Chemotherapy-induced nausea and vomiting (CINV) is one of the most troublesome side effects of anticancer drugs. Persistent nausea and vomiting can cause dehydration, electrolyte imbalance and malnutrition, and it might also decrease patient motivation for treatment. It has also been suggested that even if acute nausea and vomiting have a delayed onset, patients often experience anticipatory symptoms [1], making appropriate control of CINV extremely important for maintaining patient quality of life and general health, as well as for allowing treatment continuation. In the 1990s, nausea and vomiting were the most distressing side effects of treatment in cancer patients, but in the 2000s, a long-acting 5-hydroxytryptamine 3 receptor antagonist (5HT3RA), palonosetron (PALO), was introduced in Japan. Further, aprepitant (APR), a neurokinin-1 receptor antagonist (NK1RA), has also become available, making it possible to administer the global standard of antiemetic therapy. This drug combination has resulted in a dramatic reduction in the incidence of emesis [2]. Sasaki H conducted a survey of patients’ top concerns during cancer chemotherapy, and reported that more patients were concerned about nausea than vomiting [3]. These results suggest that, whereas advances in antiemetic drugs have reduced the incidence of emesis, the management of nausea remains inadequate and significantly affects the quality of life of patients undergoing chemotherapy.

Chemotherapy including anthracycline and cyclophosphamide is a standard treatment that plays an important role in breast cancer chemotherapy. At the time this study was planned in 2018, the antiemetic guidelines of the American Society of Clinical Oncology (ASCO) and other guidelines stated that anthracycline/cyclophosphamide (AC) or cyclophosphamide/epirubicin/5-fluorouracil (CEF) therapy is considered highly emetogenic chemotherapy (HEC), and recommended prophylactic antiemetic therapy with a combination of 5HT3RA, NK1RA and dexamethasone (DEX) for its treatment [4]. Ito et al. [5] conducted a phase III study of this drug combination in Japan and found that complete response (CR) (defined as no vomiting episodes and no use of rescue medication) was achieved within 120 hours after AC therapy. In that study, the CR rate within 120 h after AC therapy was 46.9%, and the total control (TC) rate (defined as no vomiting, no use of rescue medications, and no nausea) was 29.6% [5]. Most patients with breast cancer are female and younger than those with other types of cancer. Since female sex and young age are risk factors for CINV, patients undergoing chemotherapy for breast cancer are generally at a high risk for CINV [6]. However, even temporary use of DEX in antiemetic therapy is associated with the risks of decreased bone density and diabetes mellitus [7, 8]. In addition, use of DEX to treat the side effects of immune checkpoint inhibitors might increase the risk of infections [9]. Therefore, adverse events caused by DEX used for antiemetic purposes are a problem in cancer patients. Saito et al. [10] reported an observational study of a 4-day course of DEX in patients being treated with AC and other therapies, and found that a reduction in the DEX dose on the first day was associated with an increased incidence of nausea, but a 2- to 4-day dose reduction did not affect nausea in the delayed phase. In clinical practice, we often encounter cases where DEX cannot be used for antiemesis, such as in cases with diabetes or hepatitis B. In Japan, Hashimoto et al. [11] suggested that a four-drug combination therapy, including 5HT3RA, NK1RA, DEX and olanzapine (OLN), is effective as standard antiemetic therapy in patients receiving HEC. Consequently, OLN has become available in Japan as the standard antiemetic therapy for HEC since October 2023. However, similar to DEX, it is contraindicated in diabetic patients and therefore cannot be used in these patients. Although dexamethasone constitutes a key component of standard prophylactic antiemetic regimens for HEC, its use is also contraindicated or avoided in a subset of patients due to comorbid conditions, such as diabetes mellitus, hepatitis, or psychiatric disorders. In such populations, clinicians were often forced to rely on nonstandard, steroidfree regimens without sufficient clinical evidence regarding their efficacy.

This paper presents valuable data evaluating the management of CINV in breast cancer patients undergoing HEC, along with the two-drug anti-emetic regimen of PALO and APR, under conditions where DEX or OLN cannot be used for CINV caused by HEC regimens containing AC and CEF. At the time this study was conducted (2014–2018), evidence guiding antiemetic management for patients in whom dexamethasone could not be administered was scarce. Additionally, realworld data describing nausea and vomiting outcomes under these circumstances were particularly limited. Therefore, the present study aimed to evaluate the incidence and severity of CINV in breast cancer patients receiving HEC who were managed with a dual antiemetic regimen consisting of a 5HT3RA and an NK1RA, in the absence of DEX. Although antiemetic strategies have evolved since then, including the introduction of OLNcontaining regimens, we believe that these findings provide important baseline data that underscore the unmet clinical needs in steroidineligible patients, and support the rationale for subsequent development of alternative antiemetic approaches.

