Recent advances in antiemetics: new formulations of 5HT3-receptor antagonists.

Plain-language summary

This review article discusses different treatments that are used to prevent nausea and vomiting (NV) experienced by people with cancer who are being treated with chemotherapy: chemotherapy-induced NV (CINV). The article is about chemotherapy treatments that are the most likely to cause NV in people with cancer, called moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC). Guidelines from major medical organizations on how to prevent CINV are compared, and the problems in preventing CINV are discussed. Different types of drugs used to treat CINV and different combinations of these drugs are described. Even though several types of drugs are available to prevent CINV, many patients with cancer still suffer from NV. The advantages and disadvantages of drugs used to treat CINV are explained, and information about recently approved new drugs and new forms of existing drugs is provided. The article mainly describes a class of drugs called 5HT 3 -receptor antagonists, which are often used to prevent nausea and vomiting. New drugs and new combinations of drugs may help control CINV in people with cancer who are treated with chemotherapy.

Introduction

Chemotherapy-induced nausea and vomiting (CINV) adversely affects patient health, 1 , 2 quality of life, 3 , 4 and chemotherapy compliance, 5 and is one of the most dreaded effects of chemotherapy. 6 This review focuses on current approaches and future directions involving 5-hydroxytryptamine type 3 (5HT 3 )-receptor antagonists (RAs) for the management of CINV. Use of 5HT 3 RAs in the prevention of radiotherapy-induced and chemoradiation-induced NV is discussed briefly.

Chemotherapeutics differ in their emetogenicity. In the absence of antiemetic prophylaxis, agents associated with >90% risk of emesis are classified as highly emetogenic chemotherapy (HEC) and those associated with 30%–90% risk of emesis classified as moderately emetogenic chemotherapy (MEC). 7 – 9 Several oral targeted anticancer therapies, such as crizotinib, lenvatinib, olaparib, and panobinostat, are also recognized as being highly or moderately emetogenic. 7 The emetogenicity of combination regimens is determined by identifying the most emetogenic agent in the combination, then assessing the relative contribution of the other agents. 7 , 8 This review discusses treatment options for the prevention of CINV associated with MEC and HEC, as these are the most challenging settings; it does not discuss management of CINV associated with agents that have low-to-minimal emetogenicity.

In clinical trials, measurement of antiemetic efficacy covers a range of end points, involving emesis, nausea, and assessments of rescue medication use for breakthrough CINV (ie, CINV occurring despite the use of prophylactic anti-emetics). A commonly used end point is complete response (CR; no emesis and no rescue medication use) during the acute phase (first 24 hours), delayed phase (>24–120 hours), and overall phase (0–120 hours) following chemotherapy administration. End points that also specifically involve nausea include complete control (CC; CR and only mild nausea), total response (CR and no nausea), and no nausea or no significant nausea (typically measured as <25 mm on a 100 mm visual analogue scale).

Despite considerable advances in antiemetics over the past 20 years, beginning with the introduction of the 5HT 3 RAs, prevention of CINV remains suboptimal. For example, one study in a community hospital setting found that chemotherapy-induced nausea and vomiting was reported in approximately 50% and up to a quarter of patients, respectively, despite antiemetic prophylaxis. 10 Delayed CINV seems to be less well managed than acute CINV. In a US prospective study, 34% of patients reported experiencing acute CINV, whereas 58% of patients reported experiencing delayed CINV. 4 Both nausea and emesis appear to be more prevalent during the delayed phase than in the acute phase of CINV. 1 Lack of adequate CINV control has multiple adverse consequences. The negative effects of CINV on patient health and quality of life are well known, including reducing patient daily functioning, increasing patient anxiety and depression, and decreasing the patient’s chemotherapy treatment adherence, leading to chemotherapy reductions or delays. 1 , 3 , 5 , 10 – 12 In addition, the costs of poorly controlled CINV are considerable. Analysis of data from 2018 working-age patients in a large US employment database with information from 45 large employers and more than 100 health-insurance payers (1997–2002) found that 28% of patients had uncontrolled CINV, and the associated monthly medical costs for these patients were approximately US$1,300 higher and indirect costs US$433 higher than for patients whose CINV was well controlled. 13 Using another database of more than 19,000 patients, 14% of patients had a CINV-associated hospital visit (inpatient, outpatient, or emergency room), and the mean cost per visit was US$4,043. 14 Therefore, prevention of CINV, especially delayed CINV, is critical in patients receiving chemotherapy, for both economic reasons and patient welfare.

Most 5HT 3 -RA trials have focused on emesis control, using CR as a primary end point and nausea-control measures as secondary end points. Although emesis control has improved using new classes of antiemetics, the management of nausea, particularly in the delayed phase following HEC, is difficult. However, recent clinical trial focus has turned toward nausea control and the use of different classes of agents to prevent nausea. In a recent Phase III placebo-controlled trial of the antipsychotic olanzapine plus a three-drug antiemetic regimen (a neurokinin 1 [NK 1 ] RA plus a 5HT 3 RA plus dexamethasone) in patients receiving HEC, nausea prevention was the primary end point. The proportion of patients with no nausea was significantly higher with the addition of olanzapine across acute, delayed, and overall phases of CINV. 15

Granisetron (Kytril; Roche Laboratories Inc., Nutley, NJ, USA [oral] and Genentech, San Francisco, CA, USA [intravenous]), ondansetron (Zofran; GlaxoSmithKline, Research Triangle, NC, USA), and palonosetron (Aloxi; Eisai, Woodcliff Lake, NJ, USA), are the most commonly used 5HT 3 RAs and the focus of this review. Dolasetron IV (Anzemet; Sanofi-Aventis, Bridgewater, NJ, USA) is no longer approved in the USA to prevent CINV, because of potential cardiac effects. Other first-generation 5HT 3 RAs include azasetron, ramosetron, and tropisetron; however, they are not commercially available in the USA. 11 , 16 This review discusses new therapeutic strategies involving 5HT 3 RAs to improve management of delayed CINV following HEC and challenges associated with nausea prevention.

Antiemetic-guideline recommendations

The goal of CINV prophylaxis is to prevent NV following MEC or HEC across both acute and delayed phases. Because CINV is multifactorial, antiemetic prophylaxis often involves agents targeting neurotransmitters with complementary mechanisms of action, such as 5HT 3 RAs, NK 1 RAs, and the atypical antipsychotic olanzapine. Several antiemesis guidelines for clinical practice are available, based on clinical evidence and expert consensus, from the National Comprehensive Cancer Network (NCCN), 7 Multinational Association for Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO), 17 , 18 and American Society of Clinical Oncology (ASCO; Table 1 7 , 17 – 19 ). 19

