Safety and efficacy of a continuous infusion, patient controlled antiemetic pump to facilitate outpatient administration of high-dose chemotherapy

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1 Bone Marrow Transplantation, (1999) 24, Stockton Press All rights reserved /99 $ Safety and efficacy of a continuous infusion, patient controlled antiemetic pump to facilitate outpatient administration of high-dose chemotherapy SP Dix, MK Cord, SJ Howard, JL Coon, RJ Belt and RB Geller Blood and Marrow Transplant Program, Oncology and Hematology Associates and Saint Luke s Hospital of Kansas City, Kansas City, MO, USA Summary: We evaluated the combination of diphenhydramine, lorazepam, and dexamethasone delivered as a continuous i.v. infusion via an ambulatory infusion pump with patient-activated intermittent dosing (BAD pump) for prevention of acute and delayed nausea/vomiting in patients receiving high-dose chemotherapy () for peripheral blood progenitor cell (PBPC) mobilization () or prior to autologous PBPC rescue. The BAD pump was titrated to patient response and tolerance, and continued until the patient could tolerate oral antiemetics. Forty-four patients utilized the BAD pump during 66 chemotherapy courses, 34 (52%) for and 32 (48%) for with autologous PBPC rescue. The median number of days on the BAD pump during and was 3 (1 6) and 9 (2 19) days, respectively. Complete overall or complete emesis control occurred on 94% of and 89% of treatment days during chemotherapy administration and 72% and 43%, respectively, following chemotherapy administration. Eighty-three percent of and 55% of treatment days were associated with no nausea. While on the BAD pump, no patient experienced severe toxicity or required hospitalization for management of nausea/vomiting. The BAD pump was safe and effective in minimizing nausea and vomiting associated with, and thus, eliminated the need for hospitalization for management of chemotherapy-induced nausea and vomiting. Keywords: high-dose chemotherapy; autologous peripheral blood progenitor cell transplantation; outpatient BMT; anti-emetic therapy Introduction Historically, patients undergoing blood or marrow transplantation (BMT) have required prolonged hospitalization for administration of high-dose chemotherapy () and recovery from regimen-related toxicities. In 1994, Peters Correspondence: SP Dix, Blood and Marrow Transplant Program, Oncology and Hematology Associates of Kansas City, 4320 Wornall Road, Suite 220, Kansas City, Missouri 64111, USA Received 22 May 1998; accepted 28 January 1999 and colleagues 1 described an outpatient BMT care model utilizing intensive clinic support following inpatient administration of. This approach facilitated early patient discharge and significantly decreased the total number of days of hospitalization associated with BMT. More recently, equipped BMT centers have extended the outpatient care approach to include administration of in the clinic setting. Success of the total outpatient care approach is dependent upon the availability of experienced staff and necessary resources as well as implementation of supportive care strategies designed to minimize morbidity in the outpatient setting. Despite improvements in supportive care strategies, chemotherapy-induced nausea and vomiting continues to be a side-effect causing significant distress to BMT patients and one that could limit the use of outpatient care during administration. In a survey evaluating symptom distress in BMT patients receiving high-dose chemotherapy in the inpatient setting, frequency and severity of nausea were among the symptoms associated with the highest degree of stress upon discharge from hospital. 2 To date, limited data are available on anti-emetic regimens that can be safely and effectively administered to patients receiving in the outpatient setting. Thus, the development of such regimens is essential to help facilitate outpatient administration of during BMT. The objective of this study was to evaluate the safety and efficacy of a combination of three anti-emetics with different mechanisms of anti-emetic action, diphenhydramine (Benadryl, Parke-Davis, Morris Plains, NJ, USA), lorazepam (Ativan, Wyeth-Ayerst, Philadelphia, PA, USA), and dexamethasone (Decadron, Merck, West Point, PA, USA), also called the BAD pump, delivered as a continuous i.v. infusion with patient-controlled i.v. bolus doses, in patients undergoing chemotherapy mobilization () or followed by autologous peripheral blood progenitor cell (PBPC) transplantation in the outpatient setting. Methods Patients were enrolled and evaluated over a 1 year period from October 1996 to October All patients consented to institutional review board approved treatment protocols including assessments of toxicity and supportive care strategies. In order to participate, patients were required to have met routine clinical eligibility criteria to undergo autolog-

