(2000) 26, 203 210 2000 Mcmilln Publishers Ltd All rights reserved 0268 3369/00 $15.00 www.nture.com/bmt Double-blind, rndomized, prllel-group study on the efficcy nd sfety of orl grnisetron nd orl ondnsetron in the prophylxis of nuse nd vomiting in ptients receiving hyperfrctionted totl body irrdition TR Spitzer 1, CJ Friedmn 2, W Bushnell 2, SR Frnkel 3, J Rschko 4 1 Msschusetts Generl Hospitl, Boston, MA; 2 SmithKline Beechm Phrmceuticls, Collegeville, PA; 3 Greenebum Cncer Center, Bltimore, MD; nd 4 City of Hope Ntionl Medicl Center, Durte, CA, USA Summry: The efficcy nd sfety of grnisetron nd ondnsetron for the prophylxis of nuse nd vomiting resulting from hyperfrctionted totl body irrdition (TBI) were ssessed. Thirty-four ptients rndomly received double-blind, orl grnisetron (2 mg, 1 h before first dily frction of rdition) or ondnsetron (8 mg, 1.5 h prior to ech frction of TBI). Ninety ptients who received the sme TBI regimen prior to bone mrrow trnsplnttion (BMT), but no 5-HT 3 -receptor ntgonist, were identified nd comprised the historicl control group. By design, this study ws only powered to show difference between ech of the ctive tretment groups nd the historicl control group. Significntly more ptients given grnisetron (33.3%) or ondnsetron (26.7%) hd zero emetic episodes over 4 dys, the primry efficcy end point, thn those in the historicl control group (0%) (P 0.01; intent-to-tret). Secondry efficcy end points were lso evluted. During the first 24 h, significntly more ptients tking grnisetron (61.1%) or ondnsetron (46.7%) hd zero emetic episodes thn ptients in the historicl control group (6.7%) (P 0.01). Complete emetic control (no emesis or rescue ntiemetic) over 4 dys ws more frequent in ptients tking grnisetron (27.8%) or ondnsetron (26.7%) compred with the historicl control group (0%) (P 0.01). Significntly fewer ptients tking grnisetron (18/18), but not those tking ondnsetron (12/15), experienced more thn five emetic episodes during the 4 dys of the study compred with the historicl control group (40/90; P 0.01). Orl grnisetron nd ondnsetron re sfe nd effective for the prevention of nuse nd vomiting resulting from TBI. Bone Mrrow Trnsplnttion (2000) 26, 203 210. Keywords: grnisetron; ondnsetron; nuse; vomiting; totl body irrdition; bone mrrow trnsplnt Correspondence: Dr TR Spitzer, Bone Mrrow Trnsplnt Progrm, Msschusetts Generl Hospitl, Cox 640, 55 Fruit Street, Boston, MA 02114, USA Received 22 December 1999; ccepted 31 Mrch 2000 There hve been mny dvnces in the tretment of ptients with mlignnt diseses requiring totl body irrdition (TBI) prior to bone mrrow trnsplnttion (BMT). 1 3 These dvnces hve llowed more ptients to successfully receive TBI nd BMT while lso decresing morbidity nd mortlity resulting from tretment complictions. 2 4 Nuse nd vomiting re still mjor problems with TBI. In response to rdition, serotonin is relesed from enterochromffin cells in the gstrointestinl (GI) mucos. 5 7 Serotonin intercts with the 5-HT 3 receptors on vgl fferent neurons nd the chemoreceptor trigger zone, which elicits nuse nd vomiting. 8 The specific emetogenic potentil of TBI is difficult to evlute becuse TBI is used often in combintion with or fter emetogenic chemotherpy nd mny different TBI regimens re used in clinicl prctice. Nevertheless, nuse nd vomiting re experienced by lmost ll ptients who receive more thn 12 Gy of unfrctionted irrdition. 4 Emesis ws, in fct, universl mong ptients dministered conventionl ntiemetic regimens who received TBI in n identicl dose nd schedule to tht utilized in this study. 9 Conventionl medictions tht hve been used to prevent nuse nd vomiting resulting from TBI given prior to BMT (eg sedting ntihistmines, dopmine ntgonists, phenothizines, corticosteroids, nd benzodizepines) re not optimlly effective nd re ssocited with significnt dverse effects. 10 17 Grnisetron nd ondnsetron, when given intrvenously (i.v.), hve been proven to be more effective thn plcebo nd other ctive gents in preventing nuse nd vomiting induced by highly emetogenic chemotherpy. 11,12,18 21 Orl dministrtion of 5-HT 3 -receptor ntgonist such s grnisetron or ondnsetron not only llows the mediction to be bsorbed so it cn ct peripherlly nd in the centrl nervous system, but lso llows the mediction to ct loclly in the gut to inhibit the emetogenic stimulus. The dvntges of orl dministrtion of ntiemetic medictions re cler: reduced costs compred to i.v. dministered mediction nd incresed ese of dministrtion tht my llow for the use of these medictions in the outptient setting. Ondnsetron dministered orlly hs been shown to be effective for the prophylxis of TBI-induced nuse nd vomiting, but no studies hve
