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      Open-label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron

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          Abstract

          The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1–3 in combination with palonosetron (PALO), a second-generation 5-HT3 receptor antagonist, for chemotherapy-induced nausea and vomiting (CINV) in non-anthracycline and cyclophosphamide (AC) moderately-emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi-center, randomized, open-label, non-inferiority design. Patients who received non-AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2–3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non-inferiority margin was set at −15% (study treatment group − control group). From April 2011 to March 2013, 305 patients who received non-AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group ( N = 151) and 63.6% in the control group ( N = 154). PALO plus DEX day 1 was non-inferior to PALO plus DEX days 1–3 (difference, 2.5%; 95% confidence interval [CI]: −7.8%–12.8%; P-value for non-inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti-emetic DEX administration on days 2–3 may be eliminated when used in combination with PALO in patients receiving non-AC MEC.

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          Most cited references 14

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          Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference.

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            Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial.

            Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist that has shown better efficacy than ondansetron and dolasetron in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy, and similar efficacy to ondansetron in preventing CINV in patients receiving highly emetogenic chemotherapy. In this phase III, multicentre, randomised, double-blind, double-dummy, stratified, parallel-group, active-comparator trial, we assessed the efficacy and safety of palonosetron versus granisetron for chemotherapy-induced nausea and vomiting, both of which were administered with dexamethasone in patients receiving highly emetogenic chemotherapy. Between July 5, 2006, and May 31, 2007, 1143 patients with cancer who were receiving highly emetogenic chemotherapy (ie, cisplatin, or an anthracycline and cyclophosphamide combination [AC/EC]) were recruited from 75 institutions in Japan, and randomly assigned to either single-dose palonosetron (0.75 mg), or granisetron (40 microg/kg) 30 min before chemotherapy on day 1, both with dexamethasone (16 mg intravenously) on day 1 followed by additional doses (8 mg intravenously for patients receiving cisplatin or 4 mg orally for patients receiving AC/EC) on days 2 and 3. A non-deterministic minimisation method with a stochastic-biased coin was applied to the randomisation of patients. Covariates known to effect emetic risk, such as sex, age, and type of highly emetogenic chemotherapy, were used as stratification factors of minimisation to ensure balance between the treatment groups. Primary endpoints were the proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) during the acute phase (0-24 h postchemotherapy; non-inferiority comparison with granisetron) and the proportion of patients with a complete response during the delayed phase (24-120 h postchemotherapy; superiority comparison with granisetron). The non-inferiority margin was predefined in the study protocol as a 10% difference between groups in the proportion of patients with complete response. The palonosetron dose of 0.75 mg was chosen on the basis of two dose-determining trials in Japanese patients. All patients who received study treatment and highly emetogenic chemotherapy were included in the efficacy analyses (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00359567. 1114 patients were included in the efficacy analyses: 555 patients in the palonosetron group and 559 patients in the granisetron group. 418 of 555 patients (75.3%) in the palonosetron group had complete response during the acute phase compared with 410 of 559 patients (73.3%) in the granisetron group (mean difference 2.9% [95% CI -2.70 to 7.27]). During the delayed phase, 315 of 555 patients (56.8%) had complete response in the palonosetron group compared with 249 of 559 patients (44.5%) in the granisetron group (p<0.0001). The main treatment-related adverse events were constipation (97 of 557 patients [17.4%] in the palonosetron group vs 88 of 562 [15.7%] in the granisetron group) and raised concentrations of serum aminotransferases (aspartate aminotransferase: 24 of 557 [4.3%] vs 34 of 562 [6.0%]; alanine aminotransferase: 16 of 557 [2.9%] vs 33 of 562 [5.9%]); no grade 4 main treatment-related adverse events were reported. When administered with dexamethasone before highly emetogenic chemotherapy, palonosetron exerts efficacy against chemotherapy-induced nausea and vomiting which is non-inferior to that of granisetron in the acute phase and better than that of granisetron in the delayed phase, with a comparable safety profile for the two treatments. Taiho Pharmaceutical (Tokyo, Japan).
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              Double-blind, randomised, controlled study of the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3 in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy.