However, despite the availability of comprehensive CINV-prevention guidelines and a wide range of antiemetics, guideline adherence remains low. The INSPIRE study, involving 1,295 patients from US community practices, found that guideline-consistent CINV prophylaxis was administered in only 57% of patients. 20 Corticosteroids were commonly omitted in the delayed phase in patients receiving HEC, as were NK 1 RAs on day 1 in patients receiving MEC regimens, although NK 1 RAs are not uniformly recommended with MEC in antiemetic guidelines. 7 , 17 – 20 Data from the Pan European Emesis Registry of 991 patients found that guideline-consistent CINV prophylaxis during single-day chemotherapy was administered in only 55% of patients in the acute phase and 46% of patients in the delayed phase, and that guideline-consistent CINV prophylaxis significantly reduced the incidence of CINV compared with guideline-inconsistent prophylaxis. 21 More recently, in a retrospective analysis of a US claims database, of 1,059 patients receiving MEC or HEC, those who were given a guideline-recommended three-drug antiemetic regimen of an NK 1 RA plus a 5HT 3 RA plus dexamethasone had fewer CINV-related emergency-department visits (9%) than patients receiving a two-drug regimen of a 5HT 3 RA plus dexamethasone (15%) and had fewer CINV-related hospitalizations (4% vs 6%, respectively). 22 Poor patient adherence to antiemetic regimens, especially to prescribed oral antiemetics, may also be a barrier to effective CINV control, as reported in a multinational survey of 2,388 health-care providers. 5 Clearly, patients experiencing NV may be reluctant to take oral medications, even if they are prescribed to control CINV, and many patients undergoing chemotherapy have oral mucositis, which reduces their ability to swallow. 23

Highly emetogenic chemotherapy

For the prevention of CINV associated with single-day HEC, the NCCN and MASCC/ESMO guidelines are in agreement in recommending a three-drug regimen of a 5HT 3 RA plus an NK 1 RA plus a steroid (typically dexamethasone) on day 1 of chemotherapy, followed by dexamethasone on the subsequent 2 or 3 days, with an oral NK 1 RA on days 2 and 3 only if an oral NK 1 RA is given on day 1 ( Table 1 ). The 2017 ASCO and 2018 NCCN guidelines recommend a four-drug regimen that incorporates olanzapine on day 1, in addition to the three-drug regimen just mentioned above, followed by dexamethasone on days 2 and 3, and an oral NK 1 RA on days 2 and 3 only if an oral NK 1 RA is given on day 1; this is also an option in the NCCN guidelines. 7 , 19 The NCCN also recommends olanzapine plus palonosetron and dexamethasone as an alternative option on day 1, 7 and MASCC/ESMO guidelines recommend olanzapine plus a 5HT 3 RA plus dexamethasone for nausea control, but give a low-grade recommendation for this regimen. 7 , 17

Since 2011, the high emetogenicity of the combination of an anthracycline and cyclophosphamide (AC) has been recognized by the NCCN, ASCO, and MASCC/ESMO. AC-based regimens were reclassified from MEC to HEC in the ASCO antiemesis guidelines, and AC-based chemotherapy for patients with breast cancer has a distinct recommendation for CINV prevention within the HEC category in the MASCC/ESMO guidelines. 7 , 17 , 19 Consequently, the ASCO-recommended antiemetic regimen for AC-based regimens is now the same as that recommended by NCCN guidelines for any HEC regimen: primarily a four-drug combination of a 5HT 3 RA, dexamethasone, an NK 1 RA, and olanzapine on day 1, with olanzapine on days 2–4 and dexamethasone on days 2–4 depending on the NK 1 RA administered on day 1. 7 , 19 The MASCC/ESMO guidelines recommend the three-drug regimen for AC-based chemotherapy on day 1 for acute CINV, with aprepitant (if aprepitant was given on day 1) or dexamethasone on days 2 and 3 to prevent delayed CINV. However, if any NK 1 RA was given other than aprepitant on day 1, MASCC/ESMO guidelines state that no other treatment is necessary on subsequent days. 17

Carboplatin

Although carboplatin is classified as moderately emetogenic in MASCC/ESMO and ASCO guidelines, 17 – 19 NCCN guidelines note that carboplatin may be highly emetogenic in some patients, depending on dose (ie, if the carboplatin area under the concentration–time curve [AUC] is ≥4 mg/mL/min), and ASCO recommends an adjusted antiemetic regimen for patients receiving carboplatin with an area under the curve ≥4 mg/mL/min. 7 , 19 For patients receiving carboplatin, MASCC/ESMO guidelines recommend a three-drug antiemetic regimen of a 5HT 3 RA plus an NK 1 RA plus dexamethasone, similar to the regimen recommended for patients receiving HEC, with aprepitant on days 2 and 3 if given on day 1. 17 In a retrospective analysis of 1,059 patients in a US claims database, 73% of those treated with AC (classified as HEC) and 56% treated with cisplatin (HEC) received an antiemetic regimen containing an NK 1 RA compared with 23% treated with carboplatin. However, health-care-resource utilization (eg, emergency-room visits, hospitalization) was lower in patients whose antiemetic regimen included an NK 1 RA, suggesting that a three-drug antiemetic regimen may be more effective in preventing CINV in patients receiving carboplatin. 22

Moderately emetogenic chemotherapy

For the prevention of CINV associated with single-day MEC, all three guidelines are in agreement in recommending a two-drug regimen of a 5HT 3 RA plus dexamethasone on day 1 and dexamethasone on days 2 and 3 (with some exceptions), although ASCO and MASCC/ESMO guidelines have separate recommendations for patients receiving carboplatin ( Table 1 ). 7 , 17 – 19 The NCCN guidelines also recommend this two-drug regimen plus an NK 1 RA on day 1 or a three-drug combination of olanzapine, palonosetron, and dexamethasone on day 1. 7 If the 5HT 3 RA palonosetron, extended-release (ER) granisetron transdermal delivery system (GTDS; Sancuso, ProStrakan, Bridgewater, NJ, USA), or granisetron ER subcutaneous (GERSC; Sustol, Heron Therapeutics, Redwood City, CA, USA) is given on day 1 with dexamethasone, NCCN guidelines state that no further antiemetic therapy is necessary on days 2 and 3. 7 Details of recommended prophylaxis on days 2 and 3 by all guidelines are shown in Table 1 . For MEC, NCCN guidelines list palonosetron and GERSC as preferred 5HT 3 RAs in the absence of an NK 1 RA. 7

Multiday chemotherapy

For multiday chemotherapy, treatment guidelines are less definitive, in part because there is a lack of evidence to support recommendations in this setting. ASCO guidelines suggest using an antiemetic agent appropriate for the emetogenic risk of the chemotherapeutic agent administered on each day and for 2 days after completion of the chemotherapy regimen, and suggest that the ER agents GTDS or GERSC may be preferable to a daily 5HT 3 RA. For patients receiving multiday cisplatin regimens, the three-drug combination of an NK 1 RA, 5HT 3 RA, and dexamethasone is recommended. 19 The NCCN guidelines propose taking several factors into account when determining the appropriate antiemetic regimen, including route of administration, duration of action, and dosage regimen of the antiemetic(s); administration in an inpatient or outpatient setting; patient adherence to a regimen; and individual patient risk factors. Several general principles are proposed for each type of antiemetic agent. A 5HT 3 RA should be used before each dose of MEC or HEC, and the need for subsequent doses should be based on the antiemetic agent and route of administration. Dexamethasone is recommended for each day of chemotherapy, continuing for 2–3 days afterward for HEC or MEC regimens known to have a higher risk of causing delayed emesis, but dexamethasone administration only on day 1 is an option for patients receiving MEC or noncisplatin HEC who have few CINV risk factors. An NK 1 RA may be used with MEC or HEC regimens that have a significant risk of causing delayed CINV, but there are limited data on the use of NK 1 RAs over multiple days. 7 The most recent updates to the MASCC/ESMO guidelines do not offer specific recommendations for antiemetics to prevent CINV associated with multiday HEC or MEC chemotherapy. 17 , 18