204 ssessed the efficcy of orl grnisetron in dult ptients for this purpose. 22 This rndomized, double-blind, double-dummy tril ws designed to ssess the efficcy nd sfety of two 5-HT 3 - receptor ntgonists, grnisetron nd ondnsetron, when dministered orlly for the prevention of nuse nd vomiting in ptients receiving TBI prior to BMT compred with prospectively defined historicl negtive control group composed of ptients who did not receive 5-HT 3 -receptor ntgonist ntiemetic therpy. Mterils nd methods Ptients Thirty-six dult ptients ( 18 yers of ge) from three United Sttes medicl centers were screened for entry; 34 met study criteri nd were included in this two-rm study. The protocol ws pproved by the Institutionl Review Bord t ech site. Ptients gve written informed consent to prticipte. All ptients hd dignosis of either mlignnt disese or plstic nemi, nd were hospitlized to receive 11 frctions ech of 120 cgy of rdition over the course of 4 dys for totl rdition exposure of 1320 cgy prior to BMT nd the initition of ny conditioning chemotherpy. Totl body irrdition ws dministered prior to the initition of conditioning chemotherpy. The frctions of rdition were given from 10-MeV liner ccelertor. On dy 0 to dy 1, the chest wll ws blocked during the dministrtion of rdition to protect the lungs. The block ws removed for frctions given on dys 2 nd 3 to llow for rdition of the ribs nd soft tissue underlying the lungs. Femles of childbering potentil were required to hve negtive serum or urine hcg pregnncy test nd hd to continue using dequte contrception during the study. Mles hd to be either surgiclly sterilized or prctising dequte contrception throughout the study. Bseline evlutions were mde of ll ptients nd included demogrphics, medicl history, physicl exmintion, vitl signs, Krnofsky performnce sttus, nd prior nd concomitnt medictions. Excluded from the study were ptients with Krnofsky performnce sttus score below 60, those who hd received n investigtionl new drug within 30 dys or five hlflives of the mediction, received conditioning or intrthecl chemotherpy within 24 h of first dose of TBI, received emetogenic systemic or intrthecl chemotherpy during the study, or who hd n unstble medicl disorder or primry or secondry brin neoplsm with incresed intrcrnil pressure. Other resons for exclusion included known hypersensitivity to ny 5-HT 3 -receptor ntgonist, unwillingness or inbility to comply with the study protocol, or ny mediction with ntiemetic ctivity tken within 24 h of receiving study medictions on dy 0. Those who experienced nuse within 1 h or ny emesis (vomiting or retching) within 24 h of receiving study medictions on dy 0 were excluded from the protocol-defined popultion, but were included in the intent-to-tret popultion. Study design A historicl control group ws identified through chrt review of ptients who hd been treted t the City of Hope Ntionl Medicl Center in Durte, Cliforni prior to 1991. The chrt review ws conducted by contrcted chrt reviewer who recorded the dt of interest on the cse report form. Excluded from the historicl control group were ptients who did not meet study criteri with regrd to disese dignosis, rdition regimen, ge, or incomplete or missing dt in the ptient chrt. Use of either of the study medictions (grnisetron or ondnsetron), lso excluded the ptients. No other exclusion criteri pplied to these ptients becuse they were not redily vilble from ptient chrts. Ninety ptients were eligible to be included in the study. Eighty-eight ptients were included in the protocol-defined popultion; two ptients who received fewer thn 11 frctions of rdition were excluded. Drug dministrtion Ptients were rndomized 1:1 to receive orl grnisetron or orl ondnsetron. The study medictions were supplied by SmithKline Beechm