Jørn Herrstedt

Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients With Breast Cancer After Moderately Emetogenic Chemotherapy

PURPOSEnThis is the first study in which the NK(1)-receptor antagonist, aprepitant (APR), was evaluated for the prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy.nnnPATIENTS AND METHODSnEligible breast cancer patients were naive to emetogenic chemotherapy and treated with cyclophosphamide +/- doxorubicin or epirubicin. Patients were randomly assigned to either an aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) [DOSAGE ERROR CORRECTED] or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy end point was the proportion of patients with complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. The secondary end point was the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index-Emesis questionnaire.nnnRESULTSnOf 866 patients randomized, 857 patients (99%) were assessable. Overall complete response was greater with the aprepitant regimen than with the control regimen (50.8% v 42.5%; P = .015). More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5% v 55.6%; P = .019). Both treatments were generally well tolerated.nnnCONCLUSIONnThe aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide.

Addition of the Oral NK1 Antagonist Aprepitant to Standard Antiemetics Provides Protection Against Nausea and Vomiting During Multiple Cycles of Cisplatin-Based Chemotherapy

PURPOSEnThis analysis evaluated whether the antiemetic efficacy of the NK1 receptor antagonist aprepitant (EMEND trade mark, Merck, Whitehouse Station, NJ) plus standard antiemetics could be sustained for up to six cycles of cisplatin-based chemotherapy.nnnPATIENTS AND METHODSnPatients receiving cisplatin > or = 70 mg/m2 were blindly assigned to receive one of the following three regimens: (1) aprepitant 375 mg 1 hour before cisplatin on day 1 and aprepitant 250 mg on days 2 to 5 (n = 35); (2) aprepitant 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 (n = 81); or (3) placebo before cisplatin on days 2 to 5 (n = 86). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 5. The primary end point was complete response (no emesis and no rescue therapy) over 5 days following cisplatin in up to six cycles. A cumulative probability analysis using a model for transitional probabilities was used to analyze the data. The aprepitant 375/250-mg regimen was discontinued early in light of new pharmacokinetic data.nnnRESULTSnIn the first cycle, 64% of patients in the aprepitant group and 49% in the standard therapy group had a complete response. Thereafter, complete response rates for the aprepitant group were still 59% by cycle 6, but decreased to 34% by cycle 6 for the standard therapy group. Reasons for discontinuation were similar across treatment groups.nnnCONCLUSIONnCompared with patients who received standard therapy, those who received only the aprepitant regimen had better and more sustained protection against chemotherapy-induced nausea and vomiting over multiple cycles.

Antiemetics: an update and the MASCC guidelines applied in clinical practice

Nausea and vomiting are two of the most severe problems for patients treated with chemotherapy. Until the late 1970s, nausea and vomiting induced by chemotherapy was an almost neglected research area. With the introduction of cisplatin, the cytotoxin with the highest emetic potential, research was stimulated and has now resulted in the development of two new classes of antiemetics, the serotonin and neurokinin antagonists. A large number of trials have fine-tuned antiemetic therapy and made evidence-based recommendations possible for the majority of patients receiving chemotherapy. This Review discusses the pathophysiology of nausea and vomiting, the development of antiemetics, highlights some of the newest antiemetics, and finally summarizes recommendations from the evidence-based guidelines developed by the Multinational Association of Supportive Care in Cancer.

Efficacy and Tolerability of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Emesis over Multiple Cycles of Moderately Emetogenic Chemotherapy

An aprepitant (APR) regimen was evaluated for prevention of nausea and emesis due to moderately emetogenic chemotherapy (MEC) over multiple cycles.

Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response

Goals of workPrevention of chemotherapy-induced nausea and vomiting (CINV) with standard antiemetics has been more difficult to achieve in female patients. Data from two phase III trials of the NK1 antagonist aprepitant were assessed for potential effect of gender on treatment response.Patients and methods1,044 patients receiving cisplatin (≥70xa0mg/m2) were randomly assigned to control regimen [ondansetron (O) 32xa0mg i.v. and dexamethasone (D) 20xa0mg p.o. on dayxa01; D 8xa0mg twice daily on days 2–4] or aprepitant (A) regimen (A 125xa0mg p.o. plus O 32xa0mg and D 12xa0mg on dayxa01; A 80xa0mg and D 8xa0mg once daily on days 2–3; and D 8xa0mg on dayxa04). The primary endpoint was overall complete response (no emesis and no rescue therapy over days 1–5). Data were analyzed by a modified intent-to-treat approach. Between-treatment comparisons for each gender were made using logistic regression.Main resultsWomen comprised 42 and 43% of the aprepitant and control groups, respectively. In the control group, 41% of women had overall complete response compared with 53% of men. In the aprepitant group, 66% of women had overall complete response compared with 69% of men.ConclusionThe addition of aprepitant may negate the adverse prognostic effect of female gender on the prevention of CINV in patients receiving highly emetogenic chemotherapy.

Delayed emesis: moderately emetogenic chemotherapy

Data on the incidence and efficacy of antiemetic prophylaxis against delayed emesis induced by moderately emetogenic chemotherapy are scanty. An overview of the literature has been done that showed the efficacy of dexamethasone in two of three randomized trials. Its optimal dose and duration of administration has not been defined. Only one of four randomized studies showed a statistically significant efficacy of 5-HT3 antagonists. Finally, only weak evidence has been published on the efficacy of dopamine receptor antagonists.

Prevention and management of mucositis in patients with cancer

This review summarises the large number of locally and systemically applied preventive and therapeutic interventions of mucositis in patients with cancer. The need for further elucidation of the pathophysiology and for optimisation of trial methodology is emphasised. Data from trials in animal models and preliminary data in patients indicate that cytokines such as interleukin-1, interleukin-11, TGF-beta 3 and keratinocyte growth factor could reduce the incidence of mucositis. Other potentially useful agents are the angiogenesis-inhibiting drug thalidomide, the cytoprotector amifostine and the pineal hormone melatonin.

Ondansetron Plus Metopimazine Compared With Ondansetron Plus Metopimazine Plus Prednisolone as Antiemetic Prophylaxis in Patients Receiving Multiple Cycles of Moderately Emetogenic Chemotherapy

PURPOSEnTo compare the antiemetic efficacy and tolerability of ondansetron plus metopimazine with ondansetron plus metopimazine plus prednisolone during nine cycles of moderately emetogenic chemotherapy.nnnPATIENTS AND METHODSnA total of 221 women with stage I or II breast cancer and no prior chemotherapy who were scheduled to receive adjuvant chemotherapy with intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin, and fluorouracil given every 3 weeks were included in a double-blind parallel trial. Patients were randomized to 3 days of oral treatment with ondansetron plus metopimazine, or ondansetron plus metopimazine plus prednisolone. Ondansetron was administered as 8 mg bid, metopimazine as 30 mg qid, and prednisolone as 50 mg qd.nnnRESULTSnIn all, 216 patients (97.7%) were assessable for efficacy during a total of 1,462 cycles. In cycle 1, complete protection from emetic episodes/nausea day 1, days 2 through 5, and days 1 through 5 was achieved in 84.4%/51.4%, 82.6%/41.3%, and 79.8%/34.9% with ondansetron plus metopimazine and in 84.1%/57.0%, 86.8%/53.8%, and 79.4%/43.0% with ondansetron plus metopimazine plus prednisolone, respectively. In cycle 1, the three-drug combination was superior only in the treatment of nausea on days 2 through 5 (P =.0497). The cumulative emetic protection rate after nine cycles was 0.52 with ondansetron plus metopimazine and 0.75 with ondansetron plus metopimazine plus prednisolone. Side effects were generally few and mild with both treatments. Constipation was the only adverse event significantly more frequent with the three-drug combination (P =.029).nnnCONCLUSIONnOndansetron plus metopimazine plus prednisolone is highly effective and superior to ondansetron plus metopimazine during nine cycles of moderately emetogenic chemotherapy.

