Comparison of Antiemetic Effects of Granisetron and Palonosetron in Patients Receiving Bendamustine-Based Chemotherapy

ORIGINAL ARTICLES

Department of Pharmacy1, Kyushu University Hospital, Fukuoka; Education and Research Center for Clinical Pharmacy2, Osaka University of Pharmaceutical Sciences, Osaka, Japan: Department of Medicine and Biosystemic Science3; Department of Medicine and Bioregulatory Science4, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

Comparison of antiemetic effects of granisetron and palonosetron in patients receiving bendamustine-based chemotherapy

M. UCHIDA1,2,*, T. NAKAMURA2, Y. MAKIHARA1, K. SUETSUGU1 , H. IKESUE1, Y. MORI3, K. KATO 3, M. SHIRATSUCHI4, K. HOSOHATA2, T. M IYAMOTO3, K. AKASHI3

Received November 1, 2017, accepted February 5, 2018 *Corresponding author: Mayako Uchida, Ph.D., Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan [email protected] Pharmazie 73: 304–308 (2018) doi: 10.1691/ph.2018.7948

The antiemetic effects and safety of granisetron and palonosetron against chemotherapy-induced nausea and vomiting (CINV) were retrospectively evaluated in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy. A total of 61 patients were eligible for this study. Before starting the bendamustine-based chemotherapy, granisetron or palonosetron were intravenously administered with or without aprepitant and/or dexamethasone. The proportions of patients with complete control (CC) during the overall (during the 6 days after the start of the chemotherapy), acute (up to 2 days), and delayed (3 to 6 days) phases were assessed. CC was defined as complete response with only grade 0–1 nausea, no vomiting, and no use of antiemetic rescue medication. Granisetron or palonosetron alone were administered to 9 and 19 patients, respectively. Aprepitant and/or dexamethasone were combined with granisetron and palonosetron in 28 and 5 patients, respectively. Acute CINV was completely controlled in all patients. Both granisetron monotherapy and palonosetron combination therapy could provide good control of delayed CINV, although the CC rates during the delayed and overall phases were not significantly different among mono- and combination therapy of the antiemetics. There was no significant difference in the frequencies of adverse drug events between the granisetron and palonosetron treatment groups. The present study showed that the antiemetic efficacy and safety of granisetron-based therapy were non-inferior to those of palonosetron-based therapy. Taken together with treatment costs, granisetron monotherapy would be adequate to prevent CINV in patients with non-Hodgkin lymphoma receiving bendamustine-based chemotherapy.

1. Introduction of a 5-HT3 receptor antagonist with neurokinin-1 antagonist, such Bendamustine is a unique cytotoxic agent containing a benzim- as aprepitant and/or dexamethasone, is recommended for anti- idazole heterocyclic ring, which has multifaceted mechanisms of emetic management of CINV with MECs, although dosages and action. Several studies have demonstrated the efficacy of benda- timing of administration of these antiemetic agents are required mustine-based chemotherapy in hematological cancers, including to be adequately adjusted depending on clinical situations.The refractory and/or relapsed indolent non-Hodgkin lymphoma first-generation 5-HT3 receptor antagonists, such as ondansetron (NHL) (Czuczman et al. 2015b; Flinn et al. 2014; Kouroukis and granisetron, have shown significant antiemetic effects since et al. 2015) and mantle cell lymphoma (MCL) (Czuczman et al. the 1990s, and have been used as a prophylactic agent for CINV 2015a; Flinn et al. 2014; Rummel et al. 2013; Visco et al. 2017). (Jantunen et al. 1997). However, these agents are less effective for In Japan, some phase II clinical trials of bendamustine as mono- the treatment of delayed CINV (more than 24 h after the start of therapy