1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions.
Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics’ (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables.
Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p < 0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p < 0.05).
Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV.
Prevention of nausea and vomiting is the main goal of antiemetic treatment in cancer patients scheduled to receive chemotherapy. To prevent acute emesis, antiemetics should be administered just before chemotherapy and patients should be protected for up to 24 hours after chemotherapy initiation. The emetogenic potential of chemotherapeutic agents guides clinicians towards the most appropriate antiemetic prophylaxis. Current guidelines recommend the use of 5-HT3 receptor antagonist (RA) either alone or in combination with dexamethasone and/or a neurokinin-1 RA both in the acute and delayed phases. The second-generation 5-HT3RA palonosetron exhibits a longer half-life and a higher binding affinity than older antagonists. Palonosetron has been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients scheduled to receive either moderately (MEC) or highly emetogenic chemotherapy (HEC) and for the prevention of delayed CINV in patients receiving MEC. The present review will discuss the role of palonosetron in the prevention of acute CINV.
antiemetics; chemotherapy; nausea; vomiting; serotonin-receptor antagonists; palonosetron
In July 2003, the Food and Drug Administration approved palonosetron hydrochloride injection for the treatment of chemotherapy-induced nausea and vomiting (CINV). The newest agent in the class of 5-HT3 receptor antagonists (5-HT3RAs), palonosetron differs from other agents in its class by its higher receptor-binding affinity and longer half-life. These pharmacological properties have resulted in improved antiemetic activity in clinical trials, particularly in the treatment of delayed CINV following moderate emetogenic chemotherapy. Based on the results of these clinical studies, palonosetron is the only 5-HT3RA approved for delayed CINV. Palonosetron is given as a single 0.25-mg intravenous dose 30 minutes before the initial dose of chemotherapy. Headache and constipation were the most common adverse events reported with palonosetron therapy.
With repeated courses of chemotherapy, chemotherapy-induced nausea and vomiting (CINV) becomes progressively more difficult to control. The aim of this study was to evaluate whether the antiemetic efficacy of the triple combination aprepitant, palonosetron and dexamethasone could be sustained for up to six cycles of highly emetogenic chemotherapy (HEC) (cisplatin ≥ 50 mg/m2).
Chemotherapy-naive patients receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v. and aprepitant 125 mg/p.o. 1 h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg/p.o. were administered on days 2–3. The primary endpoint was complete response (CR, no vomiting and no use of rescue medication), over 5 days following HEC in up to six cycles. Secondary endpoints were emesis-free and nausea-free rates. Safety was also evaluated.
One hundred and fifty six lung cancer patients were included in the study; the median age was 64 years and 76.9% were men. The minimum cisplatin dosage was 75 mg/m2, and in most patients was combined with another drug (87.4%). CR ranged from 74.4% (first cycle) to 82% (sixth cycle). More than 90% and 60% of patients were emesis-free and nausea-free during all chemotherapy cycles. The most commonly reported side effects were constipation and headache.
The triple combination of aprepitant, palonosetron and dexamethasone enhanced not only the antiemetic protection during the first cycle, but its efficacy was also sustained for up to six cycles of cisplatin-based HEC in lung cancer patients.
Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. This review provides a detailed description of palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonist. The chemistry and pharmacology of palonosetron are described, as well as the initial and recent clinical trials. Palonosetron has a longer half-life and a higher binding affinity than the first-generation 5-HT3 receptor antagonists. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. In recent studies, compared to the first-generation 5-HT3 receptor antagonists, palonosetron in combination with dexamethasone demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy. There were no clinically relevant adverse reactions reported in the palonosetron clinical trials which were different from the common reactions reported for the 5-HT3 receptor antagonist class. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical setting of multiple-day chemotherapy and bone marrow transplantation.