Phrmceuticls, Collegeville, PA, USA. A round tblet contining commercilly vilble grnisetron l 1 mg ws used in conjunction with commercilly vilble 8-mg ondnsetron tblets overencpsulted with hrd, opque red, size 0 geltin cpsule to llow for double-blinding. Grnisetron 2 mg (dministered s two 1-mg tblets) ws given once dily, 1 h prior to the dministrtion of the first dily frction of rdition. Ondnsetron 8 mg ws given 1.5 h prior to every frction of rdition (three times dily for dys 0 to 3 nd twice dily on dy 4). The doses nd dministrtion times used for both medictions were the US Food nd Drug Administrtion (FDA)- pproved regimens stted in the product lbeling current t the time of the study. The ptients received either the study mediction or mtching plcebo t the scheduled dministrtion times, 1 h prior to the first dily frction of rdition nd 1.5 h prior to ech frction of rdition (doubledummy). Ptients in the historicl control group did not receive prophylxis or tretment with 5-HT 3 -receptor ntgonist. Specific ntiemetic regimens were not recorded for these ptients. Ptients requiring rescue ntiemetic mediction fter receiving the first frction of rdition were withdrwn from the study. Rescue mediction of the physicin s choosing ws permitted if ptient experienced two or more emetic episodes between ny two frctions of rdition (24-h period), totl of five or more emetic episodes during the 4 dys of the study, or if the ptient requested rescue ntiemetic mediction. The dy following the completion of the study medictions, the ptient s vitl signs nd Krnofsky performnce sttus were ssessed nd dverse experiences were recorded. Women of childbering potentil were given repet urine or serum hcg pregnncy test. Efficcy ssessment The primry efficcy vrible ws the proportion of ptients who hd zero emetic episodes over the 4-dy study period.
Emesis ws considered to be single episode of either vomiting (expulsion of stomch contents through the mouth) or retching (n ttempt to vomit tht is not productive of stomch contents). A single episode of vomiting ws defined s vomiting nd/or retching seprted by intervls of 5 min or less. The proportion of ptients who hd complete emetic control (no vomiting nd no rescue ntiemetic mediction) over the 4 dy study period ws lso ssessed. Becuse ll the ptients in this study were inptients, nurses noted when rescue medictions were dministered nd the ptients recorded efficcy dt, nuse severity, nd vomiting frequency in diry. Secondry efficcy vribles included the number of emetic episodes throughout the first 24 h (dy 0) nd during the entire 4-dy study period, the proportion of ptients with no emetic episodes on dy 0, nd the time to first emesis. The time to first emetic episode nd the number of vomiting episodes were recorded during ech 24-h intervl. When ntiemetic rescue therpy ws given in the bsence of emesis, the time to rescue mediction ws considered to be the equivlent of time to first emesis. Also evluted ws the proportion of ptients who hd complete nuse control (no nuse nd no rescue ntiemetic mediction) during the 4-dy study. The mximum severity of nuse nd time to first nuse were lso determined. When ntiemetic rescue therpy ws given in the bsence of nuse, time to rescue mediction ws considered to be the equivlent of time to first nuse. Efficcy dt for the historicl control group were recorded on the cse report form by the reviewer. Sfety All dverse events, whether observed by the investigtor or solicited from or volunteered by the ptient, were recorded. Adverse experiences were defined s ll noxious, pthologic, or unintended chnges in physicl signs, symptoms, or lbortory vlues. Included were ny excerbtions of pre-existing condition or event, intercurrent illness, drug interction, or significnt worsening of the disese under investigtion. Any chnge in study drug dministrtion, corrective therpy given, nd outcome sttus were documented on the cse report form. Adverse experiences were elicited from the ptients through stndrdized nonleding questions once dily during ech of the 4 study dys nd on the dy following completion of the study. In ddition to those elicited by the investigtors, dverse events observed by the investigtors or volunteered by the ptients were recorded on