European Journal of Cancer (2015) xxx, xxx– xxx
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial Junichi Nishimura a,⇑, Taroh Satoh b, Mutsumi Fukunaga c, Hiroyoshi Takemoto c, Ken Nakata c, Yoshihito Ide d, Takayuki Fukuzaki e, Toshihiro Kudo b, Yasuhiro Miyake f, Masayoshi Yasui g, Shunji Morita h, Daisuke Sakai b, Mamoru Uemura a, Taishi Hata a, Ichiro Takemasa a, Tsunekazu Mizushima a, Yuko Ohno i, Hirofumi Yamamoto a, Mitsugu Sekimoto j, Riichiro Nezu k, Yuichiro Doki a, Masaki Mori a, Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO) a
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, Japan Department of Frontier-Science for Cancer and Chemotherapy, Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, Japan c Department of Surgery, Sakai City Hospital, Sakai-Ward Minami Yasui-cho 1-1-1, Sakai, Osaka, Japan d Department of Surgery, Yao Municipal Hospital, Ryugecho 1-3-1, Yao, Osaka, Japan e Department of Surgery, Ikeda Municipal Hospital, Jyounan 3-1-18, Ikeda, Osaka, Japan f Department of Surgery, Minoh City Hospital, Kayano 5-7-1, Minoh, Osaka, Japan g Department of Surgery, Kaizuka City Hospital, Hori 3-10-20, Kaizuka, Osaka, Japan h Department of Surgery, Toyonaka Municipal Hospital, Shibahara 4-14-1, Toyonaka, Osaka, Japan i Department of Mathematical Health Science, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka, Japan j Department of Surgery, National Hospital Organization, Osaka National Hospital, Hoenzakka 2-1-14, Osaka, Osaka, Japan k Department of Surgery, Nishinomiya Municipal Hospital, Hayashidacho 8-24, Nishinomiya, Hyogo, Japan b
Received 9 January 2015; received in revised form 17 March 2015; accepted 30 March 2015
KEYWORDS Aprepitant Oxaliplatin Moderately emetogenic
Abstract Introduction: The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin.
⇑ Corresponding author at: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. Tel.: +81 6 6879 3251; fax: +81 6 6879 3259. E-mail address: [email protected] (J. Nishimura).
http://dx.doi.org/10.1016/j.ejca.2015.03.024 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nishimura J. et al., Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.03.024
2
J. Nishimura et al. / European Journal of Cancer xxx (2015) xxx–xxx
chemotherapy Antiemetics
Methods: In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist + dexamethasone) or aprepitant group (5-HT3-receptor antagonist + dexamethasone + aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis. Results: A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups. Conclusion: The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
of action. When combined with other antiemetic drugs, they are expected to be effective for delayed nausea and vomiting (occurring at least 24 h after antineoplastic administration), which is currently poorly controlled by antiemetics [12]. In clinical studies, the efficacies of aprepitant and fosaprepitant were confirmed in subjects receiving chemotherapy with a high emetogenic risk [13– 15]. However, their efficacies with chemotherapies that have a moderate emetogenic risk have not been confirmed even though there were some clinical studies [16–18]. In addition, in the above-mentioned guidelines on the proper use of antiemetics, oxaliplatin is not one of the agents that combination therapy with aprepitant is recommended for. Thus, it is important to investigate the usefulness of aprepitant and fosaprepitant during oxaliplatin treatment, which is regarded to have a moderate emetogenic risk. We hypothesised that the patients who received oxaliplatin-based chemotherapy were at a high risk for chemotherapy-induced nausea & vomiting (CINV), and the use of aprepitant could reduce delayed CINV. We conducted a multicentre, randomised phase III study to evaluate the usefulness of the combined use of aprepitant in colorectal cancer patients treated with oxaliplatin.
