitors bind known membrane
cell receptors. Others bind intracellular
molecules and are multitargeted, and
their toxicities may be more ubiquitous.
We will review the most common
toxicities of the classic and newer cyto-
toxic chemotherapy agents and discuss
what is known about the toxicities of
the molecularly targeted agents accord-
ing to the available clinical and radio-
logic literature. Our discussion is limited
to toxicities that may be seen on com-
puted tomographic (CT) studies of the
chest, abdomen, and pelvis, because
these are the imaging examinations most
commonly used in the follow-up of can-
cer patients. Also noted are the clinical
contexts in which these toxicities occur
and details that radiologists should look
for, not only on images but in the clini-
cal history.
Essentials
n Classic chemotherapy agents
target rapidly proliferating cells;
molecularly targeted therapies
target specific key cell membrane
and intracellular molecules.
n Radiologists may more easily rec-
ognize the manifestations of che-
motherapy toxicities by under-
standing the mechanisms of
action of the chemotherapeutic
agents.
n The radiologist should be aware
that toxicities can be asymptom-
atic and that radiologists are
instrumental in reporting early
manifestations of toxicities to
referring physicians.
42
Paradigm Shift in the Systemic
Treatment of Cancer
Cytotoxic chemotherapy agents usually
interfere with RNA and DNA synthesis
or cell division and, therefore, affect cell
growth by various mechanisms of ac-
tion. Some of the most commonly used
drugs include classic agents such as cy-
clophosphamide (an alkylating agent),
cisplatin (a DNA intercalating agent),
fluorouracil (5-FU; an antimetabolite),
doxorubicin (an anthracycline), vincris-
tine (a mitotic spindle inhibitor), and
bleomycin. Some of the more recently
developed cytotoxic agents include gem-
citabine (another antimetabolite), ox-
aliplatin (a cisplatin analog), paclitaxel
and docetaxel (the “taxanes,” which are
mitotic spindle poisons), and irinotecan
(a topoisomerase inhibitor) (Table 1).
Common trade names are provided for
reference (Table 2). If the drug’s damage
to the cell is too severe to be repaired,
cell death or apoptosis will occur. The
goal is a preferential effect on tumor over
normal tissues. Drugs that interfere with
nucleic acid synthesis and cell division have
the greatest effect on rapidly dividing cells.
Therefore, these drugs will also affect
the rapidly dividing cells of the intestine
and bone marrow, leading to common and
sometimes dose-limiting gastrointestinal
toxicity and myelosuppression. Nearly any
organ can be affected, however, de-
pending on the drug. Peripheral nerves
(eg, vinca alkaloids, cisplatin, taxanes),
lungs (eg, bleomycin and gemcitabine),
kidneys (eg, cisplatin), heart (eg, anthra-
cyclines), and central nervous system
(eg, high-dose methotrexate, 5-FU) are
only a few examples (Table 3).
Molecular therapies have developed
as a result of an improved knowledge of
cancer biology. They target cell surface
antigens (as in the case of monoclonal
antibodies) or various signaling mole-
cules (as in the case of kinase inhibitors).
Many of these agents affect multiple
targets and, therefore, have the poten-
tial to inhibit molecules that are critical
to unsuspected pathways, causing toxic-
ity that has not been previously observed
(1). While some of the toxicities of the
cytotoxic agents and molecularly targeted
therapies overlap, there is concern that
radiology.rsna.org
Torrisi et al
the toxicities of the molecularly targeted
agents are less predictable.
Targeted therapies can be classified
according to their mechanism of action
(Table 4). Monoclonal antibodies are
designed to bind to antigenic determi-
nants of specific molecules, the expres-
sion of which is sometimes upregulated
in malignancy, but the action of such
antibodies does not necessarily rely on
the activation of immune effector cells.
Several monoclonal antibodies are in
clinical use. Rituximab (Rituxan; Biogen
Idec), a chimeric monoclonal antibody
that is used to treat B-cell non-Hodgkin
lymphoma, binds to the CD20 protein
on the surface of both normal and ma-
lignant B cells (2 ). Binding the CD20
receptor initiates apoptosis, down-
regulation of CD20 expression, and
antibody-dependent cell phagocytosis
or complement-mediated lysis of the
tumor cell. The drug is also licensed for
use in the treatment of rheumatoid ar-
thritis, and efficacy has been reported
in other autoimmune disorders. More
recently, cetuximab (Erbitux; Bristol
Myers Squibb, ImClone, Merck) was li-
censed to treat colon adenocarcinoma
and squamous head and neck cancers.
It binds to the EGFR and prevents
the interaction of its ligand (epidermal
growth factor) with its receptor (EGFR),
thereby blocking the activation of intra-
cellular signaling pathways that would
normally instruct the cell to grow and
divide. Hence, it acts as a tyrosine kinase
inhibitor. Important to notice is a recent
discovery that cetuximab is active only
in tumors that are wild type for KRAS
(3). The exact mechanism of action is
unclear, as cetuximab recently demon-
strated antitumor activity in patients
with colorectal cancer whose disease
Published online
10.1148/radiol.10092129 Content Code:
Radiology 2011; 258:41–56
Abbreviations:
EGFR = epidermal growth factor receptor
5-FU = fluorouracil
TKI = tyrosine kinase inhibitor
VEGF = vascular endothelial growth factor
L.H.S. has disclosed financial relationships with
AstraZeneca and Novartis.
n Radiology: Volume 258: Number 1—January 2011
REVIEW: CT Findings of Chemotherapy-induced Toxicity Torrisi et al

Table 1 Molecular targeted therapies are

Chemotherapeutic Drugs by Class Classic Cytotoxic Agents used either alone or in combination
with standard chemotherapy agents.
Class Agents Combination chemotherapy regimens
Alkylating agents Busulfan, cyclophosphamide, ifosfamide, melphalan are designed to include agents with dif-
Nitrosoureas Carmustine ferent mechanisms of action, so that cell
Platinum analogs Carboplatin, cisplatin, oxaliplatin growth is interrupted at two or more
Antimetabolites Capecitabine, cytarabine, 5-FU, floxuridine, gemcitabine, methotrexate points of cell proliferation. The radiolo-
Antitumor antibiotics Bleomycin, dactinomycin, daunorubicin, doxorubicin gist needs to be aware of the potential
Taxanes Docetaxel, paclitaxel toxicities of both the conventional and
Vinca alkaloids Vinblastine, vincristine, vinorelbine the targeted agents when they are used
Topoisomerase inhibitors Etoposide, irinotecan, topotecan in combination therapy.

