Klinikum rechts der Isar
Technical University of Munich
Several new options for effective antiemetic treatment and prophylaxis of nausea and vomiting have arisen during the last decade. This is of particular interest in the field of oncology, where chemotherapy-induced nausea and vomiting (CINV) continue to impair patients’ quality of life and jeopardise the benefits of treatment. Therefore, antiemetic strategies as proposed by current treatment guidelines should be employed consistently in daily clinical practice; there are deficits in cancer care in that area. Along with established drug classes and compounds, newly available antiemetics such as the neurokinin-1 (NK(1)) receptor antagonist aprepitant and serotonin antagonist palonosetron should be considered.
The mechanisms by which corticosteroids prevent nausea and emesis are unclear. Nevertheless, corticosteroids have a high therapeutic index when used for acute chemotherapy-induced emesis. They are among the most frequently used antiemetics, with single-agent use being appropriate in low-risk settings. These drugs are especially valuable when given in combination with serotonin receptor antagonists in patients receiving highly emetogenic chemotherapy.
The corticosteroids most frequently studied for their use as antiemetics are dexamethasone and methylprednisolone. These agents are also the most consistently useful drugs for the prevention of delayed nausea and emesis. Several clinical trials have demonstrated that the widespread availability of corticosteroids, as well as their low cost and benefit, make them the single most appropriate agents for this indication. Side-effects are of some concern because corticosteroids are typically used for two to four days. Adrenal insufficiency after corticosteroid usage is not a problem for this relatively brief period; however, hyperglycaemia in susceptible patients requires attention.
A group of agents act as antagonists of dopamine type 2 (D(2)) receptors. Foremost in this group is the substituted benzamide metoclopramide. At higher doses, however, metoclopramide acts as a serotonin receptor antagonist. Antiemetic efficacy with metoclopramide is slightly lower than that observed with selective serotonin receptor antagonists. Several clinical trials have reported the efficacy of oral metoclopramide given in combination with corticosteroids. Doses typically vary between 20 and 40mg, given two to four times per day for three to four days. This agent is generally well tolerated, with few acute dystonic reactions in the adult population (the group for which dystonic reactions are significantly less frequent). Akathisia (restlessness) may occur in some patients. While dopamine antagonists are no longer first-choice drugs in the prevention of CINV, metoclopramide is still frequently used as a rescue medication, when patients experience CINV despite adequate prophylaxis.
Serotonin type 3 (5HT(3)) receptor antagonists
5HT(3) receptor antagonists block the 5HT(3) receptors of the vagal afferent nerves of the gastrointestinal tract. At least in the acute phase, CINV is to a large extent induced by the release of serotonin from the enterochromaffin cells of the gut. 5HT(3)-receptor antagonists have substantially improved management of CINV, especially during the first 24 hours after chemotherapy administration. They do not, however, effectively prevent vomiting occurring after the initial 24 hours, known as delayed vomiting. A survey showed that the top three most distressing side-effects listed by patients receiving highly emetogenic chemotherapy together with 5HT(3) receptor antagonists were nausea, hair loss and vomiting.(1) Currently available 5HT(3)-receptor antagonists have been evaluated as therapeutically equivalent when given at the correct dosages. A new agent in this class, palonosetron, has a longer half-life and a greater binding affinity than previously available agents. In addition, the drug appears to be more effective in patients receiving moderately emetogenic chemotherapy.(2) Table 1 lists the currently available 5HT(3)- receptor antagonists.