Breakthrough CINV

For breakthrough CINV (ie, CINV occurring despite the use of guideline-recommended prophylactic antiemetics), ASCO and NCCN guidelines suggest adding an antiemetic agent with a different mechanism of action to that of the antiemetic(s) used during the previous chemotherapy cycle. Olanzapine may be added if it was not part of the initial antiemetic regimen, and other dopamine antagonists (eg, metoclopramide, phenothiazines) may also be considered. 7 , 19 Multiple concurrent antiemetics may be required and administered continuously, rather than as needed. If a combination of a 5HT 3 RA and dexamethasone with or without an NK 1 RA has previously been used, other options of different classes include olanzapine, benzodiazepine, or metoclopramide. 7 , 19 The use of 5HT 3 RAs in the breakthrough setting is based on their efficacy as prophylactic antiemetics, as there are no published data from prospective Phase III clinical trials on the use of 5HT 3 RAs to treat breakthrough CINV. The most recent updates to the MASCC/ESMO guidelines have no specific recommendations for the prevention of breakthrough CINV associated with HEC or MEC. 17 , 18

Benefits and limitations of 5HT 3 -RA formulations

The introduction of 5HT 3 RAs dramatically improved the prevention of CINV, particularly in the acute phase. 24 Granisetron is a potent and highly selective 5HT 3 RA with little or no affinity for other serotonin receptors or for dopaminergic, adrenergic, benzodiazepine, histaminic, or opioid receptors. 25 In contrast, in addition to binding with 5HT 3 receptors, ondansetron binds with low affinity to 5HT 1B , 5HT 1C , α 1 -adrenergic, and µ-opioid receptors. 26 Ondansetron is available for intravenous (IV) or oral administration only, whereas granisetron is available in a wide range of formulations ( Table 2 25 , 27 – 37 ). Dolasetron is only available in the oral formulation in the USA for CINV prevention ( Table 2 ) due to the potential cardiac adverse events (AEs) observed with the IV formulation. Formulations of 5HT 3 RAs may affect their utility. Injectable forms have an adherence advantage, whereas compliance with oral antiemetics may be suboptimal because of difficulty ingesting pills, especially for patients with head and neck cancer or those afraid to swallow pills for fear of inducing further emesis. 38 , 39

Extending the efficacy of 5HT 3 RAs into the delayed phase: palonosetron

Palonosetron, a potent and selective 5HT 3 RA, is a second-generation agent with a half-life ( t ½ ) that is longer (~40 hours) 40 than first-generation agents ( Table 2 ). Additionally, in vitro research has suggested that palonosetron causes 5HT 3 -receptor internalization, leading to prolonged inhibition of 5HT 3 RAs. 41 These properties ( t ½ , binding affinity, and receptor internalization) of palonosetron are believed to form the basis of its pharmacologic activity in the acute and delayed CINV phases. 26 , 41 – 43 However, direct evidence linking biochemical properties of palonosetron with its clinical efficacy is lacking. Notably, palonosetron IV is indicated for CINV prevention in both acute and delayed phases following MEC, but only in the acute phase following HEC. 34 In the USA, palonosetron is available only for IV administration. 34 At the time of its approval in the USA, palonosetron had not been investigated in combination with an NK 1 RA.

In 2014, the oral fixed-dose combination of the NK 1 RA netupitant 300 mg and palonosetron 0.5 mg (NEPA; Akynzeo, Helsinn Therapeutics Inc, Iselin, NJ, USA) became available for CINV prevention in both acute and delayed phases in patients treated with MEC or HEC. 36 Approval was based on three clinical trials in patients receiving HEC, MEC, and repeated cycles of chemotherapy. 37 , 44 , 45 In single-cycle trials in patients receiving MEC or HEC, NEPA plus dexamethasone was significantly superior to the comparator regimen across the delayed and overall CINV phases in terms of CR. 44 , 45 However, in these trials, NEPA plus dexamethasone was compared with a two-drug regimen of oral palonosetron plus dexamethasone, not the three-drug regimen recommended by all guidelines for patients receiving HEC and by some guidelines for patients receiving MEC. 7 , 17 – 19 Over multiple cycles, NEPA plus dexamethasone had similar CR rates to a three-drug regimen of aprepitant, palonosetron, and dexamethasone, but a small numerical advantage in the delayed and overall phases. 37 In clinical trials, the NK 1 RA provided additional control of delayed CINV in combination with a 5HT 3 RA, suggesting that the NK 1 RA is providing the ben efit in the delayed phase. 46 , 47 In fact, the NEPA prescribing information states that palonosetron prevents CINV in the acute phase and netupitant prevents CINV in the acute and delayed phases. 36 Since NEPA provides an NK 1 RA and a 5HT 3 RA as a single oral dose, it has the potential to improve the prevention of delayed CINV and improve adherence to guidelines for CINV prevention following HEC, which recommend combined use of NK 1 RA and 5HT 3 RA plus a corticosteroid. 48 However, oral administration of NEPA may pose a challenge to some patients, as discussed earlier.

Palonosetron and its place in antiemetic treatment guidelines

Antiemesis guidelines recommend palonosetron as a preferred 5HT 3 RA in some settings. In patients with breast cancer receiving AC-based chemotherapy (ie, a HEC regimen), a three-drug regimen of a 5HT 3 RA, dexamethasone, and an NK 1 RA is recommended by the MASCC/ESMO guidelines, but palonosetron is stated as the preferred 5HT 3 RA if an NK 1 RA is not available. 17 These recommendations were based on the results of Phase III trials of palonosetron in patients receiving HEC ( Table 3 49 – 60 ). 49 , 50 In patients receiving MEC or multiday chemotherapy, either palonosetron or GERSC is recommended in NCCN guidelines as a preferred 5HT 3 RA in combination with dexamethasone for CINV prevention (ie, when no NK 1 RA is given). 7 In a recent trial in 341 patients with breast cancer receiving AC-based chemotherapy (reported as an abstract), palonosetron failed to show superiority over granisetron IV (CR 62.3% vs 60.4%, P =0.8) in the delayed phase, when each agent was combined with fosaprepitant and dexamethasone. 61 Recently, a double-blind, randomized study comparing a three-drug palonosetron regimen with a three-drug granisetron regimen in patients receiving AC-based HEC showed no significant difference between study arms in terms of delayed-phase CR, despite again using the 0.75 mg palonosetron dose. 62

The NCCN guidelines considered two Phase III trials in the MEC setting to support palonosetron as a preferred 5HT 3 RA in combination with dexamethasone to prevent CINV associated with MEC. 63 , 64 However, one study in patients receiving MEC reported that palonosetron IV was noninferior to dolasetron IV, which is no longer approved by the US Food and Drug Administration (FDA) for CINV prevention because of associated cardiac adverse effects ( Table 4 45 , 59 , 60 , 63 – 73 ). 63 , 74 The other study demonstrated superior CR in acute and delayed CINV phases of single-dose palonosetron 0.25 mg IV compared with single-dose ondansetron 32 mg IV in patients receiving MEC ( Table 4 ). 64 However, this study did not use the recommended combination of ondansetron with dexamethasone. In a subsequent Phase III trial in patients receiving HEC, palonosetron 0.25 mg IV was noninferior to a first-generation 5HT 3 RA (ondansetron 32 mg IV) in acute, delayed, and overall phases. Superiority of palonosetron to ondansetron was shown only in a post hoc analysis, where CR with palonosetron was significantly higher in the delayed and overall phases compared with ondansetron when both agents were administered with dexamethasone. 49

As such, the evidence to support the preference for palonosetron in CINV prevention in these settings has been questioned, and it has been suggested that there are insufficient data to support this designation. 75 , 76 Phase III trials evaluated single-dose palonosetron compared with single-dose dolasetron or ondansetron, both of which have shorter t ½ than palonosetron ( Table 2 ), so would be expected to be less effective at controlling CINV beyond day 1 of chemotherapy. Meta-analyses of CINV trials have been used to support the choice of palonosetron as the preferred 5HT 3 RA in CINV prevention. 77 , 78 However, such analyses may result in pooling data from trials with significant differences in study populations and dexamethasone usage, so their conclusions require validation in prospective, randomized trials.