Chemotherapy Toxicity by Organ

lacked immunohistochemical staining
for the EGFR (4 ). Trastuzumab (Her-
ceptin; Genentech), a monoclonal anti-
body directed against human EGFR-2,
is used in the treatment of breast can-
cer that expresses the Her-2 receptor.
Bevacizumab (Avastin; Genentech) is a
monoclonal antibody that targets the
VEGF receptor, which normally pro-
motes the proliferation of additional
blood vessels to support tumor growth
and the development of metastases.
Tyrosine kinases within the receptor
are transmembrane molecules that are
activated by the binding of a ligand (eg,
epidermal growth factor, VEGF) with the
extracellular domain of the receptor.
The interaction of ligand and receptor
results in activation (phosphorylation) of
the intracellular domain, which in turn
phosphorylates any number of intracel-
lular molecules (so-called second mes-
sengers) that instruct the cell to grow
and divide. When the activity of tyrosine
kinases becomes excessive, driven usu-
ally by overexpression or activating
mutations, cancer may develop accom-
panied by its hallmarks of uncontrolled
growth, invasion, neovascularization, and
metastasis, depending on the tumor
type. Tyrosine kinase inhibitors (TKIs)
prevent the phosphorylation of the sec-
ond messengers, thereby interrupting
the unregulated intracellular signaling
pathway(s). Cetuximab and bevaci-
zumab function as kinase inhibitors, as
noted above. Examples of TKIs include
gefitinib (Iressa; AstraZeneca) and erlo-
tinib (Tarceva; Genentech), which bind
to the mutationally modified intracel-
lular adenosine triphosphate–binding
domain of the EGFR and are used in the
treatment of patients with non–small
cell lung cancer. Sunitinib (Sutent; Pfizer)
and sorafenib (Nexavar; Bayer) are
multitargeted TKIs that target the in-
tracellular domain of the VEGF recep-
tor and other tyrosine kinases, and are
used to treat patients with metastatic
renal cell cancer. Imatinib (Gleevec;
Novartis) was the first approved TKI; it
binds to the c-kit oncoprotein present
in gastrointestinal stromal tumors, the
oncoprotein from the BCR/ABL translo-
cation present in chronic myelogenous
leukemia, and the mutant protein re-
sulting in a translocation involving the
platelet-derived growth factor receptor in
dermatofibrosarcoma protuberans (5–7).
Some newer molecularly targeted
therapies do not inhibit membrane re-
ceptors but rather other intracellular
molecules. For example, temsorilimus
(Torisel; Wyeth), used in the treatment
of metastatic renal cancer, blocks the
mammalian target of rapamycin, or mTor,
which is involved in translation of mes-
senger RNA proteins, nutrient metabo-
lism, and ribosomal protein synthesis.
Some of its toxic effects are immuno-
suppression, hyperlipidemia and inter-
ference with proliferation of endothe-
lial and vascular smooth muscle cells
necessary for tumor angiogenesis (8).
Bortezomib (Velcade; Millennium Phar-
maceutical), used primarily in the treat-
ment of multiple myeloma, targets the
proteasome, which is involved in pro-
tein degradation, particularly factors
important in the regulation of nuclear
factor–kappa B and its inhibitory part-
ner, I–kappa B.
Pulmonary System
Pulmonary infiltrates are the most com-
mon radiologic manifestation of both
classic and new targeted chemother-
apy toxicities. Toxicity from the classic
chemotherapy agents typically results
in bilateral interstitial infiltrates pre-
senting with progressive dyspnea. The
radiologist should be aware that some
pulmonary toxicities can be asymptom-
atic. The newer EGFR-targeted agents
can cause ground-glass infiltrates that
should not be mistaken for tumor
progression.
Pulmonary and interstitial infiltrates.—
Pulmonary infiltrates that develop in
patients undergoing chemotherapy can
result from progression of disease, in-
fection, and inflammation caused by
chemotherapy toxicity or cardiogenic
and noncardiogenic causes of intersti-
tial edema. Knowledge about which
chemotherapy agents are more likely
to cause pulmonary toxicity may
aid in judging the most likely cause.
Chemotherapy-induced lung injury can
manifest as early onset with infiltrates,
pulmonary edema, hypersensitivity
reaction, or pleural effusions or as late
onset, after 2 months or more of
therapy, with infiltrates or fibrosis.
Pulmonary toxicity of some of the older
standard chemotherapy agents can be
dose dependent—seen at high cumula-
tive doses, as in the case of bleomycin
and carmustine and can be seen several
years after completion of therapy, as
with cyclophosphamide, busulfan, and
carmustine (9). Of the standard agents,
bleomycin and methotrexate are most

Radiology: Volume 258: Number 1—January 2011 n radiology.rsna.org 43

REVIEW: CT Findings of Chemotherapy-induced Toxicity Torrisi et al

Table 2 often associated with pulmonary toxicity.

Chemotherapeutic Agents and Their Trade Names Bleomycin-induced pneumonitis is a
well-known potential toxicity. Pulmo-
Agent Trade Name* nary toxicity resulting from bleomycin
All-trans retinoic acid Vesanoid, (Roche, Basel, Switzerland)† treatment of testicular cancer, sarcoma,
Bevacizumab Avastin (Genentech, South San Francisco, Calif) and lymphoma typically presents 1–6
Bleomycin Blenoxane (Bristol Myers Squibb, New York, NY)† months after initiation of therapy with
Bortezomib Velcade (Millennium Pharmaceutical, Cambridge, Mass) progressive dyspnea. Several radiologic
Busulfan Busulfex, Myleran (Glaxo Smith Kline, Brentford, England) patterns of pulmonary toxicity have
Capecitabine Xeloda (Genentech; Roche) been associated with bleomycin, in-
Carboplatin Paraplatin (Bristol Myers Squibb)† cluding bronchiolitis obliterans orga-
Cetuximab Erbitux (Bristol Myers Squibb; ImClone, Branchburg, NJ; nizing pneumonia (now referred to as
Merck, Whitehouse Station, NJ) cryptogenic organizing pneumonia, the
Cisplatin Platinol, Platinol-AQ (Bristol Myers Squibb)† preferred term), eosinophilic hypersen-
Cyclophosphamide Cytoxan, Neosar (Bristol Myers Squibb) sitivity, and, most commonly, intersti-
Cytarabine Cytosar-U (Pfizer, New York, NY), Cytarabine tial pneumonitis, which may progress
(Bedford Laboratories, Bedford, Ohio)†
into fibrosis (10,11) (Fig 1). High intraop-
Dactinomycin (actinomycin-D) Cosmegen (Ovation Pharma, Lundbeck, Deefield, Ill)†
erative or postoperative fractional con-
Daunorubicin (daunomycin) Cerubidine (Bedford Laboratories)†
centration of inspired oxygen exposure
Docetaxel Taxotere (Sanofi-Aventis, Bridgewater, NJ)
increases the postoperative risk of acute
Doxorubicin Adriamycin (Bedford Laboratories)†
Erlotinib Tarceva (Genentech; OSI Pharmaceuticals, Melville, NY)
respiratory distress syndrome in pa-
Etoposide VePesid (Bristol-Myers Squibb)†
tients treated with bleomycin and should
Everolimus Afinitor (Novartis, Basel, Switzerland) be considered in a patient who has re-
Floxuridine FUDR (Roche; Hospira, Lake Forest, Ill)† ceived bleomycin and develops progres-
Fluorouracil 5-FU, Efudex (Roche; Teva Pharmaceutical Industries, sive postoperative pulmonary infiltrates
Petah Tikva, Israel) (12). Methotrexate pulmonary toxicity
Gefitinib Iressa (AstraZeneca) typically presents within the 1st year of
Gemcitabine Gemzar (Eli Lilly, Indianapolis, Ind) therapy with bilateral interstitial and al-
Ifosfamide Ifex (Bristol-Myers Squibb)† veolar infiltrates and pleural effusions,
Imatinib Gleevec (Novartis) is often accompanied by fever and pe-
Interferon-alpha Intron A (Schering, Berlin, Germany); Roferon (Roche) ripheral eosinophilia, and does not
Interleukin 2 (IL-2, aldesleukin) Proleukin (Novartis) progress to fibrosis if the medication is
Irinotecan (CPT 11) Camptosar (Pfizer)† stopped (10).
L-asparaginase Elspar (Ovation Pharma; Lundbeck) Pulmonary toxicity may be seen with
Melphalan Alkeran (Glaxo Smith Kline)† many of the newer cytotoxic chemothera-
Methotrexate MTX, Amethopterin (Lederle Laboratories, peutic agents. Gemcitabine may cause dif-
Philadelphia, Pa)† fuse ground-glass changes accompanied
Oxaliplatin Eloxatin (Sanofi-Aventis)†
by thickened septal lines, interstitial in-
Paclitaxel Taxol (Bristol-Myers Squibb)†
filtrates, or diffuse alveolar infiltrates,
Rituximab Rituxan (Biogen Idec, Weston, Mass; and Genentech)
which may sometimes be associated with
Sorafenib Nexavar (Bayer, Berlin, Germany)
acute respiratory distress syndrome and,
Sunitinib Sutent (Pfizer)
Temsirolimus Torisel (Wyeth, New York, NY)
rarely, death (13–15). Paclitaxel-induced
Thalidomide Thalomid (Celgene, Summit, NJ) pulmonary toxicity is nonspecific and
Topotecan Hycamtin (Glaxo Smith Kline) can manifest with bilateral reticular or
Trastuzumab Herceptin (Genentech) ground-glass infiltrates or focal consoli-
Vinblastine Velban (Eli Lilly)† dation (16) (Fig 2). These toxicities tend
Vincristine Oncovin (Eli Lilly)† to manifest with dyspnea, cough, and
Vinorelbine Navelbine (Glaxo Smith Kline)† hypoxemia, usually early after initiation
of therapy. Oxaliplatin-induced pulmo-
Sources—Chu E, DeVita VT. Cancer chemotherapy drug manual 2008. Sudbury, Mass: Jones and Bartlett, 2007. Lexi-comp
nary interstitial disease is an increasingly
Online (http://www.lexi.com). Drug Information Online (http://drugs.com). Listed manufacturers.
recognized entity. Interstitial pneumonitis
* Manufacturer name and location is in parentheses.
†
Available in generic form.
with fibrosis occurs after 3–6 months
of therapy. Patients present with slow
progressive cough and dyspnea that may
rapidly progress to fibrosis and, rarely,
fatal pneumonitis. (Fig 3) (16–18). The

