Standard Antiemetic Therapy Research Articles

Association of ABCB1, 5-HT3B Receptor and CYP2D6 Genetic Polymorphisms with Ondansetron and Metoclopramide Antiemetic Response in Indonesian Cancer Patients Treated with Highly Emetogenic Chemotherapy

Suboptimal treatment of chemotherapy-induced nausea and vomiting and unsatisfactory response to antiemetic drugs cause impairment of cancer patient's daily functioning. This study was aimed to investigate the association of selected germline polymorphisms with ondansetron and metoclopramide response in Indonesian cancer patients treated with highly emetogenic chemotherapy. We enrolled 202 chemotherapy naïve patients treated with cisplatin at a dosage of ≥50 mg/m(2) as monotherapy or as combined chemotherapy. Ondansetron 8 mg and dexamethasone 8 mg intravenously were the standard antiemetic therapy for prevention of acute chemotherapy-induced nausea and vomiting. Metoclopramide 10 mg orally, three times per day as fixed prescription, was given until 5 days after chemotherapy to prevent delayed chemotherapy-induced nausea and vomiting. Primary and secondary outcomes were the occurrence of chemotherapy-induced nausea and vomiting in the acute and delayed phase. The following single-nucleotide polymorphisms were determined in ABCB1: rs1045642, rs2032582 and rs1128503; in 5-HT3B-R: rs45460698, rs4938058 and rs7943062; and in CYP2D6: rs16947 (CYP2D6 2), rs3892097 (CYP2D6 4) and rs1065852 (CYP2D6 10) using Taqman assays. During the acute phase, 21.8 and 30.2% patients experienced Grade 3 and 4 nausea and vomiting, respectively, whereas 38.6% patients experienced nausea and/or vomiting in the delayed phase. Carriers of the CTG haplotype of the ABCB1 gene experienced Grade 3 and 4 chemotherapy-induced nausea and vomiting more often than other haplotypes in the delayed phase (P< 0.05). No associations were found with the 5-HT3B receptor haplotypes and CYP2D6-predicted phenotypes. Our study shows that in Indonesian cancer patients treated with highly cytostatic emetogenic, carriership of the CTG haplotype of the ABCB1 gene is related to an increased risk of delayed chemotherapy-induced nausea and vomiting.

Phase III, double-blind, placebo-controlled, crossover study evaluating a 5HT3 antagonist plus dexamethasone with or without aprepitant in patients with germ cell tumor receiving 5-day cisplatin combination chemotherapy: A Hoosier Oncology Group (HOG) study.

9013 Background: Aprepitant, combined with a 5HT3 antagonist plus dexamethasone, is a standard antiemetic therapy for the prevention of single day cisplatin induced nausea and vomiting. There are n...

Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy‐induced nausea and vomiting

Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV. Patients suffering from CINV despite prophylaxis with standard anti-emetic treatment were randomized to CBM or placebo, during the 120 h post-chemotherapy period, added to standard anti-emetic treatment. Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events (AEs). The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response. Seven patients were randomized to CBM and nine to placebo. Only one patient in the CBM arm was withdrawn due to AEs. A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [5/7 (71.4%) with CMB vs. 2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], due to the delayed period. The incidence of AEs was higher in the CBM group (86% vs. 67%). No serious AEs were reported. The mean daily dose was 4.8 sprays in both groups. Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial.

Randomized, controlled pilot trial of electro-acupuncture for nausea, vomiting, and myelosuppression in women receiving adjuvant chemotherapy for early breast cancer.

e19630 Background: Nausea, vomiting and myelosuppression are common side effects of chemotherapy. Despite recent advances in anti-emetic therapy, a significant percent of women still experience nausea and vomiting. Nonblinded trials have suggested acupuncture may have some benefit in controlling these side effects. The primary objective of this study was to assess feasibility and safety of electro-acupuncture (EA) used in women receiving adjuvant anthracycline based chemotherapy for early breast cancer. Secondary objectives were to assess any benefit of EA on reducing chemotherapy induced nausea, vomiting and myelosuppression. Methods: Thirty women receiving adjuvant anthracycline based chemotherapy for early breast cancer were randomized to receive sham EA (n=16) or real EA (n=14). Acupuncture was administered immediately prior to chemotherapy and on day 2 for the first 2 cycles. All patients received standard anti-emetic therapy. Nausea and vomiting were assessed in the first 3 cycles of chemotherapy wi...