the cse report form. Investigtors judged the dverse experiences to be unrelted, probbly unrelted, possibly relted, or relted to the study drugs. The mximum intensity of ll dverse experiences ws grded by the investigtor s mild (esily tolerted), moderte (tolerted but interfered with dily ctivities), or severe (incpcitting or prevented everydy ctivities). Serious dverse experiences were those tht were ftl, life-thretening, disbling, or incpcitting; resulted in hospitliztion or prolonged hospitl sty; or were ssocited with congenitl bnormlity, cncer, or overdose (ccidentl or intentionl). Additionlly, ny experience tht the investigtor felt ws serious or suggested ny sig- nificnt hzrd, contrindiction, side-effect, or precution possibly ssocited with the use of the drug ws considered to be serious dverse experience. For this study, ny dverse events tht were expected to occur s result of hyperfrctionted TBI, conditioning chemotherpy or BMT, nd were not unusul in ny wy, were recorded on the cse report form but were not recorded s serious dverse events. Events tht were unchrcteristiclly different or unusul with regrd to frequency, severity, or durtion nd were considered to be due to TBI, conditioning chemotherpy, or BMT were recorded s serious dverse experiences. Sttisticl nlysis The trget smple size ws 36 rndomized ptients. The smple sizes of 18 ptients per tretment group nd 91 ptients in the historicl control group were clculted to provide 92% sttisticl power t n djusted level of 0.01. This clcultion ws bsed on the ssumption tht ll ptients in the historicl control group would experience t lest one vomiting episode during the 4 dys of TBI nd tht 30% of ptients tking grnisetron would be free of emesis during the 4 dys. By design, the study ws only powered to show difference between ech of the ctive tretments nd the historicl control group. A minimum ptient popultion of 500 would be necessry to show difference between the grnisetron nd ondnsetron groups with 90% sttisticl power. The primry nd secondry efficcy vribles were evluted using 99% exct confidence intervls (CIs) of the difference between ptients who received grnisetron nd the historicl control group nd ptients who received ondnsetron nd the historicl control group. Becuse 99% CIs re wider, it would therefore be more difficult to show tht difference exists; these more stringent criteri would further vlidte the results of this study. The hypothesis testing of the efficcy of grnisetron vs tht of the medictions given to ptients in the historicl negtive control group ws done in the context of the 99% CI of the difference nd whether the intervl included 0. The overll level ws 0.02 djusted for the two comprisons of interest. An intent-to-tret nlysis ws performed on the primry nd secondry efficcy end points. Ptients included in this nlysis were rndomized to one of the tretment groups, nd received rdition nd t lest one post-dose efficcy ssessment. The protocol-defined popultion included ptients not identified s protocol violtors with t lest one post-dose ssessment. Results Ptients Of 36 ptients screened, 34 fitted the study criteri nd were rndomized to receive study medictions; 18 received grnisetron nd 16 received ondnsetron. For the historicl control group, 262 ptients who received frctionted TBI prior to BMT t City of Hope Ntionl Medicl Center were 205
206 identified from chrt review using predetermined criteri. Excluded from this group were 172 ptients who did not meet study criteri with regrd to rdition regimen, ge, use of study medictions (ondnsetron or grnisetron), or incomplete or missing dt in the ptient chrt. Thus, the historicl control group contined 90 ptients. There were no cliniclly importnt demogrphic differences between the grnisetron nd ondnsetron tretment groups (Tble 1). Ptients in the historicl control group were slightly younger nd weighed less thn ptients in the other two groups. These differences were not considered to influence the ssessment of efficcy. Primry efficcy The protocol-defined popultion included six ptients in the grnisetron-treted group, five ptients in the ondnsetrontreted group, nd 88 ptients in the historicl control group. Becuse of the smll number of ptients in the protocol-defined