44 radiology.rsna.org n Radiology: Volume 258: Number 1—January 2011

REVIEW: CT Findings of Chemotherapy-induced Toxicity Torrisi et al

Table 3 a nonspecific area with ground-glass

Common Chemotherapy Toxicity by Organ and Drug (Not All-inclusive) attenuation, (b) multifocal areas of air-
space consolidation, (c) patchy distribu-
Organ System and Toxicity Agents tion of ground-glass attenuation accom-
Pulmonary panied by interlobular septal thickening,
Interstitial infiltrates Bleomycin, methotrexate, gemcitabine, paclitaxel, oxaliplatin, and (d) extensive bilateral ground-glass
everolimus and temsorilimus, gefitinib, erlotinib, rituximab attenuation or airspace consolidations
Noncardiogenic pulmonary edema All-trans retinoic acid, gemcitabine, interleukin 2, interferon with traction bronchiectasis. The most
Pulmonary hemorrhage Bevacizumab common pattern is a nonspecific area of
Cardiovascular ground-glass attenuation, and the pat-
Cardiac Doxorubicin, cyclophosphamide, trastuzumab tern associated with the highest mor-
(when given with doxorubicin), sunitinib tality rate is extensive bilateral ground-
Hypertension Bevacizumab, sunitinib, sorafenib glass airspace consolidation, thought to
Vascular represent diffuse alveolar damage (22)
Arteriothromboembolic Cisplatin, gemcitabine, bevacizumab, sorafenib, sunitinib (Fig 5).
Venous Thalidomide, lenalidomide, interleukin-2, cisplatin, gemcitabine The rare pulmonary toxicity of the
Pericardial effusions All-trans retinoic acid, imatinib
monoclonal antibody rituximab has a
Liver
different mechanism of action, which is
Fatty liver Irinotecan, oxaliplatin
thought to involve complement activation
Veno-occlusive disease Bone marrow transplant regimens, oxaliplatin
and proinflammatory effects of cytokine
Pseudocirrhosis Any chemotherapy
Biliary stricture Hepatic arterial infusion with floxuridine (FUDR)
release (24). Patients on treatment can
Pancreas
be asymptomatic or present with high
Pancreatitis L-asparaginase, sorafenib
fever, dyspnea, and cough; the symptoms
Gastrointestinal typically begin after a few cycles of admin-
Enteritis 5-FU, floxuridine, irinotecan, cetuximab, EGFR agents, istration. Severe lung toxicity with inter-
VEGF receptor agents* stitial infiltrates and cryptogenic orga-
Neutropenic colitis 5-FU, paclitaxel, docetaxel; any agent causing nizing pneumonia is rare.
significant neutropenia Pulmonary hemorrhage.—Major and
Pneumatosis or perforation Bevacizumab fatal hemoptysis can occur in patients
Megacolon Vincristine treated with bevacizumab for non–small
Genitourinary cell lung cancer, reported in 5% of pa-
Hemorrhagic cystitis Cyclophosphamide, ifosfamide tients in an early clinical trial (25). The
Neurogenic bladder Bortezomib mechanism is not known, but at retro-
Peritoneum, mesentery, soft tissues spective review of CT scans from these
Ascites Docetaxel, imatinib patients, potential risk factors for pul-
Neurologic monary hemorrhage were identified as
Peripheral neuropathy Vincristine, vinblastine, paclitaxel, cisplatin
baseline tumor necrosis and cavitation
Central nervous system 5-FU, methotrexate
(26). In early clinical trials, investigators
* EGFR = epidermal growth factor receptor, VEGF = vascular endothelial growth factor. identified squamous histologic appear-
ance as a risk factor for pulmonary hem-
orrhage; this finding is now an exclu-
sion criterion for bevacizumab therapy
mammalian target of rapamycin inhibi- (21). Clinically, patients present with (27). Bevacizumab is approved for use
tor temsorilimus (and everolimus, the acute onset of dyspnea, with or without in colon, breast, lung, brain, and kidney
oral equivalent) is associated with drug- cough; symptoms may appear as early cancer.
induced pneumonitis. Patients have ground as 1 week to 1 month after initiation Capillary leak syndrome.—Capillary
glass opacities and parenchymal consol- of therapy. CT findings include airspace leak syndrome is characterized by an
idation, and may be asymptomatic (in consolidation or extensive bilateral increase in vascular permeability, caus-
50% of cases) or present with dyspnea ground-glass infiltrates (22). The mecha- ing extravasation of fluids and proteins
and dry cough (Fig 4) (19). nism of pulmonary toxicity is unknown from capillary vessels into the soft tissues
Pulmonary infiltrates are among the but it is has been suggested that repair and resulting in interstitial edema. It is
most common adverse reactions of the of damaged epithelial cells requires a systemic process leading to ARDS or
EGFR-targeted inhibitors gefitinib and activation of EGFR-mediated pneumo- noncardiogenic pulmonary edema in
erlotinib (20). The overall prevalence of cytes, which is inhibited by gefitinib and late stages. Diffuse air space disease
pulmonary toxicity with gefitinib is 1%, erlotinib (23). Four radiologic patterns with ground glass opacities is the most
and it is higher in Asia than in the US have been described on CT scans: (a) common finding on CT scans. Capillary