Electroacupoint Stimulation for Postoperative Nausea and Vomiting in Patients Undergoing Supratentorial Craniotomy

We evaluated the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) at the P6 acupoint for prevention of postoperative nausea and vomiting in patients undergoing supratentorial craniotomy. The study population was patients aged 20 to 60 years who underwent supratentorial craniotomy under general anesthesia. Exclusion criteria were obesity, diabetes mellitus, and a history of motion sickness, postoperative nausea and vomiting, or smoking. Patients were randomized into 2 groups: stimulation and control. In the former, transcutaneous stimulation electrodes were placed at the right P6 acupoint. In controls, electrodes were positioned at a nonacupoint site. Patients received a standard general anesthesia. Ondansetron was given as a routine antiemetic treatment for each patient before skin closure. Postoperatively, metoclopramide (10 mg, i.v.) was administered as a rescue antiemetic. Forty patients received TEAS and 40 were controls. In the TEAS group, 18% of patients had nausea compared with 37% of the controls. The cumulative prevalence of vomiting was 12.5% with acustimulation and 32.5% in controls (P<0.05). The prevalence of nausea, vomiting was significantly lower with TEAS at the P6 acupoint. TEAS at the P6 meridian points is an effective adjunct to standard antiemetic drug therapy for prevention of nausea and vomiting in patients undergoing supratentorial craniotomy.

Efficacy according to Dexamethasone Dose in Combination with Aprepitant and Granisetron during Cisplatin-based Chemotherapy

The purpose of this study was to evaluate the dosage of dexamethasone in combination with granisetron and aprepitant when used for the prevention of acute and delayed nausea and vomiting in patients receiving high-dose cisplatin chemotherapy. The study was retrospective. Ninety-two patients received cisplatin (≥50 mg/m 2 ) and either a high-dose (Group I, n=57) or low-dose (Group II, n=35) regimen of dexamethasone. The high-dose regimen consisted of intravenous administration of 20 mg on day 1 and 8 mg on days 2∼4. The low-dose regimen consisted of intravenous administration of 10 mg before cisplatin and oral dexamethasone 4 mg on days 2∼4. Both groups received granisetron and aprepitant. The primary endpoint was complete response over 5 days following cisplatin administration. In the acute phase, complete response occurred in 87.7% of Group I and 91.4% of Group II patients (p=0.58). In the delayed phase, the proportions of patients without emesis in Groups I and II were 84.2% and 65.7%, respectively (p=0.04). In the overall phase, the complete response rates in Groups I and II were 80.7% and 65.7%, respectively (p=0.11). The high-dose dexamethasone regimen is superior to the low-dose in preventing delayed chemotherapy-induced nausea and vomiting, with no significant differences evident in the acute and overall phases. The high-dose dexamethasone regimen should be considered as a standard antiemetic therapy for cisplatin-treated patients.

3029 The dosing frequency of sustained-release opioids and the prevalence of end-of-dose failure in cancer pain control: a Korean multicenter study

Little information exists on the functional impact of effective antiemetic protection. In the present study, the Functional Living Index—Emesis (FLIE), was used to assess patient-reported impact of chemotherapy-induced nausea and vomiting (CINV) after administration of a new NK-1 receptor antagonist (aprepitant). Cisplatin-treated patients in a double-blind randomised trial received either aprepitant+dexamethasone+ondansetron on day 1 and aprepitant+dexamethasone on days 2–5 or standard antiemetic therapy (dexamethasone and ondansetron on day 1 and dexamethasone on days 2–5). Emetic events, nausea ratings and rescue medications were recorded in a 5-day diary and the FLIE was completed on day 6. Compared with standard therapy, significantly more patients treated with the high dose aprepitant regimen achieved a Complete Response (71 vs 44%, P<0.001) and also reported no impact on daily life as indicated by the FLIE total score (84 vs 66%, P<0.01). Use of the FLIE demonstrated that improved control of emesis was highly effective in reducing the impact of CINV on patients’ daily lives.