Nausea and vomiting are frequent adverse events of cancer chemotherapy. Persistent nausea and vomiting is accompanied by decreased food and fluid intake, leading to dehydration, electrolyte abnormalities, weight loss, poor nutrition, etc., which markedly decrease the patient’s quality of life [1]. Therefore, it is very important to control and minimise nausea and vomiting to enable continuation of cancer chemotherapy. Oxaliplatin-based chemotherapies, namely FOLFOX therapy (5-fluorouracil + leucovorin + oxaliplatin) and XELOX therapy (capecitabine + oxaliplatin), are the standard treatments for colorectal cancer [2–5]. In recent guidelines, such as the National Comprehensive Cancer Network (NCCN) Antiemesis Guidelines version 22014 [6], Multinational Association of Supportive Care in Cancer (MASCC) antiemetic guidelines [7], the American Society of Clinical Oncology (ASCO) guidelines for antiemetics [8] and the Japanese guidelines on the proper use of antiemetics [9], FOLFOX and XELOX therapies are classified as having moderate emetogenic risk (emetogenic risk: 30–90% for the acute state, with a concern for the delayed state). In a phase III study (MOSAIC study) of FOLFOX therapy given as adjuvant chemotherapy, nausea and vomiting occurred at the high rates of 73.7% and 47.2%, respectively [10]. Moreover, in several phase III studies of XELOX therapy in patients with metastatic colorectal cancer, the rates of nausea and vomiting ranged from 60.5% to 66.6% and 42.7% to 44.2%, respectively [2,5,11]. Based on these findings, the control of nausea and vomiting in these oxaliplatin-based chemotherapies is inadequate, and a more optimal prophylactic control is needed. The NK1 receptor antagonists, aprepitant and fosaprepitant, are antiemetic drugs with novel mechanisms
2. Patients and methods 2.1. Inclusion criteria Patients aged 20 years and older who received an initial FOLFOX (oxaliplatin 85 mg/m2; levo-leucovorin 200 mg/m2; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion), XELOX (capecitabine 2000 mg/m2 orally on days 1–14 and oxaliplatin 130 mg/m2 intravenous infusion on day 1), or SOX (S-1 80 mg/m2 orally on days 1–14 and oxaliplatin
Please cite this article in press as: Nishimura J. et al., Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.03.024
J. Nishimura et al. / European Journal of Cancer xxx (2015) xxx–xxx
130 mg/m2 intravenous infusion on day 1) regimen including oxaliplatin at P85 mg/m2 (naive patient), or those who had already started chemotherapy and had nausea of Grade 2 or higher in the last course or an earlier course (non-naive patient) were included in this study. Colorectal cancer chemotherapy, neoadjuvant chemotherapy, adjuvant chemotherapy or recurrent/unresectable chemotherapy were included in this study. Institutional review boards at each study site approved the study protocol, and written informed consent was obtained from all participants before enrolment. Molecular targeted therapy was allowed. 2.2. Exclusion criteria Patients were excluded if they had severe liver or kidney disease; had nausea or vomiting within 24 h prior to chemotherapy; were treated with antiemetics within 24 h prior to chemotherapy; had any factors causing nausea or vomiting other than chemotherapy (e.g. gastrointestinal obstruction, active peptic ulcer disease, brain metastasis or other brain tumuors/lesions); had a disease precluding 3-day administration of dexamethasone (e.g. uncontrollable diabetes); were pregnant or lactating women, were planning on becoming pregnant; or were currently being treated with pimozide. 2.3. Study design This was a multicentre, randomised, controlled study conducted at 25 hospitals in Japan. Patients who provided written informed consent for participation in this study were assigned to receive either the two-drug combination treatment (5-HT3 receptor antagonist + dexamethasone) or the three-drug combination treatment (5-HT3 receptor antagonist + dexamethasone + aprepitant/fosaprepitant) in the first course of chemotherapy. All subjects received the three-drug combination treatment in the second course of chemotherapy. 5-HT3 receptor antagonist was each doctor’s choice. In this study, granisetron was used for 95 and 95 patients, ramosetron for 15 and 17 patients, azasetron for 2 and 0 patients, indisetron for 0 and 1 patient and palonosetron for 84 and 88 patients in the control and the aprepitant group, respectively. Patients who received the two-drug combination treatment in the first course of chemotherapy were defined as the control group, and those who received the three-drug combination treatment were defined as the aprepitant group. The allocation of patients was performed using the minimisation method with age, sex, chemotherapy-naı¨ve/non-naı¨ve status, regimen (FOLFOX, XELOX or SOX) and study centre as the adjustment factors. The trial was registered with ClinicalTrials.gov, number NCT01344304.
