Support Care Cancer DOI 10.1007/s00520-015-2760-3
ORIGINAL ARTICLE
Palonosetron in combination with 1-day versus 3-day dexamethasone to prevent nausea and vomiting in patients receiving paclitaxel and carboplatin Naoto Furukawa 1 & Seiji Kanayama 2 & Yasuhito Tanase 2 & Fuminori Ito 2
Received: 30 January 2015 / Accepted: 27 April 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose The aim of the present study was to evaluate the efficacy and toxicity of palonosetron (PAL) and dexamethasone (DEX) on day 1 only in patients with gynecologic cancer receiving paclitaxel combined with carboplatin (TC). The primary endpoint was to evaluate the complete response (CR) rate in the delayed phase. Methods This study was a randomized phase 2. Regardless of assignment to either study arm, all patients received an intravenous prophylactic regimen of DEX (20 mg) within 15 min and then an intravenous dose of PAL (0.75 mg) as a bolus given 30 min before initiation of TC on day 1. Patients in the DEX 1-day group received no additional DEX on days 2 and 3. Patients in the DEX 3-day group received DEX (8 mg) orally on days 2 and 3. Results Eighty-two patients had evaluable data on the primary outcome. The CR rates in the delayed phase between the two groups were not statistically significantly different (3-day group, 76.9 % [30/39]; 1-day group 69.8 % [30/43]; p= 0.4652). The frequency of constipation and insomnia which were antiemetic treatment-related adverse events was similar between two groups, and no serious adverse events occurred. Conclusions Administration of a combination of PAL and DEX 1 day may prevent chemotherapy-induced nausea and vomiting (CINV) in the delayed phase for TC as well as
* Naoto Furukawa [email protected] 1
Department of Obstetrics and Gynecology, Nara Prefecture Western Medical Center, 1-14-16 Mimuro, Sango-cho, Ikoma-gun, Nara 636-0802, Japan
2
Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
administration of DEX 3 days. Further evaluation of the antiemetic regimen of combination of PAL and DEX 1 day for TC is warranted in future phase 3 trials.
Keywords Chemotherapy-induced nausea and vomiting . Paclitaxel and carboplatin . Dexamethasone . Palonosetron
Introduction Paclitaxel combined with carboplatin (TC) is classified as a moderately emetogenic intravenous chemotherapeutic agent (MEC), and the regimen is frequently used to treat patients with gynecologic malignancies. According to current guidelines [1–3], the combination of palonosetron (PAL) and 3-day dexamethasone (DEX) is the standard antiemetic treatment in patients receiving MECs. PAL has prolonged efficacy in preventing chemotherapy-induced nausea and vomiting (CINV), because PAL, a second-generation 5-hydroxytryptamine (5-HT3) receptor antagonist, has higher binding affinity with 5-HT3 receptors [4] and a longer plasma half-life than other 5-HT3 receptor ligands [5]. Therefore, PAL may prevent CINV in the delayed phase without DEX on days 2 and 3. In addition, a prophylactic regimen of DEX (20 mg) plus a histamine-1 and histamine-2 receptor antagonist is recommended for hypersensitivity reaction to paclitaxel. Therefore, DEX may cause side effects in patients receiving TC. Patients receiving DEX for antiemesis reported moderate to severe problems, including insomnia (45 %), indigestion/epigastric discomfort (27 %), and agitation (27 %) in the week following chemotherapy [6]. The aim of the present study was to evaluate the efficacy and toxicity of PAL and DEX on day 1 only in patients with gynecologic cancer receiving TC.