2 562 Granisetron 1 mg or Ondansetron 32 mg i.v. and Dexamethasone 10 mg i.v. q 24 h on days of i.v. chemotherapy BAD pump with basal = ml/h with 2 3 ml bolus q 15 min lockout N/V = no N/V = yes no change appropriate use inappropriate use re-evaluate q 24 h and continue BAD pump until at least 24 h after PBPC infusion re-educate patient and caregiver constant N/V intermittent N/V increase basal by 25 50% (max = 0.6 ml/h) increase bolus by 25 50% (max = 6 ml/dose) N/V = no no change N/V = yes individualize or add rescue anti-emetics re-evaluate q 24 h and continue BAD pump until at least 24 h after PBPC infusion and patient able to tolerate oral anti-emetics Additional guidelines: 1 If assessment in outpatient clinic, BMT nurse to make adjustment. If assessment is after hours or on weekend, BMT home health care nurse to make adjustment in conjunction with BMT on-call MD. 2 Options for rescue anti-emetics include: (1) continue to increase basal and/or bolus and titrate to effect; increments must be done in clinic setting; (2) add haloperidol mg p.o. q 6 h; or (3) add prochlorperazine 10 mg p.o.q 6 h Figure 1 Outpatient anti-emetic algorithm: BAD = diphenhydramine 400 mg i.v., lorazepam 16 mg i.v., and dexamethasone 40 mg i.v. in 100 ml D5W non-pvc at ml/h with 2 3 ml bolus q15 min lockout. Doses for each drug as follows: diphenhydramine mg/h with 8 12 mg bolus; lorazepam mg/h with mg bolus; dexamethasone mg/h with mg bolus. ous BMT based on disease status and organ function along with the following criteria to undergo outpatient care during BMT: (1) the patient must have undergone a psychosocial assessment by the BMT social worker with or without additional assessment by the BMT-designated clinical psychologist or psychiatrist; (2) the patient must have an approved caregiver or caregivers available 24 h a day starting at initiation of or ; (3) the patient must have lodging, either an approved home or hotel, within a 30-min driving radius of the BMT center along with transportation; (4) the patient and caregiver must have attended the BMT Caregiver Class and met class objectives prior to initiation of or ; (5) the patient must have insurance benefits for outpatient care during BMT; and (6) the patient must have signed an informed consent to receive or followed by autologous PBPCT in the outpatient setting. Regimens for PBPC mobilization or preparative regimen were selected based on institutional disease-specific protocols. All chemotherapy doses were initiated in the morning in the BMT outpatient clinic. Patients received standard premedications consisting of a serotonin antagonist, ondansetron 32 mg i.v. or granisetron 1 mg i.v., plus dexamethasone 10 mg i.v. each day beginning 30 min before the first dose of chemotherapy. The BAD pump was initiated in the afternoon on the first day of high-dose chemotherapy and administered as outlined in Figure 1. The BAD pump was prepared by mixing diphenhydramine 400 mg i.v., lorazepam 16 mg i.v., and dexamethasone 40 mg i.v. in a total volume of 100 ml D5W in a non-polyvinylchloride bag to minimize adsorption. All patients were initiated at a dose of ml/h continuous basal rate with a 2 3 ml patient-activated bolus option programmed

3 with a 15-min lockout between boluses. Dosing was based on patient weight with patients weighing more than 80 kg initiated at the higher end of the dosing range. The pump was refilled every 48 h or sooner if needed. Dexamethasone was deleted after a maximum duration of 96 h. The pump was continued until at least 24 h after chemotherapy or PBPC infusion and the patient was able to tolerate oral antiemetics. The BAD combination was infused via the Abbott Provider 6000 ambulatory infusion pump (Abbott Laboratories, Abbott Park, IL, USA). Patients and caregivers were instructed on battery alarms and changes, and a back-up set of 9 V batteries were dispensed with each pump. Flumazenil (Romazicon; Roche Laboratories, Nutley, NJ, USA), the benzodiazepine reversing agent, with necessary supplies for administration, was also dispensed at the time of initiation of the pump and kept in the patient s home or hotel room. Patients were assessed daily in the outpatient BMT clinic while on the BAD pump and after discontinuation. After clinic hours, patients were instructed to call the on-call BMT physician or home health care nurse for any problems with the pump or refractory nausea and/or vomiting. The number of emetic episodes (EE) per day was recorded by the nurses while in the clinic. When outside the clinic, caregivers recorded the number of EE on a diary sheet. On the following day, the nurse recorded the total number of EE for each 24-h period in the patient chart. An EE was defined as a single vomit or retch or any number of continuous episodes of vomiting or