Antiemetische Prophylaxe bei der Chemotherapie gastrointestinaler Tumoren

Zusammenfassung

Die wirksamen Systemtherapien in der gastrointestinalen Tumortherapie wurden deutlich vielseitiger. Infolgedessen wurden auch die Anforderungen an die supportive Therapie komplexer. Übelkeit und Erbrechen treten bei Patienten unter Chemotherapie weiterhin häufig auf, beeinträchtigen die Lebensqualität und gefährden die Ziele einer Chemotherapie. Die Möglichkeiten der antiemetischen Prophylaxe werden zum Teil nicht konsequent genutzt. Neben der notwendigen Beseitigung dieses Defizits sind neue antiemetisch wirksame Medikamente zu berücksichtigen. Ein ganz neues Wirkprinzip nutzt Aprepitant, das die Bindung von Substanz P am Neurokinin-1-Rezeptor antagonisiert. Bei oraler Verabreichung an den Tagen 1 - 3 einer Cisplatin-haltigen Chemotherapie erwies sich Aprepitant plus antiemetischer Standardprophylaxe mit Dexamethason und Ondansetron einer Prophylaxe ohne Aprepitant signifikant überlegen. Neueste Studienergebnisse deuten eine Überlegenheit auch bei Chemotherapie mit moderatem emetogenem Potenzial an. Palonosetron unterscheidet sich von bereits zugelassenen 5-HT₃-Rezeptor-Antagonisten durch eine stärkere Rezeptoraffinität, eine längere biologische Halbwertszeit und einen geringfügig stärkeren Schutz vor Übelkeit und Erbrechen nach moderat emetogener Chemotherapie. Mit der konsequenten Einhaltung standardisierter Richtlinien der antiemetischen Prophylaxe darf eine größere Patientenzufriedenheit und letztlich auch ein effektiverer Verbrauch ökonomischer Resourcen erwartet werden.

Abstract

Systemic treatment options in gastrointestinal malignancies have increased markedly. At the same time, the need for supportive measures has become more complex. Nausea and vomiting continue to impair the patients’ quality of life and to jeopardise the goals of chemotherapy. Antiemetic strategies as proposed by treatment guidelines should be employed consistently in daily clinical practice. Deficits in cancer care exist in this area. In addition, newly available antiemetic drugs should be considered. Aprepitant is the first approved representative of a new drug class. Aprepitant inhibits substance P binding to the neurokinin-1-receptor. Given orally on the first three days of a cisplatin-based chemotherapy in combination with a standard antiemetic regimen, aprepitant proved to be significantly more effective in the prevention of nausea and vomiting compared to the standard regimen without aprepitant. Recently presented results for chemotherapy with moderate emetogenic risks indicate that aprepitant shows superior effectiveness even in this setting. Palonosetron is a new drug in the class of 5-HT₃ (serotonin) receptor antagonists. Compared to older setrones, palonosetron exhibits a higher receptor binding activity, a longer half life, and a slightly improved activity in the prevention of nausea and vomiting after chemotherapy with moderate emetogenic risks. The implementation of standardised treatment guidelines into clinical practice will contribute to a higher patient satisfaction and a more effective utilisation of economic resources.

Schlüsselwörter

Chemotherapie - Nausea - Emesis - Prophylaxe - Aprepitant - Palonosetron - Dexamethason - Metoclopramid - Kosteneffektivität

Key words

Chemotherapy - nausea - vomiting - prophylaxis - aprepitant - palonosteron - dexamethasone - metoclopramide - cost effectiveness

