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Antiemetic Effectiveness of Ondansetron and Granisetron in

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Purpose: The antiemetic effectiveness of ondansetron 8 mg i.v., ondansetron 32 mg i.v., and granisetron 10 µg/kg or 1 mg i.v. as prophylaxis in breast cancer patients receiving cyclophosphamide-containing regimens was studied.
Methods: Data from six U.S. cancer centers were collected retrospectively for 224 patients who received cyclophosphamidecontaining therapy between January 1998 and June 2002. Logistic-regression analysis was used to examine the likelihood of chemotherapy-induced nausea and vomiting (CINV) both on an unadjusted basis and controlling for concomitant radiation therapy and dexamethasone use.
Results: Seventy-six patients (34%) received ondansetron 32 mg, 68 (30%) received ondansetron 8 mg, and 80 (36%) received granisetron (either 10 µg/kg or 1 mg). Patients receiving ondansetron 8 mg were 2.5 times as likely to have CINV on an adjusted basis as granisetron recipients (p < 0.01). There was no increase in the risk of CINV with ondansetron 32 mg compared with granisetron. Patients treated with ondansetron 8 mg required more rescue antiemetics and more prophylactic antiemetics in subsequent chemotherapy cycles than patients in the other groups.
Conclusion: In a retrospective multicenter study, granisetron 1 mg or 10 µg/kg and ondansetron 32 mg appeared more effective than ondansetron 8 mg in preventing acute CINV related to cyclophosphamide therapy.

It is estimated that in 2002 more than 175,000 women in the United States were diagnosed with breast cancer and that more than 43,000 of these women died. Approximately 65-70% of breast cancers occur in women 50 years of age or older. One woman in 2,525 will have breast cancer by the age of 30, and 1 in 217 will have the disease by age 40.

Treatment of breast cancer generally involves radiation therapy, chemotherapy, hormonal therapy, or a combination of these. Antineoplastic drug combinations used most often to treat breast cancer are fluorouracil, doxorubicin, and cyclophosphamide; fluorouracil, epirubicin, and cyclophosphamide; doxorubicin and cyclophosphamide; and cyclophosphamide, methotrexate, and fluorouracil. These combinations are administered intermittently at intervals of three to four weeks. Six cycles of fluorouracil-doxorubicin- cyclophosphamide or fluorouracil- epirubicin-cyclophosphamide (duration, 18-24 weeks), six cycles of cyclophosphamide-methotrexate-fluorouracil (18-24 weeks), or four cycles of doxorubicin-cyclophosphamide (12-16 weeks) are considered standard adjuvant therapy. The addition of paclitaxel for 12-16 weeks may also improve disease-free survival time and overall survival rates. Chemotherapy-induced nausea and vomiting (CINV), one of the most common and most incapacitating experiences of patients undergoing cancer chemotherapy, can lead to electrolyte imbalances, dehydration, cachexia, and malnutrition. Poorly controlled CINV can lead patients to refuse further treatment. Serotonin type 3 (5-HT3)-receptor antagonists have demonstrated significant efficacy in preventing or controlling CINV, even in patients treated with highly emetogenic agents, such as cisplatin.

CINV involves a complex interaction among various neurotransmitters and their receptors in the central and peripheral nervous systems. These receptor areas relay information to the vomiting center in the medulla, which then coordinates the act of vomiting. The chemotherapy receptor trigger zone, also located in the medulla, serves as a "chemosensor." Acute and delayed emesis are distinguished by the times when they occur. Acute emesis is emesis occurring within 24 hours after the administration of chemotherapy, and delayed emesis occurs beyond 24 hours. Delayed emesis is considered a separate entity from acute emesis; little is known about its pathophysiology. Reports suggest a role for substance P in mediating delayed emetic responses.

The management and prevention of CINV and the efficient use of anti-emetic therapies have received considerable attention from professional organizations in recent years. This attention is well deserved, considering the high frequency of CINV in patients receiving chemotherapy and radiation therapy. Ineffective prevention of CINV may have a substantial impact on quality of life and costs. The American Society of Health-System Pharmacists (ASHP) and the American Society of Clinical Oncology (ASCO) have created evidence-based treatment guidelines to assist practitioners. A large proportion of the studies used to support the guidelines were conducted in patients receiving cisplatin, an agent that typically causes early onset of acute emesis. Both of these evidence-based guidelines recommend doses of i.v. ondansetron below those in the FDA-approved labeling.

As a result of these guidelines, and in an attempt to reduce the overall cost of antiemetic therapy, many institutions have adopted strategies to reduce the total dose of 5-HT3-receptor antagonists. One unresolved issue, however, is the effect of lower doses of these agents in patients receiving cyclophosphamide-containing regimens. Although studies have supported the effectiveness of lower doses of 5-HT3-receptor antagonists in combination with dexamethasone, few studies have evaluated the effectiveness of lower doses of 5-HT3-receptor antagonists in preventing nausea and vomiting associated with cyclophosphamide-containing chemotherapy regimens. This is an important consideration, since cyclophosphamide typically produces late-onset acute emesis related to its metabolism into emetogenic metabolites. We hypothesize that using lower doses of 5-HT3-receptor antagonists to prevent CINV may result in insufficient 5-HT3-receptor antagonists being available at the time of stimulation of late-onset acute emesis.

The objective of this study was to evaluate the antiemetic effectiveness of ondansetron 8 mg i.v., ondansetron 32 mg i.v., and granisetron 10 µg/kg or 1 mg (as the hydrochloride) i.v. as prophylaxis in breast cancer outpatients receiving cyclophosphamidecontaining regimens.

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