Comparative Safety of Filgrastim versus Sargramostim in Patients Receiving Myelosuppressive Chemotherapy

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1 Comprtive Sfety of Filgrstim versus Srgrmostim in Ptients Receiving Myelosuppressive Chemotherpy Gry Milkovich, B.S., Ronld J. Moleski, Phrm.D., John F. Reitn, Phrm.D., Dvid M. Dunning, M.D., Gene A. Gibson, Phrm.D., Thoms A. Pivns, M.H.S.A., Susn Wynt, Phrm.D., nd R. Jke Jcobs, M.P.A. Study Objective. To compre rtes of dverse events with filgrstim versus srgrmostim when given prophylcticlly to ptients receiving myelosuppressive chemotherpy. Design. Retrospective review with center crossover. Setting. Ten United Sttes outptient chemotherpy centers. Ptients. Four hundred ninety ptients treted for lung, brest, lymphtic system, or ovrin tumors. Intervention. Prophylctic use of filgrstim or srgrmostim, with dosges t investigtor discretion. Mesurements nd Min Results. The frequency nd severity of dverse events nd the frequency of switching to the lterntive CSF were ssessed. There ws no difference in infectious fever. Fever unexplined by infection ws more common with srgrmostim (7% vs 1%, p<0.001), s were ftigue, dirrhe, injection site rections, other dermtologic disorders, nd edem (ll p<0.05). Skeletl pin ws more frequent with filgrstim (p=0.06). Ptients treted with srgrmostim switched to the lterntive gent more often (p<0.001). Conclusion. Adverse events were less frequent with filgrstim thn with srgrmostim, suggesting tht qulity of life nd tretment costs lso my differ. (Phrmcotherpy 2000;20(12): ) Colony-stimulting fctors (CSFs) re recommended in certin situtions to reduce the likelihood of febrile neutropeni induced by myelosuppressive chemotherpy. 1 Recombinnt forms of grnulocyte (G)-CSF nd grnulocytemcrophge (GM)-CSF re synthesized using vriety of host expression systems. In the United Sttes, G-CSF is commercilly vilble s filgrstim, derived from bcteril cells, nd GM- CSF is vilble s srgrmostim, derived from yest cells. Only two studies directly compred the sfety of these two gents. 2, 3 Reviews of sfety bsed on plcebo-controlled trils 1, 4, 5 re problemtic, s the trils often include popultions with different underlying diseses nd concomitnt drug therpy. Bone pin is the most commonly reported dverse event with filgrstim, 6, 7 but excerbtion of preexisting inflmmtory conditions, 8 10 rsh, 11 llergic rections, 12 Sweet syndrome, 13 nd injection site rections 14 hve been reported. With srgrmostim, the most 2, 4, 15 common dverse event is fever. Nuse, ftigue, hedche, bone pin, chills, mylgi, nd injection site rections lso hve been reported Srgrmostim is lmost certinly less toxic thn GM-CSF expressed in bcteril cells (molgrmostim). Compred with molgrmostim, fluid retention, dyspepsi, fever, nd mylgi nd rthrlgi re ll less frequent with srgrmostim. 21 The initil dose of molgrmostim my cuse significnt hypoxi nd hypotension, prticulrly in ptients receiving

2 SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et l 1433 high dosges or intrvenous dministrtion. 22 The perception tht srgrmostim is less sfe thn filgrstim my be due to confusion regrding dt describing GM-CSF synthesized using bcteril or mmmlin cells. This ws the principl rtionle for the only rndomized comprison of CSF tolerbility, in which 137 ptients receiving myelosuppressive chemotherpy were ssigned to filgrstim 7 µg/kg or srgrmostim 193 µg/m 2, with regimens t investigtors discretion. 2 The gents were compred on the frequency of 11 dverse events, grded by Estern Coopertive Oncology Group (ECOG) or similr criteri. The frequency of fever, minly F, ws 2-fold greter with srgrmostim (p=0.01). Sttisticlly insignificnt trends were seen, indicting more frequent bone pin, chills, nd nuse with srgrmostim, nd more frequent hedche with filgrstim. The comprtive sfety of these gents lso ws ssessed in drug use evlution, which included 60 ptients undergoing bone mrrow trnsplnttion, dose-intensive chemotherpy, nd stndrd chemotherpy. 