Granisetron Vs Ondansetron for Prevention of Nausea and Vomiting

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Granisetron vs ondansetron for prevention of nausea and vomiting in hematopoietic stem cell transplant patients: results of a prospective, double-blind, randomized trial

T Walsh1,4, AK Morris2, LM Holle3, N Callander1,4, P Bradshaw4, AW Valley5, G Clark6 and CO Freytes1,4

1South Texas Veterans Health Care System, Audie L Murphy Division, San Antonio, TX, USA; 2Duke University Medical Center, Durham, NC, USA; 3Syntaxx Communications Inc., Storrs, CT, USA; 4University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 5Pharmacy Healthcare Solutions, San Antonio, TX, USA; and 6OSI Pharmaceuticals Inc., Boulder, CO, USA

Summary: Nausea and vomiting (N/V) are well-recognized adverse

The serotonin type-3 (5-HT3)antagonists represent a effects of chemotherapy. In the setting of hematopoietic significant advance in the prevention of acute nausea and stem cell transplantation (HSCT), where high doses of vomiting (N/V)from highly emetogenic chemotherapy. We chemotherapy are generally employed, these symptoms are sought to determine if any differences in efficacy or adverse almost universal and can have profound clinical and effects exist between two such agents, ondansetron and psychological implications for the patient. One significant granisetron, during conditioning therapy for hematopoietic advance in the prevention of chemotherapy-induced N/V stem cell transplantation (HSCT). Patients were rando- (CINV) has been the introduction of the serotonin type-3 mized to receive either ondansetron 0.15 mg/kg intrave- (5-HT3) receptor antagonists, which inhibit the binding of nously every 8 h or granisetron 10 lg/kg intravenously serotonin to vagal afferent fibers located in the gastro- daily. Additionally, all patients received scheduled dexa- intestinal tract and 5-HT3 receptors in the vomiting 1 methasone and lorazepam. Prophylaxis was continued until center. Currently, four 5-HT3 receptor antagonists are 24 h after completion of chemotherapy. Nausea and distress approved in the United States for the prevention of acute were measured subjectively with visual analog scales and N/V associated with cancer chemotherapy, including emetic episodes were quantified. Of the 110 randomized ondansetron (Zofrans, GlaxoSmithKline, Research patients, 96 were evaluable for efficacy and safety. No Triangle Park, NC, USA), granisetron (Kytrils, Roche significant differences in efficacy were observed between the Laboratories, Nutley, NJ, USA), dolasetron (Anzemets, ondansetron- and granisetron-treated patients, evaluated by Aventis Pharmaceuticals, Kansas City, MO, USA), and comparing the degree of nausea and distress, number of palonosetron (Aloxit, MGI Pharma Inc., Minneapolis, emetic episodes and overall control of emesis. The adverse MN, USA). Palonosetron is also indicated for the effects were also comparable and no patients were removed prevention of delayed N/V associated with moderately from study because of severe toxicities. This trial demon- emetogenic chemotherapy. Outside of the HSCT setting, strates that ondansetron and granisetron are equally numerous studies have concluded that these agents effective at preventing acute N/V associated with conditio- provide equivalent control of N/V induced by highly ning therapy frequently used for HSCT. The agent of choice emetogenic chemotherapy when administered at equipo- should be based on drug acquisition cost or preference. tent doses.2–8 Although three of these agents have been Bone Marrow Transplantation (2004) 34, 963–968. extensively studied in HSCT patients over the last doi:10.1038/sj.bmt.1704714 8 years,9–23 limited data directly comparing these agents 21–23 Published online 18 October 2004 is available. Ondansetron, the first 5-HT3 receptor Keywords: hematopoietic stem cell transplantation; nau- antagonist approved in the United States, has been the sea; vomiting; granisetron; ondansetron most widely studied and is most effectively used in combination with corticosteroids for prevention of CINV; granisetron’s effects are also enhanced with the use of corticosteroids. This study was designed to directly compare the efficacy and adverse effects of ondansetron and granisetron, in Correspondence: Dr T Walsh, South Texas Veterans Healthcare System, combination with other antiemetics, for the prevention of Audie L Murphy Division, 7400 Merton Minter Boulevard, Department 119, San Antonio, TX 78229, USA; E-mail: [email protected] acute CINV associated with common, nontotal body Received 29 April 2004; accepted 13 August 2004 irradiation (TBI)-containing conditioning regimens utilized Published online 18 October 2004 in HSCT. Prevention of nausea/vomiting in stem cell transplantation T Walsh et al 964 Patients and methods Granisetron 10 µg/kg intravenously daily Patient eligibility + 0.9% Normal saline intravenously twice All in-patients undergoing autologous or allogeneic HSCT daily (to maintain blind) for any malignancy who gave written informed consent + were eligible for enrollment in the study. Patients were Dexamethasone 10 mg intravenously excluded if they were scheduled to receive TBI as part of daily + their conditioning regimen or any radiation therapy within Lorazepam 1 mg intravenously every 24 h of study initiation or during the study period. Other 8 hours exclusion criteria included (1) nausea or vomiting within HSCT Patient 24 h prior to initiation of therapy, (2) receipt of any