popultion, comprtive nlysis of these ptients ws not completed. All 90 ptients in the historicl control group nd ll 18 ptients rndomized to receive grnisetron were included in the intent-to-tret popultion. All ptients but one receiving ondnsetron were included in the intent-to-tret nlysis; one ptient ws excluded becuse he never received rdition. Ondnsetron nd grnisetron were significntly more efficcious thn the ntiemetic gents used in the historicl control group for the primry end point. During the 4-dy study, irrespective of the use of rescue mediction, no emesis occurred in 33.3% of ptients tking grnisetron, 26.7% of ptients tking ondnsetron, nd 0% of ptients in the historicl control group (99% CI: 6.4, 69.2 for grni- Tble 1 Demogrphic chrcteristics of ll rndomized ptients who received study mediction Chrcteristic Grnisetron Ondnsetron Historicl control (n = 18) (n = 16) (n = 90) n % n % n % Sex Mle 12 66.7 11 68.8 57 63.3 Femle 6 33.3 5 31.3 33 36.7 Age (yers) Men ± s.d. 38.8 ± 12.2 44.1 ± 10.1 30.6 ± 8.1 Rnge 22.0 62.0 30.0 65.0 18.0 47.0 Rce White 18 100.0 13 81.3 47 52.2 Blck 0 0.0 2 12.5 2 2.2 Orientl 0 0.0 0 0.0 8 8.9 Other 0 0.0 1 6.3 31 34.4 Not known 0 0.0 0 0.0 2 2.2 Weight (1b) Men ± s.d. 178.0 ± 49.4 178.9 ± 43.9 150.7 ± 31.5 Rnge 117.5 323.0 120.7 280.3 58.6 223.5 Height (in) Men ± s.d. 67.4 ± 4.1 68.0 ± 3.5 66.1 ± 4.4 b,c Rnge 60.0 74.5 63.0 ± 75.0 54.0 74.0 b Bsed on 86 ptients, missing dt for four ptients. b Bsed on 73 ptients, missing dt for 17 ptients. c Vlue is the men ± stndrd error of the men (s.e.m.). setron vs historicl control; 0.9, 67.3 for ondnsetron vs historicl control; P 0.01) (Tble 2). Complete emetic control, defined s no emetic episodes nd no rescue ntiemetic mediction, occurred significntly more frequently in the ctive tretment groups (Tble 3). Over the course of the 4-dy study, 27.8% of ptients in the grnisetron group nd 0% of ptients in the historicl control group hd complete emetic control (99% CI: 2.9, 64.3). During this time period, 26.7% of ptients receiving ondnsetron hd complete emetic control (99% CI: 0.9, 67.3). Both ctive tretment groups experienced significntly greter efficcy thn the historicl control group for this vrible (P 0.01). Secondry efficcy The proportion of ptients experiencing more thn five emetic episodes over the 4 dys of the study ws significntly less in the grnisetron group (0%; 99% CI: 71.4, 24.2; P 0.01) vs the historicl control group (55.6%). The difference between the ondnsetron group (20%; 99% CI: 63.1, 1.8) nd the historicl control group ws not significnt (Tble 2). During dy 0, 11 of 18 ptients (61.1%) treted with grnisetron hd zero emetic episodes. In the historicl control group, only six of 90 ptients (6.7%) hd zero emetic episodes. Four of those six ptients received rescue ntiemetic mediction. The difference between the two groups ws sttisticlly significnt (99% CI: 20.9, 84.7; P 0.01). Seven of 15 ptients (46.7%) treted with ondnsetron hd zero emetic episodes on dy 0. Ptients tking ondnsetron demonstrted significntly better emetic control during the first 24 h compred with the historicl control group (99% CI: 5.5, 78.0; P 0.01). The medin time to first emesis ws 36 h for the grnisetron group nd 15.8 h for the ondnsetron group. These dt were not vilble for the historicl control group, therefore, sttisticl comprison ws not possible. Complete nuse control (no nuse nd no rescue ntiemetic mediction) throughout dy 0 occurred in eight of 18 ptients (44.4%) treted with grnisetron wheres only two of 90 ptients (2.2%) in the historicl control group hd complete nuse control (Tble 4). This difference ws sttisticlly significnt (99% CI: 11.4, 75.9). Complete nuse control occurred in 26.7% of ptients treted with ondnsetron on dy 0; comprison with the historicl control group ws not significnt (99% CI: 2.6, 64.8). The difference between the historicl control group nd ech ctive tretment group for the prmeter of complete nuse control throughout the entire 4-dy study ws not sttisticlly significnt (grnisetron vs control (99% CI: 5.4, 47.3) nd ondnsetron vs control (99% CI: 5.2, 54.5)). From the strt of the initil frction of TBI, the first experience of nuse or use of rescue ntiemetic mediction ws defined s the time to first nuse. This prmeter ws recorded for ptients in both the grnisetron nd ondnsetron tretment groups. No sttisticl comprison ws performed becuse the dt were not vilble for ptients in the historicl control group. The medin time to first nuse for ptients tking grnisetron ws 13 h, nd the medin