3 No differences were noted in frequencies of fever, nuse nd vomiting, musculoskeletl pin, dirrhe, mylgi, or locl rections. Our study ws undertken to provide dditionl dt on the comprtive sfety of filgrstim nd srgrmostim in ptients receiving myelosuppressive chemotherpy. We sought to void wht we considered importnt limittions of erlier comprtive studies; nmely, indequte sttisticl power, dt obtined from single or smll number of centers, nd pooling of ptients receiving CSFs prophylcticlly nd therpeuticlly. From the School of Phrmcy, Medicl College of Virgini, Richmond, Virgini, nd Northern Virgini Cncer Center, Alexndri, Virgini (Mr. Milkovich); RJM Assocites, Guilford, Connecticut (Dr. Moleski); The Reitn Compny, Inc., Crown Point, Indin (Dr. Reitn); Northern Virgini Oncology Group, Firfx, Virgini (Dr. Dunning); the Deprtment of Phrmcy, Hospitl of the University of Pennsylvni, Phildelphi, Pennsylvni (Dr. Gibson); the School of Public Helth nd Helth Services, George Wshington University Medicl Center, Wshington, D.C. (Mr. Pivns); The Dominion Group, McLen, Virgini (Dr. Wynt); nd Cpitol Outcomes Reserch, Inc., Alexndri, Virgini ((Mr. Jcobs). Funded by n unrestricted reserch grnt from Amgen Inc., Thousnd Oks, Cliforni. Mnuscript received July 5, Accepted pending revisions August 30, Accepted for publiction in finl form September 25, Address reprint requests to Ronld J. Moleski, Phrm.D., RJM Assocites, 195 Mups Rod North, Guilford, CT Methods This ws multicenter, retrospective exmintion in which ptients receiving CSFs for primry or secondry prophylxis were identified, nd their clinicl experiences ssessed through medicl record review. To minimize selection bis common to retrospective studies, we employed center crossover design in which prticipting sites substituted srgrmostim for filgrstim or vice vers s CSF of choice. We nticipted tht ptients treted before nd fter the policy decision would not differ systemticlly with respect to risk fctors for dverse events. By contrst, trditionl retrospective study would be bised by self-selection if one gent were reserved for ptients t greter risk of dverse events. Centers Ten U.S. outptient chemotherpy centers prticipted. All provided chemotherpy to 20 or more ptients/month nd mde decision before prticiption to substitute one CSF for the other s gent of choice for ptients receiving myelosuppressive chemotherpy. Nine substituted srgrmostim for filgrstim, nd one substituted filgrstim for srgrmostim. Ech center ws ssigned crossover dte representing the first dy of the first month during which 90% of new ptients received the subsequent gent. Filgrstim nd srgrmostim ers were defined for ech center. For centers substituting srgrmostim for filgrstim, the srgrmostim er begn with the crossover dte nd continued through 12 months or greement to prticipte in the study, whichever ws erlier; the filgrstim er begn nd ended exctly 12 months erlier. The process ws reversed for the site substituting filgrstim for srgrmostim. The men durtion of filgrstim nd srgrmostim ers ws 8 months (rnge 4 12 mo). Ptients Records of ll ptients hving received one or more doses of CSF during the filgrstim nd srgrmostim ers were exmined. Ptients were included if they were ged 18 yers or older nd received chemotherpy for lung, brest, lymphtic system, or ovrin tumor. Those with history of ny utoimmune disese or disese of the blood or blood-forming orgns were excluded, s were recent (< 90 dys) recipients of bone mrrow trnsplnts or experimentl drugs.

