As new targeted cancer
therapies come into use, side-effect
profiles are also emerging: infusion
reactions to monoclonal antibody
products such as trastuzumab
(Herceptin) and rituximab (Rituxan);
skin rashes and edema for imatinib
mesylate (Gleevec); rash and diarrhea
in patients treated with gefitinib (ZD1839, Iressa) and erlotinib (OSI-
774, Tarceva); and hypersensitivity to
paclitaxel (Taxol) and docetaxel
(Taxotere). Four leading investigators
reported these toxicities and suggested
supportive care at the 14th International
Meeting of the Multinational
Association for Supportive Care in
Cancer (MASCC). Although some
side effects require interruptions in
treatment, the researchers said that
patients usually are able to complete
the new regimens.
Cancer treatments based on monoclonal
antibodies have produced infusion
reactions ranging from flu-like
symptoms to rare but life-threatening hypotension, bronchospasm, and hypoxia,
according to Robert O. Dillman,
MD, medical director, Hoag Cancer
Center, Newport Beach, California.
He cited the following products,
all approved since 1997: rituximab
(Rituxan) and yttrium-90 ibritumomab
tiuxetan (Zevalin) for B-cell
lymphoma, trastuzumab (Herceptin)
for breast cancer, gemtuzumab
ozogamicin (Mylotarg) for acute myelogenous
(Campath 1-H) for chronic lymphocytic
Reactions With Antigens
"With monoclonal antibodies, the
key to the toxicity reflects the location
of the antigen-that is, the molecule
the monoclonal antibody reacts with,"
Dr. Dillman told ONI. "It is not an
inherent toxicity within the product
itself. It is not an allergic reaction."
For example, reactions with antigens
on epithelial cells in the gastrointestinal
tract can produce abdominal pain,
nausea, vomiting, and diarrhea. If the
antigens are expressed on neural
sheaths, neuropathy can result.
He advised caution when treating
patients with high numbers of antigen-
expressing cells circulating in the
bloodstream, especially if the patient
has underlying cardiovascular or respiratory
disease. When the white blood
cell count is high, a rapid infusion can
cause respiratory distress, he said,
warning that tumor lysis syndrome is
a risk in patients with large numbers
of antigen-dense cells that have a high
In a recent rituximab study, he said,
77% of patients had reactions during
the first infusion. Typically, slowing
the infusion provided relief. "In patients
who have an infusion reaction, once circulating cells have cleared,
there is no reaction when rechallenged,"
Because most infusion reactions have been "more of a nuisance than a
major problem," clinicians have not
focused on identifying the optimal
supportive care, Dr. Dillman said. He
advised hydrating the patient and said
that reactions have been treated with
a variety of anti-inflammatory agents,
including acetaminophen, H1
blockers, H2 blockers, nonsteroidal
anti-inflammatory drugs (NSAIDs),
and corticosteroids. "In some situations,
the reactivity of the normal tissues
is almost nonexistent," he said.
"In others, there's a very predictable
reaction, some of which you can at
least prevent, decrease, or anticipate."
The beneficial effects of imatinib
have been "amazing and better than
we would have predicted," said George
D. Demetri, MD, director of the Center
for Sarcoma and Bone Oncology,
Dana-Farber Cancer Institute. Imatinib
is benefiting about 85% of the
patients taking it for gastrointestinal
stromal tumor, he said, but virtually
all had adverse events.
Dr. Demetri said the most serious
adverse event was an abdominal tumor
rupture that contributed to a patient
death. He said that mild edema is common, occurring in 72% of patients,
and that ruptures on the skin
surface have led to unusual bleeding
and "minor to more severe" rashes.
Some adverse events are puzzling.
For example, one patient on imatinib
noted a varicose vein disappear from
the left leg while another remained
stable on the right leg. Occasionally,
patients have had asymmetrical swellings
that go away after a day or so.
Some patients were afraid they
would be removed from clinical trials if they reported side effects to their
oncologists, Dr. Demetri said. These
patients formed a support organization,
called The Life Raft Group
(www.liferaftgroup.org), and established
a limited-access mailing list
to exchange information among
"Patients were expressing concern
that if they openly discussed symptoms,
we would take them off study.
They didn't want that," he said. "They
did a survey where they tracked side
effects of the drug, and what we saw
on the Internet was somewhat more
Imanitib is so new, investigators
still have much to learn about adverse
events, he added, expressing surprise
that hematologic toxicities have not
been more of a problemin patients.
"We would have predicted greater toxicity-but there are remarkably
few sequelae," he said.
The HER1/epidermal growth factor
receptor (HER1/EGFR) inhibitors
gefitinib and erlotinib have so far
caused minimal toxicity in patients
participating in clinical trials, said Roman
Perez-Soler, MD, chair of oncology
at Montefiore Medical Center and
chief of the Division of Medical Oncology
at Albert Einstein College of
Medicine, both in New York.
About two-thirds of patients on
Iressa have some kind of rash, he said,
but 48% are grade 1 and 13% are
grade 2. Slightly more than half (57%)
develop diarrhea. Typically, treatment
is interrupted for a few days while
they take an over-the-counter remedy,
Dr. Perez-Soler said. Side effects
with Tarceva are also mild. Three of
four patients have a rash, mostly grade
1 or 2, and 61% have diarrhea.
At this point, learning to select patients
who will benefit from EGFR
inhibitors is more of a problem than
toxicity, Dr. Perez-Soler said.
Paclitaxel and docetaxel have
unique side-effect profiles that go beyond
the toxicities they share with
other cytotoxic agents, said Maurie
Markman, MD, director of the Cleveland
Clinic Taussig Cancer Center.
High risk of hypersensitivity reactions
is common for both taxanes, he said.
Peripheral neuropathies are more of
a concern with paclitaxel, as are the
feverless, flu-like symptoms that come
with arthralgias and myalgias. Significant
fluid retention, pleural effusion,
ascites, and peripheral edema have occurred
with high cumulative doses of docetaxel. These are in addition to
more common reactions such as bone
marrow suppression, alopecia, and
"Complete alopecia is absolutely
the rule," Dr. Markman said. "Anyone
suggesting a patient won't lose
hair hasn't used the agent."
Despite these toxicities, the taxanes
are highly effective agents that can be
safely administered. "Careful monitoring
for immediate side effects and
delayed toxicities is important," he
While hypersensitivity reactions
are a major concern, they are rarely
fatal. The key to managing them, he
said, is recognizing that they are instantaneous.
"I've treated a thousand
patients with Taxol," he said. "I've
never seen a reaction that wasn't immediate."
A nurse should sit with a
patient when taxanes are started and
be prepared to respond, he said. "The
nurse should not walk out of the
room," he said. If the patient has a
reaction, Dr. Markman advised waiting
30 to 60 minutes and then starting
the infusion again with diphenhydramine.
regimens can also be used to prepare
patients, he said.
Although NSAIDs can reduce the
severity of flu-like systems occurring
in 10% to 20% of patients on
paclitaxel, he advised that some patients
may require a narcotic analgesia.
He said that he has used low-dose
prednisone with some success. Oral
dexamethasone can significantly reduce
the incidence of fluid retention
in patients receiving docetaxel, Dr.
Markman said. He cautioned, however,
that steroids should be reduced
if patients are put on weekly taxane