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2.4. Treatment protocol All patients took a 5-HT3 receptor antagonist intravenously on day 1. Patients in the aprepitant group received oral aprepitant (125 mg) plus an intravenous 5-HT3 receptor antagonist and dexamethasone (6.6 mg) on day 1, and aprepitant (80 mg) and oral dexamethasone (2 mg) twice daily on days 2 and 3. In cases using fosaprepitant, patients received intravenous fosaprepitant (150 mg) plus 5-HT3 receptor antagonist and dexamethasone (6.6 mg) on day 1, oral dexamethasone (2 mg) twice daily on day 2 and oral dexamethasone (4 mg) twice daily on day 3. Patients in the control group took intravenous 5-HT3 receptor antagonist plus dexamethasone (9.9 mg) on day 1, followed by oral dexamethasone (4 mg) twice daily on days 2 and 3. In the second cycle, all patients received aprepitant or fosaprepitant by the protocol mentioned above. 2.5. Assessments From day 1 to the morning of day 6, patients recorded their response in a diary. The use of rescue therapy, defined as any medication taken to treat nausea and vomiting, was also recorded. For nausea, patients evaluated the most severe intensity on a four-grade scale (0, none; 1, mild; 2, moderate; 3, serious) once daily. No nausea and mild nausea were counted as no significant nausea. For vomiting, patients recorded the frequency. Retches were also included as vomiting. Vomiting episodes occurring with an interval of less than 1 min were counted as a single event. Tolerability was monitored by physical examinations and laboratory studies. Nausea and vomiting occurring after the efficacy evaluation period (up to the morning of day 6) were handled as adverse events. Toxicity grades were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 4.0. 2.6. Statistical analysis The sample size was calculated under the following assumptions. In an overseas aprepitant phase III study of chemotherapy with a moderate emetogenic risk, the complete vomiting inhibition rate in the overall phase (0–120 h after antineoplastic drug administration) of chemotherapy, excluding AC therapy (adriamycin + cyclophosphamide), was 83.2% in the aprepitant group, which was significantly higher compared with the rate of 70.9% in the standard treatment group (p < 0.05). If equivalent results were obtained in this study and the chi-square test, 5% level of significance (a = 0.05), and a detection power of 80% (b = 0.2) were used, the required number of subjects per group was 182. Therefore, considering a dropout rate of
Please cite this article in press as: Nishimura J. et al., Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.03.024
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J. Nishimura et al. / European Journal of Cancer xxx (2015) xxx–xxx
approximately 10%, the scheduled number of subjects in this study was set at 200 per group (400 subjects in total). The full analysis set (FAS) was defined as the group of subjects that were registered in this study and allocated to a treatment group before patient exclusion. The per-protocol set was defined as the group of subjects that were not excluded from the FAS owing to major violations such as a violation of the inclusion/exclusion criteria and patients who did not keep a symptom diary. The primary efficacy end-point was the complete vomiting inhibition rate in the overall phase. The second efficacy end-points were the proportion of patients with a complete response (no vomiting and no rescue medication use), patients with complete protection (no vomiting, no rescue medication use and no moderate or worsened nausea), patients with no nausea and patients with mild nausea (no significant nausea). Efficacy was also evaluated exploratively in the acute and delayed phases. The chi-square test was used to compare the two groups with respect to all end-points expressed by a binary variable. Wilcoxon’s rank-sum test was used to compare the two means. McNemar’s test was used to evaluate the efficacies of the first and second cycles of chemotherapy in the control group (salvage effect). All tests were two sided, and a significance level of 0.05 was used. Relative risk (RR) and 95% confidence interval (CI) were reported.