medication with antiemetic activity within 24 h of study RANDOMIZE Ondansetron 0.15 mg/kg intravenously initiation or during the study period such as metoclopra- every 8 hours mide or dronabinol, and (3) known hypersensitivity to any + Dexamethasone 10 mg intravenously 5-HT3 receptor antagonist or other study medication. Permitted medications included antihistamines as a pre- daily + medication for blood transfusions and triazolam or Lorazepam 1 mg intravenously every diphenhydramine for insomnia. Patients were required to 8 hours meet all institutional requirements for HSCT with respect Figure 1 Treatment schema. Patients randomized to ondansetron or to laboratory tests, physical examination, vital signs, and granisetron, administered in a double-blind fashion. performance status. Patients must have been X18 years of age, and a b-hCG test was performed to rule out pregnancy in female patients. episodes within a 24 h period or if the patient requested the medication. Patients were removed from the study if they Study design experienced a Southwestern Oncology Group (SWOG) grade 3 or 4 toxicity, other than myelotoxicity, unless it was This was a prospective, randomized, double-blind trial believed to be unrelated to the study medication.24 conducted at two hospitals, both affiliated with the University of Texas Health Science Center HSCT Program. Patients were evaluated and enrolled within 1 weekof study Statistical analyses initiation. It was assumed that the therapy would be 75–95% effective Patients were randomized according to a computer- in preventing N/V in this patient population. In order to generated scheme to either the granisetron group or detect a difference in response of 20% between the two ondansetron group in a 1:1 distribution. The randomiza- groups with a P-value of 0.05 and power of 80%, a total of tion tookinto account the conditioning regimen, prior 98 patients were required to complete the study (49 patients history of CINV, and previous alcohol or drug use, to per treatment arm). Nausea, distress, and overall control of assure that both arms were balanced regarding these emesis at each day were analyzed using Fisher’s exact test clinical parameters. due to small expected cell frequencies for certain categories of response. Nausea and distress were categorized into none Treatment plan to mild and moderate to severe and overall emetic control was grouped into complete to major response vs minor Following consent, eligible patients were randomized to response to failure. Differences in toxicity, measured as the receive either intravenous granisetron 10 mg/kg daily or number of adverse events per subject between the two ondansetron 0.15 mg/kg intravenously every 8 h. Addition- treatment groups over the entire study, were analyzed with ally, both treatment groups received intravenous dexa- Wilcoxon’s rank-sum test while incidence of specific events methasone 10 mg daily and lorazepam 1 mg intravenously was compared across the two groups using the w2 or every 8 h. To maintain the study blind, patients randomized Fisher’s exact test as appropriate. For the baseline to receive granisetron also received 50 ml of 0.9% normal demographics, Wilcoxon’s rank-sum tests were performed saline as a placebo twice daily (Figure 1). The first dose of for the continuous variables and Fisher’s exact test for the study drug was administered 30 min prior to the first categorical variables. The computer software used for the scheduled dose of chemotherapy and continued for 24 h statistical analyses was Stata v. 8 (College Station, TX, after the completion of chemotherapy. Patients who USA). received busulfan and cyclophosphamide as their conditioning regimen did not begin the study drug until the Efficacy measurements cyclophosphamide was administered, because busulfan alone has little emetogenic potential. The total number of The primary objectives of the study were to compare the days of study drug administration was dependent on the efficacy of granisetron and ondansetron in the prevention chemotherapy regimen administered. Rescue medication of acute N/V in this patient population by assessing nausea, with prochlorperazine 10 mg intravenous every 6 h as distress, number of emetic episodes, and overall control of needed was available if the patient had three to five emetic emesis until 24 h after completion of chemotherapy.

