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Palonosetron: an evidence-based choice
in prevention of nausea and vomiting induced
by moderately emetogenic chemotherapy
Luigi Celio, Francesco Agustoni, Isabella Testa, Katia Dotti,
and Filippo de Braud
Medical Oncology Unit 1, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
anti-emesis guidelines, CINV, moderately emetogenic chemotherapy, palonosetron.
Luigi Celio, MD, Oncologia Medica 1, Fondazione IRCCS Istituto Nazionale Tumori, Via G Venezian 1, 20133 Milan, Italy.
Received December 5, 2011;
accepted January 3, 2012.
Aims and background.
In 2003, the second-generation, 5-HT
receptor antagonist (5-HT
RA) palonosetron was approved by the FDA for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy. We reviewed the current knowledge on the role of palonosetron against acute and delayed emesis in patients with solid tumors undergoing single-day moderately emetogenic chemotherapy regimens.
A literature review in PubMed was performed to update currently available preclinical and clinical evidence on palonosetron, prioritizing randomized clinical trials.
The distinct pharmacology of palonosetron provides a rationale behind the improved efficacy observed with the drug in prevention of delayed symptoms. This may be explained by allosteric binding properties and by palonosetron-triggered receptor internalization, which result in prolonged inhibition of the 5-HT
receptor function. Very recent pharmacology experiments have also suggested that palonosetron would be able to differentially inhibit 5-HT
/neurokinin 1 (NK-1) receptor signaling cross-talk. In two recent meta-analyses, palonosetron was shown to be more effective than other available 5-HT
RAs in preventing acute and delayed nausea and vomiting for both HEC and MEC. Recent findings also suggest that a single-day regimen of palonosetron plus dexamethasone (both drugs administered intravenously) may provide a reasonable therapeutic alternative to reduce the total dexamethasone dose administered in patients undergoing moderately emetogenic chemotherapy.
On the basis of accumulating data, the evidence-based international guidelines devised from the major organizations have been recently updated to recommend the use of palonosetron plus 3-day dexamethasone for the optimal prevention of nausea and vomiting due to moderately emetogenic chemotherapy. There is still a need to investigate the efficacy of palonosetron in combination with an NK-1 receptor antagonist and dexamethasone in well-designed randomized trials.
Despite significant advancements in the management of chemotherapy-induced nausea and vomiting (CINV) in the last 20 years, these symptoms remain a significant health issue in cancer patients undergoing emetogenic chemotherapy
. CINV occur within a few hours of treatment and may continue for several days. There are frequently updated guidelines for managing CINV published by various organizations, with evidence-based recommendations developed by the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), Multinational Association for Supportive Care in Cancer (MASCC), and National Comprehensive Cancer Network (NCCN)
. In general, there is consensus among all the major guidelines on the classification of CINV into three categories: a) acute CINV which occurs in the first 24 h following chemotherapy administration; b) delayed CINV which typically describes the time period from 24 h onward and can persist as long as 5 days; and c) anticipatory emesis, where CINV occurs before chemotherapy in patients with poorly controlled emesis from previous cycles of chemotherapy
. Although patients can experience nausea and vomiting for longer than 5 days postchemotherapy, most prevention studies have assessed “overall response” during the 5 days after treatment to ensure capture of the efficacy in controlling both acute and delayed CINV.
A number of neurotransmitters have been established as important mediators of CINV, including dopamine, serotonin, and substance P (SP)
. However, there is no single neurotransmitter responsible for all forms of CINV, and no single clinically available antagonist to these neurotransmitter receptors is able to provide complete protection against all forms of CINV. Recent clinical data show that inadequate antiemetic prophylaxis may be at least partly attributable to physicians and nurses underestimating the impact of delayed CINV on patients
. It is important to differentiate between the management of acute or delayed CINV to achieve an optimal prevention of distressing symptoms
. In a recently reported multicenter, prospective, observational study of 151 patients who were scheduled for the first cycle of a new chemotherapy regimen, delayed CINV occurred more frequently than acute CINV (59%
36%), although many patients experienced both types
. Therefore, the effective management of CINV remains a challenging task for oncologists and oncology nurses.