Prospective evaluation of incidence and pattern of nausea in patients receiving combined chemotherapy and radiotherapy (RT) above the diaphragm

e20676 Background: Nausea (N), vomiting (V) remain distressing effects of chemotherapy. Prevalence of N, V in patients (pts) receiving daily (5/7) RT with weekly (wkly) doublet chemotherapy is not well studied. Methods: We used a modified Functional Living Index Emesis (FLIE) (Lindley and Mullin) to study N, V in pts receiving 2 chemotherapy agents with RT for upper aero-digestive malignancies. Exclusion criteria were: other causes of N,V or RT below the diaphragm. Pts completed a written questionnaire wkly during therapy. A 6 point scale was used, 0 representing no symptoms and 6 representing intolerable or uncontrolled symptoms. Questions addressed N, V, use of medication in daily diary and overall wkly assessment of N, V, ability to eat, effectiveness of medications and effect on daily routine. Results: 21 Patients enrolled: 15 completed 4 weekly questionnaires, 17 completed 3. Most patients received a total of 5 weekly chemotherapy treatments. Participants: 17 M: 4 F with 17 head/neck sites, 4 lung. 6 pts received wkly carboplatin (AUC 2) and paclitaxel (45/m2 for lung, 30/m2 for h/n); 15 pts cisplatin (20/m2) and paclitaxel. All patients received our standard anti emetic therapy (steroids and 5 HT3 receptor antagonist). Pts with early nausea tended to experience continued or worsened symptoms despite anti emetic therapy; at wk 4, more pts experienced V. Selected results are shown in the table . Conclusions: The modified FLIE questionnaire was a useful tool for evaluation. Despite advances in anti emetic therapy, nausea and vomiting resulting from the combination of radiation therapy with dual agent chemotherapy exerts a significant adverse effect on daily comfort but little effect on overall function. [Table: see text] [Table: see text]

Optimizing antiemetic therapy in multiple-day and multiple cycles of chemotherapy

Only a few studies have investigated the effect of antiemetic therapy in patients treated with multiple-day or multiple cycles of chemotherapy. The present review will assess the available data, highlight the current recommendations and draw attention towards the remaining problems in this field of antiemetic treatment. Evidence-based guidelines recommend a combination of a 5-HT3-receptor antagonist and dexamethasone in the prophylaxis of nausea and vomiting in multiple-day cisplatin-based chemotherapy. In patients treated with multiple cycles of chemotherapy the addition of a NK1-receptor antagonist aprepitant to standard antiemetic therapy has increased the antiemetic effect, and multiple cycle extension studies have demonstrated that this increment in effect is sustained during multiple cycles of chemotherapy. A recent study indicated that the dopamine D2-receptor antagonist metopimazine has some additive effect on delayed symptoms induced by multiple-day chemotherapy. The development of the NK1-receptor antagonist aprepitant has significantly improved the antiemetic control in patients treated with multiple cycles of chemotherapy. Far too many patients still experience considerable emetic side effects. The effect of aprepitant in multiple-day chemotherapy has yet to be defined. The effect of new antiemetic agents such as palonosetron and olanzapine also needs to be investigated in randomized trials.

