Getting it right the first time: recent progress in optimizing antiemetic usage

The goal of selecting optimal antiemetic therapy continues to be a moving target with the emergence of newer agents and patient-related risk factors, as well as the rapid evolution of guidelines for management of chemotherapy-induced nausea and vomiting (CINV). Utilizing an appropriate degree of prophylaxis for the first cycle of chemotherapy is critical to prevent breakthrough CINV, which is difficult to manage and can lead to later anticipatory vomiting during subsequent cycles of therapy. Optimizing antiemetic usage requires awareness of available and emerging agents and the unique characteristics of these therapies that impact their role in CINV management.

The first-generation 5-HT3 receptor antagonists (ondansetron, granisetron, dolasetron, and tropisetron) revolutionized the management of CINV in terms of both efficacy and safety compared to historical antiemetics (e.g., metoclopramide) [1]. These agents exhibit comparable efficacy, preventing 50 to 80% of acute CINV in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) regimens and are considered equivalent in CINV guidelines. Importantly, despite their efficacy against acute CINV, these agents are much less effective in prevention of delayed CINV.

In an effort to improve response to antiemetic therapy, the second-generation 5-HT3 receptor antagonists palonosetron and APF530 were subsequently developed and are now approved for patients with CINV [1‐3]. Palonosetron has unique, advantageous pharmacodynamic properties, including a longer half-life and higher receptor binding affinity compared to the first-generation 5-HT3 receptor antagonists [4, 5]. In addition, binding of palonosetron to the 5-HT3 receptor creates positive cooperativity that results in further palonosetron binding and eventual receptor internalization, blocking 5-HT3 signaling and preventing crosstalk with NK-1 receptor signaling. APF530 is a novel, extended-release, subcutaneous formulation of granisetron with a unique biochronomer delivery system that provides sustained release to improve the therapeutic concentration of granisetron over an extended period (> 5 days) [3]. Both palonosetron and APF530 demonstrate superior prevention of both acute and delayed CINV compared to the first-generation 5-HT3 receptor antagonists [2, 6‐8].

Several phase III trials directly compared palonosetron to either dolasetron, ondansetron, or granisetron in patients treated with MEC or HEC and demonstrated significantly higher efficacy in the acute and delayed phases in patients receiving palonosetron [6]. A pooled analysis of palonosetron phase III trials confirmed significantly higher complete response (CR, no emesis, and no rescue antiemetics) rates in the delayed (57 vs 45%; P < .0001) and overall period (51 vs 40%; P < .0001) for palonosetron compared to the first-generation 5-HT3 receptor antagonists [6]. Palonosetron also significantly decreased nausea severity in the delayed and overall periods. Based on these trials, the US Food and Drug Administration (FDA) approved palonosetron for the prevention of acute and delayed CINV associated with initial and repeat courses of MEC and HEC.

In a phase III trial of APF530 versus palonosetron in over 1400 patients receiving MEC or HEC, APF530 was noninferior to palonosetron in preventing acute CINV after MEC or HEC and delayed CINV associated with MEC [7]. A second phase III study compared APF530 to ondansetron, both in combination with fosaprepitant and dexamethasone, in patients receiving HEC [8]. Delayed phase CR was significantly more common in patients receiving APF530 compared to the delayed phase CR found with ondansetron (65 vs 57%; P = .014). The most common treatment-related adverse events were constipation, fatigue, headache, and infusion-site reactions.

Development of NK-1 receptor antagonists has greatly improved our ability to control CINV, with aprepitant, fosaprepitant, netupitant, and rolapitant demonstrating similar efficacy in the prevention of CINV. Differences in the pharmacokinetic properties of NK-1 receptor antagonists influence the dosing frequency and use of these agents (Table 1) [9‐12]. Aprepitant and its prodrug fosaprepitant have a relatively short half-life of 9–13 h, with aprepitant dosed daily for 3 days and fosaprepitant dosed on day 1 only [9, 10]. In contrast, NEPA (netupitant with palonosetron) and rolapitant have half-lives of approximately 80 and 180 h, respectively, and both agents can be administered as a single dose prior to each chemotherapy cycle [11, 12]. Another key difference in the NK-1 receptor antagonists is their interaction with other drugs. Aprepitant, fosaprepitant, and netupitant induce or inhibit cytochrome P450 3A4 (CYP3A4), while rolapitant does not [9‐13]. This interferes with the metabolism of CYP3A4 substrates, such as dexamethasone and some chemotherapeutic agents, requiring careful consideration and appropriate dose reductions of concomitant dexamethasone. Aprepitant and fosaprepitant also interact with warfarin and oral contraceptives [9, 10]. Rolapitant, on the other hand, inhibits CYP2D6, breast cancer resistance protein (BCRP), and P-glycoprotein [12]. Administration of agents metabolized by CYP2D6 with rolapitant is not recommended and concomitant use with thioridazine is contraindicated due to risk for QT prolongation.

Chemotherapy-induced nausea and vomiting is an ongoing challenge that must be effectively prevented, not only in the first cycle of chemotherapy, but each subsequent cycle as well. Aprepitant demonstrated continued activity against CINV across multiple cycles of chemotherapy in several trials [32, 33]. In a multicycle extension of the phase III trial comparing NEPA to palonosetron, the benefit observed for NEPA over palonosetron in the delayed phase and overall phase was maintained for chemotherapy cycles 1 through 4 [34]. Patients who received NEPA and responded well were also significantly more likely to sustain a CR and nausea control beyond cycle 1. Another multinational randomized phase III trial compared NEPA plus dexamethasone to aprepitant, palonosetron, and dexamethasone over multiple cycles of chemotherapy in 413 chemotherapy-naïve patients receiving HEC or MEC [35]. NEPA demonstrated a small increase in the CR rate compared to aprepitant/palonosetron during cycle 1 that was maintained through 6 cycles of chemotherapy. In both of these studies, adverse events did not appear to increase over time.

In all the rolapitant trials mentioned above, patients could choose to continue the same antiemetic regimen for subsequent cycles of chemotherapy regardless of response during cycle 1 [36]. A post hoc analysis of these trials for cycles 2 through 6 of chemotherapy showed that rolapitant continued to provide superior protection from CINV compared to the control regimen over multiple cycles of MEC or HEC. The rate of treatment-emergent adverse events was low and did not increase with each subsequent cycle. Thus, a single dose of rolapitant at the beginning of each chemotherapy cycle effectively reduced emesis and nausea that can negatively impact daily life.

Olanzapine is an atypical antipsychotic that blocks multiple neurotransmitters and interacts with dopaminergic, serotonergic, adrenergic, and histamine receptors [37]. A randomized phase III trial directly compared the efficacy of olanzapine (10 mg daily days 1 to 4) to standard 3-day aprepitant in 241 chemotherapy-naïve patients receiving HEC (cisplatin or cyclophosphamide/doxorubicin) [38]. All patients received palonosetron and dexamethasone. Rates of CR were similar between the two arms. Olanzapine nearly doubled the percentage of patients without delayed nausea or overall nausea (69 vs 38% for aprepitant), although there was no difference observed for acute nausea (87% for both arms).

To further explore the potential for olanzapine in CINV prophylaxis, a small randomized study compared the addition of olanzapine at 5 mg daily for 6 days versus placebo to standard triple antiemetic therapy with 5-HT3 and NK-1 receptor antagonists and dexamethasone in 44 patients receiving MEC or HEC [39]. Adding olanzapine to standard antiemetic therapy significantly increased the total control rate (no vomiting, no rescue medications, and maximum VAS score ≤ 5 mm) in the acute phase (86 vs 55%; P = .045) and the delayed phase (64 vs 23%; P = .014). Complete protection (no vomiting, no rescue medications, and maximum VAS score of ≤ 25 mm) was also significantly improved in the acute and delayed phase. Importantly, olanzapine was well tolerated and significantly improved patient quality of life (P = .0004).

A recent, large, randomized phase III trial evaluated the addition of olanzapine versus placebo to a standard triplet antiemetic regimen of aprepitant or fosaprepitant, a 5-HT3 receptor antagonist, and dexamethasone [37]. A total of 380 chemotherapy-naïve patients receiving HEC (cisplatin or cyclophosphamide/doxorubicin) were randomized to either olanzapine (10 mg orally) or placebo on days 1 through 4. The addition of olanzapine significantly improved the primary endpoint of no chemotherapy-induced nausea in both the acute period (74 vs 45%; P = .002) and delayed period (42 vs 25%; P = .002). Overall nausea prevention was also significantly increased (37 vs 22%; P = .002). The CR rate was also significantly improved when olanzapine was added in the acute phase (86 vs 65%; P < .001), delayed phase (67 vs 52%; P = .007), and overall (64 vs 41%; P < .001). In this phase III trial, sedation was significantly increased in those receiving olanzapine, including severe sedation in 5% of patients.

Olanzapine has also been investigated as a rescue therapy for patients with breakthrough CINV. A double-blind, randomized phase III trial directly compared olanzapine to metoclopramide in chemotherapy-naïve patients receiving HEC (cisplatin or doxorubicin/cyclophosphamide) who experienced breakthrough CINV despite prophylactic fosaprepitant, palonosetron, and dexamethasone [40]. One hundred and eight evaluable patients experiencing breakthrough CINV were randomized to receive 10 mg daily olanzapine for 3 days or 10 mg metoclopramide 3 times daily for 3 days. This reduced dose of metoclopramide had not yet demonstrated efficacy in clinical trials, but was mandated by the European Medicine Agency to reduce the risk of neurotoxicity. Olanzapine prevented vomiting in 70% compared to 31% with metoclopramide (P < .01). Nausea was also significantly reduced (68 vs 23%; P < .01).

In summary, olanzapine significantly improved nausea control and is at least as effective as aprepitant in prevention of vomiting. Drowsiness is the main adverse event to be considered and appears to be particularly evident in elderly patients [41]. Caution should be used when prescribing olanzapine with dopamine receptor antagonists such as metoclopramide or haloperidol, as there is an increased risk of extrapyramidal symptoms [42].

Radiotherapy-induced nausea and vomiting (RINV) is often underestimated by clinicians, but can occur in 50 to 80% of patients undergoing radiotherapy [43]. The risk of RINV depends on the site of irradiation, dosing, fractionation, irradiated volume, radiotherapy technique, and patient-related factors such as age < 55 years, female sex, no alcohol consumption, history of nausea and vomiting, and anxiety [43, 44]. The emetogenic potential for radiotherapy and recommended prophylaxis according to the MASCC/ESMO and ASCO guidelines are based solely on the radiation field (Table 2) [44, 45]. Those at high or moderate risk for RINV should receive a 5-HT3 receptor antagonist with or without dexamethasone. For patients undergoing fractionated radiotherapy, 5-HT3 receptor antagonist therapy should be given before each fraction and continued at least 24 h after completion of radiotherapy [45]. Clinical trial data on patients receiving chemotherapy and radiotherapy concurrently is lacking. Current guidelines recommend selection of CINV prophylaxis based on the emetic risk of the chemotherapeutic regimen, unless the emetic risk of the planned radiotherapy is greater.

A recent meta-analysis confirmed the value of 5-HT3 receptor antagonists for RINV, with these agents increasing the rate of complete control of vomiting and complete control of nausea compared to control antiemetic regimens [46]. Very few studies have examined the potential role for NK-1 receptor antagonists in RINV. A recent phase III trial compared fosaprepitant versus placebo, both in combination with palonosetron and dexamethasone, in patients receiving 5 weeks of fractionated radiotherapy and weekly cisplatin for cervical cancer [47]. The triplet combination significantly increased the proportion of patients experiencing sustained lack of emesis at 5 weeks (65.7 vs 48.7%; hazard ratio 0.58; P = .008). The addition of fosaprepitant also increased the proportion of patients with an overall complete response (24 vs 14%; P = .007) and no nausea during the 5 weeks (15 vs 8%; P = .007). Further studies of NK-1 antagonists are warranted in the setting of RINV.

Numerous therapeutic options for prevention and treatment of CINV are now available, and many of the alternatives in each class of agents are very similar to each other with regard to efficacy and safety. It is important that clinicians employ optimal CINV prophylaxis right from the start based on current guidelines and clinical trial data to improve patient QoL and prevent chemotherapy delays and discontinuations. The ultimate goal is complete control of all aspects of CINV, including both nausea and vomiting. This will require further evaluation of optimal dosing, timing of administration, and effective combination strategies.