Radiology: Volume 258: Number 1—January 2011 n radiology.rsna.org 45

REVIEW: CT Findings of Chemotherapy-induced Toxicity Torrisi et al

Table 4
Cytostatic Molecularly Targeted Therapies
Class and Agent Cancer Target* Common Cancer Uses

Monoclonal antibodies
Cetuximab EGFR Colon, head and neck
Trastuzumab EGFR Breast
Bevacizumab VEGF receptor Kidney, colon, lung
Rituximab CD20 Lymphoma
Tyrosine kinase inhibitors
Gefitinib Mutated EGFR Non-Small Cell Lung
Erlotinib Mutated EGFR Non-Small Cell Lung
Sunitinib VEGF receptor Kidney
Sorafenib VEGF receptor Kidney
Imatinib KIT, BCR/ABL protein Gastrointestinal stromal tumor, chronic myelogenous leukemia
Agents that target other molecules
Everolimus mTor Kidney
Temsorilimus mTor Kidney
Bortezomib Proteosome Myeloma
All-trans retinoic acid PML/RAR protein Acute promyelocytic leukemia
L-asparaginase Asparagine Acute lymphocytic leukemia (children)
Immunotherapy cytokines
Interleukin 2 Interleukin 2 signaling pathway Kidney
Interferon Activate natural killer cells† Kidney, chronic myelogenous leukemia
Immunomodulatory therapies
Thalidomide Antiangiogenic, immunomodulatory† Myeloma
Lenalidomide Antiangiogenic, immunomodulatory† Myeloma

* KIT = KIT receptor (c-kit), mTor = mammalian target of rapamycin.

†
Putative targets.

Figure 1

Figure 1: Bleomycin-induced pulmonary toxicity. Patient undergoing treatment for lymphoma presented with new-onset dyspnea and de-
crease in diffusing capacity 5 months after initiation of treatment. Lung window images from axial CT of lower lungs demonstrate (a) peripheral
infiltrates, which (b) subsequently improved with steroid therapy.

leak syndrome is associated with sev- been reported with gemcitabine (28,29). is crucial, since capillary leak syn-
eral chemotherapy agents, including Consideration of capillary leak syn- drome may require the addition of cor-
immune-mediated therapies such as drome in the differential diagnosis of ticosteroid therapy to diuretic therapy
interleukin 2 and interferon and has new-onset interstitial pulmonary edema (30,31).

46 radiology.rsna.org n Radiology: Volume 258: Number 1—January 2011

REVIEW: CT Findings of Chemotherapy-induced Toxicity
Figure 2
Figure 2: Paclitaxel-induced pulmonary toxicity. Patient with breast cancer who received two doses of paclitaxel, with fever immediately
after each infusion, consistent with a hypersensitivity reaction. Lung window images from axial CT demonstrate (a) faint bilateral ground-glass
infiltrates that (b) improved following discontinuation of treatment.
Cardiovascular System
Chemotherapy-induced cardiovascular
toxicity resulting in cardiomyopathy can
be detected by the radiologist as a dilated
heart or heart failure in the differential
diagnosis of new onset interstitial thick-
ening. Cardiotoxicity may be worsened
with radiation therapy. The most common
cardiovascular toxicity of the molecular
targeted therapies is arterial hyperten-
sion, which is directly related to inhibi-
tion of the VEGF receptor pathway.
Cardiotoxicity.—Cardiotoxicity is a
well-known adverse effect of the an-
thracyclines doxorubicin (Adriamycin,
Ben Venue Laboratories, Bedford, Ohio),
daunomycin (Cerubidine, Ben Venue
Laboratories; Rubidomycin, Gilead Sci-
ences, San Dimas, Calif), and, more
rarely, very high doses of the alkylat-
ing agent cyclophosphamide (32). The
risk of cardiomyopathy in patients re-
ceiving these therapies necessitates
standard monitoring of cardiac function,
including left ventricular ejection frac-
tion (LVEF) on multiple-gated acquisi-
tion (MUGA) scans or echocardiogram.
Most consensus guidelines recommend
measurement of LVEF prior to an-
thracycline administration. LVEF mea-
surement should be repeated during
therapy and after completion if doses
exceed 300mg/m2 of doxorubicin or its
equivalent or if another potentially car-
diotoxic chemotherapy agent is to be
administered. The incidence of cardio-
Radiology: Volume 258: Number 1—January 2011
Figure 3
myopathy with doxorubicin increases
exponentially when the total dose is
above 550 mg/m2, or 450 mg/m2 in
the presence of prior thoracic radia-
tion therapy, and can occasionally oc-
cur below these thresholds. During
administration of doxorubicin, a decline
in LVEF of at least 10 ejection fraction
units from baseline to below the lower
limit of normal has been defined as
cardiac toxicity (33). Trastuzumab (Her-
ceptin, Genentech) has been associated
with cardiotoxicity when administered
as a single agent, particularly when ad-
ministered with or after doxorubicin
(34) Sunitinib-associated cardiotoxic-
ity may also require cardiac monitoring
n radiology.rsna.org
Torrisi et al
Figure 3: Oxaliplatin-induced
pneumonitis. Asymptom-
atic patient with stage IV colon
cancer was found to have new
bilateral subpleural interstitial
infiltrates following completion
of bevacizumab and FOLFOX
(5-FU, leucovorin, and oxaliplatin)
regimen. Pulmonary infiltrates
were an incidental finding on first
surveillance CT scan to evaluate
for recurrent disease. Follow-up
CT (4 months later; image not
shown) demonstrated complete
resolution of infiltrates.
during therapy (35). Authors of one
study in which sunitinib cardiotoxicity
was reviewed reported that heart fail-
ure occurs early in therapy, suggesting
a mechanism different from that of an-
thracycline-induced cardiotoxicity (36).
Hypertension.—Hypertension is the
most common adverse effect of the
antiangiogenic agents (37,38). Though
hypertension is not identified on CT
studies, it has been linked to a higher
incidence of intracerebral hemorrhage
in patients with renal cell carcinoma
and brain metastases treated with
TKIs and rarely with reversible pos-
terior leukoencephalopathy syndrome
(particularly bevacizumab) (39–44 ).
47
REVIEW: CT Findings of Chemotherapy-induced Toxicity Torrisi et al

Figure 4

Figure 4: Everolimus (mammalian target of rapamycin inhibitor)-induced pneumonitis. Patient with metastatic renal cell cancer and mild
shortness of breath with intermittent fevers during the first 3 months of therapy. (a) Lung window images from axial CT obtained 1 month after
initiation of treatment with everolimus reveals focal consolidation in right lower lobe. Patient was treated with antibiotics. (b) Axial CT scan
obtained 2 months later shows new area of consolidation in right middle lobe. Transbronchial biopsy revealed interstitial inflammation and
organizing pneumonia with no evidence of infection. Infiltrates cleared with cessation of therapy and initiation of prednisone (image not shown).