Support Care Cancer
Patients and methods
Table 1
Antiemetic regimens Day 1
Day 2
Day 3
PAL 0.75 mg DEX 20 mg PAL 0.75 mg DEX 20 mg
DEX 8 mg
DEX 8 mg
–
–
Study design DEX 3-day group
This study was a single institutional, prospective, randomized phase 2, open-label study to evaluate the efficacy of a DEX 1day regimen compared with a DEX 3-day regimen for the prevention of delayed CINV after TC. This study randomized patients (1:1) to either a DEX 1-day regimen or a DEX 3-day regimen using stratified blocked randomization. Random assignment, stratified by age (>50 years or ≤50 years) and habitual alcohol intake (≥5 times a week; yes or no), was performed. Paclitaxel (175 mg/m2) was administered as a 3-h intravenous infusion followed by a 1-h intravenous infusion of carboplatin to an area under the curve of 5. The antiemetic regimens for the two groups are listed in Table 1. Regardless of assignment to either study arm, all patients received an intravenous prophylactic regimen of DEX (20 mg) plus 50 mg of diphenhydramine and 50 mg of ranitidine within 15 min and then an intravenous dose of PAL (0.75 mg) as a bolus given 30 min before initiation of TC on day 1. Patients in the DEX 1-day group received no additional DEX on days 2 and 3. Patients in the DEX 3-day group received DEX (8 mg) orally on days 2 and 3. After chemotherapy, rescue medication including DEX and/or metoclopramide for the treatment of CINV was permitted. Patients Patients were enrolled from April 2012 to January 2014. Eligible patients were chemotherapy-naïve women ≥20 years of age with a confirmed diagnosis of gynecologic malignancy and scheduled to receive TC (paclitaxel 175 mg/m2 and carboplatin of area under the curve=5). Patients with clinical evidence of heart failure, diabetes mellitus, bowel obstruction, or symptomatic brain metastases were not eligible. The protocol was approved by the institutional review boards of Nara Medical University and was registered in the University Medical Information Network Clinical Trials Registry as No. 000007491. Assessments Nausea and vomiting for the first cycle were evaluated with the Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT). The primary endpoint was the complete response (CR: no emetic episodes and no rescue medication) rate in the delayed phase for the first cycle. Secondary endpoints were the CR rates in the acute and overall phases for the first cycle; complete control (CC: no emetic episodes, no use of rescue medication, and no significant nausea) rate in acute, delayed, and overall phase for the first cycle; and total control (TCon: no emetic episodes, no use of rescue
DEX 1-day group
DEX dexamethasone, PAL palonosetron
medication, and no nausea) rate in acute, delayed, and overall phase for the first cycle. No significant nausea was defined as a MAT score ≤3. Adverse events related to the study treatment were considered antiemetic treatment-related adverse events and were evaluated according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Statistical design The primary efficacy hypothesis was that PAL plus DEX on day 1 only was non-inferior to PAL plus DEX for 3 days, estimated at 65 % [7, 8], using a non-inferiority margin of a 15 % difference between groups in the proportion of patients who had a delayed CR. A sample size of 42 subjects per group was considered sufficient to test the null hypothesis with 80 % power and an alpha error of 0.05, taking into account a 10 % dropout rate. To assess non-inferiority for the primary endpoint of CR rate in the delayed phase, the lower boundary of the two-sided 95 % confidence interval for the difference (DEX 1-day regimen minus DEX 3-day regimen) between the CR rates in the delayed phase in the two regimen arms was compared with the preset threshold. Exploratory analysis of predictive factors for delayed CR was performed by logistic regression analysis. Variables with p values of 50 Ovarian cancer vs. others DEX 3-day regimen vs. DEX 1-day regimen PS 0 vs. 1–2 Habitual alcohol intake, yes vs. no No ascites vs. ascites
Univariate odds ratio (95 % confidence interval)
Multivariate odds ratio (95 % confidence interval)
3.92 (1.30–12.12) 0.65 (0.25–1.72) 1.44 (0.54–3.98) 2.31 (0.83–6.39) 0.45 (0.09–2.47) 2.10 (0.56–7.44)
4.19 (1.36–13.25)
CR complete response, DEX dexamethasone, PS performance status
0.37 (0.07–2.13)
Support Care Cancer
