Bone Marrow Transplantation (2000) 25, 1279–1283  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Granisetron (Kytril) plus dexamethasone for antiemetic control in bone marrow transplant patients receiving highly emetogenic chemotherapy with or without total body irradiation

B Abbott, C Ippoliti, D Hecth, J Bruton, B Whaley and R Champlin

The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Summary: 5-hydroxytrypamine3 (5-HT3) receptor antagonist that has activity both in the periphery on the abdominal vagal affer- This prospective trial evaluated the efficacy and toxicity ents, and centrally on the chemoreceptor trigger zone of granisetron for antiemetic control in patients receiv- (CTZ). Emesis occurs when the vomiting center is stimu- ing high-dose cyclophosphamide (CY)-containing regi- lated by the CTZ or by afferent impulses from the cerebral mens with/without TBI for bone marrow (BM) or per- cortex, gastrointestinal tract, heart, or vestibular apparatus.4 ipheral blood stem cell (PBSC) transplantation or PBSC Several receptor types have been identified in these regions, mobilization. Granisetron 1 mg i.v. plus dexamethasone including dopaminergic, cholinergic, histaminergic, opioid, 5 10 mg i.v. were administered daily 30 min before and serotonergic (5-HT3). Chemotherapy and radiotherapy chemotherapy or radiation for a median of 5 days. cause cellular damage, eliciting a release of serotonin from Response was defined as the number of emetic episodes enterochromaffin cells in the intestinal mucosa. Serotonin per 24 h: complete response, 0 and no emetic rescue; release also activates 5-HT3 receptors in the vagal and poss- major response, 1–2; minor response, 3–5; failure, Ͼ5. ibly splanchnic afferent neurons through agonism with One hundred patients were enrolled. Ninety-eight resultant stimulation of the CTZ, causing the vomiting received CY-containing regimens and 26 of these reflex.6 Granisetron controls chemotherapy-induced nausea additionally received TBI (12 Gy divided over 4 days). and vomiting via competitive antagonism of serotonin at 7 Response was complete on 216 (47%) of a total 456 the 5-HT3 receptors. patient days, major on 222 (49%), minor on 14 (3%), Granisetron is FDA-approved for the prevention of and failure on 4 (1%). Mean number of emetic episodes nausea and vomiting associated with initial and repeated per patient per day and breakthrough medication courses of emetogenic cancer chemotherapy. Several trials required per patient per day was 0.24 (range 0–8) and have addressed the antiemetic efficacy of serotonin anta- 0.40 (range 0–8), respectively. Adverse effects were gonists for the prevention of irradiation-induced minimal, with headache (20%) reported most fre- emesis.7–11 The controversies that currently exist regarding quently. Based on these results, granisetron plus granisetron use in this patient population include optimal dexamethasone is an effective and well-tolerated anti- dose and optimal dosing frequency.11,12 emetic regimen in BMT/PBSCT recipients conditioned The main objectives of this trial were to monitor the with high-dose chemotherapy with/without TBI. Bone emetic control of granisetron plus dexamethasone in Marrow Transplantation (2000) 25, 1279–1283. patients who received chemotherapy regimens containing Keywords: antiemetic; bone marrow transplant; chemo- high-dose CY with or without TBI as a preparative regimen therapy; dexamethasone; granisetron; total body irradiation for BM or PBSC transplantation or PBSC mobilization, and evaluate any adverse effects of the combination.