Whether hypertension causes intrac- Figure 5

erebral hemorrhage independent of ce-
rebral metastasis has not been clearly
established.
Pericardial effusions.—Pericardial
effusions can be seen with any fluid
retention syndrome, such as that seen
with docetaxel in the treatment of pros-
tate, ovarian, or breast cancer. It may
also be seen in patients with acute pro-
myelocytic leukemia who are treated
with all-trans retinoic acid and develop
retinoic acid syndrome. Treatment with
all-trans retinoic acid can induce a toxic
reaction in approximately 25% of pa-
tients with acute promyelocytic leuke-
mia and can manifest as fever, dyspnea,
hypotension, and pericardial and pleu-
ral effusions (45).
Vascular System
Venous thromboembolism is most
closely associated with the hypercoagu-
lable state that occurs with malignancy
and is difficult to directly associate with
a specific chemotherapy agent. Arterial
thromboembolic events are rarely asso-
ciated with cytotoxic chemotherapy but
are a potential side effect of antiangio-
genic targeted therapies. Surveillance
for peripheral arterial thromboembo-
lism, multiorgan infarcts, and paradoxi-
cal hemorrhage is important in patients
taking antiangiogenic agents.
Thrombosis and thromboembolic
events that occur in patients with ma-
lignancy and in patients undergoing che-
motherapy are not well understood. A
number of explanations have been pro-
posed, including circulating factors such
as a “procoagulant factor” produced by the
tumor, as well as general factors such as
immobility and the use of indwelling cath-
eters. Additionally, structural deficiencies
in the vascular endothelium due to tu-
mor neovascularity or chemotherapy-
induced apoptosis of the endothelial
cells may play a role. Chemotherapy-
induced apoptosis may cause weaken-
Figure 5: Erlotinib-induced
pulmonary toxicity. Patient is
a former smoker with left lung
cancer. Lung window images
from axial CT show extensive
ground-glass opacities identified
during 4th week of treatment
with erlotinib. Despite discontinu-
ation of erlotinib and initiation of
steroids, the patient died.
ing of the endothelium, exposure of the
basement membrane, and activation of
the clotting cascade. Paradoxical hem-
orrhage seen with some chemotherapy
agents may result from the same struc-
tural alterations, with “leaking” of the
weakened basement membrane (46).
Of the classic chemotherapy agents,
gemcitabine and cisplatin are most often
associated with vascular complications.
The most common vascular complica-
tion of gemcitabine is venous thrombosis;
however, other vascular side effects in-
clude capillary leak syndrome, pedal
edema, hemolytic uremic syndrome,