Bone Marrow Transplantation Prevention of nausea/vomiting in stem cell transplantation T Walsh et al 965 Nausea and distress were subjectively evaluated using the prior to receiving the first dose of study drug, (2) five visual analog scale (VAS). For nausea, the VAS consisted patients received medications with antiemetic activity that of a 100 mm line ranging from ‘no nausea’ (VAS ¼ 0 mm) to were not permitted during the study period, (3) one patient ‘the worst possible nausea’ (VAS ¼ 100 mm). The proper received the wrong study drug, (4) one patient developed use of the scale was described to the patient. Patients were severe opiate-induced confusion and hand tremors and was asked to place a mark on the line corresponding to the unable to complete the VAS, and (5) two patients received worst degree of nausea that they experienced within the the scheduled antiemetics incorrectly. Of the 96 assessable past 24 h. For distress, the VAS consisted of a 100 mm line patients, 46 patients received granisetron and 50 patients ranging from ‘not upset at all’ (VAS ¼ 0 mm) to ‘the most received ondansetron. Patient demographics are listed in upset you’ve ever been’ (VAS ¼ 100 mm) within the past Table 2. The treatment groups were well balanced with no 24 h. As with nausea, patients were asked to place a mark statistically significant differences in age, gender, diagnosis, on the line corresponding to the greatest degree of distress previous history of N/V, alcohol intake, or chemotherapy that they experienced within the past 24 h. Nausea and regimen. distress were measured at baseline and daily throughout the study period. Mild nausea or distress were defined as a VAS score of p30 mm, moderate nausea or distress were defined Nausea and distress as a VAS score of 31–60 mm, and severe nausea or distress Patients did not receive study medication for the same were defined as a VAS score of 61–100 mm. duration because of the different conditioning regimens An emetic episode was defined as a single vomit (ie, administered. Therefore, nausea and distress were evalu- expulsion of stomach contents) or one to five retches (ie, an ated on a daily basis. In order to detect a statistically attempt to vomit) occurring within a 5-min period. Each meaningful difference, categories of nausea and distress episode of vomiting was recorded and quantified. were ranked as none to mild (VAS, 0–30 mm) and moderate Overall control of emesis was also documented. Re- to severe (VAS, 31–100 mm). The comparative results sponse criteria for control of emesis were ranked as of moderate-to-severe nausea are depicted in Figure 2. complete response, major response, minor response, and failure and included emesis plus degree of nausea (Table 1). Patients who experienced six or more emetic episodes within 24 h during the study period were considered Table 2 Baseline patient characteristics treatment failures and were subsequently treated at the Characteristic Granisetron Ondansetron P physician’s discretion. (n ¼ 46) (n ¼ 50) Age 0.543 Safety assessments Mean7s.d. 50.8712 52.3711.4 Range 20–74 23–78 Adverse events were quantified and graded for severity using the SWOG toxicity grading criteria.24 Patients were Gender 0.114 discontinued from the study if they experienced a SWOG Male 36 45 Female 10 5 grade 3 or 4 adverse event that was felt to be related to the study medication and not to the HSCT conditioning Diagnosis 0.122 regimen, if the patient requested to be removed from the NHL+HD 15 24 study, or if the investigator felt that it was unsafe to Myeloma 15 16 continue the study medication for any reason. Breast cancer 10 3 Other 6 7

History of N/V with prior 0.625 Results chemotherapy None–mild 37 39 Moderate–severe 9 10 Patient characteristics Unknown 0 1

A total of 110 patients were randomized and enrolled into Alcohol intake 0.211 the study. However, 14 patients were withdrawn for various None–minimal 30 33 reasons: (1) ﬁve patients had baseline nausea or vomiting Moderate–heavy 16 14 Unknown 0 3