or in combination with rituximab have been carried out chemotherapy) than the acute one (up to 24 h) (Geling and Eichler in patients with refractory and/or relapsed indolent B cell NHL 2005). Even when a 5-HT3 receptor antagonist was administered or MCL (Matsumoto et al. 2015; Ogura et al. 2017; Ohmachi both 2 and 3 days after the beginning of the chemotherapy, the anti- et al. 2010), providing an overall response rate of more than 90%. emetic therapy did not entirely prevent CINV beyond 24 h after the Chemotherapy-induced nausea and vomiting (CINV) is a common chemotherapy (Geling and Eichler 2005). Palonosetron has been and one of the most problematic adverse events for patients developed as a second-generation 5-HT3 receptor antagonist with with cancer (Hesketh 2008). If left uncontrolled, it can lead to a longer half-life and higher binding affinity to the 5-HT3 receptor, physical disorder, including dehydration, electrolyte abnormality, compared to the first-generation one, resulting in persistent inhi- and malnourishment, and consequently, to a poor quality of life bition of the 5-HT3 receptor function (Rojas et al. 2010b). It is (Lindley et al. 1992; Morita et al. 2003). To maintain quality of therefore expected that palonosetron can prevent delayed CINV, as life and enable patients to complete therapy, it is very important to well. To date, it has been reported that palonosetron has superior control CINV with the appropriate use of antiemetics. According antiemetic effects against delayed CINV, and equivalent effects to some antiemetic guidelines (Hesketh et al. 2017; NCCN 2017; compared with first-generation 5-HT3 receptor antagonists in Roila et al. 2017), bendamustine-based chemotherapy is classified various types of cancers (Aapro et al. 2006; Eisenberg et al. 2003; as moderately emetogenic chemotherapy (MEC). The combination Gralla et al. 2003; Saito et al. 2009). Most of these data have been 304 Pharmazie 73 (2018) ORIGINAL ARTICLES obtained from patients with solid tumors, whereas limited studies 2.2. Antiemetic effects have been conducted in patients with hematological malignancies. In all patients receiving bendamustine-based chemotherapy, acute More recently, we have evaluated the effects of palonosetron- and CINV was completely controlled by treatment with granisetron- or granisetron-based antiemetic therapy on CINV in patients with palonosetron-containing antiemetics. This indicated that the overall malignant lymphoma receiving first-line rituximab, cyclophos- CINV was reflected by the delayed one. Both granisetron mono- phamide, doxorubicin, vincristine, and prednisone, suggesting therapy and palonosetron combination therapy could completely that palonosetron was superior to granisetron for the prevention control CINV during the delayed and overall phases (Table 2). The of delayed CINV (Uchida et al. 2017). However, there appears to be little information about antiemetic efficacy and safety of palonosetron mono- or combination therapy in patients with malignant Table 2: Efficacy of granisetron- and palonosetron-contained antiemetics during delayed and overall phases lymphoma receiving bendamustine-based chemotherapy.In this retrospective study, we assessed the antiemetic efficacy and safety Variable CCa Non-CCa p value of palonosetron, comparing to those of granisetron, in patients Number of patients 48 13 with NHL receiving bendamustine-based chemotherapy. Antiemetic regimen 2. Investigations and results Granisetron 9 0 0.416 + Aprepitant 21 6 2.1. Patient baseline clinical characteristics + Dexamethasone + aprepitant 1 0 A total of 61 patients with NHL were eligible in this study. The patients’ baseline clinical characteristics are shown in Table 1. Palonosetron 12 7 0.406 There was no significant difference in the sex, age, ECOG-PS, + Aprepitant 2 0 types of lymphoma, and chemotherapy regimens. The propor- + Dexamethasone 3 0 