Controlling chemotherapy-induced nausea and vomiting — a new antiemetic delivery system

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.

Laura Boehnke Michaud

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.

Acute vs. delayed CINV

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.

New formulations

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 postchemotherapy.

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.

Which agent to use

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 patient’s 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 spray.

Laura Boehnke Michaud, PharmD, BCOP, is Manager of Clinical Pharmacology Services at The University of Texas M.D. Anderson Cancer Center.

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.