The study population comprised 42 patients who had been diagnosed with gynecological malignancies and treated with TC at Iwate Medical University between January, 2011 and March, 2013. For the assessment of therapeutic response, the following definitions were employed to describe CINV outcomes: i) complete response (CR), complete arrest/prevention of vomiting (no vomiting-related events, no antiemetic treatment -irrespective of the severity of nausea- and no rescue therapy); and ii) complete control (CC), complete control of vomiting-related episodes (no antiemetic treatment, only mild nausea, and no rescue therapy). The efficacy and safety of palonosetron + dexamethasone medications were evaluated by the self-completion method using the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (6) during an observation period lasting from day 1 through day 8 of the initial cycle of TC therapy. The severity of nausea was assessed using a visual analog scale (VAS) and scored as follows: mild, 1–2; moderate, 3–4; and severe, ≥ 5. The primary endpoint was the CR rate for the delayed period (24–96 h after initiation of TC therapy) and the secondary endpoints were as follows: i) CR rates for the acute period (0–24 h after the initiation of TC therapy) and for the overall period (0–96 h); ii) CC rates for the acute, delayed and overall periods after the initiation of TC therapy; iii) the severity of nausea during the acute, delayed and overall periods after the initiation of TC therapy; and iv) adverse reactions occurring during the observation period.

Subgroup analyses were performed to comparatively assess the delayed period CR rate in the following strata: age (≥55 vs. <55 years), body surface area (≥1.47 vs. <1.47 m²), performance status (PS) (0 vs. 1–2) and complications (present vs. absent).

Patients meeting all the following criteria were enrolled in this study: i) Aged ≥ 20 years at the time of enrollment; ii) diagnosed with gynecological cancer; iii) naïve to cancer chemotherapy or previous treatment with a single antineoplastic agent less potent than ‘drugs with slight emetogenic risk’ according to the NCCN Clinical Prectice Guidelines in Oncology (Antiemesis Version 4, 2009) (7) (however, use of hormone preparations for endocrinotherapy and use of antineoplastic agents for purposes other than cancer treatment were not considered as chemotherapy); iv) scheduled to receive the tri-weekly TC therapy regimen (paclitaxel 175 mg/m² and carboplatin area under the curve 6 administered on day 1); v) patients whose bone marrow and hepatic and renal functions were maintained and whose laboratory test values within 8 days prior to enrollment, including the day of enrollment, fulfilled the criteria of white blood cell count ≥ 3,000/mm³, aspartate aminotransferase and alanine aminotransferase < 100 IU/l [or grade ≤ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (8), in the case of hepatic metastasis evident on imaging] and creatinine clearance ≥ 60.0 ml/min; vi) Eastern Cooperative Oncology Group PS of 0 2; and vii) patients provided written informed consent to participate in this study.

The exclusion criteria were as follows: i) Severe uncontrollable complications, apart from malignant tumors (e.g., intestinal paralysis, pulmonary fibrosis, diabetes mellitus, heart failure, myocardial infarction, angina pectoris, renal failure, hepatic failure, mental disorders, cerebrovascular disorder and gastric/duodenal active ulcers); ii) symptomatic brain metastasis or clinical suspicion of brain metastasis; iii) convulsive disorder requiring treatment with anticonvulsants; iv) symptomatic ascites or pleural effusions requiring therapeutic paracentesis; v) pyloric stenosis or intestinal obstruction; vi) vomiting-related episodes or CTCAE v4.0 grade ≥ 2 nausea; vii) history of hypersensitivity to palonosetron or ingredients of any other 5-HT3RA preparation; viii) history of hypersensitivity to ingredients of dexamethasone preparations; ix) pregnancy, lactation, and/or refusal to practice contraception during the study period; x) past history of palonosetron use; xi) incapable or reluctant to cooperate with the procedures necessary for this study; and xii) any patients who were deemed inappropriate to be subjects of this study, for any reason, by the investigator (or coinvestigator).

On day 1, 0.75 mg/body of palonosetron and 19.8 mg/body of dexamethasone were dissolved in 100 ml of physiological saline and administered intravenously over 15 min immediately prior to TC therapy. Dexamethasone in daily doses of 6.6 mg/body in 100 ml physiological saline was also administered intravenously on days 2 and 3 (Fig. 1).

Dexamethasone preparations were contraindicated, unless otherwise specified, from 24 h prior to the administration of palonosetron until completion of the observation period. From 24 h prior to the administration of palonosetron until day 5, concomitant use of any of the following drugs with an antiemetic effect was prohibited, except for use as post-TC antiemetic treatment (rescue therapy): i) NK₁ receptor antagonist antiemetics; ii) 5-HT3RA antiemetics; iii) all adrenocortical steroids except dexamethasone; iv) antidopaminergic drugs, such as metoclopramide and domperidone; v) phenothiazine antipsychotics, such as prochlorperazine and perphenazine; vi) antihistamines; vii) all benzodiazepines, except for the use of triazolam for insomnia as needed; and viii) other drugs, including haloperidol, droperidol, scopolamine and olanzapine. Concomitant use of serotonin-specific reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors was also prohibited from 24 h prior to the administration of palonosetron through day 5.

Logistic regression analysis was used for comparison of background variables. Inter-group or inter-subgroup differences were considered to be statistically significant when P<0.05.

The data for background variables are presented in Table I. The median age was 60.5 years (range, 32–83 years) and the median body surface area was 1.44 m² (range, 1.19-1.87 m²). The PS score was 0 in 34, 1 in 4 and 2 in 4 patients. The diagnosis was uterine cervical cancer in 2 patients, endometrial cancer in 18, ovarian cancer in 21 and triple cancer in 1 patient. Of the 42 patients, 29 received TC therapy as adjuvant chemotherapy and 13 as systemic chemotherapy. A total of 10 patients developed complications (diabetes mellitus in 4; hypertension in 3; thrombosis in 2; and arrhythmia, hyperlipidemia, insomnia and osteoarthritis of the hip in 1 patient each), whereas 32 patients had no concurrent disorders.

For the acute, delayed and overall periods, the CR rates were 95.2, 90.5 and 85.7%, respectively, whereas the CC rates were 90.5, 85.7 and 78.6%, respectively (Table II). The severity grades of nausea during the acute, delayed and overall periods were 0.45±1.38, 1.13±2.40, and 0.79±1.99, respectively. Episodes of nausea occurred in 4 patients during the acute phase, 7 during the delayed period and 9 during the overall period. The mean severity grades of nausea for the patients with this adverse event during the periods investigated in this study were 3.17±2.19, 3.96±2.99, and 3.69±2.77, respectively (data not shown).

Rescue therapy was administered to 2, 4, and 6 patients during the acute, delayed and overall periods, respectively. Granisetron and dexamethasone were prescribed for this purpose in the 2 patients with nausea during the acute period. Granisetron and dexamethasone were used for this purpose during the delayed period in all 4 affected patients, whereas 1 patient who responded poorly also received an additional ramosetron regimen (Table III).

The subgroup analysis results are summarized in Table IV. Higher delayed period CR rates were recorded for the following subgroups: age <55 years, body surface area ≥ 1.47 m², PS score 0 and absence of complications.

Adverse event data are presented in Table V. As regards non-hematotoxic adverse events, grade ≥ 2 constipation and diarrhea occurred in 1 patient (2.4%) each. No grade ≥ 3 hematotoxicities were identified when the blood biochemical test parameters were measured.