Nausea, retching, and emesis are some of the most common Patients and methods unwanted effects associated with chemotherapy. These treatment side-effects represent a significant concern to the cancer patient.1 Nausea and vomiting are contributing fac- Study design tors to patient morbidity, and are critical factors in the This study was a single-center, open-label, prospective trial patient’s quality of life during treatment. Additionally, approved by the Institutional Review Board. Written infor- emetic episodes often influence the continuation of treat- med consent was obtained from all patients prior to 2 ment. Fortunately, with the advent of the serotonin anta- enrollment. All patients had either a hematologic or onco- gonists, there has been a major improvement in the control logic malignancy. Patients were eligible if they were receiv- 3 of nausea and vomiting. Granisetron is a potent, selective ing any high-dose chemotherapy preparative regimen con- taining cyclophosphamide (CY) (у60 mg/kg/day or у 2 Correspondence: Dr B Abbott, Clinical Affairs Department, Ortho Biotech 1.5 g/m /day) with or without TBI (12 Gy divided over Oncology, 2814 North Strathford Lane, Kingwood, Texas 77345, USA 4 days), followed by BM or PBSC transplantation or PBSC Received 22 November 1999; accepted 9 March 2000 mobilizaton. Additionally, patients had to be 16 years or Antiemetic control in BMT/chemotherapy/TBI patients B Abbott et al 1280 older and able to record daily nausea levels and daily Preparatory regimens emetic episodes in a patient diary. Patients with diabetes n = mellitus or acute central nervous system disease were not The conditioning regimens for BMT ( 31), PBSCT (n = 64), or PBSC (n = 5) mobilization generally consisted enrolled. The endpoints evaluated were control rate for nau- of high-dose CY in the following doses (2 g/m2/day, sea and vomiting throughout the treatment cycle, the need 2 for breakthrough medication for nausea and vomiting, and 4 g/m /day, and 60 mg/kg/day), and 29 regimens included TBI (12 Gy) administered over 4 days (3 Gy per day). The finally, toxicities associated with granisetron treatment. most commonly administered chemotherapy regimen (40 patients) was thiotepa (250 mg/m2) i.v. for 3 days (total Patients dose = 750 mg/m2), busulfan (1 mg/kg) p.o. every 6 h × 12 doses (total dose = 12 mg/kg), and CY (2 g/m2) i.v. for 3 One hundred patients were enrolled in the study. Salient = 2 patient demographic and clinical characteristics are shown days (total dose 6 g/m ). Most patients who underwent TBI received CY 60 mg/kg i.v. for 2 days (total in Table 1. The majority of transplants were performed for = = dose = 120 mg/kg) and thiotepa 5 mg/kg i.v. for 1 day (total breast cancer (n 55) and leukemia (n 29). Sixty-nine = patients had received autologous transplantation while 31 dose 5 mg/kg) plus TBI with 3 Gy every day for 4 days. The various preparatory regimens are shown in Table 1, received allogeneic transplantation. Patients were between 21 and 62 years of age. and dosages of agents comprising the most commonly used regimens are summarized in Table 2.