In recent years, antibody–drug conjugates (ADCs) have become an important component of breast cancer treatment, with trastuzumab deruxtecan (T‑DXd) now widely used across multiple disease settings. Unlike conventional anthracycline- and cyclophosphamide-based regimens, T‑DXd is associated with a distinct safety profile, and persistent or delayed gastrointestinal toxicities, including prolonged nausea, have been increasingly recognized as a clinical challenge. Recent clinical studies and systematic analyses have reported delayed and sustained nausea during T‑DXd therapy, highlighting its negative impact on patient quality of life and treatment continuity [12, 13].

Several reports have demonstrated that the addition of olanzapine to standard antiemetic prophylaxis improves nausea control in patients receiving T‑DXd [14]. However, both dexamethasone and olanzapine may be contraindicated or difficult to use in patients with comorbidities such as diabetes mellitus because of metabolic adverse effects. Although our study population did not include patients treated with ADC-based therapies, our findings provide important baseline real-world evidence illustrating the limitations of dual antiemetic therapy consisting of a 5‑HT3 receptor antagonist and an NK1 receptor antagonist in high-risk settings when corticosteroids cannot be administered. In the current ADC era, these results underscore the unmet need for effective steroid- and olanzapine-sparing antiemetic strategies, which may become increasingly important for patients receiving newer ADC-based treatments.

Recently, guideline-recommended antiemetic therapy has been widely adopted in patients receiving HEC, and, in principle, the recommended therapies are implemented unless the patients have specific restrictions, such as hepatitis or diabetes mellitus. However, information on antiemetic efficacy when standard therapy cannot be administered is extremely scarce. The present study evaluated the antiemetic efficacy of 5-HT3 and NK1 receptor antagonists during HEC. A phase II trial comparing 3-day DEX administration with 1-day administration as a part of standard antiemetic therapy for AC showed no significant differences in overall CR rates (82.9% and 82.1%, respectively) and complete control (CC) (defined as no vomiting episodes, no use of rescue medication, and no more than mild nausea) rates between the two groups (48.8% and 61.5%, respectively) [15]. In addition, an observational study in Japan reported a significantly greater incidence of nausea with 1-day DEX administration (overall nausea incidence: 92%, grade $\ge$2 nausea incidence: 39%) compared with 4-day DEX administration (overall nausea incidence: 73%, grade $\ge$2 nausea incidence: 17%) [16]. Furthermore, a study evaluating CINV by dividing patients into groups receiving 4 or 8 mg/day of DEX on days 2–4 of AC therapy found no significant difference in the efficacy of 4 mg DEX (CR rate 28.6%, CC rate 47.6%) versus 8 mg DEX (CR rate 50.0%, CC rate 16.7%) [17].

In the present study, CINV was evaluated in patients in whom DEX was omitted to avoid increases in blood glucose levels or reactivation of hepatitis B during chemotherapy. The overall incidences of nausea were 84.1% (all grades) and 47.6% (grade $\ge$2), which was similar to the incidence in the 1-day DEX group compared with the 4-day DEX group in the previous study [16]. The CR rate in the present study was 8.5%, which was lower than in the other studies mentioned above. This is thought to be due to the high incidence of vomiting (14.6%) and the high proportion of additional antiemetic drug usage. The increased usage of additional anti-emetics in this study could be related to the fact that when DEX was withheld from the subjects in this study, healthcare providers thoroughly explained to the patients before treatment that standard antiemetic therapy could not be administered, which could have led to early and proactive use of rescue medications, which significantly affected the CR rate.

Furthermore, 2.4% of patients required dose reduction in the subsequent chemotherapy course due to nausea and vomiting. It has been suggested that maintaining a treatment intensity of 85% or higher has beneficial effects on the prognosis of perioperative breast cancer treatment [2], indicating that sufficient alternative measures are needed to avoid dose reductions when standard antiemetic therapy cannot be implemented. Furthermore, severe CINV can lead to anticipatory nausea and vomiting, complicating subsequent treatment [18], which highlights the importance of controlling CINV.