anti-emetics; chemotherapy-induced nausea and vomiting; serotonin receptor antagonists; palonosetron
Control of chemotherapy-induced nausea and vomiting (CINV) is a crucial factor in ensuring that patients undergoing cancer chemotherapy can get the full benefit of therapy. Current antiemetic guidelines recommend that the neurokinin-1 receptor (NK-1R) antagonist aprepitant should be used as part of a combination regimen with dexamethasone and a serotonin receptor antagonist for the prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC). Fosaprepitant is a water-soluble N-phosphoryl derivative of aprepitant that, when infused, is rapidly metabolized back to an active aprepitant. The existing literature in PubMed about fosaprepitant was screened and selected in order to address the emerging data from two randomized clinical trials evaluating the efficacy and safety of a single-dose fosaprepitant regimen. These phase III trials demonstrated that fosaprepitant given as a single intravenous dose of 150 mg was either noninferior to the conventional 3-day aprepitant or significantly superior to placebo for the prevention of acute and delayed CINV in patients receiving high-dose cisplatin. In both trials, fosaprepitant was well tolerated although more frequent infusion-site adverse events were observed with fosaprepitant. The new dosage regimen of fosaprepitant, therefore, would be an option for CINV control in patients receiving cisplatin-based chemotherapy. The clinical efficacy is consistent with the findings from a time-on-target, positron-emission tomography study evaluating the NK-1R occupancy in the central nervous system (CNS) over 5 days after a single-dose infusion of 150 mg fosaprepitant in healthy participants. The single-dose regimen is capable of blocking more than 90% of the NK-1Rs in the CNS for at least 48 hours after infusion, which is sufficient to control delayed CINV for 2 to 5 days after HEC. The new dosage regimen of fosaprepitant can provide a simplified treatment option that maintains high protection while ensuring adherence to scheduled antiemetic medication throughout most of the 5-day period encompassing the major risk for CINV.
fosaprepitant; neurokinin-1 receptor antagonist; chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect. Previous studies have primarily focused on prophylactic therapy, but no published reports have evaluated the treatment of breakthrough CINV.
A prospective, pilot study was performed to provide preliminary prospective evidence of the efficacy of individual agents prescribed for the treatment of breakthrough CINV. Enrolled patients were receiving moderately or highly emetogenic chemotherapy and prophylactic treatment of CINV based on antiemetic guidelines. Patients were prescribed an antiemetic for breakthrough CINV at the discretion of their treating oncologist. If patients had breakthrough CINV that required a breakthrough antiemetic medication, they were instructed to complete a questionnaire every 30 minutes for 4 hours after taking the antiemetic. Levels of nausea (0–10), vomiting, and side effects were recorded.
Of the 96 patients enrolled, 27 (28%) reported breakthrough nausea and/or vomiting requiring medication and completed the questionniare. Eighty-eight percent (n = 24) reported the use of prochlorperazine; they experienced a 75% median nausea reduction after 4 hours, with minimal side effects. Three patients (12%) reported the use of a 5-hydroxytryptophan (5-HT) receptor antagonist for treatment of breakthrough nausea. These patients reported a median nausea reduction of 75% after 4 hours and no perceived toxicities.
Prochlorperazine and 5-HT receptor antagonists appear to be effective breakthrough antiemetic therapies. The described study methodology can be used to conduct randomized clinical trials to find more effective drugs for treating established nausea.
Palonosetron (Aloxi®, Onicit®) is a pharmacologically unique 5-HT3 receptor antagonist (RA) approved as a single IV injection for the prevention of nausea and vomiting induced by chemotherapy (CINV) of either moderate or highly emetogenic potential (MEC and HEC, respectively). An oral palonosetron formulation has been developed and compared to the IV formulation.
In this multinational, multicenter, double-blind, double-dummy, dose-ranging trial, 651 patients were randomly assigned to receive one of the following as a single dose prior to moderately emetogenic chemotherapy: oral palonosetron 0.25, 0.50, and 0.75 mg or IV palonosetron 0.25 mg. Patients were also randomized (1:1) to receive dexamethasone 8 mg IV or matched placebo on day 1. The primary endpoint was complete response (CR; no emesis, no rescue therapy) during the acute phase (0–24 h).
Acute CR rates were 73.5, 76.3, 74.1, and 70.4 % for all patients receiving the palonosetron 0.25, 0.50, and 0.75 mg oral doses, and for IV palonosetron 0.25 mg, respectively; delayed CR (24–120 h) rates were 59.4, 62.5, 60.1, and 65.4 %, and overall CR (0–120 h) rates were 53.5, 58.8, 53.2, and 59.3 %, respectively. The addition of dexamethasone improved emetic control (acute CR rate) by at least 15 % for all groups except oral palonosetron 0.25 mg, where the acute CR improvement was approximately 7 %. Adverse events were similar in nature, incidence, and intensity for all oral and IV palonosetron groups, and were the expected adverse events for 5-HT3 RAs (primarily headache and constipation).