tion of number of the patients receiving granisetron alone or in combination with other antiemetics, where aprepitant was most a CC, complete control. frequently co-administered, was significantly different compared to that of those receiving palonosetron-based antiemetic therapy (p < 0.001). CC rate in the patients whom overall CINV were well-controlled after granisetron monotherapy was higher compared to the CC Table 1: Patient characteristics rate obtained after palonosetron monotherapy, although statistical Variable Granisetron Palonosetron p valuea significance was not observed (100% and 63%, respectively; p = 0.062) (Table 2). Univariate analyses were performed to detect Number of patients 37 24 factors influencing CINV control; specifically, age was detected Sex to influence the CC rate throughout the study period (Table 3). Multivariate logistic regression analysis showed that sex and age Male 23 14 0.794 of more than 65 years were identified as significant influencing Female 14 10 factors on the CC rates during delayed and overall phases (odds ratios were 4.8 [95% confidence interval (CI) 1.1–20.4] and 10.6 Age (years) [95% CI 1.9–59.2], respectively) (Table 3). Mean ± s.d.b 61.5 ± 10.3 61.8 ± 9.9 0.901 Table 3: Factors influencing chemotherapy-induced nausea and vomit- Age (years) ing control during delayed and overall phases less than 60 17 9 0.601 Univariate Multivariate 60 and above 20 15 Variables CCa non- CCa p valuec ORb p valuec ECOG-PSc score Sex 0 16 13 0.509 Male 32 5 0.108 1 11911 Female 16 8 4.8 (1.1–20.4) 0.032 220Age (years) Diagnosis 65 and above 28 2 0.011 1 Follicular lymphoma 25 16 0.840 less than 65 20 11 10.6 (1.9–59.2) 0.007 Mantle cell lymphoma 2 1 ECOG-PSd score d MALT lymphoma 4 1 0 21 8 0.606 – – Waldenstrom macroglobulinemia 3 2 1255– Other 3 4 220–

Regimen Type of lymphoma Bendamustine 7 1 0.132 Follicular lymphoma 33 8 0.466 – – Bendamustine + Rituximab 30 23 Mantle cell lymphoma 2 1 – e Combined antiemetics MALT lymphoma 5 0 – None 9 19 <0.001 Waldenstrom macro- 32 – globulinemia + Aprepitant 27 2 Other 5 2 – + Dexamethasone 0 3 + Dexamethasone + aprepitant 1 0 Regimen Bendamustine 6 2 1.000 – – a A significant difference is in italics. b s.d., standard deviation. Bendamustine + 42 11 – c ECOG-PS, Eastern Cooperative Oncology Group performance status. Rituximab d MALT, mucosa-associated lymphoid tissue Pharmazie 73 (2018) 305 ORIGINAL ARTICLES

Univariate Multivariate the guidelines.Clinicians, however, have some concerns about the Variables CCa non- CCa p valuec ORb p valuec use of dexamethasone in clinical practice because of its potential side effects; the patients are often excessively immunosuppressed 5-HT3 receptor antagonist and thereby, they are at a greatly increased risk of infection. In the present study, regardless of whether dexamethasone and/or aprepi- Granisetron 31 6 0.338 – – tant were combined, the antiemetic therapy containing granisetron Palonosetron 17 7 – or palonosetron achieved CC for the acute CINV in the patients a CC, complete control. with NHL receiving bendamustine-based chemotherapy. All b OR, odds ratio with 95% confidence interval in parenthesis. patients receiving granisetron alone had no significant symptoms c A significant difference is in italics. associated with CINV throughout the observation period, although d ECOG-PS, Eastern Cooperative Oncology Group performance status. e MALT, mucosa-associated lymphoid tissue the combination therapy of aprepitant and/or dexamethasone with granisetron did not entirely improve the CINV control in the delayed phase (Table 2). Although the present study was limited by 2.3. Adverse drug events small sample size, CINV in patients receiving bendamustine-based The number of patients experiencing ADEs after treatment with chemotherapy could be controlled by granisetron monotherapy granisetron- or palonosetron-based antiemetics is shown in Table 