Chemotherapy 0.086 Table 1 Daily control of emesis BuCy 11 12

CBVm 13 22 Category Definition Melphalan 7 10 Other 15 6 Complete response No emetic episodes and none-to-mild nausea Major response One to two emetic episodes and none-to-moderate nausea or no emetic episodes and moderate nausea NHL ¼ non-Hodgkin’s lymphoma; HD ¼ Hodgkin’s disease; N/V ¼ nausea Minor response Three to five emetic episodes and any degree of and vomiting; BuCy ¼ busulfan+cyclophosphamide; CBVm ¼ cyclophos- nausea or zero to two emetic episodes and severe phamide+carmustine+etoposide (modified); other ¼ BEAM (carmustine+ 7 nausea etoposide+cytarabine+melphalan), cyclophosphamide+thiotepa carbo- Failure X6 emetic episodes and any degree of nausea platin, mitoxantrone or etoposide, cyclophosphamide+BEAM, ICE (ifosfamide+carboplatin+etoposide).

Bone Marrow Transplantation Prevention of nausea/vomiting in stem cell transplantation T Walsh et al 966 Regardless of severity, control of nausea declined through- granisetron experienced moderate distress. The analysis out the study duration, and it appears as though the patients was otherwise unable to detect any differences between the in the granisetron arm had a higher incidence of nausea on two treatment groups despite the type of chemotherapy day 6. However, no statistically significant differences in the regimen administered. degree of nausea occurred in either the granisetron group or ondansetron group on any given treatment day (range, Vomiting episodes and control of emesis P ¼ 0.563–1.000). Although these two agents appear equally effective, it must be noted that as a result of the small The median number of emetic episodes was 3 (range, 0–15) number of patients who received antiemetics by day 6, for the granisetron-treated group and 1 (range, 0–9) for the a small difference may be undetectable. ondansetron-treated group (P ¼ 0.228). The overall control The degree of distress for either treatment group was low of emesis was similar between treatment groups (Table 3). throughout the study period. Once again, both study drugs Although control of emesis declined throughout the study produced a similar incidence of distress until day 6 of the period, the majority of patients had a complete or major study period, when patients receiving granisetron appeared response. Only five (10.9%) and four (8%) patients to fare worse, but this difference did not attain statistical receiving granisetron and ondansetron, respectively, had significance (range, P ¼ 0.080–1.000). treatment failures during the study period. Nausea and distress were also evaluated based on the chemotherapy regimen administered (ie, busulfan/cyclo- Adverse events phosphamide-containing regimens vs other regimens). In the patients receiving nonbusulfan/cyclophosphamide-con- The most common adverse event that could be attributed to taining regimens, no significant differences between the two the study drugs was hiccups (Table 4). Diarrhea was also treatment groups occurred, except for distress at day 1, common, however, most of the patients who developed when a slightly higher incidence of patients receiving diarrhea were also receiving high-dose etoposide, which granisetron experienced moderate-to-severe distress may have played a significant role in the development of (P ¼ 0.047). A slightly higher incidence of patients receiving this complication. Other common adverse effects that occurred included constipation, headache, drowsiness, hypersensitivity and tremors. Once again, the patients 40 were receiving other medications, including dexametha- 35 P value (range) = 0.563–1.000 sone, lorazepam, and prochlorperazine, that may have 30 25 Granisetron 20 Ondansetron Table 4 Most frequent adverse effects 15 10 Adverse effect No. of patients (%) % of patients 5 Granisetron Ondansetron P 0 Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Constipation 1 (2) 2 (4) 1.00 Day of study Diarrhea 4 (8.7) 6 (12) 0.596 Headache 1 (2) 5 (10) 0.206 Figure 2 Daily moderate-to-severe nausea. Incidence of moderate-to- Hiccups 12 (26) 17 (34) 0.399 severe nausea during each day of conditioning therapy. Due to the different Hypersensitivity 3 (6.5) 1 (2) 0.347 conditioning regimens used, there were diminishing sample sizes for each Sedation 4 (8.7) 2 (4) 0.422 group. Sample sizes for granisetron from days 0 to 6 are 46, 46, 44, 36, 35, Tremors 2 (4.3) 1 (2) 0.606 23, and 14, respectively. Sample sizes for ondansetron from days 0 to 6 are Other 4 (8.7) 6 (12) 0.743 50, 50, 49, 43, 36, 17, and 13, respectively.

