A Review of the 2006 ASCO Antiemetic Guidelines Update

US Pharm. 2007;32(1)(Oncology suppl):22-28.

ABSTRACT: Emesis as an adverse event of antineoplastic therapy can be troublesome for many oncology patients. Inadequately controlling emesis can have a major impact on patient care and may even lead to refusal of treatment. Antiemetic treatment guidelines have been established to help health care professionals better understand and effectively treat this unpleasant side effect of chemotherapy. The American Society of Clinical Oncology (ASCO) previously created antiemetic treatment guidelines to assist clinicians in caring for oncology patients dealing with emesis. Recently, ASCO's Update Committee revisited the prior guidelines, as well as any new literature available on treating chemotherapy-induced emesis; as a result, a more comprehensive, updated version is now available. This article presents the conclusions and recommendations set forth by the ASCO committee regarding the management of antiemetics in oncology patients.

In early 2006, the American Society of Clinical Oncology (ASCO) set out to update their 1999 treatment guidelines regarding antiemetics in oncology.¹ An Update Committee was formed to assess all published literature pertaining to the use of antiemetics in oncology from 1998 to February 2006. Data reviewed by the committee included systematic reviews and meta-analyses, as well as randomized controlled trials.

When the committee reviewed and analyzed the literature results, they focused on the incidence of complete response--when there are no episodes of emesis and no rescue medications are dispensed after antineoplastic therapy is administered. Compared to nausea, complete response is the recommended clinical outcome measure for development of the guidelines, due to its objectivity. In contrast, nausea--the patient's perception that emesis may occur--is more subjective.

The committee also reviewed the treatment guidelines discussed at the Antiemetic Consensus Conference, hosted by the Multinational Association of Supportive Care in Cancer (MASCC) in 2004. This international conference facilitated consensus statements and recommendations by representatives from nine oncology organizations, which would be published in whole or in part with their individual organization's antiemetic guidelines. This meeting took place in the hope that although guidelines would inevitably differ between the associations, there would be a smaller number of discrepancies between the individual documents on antiemetics. The ASCO Update Committee used the findings from this meeting to expand on their own recommendations and to aid in preparing their update document.¹

Impact and Risk Factors of Chemotherapy-Related Emesis
Nausea and vomiting are the two adverse effects involved with chemotherapy that tend to be the most bothersome for patients and afflict the caregiver's or health care professional's ability to appropriately treat a patient.² Although nausea and vomiting seem common and devoid of significant harm, they can cause dehydration, malnutrition, electrolyte imbalance, treatment delays or refusal to continue treatment, and great discomfort.

Researchers have spent many years trying to determine the physiological mechanism of emesis and have made many strides toward effective therapies; however, the exact cause of emesis is still not entirely understood. Today's studies on receptors found in the chemoreceptor trigger zone (CTZ), e.g., dopamine, serotonin, and neurokinin, have made great advances for patients prone to emesis during chemotherapy treatment.²

There are several factors that can raise the risk of nausea and vomiting, such as female gender, younger patients (<50 years), those who have previously not improved with chemotherapy regimens, and patients who do not have a history of chronic, high alcohol intake and/or who experience significant fatigue.^{2 ,3} Non–patient-related factors that influence a patient's susceptibility to emesis during treatment include the specific chemotherapy agent being used, dose (especially high doses), schedule, and route in which the suspected agent is given, as well as frequent-interval dosing and intravenous administration. ³ Nausea and vomiting can create additional havoc for patients already coping with many other stresses. Consulting a health care professional about risk factors and treatment options may reduce the risk of chemotherapy-related emesis.

Types of Chemotherapy-Induced Nausea and Vomiting
Patients can experience nausea and vomiting minutes to hours after chemotherapy is administered.^1-3 This quick onset of emesis is considered acute nausea and vomiting and usually ceases within the initial 24 hours after therapy. When a patient experiences an episode that arises after the first day following treatment, it can be classified as delayed nausea and vomiting . Cisplatin is a prime example of emesis that can occur some time after treatment. In some cases, cisplatin emesis may be at its most intolerable 48 to 72 hours after chemotherapy and can even extend up to seven days in some cases. Anticipatory nausea and vomiting occurs when a patient has had a previous negative experience with chemotherapy. This frequently happens in patients who are preparing for their next treatment; they anticipate emesis and consequently cause themselves to be sick. Breakthrough and refractory nausea and vomiting are two other types of emesis that, although uncommon, tend to arise in a certain subset of people. Breakthrough vomiting occurs when the patient is undergoing current chemotherapy and is receiving optimal antiemetic treatment but is still vomiting. Refractory vomiting occurs after one or several chemotherapy cycles even though antiemetic prophylaxis was used. The prophylaxis regimen is no longer effective and the patient has stopped responding to the treatment.^1-3