Substance P, a tachykinin in the gut and the central nervous system, induces emesis by binding to NK(1)-receptors. This mechanism appears to be of particular importance in the acute and delayed phases of CINV. Selective NK(1)-receptor antagonists, such as aprepitant, block this binding. Aprepitant, the first available compound of this new class, has shown efficacy in the prevention of acute and delayed nausea and emesis in phase III trials in patients receiving cisplatin-based chemotherapy,(3,4) and in patients with breast cancer receiving anthracycline-based chemotherapy.(5) In the two studies on highly emetogenic chemotherapy, 1,099 patients were randomised to receive standard prophylaxis against nausea and vomiting or an aprepitant-containing regimen (see Table 2). Because aprepitant is a moderate inhibitor of the cytochrome P450 3A4 enzyme, it has a boosting effect on coadministered dexamethasone. To compensate for this, dosages of dexamethasone were reduced from 20 to 12mg on day 1, and from 16 to 8mg on days 2–4. Patients’ exposure to dexamethasone was thus similar in the two groups. In both trials, during the first cycle of chemotherapy, 20% more patients receiving the aprepitant regimen achieved the primary endpoint of no emetic episodes and no use of rescue therapy, compared with patients receiving standard antiemetic prophylaxis. The aprepitant regimen was well tolerated. Among the side-effects reported in at least 10% of patients in either arm of either study, only asthenia and fatigue (17.8% vs 11.8%, both studies combined) and hiccups (10.8% vs 5.6%) were more prevalent in patients receiving the aprepitant regimen. In a recent study in which patients with breast cancer receiving anthracycline- containing, moderately emetogenic chemotherapy were included, an aprepitant-containing regimen again showed superiority over conventional antiemetic prophylaxis.(5) In 2003, the US FDA approved aprepitant; this drug is also available in many European countries. Aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. However, the possibility of drug interaction should be noted as a concern for investigators, as some chemotherapy agents are also metabolised by CYP3A4.
Other drug classes, such as butyrophenones (haloperidol and droperidol) and phenothiazines (prochlorperazine), as well as cannabinoids, both as plant extracts (dronabinol) and semisynthetic agents (nabilone and levonantradol), have been found to have antiemetic activity. However, the therapeutic index of these drugs is low. Therefore, routine use of these agents as antiemetics is not justified. Benzodiazepines should be viewed as adjunctive agents rather than useful antiemetics as such, and their use should be restricted to particular indications, such as anticipatory nausea and emesis.
Previous guidelines recommended using combined therapy with a 5HT(3)-antagonist and a corticosteroid for patients receiving agents with moderate-to-high emetic risk. However, despite adherence to guidelines, approximately half of these patients continued to experience nausea and vomiting.(6,7) Nonadherence to guidelines results in even higher incidence rates of nausea and vomiting.(7) The current guidelines of the Multinational Association of Supportive Care in Cancer (MASCC) recommend to add aprepitant to a combination of a 5HT(3)-receptor antagonist and dexamethasone when highly emetogenic chemotherapy is administered, to combine corticosteroids and 5HT(3)-receptor antagonists in moderately emetogenic chemotherapy and to use dexamethasone alone, or alternatively a 5HT(3)-receptor antagonist or metoclopramide alone, when there is a low risk of emetogenicity (see Table 3). In women receiving anthracyclines plus cyclophosphamide, the particularly great risk of nausea and emesis should be taken into account. In view of the newly presented data, the use of aprepitant in addition to a standard antiemetic regimen should be considered.
Adherence to treatment guidelines results in a better control over CINV. As new drugs are brought into the armamentarium, these guidelines will need to be continually reassessed in the light of new evidence. The consequent use of aprepitant-containing regimens for the prophylaxis of nausea and emesis in cisplatin-based chemotherapy will undoubtedly reduce the burden of gastrointestinal side-effects in patients. Regarding recent data on the effects of aprepitant and palonosetron in moderately emetogenic chemotherapy, it appears that improvements in the management of moderately emetogenic chemotherapy should also be achieved in the near future. Studies combining aprepitant and palonosetron are warranted. Also, data are missing on the effect of these new agents in cancer treatment in children and, in the context of radiotherapy, very few data are available so far. Most importantly, we must continue research into the physiology of emesis to direct therapy more appropriately.
- de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perception of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer 1997;76:1055-61.
- Gralla RJ, 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;14:1570-7.
- Hesketh PJ, Grunberg SM, Gralla RJ, 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;21:4112-9.
- Polli-Bigelli S, Rodrigues-Pereira J, Carides AD, 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;97:3090-8.
- Warr DG, Eisenberg P, Hesketh PJ, 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).
- Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 2004;100:2261-8.
- 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;15:526-36.
Multinational Association for Supportive Care in Cancer: Consensus Conference on Antiemetic Therapy, Perugia, Italy,
29–31 March 2004