Extending the efficacy of 5HT 3 RAs into the delayed phase: granisetron

The short t ½ of the first-generation 5HT 3 RAs ( Table 2 ), such as granisetron, has limited their use in CINV prevention, especially for the delayed phase. Currently, two ER formulations of granisetron are available: GTDS and GERSC (previously APF530). The GTDS patch, which is 52 cm 2 in size, provides exposure similar to that of 2 mg oral granisetron. However, in contrast to oral granisetron, where maximum plasma concentration (C max ) is reached 2 hours after administration, drug exposure with GTDS is slower, with C max reached 48 hours after patch application and granisetron exposure continuing over 5 days ( Figure 1 29 – 31 , 79 ). 79 Therefore, GTDS is a convenient option for CINV prevention, because it reduces pill burden for patients, particularly those who have difficulty in swallowing oral medication. 23 However, GTDS has potential drawbacks, including patch detachment, 80 – 82 which may result in a lack of antiemetic efficacy, and the need for patch application 24–48 hours prior to chemotherapy, which may result in unnecessary exposure to antiemetic if the patient does not proceed with their next round of chemotherapy. 83

GERSC was developed as a long-acting formulation to provide prolonged 5HT 3 -RA action through sustained granisetron release, and was recently FDA-approved for use in adults in combination with other antiemetics for prevention of acute and delayed NV associated with initial and repeat courses of MEC or AC-combination chemotherapy regimens. 29 Extended granisetron release is achieved through Biochronomer technology ( Figure 2 ) using a viscous, bioerodible tri(ethylene glycol) poly(orthoester) (TEG-POE) polymer. 84 The POE polymer contains an orthoester linkage that is hydrolyzed to excreted fragments on exposure to an aqueous environment. The acid-labile nature of the TEG-POE polymer allows granisetron release by diffusion from the depot followed by controlled polymer hydrolysis, resulting in further release of granisetron. 85 In healthy subjects, granisetron is released from the polymer over an extended period (C max occurring approximately 10 hours after administration) ( Figure 1 ). The biphasic drug release from the polymer provides granisetron exposure into the delayed phase of CINV, with mean plasma concentration of 3.5 ng/mL (range 0–14 ng/mL) 5 days after a single 10 mg dose ( Figure 2 ). 29 Following a single SC injection of GERSC to patients with cancer, time to C max was reported as occurring approximately 24 hours postdose, and the t ½ of granis-etron was 26–34 hours. 30 The difference in reported time to C max in healthy subjects and patients with cancer may be an artifact of the small number of participants in these analyses and the timing of blood samples used to estimate these phar-macokinetic parameters. Overall, GERSC provides slow, controlled release of therapeutic granisetron concentrations for ≥5 days following a single SC injection. 30 , 84 The efficacy of GERSC in CINV prevention during acute and delayed phases following MEC or HEC has been shown in two large Phase III trials. 54 , 59 , 86 In contrast to GTDS, which is applied 24–48 hours prior to chemotherapy, 31 GERSC may be given shortly (≥30 minutes) before chemotherapy ( Table 2 ). However, the GERSC single-dose syringe must be prepared at least 60 minutes prior to SC administration by warming the viscous liquid to room temperature, and the contents must be injected slowly by a health-care professional. A topical anesthetic may be applied to the injection site (IS) prior to administration. 29

Clinical trial experience has established that 5HT 3 RAs effectively control emesis in the acute phase, 87 – 90 but their efficacy in the delayed phase is limited. 91 , 92 In Phase III trials, the addition of the NK 1 RA aprepitant to a regimen of a 5HT 3 RA plus dexamethasone improved CINV control over both acute and delayed phases following MEC or HEC ( Tables 3 and 4 ). 55 , 56 , 68 , 93 In the Phase III MAGIC trial of GERSC versus ondansetron, each combined with an NK 1 RA and dexamethasone, the GERSC regimen provided superior delayed-phase CR in patients receiving HEC compared with the ondansetron regimen, 54 suggesting the involvement of 5HT 3 RAs in mitigating delayed as well as acute CINV.

Efficacy of combination therapies for CINV

The three-drug antiemetic regimen (5HT 3 RA + NK 1 RA + dexamethasone)

Currently, guidelines for CINV prevention following HEC recommend a three-drug regimen of a 5HT 3 RA, an NK 1 RA, and dexamethasone as an option, with NCCN and ASCO guidelines also proposing a four-drug regimen with the addition of olanzapine ( Table 1 ). No 5HT 3 RA as a part of a three-drug regimen is preferred by any guideline for HEC. 7 , 17 , 19 Efficacy results from key Phase III trials in patients receiving HEC are summarized in Table 3 . The MAGIC trial was the first Phase III registrational efficacy study to compare single doses of two 5HT 3 RAs – GERSC and ondansetron – in a guideline-recommended three-drug versus three-drug regimen in 942 randomized patients receiving HEC 54 ( Table 3 ). As expected from the ER design, compared with the ondansetron arm, the GERSC arm demonstrated a superior delayed-phase CR rate (64.7% vs 56.6%, P =0.014, absolute treatment difference 8.0%), challenging the view that 5HT 3 RAs have equal efficacy in delayed-phase CINV prevention following HEC. 11 , 94 Consistent with the primary end point of CR, the GERSC arm versus the ondansetron arm also showed benefit in reducing rescue medication use and nausea frequency in the delayed and overall CINV phases. 54 Additionally, patient-reported satisfaction with antiemetic therapy was significantly higher in the GERSC arm versus the ondansetron arm in the delayed phase. 54

Because all patients in the MAGIC trial were from US community practices, these results are likely to be representative of outcomes in that practice setting. Importantly, the GERSC regimen demonstrated superiority to the ondansetron regimen in a population where the majority of patients were women (GERSC arm 79.6%, ondansetron arm 82.5%), a high-risk group for CINV. 54 Moreover, patients were stratified by planned use of cisplatin (≥50 mg/m 2 , yes/no), and the delayed-phase CR rate was higher in the GERSC arm (65.3%) versus the ondansetron arm (54.7%) in the 252 patients in the cisplatin stratum. 54 In a post hoc subgroup analysis of the 589 patients (65%) receiving AC-based HEC, at least 98% of whom were women, delayed-phase CR rates showed a trend favoring the GERSC arm (64%) over the ondansetron arm (56%). 95 A similar trend was found in the subgroup of 252 patients scheduled to receive cisplatin, where delayed-phase CR rates were numerically higher in the GERSC arm (65%) than in the ondansetron arm (55%). 96 These subgroup findings were consistent with the overall population, although the analyses were not powered to show a significant difference between groups.