3. Results 3.1. Patients A total of 413 patients from 25 hospitals in Japan were randomly assigned to either the aprepitant group or the control group (Fig. 1). Five patients (three in the control group and two in the aprepitant group) were randomised into the study even though they did not meet all inclusion criteria. Ten patients (seven in the control group and three in the aprepitant group) refused chemotherapy after randomisation. For the second cycle of chemotherapy, 16 patients (seven in the control group and nine in the aprepitant group) did not receive oxaliplatin-based chemotherapy. Ten patients (four in the control group and six in the aprepitant group) received oxaliplatin at a dose lower than 85 mg/m2 for the second cycle chemotherapy. Six patients did not record their response in the diary. Patient characteristics and treatment regimens are listed in Table 1. Both groups were similar with respect to baseline characteristics. The majority of patients were male (61.0%, males/females: 252/161), treated with the XELOX or SOX regimen (73.8%, XELOX or SOX/ FOLFOX: 305/108) and naı¨ve (93.0%, naı¨ve/non-naı¨ve 384/29) with an average age of 64.2 years. In the aprepitant group, oral aprepitant was used in 184 patients and,
intravenous fosaprepitant was used in three patients in the first cycle. 3.2. Efficacy in the first cycle The proportion of the patients in both groups who had no vomiting overall and in the acute and delayed phases are shown in Fig. 2. The aprepitant group had significantly higher rates of no vomiting overall (95.7% versus 83.6%; RR 1.1449; 95% CI, 1.07–1.23; p < 0.0001), as well as in the separate analyses of both the acute phase (100% versus 96.7%; RR 1.0339; 95% CI, 1.01–1.06; p = 0.013) and, notably, the delayed phase (95.7% versus 84.7%; RR 1.1301; 95% CI, 1.06– 1.21; p = 0.0003) compared with the control group. The results for the other end-points are shown in Table 2. The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. For the acute phase, there was no significant difference between the two groups for the percentages of no nausea, no significant nausea, complete response and complete protection. However, a significantly greater percentage of patients in the aprepitant group than the control group experienced no significant nausea (88.8% versus 81.4%; RR 1.0903; 95% CI, 1.00–1.19; p = 0.047), complete response (85.0% versus 75.4%; RR 1.1275; 95% CI, 1.02–1.25; p = 0.02) and complete protection (79.7% versus 69.4%; RR 1.1481; 95% CI, 1.02–1.30; p = 0.02) in the delayed phase. The number of patients who received palonosetron in the first cycle was 157 (78 in the control group and 79 in the aprepitant group; not significant). There was no significant difference in the proportion of patients with no vomiting when comparing those that used palonosetron with those that did not (89.2% versus 90.1%, not significant). Whether palonosetron was used or not, the percentage of no vomiting was higher in the aprepitant group (with palonosetron: 82.1% versus 96.2%; RR 1.1725; 95% CI, 1.05–1.31; p = 0.005; without palonosetron: 84.8% versus 95.4%; RR 1.1252; 95% CI, 1.03– 1.24; p = 0.009; in the control versus aprepitant group, respectively, Fig 3). 3.3. Efficacy of aprepitant as salvage therapy In the second cycle, both groups were treated with aprepitant therapy. Seven patients in the control group and nine patients in the aprepitant group were not treated with oxaliplatin-based chemotherapy due to adverse events. Four patients in the control group and seven patients in the aprepitant group did not meet inclusion criteria due to a lower dose of oxaliplatin (