Table 1 Characteristics of the 100 patients enrolled in this study Antiemetic regimen The protocol was originally designed to use granisetron Demographic variable n 10 ␮g/kg, the indicated dose for emetic control. Granisetron Evaluable patients 98a was administered i.v. in combination with dexamethasone Mean age, years (range) 43 (21–62) 10 mg i.v. 30 minutes prior to patients receiving chemo- Gender therapy or TBI. However, the first six patients enrolled in Male 22 the study experienced unacceptable nausea and vomiting Female 78 while receiving the conditioning regimen and elected to Diagnosis Acute leukemia 10 withdraw from the study. As a result, the protocol was Breast 55 amended to standardize antiemetic therapy to granisetron Chronic leukemia 17 1 mg i.v. plus dexamethasone 10 mg i.v. daily. Granisetron Lymphoma 11 1 mg i.v. piggyback (IVPB) plus dexamethasone 10 mg MDS 2 Multiple myeloma 1 IVPB was administered starting 30 min prior to the first Ovarian 4 dose of chemotherapy and/or TBI. This treatment was Transplant type repeated daily and continued for 24 h after the last dose Autologous 68 of chemotherapy or TBI. For breakthrough nausea and/or Allogeneic 30 emesis, an additional dose of granisetron 1 mg IVPB was Preparatory regimens TBC 41 given as needed once per 24 h. If the granisetron was inef- CY/TBI 15 fective, prochlorperazine 10 mg IVPB plus diphenhydra- CY/TBI 12 CY-containing regimen 21 CBT 4 Table 2 Most commonly used preparatory regimens CY alone 5 Nausea with prior chemotherapy None 25 Regimen Mild 34 Mild–moderate 2 TBC Thiotepa 250 mg/m2 i.v. daily × 3 days Moderate 18 Busulfan 1 mg/kg p.o. every 6 hours × 12 doses Moderate–severe 6 CY 60 mg/kg/day × 2 days Severe 15 Number of patients with prior anticipatory nausea and CT/TBI CY 60 mg/kg i.v. daily × 2 days vomiting Thiotepa 5 mg/kg i.v. daily × 1 day Male 2 TBI (total 12 Gy) × 4 days Female 10 Alcohol consumption CY/TBI CY 60 mg/kg i.v. daily × 2 days None 17 TBI (total 12 Gy) × 4 days Weekly 34 Monthly 35 CBT CY 2 g/m2 i.v. daily × 3 days Yearly 14 BCNU 150 mg/m2 i.v. daily × 3 days History of headache 44 Thiotepa 240 mg/m2/day × 3 days

2 × a TBC = thiotepa, busulfan and CY; CT/TBI = CY, thiotepa and TBI; CY CY 4 g/m /day i.v. 1 day CBT = CY, BCNU and thiotepa. aTwo patients who discontinued before receiving study drug were TBC = thiotepa, busulfan and CY; CT/TBI = CY, thiotepa and TBI; excluded from the efficacy evaluation and provided demographic data CBT = CY, BCNU and thiotepa. only. aRegimen for PBSC mobilization patients.

Bone Marrow Transplantation Antiemetic control in BMT/chemotherapy/TBI patients B Abbott et al 1281 mine 25 mg IVPB, lorazepam 2 mg IVPB, or haloperidol forms. Data from the three sources were generally consist- 2 mg IVPB plus diphenhydramine 25 mg IVPB was made ent. However, where any discrepancies were found, data available to the patients every 4 h as needed. from the nurse’s notes were used for analysis. Patient com- pliance in completing the diaries was excellent, ie 98%. The mean number of days patients received granisetron Drug discontinuation criteria was 5 (1–8). The mean oral intake per day was 1177 ml Treatment with granisetron was discontinued in patients (180–6665 ml). The mean emetic episodes per day from 0 who developed unacceptable toxicities, had an allergic to 12 h and 12 to 24 h after treatment were 0.31 (0–8) and reaction, had insufficient antiemetic control, were unable to 0.17 (0–4), respectively (mean, 0.24 per day). The mean record data in the patient diaries, or who requested that number of rescue doses required per day during 0 to 12 h treatment be terminated. and 12 to 24 h were 0.48 (0–8) and 0.33 (0–4), respectively (mean, 0.40 per day). Based on a total of 456 patient days, response was complete on 216 days (47%), major on 222 Response criteria (49%), minor on 14 (3%), and failure to respond on 4 (1%). Response was defined by the number of vomiting episodes The mean morning and evening nausea scores reported on over a 24-h period, during chemotherapy administration the visual analog scale were 1.30 cm (0–10 cm) and 1.68 and/or TBI. Vomiting, sometimes called emesis, is the centimeters (0–10 cm), respectively. The