The two-drug antiemetic regimen (5HT 3 RA + dexamethasone)

Guidelines for CINV prevention following MEC generally recommend a two-drug regimen of a 5HT 3 RA plus dexa-methasone on day 1 (with or without an NK 1 RA) and dexa-methasone on days 2 and 3, with NCCN guidelines proposing the addition of an NK 1 RA for patients with additional CINV risk factors or prior treatment failure. 7 , 18 , 19 Efficacy results from key Phase III trials in patients receiving MEC are sum-marized in Table 4 . In the Phase III trial of GERSC compared with palonosetron, both in combination with dexamethasone, in patients receiving MEC (reanalyzed according to 2011 ASCO criteria 97 ), both doses of GERSC (5 mg and 10 mg SC) were noninferior to palonosetron (0.25 mg IV) in preventing acute-phase CINV as determined by CR in cycle 1 of chemotherapy, and the 10 mg dose of GERSC was noninferior to palonosetron in preventing CINV in the delayed phase. 86

Of interest, because of AEs associated with dexametha-sone, such as insomnia, gastrointestinal symptoms, agitation, increased appetite, and weight gain, 98 several studies have investigated the efficacy of a dexamethasone-sparing palono-setron regimen involving 1-day versus 3-day dexamethasone in the MEC setting and reported the noninferiority of these regimens ( Table 4 ). 67 , 69 , 72

Nausea control

Significant advances have been made in emesis control following MEC or HEC with the use of newer agents, but nausea control following HEC remains suboptimal, especially in the delayed phase of CINV, with delayed nausea being reported by 68% of patients in one study. 10 A multinational survey of 2,388 health-care providers found delayed nausea to be most challenging to prevent, 5 and several patient-related factors, including younger age, type of cancer, and patient’s perceived susceptibility to nausea, can contribute to increased incidence of chemotherapy-induced nausea. 99 Subjectivity in the measurement of nausea and its severity and a lack of understanding of underlying mechanisms pose barriers to optimal nausea control. In clinical trials, such end points as CC (CR with no more than mild nausea) and total response (CR with no nausea) provide some measure of nausea control, but rely on the patient’s self-reporting of nausea frequency and severity.

In the MAGIC trial of GERSC, patients with CC in the delayed phase comprised 60.7% in the GERSC regimen and 53.1% in the ondansetron regimen, a treatment difference of 7.6% (95% CI 1.1%–14.0%, unadjusted P =0.022). Percentages of CC were also higher in the GERSC regimen than the ondansetron regimen in the overall phase, but the difference was not significant (54.7% vs 49.6%, respectively; unadjusted P =0.123). The proportions of patients with no nausea in the GERSC and ondansetron regimens were similar in the delayed (49.7% vs 44.2%, respectively; P =0.099) and overall phases (45.3% vs 40.5%, respectively; P =0.138). 54

A recent Phase III trial of olanzapine versus placebo, each with a three-drug regimen of a 5HT 3 RA, an NK 1 RA, and dexamethasone, focused specifically on nausea control as the primary end point, and showed effective nausea control with the olanzapine regimen compared with the placebo regimen in patients receiving cisplatin or AC-based HEC. For patients in the olanzapine group compared with the placebo group, the proportions of patients with no nausea (acute phase 74% vs 45%, respectively, P =0.002; delayed phase 42% vs 25%, P =0.002; overall phase 37% vs 22%, P =0.002) and with CR (acute phase 86% vs 65%, P <0.001; delayed phase 67% vs 52%, P =0.007; overall phase 64% vs 41%, P <0.001) were significantly higher across all CINV phases. 15

Efficacy of 5HT 3 RAs in multicycle chemotherapy

In trials evaluating antiemetics in multicycle-chemotherapy settings, the efficacy of 5HT 3 RAs in CINV prevention was generally maintained over multiple cycles ( Table 5 37 , 80 , 100 – 102 ). Palonosetron at a dose of 0.75 mg, which is three times the approved dosage in the USA, was generally well tolerated in a Phase III trial in patients receiving cisplatin or AC-based HEC in Japan ( Table 5 ). 100 CR rates were maintained across four cycles in the acute (range 72%–77%), delayed (range 56%–63%), and overall (range 52%–56%) phases. 100 A single-arm study in 156 patients receiving four to six cycles of cisplatin-based HEC evaluated CINV-prevention efficacy of palonosetron 0.25 mg IV in a three-drug regimen with oral aprepitant 125 mg and dexamethasone 20 mg IV on day 1. Overall-phase CR rates were maintained over six cycles, ranging from 74.4% to 82.0%. At least 90% of patients had no emesis, and at least 60% had no nausea across cycles. 103 The proportion of high-risk female patients in this study was 36%.

In a Phase III study of NEPA over multiple cycles, oral NEPA plus oral dexamethasone was compared with a control regimen of oral aprepitant plus oral palonosetron plus oral dexamethasone 37 ( Table 5 ). Overall-phase CR rates were maintained over multiple cycles in patients receiving the NEPA regimen (HEC 79%–91%, MEC 80%–93%) or the control regimen (HEC 58–86%, MEC 82%–89%), and were slightly lower with the latter regimen. In the delayed phase, there was a small but consistent numerical advantage in CR of 2%–6% with the NEPA regimen compared with the control regimen. The proportion of patients with no significant nausea in the overall phase remained high in both groups. Around 50% of study patients were women, and overall-phase CR rates with the NEPA regimen were generally similar in men and women across cycles (data not shown). 37

In a Phase III trial in patients receiving multiple cycles of MEC or HEC, sustainability of GERSC efficacy in CINV prevention was examined. Patients received GERSC 5 or 10 mg SC or palonosetron 0.25 mg IV in cycle 1. After cycle 1, no palonosetron was administered, and upon consent patients previously receiving palonosetron were rerandomized to receive GERSC 5 or 10 mg SC. CR rates were sustained over four cycles in patients receiving GERSC 10 mg once per cycle, with CR rates of 68.4% in patients in the acute phase of CINV, and 57.9% in the delayed phase following HEC; corresponding CR rates in patients receiving MEC were 56.5% and 41.3%, respectively. Emesis control was comparable to nausea control in patients receiving GERSC. Among patients in the MEC and HEC groups, respectively, 84%–88% and 63%–67% were women. 101 The higher proportion of women in the MEC group versus the HEC group and inclusion of AC-based regimens as MEC (as per guidelines at the time of the study design 8 ) instead of HEC (as per current guidelines 7 , 17 , 19 ) may have contributed to the lower CR rates in the MEC group compared with those in the HEC group. At the time of this study, the recommended antiemetic regimen for patients receiving multiple cycles of HEC did not include an NK 1 RA. The efficacy of GERSC as a part of a three-drug regimen remains to be investigated in the setting of multicycle MEC or HEC.