4. even without dexamethasone administration.For MEC regimens, The most frequent ADE was anorexia in both groups (62.2% and in a prospective cohort study in Japanese patients, the CC rate in 70.8%, respectively). Leucopenia, malaise, constipation, gastric the acute phases was 93.3% and the value was higher than that distress, neutropenia, fever, and renal dysfunction were also in the delayed phase (58.3%) (Tamura et al. 2015). The delayed observed with frequencies of more than 5% in either group, with CINV is more common and less responsive to antiemetic therapy no significant difference between the two groups. (Tamura et al. 2015), and its control is still suboptimal. Palono- setron, a second-generation 5-HT receptor antagonist, has higher Table 4: Number of patients experiencing ADEsa 3 5HT3 receptor binding affinity, leading to longer activity, compared ADE Granisetron-based anti- Palonosetron-based anti- p value to first-generation agents such as granisetron (Rojas et al. 2010a). emetics emetics (n = 37) (n = 24) Furthermore, it has been observed that its effectiveness for CINV is more remarked in the delayed phase than in the acute phase Anorexia 23 17 0.586 (Aapro et al. 2006; Eisenberg et al. 2003; Gralla et al. 2003; Saito (62.2%) (70.8%) et al. 2009). In current antiemetic guidelines for MECs, the use of Leucopenia 13 11 0.433 a 5-HT3 receptor antagonist and dexamethasone is recommended (35.1%) (45.8%) (Hesketh et al. 2017; NCCN 2017; Roila et al. 2017), and the Malaise 12 5 0.391 addition of aprepitant is also considered to prevent CINV (Hesketh (32.4%) (20.8%) et al. 2017; NCCN 2017; Roila et al. 2017). In the present study, Constipation 12 9 0.785 a monotherapy of either granisetron or palonosetron could exert (32.4%) (37.5%) antiemetic effects against CINV during the acute phase, resulting Gastric distress 10 6 1.000 in a CC rate of 100%. During the delayed phase, on the other hand, (27.0%) (25.0%) a CC rate of 100% was also achieved following the administration Neutropenia 8 7 0.553 of granisetron alone, but the value was 63.2% after palonosetron (21.6%) (29.2%) administration alone (Table 2). In bendamustine-based chemo- Fever 2 3 0.373 therapy, bendamustine was administered on days 1 and 2 of (5.4%) (12.5%) each cycle of the chemotherapy. In the present study, granisetron Renal dysfunction 2 0 0.515 and palonosetron were administered on day 1. Granisetron was (5.4%) (0%) administered repeatedly on day 2, whereas palonosetron was not because its administration is limited to once a week. Therefore, a ADEs, adverse drug events with frequencies of more than 5% (shown in parentheses) in either the difference in the antiemetic efficacy of monotherapy between group are listed. granisetron and palonosetron against the CINV might be attributed to the difference in their administration schedules. Although the 3. Discussion palonosetron monotherapy could not well-control the delayed Uncontrolled emesis associated with chemotherapy sometimes CINV for the bendamustine-based chemotherapy, the combination provides a negative experience, which could lead to refusal by the antiemetic therapy with either aprepitant or dexamethasone could patient to undergo potentially life-saving treatments for their malig- improve the disease control, successfully achieving a CC rate of nancy (Hesketh 2008). The present study showed that granisetron 100%, (Table 2). In case of using palonosetron, the combination mono- and palonosetron combination antiemetic therapies were therapy of other antiemetics might be more effective compared effective and well-tolerated in the patients with malignant lymphoma to the monotherapy.Previously, we compared the effects of gran- receiving bendamustine-based chemotherapy. According to recent isetron and palonosetron in patients with malignant lymphoma guidelines (Hesketh et al. 2017; NCCN 2017; Roila et al. 2017), receiving highly