Literaturangaben

• 1 Ihbe-Heffinger A, Ehlken B, Bernard R. et al . The impact of delayed chemotherapy-induced nausea and vomiting on patients, health resource utilization and costs in German cancer centers.  Ann Oncol. 2004;  15 526-536
• 2 Grunberg S M, Deuson R R, Mavros P. et al . Incidence of chemotherapy-induced nausea and emesis after modern antiemetics.  Cancer. 2004;  100 2261-2268
• 3 de Boer-Dennert M, de Wit R, Schmitz P IM. et al . Patient perception of the side-effects of chemotherapy: the influence of 5HT3 antagonists.  Br J Cancer. 1997;  76 1055-1061
• 4 Multinational Association for Supportive Care in Cancer. Consensus Conference on Antiemetic Therapy, Perugia, March 29 - 31, 2004. http://www.mascc.org. 
• 5 Hesketh P J, Kris M G, Grunberg S M. et al . Proposal for classifying the acute emtogenicity of cancer chemotherapy.  J Clin Oncol. 1997;  15 103-109
• 6 The Italian Group for Antiemetic Research . Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy.  N Engl J Med. 2000;  342 1554-1559
• 7 Tavorath R, Hesketh P J. Drug treatment of chemotherapy-induced delayed emesis.  Drugs. 1996;  52 639-648
• 8 Wilder-Smith O H, Borgeat A, Chappuis P. et al . Urinary serotonin metabolite excretion during cisplatin chemotherapy.  Cancer. 1993;  72 2239-2241
• 9 Gardner C J, Bountra C, Bunce K T. et al . Anti-emetic activity of neurokinin NK1 receptor antagonists is mediated centrally in the ferret.  Br J Pharmacol. 1994;  112; 53 (Suppl 1) 86-91
• 10 Otsuka M, Yoshioka K. Neurotransmitter functions of mammalian tachykinins.  Physiol Rev. 1993;  73 229-308
• 11 Tattersall F D, Ryeroft W, Francis B. et al . Tachykinin SK1 receptor antagonists act centrally to inhibit emesis induced by chemotherapeutic agent cisplatin in ferrets.  Neuropharmacology. 1996;  35 1121-1129
• 12 Andrykowski M. Development of anticipatory nausea in cancer chemotherapy: A review and synthesis.  Psychosom Med. 1990;  52 458-475
• 13 de Wit R, van der Berg H, Burghoudts J. et al . Initial high anti-emetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles.  Br J Cancer. 1998;  77 1487-1491
• 14 Wit, Schmitz P I, Verweij J. et al . Analysis of cumulative probabilities shows that the efficacy of the 5HT3 antagonists prophylaxis is not maintained.  J Clin Oncol. 1996;  14 644-651
• 15 Gralla R J, Osoba D, Kris M G. et al . Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology.  J Clin Oncol. 1999;  17 2971-2994
• 16 Jones A L, Hill A S, Soukop M. et al . Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy.  Lancet. 1991;  338 384-387
• 17 Navari R M, Madajewicz S, Anderson N. et al . Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo.  J Clin Oncol. 1995;  13 2408-2416
• 18 Jordan K, Hinke A, Grothey A. et al . A meta-analysis comparing the efficacy of five 5-HT3-receptor antagonists for acute chemotherapy-induced emesis.  Proc Am Soc Clin Oncol. 2004;  23 8048 (abstract)
• 19 de Wit R, de Boer A C, van de Linden G HM. et al . Effective cross-over to granisetron after failure to ondansetron, a randomised double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy.  Br J Cancer. 2001;  85 1099-1101
• 20 de Wit R. Current position of 5HT3 antangonists and the additional value of NK1 antagonists; a new class of antiemetics.  Brit J Cancer. 2003;  88 1823-1827
• 21 Kaiser R, Sezer O, Papies A. et al . Patient-tailored antiemetic treatment with 5-HT3 receptor antagonists according to cytochrome P-450 2D6 genotypes.  J Clin Oncol. 2002;  20 2805-2811
• 22 Gralla R J, Lichinitser M, Van der Vegt S. et al . Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron.  Ann Oncol. 2003;  14 1570-1577
• 23 Eisenberg P, Figueroa-Vadillo J, Zamora R. et al . Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist.  Cancer. 2003;  98 2473-2482
• 24 Aapro M S, Bertoli L, Lordick F. et al . Palonosetron (PALO) is effective in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC).  Support Care Cancer. 2003;  11 391 (abstract A-17)
• 25 Oannidis J PA, Hesketh P J, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence.  J Clin Oncol. 2000;  18 3409-3422
• 26 Goedhals L, Heron J F, Kleisbauer J P. et al . Control of delayed nausea and vomiting with granisetron plus dexamethasone or dexamethasone alone in patients receiving highly emetogenic chemotherapy: a double-blind, placebo-controlled, comparative study.  Ann Oncol. 1998;  9 661-666
• 27 Italian Group for Antiemetic Research . Dexamethasone, granisetron, or both for the prevention of nausea and vomiting during chemotherapy for cancer.  N Engl J Med. 1995;  332 1-5
• 28 Latreille J, Pater J, Johnston D. et al . Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy.  J Clin Oncol. 1998;  16 1174-1178
• 29 Hesketh P J, Gralla R J, Webb R T. et al . Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis.  J Clin Oncol. 1999;  17 338-343
• 30 Kris M G, Radford J E, Pizzo B A. et al . Use of a NK-1 receptor antagonist to prevent delayed emesis following cisplatin.  J Natl Cancer Inst. 1997;  89 53-54
• 31 Navari R M, Reinhardt R R, Gralla R J. et al . Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.  N Engl J Med. 1999;  340 190-195