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial Junichi Nishimura a,⇑, Taroh Satoh b, Mutsumi Fukunaga c, Hiroyoshi Takemoto c, Ken Nakata c, Yoshihito Ide d, Takayuki Fukuzaki e, Toshihiro Kudo b, Yasuhiro Miyake f, Masayoshi Yasui g, Shunji Morita h, Daisuke Sakai b, Mamoru Uemura a, Taishi Hata a, Ichiro Takemasa a, Tsunekazu Mizushima a, Yuko Ohno i, Hirofumi Yamamoto a, Mitsugu Sekimoto j, Riichiro Nezu k, Yuichiro Doki a, Masaki Mori a, Multi-center Clinical Study Group of Osaka, Colorectal Cancer Treatment Group (MCSGO) a
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, Japan Department of Frontier-Science for Cancer and Chemotherapy, Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, Japan c Department of Surgery, Sakai City Hospital, Sakai-Ward Minami Yasui-cho 1-1-1, Sakai, Osaka, Japan d Department of Surgery, Yao Municipal Hospital, Ryugecho 1-3-1, Yao, Osaka, Japan e Department of Surgery, Ikeda Municipal Hospital, Jyounan 3-1-18, Ikeda, Osaka, Japan f Department of Surgery, Minoh City Hospital, Kayano 5-7-1, Minoh, Osaka, Japan g Department of Surgery, Kaizuka City Hospital, Hori 3-10-20, Kaizuka, Osaka, Japan h Department of Surgery, Toyonaka Municipal Hospital, Shibahara 4-14-1, Toyonaka, Osaka, Japan i Department of Mathematical Health Science, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka, Japan j Department of Surgery, National Hospital Organization, Osaka National Hospital, Hoenzakka 2-1-14, Osaka, Osaka, Japan k Department of Surgery, Nishinomiya Municipal Hospital, Hayashidacho 8-24, Nishinomiya, Hyogo, Japan b
Received 9 January 2015; received in revised form 17 March 2015; accepted 30 March 2015
KEYWORDS Aprepitant Oxaliplatin Moderately emetogenic
Abstract Introduction: The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin.
⇑ Corresponding author at: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan. Tel.: +81 6 6879 3251; fax: +81 6 6879 3259. E-mail address: [email protected] (J. Nishimura).
http://dx.doi.org/10.1016/j.ejca.2015.03.024 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nishimura J. et al., Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.03.024
2
J. Nishimura et al. / European Journal of Cancer xxx (2015) xxx–xxx
chemotherapy Antiemetics
Methods: In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist + dexamethasone) or aprepitant group (5-HT3-receptor antagonist + dexamethasone + aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis. Results: A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups. Conclusion: The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
of action. When combined with other antiemetic drugs, they are expected to be effective for delayed nausea and vomiting (occurring at least 24 h after antineoplastic administration), which is currently poorly controlled by antiemetics [12]. In clinical studies, the efficacies of aprepitant and fosaprepitant were confirmed in subjects receiving chemotherapy with a high emetogenic risk [13– 15]. However, their efficacies with chemotherapies that have a moderate emetogenic risk have not been confirmed even though there were some clinical studies [16–18]. In addition, in the above-mentioned guidelines on the proper use of antiemetics, oxaliplatin is not one of the agents that combination therapy with aprepitant is recommended for. Thus, it is important to investigate the usefulness of aprepitant and fosaprepitant during oxaliplatin treatment, which is regarded to have a moderate emetogenic risk. We hypothesised that the patients who received oxaliplatin-based chemotherapy were at a high risk for chemotherapy-induced nausea & vomiting (CINV), and the use of aprepitant could reduce delayed CINV. We conducted a multicentre, randomised phase III study to evaluate the usefulness of the combined use of aprepitant in colorectal cancer patients treated with oxaliplatin.