Emetic Risk Categories of Antineoplastic Agents
While a few antineoplastic agents have unquestionably confirmed their potential to cause emesis after administration, most agents are classified according to risk based on experience.^1,4 Antineoplastic agents are grouped by the degree of emetic risk they pose. The percentage of emetic risk is a key factor in deciding which antiemetic treatment should be employed. ASCO has instituted four emetic risk categories that were adopted from the recommendations created during the MASCC conference of 2004: high, moderate, low, and minimal emetic risk (Table 1).^1,4

Medications Used to Treat Chemotherapy-Related Emesis
Treatment for chemotherapy-related emesis has remained the same, to an extent.¹ Along with standard medications used to treat this adverse effect, an additional agent has become available that was not yet approved when ASCO published its guidelines in 1999. Since the approval of aprepitant, it has proven through numerous studies to be a worthy addition to the antiemetic treatment regimen for oncology patients.^1,2 

5-Hydroxytryptamine-3 (5-HT₃) Serotonin Receptor Antagonists: This class of medication, which includes dolasetron, granisetron, ondansetron, palonosetron, and tropisetron, has been the primary treatment for nausea and vomiting for many years. 5-HT₃ serotonin receptor antagonists work by blocking serotonin release to the CTZ, alleviating emesis in most patients. Debate still looms over which 5-HT₃ antagonist is the preferred treatment; while some studies have shown noninferiority among the agents, there are still lingering questions regarding a possible superior agent.¹

Corticosteroids: While both dexamethasone and methylprednisolone have been used to treat chemotherapy-induced nausea and vomiting, dexamethasone is the most widely available and commonly studied. The high therapeutic index of corticosteroids and their efficacy as single agents in patients receiving chemotherapy of low emetic risk establishes this class as the most frequently used antiemetics. ¹

Neurokinin-1 (NK₁ ) Receptor Antagonists: The most recent agent included in the antiemetic guidelines is the NK₁ receptor antagonist known as aprepitant.¹ Aprepitant acts specifically on NK₁ receptors in the brain and has little affinity for any other neurokinin receptors. This NK₁ receptor antagonist competitively inhibits substance P from binding to NK₁ receptors in the brain, thus preventing emesis. Aprepitant is distinctive from other antiemetic agents in regard to mechanism of action and its unique potential for CYP-related drug interactions.^1,2 Aprepitant serves as a substrate, as well as a moderate inhibitor and inducer of cytochrome P-450 3A4 (CYP3A4) isoenzymes. Aprepitant, acting as an inhibitor, can interact with corticosteroids (CYP3A4 substrates), causing the need for decreased dosing. In addition, several chemotherapy agents (e.g., cyclophosphamide and docetaxel) are cleared by CYP3A4, potentially inhibiting clearance of these drugs and increasing the toxicity of some agents. There is no evidence of clinical complications when aprepitant is given at its standard dose and schedule with chemotherapy. ^1,2

Second-Line Agents: Patients who are unable to tolerate or are refractory to first-line antiemetics can use such agents as metoclopramide, butyrophenones, phenothiazines, cannabinoids, benzodiazepines, and antihistamines. Lorazepam and diphenhydramine can be used as adjuncts to first-line antiemetic regimens. ¹

2006 Updated Guidelines
In June 2006, ASCO released their most recent guidelines on the use of antiemetics in oncology. Last updated in 1999,⁵ these guidelines have stayed the same in various areas and have been modified or completely changed in others. All treatment recommendations discussed refer to antineoplastic agents administered intravenously.