Consensus recommendations for the prevention of vomiting and nausea following high-emetic-risk chemotherapy

In this update of our 2005 document, we used an evidence-based approach whenever possible to formulate recommendations, emphasizing the results of controlled trials concerning the best use of antiemetic agents for the prevention of emesis and nausea following anticancer chemotherapies of high emetic risk. A three-drug combination of a 5-hydroxytryptamine type 3 receptor (5-HT3) receptor antagonist, dexamethasone, and aprepitant beginning before chemotherapy and continuing for up to 4xa0days remains the standard of care. We address issues of dose, schedule, and route of administration of five selective 5-HT3 receptor antagonists. We conclude that, for each of these five drugs, there is a plateau in therapeutic efficacy above which further dose escalation does not improve outcome. In trials designed to prove the equivalence of palonosetron to ondansetron and granisetron, palonosetron proved superior in emesis prevention, while adverse effects were comparable. Furthermore, for all classes of antiemetic agents, a single dose is as effective as multiple doses or a continuous infusion. The oral route is as efficacious as the intravenous route of administration.

Nausea and emesis: still an unsolved problem in cancer patients?

J. Herrstedt (✉) Department of Oncology 54 B1, Copenhagen University Hospital Herlev, DK-2730 Herlev, Denmark e-mail: JRHE@herlevhosp.kbhamt.dk Tel.: +45-4488-3070 Fax: +45-4453-3077 remaining problems in anti-emetic therapy [2, 3, 4, 5]. Roila et al. [2] review the situation with delayed chemotherapyinduced emesis. Evidence-based treatment has not changed during the last few years and should be based on a corticosteroid. In patients receiving cisplatin a corticosteroid should be combined with a 5-HT3or a dopamine-receptor antagonist [6, 7, 8]. Given the best available treatment, 40–60% of the patients still develop delayed cisplatin-induced emesis [2]. To improve this unsatisfactory situation, we need a better understanding of the pathophysiology, and the review by Roila et al. includes comments on different potential mechanisms. One of several postulated mechanisms of action is the disruption of gastrointestinal motility and permeability. The initial 10–18 hours (acute phase) of the biphasic pattern of cisplatin-induced emesis is well understood. Cisplatin induces an increase in the release of serotonin from the enterochromaffin cells in the gut, starting approximately 2 hours after the infusion, and this release is correlated with the induction of vomiting in the patients. It is generally believed that the serotonin released binds to 5-HT3 receptors located on vagal afferent neurons in the gut, thereby initiating the emetic reflex arch. This hypothesis is in agreement with the efficacy of the 5-HT3-receptor antagonists in the initial 16–18 hours after the start of cisplatin, and also explains the decreased efficacy after the initial 18 hours, because by then the serum concentration of serotonin is back to “pre-cisplatin” levels. The mechanism behind the second (delayed) phase of cisplatin-induced emesis, starting 18–24 hours after the initiation of the treatment, has not yet been explained in detail. We know that cisplatin induces the release not only of serotonin, but also of other transmitters from the enterochromaffin cells, one of these being the neuropeptide substance P. Substance P inhibits intestinal peristalsis via agonism at NK1 receptors [9], and could in theory be the cause of the retroperistalsis induced by cisplatin. This action seems to be of only minor importance, however, because substance P antagonists have to get access into the central nervous system to exhibit anti-emetic activity. Preclinical studies have shown that nonpeptide NK1-receptor antagonists are able to inhibit not only acute but also delayed emesis, and this finding has recently been verified in clinical trials [10]. Roila et al. also discuss the role of adrenal hormones and quote an investigation showing that delayed cisplatin-induced nausea is augmented by high levels of endogenous noradrenaline [11]. In a recent study, reserpine, a monoamine depletor, prevented cisSupport Care Cancer (2002) 10:85–87 DOI 10.1007/s00520-001-0339-7 E D I T O R I A L