Chemotherapy- and Cancer-Related Nausea and Vomiting

Approximately one half of cancer patients will experience nausea or vomiting during the course of their disease either because of the cancer itself or because of their treatment. Emesis attributable to cancer warrants a careful investigation to determine whether a treatable underlying cause is responsible. Interventions using dexamethasone and octreotide may reduce vomiting attributable to bowel obstruction. In the absence of a bowel obstruction or a correctable cause, the usual approach is a sequential trial of antiemetics guided by considerations of cost and side effects.Major progress in managing chemotherapy-induced emesis followed from the use of a combination of a corticosteroid and 5-hydroxytryptamine(3) (5-HT(3)) receptor antagonist for moderately to highly emetogenic chemotherapy. Nevertheless, vomiting still occurred in approximately 40% of women receiving chemotherapy containing an anthracycline plus cyclophosphamide and in approximately 50% of patients receiving high-dose cisplatin. The addition of aprepitant, a neurokinin 1 receptor antagonist, improved control of emesis by a further 15%-20%, and that agent is now recommended as part of standard antiemetic therapy for patients at high risk of emesis. Based largely on anecdotal experience, cannabinoids and olanzapine are sometimes also recommended in patients with refractory emesis. Phase III trials are required to confirm their efficacy as add-ons to a corticosteroid, a 5-HT(3) receptor antagonist, and possibly aprepitant.

A randomized, double-blinded, pilot trial of aprepitant added to standard antiemetics during conditioning therapy for hematopoietic stem cell transplant (HSCT)

9112 Background: Antiemetic prophylaxis for standard dose chemotherapy has improved while that for high dose chemotherapy ± total body irradiation (TBI) has not. Aprepitant (A), a neurokinin-1 antagonist, was added to standard antiemetic therapy for planned conventional HSCT to test for improved emesis control. Methods: During cyclophosphamide (Cy)-based conditioning therapy patients were randomized to receive ondansetron (O) ± dexamethasone plus A or a placebo (P) on days of chemo/radiotherapy. The primary aim was to reduce N/V during and after HSCT conditioning. Nausea, emesis, and nutritional intake were evaluated from the onset of therapy through day +7. Busulfan doses were targeted to disease appropriate AUCs and pharmacokinetic (PK) analysis was performed on Cy, Cy- metabolites (HCY &amp; CEPM), and A. Responses were defined as Complete (CR) - no emesis, mild-moderate nausea, and Major (MR) - 1–2 emesis on only 1 day with any level nausea or no emesis with severe nausea. Results: Fifteen patients have been randomized per arm. Eleven patients received TBI (1,200 cGy) CY (120 mg/kg) and 19 received Bu (16 mg/kg) CY (120 mg/kg). A/P was begun on Day -7 (125 mg) with the first O dose and given daily (80 mg) through day +4 (alone on days +1 through +4). Overall responses (CR + MR) were seen in 14/15 A patients and 7/15 P patients. (p=0.014) No emesis occurred in 10/15 A patients and 5/15 P patients (p=0.143). Preliminary PK show the observed AUCs of CY, HCY and CEPM, for both regimens and PK differences between the 2 regimens, were consistent with previously published data. Most busulfan patients, 87%, required dose adjustments (primarily reductions) to stay within target AUCs. Anti-seizure prophylaxis with phenytoin may significantly decrease A levels, but this didn't appear to be clinically relevant. Adverse effects were similar between arms. One case of sinusoidal obstruction syndrome occurred in the P arm. Conclusions: In this interim analysis, aprepitant added to standard antiemetics improved emesis prevention during Cy-containing conditioning therapy prior to HSCT, without significant changes in Cy pharmacokinetics or increased toxicity. Data on the target accrual of 40 patients will be presented. [Table: see text]

