A Randomized Trial of Once Vs Twice Daily Administration of Intravenous

Home , Granisetron

Bone Marrow Transplantation, (1998) 22, 685–688  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt A randomized trial of once vs twice daily administration of intravenous granisetron with dexamethosone in patients receiving high-dose cyclophosphamide, thiotepa and carboplatin

R Birch, CH Weaver, K Carson and CD Buckner

Clinical Research Division of Response Oncology, Inc., Memphis, TN 38117, USA

Summary: order to make this form of therapy widely applicable and cost-effective, outpatient administration of chemothera- The purpose of this study was to determine the optimal peutic agents is a necessity. Nausea and vomiting, however, schedule of i.v. granisetron and dexamethosone for con- remain significant side-effects which limit the ability to trol of nausea and emesis in patients receiving high-dose conveniently administer HDC in an outpatient setting. chemotherapy (HDC). Seventy patients with breast can- Granisetron is a selective serotonin3, 5-hydroxytryta- cer received high-dose cyclophosphamide, thiotepa and mine3, receptor antagonist which has significant anti-emetic carboplatin (CTCb) for 3 consecutive days. All 70 activity against chemotherapy-induced nausea and vomit- received dexamethasone 12 mg i.v. and granisetron 1 ing. The effects of granisetron for the prevention of nausea mg i.v. prior to infusion of CTCb and were randomized and vomiting induced by anti-neoplastic therapy have been to receive placebo (n = 37) or an additional identical reviewed.5 A single prophylactic intravenous (i.v.) or oral dose of granisetron (n = 33) 12 h later. Beginning on day dose is sufficient to control acute nausea and vomiting in 2 of chemotherapy administration, 55 patients evaluable approximately 60–70% of patients.5 Granisetron is usually later self-administered a cocktail of diphenhydramine administered concomitantly with dexamethasone which (benadryl), lorazepam (ativan) and dexamethasone improves the acute anti-emetic efficacy by approximately (BAD). Fourteen of 37 patients (38%) receiving granise- 15%.6,7 Granisetron has been utilized to prevent nausea and tron once a day and 15/33 (44%) receiving it twice a vomiting in patients receiving total body irradiation as con- day had a complete response during the first 24 h fol- ditioning for bone marrow transplantation.8 There are cur- lowing the first doses of chemotherapy (P = 0.52). In the rently no reports, however, of granisetron for the prevention 55 evaluable patients receiving BAD, 18 of 29 (62%) in of nausea and vomiting for patients undergoing HDC and the once daily group and 14/26 (54%) in the twice daily stem cell infusion. group required additional medications (P = 0.54). The High-dose cyclophosphamide, thiotepa and carboplatin median time to first emetic episode was 20 h (range 6.6– (CTCb) with PBSC support has been used to treat patients 79.5) for patients receiving once a day and 21.4 hours with breast cancer in an outpatient setting.3,4 The adminis- (range 5.8–105.3) for patients receiving twice a day tration of dexamethasone with granisetron as a single i.v. granisetron (P = 0.48). Five patients in the once daily dose would have advantages over currently used anti-emet- and seven patients in the twice daily group had complete ics which require multiple dosing in a 24 h period. Granise- control of nausea and emesis throughout the study per- tron, however, has not been previously evaluated in patients iod (P = 0.37). It was concluded that there were no stat- receiving HDC and it is not clear that a single daily dose istically significant differences in nausea and emetic of granisetron with dexamethasone would be adequate to control between dexamethasone with once daily or twice prevent nausea. Before comparing granisetron with other daily i.v. granisetron administration in patients anti-emetics in patients receiving HDC a trial was carried receiving high-dose CTCb. out to determine if daily i.v. dosing was adequate. The cur- Keywords: granisetron; high-dose chemotherapy rent study compared the efficacy of administering one vs two daily doses of granisetron i.v. with dexamethasone for the management of nausea and emesis induced by high- dose CTCb. High-dose chemotherapy (HDC) with autologous stem cell support is being increasingly utilized for the treatment of patients with a variety of malignant diseases, especially bre- Patients and methods 1–3 ast cancer. The administration of HDC with peripheral Between April 1995 and May 1997, 71 patients with breast blood stem cell (PBSC) support is currently associated with cancer were enrolled in a randomized trial of i.v. granise- 4 considerable morbidity but relatively low mortality. In tron with dexamethasone. Patients were eligible for ran- domization if they had stages II–III or metastatic breast Correspondence: Dr CD Buckner, Response Oncology, Inc., 600 Broad- cancer, were scheduled to receive CTCb with PBSC sup- way, Suite 112, Seattle, WA 98122, USA port, were between the ages of 18 and 65, had an ECOG + Received 5 March 1998; accepted 19 May 1998 performance status of 0–1, had у2.5 × 106 CD34 cells/kg Once vs twice daily i.v. granisetron and dexamethosone in HDC R Birch et al 686 in the PBPC product, had no nausea or emesis in the pre- hydration with D5 NS plus 20 mEq of potassium chloride vious 24 h and had adequate hepatic, renal and cardiac at 125 cm3/h throughout the day in the outpatient center. function. All patients signed a protocol-specific informed Bumex 1–2 mg or furosemide 20–40 mg every 4–6 h was consent approved by the institutional review board of the administered to maintain a urine output of 100–200 ml/h. hospital where the therapy was administered. On each day of treatment, patients received the uro-protec- tive agent mesna, 600 mg/m2 i.v. bolus in 100 cm3 NS or Treatment centers D5W before and after cyclophosphamide. Patients received an additional 2000 ml of i.v. hydration over 14–18 h Patients were treated in one of 16 participating medical cen- following each day of treatment. ters in the United States under the care of 45 community oncologists affiliated with Response Oncology, Inc. (ROI), Memphis, TN and listed at the end of this manuscript. Record keeping Chemotherapy for all three phases of treatment was administered and PBSC harvested and infused in an outpatient Patients were given a daily worksheet to record time of the facility. Patients were admitted to hospitals meeting first emesis and/or nausea, incidence and severity of nausea, the criteria of ASCO/ASH guidelines for stem cell and the number of emetic episodes to day 6 of the study. transplantation.9 Adverse events were also reported to the study nurse and included in the case report form. Study design