Efficacy of 5HT 3 RAs in multiday chemotherapy

There have been fewer trials evaluating the antiemetic efficacy of 5HT 3 RAs in patients receiving multiday chemotherapy than in those receiving single-day chemotherapy, and the NCCN guidelines recognize the lack of evidence to support recommendations in multiday-chemotherapy settings. 7 The efficacy of transdermal (GTDS) versus oral granisetron in preventing CINV was investigated in a Phase III study of 641 patients receiving their first cycle of a multiday MEC or HEC regimen ( Table 5 ). 80 GTDS was noninferior to daily oral granisetron, and efficacy was maintained across the multiday-chemotherapy regimen (CC, GTDS 60%, oral granisetron 65%, 95% CI –13 to 3). 80 A small Phase III CINV-prevention study in 69 patients receiving 5-day cisplatin showed a significantly higher CR rate with a regimen of the NK 1 RA aprepitant plus a 5HT 3 RA (excluding palonosetron) plus dexamethasone versus a 5HT 3 RA plus dexamethasone (42% vs 13%, P <0.001) ( Table 5 ). 102

In a retrospective trial of palonosetron in comparison with ondansetron in patients receiving multiday cisplatin or carboplatin, palonosetron therapy was associated with a 63% lower risk of uncontrolled CINV (odds ratio 0.37, 95% CI 0.25–0.54 ; P <0.0001). 104 A pilot study involving administration of palo-nosetron 0.25 mg IV for 1, 2, or 3 days in patients receiving multiday high-dose melphalan and hematopoietic stem-cell transplantation suggested that multiple doses may be more effective than a single dose. 105 However, these results need confirmation in larger trials in combination with NK 1 RAs.

Factors affecting the efficacy of 5HT 3 RAs in prevention of acute and delayed CINV

In addition to chemotherapy emetogenicity, patient-related risk factors influence CINV and may affect outcomes in clinical studies. These factors include female sex, 106 younger age, 99 history of low alcohol consumption, 107 history of motion sickness, 107 and history of previous chemotherapy-induced emesis. 11 As such, young female patients receiving HEC are at particularly high risk of experiencing CINV, 108 and differences in proportions of female patients in clinical studies may affect results. The development of predictive tools with a simple scoring system to identify patients at higher risk for CINV, based on a combination of patient- and chemotherapy-related risk factors, may assist in determining the most suitable antiemetic regimen for patients. 109

Genetic variation in 5HT 3 receptors or molecules involved in their transport and metabolism may also lead to differences in antiemetic efficacy. 110 , 111 5HT 3 -RA metabolism is dependent on enzymes in the CYP450 family, with certain enzymes playing a dominant role in certain drugs. 112 – 114 For example, palonosetron and dolasetron are metabolized primarily by CYP2D6, whereas granisetron is metabolized primarily by CYP1A1; 110 , 115 , 116 there is no dominant CYP450 enzyme for metabolizing ondansetron. 110 , 112 CYP2D6 is also involved in the metabolism of a variety of drug classes, and genetic polymorphisms lead to alleles with different activities (defective, decreased, or increased), resulting in poor, intermediate, extensive, or ultrarapid metabolizers (UMs). 111 , 115 The frequency of UMs varies by race, and control of chemotherapy-induced vomiting using ondansetron or tropisetron is weakest in UM patients compared with poor or intermediate metabolizers. 117 A pharmacogenetically driven treatment pathway that accounts for CYP2D6 genotype has been proposed, suggesting that patients classed as CYP2D6 UMs receiving MEC or HEC should be given granisetron as the first-line 5HT 3 RA to circumvent the CYP2D6 pathway and reduce pharmacokinetic and pharmacodynamic variability. 115 It has been suggested that genetic polymorphisms of CYP3A4 among patients from different races influence granisetron exposure and thereby its efficacy. 114 Because the ER formulation of GERSC allows continuous exposure to granisetron, it may reduce interpatient variability in antiemetic efficacy resulting from differences in granisetron metabolism. Genetic variations in 5HT3R may also exist, which may explain in part the decreased efficacy of 5HT 3 RAs in some patients. 115 Additional prospective studies investigating 5HT 3 -receptor polymorphisms and drug transporters may further elucidate the role of genetics in antiemetic response.

Safety of 5HT 3 RAs

Most common AEs

The safety profile of 5HT 3 RAs is well documented, and these agents are typically well tolerated. The most commonly reported AEs associated with IV or PO 5HT 3 RAs are headache (0–24%, depending on the agent and formulation) and constipation (0–14%) ( Table 6 25 , 27 – 29 , 31 – 33 , 36 ). 25 , 28 , 29 , 31 – 34 , 36 Diarrhea, asthenia, and dyspepsia are other known AEs. The incidence of these AEs is generally similar across the 5HT 3 RAs 59 , 118 , 119 ( Table 6 ), and they are generally mild and manageable. In IV and oral formulations of 5HT 3 RAs, headache is reported more frequently than constipation, but in the MAGIC trial of GERSC, this finding was reversed. In the Phase III MAGIC trial, constipation occurred in 22% of patients in the GERSC arm and 15% of patients in the ondansetron IV arm, while headache was less common (12% vs 18%, respectively). 54 Similar trends were observed with GTDS, which also provides ER granisetron: a higher proportion of GTDS-treated versus oral granisetron-treated patients (7% vs 3%) had constipation, whereas a lower proportion had headache (0.3% vs 2.5%). 80

Hypersensitivity and injection-site reactions

Hypersensitivity reactions and IS reactions (ISRs) have been reported with all 5HT 3 RAs. Extremely rare instances (<1/10,000) of hypersensitivity, including anaphylaxis and ISRs, have been reported from postmarketing experience with palonosetron IV. 34 Rare and sometimes severe cases of hypersensitivity have been reported with IV granisetron (eg, anaphylaxis, hypotension, shortness of breath, and urticaria) 25 and ondansetron IV (eg, anaphylactic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngospasm, shock, shortness of breath, and stridor). 32 ISRs, including pain, redness, and burning, have also been reported with ondansetron IV. 32

The Phase III trial of GERSC versus palonosetron IV in preventing CINV in patients receiving MEC or HEC showed that the safety profiles of these two agents were similar. 59 The most common treatment-related AEs were ISRs (GERSC 10 mg SC 38.9%, palonosetron 11.2%), constipation (GERSC 10 mg SC 4.5%, palonosetron 3.0%), and headache (GERSC 10 mg SC 2.8%, palonosetron 1.9%). 59

In the Phase III MAGIC trial, GERSC was also generally well tolerated compared with ondansetron IV, and no unexpected safety findings were observed. 54 All ISRs were conservatively considered treatment-related, regardless of their time of occurrence following study-drug administration, and were graded by investigators on days 1 and 6 and at the final safety follow-up visit according to prespecified criteria representing only size differences, not functional impairment. 54 Additionally, patients were instructed to evaluate the IS on days 2 to 5 and record the ISR status in a provided diary. ISRs occurred in patients in both arms at a similar frequency (61.8% in the GERSC arm, 59.5% in the ondansetron arm), presumably because of the double-dummy design of the study, where both arms received SC and IV drug or vehicle placebo; most ISRs were mild–moderate and resolved over time. 54 No ISRs led to study discontinuation or death. 54

Compared with the earlier Phase III trial, a greater proportion of patients receiving GERSC in the MAGIC trial reported ISRs. 54 , 59 Several factors may have contributed to this finding, including the assumption that all ISRs were treatment-related, grading only according to size and not functional impairment (which may have led investigators to pay greater attention to ISRs), and the instruction for patients to evaluate the site and record any signs of ISRs in patient diaries. Further, the MAGIC trial was conducted only in the USA, whereas the previous trial also included patients from Poland and India; 54 , 59 potential differences in ISR reporting across countries may have led to the observed ISR-reporting differences in the studies. The most common ISR in both trials was bruising, which was higher in the MAGIC trial (GERSC arm 41.9%, ondansetron arm 33.6%) than in the previous Phase III trial (GERSC 10 mg, related 15.6%, unrelated 4.3%; palonosetron 0.25 mg IV, related 6.5%, unrelated 2.6%). 54 , 59 However, if ISRs in the MAGIC trial were graded by National Cancer Institute Common Terminology Criteria for AEs instead of size, all instances of IS bruising of grades 2 and 3 would have been classified as grade 1. A Phase I crossover study demonstrated that GERSC may be administered to the abdomen or nondominant upper arm, but ISR incidence was higher in patients receiving abdominal (84.5%) versus upper-arm injections (69.2%). 120 Therefore, upper-arm administration may be preferable.