Table 3 Daily control of emesis during chemotherapy

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Granisetron n ¼ 46 n ¼ 44 n ¼ 36 n ¼ 35 n ¼ 23 n ¼ 14 CR 38 (83) 31 (70) 25 (69) 19 (54) 11 (48) 7 (50) MR 6 (13) 8 (18) 6 (17) 8 (23) 8 (35) 2 (14) MinR 1 (2) 3 (7) 5 (14) 6 (17) 4 (17) 5 (36) F 1 (2) 2 (5) 0 (0) 2 (6) 0 (0) 0 (0)

Ondansetron n ¼ 50 n ¼ 49 n ¼ 43 n ¼ 36 n ¼ 17 n ¼ 13 CR 45 (90) 41 (84) 34 (79) 20 (56) 12 (71) 6 (46) MR 3 (6) 5 (10) 4 (9) 9 (25) 3 (18) 6 (46) MinR 1 (2) 2 (4) 4 (9) 6 (17) 2 (12) 1 (8) F 1 (2) 1 (2) 1 (2) 1 (3) 0 (0) 0 (0) P 1 0.47 1 0.778 1 0.165

CR ¼ complete response; MR ¼ major response; MinR ¼ minor response; F ¼ failure (P-values based on Fisher’s exact test with grouping of CR+MR vs MinR+F).