The individual patient risk for CINV is largely influenced by the type of chemotherapy administered and specific patient characteristics. Patient-related risk factors for CINV include age under 50 years, female gender, history of low chronic alcohol consumption, history of motion sickness, history of emesis during pregnancy, and previous experience with chemotherapy
. Optimal prevention for CINV depends on recognition of the intrinsic emetogenicity (based on dose, route, schedule and rate of administration) of a chemotherapeutic agent as well as an understanding of its potential to induce acute or delayed symptoms
. However, combination chemotherapy regimens often increase the potential to induce CINV compared to most individual agents
. The major international organizations producing anti-emesis guidelines have accepted that intravenous chemotherapeutic agents are grouped into four emetic risk categories: high (>90% of patients will experience acute CINV without prophylaxis), moderate (30-90% of patients will experience acute CINV without prophylaxis), low (10-30% of patients will experience acute CINV without prophylaxis), and minimal (<10% of patients will experience acute CINV without prophylaxis)
. A list of the chemotherapeutic agents defined as moderately emetogenic in accordance with the updated guidelines published by ASCO and MASCC/ESMO is shown in Table 1. A limitation to the classification of chemotherapeutic agents based on the risk of acute emesis is that it may underestimate the potential for delayed emesis resulting from certain agents. Despite this limitation, this risk classification is one of the most important tools to guide physicians to consider the need for anti-emetics and the type of anti-emetic treatment. CINV prevention is a goal shared among all of the major guidelines, as it is generally easier to prevent CINV than to treat it once it has occurred
. Since patients who experience emesis have an increased risk of developing CINV in subsequent chemotherapy cycles, there is the need to aggressively prevent CINV
The anti-emetics considered to be most active for the management of CINV are the 5-HT
receptor antagonists (5-HT
RA), neurokinin 1 (NK-1) receptor antagonists (NK-1 RA), and corticosteroids, the latter now representing a mainstay of anti-emetic regimens for prevention of CINV
. Development of the first-generation antagonists, such as ondansetron, granisetron, dolasetron, and tropisetron, dramatically improved the management of CINV in the early 1990s. Meta-analyses of multiple randomized trials demonstrated that such agents are largely therapeutically equivalent and are effective in preventing acute emesis, but are generally less effective for controlling delayed emesis
. In 2003, the second-generation 5-HT
RA palonosetron (Aloxi
, Helsinn Healthcare SA, Lugano, Switzerland) was approved by the Food and Drug Administration for the prevention of acute nausea and vomiting associated with initial and repeated courses of highly and moderately emetogenic chemotherapy (HEC and MEC) and for the prevention of delayed nausea and vomiting associated with initial and repeated courses of MEC
The present paper focuses on currently available preclinical and clinical evidence supporting the role of palonosetron as the recommended 5-HT
RA for the prevention of CINV due to single-day MEC regimens in patients with solid tumors.
Palonosetron: more than a new member
in the setron class
Palonosetron hydrochloride is based on a fused tricyclic ring system bound to a quinuclidine moiety, unique and different from those of first-generation antagonists, which are based on a 3-substituted indole structure resembling the structure of the endogenous ligand serotonin
. Palonosetron has a binding affinity for the 5-HT
receptor that is at least 30-fold higher than older 5-HT
. The plasma half-life of palonosetron is about 40 h, markedly longer than the half-life of other antagonists which ranges from 5 to 12 h
. However, the differences in half-life and affinity alone are unlikely to explain the improved clinical results of palonosetron. Therefore, additional pharmacology experiments have been performed to demonstrate whether or not the unique structural characteristics of palonosetron could enable molecular interactions with the 5-HT
receptor distinct from those of older antagonists. Recent results indicate that palonosetron exhibits both competitive and allosteric interactions with the 5-HT
receptor, in contrast to the first-generation antagonists ondansetron and granisetron, which display strictly competitive antagonism
. Ondansetron and granisetron compete directly with serotonin for the same binding site on the 5-HT
receptor as the endogenous ligand which is released from the receptor upon binding of the antagonist. In contrast to the simple bimolecular competitive binding of ondansetron or granisetron, palonosetron binds to an allosteric site in addition to the serotonin binding site, blocking access of the endogenous ligand. Structural studies have also indicated that palonosetron exhibits positive cooperativity, because the binding of the antagonist causes a conformational change in the receptor, which in turn enhances the likelihood of binding for further palonosetron molecules