emetogenic chemotherapy, in which the multi- bendamustine is classified as an MEC, and some antiemetic regi- variate logistic regression analysis showed that palonosetron use mens have been applied in patients receiving bendamustine-based and younger age were independent significant factors improving chemotherapy. Ohmachi et al. (2010) reported that nausea of any the complete response rate during the delayed phase, compared to grade occurred in 86% of patients with relapse of refractory indo- granisetron use (Uchida et al. 2017). In the present study, female lent B-cell NHL or MCL, where a particular protocol for emesis sex and age less than 65 years were significant factors associated was not provided, although prophylactic antiemetics were used. with CINV during the delayed phase (Table 3), which was almost When the intravenous and oral administration of dexamethasone consistent with the results of previous reports (Hesketh et al. 2010; together with granisetron were used as antiemetic prophylaxis, Roila et al. 1987; Tonato et al. 1991; Uchida et al. 2017; Warr nausea occurred in 34% patients with relapsed or refractory diffuse et al. 2011). There was no significant difference in the CC rate large B-cell lymphoma during the observation period; however, between granisetron- and palonosetron-based antiemetic therapies, nausea grades 3 and 4 were not observed (Ohmachi et al. 2013). suggesting that these therapies could provide equivalent antiemetic In the present study, the overall CINV in the patients receiving the efficacy during the delayed phase in patients receiving bendamus- combination antiemetic therapy of dexamethasone with the 5-HT3 tine-based chemotherapy. Some adverse events, including anorexia, receptor antagonist was successfully suppressed (Table 2). These leucopenia, malaise, and constipation were observed at a frequency findings suggested that a combined administration of dexametha- of more than 30%, although the frequency of each adverse event sone can be a useful option for CINV control, which is in line with related to the treatment was not significantly different between 306 Pharmazie 73 (2018) ORIGINAL ARTICLES the granisetron- and palonosetron-containing antiemetic treatment Conflict of interest: The authors declare no conflict of interest. groups. Besides, granisetron would have an advantage of reduced costs compared to palonosetron (Hesketh et al. 2017).In summary, References our present study demonstrated that the antiemetic efficacy and Aapro MS, Grunberg SM, Manikhas GM, Olivares G, Suarez T, Tjulandin SA, Bertoli safety of granisetron-based therapy seemed to be non-inferior to LF, Yunus F, Morrica B, Lordick F, Macciocchi A (2006) A phase III, double-blind, those of palonosetron-based therapy. Taken together with treat- randomized trial of palonosetron compared with ondansetron in preventing chemo- ment costs, granisetron monotherapy would be adequate to prevent therapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 17: 1441-1449. CINV in patients with NHL receiving bendamustine-based chemo- Czuczman MS, Goy A, Lamonica D, Graf DA, Munteanu MC, van der Jagt RH therapy, even if the administration of granisetron is required for (2015a) Phase II study of bendamustine combined with rituximab in relapsed/ two consecutive days. refractory mantle cell lymphoma: efficacy, tolerability, and safety findings. Ann Hematol 94: 2025-2032. Czuczman MS, Kahanic S, Forero A, Davis G, Munteanu M, Van Den Neste E, Offner 4. Experimental F, Bron D, Quick D, Fowler N (2015b) Results of a phase II study of bendamustine and ofatumumab in untreated indolent B cell non-Hodgkin’s lymphoma. Ann 4.1. Patients Hematol 94: 633-641. The patient’s age were between 39 and 79 years, who received bendamustine with Eisenberg P, Figueroa-Vadillo J, Zamora R, Charu V, Hajdenberg J, Cartmell A, or without rituximab as a treatment for NHL in the Department