Oral palonosetron has a similar efficacy and safety profile as IV palonosetron 0.25 mg and may be the preferred formulation in certain clinical situations. Among the tested oral treatments, a palonosetron 0.50-mg oral dose has been favored for the prevention of CINV in patients receiving moderately emetogenic chemotherapy due to a numerical gain in efficacy without a side effect disadvantage.
Palonosetron; Chemotherapy-induced nausea and vomiting; Moderately emetogenic chemotherapy; 5-Ht3 receptor antagonist
Palonosetron (Aloxi®, Onicit®, Paloxi®) is a second-generation 5-HT3 receptor antagonist (RA) with an extended half-life of ~40 hours and high binding affinity for the 5-HT3 receptor that is markedly different from other 5-HT3 RAs. Phase III trials demonstrate that a single dose of palonosetron compared with traditional 5-HT3 RAs is more effective in preventing chemotherapy-induced nausea and vomiting (CINV) during the first 24 hours following chemotherapy (acute CINV), and also exhibits prolonged efficacy to provide significantly better protection from CINV in the delayed and overall phases. This superior and extended protection from CINV conferred by palonosetron following a single intravenous dose before chemotherapy simplifies dosing schedules. Recent research has focused on optimization of palonosetron-based antiemetic regimens, particularly in combination with steroids and neurokinin-1 RAs. The available clinical data indicate high control rates for palonosetron, suggesting a synergistic potential for protection in patients scheduled to receive emetogenic drug regimens.
palonosetron; CINV; 5-HT3 receptor antagonists; moderately emetogenic chemotherapy (MEC); highly emetogenic chemotherapy (HEC)
A phase III trial assessed the efficacy of palonosetron plus dexamethasone given once in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following a broad range of moderately emetogenic chemotherapy (MEC) regimens.
This multicentre, randomized, open-label, non-inferiority trial evaluated two different treatment groups. One group received palonosetron (0.25 mg intravenously) and dexamethasone (8 mg intravenously) before chemotherapy, while the other was administered the same regimen on day 1 followed by dexamethasone 8 mg orally on days 2 and 3. The primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medication) during the overall phase (days 1–5 after chemotherapy initiation). The non-inferiority margin was predefined as a 15% difference between groups in the primary endpoint.
Of 332 chemotherapy-naïve patients included in the intention-to-treat analysis, 65.1% were female, and 35.2% received anthracycline plus cyclophosphamide (AC)-based regimens. Overall CR rates were 67.5% for those administered dexamethasone only on day 1 (n = 166), and 71.1% for those also administered dexamethasone on days 2 and 3 (n = 166; difference −3.6% (95% confidence interval, −13.5 to 6.3)). CR rates were not significantly different between groups during the acute (0–24 h post-chemotherapy; 88.6% versus 84.3%; P = 0.262) and delayed phases (days 2–5; 68.7% versus 77.7%; P = 0.116).
Palonosetron plus single-dose dexamethasone administered before common MEC regimens provide protection against acute and delayed CINV which is non-inferior to that of palonosetron plus dexamethasone for 3 days. However, the major benefit of the single-day regimen occurs in patients receiving non-AC MEC regimens.
Palonosetron; Serotonin antagonists; Dexamethasone; Moderately emetogenic chemotherapy; Nausea; 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 (NK1) 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.
Place in therapy:
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.
aprepitant; chemotherapy; evidence; nausea; vomiting
The selective neurokinin-1 receptor antagonist aprepitant is effective in the treatment of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with both moderately and highly emetogenic chemotherapy. Fosaprepitant has been developed as an intravenous prodrug of aprepitant.
To update the evidence underlying the use of fosaprepitant to prevent CINV.
Aprepitant in combination with a serotonin antagonist and a corticosteroid controls acute and delayed symptoms of CINV in patients receiving moderately to highly emetogenic chemotherapy. Bioequivalence of fosaprepitant with aprepitant has recently been demonstrated, which has led to its inclusion in clinical guidelines for treatment of acute CINV with highly, and some regimens of moderately, emetogenic chemotherapy. Early studies of the clinical efficacy of fosaprepitant have shown improvement over treatment with ondansetron. Both aprepitant and fosaprepitant are well tolerated with most adverse events observed of mild or moderate intensity. Conflicting economic evidence has shown that whilst aprepitant provides an increased quality of life in patients treated for CINV, there are differing views over its absolute cost in relation to standard therapy. The incremental cost-effectiveness ratio of aprepitant, however, appears to lie within acceptable bounds.
