Over the past two decades, serotonin antagonists have revolutionized the
way we prevent and manage chemotherapy-induced nausea and vomiting, among other
types of nausea/vomiting, with few serious adverse effects.
Despite these advances, based on the clinical trial results with these
agents there remains a large number of patients who experience vomiting and an
even larger number who experience debilitating nausea. The knowledge gained
from decades of research into the pathophysiology and pharmacology associated
with CINV and antiemetics has led clinicians to better understand the
condition. Nonetheless, there are many obstacles to achieving optimal control
of CINV across a broad range of patients and chemotherapy regimens.
Many of these obstacles are related to patient characteristics that
cannot be altered (eg, female sex, alcohol use, history of motion sickness or
pregnancy-related nausea and vomiting). Some patients are hindered in managing
CINV due to constraints on drug delivery. Other obstacles are related to the
chemotherapy regimen such as emetogenicity of the chemotherapy agents, dose,
infusion rate and what other drugs are administered in the regimen. The type of
CINV associated with the chemotherapy also influences the efficacy of the
antiemetics. The acute phase of CINV (defined as zero to 24 hours after
chemotherapy) is fairly predictable and easily defined by clinical trials
exploring single-agent chemotherapy. The delayed phase of CINV (defined as more
than 24 hours up to five to seven days after chemotherapy) is less well-defined
and not easily extrapolated from clinical trial data.
There is clear evidence that the mechanisms associated with acute and
delayed CINV are different. Antiemetics are generally less effective against
delayed CINV compared with acute CINV and serotonin appears to play only a
small role in the pathophysiology of delayed CINV (as these agents have little
benefit in this setting). The most effective class of antiemetics in the
delayed setting is corticosteroids, with others having debatable beneficial
effects (dopamine antagonists and neurokinin antagonists may or may not add to
the efficacy of the corticosteroids, see table 1).
Chemotherapy agents known to be associated with delayed CINV include
cisplatin, cyclophosphamide, and the anthracyclines. Another layer of
complexity is added when these types of chemotherapy are administered over
several days, allowing the acute phase of CINV to overlap with the delayed
phase. Many patients experience breakthrough nausea and vomiting as a result of
ineffective antiemetic therapy with these types of chemotherapy regimens. Many
of these regimens are utilized to treat cancers that affect the ability to
swallow or can cause severe mucositis.
Some antiemetics are available in alternate dosage forms (eg,
suppositories), but the use of the rectal route of administration is limited if
a patient is thrombocytopenic or neutropenic due to the risk of bleeding or
infections, respectively, and intravenous agents must be administered by a
health care professional in a supervised setting.
Agents available in suppository formulations are also typically not the
most effective agents for treatment of breakthrough CINV. The serotonin
antagonists, which are considered the most effective agents for preventing
acute CINV, are available as oral tablets or intravenous solutions. Ondansetron
is also available as an orally disintegrating tablet (ODT), but the taste of
this product is bothersome for many patients. Therefore, new formulations that
avoid the need for oral administration (eg, transdermal delivery, nasal
administration) may offer an advantage in this complex situation.
Granisetron (Kytril, GlaxoSmithKline), a serotonin antagonist, is now
available as a patch (Sancuso, ProStrakan) in addition to its oral and
intravenous formulations. The granisetron transdermal delivery system (GTDS)
provides the equivalent of 3.1 mg per 24 hours administered over a maximum of
seven days (total granisetron=34.3 mg/52 cm2 patch; delivering 66%
of total granisetron over seven days). It must be placed 24 to 48 hours prior
to chemotherapy to ensure adequate blood levels are achieved prior to
chemotherapy. Although the patch can be worn for up to seven days, its efficacy
has only been tested in patients receiving up to a five-day moderately or
highly-emetogenic chemotherapy regimen. This allows for two days of coverage
When compared with 2 mg daily oral granisetron, the transdermal delivery
system demonstrated noninferiority in complete control of CINV (no vomiting
and/or retching, no more than mild nausea, and no use of rescue medication)
from the first administration until 24 hours after the last administration of
chemotherapy (GTDS 60.2% vs. oral 64.8%; difference 4.89%, 95% CI,
12.9% to 3.13%). Although details regarding these data are limited the
FDA has deemed the two forms of delivery therapeutically equivalent.