of Hematology, Macciocchi A, Grunberg S, Palonosetron Study G (2003) Improved prevention of Kyushu University Hospital (April 2007 to December 2015). Patients were excluded moderately emetogenic chemotherapy-induced nausea and vomiting with palono- as follows: (a) if they had hyponatremia, hypercalcemia, adrenal metastasis, or an setron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, Eastern Cooperative Oncology Group performance status (ECOG-PS) score of more single-dose trial versus dolasetron. Cancer 98: 2473-2482. than 3; (b) if they had nausea and/or vomiting in the last 24 h prior to treatment Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg initiation; or (c) if they were taking laxative agents and antiemetic drugs, including M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, olanzapine and lorazepam. Munteanu M, Chen L, Burke JM (2014) Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 123: 2944-2952. 4.2. Dosage and administration of therapy Geling O, Eichler HG (2005) Should 5-hydroxytryptamine-3 receptor antagonists The regimens of bendamustine-based chemotherapy are shown in Table 5. Benda- be administered beyond 24 hours after chemotherapy to prevent delayed emesis? mustine was administered alone at a dose of 120 mg/m2 on days 1 and 2 in regimen Systematic re-evaluation of clinical evidence and drug cost implications. J Clin A, or at a dose of 90 mg/m2 in combination with rituximab (375 mg/m2) in regimen Oncol 23: 1289-1294. B; patients were received either chemotherapy regimen. Granisetron (3.0 mg/body) Gralla R, Lichinitser M, Van Der Vegt S, Sleeboom H, Mezger J, Peschel C, Tonini or palonosetron (0.75 mg/body) were intravenously administered 30 min before the G, Labianca R, Macciocchi A, Aapro M (2003) Palonosetron improves prevention initiation of the bendamustine-based chemotherapy. Granisetron was administered on of chemotherapy-induced nausea and vomiting following moderately emetogenic days 1 and 2, whereas palonosetron on day 1. Aprepitant was orally administered at a chemotherapy: results of a double-blind randomized phase III trial comparing dose of 125 mg once daily, 1 h before start of chemotherapy on day 1, and at a dose of single doses of palonosetron with ondansetron. Ann Oncol 14: 1570-1577. 80 mg once daily on days 2 and 3 in the morning for each cycle. Dexamethasone (6.6 Hesketh PJ (2008) Chemotherapy-induced nausea and vomiting. N Engl J Med 358: 2482-2494. mg/body) was intravenously administered 30 min prior to chemotherapy once daily Hesketh PJ, Aapro M, Street JC, Carides AD (2010) Evaluation of risk factors predic- on days 1 and 2. Metoclopramide, prochlorperazine, haloperidol, and/or hydroxyzine tive of nausea and vomiting with current standard-of-care antiemetic treatment: were used as rescue medications. analysis of two phase III trials of aprepitant in patients receiving cisplatin-based chemotherapy. Support Care Cancer 18: 1171-1177. Table 5: Regimens of bendamustine-based chemotherapy Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Regimen Drugsa,b Daily dosage Timing of administration Sparacio D, Somerfield MR, Lyman GH (2017) Antiemetics: American society of A Bendamustine 120 mg/m2 once daily on days 1 and 2 clinical oncology clinical practice guideline update. J Clin Oncol 35: 3240-3261. Jantunen IT, Kataja VV, Muhonen TT (1997) An overview of randomised studies B Bendamustine 90 mg/m2 once daily on days 1 and 2 comparing 5-HT3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting. Eur J Cancer 33: 66-74. Rituximab 375 mg/m2 once daily on day 1 Kouroukis CT, Crump M, MacDonald D, Larouche JF, Stewart DA, Johnston J, Sauvageau S, Beausoleil E, Sage P, Dubois SG, Christofides A, Di Clemente S, a Granisetron (3 mg/body) was intravenously administered on days 1 and 2. Sehn L (2015) An open-label expanded-access trial of bendamustine in patients b Palonosetron (0.75 mg/body) was intravenously administered on day 1. with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT. Curr Oncol 22: 260-271. 