retching occurring within 1 min of each other. Response per 24 h was categorized as follows: complete overall control = no EE, no nausea, and no rescue medications; complete emesis control = no EE, no rescue medications; major emesis control = 1 2 EE per day. Nausea and other toxicities were also assessed daily and graded based on National Cancer Institute Common Toxicity Criteria. Other data endpoints collected included the duration of the BAD pump, the number of BAD pump dose adjustments required, the name and duration of rescue antiemetics prescribed, and the number of hospitalizations for nausea and/or vomiting. Results Over the 1 year period, the BAD pump was used with a total of 66 high-dose chemotherapy treatment regimens in 44 patients. Demographic information and chemotherapy regimens are outlined in Table 1. In terms of emetogenic potential, all chemotherapy regimens were classified as highly emetogenic based on the Hesketh criteria with the exception of high-dose melphalan which is not included in the Hesketh proposal. 3 Of the 66 treatment regimens, 34 (52%) were for PBPC mobilization and 32 (48%) treatment regimens were for followed by autologous PBPC transplant. All patients received hydration with 1 2 liters overnight on the days of chemotherapy. On cyclophosphamide days, hydration included mesna given as a continuous 24-h infusion at 100% of the cyclophosphamide dose. The initiation dose of the BAD pump was 0.2 ml/h with a 2 ml bolus every 15 min lockout for 49 (74%) of the Table 1 Demographics and results No. of BAD pump courses 66 No. of mobilization courses 34 (52%) (Regimen = cyclophosphamide 4000 mg/m 2 i.v. on day 1, then G-CSF 10 g/kg/d s.c. day 2 or GM-CSF 500 g/d s.c. day 2 to pheresis) No. of with autologous PBPCT courses 32 (48%) Breast CA Cyclophosphamide 2000 mg/m 2 /d days 5, 19 4, 3 Thiotepa 167 mg/m 2 /d days 5, 4, 3 Carboplatin 267 mg/m 2 /d days 5, 4, 3 Multiple myeloma: Melphalan 100 mg/m 2 /d 6 days 3, 2 NHL: Carmustine 300 mg/m 2 /d day 7 3 Cytarabine 100 mg/m 2 bid days 6, 5, 4, 3 Etoposide 100 mg/m 2 bid days 6, 5, 4, 3 Cyclophosphamide 35 mg/kg/d days 6, 5, 4, 3 Other regimen a 4 Initiation dose = 0.2 ml/h with 2 ml bolus 49 (74%) q15 min lockout Initiation dose = 0.3 ml/h with 3 ml bolus 17 (26%) q15 min lockout Median duration of BAD pump during 3 days (1 6) (range) Median duration of BAD pump during 9 days (2 19) (range) No. of BAD courses requiring dose adjustment 17 (26%) No. of BAD courses requiring rescue anti- 5 (7.6%) emetics No. of hospitalization for nausea/vomiting 0 during BAD courses a High-dose combination chemotherapy cyclophosphamide based. treatment courses and 0.3 ml/h with a 3 ml bolus every 15 min lockout for the remaining 17 (26%) of the treatment courses (Table 1). Four patients (9%) did not receive dexamethasone because of a history of diabetes (n = 3) or an allergy (n = 1). During regimens, the median number of days on the BAD pump was 3 days (range 1 6 days). During regimens, the median number of days on the pump was 9 days (range 2 19 days). Of the 66 treatment courses, 57 (86%) had data evaluable for efficacy in preventing nausea and vomiting, 33 regimens and 24 regimens. Nine courses were not evaluable for efficacy due to incomplete or missing data. During, complete overall or complete emesis control occurred on all days of chemotherapy administration in 88% of BAD treatment courses and on all days following chemotherapy administration while on the BAD pump in 64% of courses. During, complete overall or complete emesis control occurred on all days of chemotherapy administration in 75% of BAD treatment courses and on all days following chemotherapy administration while on the BAD pump in 35% of courses. These data are subdivided for complete overall and complete emesis control and depicted graphically in Figure 2. When evaluating treatment days on the BAD pump, 59% and 81% of treatment 563

4 564 % of treatment courses Post CEC COC COC 26/33 (79%) 11/33 (33%) 12/33 (36%) 7/24 (29%) 3/20 (15%) 5/24 (21%) CEC 9/33 (29%) 10/33 (31%) 10/33 (31%) 11/24 (46%) 4/20 (20%) 5/24 (21%) Figure 2 Response rate by treatment course: percentage of patients per phase of treatment course who experienced complete overall control (COC) or complete emesis control (CEC) on all days of treatment course. % of treatment days Post Post MEC CEC COC COC 29/35 (83%) 21/58 (36%) 50/93 (54%) 40/72 (56%) 25/145 (17%) 65/217 (30%) CEC 4/35 (11%) 21/58 (36%) 25/93 (27%) 24/72 (33%) 38/145 (26%) 62/217 (29%) MEC 2/35 (6%) 12/58 (21%) 14/93 (15%) 8/72 (11%) 66/145 (46%) 74/217 (34%) Figure 3 Response rate by treatment days: percentage of treatment days per phase where patient experienced complete overall control, complete emesis control, or major emesis control (MEC). days had complete overall or complete emesis control during and mobilization