3 1434 PHARMACOTHERAPY Volume 20, Number 12, 2000 Tble 1. Bseline Chrcteristics Vrible Filgrstim Srgrmostim p Vlue No. of ptients (by initil CSF) Men (SD) ge, yrs 62 (14) 61 (14) 0.43 b No. (%) women c 176 (74) 176 (71) 0.56 d Men (SD) body surfce re, e m (0.2) 1.8 (0.3) 0.38 b Men (SD) months since cncer dignosis f 26 (48) 19 (36) 0.62 b No. (%) of ptients covered by Medicre g 115 (51) 122 (47) 0.49 d No. (%) of ptients covered by mnged cre g 6 (3) 10 (4) 0.33 d No. (%) of ptients by tumor type 0.07 d Brest 97 (41) 88 (35) Lung 52 (22) 84 (33) Lymphom 56 (23) 48 (19) Ovrin 34 (14) 31 (12) No. (%) of ptients by study center 0.41 d A 10 (4) 20 (8) B 31 (13) 39 (16) C 22 (9) 26 (10) D 19 (8) 16 (6) E 10 (4) 12 (5) F 8 (3) 7 (3) G 9 (4) 18 (7) H 5 (2) 6 (2) I 70 (29) 61 (24) J 55 (23) 46 (18) Missing dt for one srgrmostim recipient. b Wilcoxon rnk sum test. c Missing dt for four srgrmostim recipients. d 2 test. e Missing dt for 15 filgrstim nd 20 srgrmostim recipients. f Missing dt for 13 filgrstim nd 21 srgrmostim recipients. g Missing dt for 12 filgrstim nd 19 srgrmostim recipients. Chemotherpy nd CSF Cycles Dt describing chemotherpy regimens, CSF dosing, blood counts, nd dverse events were recorded for ll cycles, to mximum of six/ptient. Dily CSF doses were estblished t investigtors discretion. Men doses were 369 µg (5.5 µg/kg) for filgrstim nd 474 µg (6.9 µg/kg) for srgrmostim. Eligible cycles were those beginning within 7 dys of the most recent chemotherpy dose, if the ptient ws febrile (< F) nd did not otherwise meet criteri for therpeutic dministrtion of CSFs. 1 If inclusion nd exclusion criteri no longer were met during follow-up, ll subsequent cycles were excluded. Recording the Response Cse report forms were completed by four clinicl monitors, nd their ccurcy ws confirmed by center investigtors. Dt were recorded covering inclusion nd exclusion criteri, demogrphic nd clinicl chrcteristics, CSF dosges nd cycle durtion, nd dverse events including symptom description, onset nd resolution dtes, nd ssessments of severity nd reltionship to CSF. Adverse events were monitored beginning with the first CSF dose through 24 hours fter the lst dose. Most ptients received one CSF dose/dy on consecutive dys, s evidenced by the similrity between men (SD) doses/cycle [7.5 (3.1)] nd cycle durtion [8.0 dys (3.3 dys)]. During occsionl gps of 1 or more dys between doses, dverse event monitoring ws suspended. Clinicl monitors recorded informtion explicitly stted in medicl records, including verbtim description of dverse events. Two reviewers blinded to CSF reviewed dverse event reports nd clssified them into predetermined ctegories: fever, ftigue, chills, hedche, skeletl pin, nuse nd vomiting, constiption, dirrhe, other digestive disorder, injection site rection, other dermtologic disorder, chest discomfort, edem, hemtologic rection, centrl nervous system disorder, or other. Disgreement between reviewers on dverse event clssifiction ws rre (9/555 cses) nd resolved through consulttion with the prescribing physicin or nursing stff. Febrile episodes were defined s single reding of F or greter obtined by ny helth professionl nd were subclssified s being of

4 SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et l 1435 Tble 2. Chemotherpy Regimens Vrible Filgrstim Srgrmostim p Vlue No. of ptients (by initil CSF) No. (%) receiving ech gent Bleomycin 9 (4) 5 (2) 0.24 b Crbopltin 51 (21) 73 (29) 0.05 b Cispltin 24 (10) 22 (9) 0.63 b Cyclophosphmide 104 (44) 90 (36) 0.08 b Cytrbine 6 (3) 6 (2) 0.93 b Dcrbzine 3 (1) 4 (2) 1.0 c Docetxel 21 (9) 20 (8) 0.74 b Doxorubicin 93 (39) 81 (32) 0.13 b Etoposide 42 (18) 35 (14) 0.27 b Fludrbine 9 (4) 5 (2) 0.24 b Fluorourcil (5-FU) 39 (16) 42 (17) 0.90 b Gemcitbine 2 (1) 15 (6) <0.01 b Ifosfmide 8 (3) 10 (4) 0.71 b Melphln 1 (< 1) 0 (0) 0.49 c Methotrexte 19 (8) 23 (9) 0.63 b Mitoxntrone 11 (5) 12 (5) 