efficacy data are mechanical expulsion of gastric contents by coordinated summarized in Table 3. When the emetic control rate was respiratory and abdominal muscles. Each vomiting episode analyzed by day, a sustained effect was demonstrated for experienced by the patient was recorded by the patient and the study duration (Figure 1). The majority of patients (91– the nurse. Instances of vomiting separated by 1 min or more 98%) achieved either a complete response or a major were counted as individual vomiting episodes. Complete response during the first 4 days of the study, and all patients response was defined as no episode of vomiting in any 24- achieved this level of response over the last 4 days. h period and no rescue antiemetic needed. A major response was defined as one or two episodes of vomiting Patient diary questionnaire in any 24-h period with or without the addition of rescue antiemetics. A minor response was defined as three to five On a daily basis, 57% of patients were able to eat and get vomiting episodes in any 24-h period with or without the out of bed without any problem. Thirty-four percent experi- addition of rescue antiemetics. Failure to respond was enced some nausea and difficulty eating but would get out defined as more than five vomiting episodes in any 24-h of bed, while 9% vomited almost everything and stayed in period over the treatment cycle. bed. The patients’ perception of antinausea effectiveness was either very effective (59%), somewhat effective (36%), Patient diary data or not effective (5%). Patient diary questionnaire data are summarized in Table 4. Each enrolled patient was provided a diary that was to be completed each day the patient received chemotherapy or a combination of chemotherapy and TBI, and continued until 24 h after the last treatment. The diary record con- Table 3 Efficacy data sisted of 24-h total oral fluid intake, the number of vomiting episodes per day, a visual analog scale to evaluate morning Parameter and evening nausea, and a questionnaire to assess patient perception of treatment outcomes. The record of daily oral Days of granisetron treatment Mean (range) 5 (1–8) fluid intake and the number of vomiting episodes was com- Median (range) 5 (1–8) pared with the patient chart and nursing documentation. Mean oral fluid intake per day (range) 1177 ml (180–6665 ml) The standard visual analog scale used to assess nausea Mean vomiting episodes per day ranged from 0 cm (no nausea) to 10 cm (the worst possible 0–12 h (range) 0.31 (0–8) 12–24 h (range) 0.17 (0–4) nausea). The patient questionnaire assessed the patients’ Mean number of rescue doses required per day daily routine and diet (how well they were able to eat and 0–12 h (range) 0.48 (0–8) how well they felt with treatment) and the effectiveness 12–24 h (range) 0.33 (0–4) of the antiemetic with the current chemotherapy regimen Mean number on nausea scale per day (compared with previous chemotherapy experience); also, a.m. (range) 1.30 (0–10 cm) p.m. (range) 1.68 (0–10 cm) any unwanted effects of the antiemetic medication were Response assessed. Complete response 216/456 (47%) Major response 222/456 (49%) Minor response 14/456 (3%) Failure to respond 4/456 (1%) Results Response = total number of patient responses per total number of patient Acute emesis and nausea days (% response). Complete response = 0 vomiting episodes and no emetic rescue; major response = р2 vomiting episodes, with or without Information on oral fluid intake and vomiting was obtained antimetic rescue; minor response = 3–5 vomiting episodes, with or without from the patient diary, nursing notes, and protocol tracking antiemetic rescue.