Nausea and vomiting are frequent adverse events of cancer chemotherapy. Persistent nausea and vomiting is accompanied by decreased food and fluid intake, leading to dehydration, electrolyte abnormalities, weight loss, poor nutrition, etc., which markedly decrease the patient’s quality of life [1]. Therefore, it is very important to control and minimise nausea and vomiting to enable continuation of cancer chemotherapy. Oxaliplatin-based chemotherapies, namely FOLFOX therapy (5-fluorouracil + leucovorin + oxaliplatin) and XELOX therapy (capecitabine + oxaliplatin), are the standard treatments for colorectal cancer [2–5]. In recent guidelines, such as the National Comprehensive Cancer Network (NCCN) Antiemesis Guidelines version 22014 [6], Multinational Association of Supportive Care in Cancer (MASCC) antiemetic guidelines [7], the American Society of Clinical Oncology (ASCO) guidelines for antiemetics [8] and the Japanese guidelines on the proper use of antiemetics [9], FOLFOX and XELOX therapies are classified as having moderate emetogenic risk (emetogenic risk: 30–90% for the acute state, with a concern for the delayed state). In a phase III study (MOSAIC study) of FOLFOX therapy given as adjuvant chemotherapy, nausea and vomiting occurred at the high rates of 73.7% and 47.2%, respectively [10]. Moreover, in several phase III studies of XELOX therapy in patients with metastatic colorectal cancer, the rates of nausea and vomiting ranged from 60.5% to 66.6% and 42.7% to 44.2%, respectively [2,5,11]. Based on these findings, the control of nausea and vomiting in these oxaliplatin-based chemotherapies is inadequate, and a more optimal prophylactic control is needed. The NK1 receptor antagonists, aprepitant and fosaprepitant, are antiemetic drugs with novel mechanisms
2. Patients and methods 2.1. Inclusion criteria Patients aged 20 years and older who received an initial FOLFOX (oxaliplatin 85 mg/m2; levo-leucovorin 200 mg/m2; fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion), XELOX (capecitabine 2000 mg/m2 orally on days 1–14 and oxaliplatin 130 mg/m2 intravenous infusion on day 1), or SOX (S-1 80 mg/m2 orally on days 1–14 and oxaliplatin
Please cite this article in press as: Nishimura J. et al., Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.03.024
J. Nishimura et al. / European Journal of Cancer xxx (2015) xxx–xxx
130 mg/m2 intravenous infusion on day 1) regimen including oxaliplatin at P85 mg/m2 (naive patient), or those who had already started chemotherapy and had nausea of Grade 2 or higher in the last course or an earlier course (non-naive patient) were included in this study. Colorectal cancer chemotherapy, neoadjuvant chemotherapy, adjuvant chemotherapy or recurrent/unresectable chemotherapy were included in this study. Institutional review boards at each study site approved the study protocol, and written informed consent was obtained from all participants before enrolment. Molecular targeted therapy was allowed. 2.2. Exclusion criteria Patients were excluded if they had severe liver or kidney disease; had nausea or vomiting within 24 h prior to chemotherapy; were treated with antiemetics within 24 h prior to chemotherapy; had any factors causing nausea or vomiting other than chemotherapy (e.g. gastrointestinal obstruction, active peptic ulcer disease, brain metastasis or other brain tumuors/lesions); had a disease precluding 3-day administration of dexamethasone (e.g. uncontrollable diabetes); were pregnant or lactating women, were planning on becoming pregnant; or were currently being treated with pimozide. 2.3. Study design This was a multicentre, randomised, controlled study conducted at 25 hospitals in Japan. Patients who provided written informed consent for participation in this study were assigned to receive either the two-drug combination treatment (5-HT3 receptor antagonist + dexamethasone) or the three-drug combination treatment (5-HT3 receptor antagonist + dexamethasone + aprepitant/fosaprepitant) in the first course of chemotherapy. All subjects received the three-drug combination treatment in the second course of chemotherapy. 5-HT3 receptor antagonist was each doctor’s choice. In this study, granisetron was used for 95 and 95 patients, ramosetron for 15 and 17 patients, azasetron for 2 and 0 patients, indisetron for 0 and 1 patient and palonosetron for 84 and 88 patients in the control and the aprepitant group, respectively. Patients who received the two-drug combination treatment in the first course of chemotherapy were defined as the control group, and those who received the three-drug combination treatment were defined as the aprepitant group. The allocation of patients was performed using the minimisation method with age, sex, chemotherapy-naı¨ve/non-naı¨ve status, regimen (FOLFOX, XELOX or SOX) and study centre as the adjustment factors. The trial was registered with ClinicalTrials.gov, number NCT01344304.