Pilot study of dronabinol for adult patients with primary malignant gliomas

19607 Background: Chemotherapy-induced nausea and vomiting (CINV) are common adverse effects from chemotherapy. While most treatments administered in patients with primary gliomas are not highly emetogenic, up to 50% of neuro-oncology patients report CINV despite 5HT3 or steroid therapies. Adjuvant benzodiazepines frequently alter mental status. Dronabinol may provide a safe alternative option without compromise of neurological status. his study seeks to describe toxicities (TOX) associated with dronabinol administration in neuro-oncology patients. A secondary aim is to describe the impact that dronabinol has on their quality of life (QOL). Methods: This is an exploratory study of adult patients with WHO Grade III/IV primary gliomas on adjuvant chemotherapy. Power analysis determined a sample size of 34 subjects for 0.80 effect size. Enrollment is ongoing with 18/34 adult patients accrued. Patients take dronabinol 5 mg BID 24 hours prior to, during, and 48 hours after completion of oral/IV chemotherapy. Patients continue their established antiemetic regimen. Between chemotherapy doses, dronabinol is reduced to 2.5 mg daily. Intolerance of dronabinol is defined as 2 or more Grade 3 or greater non-hematologic TOX according to the CTC v.3 definition handbook. Modified Functional Living Index-Emesis (FLIE), Functional Assessment of Cancer Therapy-Brain Tumor (FACT-Br), Mini Mental Status Exam (MMSE), and CINV visual analog scales are collected at specific points for 2 cycles for TOX and QOL data. Results: Subjects are predominately male (n=10); mean age of 45.2 years. Four withdrew due to Grade 3 neurologic TOX of cognitive changes (n=3) despite decreasing dosages; Grade 3 persistent CINV (n=1) despite increasing dronabinol dosage. Increased dosages were required in 4 subjects to better manage CINV. Two required decreased doses for Grade 2 neurologic TOX. Most subjects (n=14) reported stable or improved QOL by FACT-Br and FLIE while the 4 withdrawn subjects reported worsening QOL related to TOX. Conclusions: Dronabinol is safe and effective for administration as an adjunct to standard antiemetic therapy during treatment for primary glioma. The dose may be titrated with minimal toxicities and improvement in QOL. No significant financial relationships to disclose.

Efficacy of aprepitant in management of chemotherapy‐induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is an important cause of distress for cancer patients. We have evaluated the effectiveness and safety of a new antiemetic aprepitant in improving management of CINV refractory to standard antiemetic therapy in the general oncology setting. Retrospective chart review of all patients who received aprepitant from 1 January 2004 to 31 May 2005. Twenty-six patients received oral aprepitant in addition to 5-hydroxytryptamine blocker and corticosteroid. Eighty-five per cent of the patients were women. Median age was 49 years. More than half patients had early-stage cancers. Majority received anthracycline-based chemotherapy for breast cancer. Fourteen (54%) patients received aprepitant during cycle 2, seven patients (27%) started aprepitant during cycle 4 and one (4%) during cycle 5. Side-effects observed included constipation (27%), fatigue (27%) and diarrhoea (8%). Six (23%) patients did not complete chemotherapy. Two of these had persistent nausea and vomiting, and four experienced diarrhoea, febrile neutropenia and other chemotherapy-related events. Three patients (12%) were hospitalized prior to starting aprepitant because of CINV, and one patient was hospitalized because of CINV while receiving aprepitant. Only six (23%) patients would have been eligible for aprepitant under the reimbursement scheme available at the time. The addition of aprepitant was associated with improved control of nausea and vomiting and reduction in hospitalization in patients receiving chemotherapy.

Aprepitant: the evidence for its place in the prevention of chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) represents a significant burden on patients and healthcare systems. Despite the introduction of serotonin antagonists, many patients still experience CINV, particularly delayed symptoms occurring more than 24 hours after chemotherapy. Aprepitant is a selective neurokinin-1 (NK(1)) receptor antagonist approved for use with other antiemetics to prevent CINV caused by moderately to highly emetogenic chemotherapy. To review the evidence underlying the use of aprepitant to prevent CINV. In patients receiving moderately and highly emetogenic chemotherapy, adding aprepitant to standard antiemetic therapy with dexamethasone and a serotonin antagonist significantly improved control of CINV. The degree of control of delayed CINV was particularly pronounced, and effectiveness was more likely to be maintained in multiple cycles compared with standard therapy. Nausea was generally less frequent among patients taking aprepitant. More patients receiving aprepitant were satisfied with their treatment and reported minimal/no impact of CINV on daily activities. Aprepitant appears to be well tolerated, with fatigue being the most commonly reported adverse event. The drug is an inhibitor and inducer of cytochrome P450 (CYP) 3A4, resulting in contraindications and caution with some concomitant medication. Limited economic evidence suggests that a proportion of the acquisition cost of aprepitant may be offset by savings in overall direct costs of managing CINV. The evidence supports the recommended use of aprepitant in clinical guidelines for the prevention of CINV due to highly emetogenic chemotherapy, and its recently approved role in regimens with moderate risk. It is particularly useful for delayed symptoms.