Place in therapy:
Fosaprepitant and aprepitant are recommended in guidelines for preventing CINV due to moderately and highly emetogenic chemotherapy. Fosaprepitant is bioequivalent to aprepitant, and could offer potential benefits for patients who may be unable to tolerate oral administration of antiemetics during an episode of nausea or vomiting.
fosaprepitant; aprepitant; chemotherapy; nausea; vomiting
The goal of pharmacological prophylaxis of chemotherapy-induced nausea and vomiting (CINV) should be the elimination of both nausea and vomiting symptoms during all planned chemotherapy cycles. The aim of this study was to assess the efficacy of a single dose of palonosetron and dexamethasone to prevent CINV and to guarantee an adequate food intake (FI) in patients receiving several cycles of multiple day-based chemotherapy (MD-CT).
Patients with advanced cancer but without a compromised nutritional status (bone mass index ≥ 18.5) were treated with 0.25 mg palonosetron plus 20 mg dexamethasone before MD-CT. The MD-CT regimen was either epirubicin plus ifosfamide or paclitaxel plus cisplatin and ifosfamide. Nausea, vomiting, and FI were monitored in a 7-day diary. Complete response (CR: no vomiting and no rescue therapy) was the primary endpoint, while complete control (CC: CR and no more than mild nausea) and the evaluation of FI were secondary endpoints. The endpoints were evaluated during the overall timescale (0–168 h) of the chemotherapy regimen.
Fifty patients were enrolled, 80% of whom achieved CR and 78% achieved CC. During the six chemotherapy cycles, CR and CC ranged from 76% to 88% and from 62% to 88%, respectively. Moreover, patients with CR had a significantly (p < 0.0001) higher weekly food intake compared with patients not achieving CR.
This trial was the first to assess the efficacy of palonosetron and dexamethasone for the prevention of both nausea and vomiting in patients receiving multiple cycles of MD-CT. In this trial, the ability of patients to intake an adequate amount of food each week was correlated with nausea, thus providing clinicians with an objective parameter for the measurement of the effects of nausea. A single dose of palonosetron and dexamethasone was able to prevent CINV in most patients receiving 3 days of chemotherapy during all planned chemotherapy cycles.
Chemotherapy-induced nausea and vomiting (CINV); Food intake; Multiple day chemotherapy; Multiple cycles; Palonosetron
Chemotherapy-induced nausea and vomiting (CINV) are major adverse effects of cancer chemotherapy. This study investigated: (1) the impact of CINV on patients' health-related quality of life (HRQL) in daily clinical practice; (2) the association between patient characteristics and type of antiemetics and CINV; and (3) the role of CINV in physicians' decisions to modify antiemetic treatment.
Patients and methods
This prospective, multicenter study was conducted in nine general hospitals in the Netherlands. During three consecutive chemotherapy cycles, patients used a diary to record episodes of nausea, vomiting and antiemetic use. For each cycle, these ratings were made 1 day prior to and 7 days after having received chemotherapy. The influence of CINV on patients' HRQL was evaluated with the Functional Living Index-Emesis (FLIE) questionnaire at day 6 of each treatment cycle. (Changes in) antiemetic use were recorded by the treating nurse. Patient inclusion took place between May 2005 and May 2007.
Two hundred seventy-seven patients were enrolled in the study. Acute and delayed nausea during the first treatment cycle was reported by 39% and 68% of the patients, respectively. The comparable figures for acute and delayed vomiting were 12% and 23%. During the first and subsequent treatment cycle, approximately one-third of the patients indicated that CINV had a substantial impact on their daily lives. Female patients and younger patients reported significantly more CINV than male and older patients. At all treatment cycles, patients receiving treatment with moderately emetogenic chemotherapy, containing anthracycline, reported more acute nausea than patients receiving highly emetogenic chemotherapy. Acute vomiting was associated significantly with change in (i.e., additional) antiemetic treatment. Delayed CINV did not influence antiemetic treatment.
CINV continues to be a problem that adversely affects the daily lives of patients. CINV is worse in women and in younger patients. In daily clinical practice, acute CINV, but not delayed CINV, results in changes in antiemetic treatment. In view of the effects of not only acute, but also delayed CINV on daily life, more attention should be paid to adjustment of antiemetic treatment to cover CINV complaints, later during the chemotherapy cycle.