. The high affinity, allosteric and positively cooperative binding properties of palonosetron make it a much more efficient antagonist, since an allosteric antagonist is harder to displace by the endogenous ligand and stays longer on the receptor. Subsequent experimental studies have showed that palonosetron’s differential binding triggers internalization of cell surface 5-HT
-receptor sites and induces prolonged inhibition of receptor function that outlasts the presence of the drug on the receptor
Accumulating evidence suggests that SP, the endogenous ligand acting on the NK-1 receptor, is the dominant mediator of delayed emesis
. Although palonosetron has shown efficacy against both acute and delayed CINV, it does not bind to NK-1 receptors
. Recent reports have shown that there is receptor cross-talk, defined as activation of one receptor by its ligand affecting cellular responses to another receptor system, between 5-HT
receptor signaling pathways
. Very recent experiments have evaluated the effect of palonosetron, ondansetron, and granisetron on responses induced by SP in preclinical models
. In a cell line expressing both 5-HT
and NK-1 receptors, exposure to palonosetron uniquely inhibited the serotonin-induced activation of the SP response even after the drug was completely removed from the media. In contrast, no inhibition of receptor signaling cross-talk was observed when cells were pre-incubated with ondansetron or granisetron. The
results were also confirmed
, since palonosetron, but not ondansetron or granisetron, could uniquely inhibit the cisplatin-induced neuronal response to SP in rats. Therefore, palonosetron would be able to differentially inhibit 5-HT
/NK-1 receptor signaling cross-talk. These findings are likely due to palonosetron-triggered 5HT
receptor internalization, which would provide more persistent receptor functional inhibition than simple binding followed by dissociation at the receptor on the cell surface, as occurs with the first-generation tested antagonists. Figure 1 shows how palonosetron differentially interacts with the 5-HT
receptor and inhibits 5-HT
/NK-1 receptor signaling cross-talk.
Overview of palonosetron in the prevention
Three registration phase III trials were conducted to compare palonosetron to older 5-HT
RA. All three randomized studies defined the primary end point as complete response (CR, defined as no vomiting and no need for rescue anti-emetics) in the acute phase. Two trials with an identical non-inferiority design using MEC compared a single intravenous dose of palonosetron (0.25 mg or 0.75 mg) with a single intravenous dose of ondansetron (32 mg) or dolasetron (100 mg), all given immediately prior to chemotherapy on day 1
. These trials revealed that, compared with ondansetron and dolasetron, palonosetron (0.25 mg) was associated with significantly higher rates of CR in the acute (palonosetron
= 0.008; palonosetron
= 0.049), delayed (palonosetron
= 0.004), and overall (palonosetron
= 0.021) time periods. In addition, studies in patients undergoing MEC showed that the 0.25-mg dose of palonosetron (the approved dose) is as effective as the 0.75-mg dose. The third phase III trial comparing a single intravenous dose of palonosetron (0.25 or 0.75 mg) to ondansetron in the prevention of CINV following HEC found no statistically significant difference between the treatment groups, regardless of the palonosetron dose administered, during all time periods
. However, most patients (67%) also received concomitant dexamethasone on day 1, and significantly higher CR rates were observed among patients treated with palonosetron (0.25 mg) plus dexamethasone than in those treated with ondansetron plus dexamethasone during the delayed and overall time periods (42%
= 0.021 and 41%
= 0.005, respectively). The registration trials were criticized because: 1) they were designed as non-inferiority studies; and 2) the studies were carried out without the use of concomitant corticosteroids as recommended by the international guidelines
. Such limitations have, until recently, led to much controversy on the superiority of palonosetron over ondansetron and dolasetron. A recently published meta-analysis of five randomized controlled trials (2,057 patients) comparing palonosetron to ondansetron, dolasetron or granisetron in patients receiving MEC or HEC demonstrated that patients receiving palonosetron experienced significantly less nausea and vomiting during the acute (nausea, relative risk [RR] = 0.86,
= 0.007; vomiting, RR = 0.76,
= 0.0002) and delayed (nausea, RR = 0.82,
<0.00001; vomiting, RR = 0.76,
<0.00001) time periods
. Since concomitant dexamethasone was effectively used in only one of the included studies
, the superiority of palonosetron over other 5-HT
RA when used in combination with dexamethasone remained to be established in appropriately designed randomized trials.