The neurokinin1 receptor antagonist aprepitant as an antiemetic for moderately emetogenic chemotherapy

The neurokinin-1 (NK1) receptor antagonist aprepitant has become part of standard antiemetic therapy for high-dose cisplatin. Recent results indicate that chemotherapy for breast cancer that contains an anthracycline plus cyclophosphamide is more emetogenic than has been previously realised. One large randomised trial demonstrated that aprepitant substantially reduces the risk of vomiting or retching when added to a corticosteroid and a 5-hydroxytryptamine 3 (HT3) receptor antagonist. The adverse effects of standard antiemetics and chemotherapy do not appear to be increased by the addition of this novel antiemetic agent. Aprepitant should now also be considered to be part of prophylactic antiemetic therapy for women who receive chemotherapy that contains an anthracycline and cyclophosphamide. The role of NK1 receptor antagonists in preventing emesis due to other cytotoxic agents that are deemed to be moderately emetogenic is still unclear.

Dronabinol zur supportiven Therapie metastasierter maligner Melanome mit Lebermetastasen

Loss of appetite and nausea can reduce the quality of life of patients with malignant melanoma and liver metastases. Often established antiemetic drugs fail to bring relief. Tetrahydrocannabinol (THC, Marinol), which is the active agent of Indian hemp, has been used successfully in this situation for other malignant tumors. We treated 7 patients with hematogenous metastatic melanoma and liver metastases suffering from extensive loss of appetite and nausea supportively with dronabinol (Marinol. All of these patients had previously received standard antiemetic therapy without adequate relief. Dronabinol is a synthetic Delta-tetrahydrocannabinol. The drug was administered in capsule form. We evaluated the palliative effects of dronabinol with a special patient evaluation form, which was filled out at the beginning of the therapy and again after 4 weeks. The majority of patients described a significant increase in appetite and decrease in nausea. These effects remained for some weeks, but then decreased as metastases progressed and the general condition worsened. All of the patients experienced slight to moderate dizziness, but it was not sufficiently troubling to cause interruption or termination of therapy. Loss of appetite and nausea due to liver metastases of malignant melanoma can be treated in individual cases supportively with Dronabinol.

Acute and delayed nausea and emesis control in pediatric oncology patients

To the authors' knowledge there is little information available regarding the effectiveness of standard antiemetic therapy among cancer patients who receive emetogenic chemotherapy in clinical practice, especially in the pediatric population. The current study was undertaken to determine the effectiveness of standard antiemetic interventions among children receiving emetogenic chemotherapy. The authors conducted a retrospective review of antiemetic surveys for children who received emetogenic chemotherapy. Patients and/or their parents were surveyed for acute and delayed nausea and emesis after each course of emetogenic chemotherapy. The survey consisted of validated measures of the severity of nausea and emesis. Complete protection (CP) rates were calculated for each chemotherapy regimen during both the acute and delayed phases and also by gender and age group (ages birth-3 yrs, 4-11 yrs, and 12-20 yrs). Antiemetic therapy consisted of intravenous ondansetron administered once daily during chemotherapy either alone (for moderately emetogenic chemotherapy) or in combination with dexamethasone (for severely emetogenic chemotherapy). In total, 224 different patients completed 1256 surveys. CP from both acute and delayed nausea and emesis was more likely in the children ages birth-3 years than in older children. For moderately emetogenic regimens, nausea and emesis in the acute and delayed phases were controlled well. Among severely emetogenic chemotherapy regimens, 7 of 12 different regimen types had CP rates < 50% in either the acute phase or the delayed phase. CP rates were particularly low for cisplatin-based and cyclophosphamide-based regimens. Nausea and emesis remain significant problems among children who receive emetogenic chemotherapy. CP rates were associated significantly with patient age, and higher rates were observed among very young children.