Bone Marrow Transplantation Antiemetic control in BMT/chemotherapy/TBI patients B Abbott et al 1282 Complete response Major response day 4. However, data were collected and analyzed for these 100 six patients. Based on the experience of these patients, the 62 60 73 57 67 protocol was amended to standardize antiemetic therapy to 34 28 47 granisetron 1 mg i.v. plus dexamethasone 10 mg i.v. daily. 80 After the granisetron dose adjustment was implemented, six additional patients withdrew from the study. Two patients withdrew on day 2 because of excessive nausea and vomit- 67 60 ing, and two others withdrew on day 4 because they were 61 unable to record data in their patient diaries. The data for these four patients were also included in the analysis. The two remaining patients withdrew from study prior to receiv- 40 44 43 40 36 ing therapy and therefore provided only demographic infor- Reponse rate (%) 33 mation. One of the two patients withdrew before receiving 27 20 the preparative regimen and antiemetic therapy because of a severe migraine headache. The second patient was enrolled in the study, but developed a severe infection 0 before treatment and subsequently had transplantation 12345678 delayed. Study days

Figure 1 Emetic control rate by study day in patients who received gran- isetron and dexamethasone during conditioning therapy prior to BMT, Discussion PBSCT, or PBSC mobilization. Complete response = vomiting episodes = р and no emetic rescue; major response 2 vomiting episodes, with or Although the 5-HT3-receptor antagonists have demon- without antiemetic rescue. Minor response (3–5 vomiting episodes) and Ͼ strated significant activity in patients undergoing chemo- response failure ( 5 vomiting episodes) are not depicted. therapy, the challenges presented in patients undergoing high-dose chemotherapy, with or without TBI, in BMT or Table 4 Patient diary questionnaire results PBSC transplantation still remain a significant concern. These treatment modalities are highly emetogenic, and Parameter Patient response although the antiemetic utility of corticosteroids, such as dexamethasone, in combination with other agents is well 13 Response for daily routine and diet established, few trials have evaluated combinations of 5- Vomit almost everything and stay in bed routine 9% HT3-receptor antagonists and dexamethasone in this clinical and eating setting. This single-center, open-label, prospective trial was Some nausea and difficulty eating but get out of 34% conducted primarily to evaluate the efficacy and safety of bed Able to eat and get out of bed without any 57% granisetron plus dexamethasone in BMT/PBSCT patients problem conditioned with CY-containing regimens with or without Response for effectiveness of antiemetic mediation TBI. (compared with previous chemotherapy) The results of this trial demonstrated that granisetron Very effective 59% Somewhat effective 36% 1 mg i.v. plus dexamethasone 10 mg i.v. daily was effective Not effective 5% in the prophylactic management of nausea and vomiting Response for adverse effects from medication in patients who were being prepared for BMT or PBSC Headache 20% transplantation, or PBSC mobilization. The preparatory Diarrhea 15% regimens contained high-dose CY with or without TBI. A Constipation 12% complete response to treatment with granisetron and dexamethasone was noted on 47% of 255 patient-days, a major response was noted on 49% of days (complete + = Toxicities response major response 96%), a minor response on 3% of days, and failure to respond on only 1% of the days. Adverse effects are also presented in Table 4. The majority The clinical effectiveness of the combination of granisetron of toxicities were minimal, with headache, diarrhea, and and dexamethasone was also reflected in the patients’ per- constipation reported in 20%, 15%, and 12% of patients, ception of treatment success as evaluated by means of the respectively. Two patients required discontinuation of gran- questionnaire in the patient diary. Nearly 60% of patients isetron and dexamethasone because of excessive nausea and reported the treatment to be very effective, and only 5% vomiting during their conditioning regimen. reported that treatment was not effective. The study patients had received emetogenic chemotherapy in the past, and Patient withdrawals 75% had experienced nausea and 12% had prior anticipat- ory nausea and vomiting. It should be noted that, overall, The first six patients enrolled in the study received granise- the patients were very involved in participating in the study tron at a dose of 10 ␮g/kg. These patients experienced and kept accurate diaries. As mentioned above, the com- unacceptable nausea and vomiting subsequent to adminis- pliance rate for completion of the patient-questionnaire tration of CY and elected to withdraw from the study on diary was approximately 98%. Only two patients were