High-Risk Guidelines (>90%)
Acute Emesis (0 to 24 hours after chemotherapy): In terms of treating nausea and vomiting in patients who experience symptoms due to chemotherapy of high emetic risk (cisplatin and noncisplatin groups) within 24 hours after treatment, three agents are included in the 2006 guidelines.¹ 5-HT ₃ serotonin receptor antagonists, corticosteroids (dexamethasone), and aprepitant are all effective in the acute treatment of emetic symptoms related to chemotherapy. The addition of aprepitant to ASCO's updated guidelines is the one major difference from their previous recommendations. The Update Committee, after analyzing numerous studies involving these three agents and cisplatin, states that all three agents improve the symptoms of cisplatin-induced emesis.¹ The committee is able to generalize this claim to include other agents in the high-risk emesis category due to the universal incidence of emesis with cisplatin (>99%). The incidence is so great that if an antiemetic agent is effective against cisplatin, efficacy against other chemotherapy agents in this high-risk category is assumed.^1,6

Delayed Emesis (?24 hours after chemotherapy): Recommendations for the prevention of delayed emesis in oncology patients receiving cisplatin and other agents of high emetic risk include the use of dexa­ methasone and aprepitant.¹ This two-drug combination for the prevention of cisplatin and noncisplatin delayed emesis is a change from previous guidelines,  which advised the use of a corticosteroid alone or in combination with metoclopramide or a 5-HT₃ antagonist.¹ The combination of a 5-HT₃ serotonin receptor antagonist with dexamethasone is no longer recommended by the Update Committee due to study results suggesting inferiority of the combination compared to dexamethasone alone.^7-9 Furthermore, a trial published in 2005 found dexamethasone in combination with aprepitant superior to dexamethasone in combination with ondansetron, thus supporting ASCO's most updated recommendation of dexamethasone and aprepitant.¹⁰

Moderate-Risk Guidelines (30% to 90%)
Acute Emesis: This updated category includes some agents previously considered to carry high emetic risk in the original 1999 guidelines.¹ Currently, the Update Committee recommends a three-drug combination--a 5-HT₃ serotonin receptor antagonist, dexamethasone, and aprepitant--for all patients receiving anthracycline and cyclophosphamide (AC). For patients who receive an antineoplastic agent of moderate emetic risk other than AC, ASCO recommends a two-drug combination: a 5-HT₃ serotonin receptor antagonist and dexamethasone.¹ While this combination for all moderate-risk agents (excluding AC) has not changed since the previous guideline, aprepitant was added to regimens involving AC due to recent studies indicating increased emetic potential with these two antineoplastic agents, along with trials showing the efficacy of aprepitant against these agents.¹¹ It is important to note that in this particular case, regardless of aprepitant's potential CYP3A4 inhibition, the Update Committee advises that the concomitant use of cortico­ steroids should not be reduced with the administration of aprepitant.¹

Delayed Emesis: For patients who receive AC therapy, single-agent aprepitant should be used to prevent delayed-onset emesis; this is a change from the original antiemetic guidelines. Dexamethasone as a single agent or a 5-HT₃ serotonin receptor antagonist is preferred for delayed emesis regarding all other agents of moderate emetic risk. ¹

Low-Risk Guidelines (10% to 30%)

Acute Emesis: The 1999 guidelines recommended no antiemetic agent for the prevention and/or treatment of chemotherapy-induced emesis. However, the updated recommendations advise 8 mg of dexamethasone for the treatment of patients at low emetic risk. Although the majority of patients given low-risk chemotherapy do not experience emesis, many patients do undergo this side effect. No relevant clinical trials address an optimal agent to be used for antineoplastics of low risk.¹  

Delayed Emesis: Preventive use of antiemetic agents for delayed emesis is discouraged in patients who receive low-risk chemotherapy.¹

Minimal-Risk Guidelines (<10%)
Acute and Delayed Emesis: This risk category is a new addition in the 2006 antiemetic guidelines; a number of agents in this category were considered low risk in 1999.¹ Bleomycin, 2-chlorodeoxyadenosine, fludarabine, vinblastine, and vincristine are among the chemotherapy agents that are now categorized as minimal risk. Few antiemetic studies were appropriate for guideline development regarding this risk category, since the risk of emesis was so low in these agents. Trials assessing antineoplastics in this risk category have not been conducted. Thus, recommendations are unchanged from the original guideline for "low-risk" agents.

Regarding acute emesis with minimal-risk agents, the routine administration of antiemetics is not advised. Depending on the patient and history of poor emetic control with these agents, a small percentage of patients may require pretreatment with antiemetics. In these rare cases, a one-time dose of dexamethasone 8 mg, phenothiazine, or metoclopramide (as needed) is common. Routine antiemetics for the prevention of delayed emesis are also not indicated for agents in this category.

