Japanese Journal of Clinical Oncology

Nagahiro Saijo, Medical Oncology Division, National Cancer Center Hospital, Tokyo

Nausea and vomiting are the most problematic adverse drug reactions in patients receiving chemotherapy. The grade of drug-induced emesis depends mainly on the intrinsic emetogenicity of the drug although the dose of the drug and host factors such as age, sex, food, etc. relates with the severity and incidence of emesis. Cisplatin has been demonstrated to be one of the most effective chemotherapeutic agents against a variety of solid tumors. However, it has a strong emetic effect and some patients refuse to receive effective chemotherapy because of severe nausea and vomiting. Therefore, optimal control of emesis in patients receiving emetogenic chemotherapy remains an important objective of supportive care in cancer chemotherapy.

In the 1980s, many trials were conducted to reduce cisplatin-induced emesis by using high dose metoclopramide, an antagonist acting on both dopamine and serotonin receptors with or without dexamethasone. The trials in the National Cancer Center Hospital demonstrated that high dose metoclopramide was more effective than dexamethasone and the combination of high dose metoclopramide plus dexamethasone showed better antiemetic effect than high dose metoclopramide alone (1,2). In addition, this combination was demonstrated to be also effective on cisplatin-induced delayed emesis (3). However, extrapyramial symptoms are major adverse drug reactions of high dose metoclopramide.

In early 1990, selective 5-HT3 (5-hydroxy tryptamine) receptor antagonists demonstrated an extremely favorable effect on chemotherapy-induced emesis by numerous clinical trials. In the National Cancer Center Hospital, we have conducted a randomized cross-over study of high dose metoclopramide plus dexamethasone versus granisetron, one of the 5-HT3 receptor antagonists plus dexamethasone in patients receiving chemotherapy with cisplatin. Granisetron and dexamethasone more efficiently suppressed cisplatin induced vomiting than high dose metoclopramide and dexamethasone on day 1. Granisetron and dexamethasone almost completely inhibited acute emesis accompanying chemotherapy with cisplatin (4). This observation is similar to those reported by Hainsworth et al. and Chevallier et al. (5,6). Twenty-one percent of patients in high dose metoclopramide and dexamethasone group experienced extrapyramidal reactions and 43% of patients in granisetron and dexamethasone group experienced constipation. On days 2-4 the granisetron and dexamethasone group had more episode of vomiting although there was no statistical difference. The cost for the treatment was significantly higher in granisetrone and dexamethasone ($1100) compared with high dose metoclopramide and dexamethasone ($99) per each course. Because of the outstanding antiemetic effect of 5-HT3 receptor antagonists, they have widely been used to reduce uncomfortable adverse drug reactions of chemotherapy despite the high cost.

Uchida et al. reported that granisetron was highly effective against nausea and vomiting induced by intraarterial cisplatin (7). The dose of cisplatin was low (50 mg/m2), they observed almost complete suppression of delayed emesis. Özkan et al. classified anticancer drugs to four categories based on the emetic grade (8). They reported 5-HT3 receptor antagonists were effective against emetic episode induced by combination chemotherapy even in children. They observed that combination of 5-HT3 receptor antagonists and dexamethasone was much more effective than 5-HT3-receptor antagonists alone.

Accordingly the treatment strategy of chemotherapy-induced emesis has been well developed. To establish the state of the art antiemetic therapy, the cost-effectiveness should more intensively be analysed.

References

1. Shinkai T, Saijo N, Eguchi K, Sasaki Y, Tamura T, Tominaga K, Sakurai M, Sano T, Taito H, Takahashi H, Nakano H, Nakagawa K, Suemasu K. Antiemetic efficacy of high-dose intravenous metoclopramide and dexamethasone in patients receiving cisplatin-based chemotherapy: a randomized controlled trial. Jpn J Clin Oncol 1986;16:279-87. MEDLINE Abstract

2. Nino S, Umehara H, Inoue I, Tamura T, Sasaki Y, Eguchi K, Saijo N, Suemasu K. A randomized controlled trial of acute and delayed cisplatin-induced emesis with metoclopramide, dexamethasone and prochlorperazine. Gan To Kagaku Ryoho 1987;14:2881-4. MEDLINE Abstract

3. Shinkai T, Saijo N, Eguchi K, Sasaki Y, Tamura T, Fujiwara Y, Mae M, Fukuda M, Ohe Y, Sasaki S, Nakagawa K, Minato K, Hong W-S, Suemasu K. Control of cisplatin-induced delayed emesis with metoclopramide and dexamethasone: a randomized controlled trial. Jpn J Clin Oncol 1989;19:40-4. MEDLINE Abstract

4. Ohmatsu H, Eguchi K, Shinkai T, Tamura T, Ohe Y, Nishio M, Kunikane H, Arioka H, Karato A, Nakashima H, Sasaki Y, Tajima K, Tada N, Saijo N. A randomized cross-over study of high-dose metoclopramide plus dexamethasone versus granisetron plus dexamethasone in patients receiving chemotherapy with high-dose cisplatin. Jpn J Cancer Res 1994;85:1151-8. MEDLINE Abstract

5. Hainsworth J, Harvey W, Pendergrass K, Kasimis B, Oblon D, Monaghan G, Gandara D, Hesketh P, Khojasteh A, Harker G, York M, Siddiqui T, Finn A. A single blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high dose cisplatin chemotherapy. J Clin Oncol 1991;9:721-8. MEDLINE Abstract

6. Chevallier B. Efficacy and safety of granisetron compared with high dose metoclopramide plus dexamethasone in patients receiving high dose cisplatin in a single-blind study. Eur J Cancer 1990;26:S33-6. MEDLINE Abstract

7. Uchida K, Akaza H, Hattori K, Noguchi R, Kondo F, Ishikawa S, et al. Antiemetic efficacy of granisetron: a randomized crossover study in patients receiving cisplatin-containing intraarterial chemotherapy. Jpn J Clin Oncol 1999;29:87-91.

8. Özkan A, Yildiz I, Yüksel L, Apak H, Celkan T. Tropisetron (Navoban) in the control of nausea and vomiting induced by combined cancer chemotherapy in children. Jpn J Clin Oncol 1999;29:92-5.

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