Employment of Substandard Antiemetic Prophylaxis in Recent Trials of Chemotherapy-Induced Nausea and Vomiting

To determine the prevalence of substandard antiemetic therapy among recently published trials conducted in patients with cancer who received emetogenic chemotherapy. A MEDLINE search was conducted (2000-July 2004) using the key words 5-HT(3) antagonists, ondansetron, granisetron, dolasetron, tropisetron, ramosetron, palonosetron, NK-1 antagonists, and aprepitant. All antiemetic trials in patients receiving chemotherapy that were published from January 2000 to July 2004 were evaluated. Standard prophylactic antiemetic therapy was derived from contemporary antiemetic guidelines published by oncology professional organizations and expert panels. The number of patients and studies in which patients received standard and substandard antiemetic therapy was determined for both the acute and delayed phases of chemotherapy-induced nausea and vomiting (CINV). Separate determinations were made for severely and moderately emetogenic chemotherapy. The annual percentage of studies in which substandard antiemetic prophylaxis was given and the percentage of patients who received substandard prophylaxis also were determined. Fifty-six studies were reviewed, which included a total of 10 274 patients and 125 study arms. The percentage of patients who received substandard antiemetic prophylaxis was 30% (n = 3063) for acute CINV and 33% (n = 3413) for delayed CINV. The average annual percentage of studies that employed substandard prophylaxis during this time period was 54%. In recent antiemetic trials for CINV, the employment of substandard antiemetic therapy is common. These results raise important ethical questions regarding contemporary antiemetic trial design.

Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism

Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist aprepitant in addition to standard anti-emetic therapy. As aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of aprepitant in the CTC regimen are reported. Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m2/day), thiotepa (120 mg/m2/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without aprepitant. Inhibitory activity of aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes. In our patient population, the rate of autoinduction of cyclophosphamide (P=0.040) and the formation clearance of tepa (P<0.001) were reduced with 23% and 33% when aprepitant was co-administered, respectively. Exposures to the active metabolite 4-hydroxycyclophosphamide and tepa were therefore reduced (5% and 20%, respectively) in the presence of aprepitant. In human liver microsomes, the 50% inhibitory concentrations (IC50) of aprepitant for inhibition of cyclophosphamide (IC50=1.3 microg/ml) and thiotepa (IC50=0.27 microg/ml) metabolism were within the therapeutic range. Patients receiving aprepitant experienced less frequently CINV both during and after the CTC course compared with the reference population (nausea 3.7 days vs. 5.8 days, P=0.052; vomiting 0.5 days vs. 4.8 days, P<0.001). Aprepitant inhibited both cyclophosphamide and thiotepa metabolism, most probably due to inhibition of the CYP 3A4 and/or 2B6 isoenzymes. The effects of this interaction are, however, small compared to the total variability. Addition of aprepitant may provide superior protection against vomiting in patients receiving the highly emetogenic high-dose CTC chemotherapy.

Aprepitant for the control of chemotherapy induced nausea and vomiting in adolescents

Nausea and vomiting are common side effects of chemotherapy in adult and pediatric patients. Even with standard antiemetic therapy, a significant number of patients continue to experience acute and delayed symptoms. When used in combination with standard antiemetic therapy, a new class of antiemetics, the neurokinin-1 (NK-1) receptor antagonists, have been shown to improve both acute and delayed nausea and vomiting in adults. In this report, we describe the NK-1 receptor antagonist aprepitant in two adolescent patients receiving highly emetogenic chemotherapy who had experienced refractory nausea and vomiting with previous chemotherapy courses. The addition of aprepitant to the antiemetic regimen in the patients resulted in significant subjective improvement in nausea and vomiting as well as quality of life. These results in our adolescent patients are promising, but there is a need for well-designed studies to determine the efficacy, dosing, and safety of aprepitant in children of all ages.