Tble 2 Emetic episodes by dy (intent-to-tret popultion) 207 Dy Emetic Grnisetron (n = 18) Ondnsetron (n = 15) (n = 90) 99% CI episodes n % n % n % Grnisetron vs Ondnsetron vs 0 0 11 61.1 7 46.7 6 6.7 (20.9, 84.7) (5.5, 78.0) 1 2 1 5.6 4 26.7 48 53.3 b b 3 5 6 33.3 4 26.7 31 34.4 b b 5 0 0.0 0 0.0 5 5.6 ( 17.7, 23.8) ( 17.8, 27.7) Overll (4 dys) 0 6 33.3 4 26.7 0 0.0 (6.4, 69.2) (0.9, 67.3) 1 2 4 22.2 3 20.0 10 11.1 b b 3 5 8 44.4 5 33.3 30 33.3 b b 5 0 0.0 3 20.0 50 55.6 ( 71.4, 24.2) ( 63.1, 1.8) CI = confidence intervl; = historicl control. P 0.01; b no sttisticl comprison ws performed. Tble 3 Complete emetic control by dy (intent-to-tret popultion) Dy Grnisetron Ondnsetron 99% CI n/n % n/n % n/n % Grnisetron vs Ondnsetron vs 0 11/18 61.1 7/15 46.7 2/90 2.0 (25.9, 87.6) (10.9, 80.4) 1 5/10 50.0 6/11 54.5 18/90 20.0 b b 2 7/8 87.5 7/8 87.5 4/90 4.4 b b 3 5/8 62.5 4/6 66.7 17/90 18.9 b b Overll (4 dys) 5/18 27.8 4/15 26.7 0/90 0.0 (2.9, 64.3) (0.9, 67.3) CI = confidence intervl; = historicl control. P 0.01; b no sttisticl comprison ws performed. Tble 4 Occurrence of complete nuse control by dy nd overll intent-to-tret popultion Dy Grnisetron Ondnsetron 99% CI n/n % n/n % n/n % Grnisetron vs Ondnsetron vs 0 8/18 44.4 4/15 26.7 2/90 2.2 (11.4, 75.9) ( 2.6, 64.8) 1 2/10 20.0 4/11 36.4 8/89 9.0 b b 2 2/7 28.6 4/8 50.0 1/89 1.1 b b 3 3/8 37.5 4/6 66.7 9/87 10.3 b b Overll (4 dys) 2/18 11.1 2/15 13.3 0/90 0.0 ( 5.4, 47.3) ( 5.2, 54.5) CI = confidence intervl; = historicl control. P 0.01; b no sttisticl comprison ws performed. time to first nuse for ptients tking ondnsetron ws 13.5 h. Sfety The most frequently reported dverse experience in both tretment groups ws hedche (Tble 5). Ptients treted with grnisetron most frequently reported dirrhe nd stheni. The most frequently reported complints from ptients treted with ondnsetron included insomni, peripherl edem, bck pin, nd rsh. Eleven ptients reported dverse experiences tht were judged possibly relted/probbly unrelted to study mediction: seven of 18 ptients (38.9%) who received grnisetron nd four of 16 ptients (25%) who received ondnsetron. The remining dverse events were considered to be unrelted to study mediction. The severity of the dverse events ws evluted by the investigtor nd ws determined to be mild, moderte, or severe. The investigtors clssified five mild, six moderte, nd two severe dverse rections in the grnisetron-treted group nd five mild, four moderte, nd two severe dverse rections in the ondnsetron-treted group. Two ptients who received grnisetron reported severe hedche. The
208 Tble 5 Most frequently reported dverse experiences (AEs) (overll incidence 7%) AE Grnisetron Ondnsetron (n = 18) (n = 16) n % n % Hedche 5 27.8 3 18.8 Dirrhe 4 22.2 1 6.3 Astheni 2 11.1 0 0.0 Insomni 1 5.6 2 12.5 Peripherl edem 1 5.6 2 12.5 Bck pin 0 0.0 2 12.5 Rsh 0 0.0 2 12.5 Grnisetron nd ondensetron were not sttisticlly compred. two severe dverse events in ptients who received ondnsetron included one severe infection nd one episode of severe nervousness. Serious dverse experiences occurred in two ptients in the study. One ptient who received ondnsetron died from disseminted Aspergillus infection 7 dys fter successfully completing the study. The investigtor deemed the deth unrelted to study mediction. Another ptient developed nonftl irregulr pulse shortly fter receiving the first dose of ondnsetron on dy 0. The rrhythmi ws ruled secondry to the ptient s underlying hert disese nd superimposed nxiety. This ptient withdrew from the study. Discussion Until the dvent of the selective 5-HT 3 -receptor ntgonists, nuse nd vomiting were the most dreded sideeffects of cncer tretment. 20 Control of nuse nd vomiting is crucil to the successful completion of TBI becuse ptients must remin immobilized while receiving ech frction of rdition. It is lso importnt to control nuse nd vomiting, not only for the immedite nutritionl nd emotionl support of the ptient, but lso becuse ptients who hve hd prior exposure to emetogenic chemotherpy my experience nticiptory nuse nd vomiting during subsequent tretments. 