Perugia Consensus Conference: Guidelines on Chemotherapy- and Radiation Therapy-Induced Emesis

Clinical Review

Synopsis: Cancer treatments can be grouped on the basis of emetogenic effects into highly emetogenic, moderate-high, low-moderate, and low. Emesis can be acute (occurring within 24 hours of treatment), delayed (occurring between day 2 and day 7 after treatment), or anticipatory (occurring before treatment). Anticipatory emesis is best prevented by effectively managing acute and delayed emesis. Emesis prevention has become significantly more likely because of the introduction of serotonin receptor type 3 (5-HT) antagonists and their use in combination with dexamethasone.

Source: Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811-819.

Treatment-induced nausea and vomiting are some of the most common and distressing side effects of cancer treatment. In some instances, the desire to avoid this complication may make a patient refuse treatment with the potential to prolong survival. Much is known about the mechanisms of treatment-induced emesis, but the ability to intervene and prevent this problem has been considerably improved with the introduction of serotonin (5-hydroxytryptamine or 5-HT) receptor type 3 antagonists, such as ondansetron, granisetron, tropisetron, and dolasetron. The Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC) held a consensus conference in Perugia, April 28-29, 1997, and produced consensus documents regarding eight areas of interest. These documents have been published in full in the journal of the MASCC called Supportive Care in Cancer.1

Table 1 groups cancer treatments by emetogenic potential. (See Table 1.) This effort is, of course, flawed because emesis can be influenced by a variety of factors, including those related to the treatment (other agents being given, dose, schedule, etc.) and those related to the patient (primary tumor, sites of involvement, age, sex, propensity to develop motion sickness, and others).

Table 1
Emetogenic potential of chemotherapeutic agents
Degree of Emetogenic Potential Agents
High   cisplatin > 50 mg/m2, mechlorethamine streptozocin, dacarbazine cyclophosphamide > 1500 mg/m2, carmustine >250 mg/m2
Moderate-high  cisplatin < 50 mg/m2, cytarabine > 1 g/m2, carboplatin, ifosfamide, doxorubicin carmustine < 250 mg/m2, epirubicin cyclophosphamide < 1500 mg/m2 epirubicin, topotecan, irinotecan procarbazine, mitoxantrone methotrexate > 250 mg/m2 
Low-moderate  docetaxel, paclitaxel, etoposide methotrexate > 50 or < 250 mg/m2, mitomycin C, gemcitabine fluorouracil < 1000 mg/m2 
Low  bleomycin, busulfan, chlorambucil cladribine, fludarabine, hydroxyurea melphalan, methotrexate < 50 mg/m2 6-thioguanine, vinblastine, vincristine vinorelbine 

A large number of controlled trials have been performed in chemotherapy-induced emesis, a fact that has made it difficult to keep up with the literature. However, a few general principles have emerged from these studies and they are summarized in Table 2. Certainly, a 5-HT antagonist plus dexamethasone has become the prevention of choice for highly emetogenic chemotherapy. Complete protection against vomiting has been documented in 70-90% of patients treated with this combination.2 It appears that the oral route of administration is just as effective as intravenous administration.3 The combination prevention regimens that include 5-HT antagonists are probably more effective and are certainly less toxic than regimens including metoclopramide. The addition of a dopamine antagonist (metopimazine) to a 5-HT antagonist appears to increase the antiemetic efficacy, but additional randomized studies are needed.4

The optimal 5-HT antagonist has not been determined. Some pharmacologic differences have been described, but, in general, their efficacy and tolerability are comparable. Data are conflicting about equivalent doses of the agents. In the United States, the most commonly used single IV dose of ondansetron is 32 mg or about 0.45 mg/kg. This is four times higher than the most commonly used single IV dose of ondansetron (8 mg) in Europe. By contrast, the single agent dose of granisetron is higher in Europe than in the United States (3 mg vs 1 mg). Table 3 lists the recommended doses for the individual 5-HT antagonists in the setting of highly emetogenic and moderate-high emetogenic agents. Decisions about use are mainly based on convenience of use and cost.

Table 2
Recommendations for specific clinical settings
Clinical Problems Consensus Treatment of Choice
Single high-dose cisplatin
   Acute emesis
   Delayed emesis
 
5-HT antagonist + dexamethasone
dexamethasone + metoclopramide or 5-HT antagonist 
Single dose of moderate-high agents 
   Acute emesis
   Delayed emesis
 
5-HT antagonist + dexamethasone
dexamethasone and/or 5-HT antagonist 
Cisplatin at low doses daily 5-HT antagonist + dexamethasone daily 
Oral CMF dexamethasone + metoclopramide or 5-HT antagonist
Refractory emesis in patients failing prophylaxis 5-HT antagonist + dexamethasone +  metopimazine
Anticipatory emesis Alprazolam Behavioral therapy (hypnosis, etc.)
High-dose chemotherapy 5-HT antagonist ± dexamethasone
Radiation therapy
   Highly emetogenic
   Moderately emetogenic
 
5-HT antagonist ± dexamethasone
5-HT antagonist
Emetogenic therapy in children 5-HT antagonist + dexamethasone

Anticipatory nausea occurs in up to 20% of patients but is mainly a problem for patients in whom emesis prevention therapy was ineffective and resulted in frequent or severe nausea and vomiting. The use of low-dose alprazolam (0.5-2 mg) taken daily significantly reduced the incidence of anticipatory nausea and vomiting from 18% to 0% in one prospective, randomized, double-blind placebo-controlled study.5 But, the effects may not last through prolonged courses of chemotherapy. Behavioral interventions, such as desensitization and hypnosis, have also been shown to be beneficial in some instances.

Table 3
Dosage and schedule of 5-HT antagonists
Agent Dose and Schedule for
Highly Emetogenic Agents
Dose and Schedule for 
Moderately-High Agents
Ondansetron 8 mg single IV dose, 24 mg single oral dose  4-8 mg PO tid or bid
Granisetron 10 mcg/kg single IV dose, 2 mg single oral dose 2 mg PO qd or bid
Tropisetron 5 mg single IV dose insufficient data
Dolasetron 1.8 mg/kg single IV dose, 200 mg single oral dose 100-200 mg PO qd

Antiemetic prophylaxis, together with the prevention of infectious death during treatment-induced granulocytopenia, is among the most impressive advances in cancer treatment. Despite the progress in prevention, numerous areas remain insufficiently researched to provide guidelines for management of proven value. For example, the rescue of patients in whom prophylaxis fails remains a difficult problem. New agents in development (for example, neurokinin inhibitors)6 may make antiemetic therapy even more effective and relegate concerns about this important complication to the trash heap of issues no longer justifying any concern when choosing cancer treatment.

References

1. Support Care Cancer 1998;6:197-265.

2. Roila F, et al. Support Care Cancer 1996;4:270-280.

3. Gralla RJ, et al. Proc Am Soc Clin Oncol 1997;16:52a.

4. Herrstedt J, et al. J Clin Oncol 1997;15:1690-1696.

5. Razavi D, et al. J Clin Oncol 1993;11:1384-1390.

6. Kris MG, et al. J Natl Cancer Inst 1997;89:817-818.