48 radiology.rsna.org n Radiology: Volume 258: Number 1—January 2011

REVIEW: CT Findings of Chemotherapy-induced Toxicity
Figure 6
thrombotic thrombocytopenic purpura,
necrotizing vasculitis, and arterial throm-
bosis (29). Radiographic changes of vas-
culitis can be seen as diffuse vessel wall
thickening on ultrasonographic (US), CT,
and magnetic resonance (MR) images
(47) (Fig 6). Platinum-based therapies
are known to have an increased risk of
thrombus formation (48,49). Cisplatin-
induced thromboembolic events have
been reported to occur during treat-
ment in a particular subset of patients
with germ cell tumor (50–52) (Figs 7, 8).
These patients are also at risk for
the development of late cardiovascular
toxicity with Raynaud phenomenon, an-
gina pectoris, and myocardial infarc-
tion (53).
Antiangiogenic therapies, including
molecularly targeted agents, are also as-
sociated with thromboembolic side ef-
fects. An increased incidence of venous
thromboembolism is seen with thali-
domide-based therapy; thalidomide is
both an immunomodulatory agent and
an antiangiogenic agent used primarily
in the treatment of multiple myeloma
(46,54). In randomized trials, arterial
Radiology: Volume 258: Number 1—January 2011
Figure 6: Gemcitabine-induced vasculitis.
Patient with advanced small cell lung cancer de-
veloped painful blue fingers in the left hand during
treatment with gemcitabine. (a) Axial contrast-
enhanced CT image at the level of the great vessels
demonstrates diffuse wall thickening of the right
brachiocephalic artery, indicative of reactive vas-
culitis (arrow), and stenosis of the left subclavian
artery (not shown). (b) Baseline CT image obtained
several months earlier shows no arterial wall thick-
ening of right brachiocephalic artery. (c) Oblique
coronal MR angiographic image from confirmed
both narrowing of the right brachiocephalic artery
(arrow) and stenosis of the left subclavian artery.
thromboembolic events occurred more
frequently in patients treated with
the VEGF receptor–targeted therapies
(3.8%) than in control patients (1.7%).
The mechanism is unknown, but the
role of VEGF in the maintenance of the
integrity of the vascular endothelium
is suspected. These side effects are
mostly cardiac and cerebrovascular, but
thrombus formation in the aorta and
arteries of the mesentery, pelvis, and
extremities has been reported (37,55).
The risk factors associated with vascu-
lar complications include prior arterial
thromboembolic events and age older
than 65 years. Other reported vascu-
lar complications associated with be-
vacizumab treatment include impaired
wound healing, gastrointestinal perfo-
ration, and hypertension (56). Bevaci-
zumab is usually discontinued before
and after elective surgery owing to risk
of impaired wound healing (57).
n radiology.rsna.org
Torrisi et al
Liver
Liver toxicity can occur in any patient
undergoing cytotoxic chemotherapy.
Hepatic steatosis can develop but may
be clinically important in the treatment
of hepatic colorectal metastasis with
irinotecan before hepatic resection.
Hepatic steatosis, or fatty liver, may alter
surgical management of large hepatic
resections. It is seen less often after tar-
geted therapy. Veno-occlusive disease is
a major complication of bone marrow
transplantation.
Fatty liver.—Chemical hepatitis, re-
activation of hepatitis B, and fatty liver
are a few of the hepatotoxicities en-
countered in patients undergoing che-
motherapy (58). Fatty liver can be de-
tected by the radiologist and reported
as a possible explanation for elevated
transaminases. Fatty liver may also
have increased importance in patients
undergoing neoadjuvant chemotherapy
for liver metastases from colorectal
cancer. Steatosis, defined as accumula-
tion of fat globules in the hepatocytes,
and steatohepatitis, a more serious
histologic finding that manifests as bal-
looning and hepatocyte degeneration,
may develop during prolonged admin-
istration of irinotecan used in the treat-
ment of metastases from colorectal can-
cer. The frequency of this occurrence is
unknown (59–61). Steatohepatitis may
limit hepatic reserve for regeneration
and place patients who subsequently
undergo resection of hepatic metas-
tases at risk for postoperative hepatic
insufficiency. Although the two histo-
logic subtypes of steatosis can only be
distinguished by examining pathologic
specimens obtained at biopsy or at the
time of resection, development of fatty
changes on CT studies is an important
observation to report. The demonstra-
tion of fatty liver may alter plans for
surgical resection or suggest alternative
therapeutic approaches, including more
minimally invasive therapies (62).
Pseudocirrhosis.—Hepatic capsular
retraction can be seen at presentation
with any primary or secondary hepatic
tumor and in patients with liver metas-
tases following treatment with chemo-
therapy (63) (Fig 9). Retraction typi-
cally occurs subjacent to a metastatic
49
REVIEW: CT Findings of Chemotherapy-induced Toxicity
Figure 7
Figure 7: Cisplatin-induced thrombosis in large
arteries. Patient with metastatic gastroesophageal
junction adenocarcinoma was started with cisplatin-
based chemotherapy. (a) Axial contrast-enhanced
CT image at baseline. (b) At 1 month after initiation
of therapy, patient developed thrombus in the aorta.
lesion after chemotherapy treatment
and can evolve rapidly over 1–3 months
(64). Changes can be focal or diffuse
depending on the extent of metastatic
disease, mimicking cirrhosis in cases
of extensive metastatic disease. His-
tologic findings suggest that capsular
retraction is due to nodular regen-
erative hyperplasia (64). Morphologic
changes of pseudocirrhosis may be
associated with signs of portal hyper-
tension, including ascites, portosys-
temic collateral veins, and splenom-
egaly (65). Extreme capsular retraction
with a pseudocirrhotic appearance has
been encountered in patients with hepatic
metastases from breast cancer. Pseudo-
cirrhosis is not associated with any one
therapy or treatment response and can
be seen in lesions that are both increas-
ing and decreasing in size (66 ). Pro-
gressive inhomogeneity of the liver at
CT can make it increasingly difficult
50
Figure 8
Figure 8: Cisplatin-induced arterial thrombosis.
Patient with germ cell tumor of the testis developed
left upper quadrant pain 2 weeks after initiation of
cisplatin-based therapy. (a) Axial contrast-enhanced
CT image demonstrates thrombus in celiac (small
arrow) and right hepatic (large arrow) arteries and
new splenic infarct. (b) Thin-section CT image
demonstrates small distal splenic artery thrombosis
(arrow).
to evaluate extent of disease, and MR
imaging may be helpful in these ad-
vanced cases.
Biliary sclerosis.—Jaundice that oc-
curs during hepatic arterial infusion with
floxuridine (FUDR) is most commonly
due to biliary stricture or chemical hep-
atitis (67). Differentiation between the
two and identification of biliary changes
is important because hepatic parenchy-
mal toxicity is treated with cessation of
therapy, while biliary toxicity may require
stent placement in addition to discon-
tinuation of therapy (68). Biliary sclero-
sis, also known as CIBS (chemotherapy-
induced biliary sclerosis) results either
from toxic effects on the biliary system or
ischemic changes secondary to fibrosis
of the pericholangitic venous plexus,
radiology.rsna.org
Torrisi et al
Figure 9
Figure 9: Chemotherapy-induced pseudocirrhosis.
Patient with metastatic breast cancer developed
pseudocirrhosis 2 months after initiation of therapy.
Axial contrast-enhanced images from (a) baseline
CT and (b) follow-up CT demonstrate interval
development of multifocal capsular retraction with
pseudocirrhosis appearance.
both of which can result in stricture of
the duct. The CT findings mimic those
of sclerosing cholangitis, with segmental
narrowing of the bile ducts. The com-
mon hepatic duct and bifurcation of the
common hepatic ducts are most com-
monly affected, with lesser involvement
of the common bile duct and intrahepatic
bile ducts (69) (Fig 10). Subtle findings
of periductal edema and fat stranding in
the hepatoduodenal ligament, enhanced
and thickened bile duct wall (short axis,
.1.5 mm), or stricture with lumen smaller
than 3 mm may suggest the diagnosis
of chemotherapy-induced biliary scle-
rosis in the clinical setting of possible
cholangitis (68). Development of biliary
sclerosis will lead to alternate infusions
of intrahepatic steroid with the chemo-
therapeutic agent or reduction in dose.
Hepatoveno–occlusive disease or
sinusoidal obstruction syndrome.—Hepa-
toveno-occlusive disease is perhaps the
best known serious hepatic complication
n Radiology: Volume 258: Number 1—January 2011
REVIEW: CT Findings of Chemotherapy-induced Toxicity
Figure 10
of myeloablative chemotherapy and to-
tal body irradiation prior to allogeneic
bone marrow transplantation. It is char-
acterized pathologically by obliteration
of small hepatic venules with surround-
ing fibrosis and clogging of the sinusoids
with debris from endothelial cell necro-
sis. The entity is also called sinusoidal
obstruction syndrome (70). It clinically
manifests with jaundice, ascites, and
hepatomegaly, typically in the first three
weeks of treatment (71). Hepatoveno-
occlusive disease is most often evalu-
ated with US. The gray-scale findings at
US are nonspecific and include ascites,
gallbladder wall thickening, and hepa-