Bone Marrow Transplantation Prevention of nausea/vomiting in stem cell transplantation T Walsh et al 967 contributed to these adverse events. The median number of was graded subjectively, only 50% of the patients adverse effects was one for both the ondansetron- and completed diaries, and the differences between the treat- granisetron-treated groups (range, 0–3 (ondansetron); ment groups were not reported. However, 73% of all range, 0–5 (granisetron)). The incidence of adverse events patients enrolled in the study experienced moderate-to- was similar between the treatment groups (P ¼ 0.294). severe nausea. Another comparative review conducted by Additionally, no patients were removed from the study Orchard et al22 randomized 136 pediatric and adult because of severe toxicities. patients to receive ondansetron by continuous intravenous infusion or granisetron intravenously every 12 h. All patients also received dexamethasone, and those o18 years Discussion old additionally received scheduled lorazepam and pro- methazine. Once again, no significant differences were This study was designed to compare the differences in observed between ondansetron- and granisetron-treated efficacy and adverse effects between intravenous ondanse- patients. tron and granisetron in combination with dexamethasone Comparisons of the results of our study with the other and lorazepam over the course of standard conditioning phase III study results are difficult because of the regimens administered in preparation for HSCT. Based on differences in efficacy parameters, patient populations, comparative studies using conventional chemotherapy, it and dosing strategies. These varied approaches are was not surprising that these agents, administered intrave- common limitations when evaluating antiemetic studies. nously, were found to be equivalent for all subjective and Most patients in our study were recruited from a objective measures of this study in HSCT recipients. Veterans’ Administration hospital and, therefore, Failure of emesis control occurred in only five (10.9%) included primarily older men with non-Hodgkin’s lym- and four (8%) of the granisetron- and ondansetron-treated phoma and multiple myeloma, whereas the Kalaycio patients, respectively. Unfortunately, as chemotherapy study included only middle-aged women with breast continued, daily control of all end points decreased with cancer and the Orchard study included pediatric and loss of efficacy for both agents. adult patients who received primarily TBI-containing The regimen selected for this study was based on the conditioning regimens. Our dosing strategy provided current practice at our institution at the time the protocol intermittent schedules of all antiemetics, whereas the was developed. Multiple phase II studies in the HSCT other studies varied in their approaches. These varied setting have been published since enrollment into this trial approaches could possibly impact the results, although began. These studies have substantiated the efficacy of the data on intermittent vs continuous infusion ondanse- granisetron and ondansetron for prevention of N/V tron in HSCT suggests that dosing strategy does not associated with high-dose conditioning regimens, however, matter. One unique feature of our analysis is the different dosing strategies and end points have made evaluation of total emesis control. We believe that it is comparisons of these results difficult. One such study was important to lookat the total impact of emesis and conducted by Abbott et al18 and evaluated the efficacy of nausea, as they both negatively affect the patient’s quality intravenous granisetron plus intravenous dexamethasone of life, however, by doing this our results may appear 10 mg administered daily until 24 h after conditioning worse than other published studies. The ideal strategy therapy was complete. Only 1% of 100 patients enrolled would be to evaluate one disease state and one failed to respond, however, the response criteria were conditioning regimen to eliminate multiple factors that different than those used in our study. Additionally, could influence the comparative responses between patients receiving single-agent cyclophosphamide for stem antiemetics, however, accrual in such a study would be cell mobilization were included in the study by Abbott, difficult to complete in a reasonable time frame. which, in our experience, cause a lower incidence of N/V We conducted this randomized, double-blind study to compared to commonly used multi-agent conditioning compare the efficacy and toxicity of two different 5HT3 regimens. Interestingly, most patients in this study were antagonists for the prevention of N/V during non-TBI- younger and female and would, therefore, be expected containing conditioning therapy for HSCT. Standardized to have a higher degree of N/V, which was not the case measures of nausea revealed no significant difference when compared with the results of our study, 84% of which between granisetron and ondansetron and, although were men. control of emesis decreased throughout the treatment Since the initiation of this trial, there have been two period, the degree of success was similar between the two publications comparing granisetron with ondansetron for treatment groups. Additionally, the overall incidence of the prevention of N/V with conditioning therapy for adverse effects was similar, and no patients were removed HSCT.21,22 Kalaycio et al21 randomized 48 adult patients from study because of severe toxicities. Based on these with breast cancer to receive granisetron or ondansetron as results, the choice of therapy should be based on drug a continuous intravenous infusion for a total of 7 days, acquisition cost. Future clinical trials should focus on oral with daily intravenous dexamethasone. Efficacy measures antiemetics to accommodate outpatient transplant practice included subjective nausea, mean number of emetic models or novel pharmacologic entities such as aprepitant episodes, number of salvage antiemetics, and days to first (Emends, Merck& Co. Inc., Whitehouse Station, NJ, salvage antiemetic. Of the 45 evaluable patients, no USA), a neurokinin-1 receptor antagonist, in an attempt significant differences in efficacy or adverse effects between to improve emesis control throughout conditioning the two treatment groups were observed. Although nausea chemotherapy.

Bone Marrow Transplantation Prevention of nausea/vomiting in stem cell transplantation T Walsh et al 968 Acknowledgements 11 Agura ED, Brown MC, Schaffer R et al. Antiemetic efﬁcacy and pharmacokinetics of intravenous ondansetron infusion We thankall of the BMT-unit physician assistants, nurses, staff during chemotherapy conditioning for bone marrow trans- and participating patients at the South Texas Veteran’s plant. Bone Marrow Transplant 1995; 16: 213–222. Healthcare System, Audie L Murphy Division and University 12 Barbounis V, Koumakis G, Vassilomanolakis M et al. A phase Hospital, San Antonio, Texas. Additionally, we would also like II study of ondansetron as antiemetic prophylaxis in patients to thankVirginia Doyle, RPh, who managed the randomization, receiving high-dose polychemotherapy and stem cell trans- blinding, and drug preparation aspects of the study and Vanessa plantation. Support Care Cancer 1995; 3: 301–306. Garza, Pharm.D. who assisted with data entry. This study was 13 Fauser AA, Russ W, Bischoff M. Oral dolasetron mesilate supported, in part, by an unrestricted educational grant from (MDL 73,147EF) for the control of emesis during fractionated SmithKline Beecham Pharmaceuticals. total-body irradiation and high-dose cyclophosphamide in patients undergoing allogeneic bone marrow transplantation. Support Care Cancer 1997; 5: 219–222. References 14 Frakes LA, Brehm TL, Kosty MP et al. An all oral antiemetic regimen for patients undergoing high-dose chemotherapy with

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