Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists

Abstract

Chemotherapy-induced nausea (CIN) has a significant negative impact on the quality of life of cancer patients. The use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists (RAs) has reduced the risk of vomiting, but (except for palonosetron) their effect on nausea, especially delayed nausea, is limited. This article reviews the role of NK1RAs when combined with 5-HT3RA–dexamethasone in CIN prophylaxis. Aprepitant has not shown consistent superiority over a two-drug (ondansetron–dexamethasone) combination in nausea control after cisplatin– or anthracycline–cyclophosphamide (AC)-based highly emetogenic chemotherapy (HEC). Recently, dexamethasone and dexamethasone–metoclopramide were demonstrated to be non-inferior to aprepitant and aprepitant–dexamethasone, respectively, for the control of delayed nausea after HEC (AC/cisplatin), and are now recognized in the guidelines. The potential impact of the new NK1RAs rolapitant and netupitant (oral fixed combination with palonosetron, as NEPA) in CIN prophylaxis is discussed. While the clinical significance of the effect on nausea of the rolapitant–granisetron–dexamethasone combination after cisplatin is not conclusive, rolapitant addition showed no improvement in nausea prophylaxis after AC or moderately emetogenic chemotherapy (MEC). NEPA was superior to palonosetron in the control of nausea after HEC (AC/cisplatin). Moreover, the efficacy of NEPA in nausea control was maintained over multiple cycles of HEC/MEC. Recently, NK1RAs have been challenged by olanzapine, with olanzapine showing superior efficacy in nausea prevention after HEC. Fixed antiemetic combinations (such as NEPA) or new antiemetics with a long half-life that may be given once per chemotherapy cycle (rolapitant or NEPA) may improve patient compliance with antiemetic treatment.

Efficacy and Safety of Oral NEPA (Netupitant/Palonosetron), the First Fixed-Combination Antiemetic, in Patients With Gynecological Cancers Receiving Platinum-Based Chemotherapy

“…The roles of different NK 1 RAs in the prevention of nausea were recently analyzed. 27 Studies of APR have not shown consistent superiority over a 2-drug combination (ondansetron-DEX) in the control of nausea after cisplatin or AC HEC. 27 In addition, no clear conclusions can be inferred on the clinical significance of combining rolapitant and granisetron-DEX with regard to nausea outcomes (HEC or MEC setting).…”

“…27 Studies of APR have not shown consistent superiority over a 2-drug combination (ondansetron-DEX) in the control of nausea after cisplatin or AC HEC. 27 In addition, no clear conclusions can be inferred on the clinical significance of combining rolapitant and granisetron-DEX with regard to nausea outcomes (HEC or MEC setting). 27 The addition of NETU to PALO (as the fixed-combination antiemetic NEPA) suggested results superior to those obtained with PALO alone in controlling nausea, with overall NSN rates, for 4 cycles, ranging from 75% to 80% after NEPA administration, versus 69% to 76% after PALO.…”

“…27 In addition, no clear conclusions can be inferred on the clinical significance of combining rolapitant and granisetron-DEX with regard to nausea outcomes (HEC or MEC setting). 27 The addition of NETU to PALO (as the fixed-combination antiemetic NEPA) suggested results superior to those obtained with PALO alone in controlling nausea, with overall NSN rates, for 4 cycles, ranging from 75% to 80% after NEPA administration, versus 69% to 76% after PALO. 19 The rates of CR and NSN in female patients with nongynecological cancers treated with NEPAwere also explored.…”

Rolapitant for the prevention of nausea in patients receiving highly or moderately emetogenic chemotherapy

“…Whereas the addition of NK-1RAs to the combination of 5-HT 3 RA and dexamethasone has significantly reduced rates of emesis in CINV, control of nausea, especially in the delayed phase, remains a clinical challenge. [13][14][15][16]23 Given the subjective nature of measuring nausea, 17 patients may find it easier to report the presence or absence of nausea (using NN) rather than the varying degrees of nausea (using NSN), rendering NN a more quantifiable endpoint than NSN. 14,16 In this analysis, rolapitant significantly improved NN rates during the delayed and overall phases in patients receiving carboplatin-based chemotherapy.…”

“…11,12 The NK-1RAs aprepitant and netupitant have reported inconsistent results. 13 The primary endpoint of many clinical trials evaluating CINV is complete response (CR), defined as no emesis and no use of rescue medication (RM; ie, antiemetics used after chemotherapy administration). 14,15 This endpoint may not reflect the experience of patients receiving chemotherapy, 16 as patients may experience nausea without emesis or vice versa.…”