courses, respectively. Control rates achieved based on treatment days are subdivided for complete overall control, complete emesis control, and major emesis control and depicted graphically in Figure 3. During mobilization, 67% (22/33) of courses were associated with no EE while on the BAD pump. While on the BAD pump during regimens, 38% (9/24) of courses were also associated with no EE on any day, 21% (5/24) with a maximum of one EE per day, and 29% (7/24) with a maximum of two EE per day. During and following, patients experienced no nausea on 83% (29/35) and 36% (21/58) of treatment days, respectively. During and following, patients experienced no nausea on 55% (40/72) and 17% (25/145) of treatment days, respectively. In terms of severity of nausea during mobilization, the maximum nausea grade experienced on any given day while on the BAD pump was grade 0 for 44% of courses, grade I for 35%, grade 2 for 18%, and grade 3 for 3%. During regimens, the maximum nausea grade experienced on any given day while on the BAD pump was grade 0 for 20%, grade 1 for 20%, grade 2 for 40%, and grade 3 for 20%. All patients were evaluated in the outpatient clinic daily; however, no patient required hospitalization for management of refractory nausea and/or vomiting while on the BAD pump. Seventeen of the 66 (25%) treatment courses required a median of one dose adjustment in the BAD pump with 82% of dose adjustments occurring during the treatment courses. The maximum dose delivered was 0.4 ml/h with 4 ml bolus every 15 min lockout and was given to only one patient. No patient required rescue anti-emetics while on the BAD pump during. During, five (16%) BAD treatment courses required the addition of rescue antiemetics (Table 1). In terms of toxicity, patients reported mild (grade I) headache during 12.5% of treatment courses. On at least 1 day on the BAD pump, all patients experienced grade I II depressed levels of consciousness consisting of somnolence or sedation with or without interference in function, but not interfering with activities of daily living. Dexamethasone was discontinued early during four treatment courses secondary to indigestion (n = 2), hiccoughs (n = 1), and restlessness (n = 1). No severe toxicities related to the BAD pump occurred. No pump malfunctions occurred which resulted in inaccurate dosing or administration of the BAD infusion. One patient had the pump replaced three times because of an inability to infuse; however, this was later determined to be a central line problem requiring line replacement. Discussion Given the complexity of BMT and differences in resources available among centers, various models have been developed and implemented to facilitate outpatient care during BMT. The first model to be widely publicized and noted to decrease hospitalization was the model developed at Duke University where the regimen is delivered in the inpatient setting and then patients are discharged to the outpatient setting for supportive care management during neutropenia and the early recovery phase. 1 More recently, certain BMT centers have attempted to expand the outpatient care model to include delivery of high-dose chemotherapy in the outpatient setting. 4 In order to implement this total outpatient care approach, supportive care protocols must be implemented and include management of acute chemotherapy-related toxicity, particularly gastrointestinal complications. While various studies have described successful outpatient management of other BMT-related supportive care issues such as infectious complications, limited data are available describing successful strategies to prevent and manage acute nausea and vomiting associated with delivery of in the outpatient setting. 5 In the Duke University outpatient model, the anti-emetic regimen initially implemented consisted of a continuous infusion of prochlorperazine in combination with lorazepam or other individualized rescue anti-emetics. 1 Following completion of in the inpatient setting, patients were often discharged on continuous or twice daily doses of i.v. ondansetron delivered via an ambulatory infusion pump for management of delayed nausea and vomiting. Miyahara et al 6 evaluated the efficacy of an oral anti-emetic