14,18,23 25 The efficcy of grnisetron dministered i.v. for prophylxis of nuse nd vomiting induced by highly emetogenic chemotherpy or irrdition hs been previously evluted. 26 32 The indequcy of stndrd ntiemetic regimens consisting minly of metocloprmide is demonstrted by studies tht used these regimens s the tretment for the control group nd compred them with group of ptients given grnisetron. 29,31 Significntly more ptients treted with grnisetron hd emetic control ( 3 emetic episodes) in the first 24 h following the beginning of their conditioning regimens nd sustined the emetic control throughout the study (87.1% nd 51.0%, respectively) compred with the control group (37% nd 0%, respectively; P 0.001). 31 A complete response to the ntiemetic medictions during the first 24 h following fst dose rte, single frction TBI ws observed in significntly more ptients treted with grnisetron (53%) thn those treted with combintion of metocloprmide, dexmethsone, nd lorzepm (13%; P = 0.02). 29 The specific ntiemetic medictions nd dosges dministered to the ptients in the historicl control group were not recorded in the present study except to specify tht the regimens did not include 5-HT 3 -receptor ntgonist. It cn be ssumed tht these ptients received the stndrd ntiemetics routinely prescribed by the oncologists t the City of Hope Medicl Center. As discussed previously, even in studies in which pproprite doses of conventionl ntiemetic medictions were used, these drugs nd regimens were shown to be ineffective. Therefore, regrdless of which medictions the ptients in the historicl control group received, they were ineffective nd thus, constituted negtive control. In the present study, designed to exmine the efficcy of orl grnisetron nd orl ondnsetron in prllel for prevention of nuse nd vomiting in ptients receiving hyperfrctionted TBI prior to BMT, both 5-HT 3 -receptor ntgonists were significntly more effective thn the gents used in the historicl control group s shown by the proportion of ptients who hd zero emetic episodes on dy 0 nd throughout the entire 4-dy study. Ptients tking grnisetron or ondnsetron lso hd complete emetic control significntly more frequently thn ptients in the historicl control group during the 4 dys of the study. No ptients in the grnisetron group hd more thn five emetic episodes during the entire course of the study. This ws lso significnt benefit of grnisetron compred with the historicl control group (P 0.01). Grnisetron-treted ptients hd significntly better nuse control on dy 0 compred with the historicl control group (P 0.01). This difference did not continue throughout the rest of the study, however, nd did not occur in the ondnsetron-treted group. The results of this study correlte well with those of previous study tht compred orl ondnsetron with plcebo using the sme TBI regimen. 22 The comprbility of the results vlidte this study design nd emphsize the significnce of the findings regrding the efficcy of orl grnisetron. The results of the first study show tht 30% of ondnsetron-treted ptients experienced no vomiting episodes, wheres the results of the current study show tht 26.7% of ondnsetron-treted ptients experienced complete emetic control. Time to first vomiting ws lso similr between the two trils (14.6 h vs 15.8 h). Among ptients treted with ondnsetron, 40% in the previous study compred with 20% in the current study experienced five or more emetic episodes. The results in the historicl control group re consistent with those in the plcebo group of the previous study. 22 None of the ptients in either the historicl control group or the plcebo group from the two studies hd complete emetic control over the 4-dy study period. All of the ptients who received plcebo or were in the historicl control group required rescue ntiemetic mediction. This comprison emphsizes the fct tht conventionl ntiemetic medictions prior to the dvent of the selective 5-HT 3 - receptor ntgonists were no better thn plcebo. In light of these dt, withholding 5-HT 3 -receptor ntgonist from ptient undergoing TBI would be unethicl.