4.3. Data collection and assessment Lindley CM, Hirsch JD, O’Neill CV, Transau MC, Gilbert CS, Osterhaus JT (1992) Quality of life consequences of chemotherapy-induced emesis. Qual Life Res 1: All data were retrospectively collected from the electronic medical record system. 331-340. Occurrences of nausea, vomiting, or use of rescue medication during overall (during Matsumoto K, Takayama N, Aisa Y, Ueno H, Hagihara M, Watanabe K, Nakaya A, the 6 days after the start of the chemotherapy), acute (up to 2 days), and delayed Chen K, Shimizu T, Tsukada Y, Yamada Y, Nakazato T, Ishida A, Miyakawa Y, (3 to 6 days) phases were assessed. Adverse drug events (ADEs), including nausea Yokoyama K, Nakajima H, Masuda Y, Yano T, Okamoto S, Keio BRBSG (2015) A and vomiting, were monitored during the overall study period and described in the phase II study of bendamustine plus rituximab in Japanese patients with relapsed electronic medical record system twice a day (morning and evening) by doctors, or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma nurses, and pharmacists, according to the Common Terminology Criteria for Adverse previously treated with rituximab: BRB study. Int J Hematol 101: 554-562. Events (CTCAE) v.4.0. This study was conducted in accordance with the Declaration Morita S, Kobayashi K, Eguchi K, Matsumoto T, Shibuya M, Yamaji Y, Sakamoto J, of Helsinki and its amendments and with the approval of Kyushu University Graduate Ohashi Y (2003) Influence of clinical parameters on quality of life during chemo- School and Faculty of Medicine (approval Nos. 24-12 and 24-359 of the institutional therapy in patients with advanced non-small cell lung cancer: application of a review board).The endpoint of this study was the proportion of patients with complete general linear model. Jpn J Clin Oncol 33: 470-476. control (CC) during the overall, acute, and delayed phases. CC was defined as NCCN (2017) Clinical Practice Guidelines in Oncology-Antiemesis-Version II. complete response and no more than mild nausea (grade 0 or 1). Ogura M, Ishizawa K, Maruyama D, Uike N, Ando K, Izutsu K, Terui Y, Imaizumi Y, Tsukasaki K, Suzuki K, Izumi T, Usuki K, Kinoshita T, Taniwaki M, Uoshima N, Suzumiya J, Kurosawa M, Nagai H, Uchida T, Fukuhara N, Choi I, Ohmachi 4.4. Statistical analysis K, Yamamoto G, Tobinai K, Japanese Bendamustine Lymphoma Study G (2017) Statistical analysis was performed using IBM SPSS Statistics package, version Bendamustine plus rituximab for previously untreated patients with indolent B-cell 24, software (IBM Corp, Armonk, NY). Fisher’s exact test was used to examine non-Hodgkin lymphoma or mantle cell lymphoma: a multicenter Phase II clinical differences in frequencies of categorical data between the granisetron- and palo- trial in Japan. Int J Hematol 105: 470-477. nosetron-based antiemetic treatments. The statistical significance of the difference Ohmachi K, Ando K, Ogura M, Uchida T, Itoh K, Kubota N, Ishizawa K, Yamamoto between the mean values of age was calculated using the unpaired t-test. In the J, Watanabe T, Uike N, Choi I, Terui Y, Usuki K, Nagai H, Uoshima N, Tobinai K, univariate analysis, sex, age, ECOG-PS, types of lymphoma, chemotherapy regimens, Japanese Bendamustine Lymphoma Study G (2010) Multicenter phase II study of and use of granisetron or palonosetron were chosen as variables. The factors with p bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma values < 0.25 in univariate analyses were included in a stepwise multivariate logistic and mantle cell lymphoma. Cancer Sci 101: 2059-2064. regression analysis with backward selection. Two-tailed p values of less than 0.05 Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, were considered to indicate a statistically significant difference. Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh Funding: The present study was supported in part by a Grant-in-Aid for Research C, Ogura M (2013) Multicenter phase II study of bendamustine plus rituximab in Activity Start-up from the Japan Society for the Promotion of Science [grant number patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 16H07349]. 31: 2103-2109. Roila F, Tonato M, Basurto C, Bella M, Passalacqua R, Morsia D, DiCostanzo F, Acknowledgements: We would like to thank patients, doctors, nurses, pharmacists, Donati D, Ballatori E, Tognoni G, Franzosi MG, Del Favero A (1987) Antiemetic and all medical staff at the Kyushu University Hospital, and the staff of the Osaka activity of high doses of metoclopramide combined with methylprednisolone University of Pharmaceutical Sciences who contributed to this study. versus metoclopramide alone in cisplatin-treated cancer patients: a randomized Pharmazie 73 (2018) 307 ORIGINAL ARTICLES

double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Tamura K, Aiba K, Saeki T, Nakanishi Y, Kamura T, Baba H, Yoshida K, Yamamoto Oncol 5: 141-149. N, Kitagawa Y, Maehara Y, Shimokawa M, Hirata K, Kitajima M, Japan CSGo Roila F, Warr D, Hesketh PJ, Gralla R, Herrstedt J, Jordan K, Aapro M, Ballatori E, (2015) Testing the effectiveness of antiemetic guidelines: results of a prospective Rapoport B (2017) 2016 updated MASCC/ESMO consensus recommendations: registry by the CINV Study Group of Japan. Int J Clin Oncol 20: 855-865. Prevention of nausea and vomiting following moderately emetogenic chemo- Tonato M, Roila F, Del Favero A (1991) Methodology of antiemetic trials: a review. therapy. Support Care Cancer 25: 289-294. Ann Oncol 2: 107-114. Rojas C, Li Y, Zhang J, Stathis M, Alt J, Thomas AG, Cantoreggi S, Sebastiani S, Uchida M, Mori Y, Nakamura T, Kato K, Kamezaki K, Takenaka K, Shiratsuchi M,

Pietra C, Slusher BS (2010a) The antiemetic 5-HT3 receptor antagonist Palono- Kadoyama K, Miyamoto T, Akashi K (2017) Comparison between antiemetic setron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol effects of palonosetron and granisetron on chemotherapy-induced nausea and Exp Ther 335: 362-368. vomiting in Japanese patients treated with R-CHOP. Biol Pharm Bull 40: 1499- Rojas C, Thomas AG, Alt J, Stathis M, Zhang J, Rubenstein EB, Sebastiani S, 1505.

Cantoreggi S, Slusher BS (2010b) Palonosetron triggers 5-HT3 receptor internal- Visco C, Chiappella A, Nassi L, Patti C, Ferrero S, Barbero D, Evangelista A, Spina ization and causes prolonged inhibition of receptor function. Eur J Pharmacol 626: M, Molinari A, Rigacci L, Tani M, Rocco AD, Pinotti G, Fabbri A, Zambello 193-199. R, Finotto S, Gotti M, Carella AM, Salvi F, Pileri SA, Ladetto M, Ciccone G, Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, Gaidano G, Ruggeri M, Martelli M, Vitolo U (2017) Rituximab, bendamustine, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Durk and low-dose cytarabine as induction therapy in elderly patients with mantle cell H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W, Study lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet group indolent L (2013) Bendamustine plus rituximab versus CHOP plus ritux- Haematol 4: e15-e23. imab as first-line treatment for patients with indolent and mantle-cell lymphomas: Warr DG, Street JC, Carides AD (2011) Evaluation of risk factors predictive of nausea an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381: and vomiting with current standard-of-care antiemetic treatment: analysis of phase 1203-1210. 3 trial of aprepitant in patients receiving adriamycin-cyclophosphamide-based Saito M, Aogi K, Sekine I, Yoshizawa H, Yanagita Y, Sakai H, Inoue K, Kitagawa C, chemotherapy. Support Care Cancer 19: 807-813. Ogura T, Mitsuhashi S (2009) 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. Lancet Oncol 10: 115-124.

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