Chemotherapy-induced nausea and vomiting; Antiemetics; Symptom management
Nausea and vomiting are among the most feared complications of chemotherapy reported by patients. The objective of this study was to establish the overall complete response (CR; no emesis or use of rescue medication 0–120 h after chemotherapy) with either ondansetron- or palonosetron-containing antiemetic regimens in patients receiving highly emetogenic chemotherapy (HEC).
This was a prospective, open-label, randomized, single-center, pilot study that enrolled patients receiving their first cycle of HEC. Patients were randomized to receive either palonosetron 0.25 mg IV (PAD) or ondansetron 24 mg orally (OAD) on day 1 prior to HEC. All patients received oral aprepitant 125 mg on day 1, then 80 mg on days 2 and 3, and oral dexamethasone 12 mg on day 1, then 8 mg on days 2, 3, and 4. Descriptive statistics were used to summarize the data.
A total of 40 patients were enrolled, 20 in each arm. All patients were female, and 39 received doxorubicin/cyclophosphamide chemotherapy for breast cancer. For the primary endpoint, 65 % (95 % CI, 40.8–84.6 %) of patients in the PAD arm and 40 % (95 % CI, 19.1–63.9 %) of patients in the OAD arm achieved an overall CR.
While CR rates for aprepitant and dexamethasone plus palonosetron or ondansetron-containing regimens have been published previously, this is the first documentation of CR rates with these regimens in the same patient population. These results may be used to design a larger, adequately powered, prospective study comparing these regimens.
Ondansetron; Palonosetron; Aprepitant; Dexamethasone; Highly emetogenic chemotherapy
Nausea and vomiting remain among the most feared side effects of chemotherapy for cancer patients. Significant progress has been made in the last 15 years in developing more effective and better-tolerated measures to minimize chemotherapy-induced nausea and vomiting (CINV). During the 1990s, the selective 5-hydroxytryptamine receptor antagonists were first introduced for the treatment of CINV, and resulted in more effective and better tolerated treatment of CINV. Despite recent progress, however, a significant number of patients still develop CINV, particularly during the 2-5-day period (delayed emesis) following chemotherapy. There is evidence that this may be an underappreciated problem on the part of some caregivers. Recently, two new antiemetics, aprepitant, the first member of the neurokinin-1 antagonists, and palonosetron, a second-generation 5-hydroxytryptamine receptor antagonist, received regulatory approval in the U.S. Both represent useful additions to the therapeutic armamentarium for the management of CINV.
Antiemetics; cancer; chemotherapy; nausea; vomiting
A systematic review and meta-analysis was performed to compare treatment effectiveness and adverse effects in cancer patients receiving chemotherapy with palonosetron to prevent chemotherapy-induced nausea and vomiting (CINV). The use of palonosetron should be considered an integral part of adjuvant therapy for prevention of the acute, delayed, and overall phases of chemotherapy-induced nausea and vomiting.
We performed a systematic review and meta-analysis to compare treatment effectiveness and adverse effects in cancer patients receiving chemotherapy with palonosetron to prevent chemotherapy-induced nausea and vomiting (CINV).
We identified randomized controlled clinical trials (RCT) comparing palonosetron with first-generation 5-HT3RA in the prevention of CINV in cancer patients. Meta-analyses were performed on homogeneous studies. Fixed or random-effects models were used to combine data.
Eight eligible trials were identified, reporting outcomes on 3,592 patients. Meta-analyses showed statistically significant differences in favor of palonosetron compared with first-generation 5-HT3RA in prevention of acute CINV (p = .0003), delayed CINV (p < .00001), and overall phase of CINV (p < .00001). Subgroup analyses showed statistically significant differences in favor of both 0.25 mg and 0.75 mg of palonosetron in prevention of all phases of CINV. There were no statistically significant differences between 0.25 and 0.75 mg of palonosetron. Compared with the first-generation 5-HT3RA, 0.75 mg of palonosetron showed a statistically significant difference in the occurrence of constipation (p = .04).
The use of palonosetron should be considered an integral part of adjuvant therapy for prevention of the acute, delayed, and overall phases of CINV. The 0.25 mg intravenous palonosetron dose is as effective as the 0.75 mg intravenous palonosetron dose. However, 0.75 mg intravenous palonosetron causes constipation more frequently than the first-generation 5-HT3RA.