A Japanese, registration phase III trial assessed the efficacy of single-dose palonosetron (0.75 mg) in combination with dexamethasone (n = 555) compared with single-dose intravenous granisetron (40 ?g/kg) plus dexamethasone (n = 559) in patients receiving either cisplatin ?50 mg/m
(n = 639) or anthracycline and cyclophosphamide (AC)-containing chemotherapy (n = 475)
. Concomitant dexamethasone was administered as a 16-mg intravenous dose on day 1 followed by either 8 mg intravenously (for cisplatin) or 4 mg orally (for AC) on days 2 and 3. The primary end points were to demonstrate non-inferiority of palonosetron in the acute phase and superiority in the delayed phase to granisetron. The CR rate during the acute phase was similar in both treatment groups (75%
73%, in the palonosetron and granisetron groups, respectively), whereas the proportion of patients with a CR was significantly higher in the palonosetron group than in the granisetron group during the delayed (57%
<0.0001) and overall (52%
= 0.0001) time periods. In addition, improved CR rates for palonosetron were also observed in the subgroups of patients receiving either cisplatin or AC-containing chemotherapy as well as the subgroups for age and gender. However, these conclusions have been questioned because of potentially inadequate dosing in the control arm and the use of a larger (non-approved) dose of palonosetron. Before this phase III trial, two phase II studies (n = 231 for HEC, n = 204 for MEC) in Japan showed a tendency toward better efficacy with the 0.75-mg dose than with 0.25-mg and 0.075-mg doses of palonosetron
. This finding in association with the excellent safety profile of all doses suggested that 0.75-mg palonosetron could be the recommended dose for use in the phase III trial in Japan. However, a very recent meta-analysis including eight randomized controlled trials (3,592 patients) showed that both doses of palonosetron were more effective than other available 5-HT
RA, and that there were no statistically significant differences between the 0.25-mg and 0.75-mg doses in preventing acute, delayed, and overall CINV. Only the 0.75-mg dose caused significantly more constipation than older antagonists (
. In addition, the results of subgroup analyses of trials comparing palonosetron with older 5-HT
RA confirmed that palonosetron was significantly more effective in preventing CINV for both MEC and HEC during acute, delayed and overall time periods
Only a few phase II non-comparative trials have evaluated the efficacy of palonosetron in combination with dexamethasone in controlling CINV following MEC. The study by Hajdenberg
was conducted on 32 patients who had a mean age of 65 years, and most of them were women (62.5%). All patients received palonosetron and dexamethasone (8 mg intravenously) only on day 1 before chemotherapy initiation. In order to provide a framework for interpretation of the results, the analysis of pooled data from two pivotal trials using palonosetron (0.25 mg) alone in a similar population (n = 378) receiving MEC was also presented in the report. The addition of a single dose of dexamethasone resulted in 84% acute CR and in 59% delayed CR, compared with 72% and 64%, respectively, reported for the historic population.
An Italian, multicenter, phase II trial evaluated whether the single-day regimen of palonosetron plus dexamethasone (8 mg intravenously) was able to effectively control acute and delayed CINV in chemo-naïve patients with colon cancer who received the FOLFOX-4 (fluorouracil, folinic acid, and oxaliplatin) regimen as an adjuvant
. The primary end point of the study was the CR rate during the overall time period. The median age of the study cohort was 67 years; most of the patients were men (66%). For the first course of chemotherapy, a CR occurred in 96% of patients during the overall time period.
A very recently published phase II trial assessed the efficacy of single-dose palonosetron and dexamethasone in chemo-naïve patients receiving MEC
. The mean age for the study cohort was 61 years, and most of the patients were women (79%). The primary end point of the study was the CR rate during the overall time period. Most of the patients (59%) were treated with AC-containing chemotherapy for breast cancer, whereas 28 (41%) patients received either a FOLFOX or FOLFIRI (fluorouracil, folinic acid, and irinotecan) regimen for colorectal cancer. In breast cancer patients, CR occurred in 55%, 65%, and 68% of patients during the overall, acute, and delayed time periods, respectively. In colorectal cancer patients, CR occurred in 79%, 89%, and 86% of patients during the overall, acute, and delayed time periods, respectively.