tosplenomegaly. Doppler US may show
decreased flow in the portal vein. These
changes may occur within 3 weeks of
bone marrow transplantation (72). CT
findings that have been described include
periportal edema, ascites, and decreased
right hepatic vein diameter (,0.45 cm)
(73). Veno-occlusive disease is an un-
common and less well-known compli-
cation of oxaliplatin therapy (61,74).
CT findings of new-onset portal hyper-
Radiology: Volume 258: Number 1—January 2011
Figure 10: Biliary sclerosis induced by hepatic
arterial infusion of floxuridine. Patient with colon
carcinoma with liver metastases underwent right
hepatic resection, with pump-based and systemic
treatment with 5-FU and leucovorin. Three years
after last hepatic arterial infusion floxuridine pump
treatment, patient developed itching. Bilirubin
measurement was 2.2, and the patient was not
responsive to decadron pump treatment. Axial
contrast-enhanced CT images of the liver demon-
strate (a) mild enhancement of common hepatic
duct (arrow) and (b) mild intrahepatic duct dilata-
tion. (c) Two years later, when the patient became
symptomatic, MR cholangiogram was obtained and
revealed biliary stricture at the confluence of left
hepatic ducts (arrow).
tension, including ascites, splenomegaly,
periesophageal varices, and recanaliza-
tion of the umbilical vein, should prompt
the radiologist to suggest the develop-
ment of oxaliplatin-induced hepatoveno-
occlusive disease. (75). It is also im-
portant to consider veno-occlusive dis-
ease in patients receiving oxaliplatin for
the treatment of colon cancer to avoid
mistaking new-onset ascites for evidence
of recurrent disease (76).
Pancreas
Clinical pancreatitis may be seen with
selected cytotoxic chemotherapies and
targeted therapies. Among the targeted
therapies, pancreatitis caused by the
antiangiogenic TKIs may be encountered
with or without findings at CT.
Chemotherapy-induced pancrea-
titis is most closely associated with
L-asparaginase therapy in the treatment
of acute leukemia. The time to onset is
variable, and serum amylase levels may
be only mildly elevated, but the pancrea-
titis can progress rapidly (77). Among the
molecularly targeted agents, both chemi-
n radiology.rsna.org
Torrisi et al
cal and clinical pancreatitis have been
reported with sunitinib and sorafenib.
Among patients with metastatic renal
cell carcinoma treated with sunitinib,
approximately 30% developed elevated
lipase not associated with clinical signs or
symptoms of pancreatitis (78). Case re-
ports of clinical pancreatitis manifesting
with abdominal pain within 3–4 weeks
of initiation of therapy are described in
patients with metastatic renal cell car-
cinoma treated with sorafenib, with or
without findings at CT (79,80).
Bowel
Chemotherapy-induced enteritis is com-
mon with cytotoxic chemotherapy. Toxici-
ties associated with epidermal growth
factor–targeted therapies include enter-
itis and acneiform skin rash. Oncologists
may report the rash in the clinical history
to provide additional information to the
interpreting radiologist. Pneumatosis
intestinalis is a nonspecific radiologic
finding, which may have an important
adverse outcome if not recognized, de-
pending on its cause. Both symptomatic
and asymptomatic pneumatosis intesti-
nalis have been described with numerous
classic chemotherapy agents and have
been reported with targeted therapy as
well.
Enteritis.—Chemotherapy-induced
enteritis, manifesting as abdominal
pain, bloating, and diarrhea, is one of
the most common toxicities associated
with the classic cytotoxic agents. It is
due to nonspecific targeting of the rap-
idly dividing cells in the gastrointestinal
mucosa. Several chemotherapy agents
used in the treatment of metastatic
colorectal cancer, including 5-FU plus
leucovorin, which is administered sys-
temically, and floxuridine, which is
most commonly administered by means
of hepatic arterial infusion, can cause
enteritis. The enteritis may be diffuse
or predominantly involve the distal il-
eum (81–83). Rarely, diffuse gastritis,
duodenitis, and ulcer formation can
occur with hepatic arterial infusion of
floxuridine, and this has been partially
attributed to poor catheter placement
and misperfusion of the chemotherapy
agent to the upper gastrointestinal
tract (84–86). Gastrointestinal toxicity
51
REVIEW: CT Findings of Chemotherapy-induced Toxicity
Figure 11
Figure 11: Irinotecan-induced enteritis. Patient
with recurrent metastatic colorectal cancer
developed abdominal pain and constipation
2 months after initiation of chemotherapy regimen
containing irinotecan. (a) Axial contrast-enhanced
CT image reveals mild small-bowel wall thickening
and dilatation. (b) Upper gastrointestinal tract
series demonstrates terminal ileitis with featureless
small bowel and loss of normal fold pattern.
is preventable if small arterial branches
between the catheter tip and the liver are
ligated at the time of catheter placement
to prevent extrahepatic perfusion to the
stomach and duodenum and absence
of extrahepatic perfusion is confirmed
with postoperative Tc-99m macroag-
gregated albumin radionuclide imag-
ing (68). Irinotecan is associated with
a high incidence of diarrhea and neu-
tropenia. When irinotecan is used in
combination with 5-FU and leucovorin
(ie, FOLFIRI), there is an increased
risk of gastrointestinal complications
(87 ). The radiographic findings may
include dilated bowel, air-fluid levels,
and bowel wall thickening (Fig 11). The
52
Figure 12
Figure 12: Sunitinib-induced enteritis. Patient
with metastatic renal cell carcinoma had been
undergoing treatment with sunitinib for approximately
1 year. Patient complained of abdominal pain
during the course of sunitinib therapy, with
new-onset diarrhea. Axial contrast-enhanced
CT image through the abdomen reveals
bowel wall thickening in the left lower
quadrant (arrow).
typical appearance of enteritis on CT
images includes submucosal edema
and hyperemia of the mucosa and se-
rosa to yield a target sign. Other entities
such as ischemia and radiation enteritis
can have a similar appearance. Bowel
wall thickening can also be uniform in
attenuation.
Anti-EGFR therapies including cetux-
imab, gefitinib, and erlotinib are asso-
ciated with skin and gastrointestinal
toxicities, in addition to pulmonary com-
plications described above, all having in
common the disruption of normal EGFR
effects of maintenance and repair of tis-
sue of epithelial origin (88). The rash
is a follicular acneiform eruption and is
seen in approximately 85% of patients
treated with cetuximab. Chemotherapy-
induced diarrhea is reported in up to
60% of patients treated with anti-EGFR
therapies and in 20%–40% of patients
treated with anti–VEGF-receptor ther-
apies (89). Erlotinib-induced diarrhea
appears early in the course of therapy.
The pathophysiology of this toxicity is
thought to result from a direct effect on
the gastrointestinal tract, with disrup-
tion of regulation of chloride secretion
thereby inducing a secretory diarrhea
(89). The mechanism of diarrhea as-
sociated with the anti–VEGF-receptor
agents sorafenib and sunitinib is not
known. The radiologic manifestation of
radiology.rsna.org
Torrisi et al
enteritis is encountered much less fre-
quently (89,90) (Fig 12).
Neutropenic enterocolitis.—Neu-
tropenic enterocolitis typically mani-
fests with fever, abdominal pain, and
diarrhea. It is due to chemotherapy-
induced mucosal injury and secondary
superinfection, whereby neutropenia
allows bacterial invasion that leads to
necrosis of the bowel wall (91). It has
variable manifestations and outcomes,
possibly owing to the range of pathologic
changes from mucosal inflammation to
transmural necrosis (91,92). Typhlitis is
a localized form of neutropenic entero-
colitis limited to the cecum and right
colon. Neutropenic enterocolitis is most
commonly associated with the treatment
of acute leukemia but can occur in patients
undergoing myelosuppressive therapy
for any cancer and in neutropenic states
of various causes.
Pneumatosis.—Pneumatosis intesti-
nalis is a radiologic finding of subserosal
or submucosal gas in the small- or large-
bowel wall. It is most commonly due to
a disruption in mucosal integrity, which
can occur in necrotizing enterocolitis,
bowel ischemia, bowel infarction, and
neutropenic colitis or during cytotoxic
or immunosuppressive therapy (93,94).
This finding can occur with many clas-
sic chemotherapy agents, such as those
used for treatment of hematologic
malignancies, and has been recently
described with bevacizumab (93–96)
(Fig 13a). Pneumatosis can be asymp-
tomatic and encountered at routine sur-
veillance imaging. Reporting this finding
to the oncologist is important, because
he or she may choose to discontinue
therapy. Pneumatosis intestinalis does
not always indicate transmural infarc-
tion and can occasionally manifest with
the more ominous finding of portal
venous air in the absence of true trans-
mural ischemia (97,98). A conservative
nonsurgical approach is advocated in
patients without signs of peritonitis or
sepsis (94).
Bowel perforation.—Gastrointes-
tinal perforation is an infrequent but
potentially fatal toxicity related to beva-
cizumab therapy. The pathogenesis of
bowel perforation is unknown, but sug-
gested mechanisms include ischemia
n Radiology: Volume 258: Number 1—January 2011
REVIEW: CT Findings of Chemotherapy-induced Toxicity Torrisi et al