In future, when performing AC therapy, three-drug combination therapy including OLN should be implemented in patients in whom DEX is contraindicated due to hepatitis or other reasons. Saito et al. [10] demonstrated the efficacy of a four-drug combination therapy, including 5 mg OLN, in a Phase III trial for triple-drug antiemetic therapy in AC. Their results suggested that when DEX cannot be used, OLN can be one of the treatment options. However, in patients with diabetes mellitus, OLN is contraindicated, and DEX should be avoided due to the risk of hyperglycemia. Therefore, an alternative combination of antiemetic drugs other than OLN and DEX should be considered. For example, metoclopramide, which is recommended by various guidelines for breakthrough nausea and vomiting, lorazepam [19] or alprazolam [20], which are recommended for anticipatory nausea and vomiting, are other options. In addition, mirtazapine, which has antagonistic effects on receptors such as 5-HT₃ and H₁ that are related to emesis, and can be used in patients with concomitant diabetes mellitus or hepatitis, has been suggested to have antiemetic effects in observational studies and may be one of the options for CINV in these patients [21, 22].

In this study, analysis was performed for factors such as treatment regimens, age, gender, history of alcohol consumption, prior chemotherapy, and reasons for not using DEX; however, no significant correlations were observed between these factors and CINV. The following limitations of this study should be noted. Although factors such as nausea, motion sickness, and insomnia have also been suggested as risk factors for CINV [23], these factors could not be evaluated in this study. Other limitations include the retrospective, single-center nature of the study, the fact that rescue antiemetics were pre-prescribed in 81.7% of cases (which may have influenced CINV occurrence or severity), and the lack of patient-reported outcomes (PROs), potentially limiting the accuracy of CINV assessment. Further, since the sample size was small, insufficient power cannot be ruled out. Further studies with larger sample sizes are needed to confirm our results.

In breast cancer patients receiving HEC, a two-drug antiemetic regimen consisting of PALO and APR without DEX might be insufficient for control of CINV. This highlights the need for alternative prophylactic antiemetic strategies in patients who are ineligible for DEX, and supports the development and optimization of steroid-sparing antiemetic approaches in clinical practice.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Study conception: WS, TT, MY; study design: WS, KS, TY, KKaw, TA; data acquisition: WS, TS, NS, MH, KKob, KS. WS drafted and revised the manuscript. All authors have revised and approved the final version. All authors contributed to editorial changes in the manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study was approved by the Medical Ethics Review Board of the Japanese Foundation for Cancer Research, Cancer Institute Hospital (IRB approval number: 2018-GA-1113, approval date: October 1, 2018). This study was also approved by the Cancer Research Institute Medical Research Ethics Committee. The study complied with the Declaration of Helsinki, and patient informed consent was obtained through an opt-out method on our hospital’s website.

The authors would like to acknowledge the contributions of all those who contributed to this article and all the participants. The authors would also like to thank FORTE Science Communications for English language editing.

This research received no external funding.

All authors declare that the following competing interests are outside the submitted work. WS reports personal fees from AstraZeneca and Eli Lilly Japan K.K. outside the submitted work. KS reports personal fees from Taiho, Daiichi-Sankyo, Bristol Myers Squibb, Takata Pharmaceutical, Nippon Kayaku, and Nipro Pharma outside the submitted work. TY reports personal fees from AstraZeneca, Astellas Pharma Inc., Janssen Pharmaceutical K.K., and Ono Pharmaceuticals outside the submitted work. TA reports personal fees from Ono Pharmaceuticals, Yakult Pharmaceutical Industry Co., Ltd., and Taiho Pharmaceutical Co., Ltd. outside the submitted work. NS reports personal fees from AbbVie GK, Astellas Pharma Inc., and Nippon Shinyaku Co., Ltd. outside the submitted work. MH reports personal fees from Bayer and Merck & Company, Inc. outside the submitted work. KK reports personal fees from Ono Pharmaceuticals, Astellas Pharma Inc., and Daiichi Sankyo Company, Ltd. outside the submitted work. TT reports personal fees from Chugai, Daiichi-Sankyo, and Eli Lilly outside the submitted work. MY reports personal fees from Daiichi Sankyo Company, Ltd., Takata Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd, Eisai Co., Ltd., and AbbVie GK outside the submitted work.