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2.4. Treatment protocol All patients took a 5-HT3 receptor antagonist intravenously on day 1. Patients in the aprepitant group received oral aprepitant (125 mg) plus an intravenous 5-HT3 receptor antagonist and dexamethasone (6.6 mg) on day 1, and aprepitant (80 mg) and oral dexamethasone (2 mg) twice daily on days 2 and 3. In cases using fosaprepitant, patients received intravenous fosaprepitant (150 mg) plus 5-HT3 receptor antagonist and dexamethasone (6.6 mg) on day 1, oral dexamethasone (2 mg) twice daily on day 2 and oral dexamethasone (4 mg) twice daily on day 3. Patients in the control group took intravenous 5-HT3 receptor antagonist plus dexamethasone (9.9 mg) on day 1, followed by oral dexamethasone (4 mg) twice daily on days 2 and 3. In the second cycle, all patients received aprepitant or fosaprepitant by the protocol mentioned above. 2.5. Assessments From day 1 to the morning of day 6, patients recorded their response in a diary. The use of rescue therapy, defined as any medication taken to treat nausea and vomiting, was also recorded. For nausea, patients evaluated the most severe intensity on a four-grade scale (0, none; 1, mild; 2, moderate; 3, serious) once daily. No nausea and mild nausea were counted as no significant nausea. For vomiting, patients recorded the frequency. Retches were also included as vomiting. Vomiting episodes occurring with an interval of less than 1 min were counted as a single event. Tolerability was monitored by physical examinations and laboratory studies. Nausea and vomiting occurring after the efficacy evaluation period (up to the morning of day 6) were handled as adverse events. Toxicity grades were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 4.0. 2.6. Statistical analysis The sample size was calculated under the following assumptions. In an overseas aprepitant phase III study of chemotherapy with a moderate emetogenic risk, the complete vomiting inhibition rate in the overall phase (0–120 h after antineoplastic drug administration) of chemotherapy, excluding AC therapy (adriamycin + cyclophosphamide), was 83.2% in the aprepitant group, which was significantly higher compared with the rate of 70.9% in the standard treatment group (p < 0.05). If equivalent results were obtained in this study and the chi-square test, 5% level of significance (a = 0.05), and a detection power of 80% (b = 0.2) were used, the required number of subjects per group was 182. Therefore, considering a dropout rate of
Please cite this article in press as: Nishimura J. et al., Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre, randomised, controlled phase 3 trial, Eur J Cancer (2015), http://dx.doi.org/10.1016/j.ejca.2015.03.024
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J. Nishimura et al. / European Journal of Cancer xxx (2015) xxx–xxx
approximately 10%, the scheduled number of subjects in this study was set at 200 per group (400 subjects in total). The full analysis set (FAS) was defined as the group of subjects that were registered in this study and allocated to a treatment group before patient exclusion. The per-protocol set was defined as the group of subjects that were not excluded from the FAS owing to major violations such as a violation of the inclusion/exclusion criteria and patients who did not keep a symptom diary. The primary efficacy end-point was the complete vomiting inhibition rate in the overall phase. The second efficacy end-points were the proportion of patients with a complete response (no vomiting and no rescue medication use), patients with complete protection (no vomiting, no rescue medication use and no moderate or worsened nausea), patients with no nausea and patients with mild nausea (no significant nausea). Efficacy was also evaluated exploratively in the acute and delayed phases. The chi-square test was used to compare the two groups with respect to all end-points expressed by a binary variable. Wilcoxon’s rank-sum test was used to compare the two means. McNemar’s test was used to evaluate the efficacies of the first and second cycles of chemotherapy in the control group (salvage effect). All tests were two sided, and a significance level of 0.05 was used. Relative risk (RR) and 95% confidence interval (CI) were reported.