               M Aapro,  A Fabi,  F Nolè (2010)
              To reduce side-effects of corticosteroid-containing antiemetic regimens, tailoring antiemetic schedules to specific requirements of different patients could be of benefit. We evaluated the possibility to reduce the total dose of corticosteroids when palonosetron, a long-acting second-generation 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonist, is used. Double-blind, multicentre, noninferiority study of chemotherapy-naive breast cancer patients receiving 0.25 mg palonosetron and 8 mg dexamethasone on day 1, randomly assigned to receive placebo (n = 151) or 4 mg b.i.d. dexamethasone (n = 149) on days 2 and 3. Primary end point was complete response (CR) rate (no emesis, no rescue medication) in the overall (days 1-5) period. Secondary end points were CR rates in the acute (day 1) and delayed (days 2-5) periods, rates of no emesis and no nausea and impact on daily functioning (Functional Living Index-Emesis). Noninferiority between the two treatments was demonstrated by similar CR rates (P = 0.487) in the overall period. Most parameters showed that palonosetron and dexamethasone on day 1 only offer chemotherapy-induced nausea and vomiting protection similar to multiple-day dexamethasone administration. In patients treated with a single injection of palonosetron on day 1, reducing dexamethasone is an option that is not associated with significant reduction in antiemetic control during the 5-day period or an impact on patient functioning.
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                Author and article information

                Journal
                Cancer Sci
                Cancer Sci
                cas
                Cancer Science
                John Wiley & Sons, Ltd (Chichester, UK )
                1347-9032
                1349-7006
                July 2015
                27 May 2015
                : 106
                : 7
                : 891-895
                Affiliations
                [1 ]Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center Sapporo, Japan
                [2 ]Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Sapporo, Japan
                [3 ]Cancer Center, Hokkaido University Hospital Sapporo, Japan
                [4 ]School of Health Sciences, Sapporo Medical University Sapporo, Japan
                [5 ]Surgery, Sapporo-Kosei General Hospital Sapporo, Japan
                [6 ]Department of Gastroenterology, Hakodate Municipal Hospital Hakodate, Japan
                [7 ]Department of Medical Oncology, KKR Sapporo Medical Center Sapporo, Japan
                [8 ]Department of Internal Medicine, Kushiro Rosai Hospital Kushiro, Japan
                [9 ]Surgery, Otaru Ekisaikai Hospital Otaru, Japan
                [10 ]Gastroenterology, Sapporo City General Hospital Sapporo, Japan
                [11 ]Respiratory Center, Asahikawa Medical University Asahikawa, Japan
                [12 ]Department of 3rd Internal Medicine, Obihiro Kousei General Hospital Obihiro, Japan
                [13 ]Internal Medicine, Tomakomai Nisshou Hospital Tomakomai, Japan
                [14 ]Gastroenterology, Tomakomai City Hospital Tomakomai, Japan
                [15 ]Gastroenterology, Oji General Hospital Tomakomai, Japan
                [16 ]Surgery, Iwamizawa Municipal General Hospital Iwamizawa, Japan
                [17 ]Gastroenterology, Japanese Red Cross Kitami Hospital Kitami, Japan
                [18 ]Surgery, Muroran City General Hospital Muroran, Japan
                [19 ]Gastroenterology, Sapporo Hokuyu Hospital Sapporo, Japan
                [20 ]Department of Biostatistics, Graduate School of Medicine, The University of Tokyo Tokyo, Japan
                [21 ]Department of Gastroenterology, Hokkaido Cancer Center Sapporo, Japan
                Author notes
                Correspondence Yoshito Komatsu, Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, North 14, West 5, Kita-ku, Sapporo 060-8638, Japan., Tel: +81-11-706-5657; Fax: +81-11-706-5657;, E-mail: ykomatsu@ 123456med.hokudai.ac.jp

                Funding InformationHokkaido Gastrointestinal Cancer Study Group(HGCSG)

                Trial Registration: UMIN000009403

                Article
                10.1111/cas.12675
                4520641
                25872578
                © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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