In these phase II MEC trials, no additional dexamethasone doses were administered on days 2 and 3 for the prevention of delayed CINV, as recommended by international guidelines
. However, a recent phase III trial demonstrated that palonosetron plus single-dose dexamethasone administered before a wide range of MEC regimens provided protection against CINV that was not inferior to that of palonosetron plus conventional 3-day dexamethasone
. The finding is consistent with the results reported by Aapro
, who demonstrated, in a similar phase III trial, the non-inferiority of palonosetron plus 1-day dexamethasone
3-day dexamethasone in chemotherapy-naïve women receiving AC-containing chemotherapy for breast cancer. Overall, such results suggest that tailoring dexamethasone dosing to reduce exposure in patients treated with palonosetron on day 1 is not associated with a clinically significant loss in anti-emetic protection during the 5-day observation period. The results of the two phase III studies evaluating the dexamethasone-sparing approach are shown in Table 2.
Palonosetron in MEC: international guidelines
Most patients with solid tumors undergo chemotherapy regimens that most frequently are administered intravenously over the course of a single day. In this chemotherapy setting, clinical data from prospective, controlled trials on the use of anti-emetics are also most abundant. There is consensus among anti-emesis guidelines devised from major organizations on a combination of a 5-HT
RA plus dexamethasone to optimally prevent CINV caused by intravenous chemotherapy agents with a moderate risk of emetogenicity
. The only exception is the AC combination, which is frequently used to treat a large group of cancer patients, most typically women with breast cancer. Women receiving the AC combination represent a situation with a particularly high emetic potential
. In light of this, ASCO and NCCN guidelines have reclassified the AC combination as highly emetogenic, whereas MASCC/ESMO guidelines still label the regimen as having a moderate risk of emetogenicity
. However, MASCC/ESMO guidelines separate the AC combination from other MEC. The updated guidelines recently published from ASCO and MASCC/ESMO recommend palonosetron (day 1 only) and dexamethasone (days 1 through 3) for the prevention of CINV in patients undergoing MEC (Table 3). The preference for palonosetron is an extrapolation from the improved results observed in the study of Saito
, who evaluated the efficacy of palonosetron plus multiple-day dexamethasone in the high-risk setting of either cisplatin or AC-containing chemotherapy. By inference, palonosetron and dexamethasone are likely to be superior to an older 5-HT
RA and dexamethasone in the MEC setting. Since a recent meta-analysis showed that palonosetron is more effective than other available antagonists against acute and delayed CINV following both HEC and MEC regimens
, NCCN guidelines recommend palonosetron as the preferred 5-HT
RA in the setting of both HEC and MEC
. All the major organizations recommend a three-drug combination including a 5-HT
RA, dexamethasone, and an NK-1 RA for the prevention of CINV following the AC combination. However, if an NK-1 RA is not available, the MASCC/ESMO guidelines recommend that women undergoing AC-containing chemotherapy should receive a combination of palonosetron plus dexamethasone
Conclusions and future perspectives
The distinct pharmacology of palonosetron provides a rationale behind the improved efficacy observed with the drug in the prevention of delayed CINV in clinical studies. This may be explained by allosteric binding properties and by palonosetron-triggered receptor internalization, which result in prolonged inhibition of receptor function. In addition, palonosetron would be able to differentially inhibit 5-HT
/NK-1 receptor signaling cross-talk. On the basis of accumulating data, the anti-emesis clinical guidelines devised from ASCO and MASCC/ESMO have been recently updated to recommend the use of palonosetron plus 3-day dexamethasone for the optimal prevention of CINV due to MEC, whereas the NCCN panel also recommends palonosetron as the preferred 5-HT
RA in this setting. However, the use of dexamethasone in clinical practice may remain limited because of concerns about potential side effects
. Recent findings suggest that a single-day regimen of palonosetron and dexamethasone may provide a reasonable therapeutic alternative to reduce the total dexamethasone dose administered in patients undergoing MEC.
Additional investigations to validate the dexamethasone-sparing approach are warranted also considering a potential treatment simplification strategy to administer all anti-emetic prophylaxis just on day 1. An interesting preliminary finding from a small phase II study indicated that a three-drug regimen of palonosetron, dexamethasone and the NK-1 RA aprepitant, all administered before chemotherapy, was able to achieve a high protection rate against acute and delayed CINV in patients receiving MEC
. Therefore, this convenient three-drug regimen should be formally compared to the conventional 3-day regimen in a randomized, double-blind, phase III trial. From an evidence-based point of view, a more frequent use of palonosetron in the clinical setting might be prevented from the lack of data from prospective randomized trials comparing palonosetron
other available antagonists when used in combination with a NK-1 RA and dexamethasone in accordance with the latest anti-emesis guidelines.
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ISSN online: 2038-2529