3. Results 3.1. Patients A total of 413 patients from 25 hospitals in Japan were randomly assigned to either the aprepitant group or the control group (Fig. 1). Five patients (three in the control group and two in the aprepitant group) were randomised into the study even though they did not meet all inclusion criteria. Ten patients (seven in the control group and three in the aprepitant group) refused chemotherapy after randomisation. For the second cycle of chemotherapy, 16 patients (seven in the control group and nine in the aprepitant group) did not receive oxaliplatin-based chemotherapy. Ten patients (four in the control group and six in the aprepitant group) received oxaliplatin at a dose lower than 85 mg/m2 for the second cycle chemotherapy. Six patients did not record their response in the diary. Patient characteristics and treatment regimens are listed in Table 1. Both groups were similar with respect to baseline characteristics. The majority of patients were male (61.0%, males/females: 252/161), treated with the XELOX or SOX regimen (73.8%, XELOX or SOX/ FOLFOX: 305/108) and naı¨ve (93.0%, naı¨ve/non-naı¨ve 384/29) with an average age of 64.2 years. In the aprepitant group, oral aprepitant was used in 184 patients and,
intravenous fosaprepitant was used in three patients in the first cycle. 3.2. Efficacy in the first cycle The proportion of the patients in both groups who had no vomiting overall and in the acute and delayed phases are shown in Fig. 2. The aprepitant group had significantly higher rates of no vomiting overall (95.7% versus 83.6%; RR 1.1449; 95% CI, 1.07–1.23; p < 0.0001), as well as in the separate analyses of both the acute phase (100% versus 96.7%; RR 1.0339; 95% CI, 1.01–1.06; p = 0.013) and, notably, the delayed phase (95.7% versus 84.7%; RR 1.1301; 95% CI, 1.06– 1.21; p = 0.0003) compared with the control group. The results for the other end-points are shown in Table 2. The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. For the acute phase, there was no significant difference between the two groups for the percentages of no nausea, no significant nausea, complete response and complete protection. However, a significantly greater percentage of patients in the aprepitant group than the control group experienced no significant nausea (88.8% versus 81.4%; RR 1.0903; 95% CI, 1.00–1.19; p = 0.047), complete response (85.0% versus 75.4%; RR 1.1275; 95% CI, 1.02–1.25; p = 0.02) and complete protection (79.7% versus 69.4%; RR 1.1481; 95% CI, 1.02–1.30; p = 0.02) in the delayed phase. The number of patients who received palonosetron in the first cycle was 157 (78 in the control group and 79 in the aprepitant group; not significant). There was no significant difference in the proportion of patients with no vomiting when comparing those that used palonosetron with those that did not (89.2% versus 90.1%, not significant). Whether palonosetron was used or not, the percentage of no vomiting was higher in the aprepitant group (with palonosetron: 82.1% versus 96.2%; RR 1.1725; 95% CI, 1.05–1.31; p = 0.005; without palonosetron: 84.8% versus 95.4%; RR 1.1252; 95% CI, 1.03– 1.24; p = 0.009; in the control versus aprepitant group, respectively, Fig 3). 3.3. Efficacy of aprepitant as salvage therapy In the second cycle, both groups were treated with aprepitant therapy. Seven patients in the control group and nine patients in the aprepitant group were not treated with oxaliplatin-based chemotherapy due to adverse events. Four patients in the control group and seven patients in the aprepitant group did not meet inclusion criteria due to a lower dose of oxaliplatin (