This was a randomized phase III double blind placebo con- Endpoints and definitions of response trolled study with patients being randomized in a one-to- one ratio between two treatment groups. Patients were The primary endpoint was response to granisetron in the stratified by stage of breast cancer and treatment center. first 24 h. Secondary endpoints were: time to first emetic episode; incidence, frequency, and duration of additional Dexamethasone: All patients received dexamethasone 12 anti-emetic agents; severity of nausea over a 6 day period. mg, i.v. 30 min prior to the administration of chemotherapy The definitions of response were similar to those of the on each of 3 consecutive days. Granisetron Study Group:10

Once daily granisetron group: Patients randomized to this Complete response was no emesis and no or only mild group received granisetron 1 mg i.v over 15 min beginning nausea. 30 minutes prior to administration of chemotherapy on each Major response was 1–2 emetic episodes with moderate of 3 consecutive days. Placebo was infused i.v. over 15 min to severe nausea. 12 h after the first dose of granisetron. Minor response was defined as three emetic episodes. Failure was у4 emetic episodes. Twice daily granisetron group: Patients randomized to this group received the same dose and schedule as above except that placebo was replaced by 1 mg of granisetron. The time to the first emetic episode was defined as the period of time between administration of the first dose of granisetron to the time the patient experienced one of the fol- Other anti-emetic drugs lowing: any number of retches in a 5 min period, or two After the first 13 patients were accrued a preliminary analy- or more vomits in close succession not relieved by a period sis indicated poor emetic control in both groups of patients. of relaxation, or retching of less than 5 min combined with Thus, all further patients (n = 55) received a cocktail of a single episode of vomiting, or a single episode of vomit- diphenhydramine (benadryl) (200 mg), lorazepam (ativan) ing. Each episode was separated by the absence of vomiting (8 mg) and dexamethasone (20 mg) (BAD) i.v. via an or retching for at least 1 min. infusion pump at a constant rate of 0.2–0.4 ml/h beginning A major endpoint was the utilization of additional agents after the administration of chemotherapy on day 2. A 2.0– for control of nausea and emesis. 4.0 ml bolus dose could be self administered by the patient every 15 min for nausea and/or vomiting. Additional anti- emetic medications could only be given after a significant Statistics emetic episode or profound degree of nausea. For purposes of this study, ‘additional’ medication was defined as drugs Data were collected using a custom designed distributed other than specified above given specifically to treat nausea data system, reviewed at a central clinical trials center or emesis. (ROI) and analyzed using the SAS system (SAS Institute, Cary, NC, USA). Time to first emetic episode was plotted using the method of Kaplan and Meier11 and results were High-dose chemotherapy (CTCb) compared using a log-rank test.12 Proportions were com- Cyclophosphamide 2 g/m2/day, thiotepa 167 mg/m2/day pared using an adjusted ␹2 test of Fisher’s exact test and carboplatin 267 mg/m2/day were administered as 1 h depending upon sample size. Mean values were compared infusions for 3 consecutive days. Patients received i.v. using Student’s t-test. Once vs twice daily i.v. granisetron and dexamethosone in HDC R Birch et al 687 Results days 2–5 were 31, 31, 12 and 27% for the twice daily group and 28, 28, 28 and 28% for the once daily group. Fourteen Patient characteristics (Table 1) of 26 patients (54%) in the twice daily and 18/29 (62%) in the once daily group required additional medications to Patient characteristics are shown in Table 1. control nausea and vomiting during the days 2–5 study period (P = 0.54). Data were available on the quantity of BAD Protocol compliance used in 15 patients receiving twice daily and 19 receiving once daily granisetron. The twice daily granisetron group Seventy of 71 patients were eligible for the study. One was infused with a mean 67.2 ml of BAD (range 4–227.5) patient was ineligible due to a history of nausea immedi- compared to 80.8 ml (range 10–380) for the once daily ately prior to treatment and was excluded from analysis. group (P = 0.62). Two patients were not evaluable because of non-compliance after one and two doses of study drug, respectively. All 70 patients were included in the analysis of day 1 anti- Time to first emetic episode for all 70 patients emetic response and 68 were evaluable for subsequent Figure 1 shows the probability of time to first emetic response. episode for all 70 patients (P = 0.48). Fifty-five of 68 evaluable patients received BAD on days 2–5. Discussion Effects of dexamethasone and granisetron in the first 24 h following day 1 chemotherapy In this study the effects of once daily or twice daily granisetron on nausea and vomiting following HDC with CTCb The number of patients achieving complete, major and were evaluated. In the first 24 h after the first dose of CTCb minor responses were 15 (45%), 14 (43%) and 2 (6%), no other anti-emetics were administered prophylactically. respectively, for the twice daily group and 14 (38%), 15 Forty-one per cent of patients receiving twice daily and (41%) and 2 (5%) for the once daily group. The difference 38% receiving once daily granisetron had complete control in complete response rate between the twice daily and the of emesis during the first 24 h after day 1 chemotherapy once daily granisetron group was not statistically significant (P = 0.52) (P = 0.52). Fifty-five per cent of patients in the twice daily and 58% in the once daily granisetron group required 0.9 additional medications for control of nausea and vomiting after initiation of chemotherapy (P = 0.85). 0.8 0.7