This study was designed to mainly evaluate the activity and safety of olanzapine compared with 5-hydroxytryptamine3(5-HT3) receptor antagonists for prevention of chemotherapy-induced nausea and vomiting(CINV) in patients receiving highly or moderately emetogenic chemotherapy (HEC or MEC). The second goal was to evaluate the impact of olanzapine on quality of life (QoL) of cancer patients during the period of chemotherapy.
229 patients receiving highly or moderately emetogenic chemotherapy were randomly assigned to the test group [olanzapine(O) 10 mg p.o. plus azasetron (A) 10 mg i.v. and dexamethasone (D) 10 mg i.v. on day 1; O 10 mg once a day on days 2-5] or the control group (A 10 mg i.v. and D 10 mg i.v. on day 1; D 10 mg i.v. once a day on days 2-5). All the patients filled the observation table of CINV once a day on days 1-5, patients were instructed to fill the EORTC QLQ-C30 QoL observation table on day 0 and day 6. The primary endpoint was the complete response (CR) (without nausea and vomiting, no rescue therapy) for the acute period (24 h postchemotherapy), delayed period (days 2-5 poschemotherapy), the whole period (days 1-5 postchemotherapy). The second endpoint was QoL during chemotherapy administration, drug safety and toxicity.
229 patients were evaluable for efficacy. Compared with control group, complete response for acute nausea and vomiting in test group had no difference (p > 0.05), complete response for delayed nausea and vomiting in patients with highly emetogenic chemotherapy respectively improved 39.21% (69.64% versus 30.43%, p < 0.05), 22.05% (78.57% versus 56.52%, p < 0.05), complete response for delayed nausea and vomiting in patients with moderately emetogenic chemotherapy respectively improved 25.01% (83.07% versus 58.06%, p < 0.05), 13.43% (89.23% versus 75.80%, p < 0.05), complete response for the whole period of nausea and vomiting in patients with highly emetogenic chemotherapy respectively improved 41.38% (69.64% versus 28.26%, p < 0.05), 22.05% (78.57% versus 56.52%, p < 0.05), complete response for the whole period of nausea and vomiting in patients with moderately emetogenic chemotherapy respectively improved 26.62% (83.07% versus 56.45%, p < 0.05), 13.43% (89.23% versus 75.80%, p < 0.05). 214 of 299 patients were evaluable for QoL. Comparing test group with control group in QoL evolution, significant differences were seen in global health status, emotional functioning, social functioning, fatigue, nausea and vomiting, insomnia and appetite loss evolution in favour of the test group (p < 0.01). Both treatments were well tolerated.
Olanzapine can improve the complete response of delayed nausea and vomiting in patients receiving the highly or moderately emetogenic chemotherapy comparing with the standard therapy of antiemesis, as well as improve the QoL of the cancer patients during chemotherapy administration. Olanzapine is a safe and efficient drug for prevention of CINV.
Chemotherapy-induced nausea and vomiting (CINV) is a common, but now often overlooked side effect of cancer treatment, and one that can be largely prevented through the implementation of international evidence-based guidelines. The European CINV Forum, comprising nurses from France, Germany, Portugal, Spain and the UK, discussed the use of CINV preventive strategies in routine practice, and the factors that affect optimal delivery of antiemetic therapies. Based on these discussions, they developed a series of recommendations for optimal, evidence-based management of CINV. These state that all patients receiving chemotherapy should undergo full assessment of their risk of CINV and receive appropriate prophylactic treatment based on guidelines from the Multinational Association of Supportive Care in Cancer (MASCC) and the National Comprehensive Cancer Network (NCCN), which were both updated in 2011. Other recommendations, aimed at raising awareness of CINV and its management, include timely updates of relevant local practice guidelines and protocols, translation of the MASCC and NCCN guidelines into all European languages and their dissemination through accessible articles in nursing journals and newsletters and via nursing conferences and study days, improved training for nurses on CINV, collaboration between the European Oncology Nursing Society and national nursing organisations to promote consistent practice, the development of a CINV toolkit, information provision for patients, local audits of CINV management, and a survey of CINV management between and within European countries.