5 strategy of granisetron 1 mg twice daily combined with lorazepam or other agents as first-line therapy for management of acute and delayed nausea and vomiting in a prospective study conducted in the inpatient setting. The objective of this pilot study was to evaluate the feasibility of outpatient care during and after delivery of the STAMP V preparative regimen followed by autologous bone marrow rescue. Despite aggressive efforts to manage patients with oral medications, Miyahara et al 6 reported that over 40% of patients required a median of 7 days of i.v. anti-emetics, primarily lorazepam, for management of chemotherapyinduced nausea and vomiting. These data suggest a need to develop a strategy incorporating i.v. anti-emetics in order to successfully deliver in the outpatient setting. Meisenberg et al 4 recently published data describing their experience on a subtotal outpatient BMT care model where was administered in the hospital and a total outpatient BMT care model where was administered in the clinic. Meisenberg et al 4 report that most patients received a combination of continuous infusions of lorazepam, prochlorperazine, and diphenhydramine for antiemetic prophylaxis. These authors do not provide specific information on dosing or administration and do not report data on specific response rates to this regimen in terms of management of nausea and vomiting. Of note, no patient in the total outpatient program was admitted for refractory nausea and vomiting. These data are, thus, encouraging and suggest that can be safely administered in the outpatient setting, yet fail to provide descriptive details on outpatient management of -associated nausea and vomiting. In our study, the objective was to evaluate the safety and efficacy of a combination i.v. anti-emetics given as a continuous infusion with patient-activated bolus dosing in patients receiving in the outpatient setting. This evaluation also provides practical and descriptive information to the clinician using such treatment regimens. The combination of diphenhydramine, lorazepam, and dexamethasone, called the BAD pump, was delivered as a very low basal rate with patient-activated, bolus doses, much like a patient-controlled analgesia pump administered for control of acute pain. The drugs used in this combination were selected for their different mechanisms of action against the emetic center and potential to provide a broad scope of antiemetic action. Potential advantages of this regimen include the psychological benefit of patient control by allowing for self-dosing and the relative ease of delivery by using the ambulatory pump. 7 Possible disadvantages include the potential for excess sedation with the use of diphenhydramine and lorazepam, short-term side-effects related to dexamethasone, overuse by the patient, and pump malfunction. In terms of efficacy, we found the BAD pump in combination with standard pre-medications of a serotonin antagonist plus dexamethasone to provide at least comparable efficacy to first-line anti-emetic regimens used with nontransplant, highly emetogenic regimens such as high-dose cisplatin. 8,9 The BAD pump was most effective on days of chemotherapy administration. On days following chemotherapy administration, the BAD pump was less effective in providing complete control; however, it did provide at least major emesis control in the majority of patients. Although limited, other data evaluating anti-emetic prophylaxis consisting of a serotonin antagonist alone during stem cell transplantation report complete or major response rates of 51 58% during the regimen. 10,11 Our response rates were at least comparable to these reports, but more importantly facilitated outpatient admininstration of, the primary goal of this study. In terms of safety, this regimen was not associated with any serious toxicity, despite the continuous use of medications with sedative properties. No patient experienced any serious adverse effect due to overuse or pump malfunction. Patients did experience sedation or somnolence at some time on the pump, but this was easily managed by dose titration and the continued presence of a caregiver for assistance. The ambulatory infusion pumps were associated with only minor maintenance needs, primarily battery changes, once the patient was discharged from the clinic. Routine nursing procedures to minimize potential pump malfunctions such as requiring two nurses to check the settings prior to discharge and daily heparin flushes of the BAD infusion lumen of the central catheter were most likely responsible for the surprisingly low rate of ambulatory infusion pump-related problems. While on the BAD pump, four patients did experience adverse effects presumed to be related to the dexamethasone including indigestion, hiccoughs, and restlessness. These adverse effects resolved upon discontinuation of the dexamethasone, and patients were then able to be effectively controlled on just the combination of diphenhydramine and lorazepam in the pump. No other clinically significant, potentially steroid-related adverse effects were observed. The low rate of steroid-induced adverse effects is most likely related to the short duration of the therapy, but may also have been due to careful patient screening. To minimize adverse effects, patients with diabetes (n = 3) or a previously documented intolerance to steroids (n = 1) did not receive dexamethasone in the anti-emetic pump. Other initial concerns with the use of the BAD pump