Figure 13 than in those of colon cancer (5.4% vs Nephrotoxicity.— Chemotherapy-

Figure 13: Two patients with bevacizumab-
induced bowel toxicity. (a) Axial contrast-enhanced
multidetector CT image in a patient with benign
asymptomatic pneumatosis of the right colon
(arrow) discovered at routine imaging 5 weeks
after initiation of bevacizumab chemotherapy for
metastatic gastroesophageal junction carcinoma.
(b) Axial contrast-enhanced CT image in a patient
with gastric cancer who developed perforation
at the site of tumor 10 days after initiation of
bevacizumab chemotherapy. Extravasation of
oral contrast material lateral to the spleen
(small arrow) and large pneumoperitoneum
(large arrow) are shown.
with thrombosis of intestinal mesen-
teric vessels, necrosis of primary tumor
or cancers involving the bowel serosa
with weakening of the intestinal wall,
and predisposing bowel conditions such
as diverticulitis, prior surgery, or radia-
tion enteritis (99) (Fig 13b). The inci-
dence of gastrointestinal perforation is
1.5%–1.7% in patients with metastatic
colorectal cancer (100,101). Most pa-
tients present within the first 3 months
of treatment with abdominal pain and
vomiting. The incidence of bevacizumab-
associated gastrointestinal perforation is
slightly higher in cases of ovarian cancer
1.7%) (99). Early reports suggested
that the risk of gastrointestinal perfora-
tion is linked to whether the primary
tumor is intact (in the case of colorec-
tal cancer) or whether there is bowel
involvement (in the case of ovarian
cancer) (102,103). However, authors of
subsequent reviews note perforation can
happen anywhere along the gastrointes-
tinal tract and can occur during treat-
ment of malignancies that lack disease
within the peritoneal cavity (1,100).
Bowel dilatation.—Ileus is a well-
known complication of a few classic
chemotherapy agents, such as the vinca
alkaloids (vincristine and vinblastine),
which are used in the treatment of several
malignancies. Bowel dilatation, mani-
festing as colonic dilatation or pseudo-
obstruction, has been reported to occur
with vincristine and can be attributed
to neurotoxicity of the autonomic
nervous system in the gastrointestinal
tract (104).
Bleeding.—Gastrointestinal stromal
tumors are typically large, hypervas-
cular, enhancing masses on contrast-
enhanced CT images and often contain
areas of necrosis or hemorrhage at the
time of presentation. Chemotherapy-
induced intratumoral hemorrhage is
often clinically suspected owing to de-
creases in hemoglobin during the first
4–8 weeks of imatinib treatment and
has been observed in up to 5% of pa-
tients with bulky gastrointestinal stromal
tumors undergoing treatment with ima-
tinib (105).
Genitourinary System
Cytotoxic chemotherapy may result
in the development of nephrotoxicity,
hemorrhagic cystitis, or, rarely, neuro-
genic bladder. Nephrotoxicity is a com-
mon toxicity of several of the classic
chemotherapies but has been reported
with newer targeted therapies as well.
Hemorrhagic cystitis can occur as the
result of the administration of cyclo-
phosphamide or ifosfamide. The onset
of neurogenic bladder typically parallels
the clinical onset of peripheral neuro-
toxicity. Imaging can help to distinguish
the cause of neurogenic bladder and
help to exclude cord compression.
induced nephrotoxicity is most com-
monly associated with cisplatin, ifosf-
amide, and methotrexate. Impairment
of renal function is due to proximal
tubular injury or acute tubular necro-
sis in the case of methotrexate neph-
rotoxicity (106).Tumor lysis syndrome
is a metabolic complication caused by
chemotherapy-induced sudden death
of rapidly proliferating cancer cells
and the release of cellular products
that overwhelm the kidney’s ability to
metabolize or excrete them, leading to
hyperkalemia, hyperphosphatemia, hy-
peruricemia, and acute renal failure.
Although infrequent and usually pre-
ventable, tumor lysis syndrome typi-
cally occurs after treatment of very rap-
idly growing lymphomas and leukemias
(107). Nephrotoxic effects can also be
seen with the VEGF receptor–targeted
molecular agents, because VEGF is im-
portant in maintaining any fenestrated
endothelium and, therefore, the glom-
erular endothelium and glomerular
function (108). Proteinuria, nephrotic
syndrome, and hypertension are seen
with the VEGF receptor inhibitors.
Hypertension is most likely related to
the renal toxicity of these agents.
Hemorrhagic cystitis.—Hemorrhagic
cystitis is the result of urothelial toxic-
ity with mucosal hyperemia and ulcer-
ations complicated by hemorrhage and
focal necrosis. It is a known toxicity of
the classic chemotherapy agents cyclo-
phosphamide and ifosfamide used in
bone marrow transplantation patients
and the management of some solid tu-
mors (109). Radiologic findings include
diffuse thickening and nodularity of the
bladder wall. Drug-induced occurrences
must be differentiated from other causes
of hemorrhagic cystitis in the immuno-
compromised patient, such as graft-
versus-host disease and viral infections.
Drug-induced hemorrhagic cystitis usu-
ally occurs early in the course of treat-
ment and is largely preventable with
adequate hydration and simultaneous
treatment with mesna, which neutral-
izes the toxic metabolic products in the
bladder.
Neurogenic bladder.—Peripheral
neurotoxicity is associated with many

Radiology: Volume 258: Number 1—January 2011 n radiology.rsna.org 53

REVIEW: CT Findings of Chemotherapy-induced Toxicity
chemotherapeutic agents, including the
vinca alkaloids, cisplatin, the taxanes,
and, more recently, the proteasome in-
hibitor bortezomib. Neurogenic blad-
der, which may manifest radiologi-
cally as bladder distention, has been
reported with vincristine and borte-
zomib (110,111). Development of neu-
rogenic bladder typically parallels the
clinical onset of peripheral neurotoxicity,
suggesting a similar mechanism. Ra-
diologic findings of neurogenic bladder
may raise concern for cord compres-
sion. The two can be distinguished by
means of clinical correlation or further
MR imaging of the spine.
Peritoneum, Mesentery, and Soft Tissues
Fluid retention can occur as part of
capillary leak syndrome during the
course of chemotherapy in both classic
and targeted therapies. Ascites alone
should not be mistaken for disease
progression.
Ascites due to fluid retention can be
mistaken for tumor progression. Fluid
retention, manifesting with weight gain,
peripheral edema, and, less commonly,
pleural effusion, pericardial effusion, and
ascites, is not uncommon in patients
treated with docetaxel (112). Fluid re-
tention is thought to be due to capillary
protein leak syndrome (113). Treatment-
related fluid overload may also be seen
with imatinib therapy, used in the treat-
ment of gastrointestinal stromal tu-
mors and renal cell carcinomas (105).
Associated anasarca may help differ-
entiate the cause of ascites in cases of
fluid retention.
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