0.93 b Nitrogen mustrd 0 (0) 1 (< 1) 1.0 c Pclitxel 52 (22) 73 (29) 0.06 b Procrbzine 1 (< 1) 1(< 1) 1.0 c Rituximb 0 (0) 2 (1) 0.50 c Topotecn 20 (8) 14 (6) 0.22 b Vinblstine 6 (3) 7 (3) 0.85 b Vincristine 39 (16) 35 (14) 0.46 b Vinorelbine 7 (3) 11 (4) 0.39 b Includes gents dministered during ny of up to six chemotherpy cycles. b 2 test. c Fisher s exct test. presumed infectious cuse or unexplined by infection, bsed on the presence or bsence of documented pthogen(s) or other clinicl signs of infection (e.g., drk, cloudy urine; positive chest rdiogrph). Adverse events other thn fever were rted for severity. They were considered t lest moderte if drug therpy or other intervention ws required, nd severe if intervention included nrcotic, invsive procedure, or hospitliztion. Otherwise, they were ctegorized bsed on expressions in medicl records nd considered mild unless evidence ws recorded to the contrry. Reltionship to CSF ws ctegorized bsed on World Helth Orgniztion definitions 23 s probbly, possibly, or probbly not relted. The lst ctegory included conditions present before CSF ws begun or ttributed in medicl records to n underlying disese or concomitnt drug. Otherwise, events were considered possibly relted unless medicl records indicted stronger ssocition. Sttisticl Methods The study ws powered to detect 3% versus 9% difference in frequency of fever unexplined by infection, with nticipted fever risk derived from n erlier comprtive study 2 djusted to reflect n expected three cycles/ptient. We intended to conduct nlyses on per-ptient bsis nd determined 245 ptients in ech rm would provide 80% power, ssuming n of 0.05 nd two-tiled test. Ptients first prescribed srgrmostim frequently switched to filgrstim, requiring modifiction of the nlysis becuse durtion of follow-up differed between CSFs. We therefore ssessed dverse event frequency on per-cycle bsis, ssigning cycles fter switch to the lterntive CSF. Bsed on the ctul numbers of 958 filgrstim nd 644 srgrmostim cycles, the smple provided bundnt sttisticl power to detect meningful differences. For dverse events occurring in one rm t rtes of 3%, 4%, nd 5%/cycle, the smple provides 82%, 91%, nd 96% power to detect 2-fold greter rtes in the other rm. Ctegoric dt were compred by 2, unless low frequency of dverse events required Fisher s exct test. For intervl dt, the normlity of distributions ws determined by Kolmogorov D test. Student s t test ws used when dt were

5 1436 PHARMACOTHERAPY Volume 20, Number 12, 2000 Tble 3. Numbers of CSF Cycles nd Doses Vrible Filgrstim Srgrmostim p Vlue No. of ptients (by initil CSF) Use of either CSF Men (SD) cycles 3.5 (1.9) 3.4 (1.9) 0.76 Men (SD) doses 24.1 (15.9) 25.1 (17.1) 0.65 Use of first prescribed CSF Men (SD) cycles 3.4 (1.9) 2.6 (1.6) <0.001 Men (SD) doses 23.9 (16.0) 19.5 (15.3) <0.001 Use of lterntive CSF Men (SD) cycles < 0.1 (0.2) 0.8 (1.5) <0.001 Men (SD) doses 0.1 (1.5) 5.5 (10.8) <0.001 Wilcoxon rnk sum test. Tble 4. Frequency of Fever Vrible Filgrstim Srgrmostim p Vlue No. of cycles No. (%) of cycles with report of Fever F 39 (4) 57 (9) <0.001 Fever of presumed infectious origin 25 (3) 15 (2) 0.72 Fever unexplined by infection 14 (1) 42 (7) < test. normlly distributed, nd Wilcoxon rnk sum test when the distribution ws not norml. All tests were two-tiled, nd p vlue below 0.05 ws considered sttisticlly significnt. Results There were no significnt differences in bseline chrcteristics between ptients initilly receiving filgrstim versus srgrmostim (Tble 1). Ptients were typicl of those seen in office-bsed oncology prctices. The srgrmostim rm hd proportionlly more ptients with lung cncer, nd the filgrstim rm hd more with brest cncer nd lymphom. No differences in disese stge were detected between rms (dt not shown). Ptients received 24 chemotherpeutic gents (Tble 2), with cyclophosphmide, doxorubicin, pclitxel, crbopltin, nd