were the lack of compatibility information available on this combination and the potential for the BAD pump to constantly occupy i.v. access. Although chemical compatibility data are lacking, this combination was physically compatible for at least 48 h based on visual observation. To minimize adsorption of lorazepam to the plastic containers, nonpolyvinyl-chloride containers were used. 12 In addition, dextrose was used as a diluent instead of saline to minimize decomposition of lorazepam. With these concessions to enhance potency of the lorazepam and based on the premise that the combination was titrated to effect, we felt a chemical compatibility test was not warranted in order to proceed with the study objective. In addition to being a safe and effective anti-emetic regimen, our regimen is also less costly than some other combinations implemented during stem cell transplantation. For example, the regimen published by Barbounis et al 11 utilizing a total of 28 i.v. doses of ondansetron 8 mg over an 8- day period is associated with a total drug cost of approximately $1400 based on 1998 average wholesale prices. 12 Our regimen was associated with a comparable response rate and incorporated more drugs, yet costs less than the 565

6 566 regimen of Barbounis et al. Considering drug costs only, our regimen, including granisetron 1 mg i.v. plus dexamethasone 10 mg i.v. daily during chemotherapy for 3 days plus the BAD pump for a median of 9 days, costs approximately $700 for the entire regimen. In addition, our regimen facilitates outpatient administration of and prevents the need for hospitalization, which has the potential to further substantially decrease the overall cost of care during BMT. In summary, we found this combination of diphenydramine, lorazepam, and dexamethasone, the BAD pump, along with a serotonin antagonist plus dexamethasone on days of chemotherapy to be effective in preventing or minimizing nausea and vomiting during chemotherapy-based and with autologous PBPC transplantation. In addition, the safety and effectiveness of this regimen facilitated outpatient care and eliminated the need for hospitalization to administer, as has been the standard of care in most BMT centers. By continuing the BAD pump until the patient could be maintained on oral medication, we were also able to control and eliminate hospitalization for management of delayed nausea and vomiting. Further studies are warranted to evaluate the role of the BAD pump to facilitate outpatient care in other patient populations receiving highly emetogenic chemotherapy regimens. Acknowledgements We are grateful to Keely Hotchkiss RN, and Elaine Stenstrup RN, for their assistance in development and implementation of this research protocol. References 1 Peters WP, Ross M, Vredenburgh JJ et al. The use of intensive clinic support to permit outpatient autologous bone marrow transplantation for breast cancer. Semin Oncol 1994; 21 (Suppl. 7): Lawrence CC, Gilbert CJ, Peters WP. Evaluation of symptom distress in a bone marrow transplant outpatient environment. Ann Pharmacother 1996; 30: Hesketh PJ, Kris MG, Grunberg SM et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997; 15: Meisenberg BR, Miller WE, McMillan R et al. Outpatient high-dose chemotherapy with autologous stem-cell rescue for hematologic and nonhematologic malignancies. J Clin Oncol 1997; 15: Gilbert C, Meisenbert B, Vrendenburgh J et al. Sequential prophylactic oral and empiric once-daily parenteral antibiotics for neutropenia and fever after high-dose chemotherapy and autologous bone marrow support. J Clin Oncol 1994; 12: Miyahara TT, Dix SP, Devine SM et al. Evaluation of supportive care guidelines for monitoring breast cancer bone marrow transplant patients in the outpatient setting. Blood 1995; 86 (Suppl. 1): 213a (Abstr.). 7 Thomas V, Heath M, Rose D et al. Psychological characteristics and the effectiveness of patient-controlled analgesia. Br J Anaesthesia 1995; 74: Hesketh PJ, Harvey WH, Harket WG et al. A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of emesis of high-dose cisplatin-induced emesis. J Clin Oncol 1994; 12: Kris MG, Pendergrass KB, Navari R et al. Prevention of acute emesis in cancer patients following high-dose cisplatin with the combination of oral dolasetron and dexamethasone. J Clin Oncol 1997; 15: Okamoto S, Takahaski S, Tanosaki R et al. Granisetron in the prevention of vomiting induced by conditioning for stem cell transplantation: a prospective randomized study. Bone Marrow Transplant 1996; 17: Barbounis V, Koumakis G, Vassilomanolakis M et al. A phase II study of ondansetron as antiemetic prophylaxis in patients receiving high-dose polychemotherapy and stem cell transplantation. Support Care Cancer 1995; 3: Trissel LA. Handbook on Injectable Drugs. American Society of Health-System Pharmacists: Bethesda, MD, 1996, pp