dose of 0.75 mg is adopted, and thus this dose was used in the present study. A PAL dose of 0.75 mg is effective for MEC. The present study was conducted to evaluate the side effects related to DEX in addition to CR in the delayed phase. The frequency of side effects, however, did not differ between the DEX 3-day and DEX 1-day groups, and side effects in the present study were not severe (grade 1 insomnia in 12.8 and 16.3 % in DEX 3-day and DEX 1-day, respectively). Evaluation of side effects from DEX administered for prophylaxis against delayed emesis after MEC indicated moderate to severe insomnia in 45 % [6]. In the present study, CR, CC, and Tcon did not differ significantly between the DEX 3-day and DEX 1-day groups. On the other hand, contrary to our expectation, the frequency of side effects was not significantly different between the two groups. A randomized phase 3 study should be conducted to evaluate the efficacy and safety of DEX 1-day in combination with PAL to prevent CINV in patients receiving TC. Some reports indicate that female, younger age, and habitual alcohol drinking and smoking are important risk factors for predicting a higher risk for CINV [15–20]. There is basically a high risk for CINV in gynecologic oncology. Risk factors for CINV were analyzed using data of a phase 3 study in patients with breast cancer receiving anthracycline plus cyclophosphamide-based chemotherapy with a combination of ondansetron and DEX and aprepitant as an antiemetic regimen [21]. Based on analysis of these data, age ≥55 years, alcohol use, and no history of morning sickness associated with pregnancy were all significantly associated with a decreased likelihood of experiencing vomiting. On the other hand, another report indicated that younger age (
ORIGINAL ARTICLE
Palonosetron in combination with 1-day versus 3-day dexamethasone to prevent nausea and vomiting in patients receiving paclitaxel and carboplatin Naoto Furukawa 1 & Seiji Kanayama 2 & Yasuhito Tanase 2 & Fuminori Ito 2
Received: 30 January 2015 / Accepted: 27 April 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose The aim of the present study was to evaluate the efficacy and toxicity of palonosetron (PAL) and dexamethasone (DEX) on day 1 only in patients with gynecologic cancer receiving paclitaxel combined with carboplatin (TC). The primary endpoint was to evaluate the complete response (CR) rate in the delayed phase. Methods This study was a randomized phase 2. Regardless of assignment to either study arm, all patients received an intravenous prophylactic regimen of DEX (20 mg) within 15 min and then an intravenous dose of PAL (0.75 mg) as a bolus given 30 min before initiation of TC on day 1. Patients in the DEX 1-day group received no additional DEX on days 2 and 3. Patients in the DEX 3-day group received DEX (8 mg) orally on days 2 and 3. Results Eighty-two patients had evaluable data on the primary outcome. The CR rates in the delayed phase between the two groups were not statistically significantly different (3-day group, 76.9 % [30/39]; 1-day group 69.8 % [30/43]; p= 0.4652). The frequency of constipation and insomnia which were antiemetic treatment-related adverse events was similar between two groups, and no serious adverse events occurred. Conclusions Administration of a combination of PAL and DEX 1 day may prevent chemotherapy-induced nausea and vomiting (CINV) in the delayed phase for TC as well as
* Naoto Furukawa [email protected] 1
Department of Obstetrics and Gynecology, Nara Prefecture Western Medical Center, 1-14-16 Mimuro, Sango-cho, Ikoma-gun, Nara 636-0802, Japan
2
Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
administration of DEX 3 days. Further evaluation of the antiemetic regimen of combination of PAL and DEX 1 day for TC is warranted in future phase 3 trials.
Keywords Chemotherapy-induced nausea and vomiting . Paclitaxel and carboplatin . Dexamethasone . Palonosetron
Introduction Paclitaxel combined with carboplatin (TC) is classified as a moderately emetogenic intravenous chemotherapeutic agent (MEC), and the regimen is frequently used to treat patients with gynecologic malignancies. According to current guidelines [1–3], the combination of palonosetron (PAL) and 3-day dexamethasone (DEX) is the standard antiemetic treatment in patients receiving MECs. PAL has prolonged efficacy in preventing chemotherapy-induced nausea and vomiting (CINV), because PAL, a second-generation 5-hydroxytryptamine (5-HT3) receptor antagonist, has higher binding affinity with 5-HT3 receptors [4] and a longer plasma half-life than other 5-HT3 receptor ligands [5]. Therefore, PAL may prevent CINV in the delayed phase without DEX on days 2 and 3. In addition, a prophylactic regimen of DEX (20 mg) plus a histamine-1 and histamine-2 receptor antagonist is recommended for hypersensitivity reaction to paclitaxel. Therefore, DEX may cause side effects in patients receiving TC. Patients receiving DEX for antiemesis reported moderate to severe problems, including insomnia (45 %), indigestion/epigastric discomfort (27 %), and agitation (27 %) in the week following chemotherapy [6]. The aim of the present study was to evaluate the efficacy and toxicity of PAL and DEX on day 1 only in patients with gynecologic cancer receiving TC.
