Dexamethasone for Antiemetic Control in Bone Marrow Transplant Patients Receiving Highly Emetogenic Chemotherapy with Or Without Total Body Irradiation
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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.