etoposide most common in both groups. Those in the srgrmostim rm were most likely to receive crbopltin (29% vs 21%, p=0.05) nd gemcitbine (6% vs 1%, p<0.01). Given the lrge number of comprisons, these differences pproximte wht would be expected by chnce. We found no differences between rms with respect to combintions of chemotherpeutic gents or chemotherpy dosges (dt not shown). We found no differences in numbers of chemotherpy-csf cycles (p=0.76) or CSF doses (p=0.65) between ptients initilly prescribed filgrstim versus srgrmostim (Tble 3). The proportions of filgrstim recipients proceeding to second, third, fourth, fifth, nd sixth CSF cycles were 80%, 58%, 44%, 29%, nd 18%, versus 77%, 58%, 41%, 28%, nd 21% for srgrmostim (ll NS). Ptients first prescribed srgrmostim were more likely to be switched to filgrstim thn vice vers. Consequently, they received fewer cycles (2.6 vs 3.4, p<0.001) nd doses (19.5 vs 23.9, p<0.001) of their initil CSF. Tble 4 shows the frequency of fever during filgrstim nd srgrmostim cycles. Febrile episodes occurred more thn twice s frequently with srgrmostim (9% vs 4%, p<0.001), with the entire difference represented by fever unexplined by infection (7% vs 1%, p<0.001). Among the 56 febrile episodes, no differences were seen between CSFs in fever durtion or mximum recorded temperture. Fever unexplined by infection ws most common during the first srgrmostim cycle (10% vs 1% with filgrstim, p<0.001), lthough lesser reltionship persisted during subsequent cycles (4% vs 2%, p<0.01). The most frequently reported dverse event ws skeletl pin (Tble 5), which tended to occur more frequently with filgrstim (11% vs

6 SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et l 1437 Tble 5. Frequency of Adverse Events other thn Fever Adverse Event Adverse Event Possibly or Probbly of Moderte or Any Adverse Event Relted to Cytokine Greter Severity Vrible Filg Srg Filg Srg Filg Srg % of cycles with report of Ftigue b < 1 3 b Chills < 1 1 < 1 1 < 1 < 1 Hedche < 1 1 < 1 1 < 1 1 Skeletl pin Nuse, vomiting Constiption < 1 1 Dirrhe Other digestive disorder < 1 1 < 1 1 < 1 1 Injection site rection < 1 6 b < 1 6 b 0 5 b Other skin disorder < 1 3 b < 1 2 b < 1 1 b Chest discomfort < 1 1 < 1 1 < 1 1 Edem < 1 2 b < 1 2 b < 1 2 b Hemtologic rection < 1 0 < 1 CNS disorder < 1 Other dverse event 1 1 < 1 1 < 1 1 Filg = filgrstim; Srg = srgrmostim; CNS = centrl nervous system. p<0.05, 2 or Fisher s exct test. b p<0.01, 2 or Fisher s exct test. Tble 6. Switching between CSFs Vrible Filgrstim Srgrmostim p Vlue No. of ptients (by initil CSF) No. (%) of ptients switching CSF for ny reson 2 (1) 74 (29) <0.001 No. (%) of ptients switching CSF due to Adverse event 0 (0) 45 (18) <0.001 Poor ANC response 0 (0) 11 (4) <0.001 Formulry restriction 0 (0) 2 (1) 0.50 b Undetermined reson 2 (1) 17 (7) <0.001 Frequency of switching by cycle c Cycle 1 0/239 (0) 11/251 (4) <0.001 Cycle 2 1/192 (1) 33/193 (17) <0.001 Cycle 3 1/138 (1) 16/146 (11) <0.001 Cycle 4 0/104 (0) 8/103 (8) <0.01 b Cycle 5 0/ 69 (0) 4/ 71 (6) 0.12 b Cycle 6 0/ 43 (0) 2/ 53 (4) 0.50 b ANC = bsolute neutrophil count. 2 test. b Fisher s exct test. c Ptients switched during cycle/ptients beginning cycle (%). 8%, p=0.06). Severl dverse events occurred significntly more frequently with srgrmostim ftigue (4% vs 2%, p<0.05), dirrhe (3% vs 2%, p<0.05), injection site rection (6% vs < 1%, p<0.01), other dermtologic disorders (3% vs < 1%, p<0.01), nd edem (2% vs < 1%, p<0.01). Limiting the nlysis to dverse events judged probbly or possibly relted to CSFs lowered totl event rtes, but the frequency of ftigue (p<0.01), injection site rections (p<0.01), other dermtologic disorders (p<0.01), nd edem (p<0.01) remined higher with srgrmostim. Results were similr when the nlysis ws limited to dverse events rted moderte or severe. The lone injection site rection ttributed to filgrstim ws rted mild. With srgrmostim, 4 of 41 injection site rections were severe nd 29 were moderte. Switching from filgrstim to srgrmostim ws uncommon, wheres more thn one-fourth of srgrmostim recipients switched to filgrstim (p<0.001; Tble 6). Adverse events were the most frequent reson for switching, with