Support Care Cancer
Patients and methods
Table 1
Antiemetic regimens Day 1
Day 2
Day 3
PAL 0.75 mg DEX 20 mg PAL 0.75 mg DEX 20 mg
DEX 8 mg
DEX 8 mg
–
–
Study design DEX 3-day group
This study was a single institutional, prospective, randomized phase 2, open-label study to evaluate the efficacy of a DEX 1day regimen compared with a DEX 3-day regimen for the prevention of delayed CINV after TC. This study randomized patients (1:1) to either a DEX 1-day regimen or a DEX 3-day regimen using stratified blocked randomization. Random assignment, stratified by age (>50 years or ≤50 years) and habitual alcohol intake (≥5 times a week; yes or no), was performed. Paclitaxel (175 mg/m2) was administered as a 3-h intravenous infusion followed by a 1-h intravenous infusion of carboplatin to an area under the curve of 5. The antiemetic regimens for the two groups are listed in Table 1. Regardless of assignment to either study arm, all patients received an intravenous prophylactic regimen of DEX (20 mg) plus 50 mg of diphenhydramine and 50 mg of ranitidine within 15 min and then an intravenous dose of PAL (0.75 mg) as a bolus given 30 min before initiation of TC on day 1. Patients in the DEX 1-day group received no additional DEX on days 2 and 3. Patients in the DEX 3-day group received DEX (8 mg) orally on days 2 and 3. After chemotherapy, rescue medication including DEX and/or metoclopramide for the treatment of CINV was permitted. Patients Patients were enrolled from April 2012 to January 2014. Eligible patients were chemotherapy-naïve women ≥20 years of age with a confirmed diagnosis of gynecologic malignancy and scheduled to receive TC (paclitaxel 175 mg/m2 and carboplatin of area under the curve=5). Patients with clinical evidence of heart failure, diabetes mellitus, bowel obstruction, or symptomatic brain metastases were not eligible. The protocol was approved by the institutional review boards of Nara Medical University and was registered in the University Medical Information Network Clinical Trials Registry as No. 000007491. Assessments Nausea and vomiting for the first cycle were evaluated with the Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT). The primary endpoint was the complete response (CR: no emetic episodes and no rescue medication) rate in the delayed phase for the first cycle. Secondary endpoints were the CR rates in the acute and overall phases for the first cycle; complete control (CC: no emetic episodes, no use of rescue medication, and no significant nausea) rate in acute, delayed, and overall phase for the first cycle; and total control (TCon: no emetic episodes, no use of rescue
DEX 1-day group
DEX dexamethasone, PAL palonosetron
medication, and no nausea) rate in acute, delayed, and overall phase for the first cycle. No significant nausea was defined as a MAT score ≤3. Adverse events related to the study treatment were considered antiemetic treatment-related adverse events and were evaluated according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Statistical design The primary efficacy hypothesis was that PAL plus DEX on day 1 only was non-inferior to PAL plus DEX for 3 days, estimated at 65 % [7, 8], using a non-inferiority margin of a 15 % difference between groups in the proportion of patients who had a delayed CR. A sample size of 42 subjects per group was considered sufficient to test the null hypothesis with 80 % power and an alpha error of 0.05, taking into account a 10 % dropout rate. To assess non-inferiority for the primary endpoint of CR rate in the delayed phase, the lower boundary of the two-sided 95 % confidence interval for the difference (DEX 1-day regimen minus DEX 3-day regimen) between the CR rates in the delayed phase in the two regimen arms was compared with the preset threshold. Exploratory analysis of predictive factors for delayed CR was performed by logistic regression analysis. Variables with p values of 50 Ovarian cancer vs. others DEX 3-day regimen vs. DEX 1-day regimen PS 0 vs. 1–2 Habitual alcohol intake, yes vs. no No ascites vs. ascites
Univariate odds ratio (95 % confidence interval)
Multivariate odds ratio (95 % confidence interval)
3.92 (1.30–12.12) 0.65 (0.25–1.72) 1.44 (0.54–3.98) 2.31 (0.83–6.39) 0.45 (0.09–2.47) 2.10 (0.56–7.44)
4.19 (1.36–13.25)
CR complete response, DEX dexamethasone, PS performance status
0.37 (0.07–2.13)
Support Care Cancer
dose of 0.75 mg is adopted, and thus this dose was used in the present study. A PAL dose of 0.75 mg is effective for MEC. The present study was conducted to evaluate the side effects related to DEX in addition to CR in the delayed phase. The frequency of side effects, however, did not differ between the DEX 3-day and DEX 1-day groups, and side effects in the present study were not severe (grade 1 insomnia in 12.8 and 16.3 % in DEX 3-day and DEX 1-day, respectively). Evaluation of side effects from DEX administered for prophylaxis against delayed emesis after MEC indicated moderate to severe insomnia in 45 % [6]. In the present study, CR, CC, and Tcon did not differ significantly between the DEX 3-day and DEX 1-day groups. On the other hand, contrary to our expectation, the frequency of side effects was not significantly different between the two groups. A randomized phase 3 study should be conducted to evaluate the efficacy and safety of DEX 1-day in combination with PAL to prevent CINV in patients receiving TC. Some reports indicate that female, younger age, and habitual alcohol drinking and smoking are important risk factors for predicting a higher risk for CINV [15–20]. There is basically a high risk for CINV in gynecologic oncology. Risk factors for CINV were analyzed using data of a phase 3 study in patients with breast cancer receiving anthracycline plus cyclophosphamide-based chemotherapy with a combination of ondansetron and DEX and aprepitant as an antiemetic regimen [21]. Based on analysis of these data, age ≥55 years, alcohol use, and no history of morning sickness associated with pregnancy were all significantly associated with a decreased likelihood of experiencing vomiting. On the other hand, another report indicated that younger age (