The use of historicl negtive control group in this study requires prticulr ttention becuse of bises tht my be introduced by compring results obtined t different times nd under different conditions. Severl importnt issues need to be ddressed when considering use of historicl control group. 33 First, the historicl control group must hve hd clerly defined criteri for ptient inclusion. In this cse, ptients needed to hve condition tht would necessitte TBI nd BMT; only those receiving the specific TBI regimen used in this study were included in the historicl control group to ensure tht the ptients were receiving the sme emetogenic stimulus. The 90 ptients included in the historicl control group were identified through chrt review. Eighty-eight of the 90 ptients received the sme emetogenic stimulus s the ptients in the ctive tretment groups. None of the ptients received 5-HT 3 -receptor ntgonist prior to or during TBI, nd ll were treted prior to the vilbility of ondnsetron in 1991. These were the principl considertions in selecting ptients for the historicl control group. Second, historicl controls were recruited erlier nd possibly from different source thn the ptients in the tretment groups, thus ffecting the type of ptient vilble for selection. Ptients evluted for inclusion into this study received their tretment t one of the institutions tht prticipted in this study, the City of Hope Ntionl Medicl Center. If there were chnge in the criteri for selecting ptient to receive BMT, the selection would be more liberl thn it hd been before 1991, llowing for ptients with more dvnced disese to enter the current study. Liberliztion could theoreticlly mke emesis greter problem in the ptients enrolled in this study compred with those in the historicl control group. Any such bis would likely mke it more difficult to demonstrte efficcy of either grnisetron or ondnsetron compred with the historicl controls. Relted to this considertion is the fct tht investigtors my be restrictive, either delibertely or subconsciously, when choosing ptients for new tretment. The mgnitude of this concern is diminished by the fct tht both gents used in this tril re commercilly vilble, widely used, nd recognized to be dvnces over previously vilble ntiemetics. Investigtors were therefore unlikely to be restrictive in selecting ptients for entry into this study. Third, vilble dt for ptients in the historicl control group my not be the sme s dt collected from ptients during the study. In this cse, demogrphic informtion, the detils of medictions used, TBI dministered, nd the presence or bsence of emesis were obtined from hospitl chrts nd medicl records. In ddition, dt for the ptients in the historicl control group were collected on the sme cse report form tht ws utilized by the investigtors in this study to ensure comprble methods of dt collection. Fourth, the criteri of response my differ between the two groups of ptients. However, the presence or bsence of emesis is not redily subject to interprettion, nd this is the only criterion of response evluted for the historicl control group. Finlly, there is tendency to invlidte more ptients on new tretment thn to invlidte historicl controls. Ptients on new therpy who fre bdly my be excluded fter subsequent inquiry revels some protocol violtion, wheres the corresponding exclusion of ny historicl control is mde difficult becuse considerble time will hve elpsed since they were treted. This concern ws negted by conducting n intention-to-tret nlysis in the current study. Therefore, the procedure in this study ddresses ll of the significnt concerns tht rise with the use of historicl controls. Becuse ondnsetron hd previously been shown to be effective for prevention of nuse nd vomiting cused by hyperfrctionted TBI, negtive control group, plcebo or otherwise, ws unethicl. 12,13,22,34 A tril of dequte sttisticl power (90%) to compre grnisetron with ondnsetron would require such lrge ptient popultion (t lest 500 ptients) tht recruitment of ptients nd ensuring tht stndrdized regimen of TBI would continue to be used prior to the dministrtion of conditioning chemotherpy would be difficult. Thus, prospectively defined, historicl negtive control group ws used s comprtor ginst the two tretment groups. The two tretment rms llowed for rndomiztion into n ctive tretment group. This llowed for doubleblinding, nd creted bsis for compring the results of this study with those of previous plcebo-controlled study using the sme TBI regimen to determine the efficcy of ondnsetron, lthough it did not llow for hed-to-hed comprison of grnisetron nd ondnsetron. 22 The sfety of grnisetron nd ondnsetron ws demonstrted in this study. The most frequently reported dverse event in both tretment groups ws hedche. Dirrhe nd stheni were frequently reported by those treted with grnisetron wheres those treted with ondnsetron reported insomni, peripherl edem, bck pin, nd rsh. These dverse events were similr to those tht occurred in previous studies using 5-HT 3 -receptor ntgonists, further supporting the sfety of these gents. 11,20,21 The mjority of dverse experiences were judged to be either mild or moderte in severity nd were considered to be possibly relted/probbly unrelted to study mediction. Only one serious life-thretening dverse experience occurred. This ptient ws withdrwn from the study prior to receiving the first frction of rdition. One deth occurred 7 dys fter the ptient ws given the lst dose of study mediction nd ws considered to be unrelted to study mediction. In conclusion, orl grnisetron, given s single 2-mg dose on ech dy of TBI, nd orl ondnsetron, given s n 8-mg dose three times dily, re sfe nd effective for the prevention of nuse nd vomiting induced by highly emetogenic regimen of hyperfrctionted TBI. Efficcy in the prevention of emesis ws demonstrted over the 4-dy course of TBI nd especilly during the first 24 h fter TBI. Becuse complete emetic control did not occur for ll ptients, future studies, possibly evluting combintion drug therpy, will be necessry to optimize the ntiemetic mngement of ptients receiving TBI prior to BMT. References 1 Bsr N, Blu WI, Kiehl MG et l. Efficcy nd sfety of mycophenolte mofetil for the tretment of cute nd chronic 209
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