7 1438 PHARMACOTHERAPY Volume 20, Number 12, 2000 injection site rections (10), fever (8), skeletl pin (6), nd other dermtologic disorders (5) being most common. Although the reson for CSF switching ws considered undetermined unless medicl record nottions were specific, dverse events were probbly most often responsible in these cses s well. In the undetermined ctegory, both switches of filgrstim to srgrmostim nd 8 of 17 switches of srgrmostim to filgrstim followed cycles with dverse events. The determintion tht switching ws due to poor bsolute neutrophil count (ANC) response ws bsed on medicl record nottions (e.g., ANC still flling fter X dys srgrmostim ). In 9 of 11 cses the ANC ws below bseline fter 5 14 dys of srgrmostim. We investigted whether suboptiml dosges were responsible for poor ANC response but found men dily doses were similr for these (6.7 µg/kg) nd other (6.9 µg/kg) srgrmostim cycles. Switching ws most frequent during the second nd third cycles. Only 11 (4%) srgrmostim recipients switched during the first cycle, nd the rte of switching declined consistently between cycles 2 nd 6. Discussion In the 6 yers since the Americn Society of Clinicl Oncology clled for more investigtion of the comprtive toxicity of filgrstim nd srgrmostim, 1 few dt hve been published on the subject. Adverse events were ssessed in retrospective cohort study considering 680 dys of CSF dministrtion 3 nd rndomized tril tht included 820 dys of CSFs. 2 Neither study detected differences between CSFs, with the exception of more grde 1 fever ( F) with srgrmostim. 2 We ssessed dverse events during 12,060 dys of CSF tretment nd found importnt differences tht generlly fvored filgrstim over srgrmostim. The dissimilrity between our results nd those of other studies my be due to severl fctors, including our exclusion of ptients receiving CSFs therpeuticlly, pssive surveillnce for dverse event reporting, method of ctegorizing dverse events, nd greter sttisticl power. It is unlikely to be due to differences in composition of ptient smples. Although our study ws limited to ptients with lung, brest, lymphtic system, or ovrin tumors, these dignoses represented 65 80% of ptients in erlier studies. 2, 3 Our smple ws somewht older, but this ws unlikely to hve hd n effect, s we detected no reltionship between ge nd frequency of dverse events. Our decision to limit the study to prophylctic CSF my hve ffected results, but the extent nd direction of such n effect re uncler. In other studies, 18 28% of ptients received CSFs therpeuticlly, 2, 3 nd results were not strtified by therpeutic versus prophylctic dministrtion. It is uncler how erlier studies exmined fever frequency for ptients lredy febrile t the first CSF dose. Our study used pssive dverse event surveillnce, similr to the other retrospective study. 3 By contrst, the prospective CSF sfety tril 2 included rigorous monitoring. Ptients completed evlution forms nd home diries, nd were telephoned every 1 2 dys to review dverse events. Although pssive surveillnce probbly provides more flse negtive results, this is unlikely to hve impired our bility to ssess comprtive sfety. Active surveillnce seems to increse the number of mild dverse events rther thn moderte or severe events. In our study, for exmple, only 26% of reports of nuse nd vomiting were rted mild, versus 67% in the prospective tril. Corresponding dt for reports of skeletl pin nd chills were 31% nd 43% in our study versus 57% nd 75% in the prospective tril. Unfortuntely, medicl records did not provide sufficient informtion to llow us to ctegorize dverse events by ECOG or similr criteri, s ws done in the prospective tril. 2 Although we cnnot determine whether our methods cused more or fewer dverse events to be identified, we see no reson why either method would cuse more events to be detected with one cytokine versus the other. This study most likely detected differences not found in prior reserch due to its greter sttisticl power. We studied 490 ptients through 1602 chemotherpy-csf cycles, wheres other studies included 60 nd 137 ptients, ll followed through single cycle. 