Latest developments in the treatment of CINV

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Rudolph M Navari
MD PhD
Associate Dean, College of Science/Director, Walther Cancer Research Center
University of Notre Dame
Notre Dame, IN
USA
E:[email protected]

Chemotherapy-induced nausea and vomiting (CINV) can be a significant problem for patients. Patients consistently report that vomiting and nausea are among the most unpleasant and distressing aspects of chemotherapy.(1,2) Even only one emetic episode is associated with a significant deterioration in the quality of life, as well as physical and cognitive functioning, and may cause patients to delay or refuse potentially curative therapy.(3) There are five distinct but related CINV syndromes:(4)

• Acute CINV.
• Delayed CINV.
• Anticipatory CINV.
• Breakthrough CINV.
• Refractory CINV.

Acute CINV has been traditionally defined as nausea and vomiting occurring within the first 24 hours after chemotherapy administration. Delayed CINV has been defined as nausea and vomiting occurring 24 hours after chemotherapy and lasting up to five days, with recent evidence suggesting that it may begin as early as 16 hours after chemotherapy administration. Anticipatory CINV is a conditioned response that occurs, before a planned course of chemotherapy, following significant nausea and vomiting due to previous chemotherapy. Breakthrough CINV occurs despite patients being treated with preventive therapy, and refractory CINV occurs during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in earlier cycles.

The potential for CINV is influenced by the emetogenicity of the chemotherapeutic agents(5,6) and patient characteristics.(7–9) Table 1 lists the emetic risk groups with representative agents, and although the emetogenicity of a chemotherapeutic agent is the primary risk factor, coadministration of chemotherapeutic agents,(5,6) as well as repeated cycles of chemotherapy,(5,6) increases the potential for nausea and vomiting. Additional factors contributing to an increased risk for CINV are female gender, younger age, a history of motion sickness and lack of a history of heavy alcohol consumption.(7–9) The presence or absence of these risk factors and the emetogenicity of the chemotherapeutic agents being administered determine each patient’s risk of CINV.

[[HPE20_table1_37]]

Agents in clinical use for the treatment of CINV

5-HT(3)-receptor antagonists
Over the past 10 years, the introduction of
5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists for the prevention of CINV and postoperative and radiotherapy- induced nausea and vomiting has resulted in a major improvement in supportive care.(10–12) Current treatment guidelines for the prevention of CINV, recommended by a number of international groups,(12) suggest the use of a 5-HT(3)-receptor antagonist and dexamethasone prechemotherapy for the prevention of acute CINV and the use of dexamethasone with or without a 5-HT(3)-receptor antagonist or metoclopramide following chemotherapy for the prevention of delayed nausea and vomiting.

Table 2 shows the 5-HT(3)-receptor antagonists currently in use. First-generation 5-HT(3)-receptor antagonists dolasetron, granisetron and ondansetron, tropisetron,(13) azasetron(14) and ramosetron(15) are equivalent in efficacy and toxicities when used in the recommended doses, and compete only on an economic basis.(11) They have not been associated with major toxicities, with the most commonly reported adverse events being mild headache and mild diarrhoea.(10,16)

[[HPE20_table2_38]]

First-generation 5-HT(3)-receptor antagonists are not as effective against delayed emesis as they are against acute CINV.(17–19) Studies have shown that, with corticosteroids alone or combined with either metoclopramide or a 5-HT(3)-receptor antagonist in patients receiving cisplatin, the incidence of delayed emesis is reduced, although it remains a significant problem.(10,19) First-generation 5-HT(3)- receptor antagonists do not add significant efficacy to that obtained by dexamethasone alone in the control of delayed emesis.(18) These regimens require multiple daily doses, and metoclopramide can cause sedation and extrapyramidal side-effects.(10)

The second-generation 5-HT(3)-receptor antagonist palonosetron has recently been approved for clinical use, and recent studies suggest that it may have efficacy in controlling delayed CINV compared with first-generation drugs.

Palonosetron
Palonosetron is a new 5-HT(3)-receptor antagonist with antiemetic activity at both central and gastrointestinal sites. Compared with first-generation drugs, it has a higher binding affinity to the 5-HT(3) receptors, a higher potency, a significantly longer half-life (approximately 40 hours, ie, four to five times longer than that of dolasetron, granisetron or ondansetron) and an excellent safety profile.(20) A dose-finding study demonstrated that the effective dose was Ž0.25 mg.(20)

In two large studies in patients receiving moderately emetogenic chemotherapy, complete response (CR; no emesis, no rescue) was significantly improved in the acute and the delayed period for the patients who received 0.25mg of palonosetron alone, compared with either ondansetron or dolasetron alone.(21,22) Dexamethasone was not given with the 5-HT(3)-receptor antagonists in these studies, and it remains to be determined whether the differences in CR would persist if dexamethasone was used. In another study of 650 patients receiving highly emetogenic chemotherapy (cisplatin, Ž60mg/m(2)), the prevention of acute and delayed CINV was similar with the use of either palonosetron and dexamethasone or ondansetron and dexamethasone.(23)

In an analysis of the patients in the above studies who received repeated cycles of chemotherapy, Cartmell et al reported that the CR rates for both acute and delayed CINV were maintained with single intravenous doses of palonosetron without concomitant corticosteroids.(24)

Based on the above studies, palonosetron was approved by the FDA in July 2003 for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy, and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Despite the use of both first- and second-generation 5-HT(3)-receptor antagonists, the control of acute CINV, and especially delayed nausea and vomiting, is suboptimal with the agents listed in Table 2, and there is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens.(10,19,25)

NK-1-receptor antagonists
Initial clinical studies using the substance P (NK-1) receptor antagonists demonstrated that the addition of an NK-1- receptor antagonist (such as CP-122,721, CJ-11,794 or MK-0869) to a 5-HT(3)-receptor antagonist and dexamethasone before cisplatin chemotherapy improved the control of acute emesis compared with a 5-HT(3) antagonist and dexamethasone, and improved the control of delayed emesis compared with placebo.(26–28) In addition, the effect of single-agent L-758,298 on cisplatin-induced acute emesis was similar to that of ondansetron, but was superior in the control of delayed emesis.(29) Subsequent studies showed that the combination of aprepitant (MK-0869) and dexamethasone was similar to a 5-HT(3)-receptor antagonist and dexamethasone in controlling acute emesis. This combination was inferior in controlling acute emesis compared with triple therapy (aprepitant, 5-HT(3)-receptor antagonist and dexamethasone), and the improvement of delayed emesis with the use of aprepitant was confirmed, compared with placebo.(30,31)

In a dosing study of oral MK-869 (the final capsule formulation of aprepitant) involving 563 chemotherapy-naive patients receiving cisplatin (Ž70mg/m(2)), Chawla et al reported an improvement in the control of acute emesis when MK-869 was added to ondansetron and dexamethasone, and an improvement in the control of delayed emesis with the combination of MK-869 and dexamethasone, compared with dexamethasone alone.(32)

In two randomised, double-blind, parallel, multicentre, controlled studies (520 patients in each study), patients received cisplatin (>/=70mg/m(2)) and were randomised to receive “standard therapy” of a 5-HT(3)-receptor antagonist (ondansetron), dexamethasone prechemotherapy and dexamethasone post- chemotherapy (days 2–4), or “standard therapy” plus aprepitant given before chemotherapy and on days 2 and 3 postchemotherapy. (33,34) In both studies, the CR (no emesis, no rescue) of the aprepitant group was significantly higher in the acute period (83%–89%), the delayed period (68%–75%) and overall (days 1–5; 62.7%–72.7%) compared with that in the acute period (68%–78%), the delayed period (47%–56%) and overall (days 1–5; 43.3%-52.3%) of the “standard therapy”. The improvement in CR with the addition of aprepitant was maintained over multiple cycles of chemotherapy.(35,36) Nausea was improved only in the aprepitant group in the delayed period in only one of the studies.(34)

The studies discussed above formed the basis for the approval of aprepitant by the FDA in March 2003. In combination with other antiemetics, aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.

All currently published studies on aprepitant have been carried out with cisplatin chemotherapy. Warr et al recently presented a study on the use of aprepitant in 862 breast cancer patients receiving moderately emetogenic chemotherapy.(37) There was a significant improvement in CR (no emesis, no rescue) in the 24 hours after chemotherapy in patients receiving aprepitant, ondansetron and dexamethasone prechemotherapy compared with ondasetron and dexamethasone, but there was no significant improvement in CR days 2–5 in the postchemotherapy period when aprepitant alone was compared with ondansetron alone. The overall (days 1–5) CR was significantly improved for the aprepitant-containing regimen, most likely due to the improvement in the first 24 hours. The control of nausea was not improved with the use of aprepitant.

Olanzapine
Olanzapine is an antipsychotic of the thienobenzodiazepine drug class that blocks multiple neurotransmitters: dopamine at D(1), D(2), D(3) and D(4) brain receptors, serotonin at 5-HT(2a), 5-HT(2c), 5-HT(3) and 5-HT(6) receptors, catecholamines at a(1)-adrenergic receptors, acetylcholine at muscarinic receptors and histamine at H(1) receptors. (38,39) Common side-effects are sedation and weight gain,(40,41) as well as an association with the onset of diabetes mellitus.(42) Olanzapine’s activity at multiple receptors, particularly at the D(2) and 5-HT(3) receptors, which appear to be involved in nausea and emesis, suggest that it may have significant antiemetic properties.