The control of nausea and vomiting induced by chemotherapy is paramount for overall treatment success in cancer patients. Antiemetic therapy during chemotherapy in lymphoma patients generally consists of anti-serotoninergic drugs and dexamethasone. The aim of this trial was to evaluate the efficacy of a single dose of palonosetron, a second-generation serotonin type 3 (5-HT3) receptor antagonist, in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy (MEC) containing steroids.
Patients received a single intravenous bolus of palonosetron (0.25 mg) before administration of chemotherapy. Complete response (CR) defined as no vomiting and no rescue therapy during overall phase (0–120 h) was the primary endpoint. Complete control (CC) defined as CR and only mild nausea was a secondary endpoint.
Eighty-six evaluable patients entered in the study. A CR was observed in 74 patients (86.0%) during the overall phase; the CR during the acute (0–24 h) and delayed (24–120 h) phases was 90.7% and 88.4%, respectively. CC was 89.5% during the acute and 84.9% during the delayed phase; the overall CC was 82.6%.
This was the first trial, which demonstrated the efficacy of a single dose of palonosetron in control CINV in patients with aggressive non-Hodgkin’s lymphoma receiving MEC regimen containing steroids.
CHOP; CINV; Emesis; Nausea; NHL; Palonosetron
Prevention of chemotherapy-induced nausea and vomiting (CINV) remains an important goal for patients receiving chemotherapy. The objective of this study was to define, from the UK payer perspective, the cost-effectiveness of an antiemetic regimen using aprepitant, a selective neurokinin-1 receptor antagonist, for patients receiving chemotherapy for breast cancer.
A decision-analytic model was developed to compare an aprepitant regimen (aprepitant, ondansetron, and dexamethasone) with a standard UK antiemetic regimen (ondansetron, dexamethasone, and metoclopramide) for expected costs and health outcomes after single-day adjuvant chemotherapy for breast cancer. The model was populated with results from patients with breast cancer participating in a randomized trial of CINV preventative therapy for cycle 1 of single-day chemotherapy.
During 5 days after chemotherapy, 64% of patients receiving the aprepitant regimen and 47% of those receiving the UK comparator regimen had a complete response to antiemetic therapy (no emesis and no rescue antiemetic therapy). A mean of £37.11 (78%) of the cost of aprepitant was offset by reduced health care resource utilization costs. The predicted gain in quality-adjusted lifeyears (QALYs) with the aprepitant regimen was 0.0048. The incremental cost effectiveness ratio (ICER) with aprepitant, relative to the UK comparator, was £10,847/QALY, which is well below the threshold commonly accepted in the UK of £20,000–£30,000/QALY.
The results of this study suggest that aprepitant is cost-effective for preventing CINV associated with chemotherapy for patients with breast cancer in the UK health care setting.
antiemetic therapy; emesis; CINV
Chemotherapy induced nausea and vomiting (CINV) remains a major problem that seriously impairs the quality of life (QoL) in cancer patients receiving chemotherapy regimens. Complementary medicines, including homeopathy, are used by many patients with cancer, usually alongside with conventional treatment. A randomized, placebo-controlled Phase III study was conducted to evaluate the efficacy of a complex homeopathic medicine, Cocculine, in the control of CINV in non-metastatic breast cancer patients treated by standard chemotherapy regimens.
Chemotherapy-naïve patients with non-metastatic breast cancer scheduled to receive 6 cycles of chemotherapy including at least three initial cycles of FAC 50, FEC 100 or TAC were randomized to receive standard anti-emetic treatment plus either a complex homeopathic remedy (Cocculine, registered in France for treatment of nausea and travel sickness) or the matching placebo (NCT00409071 clinicaltrials.gov). The primary endpoint was nausea score measured after the 1st chemotherapy course using the FLIE questionnaire (Functional Living Index for Emesis) with 5-day recall. Secondary endpoints were: vomiting measured by the FLIE score, nausea and vomiting measured by patient self-evaluation (EVA) and investigator recording (NCI-CTC AE V3.0) and treatment compliance.