• 32 Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography.  J Clin Psychiatry. 2002;  63 (Suppl 11) 18-24
• 33 Majumdar A K, McCrea J B, Panebianco D L. et al . Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.  Clin Pharmacol Ther. 2003;  74 150-156
• 34 Shadle C R, Lee Y, Majumdar A K. et al . Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity.  J Clin Pharmacol. 2004;  44 215-223
• 35 McCrea J B, Majumdar A K, Goldberg M. et al . Effects of the neurokinin-1-receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.  Clin Pharmacol Ther. 2003;  74 17-24
• 36 Hesketh P J, Grunberg S M, Gralla R J. et al . The oral neurokinin-1-antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin - the aprepitant protocol 052 study group.  J Clin Oncol. 2003;  21 4112-4119
• 37 Polli-Bigelli S, Rodrigues-Pereira J, Carides A D. et al . Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America.  Cancer. 2003;  97 3090-3098
• 38 de Wit R, Herrstedt J, Rapoport B. et al . Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy.  J Clin Oncol. 2003;  21 4105-4111
• 39 de Wit R, Herrstedt J, Rapoport B. et al . The oral NK1 antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebo-controlled phase III clinical trials.  Eur J Cancer. 2004;  40 403-410
• 40 Warr D G, Eisenberg P, Hesketh P J. et al . Phase III, double-blind study to assess an aprepitant-containing regimen for the prevention of nausea and vomiting due to moderately emetogenic chemotherapy.  Proc Am Soc Clin Oncol. 2004;  23 8007 (abstract)
• 41 Fozard J R, Mobarok A li ATM. Blockade of neuronal tryptamine receptors by metoclopramide.  Eur J Pharmacol. 1978;  49 109-112
• 42 Bonneterre J, Chevallier B, Metz R. et al . A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy.  J Clin Oncol. 1990;  8 1063-1069
• 43 Kaasa S, Kvaly S, Dicato M A. et al . A comparison of ondansetron with metoclopramide in the prophylaxis of chemotherapy-induced nausea and vomiting: A randomized double-blind study - International Emesis Study Group.  Eur J Cancer. 1990;  26 311-314
• 44 Marty M, Pouillart P, Scholl S. et al . Comparison of the 5-hydroxytryptamine 3 (serotonine) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis.  N Engl J Med. 1990;  332 816-821
• 45 De Mulder P HM, Seynaeve C, Vermorken J B. et al . Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting.  Ann Intern Med. 1990;  113 834-840
• 46 Hainsworth J, Harvey W, Pendergrass K. et al . 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;  9 721-728
• 47 Soukop M, McQuade B, Hunter E. et al . Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer.  Oncology. 1992;  49 295-304
• 48 Fauser A A, Bleiberg H, Chevallier B. et al . A double-blind, randomized, parallel study of IV dolasetron mesylate versus IV metoclopramide in patients receiving moderately emetogenic chemotherapy.  Cancer. 1996;  9 196-202
• 49 Tsavaris N, Charalambidis G, Ganas N. et al . Ondansetron versus metoclopramide as antiemetic treatment during cisplatin-based chemotherapy.  Acta Oncol. 1995;  34 243-246
• 50 Chevallier B, Cappelaere B, Splinter T. et al . A double-blind, multicentre comparison of intravenous dolasetron mesylate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy.  Support Care Cancer. 1997;  5 22-30
• 51 Ballatori E, Roila F, Berto P. et al . Cost and cost-effectiveness analysis of ondansetron versus metoclopramide regimes; a hospital perspective from Italy.  PharmacoEconomics. 1994;  5 227-237
• 52 Cunningham D, Gore M, Davidson N. et al . The real costs of emesis - an economic analysis of ondansetron vs. metoclopramide in controlling emesis in patients receiving chemotherapy for cancer.  Eur J Cancer. 1993;  29A 303-306
• 53 Zbrozek A S, Cantor S B, Cardenas M P. et al . Pharmacoeconomic analysis of ondansetron versus metoclopramide for cisplatin-induced nausea and vomiting.  Am J Hosp Pharm. 1994;  51 1555-1563
• 54 Jones A L, Lee G J, Bosanquet N. The budgetary impact of 5HT3 receptor antagonists in the management of chemotherapy-induced emesis.  Eur J Cancer. 1992;  29A 1-6
• 55 Steward D J, Dahrouge S, Coyle D. et al . Cost of treating and preventing nausea and vomiting in patients receiving chemotherapy.  J Clin Oncol. 1999;  17 344-351
• 56 Brüggenjürgen B, du Dois A. Wirksamkeit und Kosten der 5HT3-Antagonisten beim akuten chemotherapieinduzierten Erbrechen; Gesundheitsökonomische Analyse auf der Basis aktueller metaanalytischer Daten.  Med Klinik. 1997;  92 747-752
• 57 Aapro M S. A framework for assessing therapeutic innovation.  Anti-Cancer Drugs. 1993;  4 (Suppl 3) 27-31
• 58 Pon D, Lill M, Tan S. et al . Improved economic and patient satisfaction outcomes after implementation of antiemetic dosing guidelines.  Proc Am Soc Clin Oncol. 2002;  21 1527 (abstract)
• 59 Burish T G, Lyles J N. Effectiveness of relaxation training in reducing the aversiveness of chemotherapy in the treatment of cancer.  J Behav Ther Exp Psychiatr. 1979;  10 357-361
• 60 Morrow G R, Morell C. Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy.  N Engl J Med. 1982;  307 1474-1480