There have been case reports on the use of olanzapine as an antiemetic.(43–47) These case reports prompted a phase I study in which olanzapine was used for the prevention of delayed emesis in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin and/or irinotecan.(48) Fifteen patients completed the protocol, and no grade 4 toxicities were seen. The maximum tolerated dose was 5mg per day for the two days before chemotherapy and 10mg per day for seven days postchemotherapy. Based on these data, olanzapine appeared to be a safe and effective agent for the prevention of delayed emesis in chemotherapy-naive cancer patients receiving cyclophosphamide, doxorubicin, cisplatin and/or irinotecan.

Using the maximum tolerated dose of olanzapine in the phase I trial, a phase II trial was performed for the prevention of CINV in patients receiving their first course of either highly emetogenic or moderately emetogenic chemotherapy. CR (no emesis, no rescue) was 100% for the acute period (24 hours postchemotherapy), 80% for the delayed period (days 2–5 postchemotherapy) and 80% for the overall period (0–120 hours postchemotherapy) in 10 patients receiving highly emetogenic chemotherapy (cisplatin Ž70mg/m(2)). CR was also 100% for the acute period, 85% for the delayed period and 85% for the overall period in 20 patients receiving moderately emetogenic chemotherapy (doxorubicin Ž50mg/m(2)). Nausea was very well controlled in patients receiving highly emetogenic chemotherapy, with no patient having nausea (0 on scale of 0–10, MD Anderson Symptom Inventory, MDASI) in the acute or delayed periods. Nausea was also well controlled in patients receiving moderately emetogenic chemotherapy, with no nausea in 85% of patients in the acute period, and 65% in the delayed and overall periods. There were no grade 3 or 4 toxicities. The study concluded that olanzapine was safe and highly effective in controlling acute and delayed CINV in patients receiving highly emetogenic and moderately emetogenic chemotherapy.(49)

Gabapentin
A recent report in a small number of patients receiving adjuvant chemotherapy (doxorubicin and cyclophosphamide) for breast cancer suggested that the anticonvulsant gabapentin might reduce delayed nausea. Further studies will be necessary to determine the efficacy of this agent.(50)

Conclusions
Table 3 summarises the current recommendations for the prevention of emesis. It should be noted that all four of the 5-HT(3)-receptor antagonists available in the USA are approved for the prevention of acute CINV, with palonosetron being the only 5-HT(3)-receptor antagonist approved for the control of delayed CINV (in patients receiving moderately emetogenic chemotherapy). The National Comprehensive Cancer Network (NCCN) recently issued updated guidelines for the prevention of CINV,(51) and listed palonosetron as the preferred 5-HT(3)-receptor antagonist for patients receiving moderately emetogenic chemotherapy. The use of aprepitant in patients receiving moderately emetogenic chemotherapy will await review of the recently presented data.(37) Antiemetic guidelines of the recent past,(12) as well as more recent guidelines, (51,52) have included the available oral 5-HT(3)-receptor antagonists as optional therapy for the prevention of delayed emesis, but the level of evidence supporting this practice is low.(10) For patients receiving low-emetogenic chemotherapy, a single agent, in the form of a 5-HT(3)- receptor antagonist (dexamethasone) or a phenothiazine depending on the clinical situation, should be used prechemotherapy, and an antiemetic following chemotherapy should be given only as needed.

[[HPE20_table3_40]]

Clinicians and other healthcare professionals who are involved in administering chemotherapy should be aware that studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners,(53) and patients often do not receive adequate prophylaxis.(25,54) In addition, it is essential to emphasise that current and new agents have been used as prophylaxis for acute and delayed CINV, and have not been studied for use in established CINV.(10,25)

Oncology practitioners now have a number of new antiemetics for use in preventing acute and delayed CINV. Future studies will determine how these agents are best used and what combinations of new and older agents will be the most beneficial for patients. Current studies of palonosetron and aprepitant are exploring their use in moderately emetogenic chemotherapy as well as in specific clinical situations, such as bone marrow transplantation and multiple-day chemotherapy regimens. Such studies will also determine the most effective use of these agents, both alone and in combination with other antiemetics. Current studies on the use of agents such as olanzapine and gabapentin as antiemetics (both agents having been initially used for other clinical indications) not only could provide additional options for the control of acute and delayed CINV, but could also provide new information on the mechanism of CINV.

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