Bone Marrow Transplantation Antiemetic control in BMT/chemotherapy/TBI patients B Abbott et al 1283 withdrawn from the study because of failure to complete receiving conditioning regimens and to explore the use of the patient diary. The high compliance rate for completion oral 5-HT3-containing antiemetic regimens for managing of the patient diary was largely due to nursing support as nausea and vomiting in this population. well as a having a designated pharmacist who visited the patients daily to assess completion of the forms. Nursing records were also reviewed at this time. Any discrepancies References between the nurses’ and patients’ reports were resolved on a daily basis, and patient education relative to completing 1 Coates A, Abraham S, Haye SB et al. On the receiving end – the diary was provided if necessary. patient perception of the side effects of cancer chemotherapy. The combination of granisetron plus dexamethasone used Eur J Cancer Clin Oncol 1983; 19: 203–208. in this study was equally effective in both subgroups of 2 Clavel M, Soukop M, Greenstreet YL. Improved control of emesis and quality of life with ondansetron in breast cancer. patients, ie, those who received chemotherapy alone, and Oncology 1993; 50: 180–185. those who received chemotherapy and TBI. We recently 3 Perez EA, Gandara DR. Advances in the control of chemo- reported the results of 26 evaluable patients from this study therapy-induced emesis. Ann Oncol 1992; 3: S47-S50. who had received high-dose chemotherapy with TBI.14 For 4 Mitchell EP, Schein PS. Gastrointestinal toxicity of chemo- 25 patients who completed 186 evaluable treatment days, therapy agents. In: Perry MC (ed). The Chemotherapy a complete response to treatment with granisetron and Sourcebook. Williams & Wilkins: Baltimore, 1992, pp 620– dexamethasone was noted on 50% of patient-days, a major 634. response on 48%, and a minor response on 2%; no failures 5 Dodds LJ. The control of cancer chemotherapy-induced nau- were recorded. These results were very similar to those for sea and vomiting. J Clin Hosp Pharm 1995; 10: 143–166. the total population described here. Impact of this treatment 6 Ettinger CS. Preventing chemotherapy-induced nausea and vomiting: an update and a review of emesis. Semin Oncol regimen on patient perception of treatment outcomes, as 1995; 22 (Suppl. 10): 6–18. well as the adverse events profile, was also similar in the 7 Plosker GL, Goa KL. Granisetron: a review of its pharmaco- TBI subgroup compared with the entire study population. logical properties and therapeutic use as an antiemetic. Drugs Granisetron was well tolerated in the total patient popu- 1991; 42: 805–824. lation. The major adverse effects reported were headache 8 Okamoto S, Takahashi S, Tanosaki R et al. Granisetron in the (20%), diarrhea (15%), and constipation (12%), none of prevention of vomiting induced by conditioning for stem cell which caused any patient to withdraw from the trial. transplantation: a prospective randomized study. Bone Marrow Transplant 1996; 17: 679–683. Few trials have investigated the efficacy of 5-HT3-recep- tor antagonists in BMT and PBSC patients, but increasing 9 Hunter AE, Prentice HG, Pothcary K et al. Granisetron, a selective 5-HT receptor antagonist, for the prevention of radi- evidence supports the use of these agents for antiemetic 3 ation induced emesis during total body irradiation. Bone prophylaxis in patients undergoing preparatory regimens. Marrow Transplant 1991; 7: 439–441. In several studies, i.v. granisetron and i.v. ondansetron have 10 Prentice HG, Cunningham S, Ghandhi L et al. 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Oral granisetron alone Ͻ and in combination with dexamethasone: a double-blind ran- tive (87.1% vs 37.0%, P 0.001) than the standard antiem- domized comparison against high-dose metoclopramide plus etic regimens used. Reported adverse events were few and dexamethasone in prevention of cisplatin-induced emesis. Ann not serious. We have augmented this work with a trial of Oncol 1994; 5: 579–584. granisetron plus dexamethasone in a similar patient popu- 14 Abbott B, Ippoliti C, Bruton J et al. Antiemetic efficacy of lation. Our experience in patients being conditioned for granisetron plus dexamethasone in bone marrow transplant marrow or PBSC transplantation suggests that granisetron patients receiving chemotherapy and total body irradiation. 1 mg i.v. plus dexamethasone 10 mg i.v. administered 30 Bone Marrow Transplant 1999; 23: 265–269. min prior to marrow ablative therapy is effective and well 15 Hewitt M, Cornish J, Pamphilon D et al. 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