From September 2005 to January 2008, 431 patients were randomized: 214 to Cocculine (C) and 217 to placebo (P). Patient characteristics were well-balanced between the 2 arms. Overall, compliance to study treatments was excellent and similar between the 2 arms. A total of 205 patients (50.9%; 103 patients in the placebo and 102 in the homeopathy arms) had nausea FLIE scores > 6 indicative of no impact of nausea on quality of life during the 1st chemotherapy course. There was no difference between the 2 arms when primary endpoint analysis was performed by chemotherapy stratum; or in the subgroup of patients with susceptibility to nausea and vomiting before inclusion. In addition, nausea, vomiting and global emesis FLIE scores were not statistically different at any time between the two study arms. The frequencies of severe (Grade ≥ 2) nausea and vomiting were low in our study (nausea: P: 17.6% vs C: 15.7%, p=0.62; vomiting: P: 10.8% vs C: 12.0%, p=0.72 during the first course).
This double-blinded, placebo-controlled, randomised Phase III study showed that adding a complex homeopathic medicine (Cocculine) to standard anti-emetic prophylaxis does not improve the control of CINV in early breast cancer patients.
Early breast cancer; Adjuvant chemotherapy; Homeopathy; Nausea and vomiting; Quality of life
This study is aimed at determining the efficacy of Mentha spicata (M. spicata) and Mentha × piperita (M. × piperita) in preventing chemotherapy-induced nausea and vomiting (CINV).
This was a randomised, double-blind clinical trial study. Prior to the study, patients were randomly assigned into four groups to receive M. spicata or M. × piperita. Statistical analysis included the χ2 test, relative risk, and Student’s t-test. Fifty courses were analysed for each group that met our eligibility criteria. The treatment and placebo groups applied essential oils of M. spicata, M. × piperita, or a placebo, while the control group continued with their previous antiemetic regimen. Patients or guardians recorded the number of emetic events, the intensity of nausea over 20 h of chemotherapy, as well as any possible adverse effects that occurred during this time.
There was a significant reduction in the intensity and number of emetic events in the first 24 h with M. spicata and M. × piperita in both treatment groups (p < 0.05) when compared with the control and no adverse effects were reported. The cost of treatment was also reduced when essential oils were used.
M. spicata or M. × piperita essential oils are safe and effective for antiemetic treatment in patients, as well as being cost effective.
chemotherapy-induced nausea and vomiting (CINV); essential oils; Mentha spicata; Mentha × piperita; Lamiaceae
In 1983, Coates conducted a survey that ranked the side-effects perceived by patients receiving chemotherapy in the order of their severity. Vomiting and nausea were found to be the two most distressing side-effects. They have an impact on quality of life and compliance with treatment. The development of 5HT3 antagonists has been a major step forward in the prevention and treatment of chemotherapy-induced nausea and vomiting. Presently, these antiemetics are routinely used as concomitant therapy in emetogenic chemotherapy regimens. The purpose of this study was to evaluate the impact of 5HT3 antagonists on patient perceptions of the side-effects of chemotherapy. Coates' survey was replicated in patients who received 5HT3 antagonists for acute nausea and vomiting resulting from emetogenic chemotherapy. Patients received the survey to identify those physical and non-physical side-effects that they attributed to chemotherapy and were asked to rank the five most distressing side-effects. Of the 197 patients who consented to take part in the study, 181 were evaluable. Nausea, hair loss and vomiting were described as the three most distressing side-effects of chemotherapy. Eighty per cent of all the patients actually experienced nausea and 57% experienced vomiting. Hair loss appeared to be more distressing to women (P < 0.001) but, in other aspects, gender, age and marital status did not influence the ranking of the three most distressing side-effects. Constipation was ranked as 6th and was not identified as a distressing side-effect in 1983. Nausea and vomiting remain to be the first and third most distressing side-effects of chemotherapy, even though the incidence and severity of acute nausea and vomiting are now significantly reduced.
Chemotherapy-induced nausea and vomiting (CINV) are among the most feared and distressing symptoms experienced by patients with cancer. The knowledge of the pathogenesis and neuropharmacology of CINV has expanded enormously over the last decades, the most significant discoveries being the role of 5-hydroxytryptamine (5-HT)3- and neurokinin (NK)1 receptors in the emetic reflex arch. This has led to the development of two new classes of antiemetics acting as highly selective antagonists at one of these receptors. These drugs have had a huge impact in the protection from chemotherapy-induced vomiting, whereas the effect on nausea seems to be limited. The first NK1 receptor antagonist, aprepitant, became clinically available in 2003, and casopitant, the second in this class of antiemetics, has now completed phase III trials. This review delineates the properties and clinical use of casopitant in the prevention of CINV.
casopitant; GW679769; NK1 receptor antagonist; chemotherapy; emesis