Other Emetic Problems
Combination Chemotherapy: Guidelines remain unchanged for the use of antiemetics in patients who receive combination chemotherapy regimens. Antiemetic treatment should be determined based on the chemotherapy agent that poses the greatest emetic risk.¹

Numerous Consecutive Days of Chemotherapy: Antiemetics appropriate to the specific risk category of the chemotherapeutic agent should be administered for each day of chemotherapy. This remains identical to the previous 1999 guidelines.¹

Anticipatory Emesis: Anticipatory emesis or conditioned emesis prevention and treatment guidelines have not changed from the original recommendations. For the prevention of anticipatory emesis, antiemetic treatment should be administered with initial chemotherapy and should be the most appropriate choice in terms of emetic risk for that particular chemotherapy agent. For the treatment of anticipatory emesis, systematic desensitization, along with behavioral therapy, appears effective and is recommended by the Update Committee. Although no prospective trials have confirmed the efficacy of alprazolam and lorazepam in these patients, both are recommended as treatment options by many committee members. ¹

Emesis in Pediatric Patients: Guidelines previously suggested the use of a 5-HT₃ antagonist plus a corticosteroid in children receiving chemotherapy of high emetic risk.¹ Recent guidelines have expanded this recommendation and now advise that moderate-risk chemotherapy be given with these antiemetics. Cancer research involving the use of antiemetics in the pediatric population is limited, but one important factor to be aware of in this population is the large interpatient variations in clearance and metabolism of antineoplastics. Due to this interpatient variation, substandard dosing of antiemetic agents is possible.¹ Higher weight–based dosing is imperative in order to provide reliable protection against emesis in this population.^12,13 

High-Dose Chemotherapy: High-dose chemotherapy guidelines have not changed from the original recommendations. A 5-HT₃ serotonin receptor antagonist in combination with a corticosteroid is advised in any patient who is receiving an antineoplastic in extremely high doses. During their review of the literature, ASCO found no existing study evaluating antiemetic agents in high-dose chemotherapy. The Update Committee therefore recommends investigation of aprepitant as a potential addition to this course of therapy based purely on the highly emetic nature of increased doses of antineoplastics. Caution is advised in patients who receive aprepitant for this indication due to aprepitant's moderate CYP3A4 inhibition, potentially leading to increased toxic effects of antineoplastic agents.¹

Continued Emesis Regardless of Prophylaxis: Despite treatment with recommended antiemetic prophylaxis, emesis can still persist in some patients. The Update Committee makes no change from previous guidelines and instead suggests that health care professionals consider four elements: patient factors, antiemetic regimen, addition of lorazepam or alprazolam, and the possibility of adding either high-dose intravenous metoclopramide or a dopamine antagonist to the treatment regimen.¹

Radiation-Induced Emesis

Emetic risk associated with radiotherapy can vary depending on the type of treatment. Radiation therapy of high emetic risk can be difficult to control and occurs in a small number of patients. While the 1999 guidelines defined only three radiotherapy-induced emesis risk groups, the newest update from ASCO incorporated one additional emetic risk group (minimal risk [<30%]), which is seen in Table 2. ¹

ASCO's current recommendations for high radiation-induced emesis treatment are a 5-HT₃ serotonin receptor antagonist with or without a corticosteroid prior to each fraction lasting at least 24 hours after treatment. Moderate- and low-risk radiation-induced emesis recommendations involve administering a 5-HT₃ serotonin receptor antagonist prior to each fraction. Lastly, in patients who receive radiotherapy of minimal emetic risk, the Update Committee advises that treatment be given on an as-needed basis with either dopamine or serotonin receptor antagonists. The as-needed therapy should be continued prophylactically for each additional radiation treatment day.¹

Conclusion
Table 3 addresses preferred drug regimens for each emetic risk category. Dosage, schedule, and route of administration for these agents can be found in the 2006 ASCO update.¹ Table 4 summarizes the recommendations for chemotherapy-induced emesis.

While these guidelines provide a strong foundation on which clinicians can base their treatment decisions, they should not be used as the definitive resource. Adherence to these guidelines is voluntary, and ASCO maintains that each patient's circumstance is different and the guidelines should be applied appropriately. Much of the literature and clinical trials that were reviewed by ASCO's Update Committee do not address specific treatment decisions that come up in practice. Thus, these updated guidelines are not only accessible for current recommendations but can also be used as a starting point for investigation in the future.

References
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