Effects of dexamethasone and granisetron following days 0.6 2 and 3 chemotherapy 0.5

Thirteen patients enrolled in the study did not receive 0.4

prophylactic BAD during the 6 day study period. Three of Probability ﬁve on the twice daily and 8/8 on the once daily schedule 0.3 of granisetron required additional medications to control 0.2 nausea and emesis at some time from days 2 to 5 (P = 0.13). 0.1

0 Effects of dexamethasone, granisetron and BAD following 02040 60 80 100 120 days 2 and 3 chemotherapy Hours

The proportions of patients requiring additional anti-emetic Figure 1 The probability of ﬁrst emetic episode for 33 patients receiving medications for the control of nausea and vomiting from twice daily (—) or for 37 patients receiving once daily (····) granisetron.

Table 1 Patient characteristics

Granisetron × 1 per day Granisetron × 2 per day

Median age (range) 45 (27–63) 47 (34–67) Stage II–III breast cancer 32 (86%) 29 (88%) Stage IV breast cancer 5 (14%) 4 (12%) ECOG performance = 0 37 (100%) 33 (100%) Prior chemotherapy regimens Induction/mobilization 35 (95%) 31 (94%) Adjuvant/induction/mobilization 2 (5%) 2 (6%) Median granisetron dose ␮g/kg (range) 13.4 (6.8–22.5) 13.8 (8.8–18.5)