Serotonin syndrome

5HT 3 RAs have been associated with serious AEs, such as serotonin syndrome (involving symptoms of mental status changes), autonomic instability, neuromuscular symptoms, and seizures with or without gastrointestinal symptoms. 25 , 32 – 34 , 36 Serotonin syndrome results from increased serotonin signaling in the central nervous system. 121 Occurrences of serotonin syndrome have generally been associated with concomitant use of serotonergic drugs and 5HT RAs or with an overdose of 5HT 3 RAs. 33 Some fatalities resulting from serotonin syndrome have been reported with 5HT 3 RAs. 121 Patient monitoring for symptoms of serotonin syndrome and discontinuation of 5HT 3 RAs on their occurrence is recommended.

Cardiac effects

As a class, 5HT 3 RAs block cardiac hERG potassium channels with varying effectiveness, 83 so may be associated with abnormal cardiac electrical activity, such as a prolonged QT interval on electrocardiography (ECG). Dolasetron and ondansetron have lower clinical cardiac safety margins compared with granisetron and palonosetron. 83 In 2010, the FDA requested the withdrawal of the CINV indication for dolasetron IV, because of the possibility of life-threatening cardiac arrhythmias, such as QT-interval prolongation. 74 In 2012, the FDA restricted IV doses of ondansetron to three doses of 0.15 mg/kg administered every 4 hours to a maximum of 16 mg, given the risk of QT-interval prolongation. 122 Postmarketing reports of torsades de pointes have also been documented in patients using ondansetron. 32

Other 5HT 3 RAs have demonstrated no clinically significant changes in QT interval. Palonosetron 0.25, 0.75, or 2.25 mg IV showed no significant effect on cardiac QT intervals in healthy volunteers. 123 Supratherapeutic doses of NEPA (netupitant 600 mg and palonosetron 1.5 mg) produced no significant change in QTc, PR, or QRS intervals in healthy volunteers. 124 In a thorough QT/QTc study in healthy volunteers, granisetron administered via GTDS achieved prolonged therapeutic plasma concentrations compared with granisetron IV, but this did not lead to significant or progressive QT prolongation. 125 In a similar study, GERSC 20 mg (twice the approved dose) elicited no clinically significant effect on QT interval compared with placebo. 126 Although ECG changes induced by 5HT 3 RAs can be asymptomatic and reversible, fatal cardiac arrhythmias can occur in certain cases. 127 NCCN guidelines recommend that patients at high risk of developing life-threatening cardiac arrhythmias, such as those with torsades de pointes, receive routine ECG monitoring during treatment with 5HT 3 RAs. 7

Special populations

For ondansetron IV and PO and palonosetron IV, no dosage adjustment is recommended for patients with renal impairment or mild–moderate hepatic impairment. 32 – 34 In patients with severe hepatic impairment (Child–Pugh score ≥10), the maximum total daily dose of ondansetron should not exceed 8 mg. 32 , 33 For NEPA, no dosage adjustment is necessary in patients with mild–moderate renal or hepatic impairment, but NEPA should be avoided in patients with severe hepatic or renal impairment or end-stage renal disease. 36 Total granisetron clearance is not affected in patients with severe renal failure receiving a single IV dose of granisetron, and no dosage adjustment is necessary in patients with hepatic impairment. 25 For granisetron PO, no dosage adjustment is recommended for patients with either renal or hepatic impairment. 28 No studies have investigated the pharmacokinetics of GTDS in patients with renal or hepatic impairment. 31 For GERSC, there are no pharmacokinetic data on the elimination of the TEG-POE polymer vehicle in patients with renal impairment, and the clinical significance of prolonged granisetron elimination in patients with cancer is unknown. Consequently, current recommendations are that GERSC should not be administered more than once every 14 days in patients with moderate renal impairment and should be avoided in patients with severe renal impairment. 29

Clearance of ondansetron IV in pediatric patients aged 1–4 months is slower, and the t ½ is ~2.5-fold longer than in patients aged >4–24 months, so patients <4 months old receiving ondansetron IV should be closely monitored. 32 The safety and effectiveness of ondansetron PO have been established in pediatric patients ≥4 years of age receiving MEC, but not HEC. 33 The safety and effectiveness of palonosetron IV have been established in pediatric patients aged 1 month to <17 years. Pediatric patients require a higher IV dose of palono-setron than adults to prevent CINV, but the safety profile is consistent with that in adults. 34 For NEPA, safety and effectiveness in patients <18 years of age have not been established. For granisetron, the recommended IV dose in pediatric patients 2–16 years of age is 10 µg/kg. Benzyl alcohol, a component of granisetron 1 mg/mL IV, has been associated with serious adverse reactions and death, particularly in neonates. 25 The safety and effectiveness of granisetron PO, GTDS, and GERSC in pediatric patients have not been established. 28 , 29 , 31

For ondansetron IV and PO, no overall differences in safety or effectiveness have been observed between elderly and younger patients, and no dosage adjustment is needed in patients >65 years of age. However, greater sensitivity of some older patients to ondansetron cannot be ruled out. 32 , 33 Population pharmacokinetic analyses of palonosetron IV have not revealed any differences between patients ≥65 years of age and younger adult patients. 34 For NEPA PO, the safety profiles in elderly and younger patients are similar. 36 For different formulations of granisetron, the safety and effectiveness of granisetron IV and PO are similar in patients of various ages. 25 , 28 For GTDS and GERSC, clinical experience has not identified any differences in safety or effectiveness between elderly and younger patients. 29 , 31 In general, caution should be used when administering any of these agents to elderly patients, because of their increased likelihood of having decreased hepatic, renal, or cardiac function, concomitant diseases, and receiving other drug therapies.

Safety of 5HT 3 RAs in multicycle chemotherapy

5HT 3 RAs have generally been well tolerated in multicycle CINV-prevention trials. NEPA was generally safe when administered over multiple cycles to patients receiving MEC: the incidence of AEs did not increase across cycles. 37 Serious treatment-emergent AEs occurred in 16.2% of patients in the NEPA group (two were treatment-related) and 18.3% of patients in the aprepitant plus palonosetron group. GERSC was generally safe in patients receiving up to four cycles of MEC or HEC. 101 No treatment-related serious AEs were observed. Most ISRs were mild, and those of moderate severity occurred in less than 3% of patients. ISRs included bruising (GERSC 500 mg, 29.7%), nodules (GERSC 500 mg, 17.5%), erythema (GERSC 500 mg, 11.8%), pain (GERSC 500 mg, 7.2%), and bleeding (GERSC 500 mg, 6.6%). 101

Safety of 5HT 3 RAs in multiday chemotherapy

In a Phase III trial of GTDS in patients receiving multiday chemotherapy, the most common AE was constipation, occurring in 7% of patients, 80 and no QTc prolongation occurred with GTDS. Multiple doses of palonosetron 0.25 mg IV administered with dexamethasone were well tolerated in patients with multiple myeloma receiving multiday melphalan and hematopoietic stem-cell transplantation, and no serious drug-related AEs were reported. 105 In patients receiving up to six cycles of cisplatin, a combination of palonosetron 0.25 mg IV, aprepitant 125 mg PO, and dexamethasone 20 mg IV on day 1 of chemotherapy was well tolerated. 103

5HT 3 RAs for radiotherapy-induced NV and chemoradiation-induced NV

In addition to chemotherapy, other causes of NV include radiotherapy and concomitant chemotherapy and radiotherapy. Among patients receiving radiotherapy, 50%–80% may experience radiotherapy-induced NV (RINV), depending on the site of irradiation, dose, fractionation schedule, and patient-related risk factors. 128 5HT 3 RAs have been widely used for RINV prophylaxis, 128 and NCCN guidelines recommend pretreatment with oral granisetron or oral ondansetron, with or without oral dexamethasone, for each day of upper-abdomen, localized, or total-body irradiation. 7

Despite widespread use of chemoradiation to treat gynecologic and other cancers, prophylactic antiemetic regimens for RINV and chemoradiation-induced NV (CRINV) are relatively underexplored. 129 The standard of care for women with cervical cancer involves weekly cisplatin-based HEC and concomitant fractionated radiotherapy, resulting in increased CINV risk in these patients, due to their young age, female sex, and the high emetogenicity of cisplatin. 129 In a Phase II study in 48 women receiving concomitant radiotherapy and cisplatin therapy for gynecologic cancers, prophylaxis with palonosetron 0.25 mg IV once on day 1 and prednisolone 100 mg once on day 1 followed by 50 mg twice on day 2, 25 mg twice on day 3, and 25 mg once on day 4 was insufficient for emesis control. 130 The primary end point, cumulative probability of patients completing five cycles of chemoradiation without emesis, was 57%. 130 A recent Phase III study in 246 women with cervical cancer receiving fractionated radiotherapy and weekly cisplatin for 5 weeks compared fosaprepitant 150 mg IV versus placebo, each combined with palonosetron 0.25 mg IV and dexamethasone 16 mg PO, for the control of CRINV. 131 All patients received dexamethasone 8 mg PO twice on day 2, 4 mg PO twice on day 3, and 4 mg once on day 4. This was the first study to investigate the efficacy of a three-drug regimen in CRINV prevention. A greater proportion of patients receiving the fosaprepitant three-drug regimen did not experience emesis at 5 weeks (65.7% vs 48.7%), with a lower cumulative risk of emesis in these patients ( P =0.008). These results represent a significant advance in CRINV management.

Conclusion

With the recent addition of new formulations of 5HT 3 RAs, health-care providers have a variety of agents to choose from. However, these agents have important differences in efficacy and safety, and the appropriate antiemetic regimen must be selected carefully, considering both chemotherapy regimen and schedule and patient-related risk factors.

For patients receiving single-day HEC, a three-drug anti-emetic regimen is recommended, and the 5HT 3 RA included in this regimen may influence the combination’s efficacy in preventing CINV. Ideally, the 5HT 3 RA in combination with an NK 1 RA and a corticosteroid should prevent CINV across both acute and delayed phases following HEC. Based on clinical experience, first-generation 5HT 3 RAs such as ondansetron, older formulations of granisetron, and dolasetron IV (no longer approved in the USA to prevent CINV, because of potential cardiac effects) are considered similar in efficacy for preventing acute CINV following MEC or HEC, but considered inadequate for preventing delayed CINV following HEC. 11 Recent results with GERSC, the ER polymer formulation of granisetron using novel Biochronomer technology, change this view. 54 Two large Phase III trials in 2,370 patients have demonstrated that a single dose of GERSC is effective in preventing CINV following MEC and HEC regimens. 54 , 59 , 86 GERSC was noninferior to the standard of care, palonosetron, in preventing CINV in the acute and delayed phases following MEC and in the acute phase following HEC, and numerically superior to palonosetron in preventing delayed CINV following HEC. 86 GERSC was also superior to ondansetron (when both agents were administered in the guideline-recommended three-drug regimen) in preventing delayed CINV following HEC. 54 In light of the need for better therapies to manage delayed CINV following HEC, GERSC provides a new and effective option. Furthermore, GERSC efficacy has been maintained over successive cycles of MEC or HEC. 101 Therefore, GERSC is a convenient and effective SC option for acute and delayed CINV prevention following MEC or HEC administered over single or multiple cycles. In the USA, GERSC is indicated for use in combination with other antiemetics for the prevention of acute and delayed NV associated with initial and repeat courses of MEC and AC combination-chemotherapy regimens.

Another recent formulation, NEPA (fixed-dose netupitant and palonosetron), in combination with dexamethasone, has shown superiority to palonosetron plus dexamethasone in controlling CINV following MEC in acute, delayed, and overall phases and was effective over multiple cycles of MEC or HEC. 37 , 45 As such, NEPA is an additional oral antiemetic option for patients receiving MEC or HEC.

Historically, CINV-prevention trials have typically used CR as the primary end point and focused on emesis control in both the acute and delayed phases of CINV, but delayed nausea, especially following HEC, continues to be inadequately controlled. The subjectivity in measuring nausea and the lack of understanding of its underlying pathophysiology have hindered the study of nausea control and the development of effective agents to prevent nausea. The use of a stringent no-nausea end point in clinical trials and a better understanding of the underlying pathophysiology are likely to lead to improved nausea control. Given the efficacy of olanzapine in nausea control, its addition to the existing three-drug regimen may improve nausea management and may be the next step in CINV-prevention regimens. The continued occurrence of CINV, despite the availability of effective antiemetic regimens and comprehensive clinical practice guidelines, suggests the need for greater adherence to guidelines and better understanding of patient characteristics and genetic differences. Future research on 5HT 3 -RA pharmacogenetics may improve the understanding of variability in patient response to antiemetics. 110 , 132

Acknowledgments

Research support was provided by Heron Therapeutics Inc (Redwood City, CA, USA). Medical writing assistance was provided by Doyel Mitra, PhD, Yvonne E Yarker, PhD, and Joanna Sandilos Rega, PhD, of SciStrategy Communications (Conshohocken, PA, USA).

Footnotes

Disclosure

JG has served as a member of a speaker bureau or advisory committee for Heron Therapeutics. LS has acted in a consultant/advisory role for Eisai, Helsinn, Merck, and Tesaro, received research funding from Helsinn, and served as a member of a speaker bureau or advisory committee for Helsinn and Merck. NG has served as a member of a speaker bureau or advisory committee for Eisai, Heron, and Tesaro. The authors report no other conflicts of interest in this work.

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