Unfortunately, the specific efficacy in the delayed setting is currently
unknown given the sparse amount of available data. It is unlikely that the GTDS
faired any better than oral granisetron in the delayed setting, but the oral
granisetron was not administered after chemotherapy on days six and seven.
The use of serotonin antagonists in the delayed setting is controversial
and it remains unclear whether the use of these agents after chemotherapy is
beneficial. This controversy exists due to conflicting data from randomized
trials. For patients who experience delayed CINV, the use of other agents in
addition to a serotonin antagonist is vital for subsequent management and
continuation of the chemotherapy regimen (eg, corticosteroids, dopamine
antagonists, neurokinin antagonists). Therefore, this caveat would also apply
to the GTDS.
Due to the availability of multiple serotonin antagonists, many
clinicians are met with the quandary of which one to use in which clinical
situations. Due to the historical high cost of these agents, many hospitals and
pharmacy benefit plans limited their formulary to include only one of the
agents from this class. The decision of which to choose was often based not on
clinical differences as they are generally considered therapeutically
equivalent but instead on financial criteria such as institutional cost,
contracting incentives, and other factors such as flexibility in dosing and/or
supporting evidence crossing all uses of these agents (eg, postoperative
nausea/vomiting, radiation-induced nausea/vomiting, etc).
Since ondansetron became available as a generic equivalent, the costs of
these agents have fallen considerably. However, these agents remain fairly
expensive and out-of-pocket expenditures are typically quite high. When
determining cost comparisons with the GTDS, it is prudent to include adequate
comparators in order to provide a clinically useful comparison.
In table 2, the GTDS is compared with its oral equivalent as well as
ondansetron ODT, which is also an alternative for patients unable to swallow
tablets. If a chemotherapy regimen requires three days of antiemetic coverage,
the cost of the GTDS is comparable. However, it is interesting that if a
chemotherapy regimen requires more than three days of antiemetic therapy, the
patch is less costly. Therefore, for individual chemotherapy regimens and
patient populations, the patch may indeed be a cost-effective alternative. For
others, it may be chosen for convenience alone.
It is unclear whether pharmacy benefit plans will include the GTDS
formulation as a covered medication and/or what the out-of-pocket costs will be
for the patients. It is also likely that a serotonin antagonist alone may not
be adequate to manage a patients CINV. Therefore, clinicians should be
encouraged to explore all options for managing CINV, optimally utilizing all of
the agents in our toolbox in order to maximize benefits.
Older agents, often put aside due to concerns over adverse effects,
should be considered and can increase the efficacy of the other antiemetics
when used appropriately. Adverse effects can be minimized when antiemetics are
dosed appropriately and patients receive adequate counseling. Examples of this
are the judicious use of corticosteroids to enhance antiemetic efficacy in both
the acute and delayed settings. Also, the use of benzodiazepines, such as
lorazepam, to prevent and treat anticipatory nausea and vomiting is also very
beneficial and can be administered sublingually. Other novel formulations are
also under development, including a serotonin antagonist delivered as a nasal
Laura Boehnke Michaud, PharmD, BCOP, is Manager of Clinical
Pharmacology Services at The University of Texas M.D. Anderson Cancer
For more information:
- N Engl J Med. 2008;358:2482-2494.
- J Clin Oncol. 2006;24:2932-2947.
- Sancuso (granisetron transdermal system) product information.
ProStrakan Inc., Bedminster, NJ. August 2008.
- RedBook for Windows. Accessed Feb. 10, 2009.