ECOG = Eastern Cooperative Group. Once vs twice daily i.v. granisetron and dexamethosone in HDC R Birch et al 688 Following day 2 chemotherapy, 13 patients entered on References this study did not receive prophylactic treatment with BAD and 11/13 required additional medications for control of nausea and vomiting, 3/5 in the twice daily and 8/8 in the 1 Weaver C, Birch R, Schwartzberg L, West W. High-dose once daily granisetron groups (P = 0.13). These small num- chemotherapy and autologous stem cell transplantation for bers preclude any meaningful comparisons between the breast cancer. In: Buckner CD, Clift R (eds). Technical and two groups. Biological Components of Marrow Transplantation. Kluwer For the subsequent 55 evaluable patients, BAD was Academic Publishers: Boston, MA, 1995, pp 59–85. 2 Antman K, Rowlings P, Vaughan W et al. High-dose chemo- administered prophylactically, in addition to granisetron therapy with autologous hematopoietic stem-cell support for and dexamethasone. Following days 2 and 3 chemotherapy, breast cancer in North America. J Clin Oncol 1997; 15: 54% of patients on the twice daily and 62% on the once 1870–1879. daily granisetron schedule required additional medications 3 Weaver CH, West WH, Schwartzberg LS et al. Induction, for control of nausea and emesis (P = 0.54). mobilization of peripheral blood stem cells (PBSC), high-dose In all analyses performed there were no statistically sig- chemotherapy and PBSC infusion in patients with untreated nificant differences in the control of nausea and emesis stage IV breast cancer: outcomes by intent to treat analyses. between patients receiving once daily or twice daily grani- Bone Marrow Transplant 1997; 19: 661–670. setron. Results from a large multi-center, randomized, dou- 4 Weaver CH, Schwartzberg LS, Hainsworth J et al. Treatment ble-blind study conducted in 930 patients receiving moder- related mortality in 1000 consecutive patients receiving high- dose chemotherapy and peripheral blood progenitor cell trans- ately emetogenic chemotherapy indicated that twice daily plantation in community cancer centers. Bone Marrow Trans- administration of an oral dose of 1 mg of granisetron was plant 1997; 19: 671–678. 13 more effective than once daily administration. Recent data 5 Yarker Y, McTavish D. Granisetron. An update of its thera- from 697 chemotherapy naı¨ve patients who received mod- peutic use in nausea and vomiting induced by antineoplastic erately emetogenic chemotherapy, however, have suggested therapy. Drugs 1994; 48: 761–793. that a single 2 mg dose of oral granisetron given 1 h before 6 Carmichael J, Bessell E, Harris A et al. Comparison of grani- chemotherapy was as effective as 1 mg given 1 hour before setron alone and granisetron plus dexamethasone in the and 12 h following chemotherapy.14 prophylaxis of cytotoxic-induced emesis. Br J Cancer 1994; In the current study there were only slight trends toward 70: 1161–1164. more effectiveness of the twice daily dosing as compared 7 Latreille J, Stewart D, Laberge F et al. Dexamethasone improves the efficacy of granisetron in the first 24 h following to the once daily dosing of granisetron. It is possible that high-dose cisplatin chemotherapy. Support Care Cancer 1995; larger numbers of patients in each group would uncover 3: 307–312. significant differences between the two dose schedules. 8 Hunter A, Prentice H, Pothecary K et al. Granisetron, a selec- However, with the numbers of patients involved in the cur- tive 5-HT3 receptor antagonist, for the prevention of radiation rent study no advantage could be detected for the twice induced emesis during total body irradiation. Bone Marrow daily dosing. Transplant 1991; 7: 439–441. 9 The American Society of Clinical Oncology and American Society of Hematology recommended criteria for the performance of bone marrow transplantation. J Clin Oncol 1990; 8: Acknowledegments 563–564. 10 The Granisetron Study Group. The antiemetic efficacy and The following physicians participated in this study: D Iyengar safety of granisetron compared with metoclopramide plus (Bayonne, LA); J McElveen (Columbia, SC); G Monahan, M Vel- dexamethasone in patients receiving fractionated chemo- lek (Columbia, MO); A Hano, I Marte, R Drapkin (Clearwater, therapy over 5 days. J Cancer Res Clin Oncol 1993; 119: FL); G Gize (Ft. Wayne, IN); E Sobong, K Yost (Grand Rapids, 555–559. MI); C Rosenfeld, D Faig, F Wittlin, J Cohen, S Weisberg 11 Kaplan EL, Meier P. Nonparametric estimation from incom- (Hollywood, FL); K Pendergrass, L Geier (Kansas City, MO); A plete observations. J Am Stat Assoc 1958; 53: 457–481. Grossman, RB Avery, R Antonucci (Knoxville, TN); F Schnell, 12 Peto R, Peto J. Asymptotically efficient rank invariant test pro- M Mangum (Macon, GA); A Weir III, B Wheeler, K Tauer, L cedures. J Royal Stat Soc 1972; 135: 185–198. Schwartzberg (Memphis, TN); A Feinberg, A Larcada, G Wang, 13 Hacking A. Oral granisetron – simple and effective: a prelimi- H Lessner, H Wallach, L Kalman, P Kaywin, P Citron (Miami, nary report on behalf of the Granisetron Study Group. Eur J FL); A Meluch, D Thompson, J Hainsworth (Nashville, TN); J Cancer 1992; 28A: S28–S32. Redmond, P Pickens, R Maxwell (Philadelphia, PA); A Bala 14 Johnsonbaugh R, Mason BA, Friedman C et al. Oral granise- (Savannah, GA); C George, J Sinkovics, R Altemose (Tampa, tron is an effective anti-emetic in patients receiving moder- FL). This study was supported by a grant from Smith-Kline ately emetogenic chemotherapy. Am Soc Clin Oncol 1994; Beecham, Philadelphia, PA. 13: 437.