2, 3 Given the frequency of grde 2 fever with filgrstim in the prospective tril, the study hd only 9% power to detect 2-fold increse with srgrmostim. Our most importnt results relte to switching between CSFs, nd frequencies of injection site rections nd fever unexplined by infection. Wheres switching from srgrmostim to filgrstim ws common, this prtilly my reflect study design; 9 of 10 centers substituted srgrmostim for filgrstim, thereby being experienced with both gents when ptients in the srgrmostim rm were treted. They my

8 SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et l 1439 hve been inexperienced with srgrmostim during the filgrstim er, mking switch to srgrmostim in the fce of efficcy or sfety concerns unusul. Unlike erlier studies tht reported no differences in locl rections, we identified just 1 (< 1%) injection site rection during 958 filgrstim cycles, but 41 (6%) during 644 srgrmostim cycles. Most were rted moderte or severe, nd in 10 ptients (24%) led to switch to filgrstim. Like the prospective tril, fever unexplined by infection ws more common with srgrmostim in this series of ptients. With threshold of F, we found difference of 7% versus 1%. In the prospective tril, the difference in fever F or greter ws 4% versus 2%. Despite lck of documented pthogens, the febrile episodes we detected were costly. Those occurring with filgrstim resulted in 15 dys of inptient cre nd 115 doses of ntiinfective drugs/1000 chemotherpy-csf cycles. Episodes occurring with srgrmostim resulted in 93 dys of inptient cre nd 634 doses of ntiinfective drugs/1000 cycles. Blood chemistries, microbiology tests, nd rdiologic exmintions were commonly performed. Assessments of CSF prophylxis should consider the gents bility to extend survivl, improve qulity of life, nd reduce use of other helth cre services. In certin popultions, CSFs hve lowered ntibiotic requirements 6, 24, 25 nd 6, hospitliztion for febrile neutropeni. These end points re resonble mrkers for both cost svings nd qulity of life. Bsed on the experience of this series, filgrstim my offer benefits of less fever, ftigue, dirrhe, locl rections, other dermtologic disorders, nd edem. Whether such differences significntly ffect survivl, qulity of life, nd costs in the presence of considerble bckground toxicity from chemotherpy hs not been determined nd wrrnts further study. Acknowledgments We re grteful to Lis Lynch, R.N., nd Nncy Blck, R.N., for their creful review of ptient records. References 1. Americn Society for Clinicl Oncology. Recommendtions for the use of hemtopoietic colony-stimulting fctors: evidence-bsed, clinicl prctice guidelines. J Clin Oncol 1994;12: Beveridge RA, Miller JA, Kles AN, et l. Rndomized tril compring the tolerbility of srgrmostim (yest-derived RhuGM-CSF) nd filgrstim (bcteri-derived RhuG-CSF) in cncer ptients receiving myelosuppressive chemotherpy. Support Cre Cncer 1997;5: Rotell DL. A mediction use evlution of dverse events ssocited with colony-stimulting fctors. Hosp Phrm 1999;34: Root RK, Dle DC. Grnulocyte colony-stimulting fctor nd grnulocyte-mcrophge colony-stimulting fctor: comprisons nd potentil for use in tretment of infections in nonneutropenic ptients. J Infect Dis 1999;179(suppl 2):S Kellihn MJ. Drug formulry review process for srgrmostim nd filgrstim: focus on nlysis of dverse drug rections. Clin Ther 1993;15: Crwford J, Ozer H, Stoller R, et l. Reduction by grnulocyte colony-stimulting fctor of fever nd neutropeni induced by chemotherpy in ptients with smll-cell lung cncer. N Engl J Med 1991;325: Pettengell R, Gurney H, Rdford JA, et l. Grnulocyte colony-stimulting fctor to prevent dose-limiting neutropeni in non-hodgkin s lymphom: rndomized controlled tril. Blood 1992;80: Ross HJ, Moy LA, Kpln R, Figlin RA. Bullous pyoderm gngrenosum fter grnulocyte colony-stimulting fctor tretment. Cncer 1991;36: Negrin RS, Heuber DH, Ngler A, et l. Tretment of myelodysplstic syndromes with recombinnt humn grnulocyte colony-stimulting fctor: phse I/II tril. Ann Intern Med 1989;110: Glspy JA, Bldwin GC, Robertson PA, et l. Therpy for neutropeni in hiry cell leukemi with recombinnt humn grnulocyte colony-stimulting fctor. Ann Intern Med 1988;109: Dle DC, Bonill MA, Dvis MW, et l. A rndomized controlled phse III tril of recombinnt humn grnulocyte colony-stimulting fctor (filgrstim) for tretment of severe chronic neutropeni. Blood 1993;81: Hudis C, Lebwohl D, Crown J, et l. Fesibility of djuvnt dose-intensive cyclophosphmide with G-CSF fter doxorubicin in women with high-risk stge II/III resectble brest cncer [bstr]. Proc Am Soc Clin Oncol 1992;11: Prk JW, Mehrotr B, Brnett BO, Bron AD, Vernook AP. The Sweet syndrome during therpy with grnulocyte colonystimulting fctor. Ann Intern Med 1988;116: Mueller BU, Jcobsen F, Butler KM, Husson RN, Lewis LL, Pizzo PA. Combintion tretment with zidothymidine nd grnulocyte colony-stimulting fctor in children with humn immunodeficiency virus infection. J Peditr 1992;121: Peters WP, Shogn J, Shpll EJ, Jones RB, Kim CS. Recombinnt humn grnulocyte-mcrophge colonystimulting fctor produces fever [letter]. Lncet 1998;1(8591): Neidhrt JA, Mnglik A, Stidley CA, et l. Dosing regimen of grnulocyte-mcrophge colony-stimulting fctor to support dose-intensive chemotherpy. J Clin Oncol 1992;10: Vdhn-Rj S, Keting M, LeMistre A, et l. Effects of recombinnt humn grnulocyte-mcrophge colonystimulting fctor in ptients with myelodysplstic syndromes. N Engl J Med 1987;317: Gnser A, Volkers B, Gerher J, et l. Recombinnt humn grnulocyte-mcrophge colony-stimulting fctor in ptients with myelodysplstic syndromes: phse I/II tril. Blood 1989;73: Nemunitis J, Singer J, Buckner C, et l. Use of recombinnt humn grnulocyte-mcrophge colony-stimulting fctor in grft filure fter bone mrrow trnsplnttion. Blood 1990;76: Jones SE, Schottstedt MW, Duncn LA, et l. Rndomized double-blind prospective tril to evlute the effects of srgrmostim versus plcebo in moderte-dose fluorourcil, doxorubicin, nd cyclophosphmide djuvnt chemotherpy progrm for stge II nd III brest cncer. J Clin Oncol 1996;14: Dorr RT. Clinicl properties of yest-derived versus Escherichi

9 1440 PHARMACOTHERAPY Volume 20, Number 12, 2000 coli-derived grnulocyte-mcrophge colony-stimulting fctor. Clin Ther 1993;15: Lieschke GJ, Cebon J, Morstyn G. Chrcteriztion of the clinicl effects fter the first dose of bcterilly synthesized recombinnt humn grnulocyte-mcrophge colonystimulting fctor. Blood 1989;74: World Helth Orgniztion. Interntionl drug monitoring. The role of the hospitl. WHO Tech Rep Ser 1969;425: Trillet-Lenoir V, Green J, Mnegold C, et l. Recombinnt grnulocyte colony-stimulting fctor reduces the infectious complictions of cytotoxic chemotherpy. Eur J Cncer 1993;29A: Gerhrtz HH, Engelhrd M, Meusers P, et l. Rndomized, double-blind, plcebo-controlled phse III study of recombinnt humn grnulocyte-mcrophge colonystimulting fctor s djunct to induction tretment of highgrde mlignnt non-hodgkin s lymphoms. Blood 1993;82: Kpln LD, Khn JO, Crowe F, et l. Clinicl nd virologicl effects of recombinnt humn grnulocyte-mcrophge colonystimulting fctor in ptients receiving chemotherpy for humn immunodeficiency virus-ssocited non-hodgkin s lymphom: results of rndomized tril. J Clin Oncol 1991;9: