Symptom Management and Supportive Care

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1 This mteril is protected y U.S. Copyright lw. Unuthorized reproduction is prohiited. For reprints contct: Reprints@AlphMedPress.com Symptom Mngement nd Supportive Cre Erly Intervention with Epoetin Alf During Pltinum-Bsed Chemotherpy: An Anlysis of the Results of Multicenter, Rndomized, Controlled Tril Bsed on Initil Hemogloin Level Jorine H. Svonije, Cees J. vn Groeningen, Lrs W. Wormhoudt, Guiseppe Giccone VU Medisch Centrum, Amsterdm, The Netherlnds; Ortho Biotech, division of Jnssen-Cilg B.V., Tilurg, The Netherlnds Key Words. Epoetin lf Anemi Hemogloin Cncer Qulity of life Lerning Ojectives After completing this course, the reder will e le to: 1. Descrie the implictions of untreted nemi nd the enefits of nemi prevention/erly correction in ptients with cncer receiving chemotherpy. 2. Discuss the effect of initil H level on the results of prospective, rndomized study in which cncer ptients with seline H levels 12.1 g/dl received epoetin lf or est supportive cre. 3. Explin tht the positive effects of erly intervention with epoetin lf on the trnsfusion rte, hemtopoietic response, nd qulity of life in ptients with chemotherpy-relted nemi occur regrdless of seline H level, nd tht treting ptients to H vlue of 12. g/dl is cliniclly pproprite to optimize qulity-of-life outcomes. CME Access nd tke the CME test online nd receive 1 AMA PRA ctegory 1 credit t CME.TheOncologist.com Astrct Ojective. This nlysis of the results of rndomized, controlled tril evluting the effects of epoetin lf (EPO) therpy on trnsfusion requirements, hemogloin (H), nd qulity of life (QOL) in ptients with cncer receiving pltinum-sed chemotherpy ws conducted to evlute the effect of initil H level on study outcomes. Methods. Ptients with H levels 12.1 g/dl were rndomized 2:1 to receive EPO, 1, U three times weekly s.c. or est supportive cre (BSC) until 4 weeks fter their lst chemotherpy cycle. For this nlysis, ptients were strtified y seline H level ( 9.7 g/dl, >9.7 g/dl to 1.5 g/dl, >1.5 g/dl to 11.3 g/ dl, nd >11.3 g/dl to 12.1 g/dl), nd study results were renlyzed. Results. Significntly fewer EPO ptients thn BSC ptients with initil H levels >9.7 g/dl to 12.1 g/dl required trnsfusions. EPO mintined H levels throughout the study for ptients with H levels >11.3 g/dl to 12.1 g/dl, compred with decrese with BSC. For ptients with seline H levels >1.5 g/dl, for whom the men chnges from seline to lst ssessment were mesured y the Cncer Liner Anlogue Scle ssessments of energy nd overll QOL s well s y the Functionl Assessment of Cncer Therpy (FACT)-Ftigue nd FACT-An Anemi suscle, QOL scores were significntly greter with EPO thn with BSC. QOL declined in ptients receiving BSC, nd the men decreses in QOL scores were greter for BSC ptients with seline H levels >1.5 g/dl, compred with the overll BSC group. Correspondence: Guiseppe Giccone, VU Medisch Centrum, De Boeleln 1117, 181 HV Amsterdm, The Netherlnds. Telephone: ; Fx: ; e-mil: g.giccone@vumc.nl Received August 15, 25; ccepted for puliction Novemer 29, 25. AlphMed Press /26/$2./ The Oncologist 26;11:

2 Svonije, vn Groeningen, Wormhoudt et l. 27 Conclusion. In ptients with cncer receiving pltinum-sed chemotherpy nd with seline H levels >1.5 g/dl, erly intervention with EPO reduces trnsfusions, mintins H level, nd mintins or improves QOL. This study supports the positive effects of erly intervention when nlyzed ccording to initil H vlue. The Oncologist 26;11: Introduction Anemi commonly occurs in ptients with cncer receiving chemotherpy nd leds to impired qulity of life (QOL) [1, 2]. Erythropoietic gents such s epoetin lf re wellestlished tretment options for ptients with chemotherpy-relted nemi. In rndomized, plceo-controlled clinicl trils s well s lrge community-sed studies of ptients with cncer nd nemi receiving pltinum- or nonpltinum-sed chemotherpy, epoetin lf hs een shown to significntly increse hemogloin (H), decrese trnsfusion requirements, nd meliorte symptoms tht negtively ffect QOL (e.g., ftigue) [3 5]. The QOL enefits linked to epoetin lf therpy re cliniclly importnt [2, 6] nd significntly correlted with incresed H level [3, 7 9], even fter ccounting for the effects of disese progression nd other potentil confounding fctors [1]. Trditionlly, nemi tretment hs een delyed until H decreses to <1. g/dl nd my even e withheld until H decreses to <9. g/dl [11 13]. In the Europen Cncer Anemi Survey (ECAS), only 38.9% of nemic ptients with cncer received nemi tretment [11]. Further, tretment ws not initited until men H decresed to 9.7 g/dl [11]. Current guidelines pulished jointly y the Americn Society of Clinicl Oncology nd the Americn Society of Hemtology recommend epoetin therpy for ptients with H levels <1. g/dl ut stte tht tretment of mild-to-moderte nemi (H 1. g/dl ut <12. g/dl) should depend on clinicl circumstnces [14]. Similr guidelines hve een pulished y the U.S. Ntionl Comprehensive Cncer Network in which nemi tretment is recommended for ptients with H levels <11. g/dl [15]. The results of severl studies suggest tht erly intervention with epoetin lf (i.e., in ptients with seline H levels 12. g/dl) my prevent the development of moderte or severe nemi in cncer ptients receiving chemotherpy y mintining ner-norml H levels nd my lso prevent or meliorte ftigue nd other symptoms tht dversely ffect QOL [16 18]. A previously pulished multicenter, rndomized study ws conducted to investigte the effects of epoetin lf therpy in ptients with seline H levels 12.1 g/dl [19]. The suset nlysis of this study descried here ws conducted to evlute the effect of seline H level on trnsfusion requirements, susequent H levels, nd QOL, nd to compre these results with the overll results of the primry study. Methods Ptients The methodologicl detils of the originl study hve een pulished previously [19]. Briefly, men nd women t lest 18 yers of ge who hd n Estern Coopertive Oncology Group (ECOG) performnce sttus score of 3, confirmed dignosis of solid mlignncy tht required pltinum-sed chemotherpy, nd seline H level 12.1 g/dl were eligile to prticipte. Ptients lso hd to hve een le to understnd nd complete QOL questionnires in Dutch. Ptients were excluded if they hd therpy-resistnt hypertension; cliniclly significnt dysfunction of ny orgn system not ttriutle to mlignncy or chemotherpy; history of seizures; relevnt cute or chronic leeding; or evidence of untreted iron, folte, or vitmin B 12 deficiencies. Study Design This prospective, open-lel, rndomized, multicenter study enrolled ptients from Novemer 1999 to Decemer 22 t 15 hospitls in The Netherlnds. Rndomiztion ws performed centrlly. The design nd conduct of the study complied with the ethicl principles of good clinicl prctice, in ccordnce with the Declrtion of Helsinki nd locl legl requirements. The study ws pproved y n independent centrlized ethics committee (Medisch-Ethische Toetsing Onderzoele Ptiënten en Proefpersonen, Tilurg, The Netherlnds) nd y the independent locl ethics committee in ech prticipting hospitl. Ptients were rndomized in 2:1 rtio to receive either epoetin lf (Eprex ; Ortho Biotech/Jnssen-Cilg, High Wycome, United Kingdom; [lso mrketed in the U.S. s Procrit ; Ortho Biotech Products, L.P., Bridgewter, NJ]) or est supportive cre (BSC). Orl iron supplements (2 mg elementl iron/dy) were recommended during the study period if seline trnsferrin sturtion ws <2% nd/or serum ferritin ws <1 μg/l. The study protocol specified tht trnsfusions should only e dministered to ptients with significnt complints of nemi nd tht every effort should e mde not to trnsfuse t H levels 9.7 g/dl to minimize differences in trnsfusion policies mong study sites.

3 28 Effect of Initil H on Epoetin Alf Efficcy Tretment Epoetin lf ws initited t 1, U s.c. three times weekly (TIW) for 4 weeks. After 4 weeks, if H hd incresed y 1. g/dl from seline or H ws 12.1 g/dl, epoetin lf ws continued t the originl dose. If the H increse ws <1. g/dl from seline nd H ws <12.1 g/dl, the epoetin lf dose ws incresed to 2, U TIW. After nother 4 weeks following dose increse to 2, U TIW, if H hd incresed y <1. g/dl from seline nd H ws still <12.1 g/dl, epoetin lf ws discontinued, lthough these ptients remined in the study nd were included in the nlysis. If ptient hd n H level >14. g/dl t ny time during the study, epoetin lf therpy ws discontinued until the H level decresed to <13. g/dl. Epoetin lf ws then reinitited t dose of 1, U twice weekly. The epoetin lf dose ws lso decresed to 1, U twice weekly if H incresed y >2. g/dl in ny 4-week period. Efficcy nd Sfety Assessments The primry efficcy mesure for the overll study ws the proportion of ptients requiring trnsfusions during the tretment phse (i.e., up to 4 weeks fter the lst dministrtion of pltinum-sed chemotherpy) for the epoetin lf group compred with the BSC group. Secondry efficcy prmeters were the effect of epoetin lf on H level nd QOL. For this suset nlysis, ptients were strtified y seline H level: 9.7 g/dl, >9.7 g/dl to 1.5 g/dl, >1.5 g/dl to 11.3 g/dl, nd >11.3 g/dl to 12.1 g/dl. For QOL nlyses, ptients were lso strtified s H 1.5 g/dl nd H >1.5 g/dl t seline. Hemogloin vlues were mesured prior to initition of tretment nd t the eginning of ech chemotherpy cycle. Dt from routine H evlutions were lso collected. For ptients receiving lood trnsfusions, the dte of trnsfusion nd mount of lood product used ws recorded. The proportions of responders (ptients who chieved 2.-g/dl H increse unrelted to trnsfusion [i.e., no trnsfusion within 28 dys efore mesurement]), correctors (ptients who chieved n H level 12.1 g/dl unrelted to trnsfusion), nd hemtopoietic responders (correctors or responders) were determined s n dditionl efficcy mesure. QOL ws self-reported y the ptients using the Functionl Assessment of Cncer Therpy-Generl (FACT-G) questionnire, consisting of physicl welleing, socil/fmily well-eing, emotionl well-eing, nd functionl well-eing suscles, nd n nemi suscle questionnire comprising 13 ftigue-relted questions nd seven questions unrelted to ftigue, ut relted to nemi. Two tools were used to mesure QOL sed on the ove questionnires: the FACT-Ftigue (FACT-F) scle, consisting of FACT-G plus the 13 ftigue-relted items of the nemi suscle, nd the FACT-Anemi (FACT-An) scle, comprising FACT-F plus the seven nonftigue items of the nemi suscle [2 22]. Another tool used to mesure QOL ws the 1-mm Cncer Liner Anlogue Scle (CLAS, lso known s the Liner Anlogue Scle Assessment [LASA]), mesuring the domins of energy, ctivity, nd overll QOL. Assessments for QOL were completed t study initition (QOL-1), efore the third chemotherpy cycle fter rndomiztion (QOL-2), nd 4 weeks fter the lst cycle of pltinum-contining chemotherpy or t erly withdrwl (QOL-end). Adverse events were reported throughout the study, either spontneously y the ptient or y investigtor-initited questioning. Sttisticl Anlyses A smple size of 3 ptients (2 in the epoetin lf group nd 1 in the BSC group) ws trgeted for ccrul. This smple size ws clculted to provide n 8% power to detect 15% reduction in the proportion of ptients with t lest one trnsfusion during the study period t significnce level of 5%. It ws nticipted tht pproximtely 3% of the ptients would withdrw from the study erly. Two popultions were designted for the intent-totret (ITT) nlyses: sfety popultion tht included ll ptients for whom sfety dt were ville (sfety popultion) nd n efficcy popultion tht included ptients for whom efficcy dt were ville from t lest one time point fter rndomiztion (ITT popultion). Anlyses were lso conducted on modified ITT (mitt) popultion, which included ll ptients who received t lest 8 weeks of chemotherpy. However, only dt for the ITT popultion re reported here, s there were no significnt differences in the results of the nlyses etween the ITT nd mitt popultions. The Wilcoxon signed rnk test ws used to nlyze shifts in continuous or ordinl prmeters. For ll nlyses, p <.5 ws considered sttisticlly significnt. Results Ptients Of the 316 ptients enrolled, one ptient who ws rndomized to BSC withdrew informed consent immeditely fter rndomiztion nd ws excluded from oth the sfety nd efficcy nlyses. Two dditionl ptients, oth of whom were rndomized to BSC, were excluded from the efficcy nlysis prior to collection of ny efficcy dt (one ptient died nd one withdrew informed consent). Thus, the sfety popultion comprised 315 ptients (epoetin lf, n = 211; BSC, n = 14), nd the efficcy popultion comprised 313 ptients (epoetin lf, The Oncologist

4 H suctegory, n (%) f >1.5 g/dl 126 (6) 66 (65) Svonije, vn Groeningen, Wormhoudt et l. 29 n = 211; BSC, n = 12). Demogrphic nd seline chrcteristics for the entire popultion hve previously een reported nd re shown in Tle 1 [19]. Ptients in the epoetin lf group were on study for men of 13.9 weeks nd ptients in the BSC group were on study for men of 14.5 weeks (p =.33). Trnsfusion Requirements A lower proportion of ptients receiving epoetin lf required trnsfusions during the study, compred with ptients receiving BSC, regrdless of seline H level (Fig. 1). A significntly lower proportion of ptients with seline H levels >9.7 g/dl to 1.5 g/dl (p =.7), Tle 1. Bseline demogrphics nd clinicl chrcteristics Epoetin lf (n = 211) BSC (n = 14) Chrcteristic Sex, n (%) Mle 117 (55) 61 (59) Femle 94 (45) 43 (41) Age, yers, men ± SD (rnge) 57 ± 11 (2 8) 58 ± 1 (27 78) Rce, n (%) White 2 (95) 13 (99) Asin 5 (2) Blck 1 (1) 1 (1) Other 5 (2) ECOG performnce sttus score, men ± SD 1.1 ±.6.9 ±.7 Primry site of mlignncy, n (%) NSCLC 54 (26) 23 (22) SCLC 14 (7) 5 (5) Upper GI trct 51 (24) 29 (28) Gynecologic c 36 (17) 23 (22) Other d 56 (26) 24 (23) Missing 1 (1) Metsttic disese, n (%) Yes 165 (78) e 63 (61) No 46 (22) e 41 (39) H, g/dl (men ± SD) f 1.7 ± 1. ( ) 1.8 ± 1. ( ) 1.5 g/dl 84 (4) 35 (35) 9.7 g/dl 42 (2) 18 (18) >9.7 g/dl 42 (2) 17 (17) >1.5 to 11.3 g/dl 68 (32) 3 (3) >11.3 to 12.1 g/dl 57 (27) 34 (34) >12.1 g/dl 1 (.5) 2 (2) Trnsfused 4 weeks prestudy, n (%) 23 (11) 11 (11) Men FACT score, points FACT-G Totl FACT-F FACT-An (continued)

5 21 Effect of Initil H on Epoetin Alf Efficcy Tle 1. (continued) Chrcteristic Men CLAS score, mm Chemotherpy regimen, n (%) Epoetin lf (n = 211) BSC (n = 14) FACT-An Anemi suscle FACT-An Ftigue suscle FACT-An NonFtigue suscle Energy Activity Overll QOL Gemcitine/cispltin 79 (37) 45 (43) Cropltin/pclitxel 33 (16) 16 (15) Cropltin/gemcitine 22 (1) 7 (7) Other cispltin contining 53 (25) 25 (24) Other cropltin contining 12 (6) 5 (5) Oxlipltin contining 12 (6) 6 (6) p =.15 versus BSC. Includes gstric cncer nd esophgel cncer. c Includes ovrin cncer, cervicl cncer, nd cncer of the uterine tue. d All other primry tumor types ech represent <7% of ptients; clcultion includes 1 tumors (eight epoetin lf, two BSC) of unknown origin. e p =.1 versus BSC. f Bsed on ptients with n evlule seline H vlue (epoetin lf, n = 21; BSC, n = 11). Arevitions: An, nemi; BSC, est supportive cre; CLAS, Cncer Liner Anlogue Scle; ECOG, Estern Coopertive Oncology Group; F, ftigue; FACT, Functionl Assessment of Cncer Therpy; GI, gstrointestinl; G, generl; H, hemogloin; NSCLC, non-smll cell lung cncer; QOL, qulity of life; SCLC, smll-cell lung cncer; SD, stndrd devition. >1.5 g/dl to 11.3 g/dl (p =.8), nd >11.3 g/dl to 12.1 g/dl (p =.14) required trnsfusions t ny time during the study, compred with ptients receiving BSC. Trnsfusion requirements were lso significntly lower fter dy 28 for ptients in the epoetin lf group with seline H levels 9.7 g/dl (p =.18), >9.7 g/dl to 1.5 g/dl (p =.3), nd >11.3 g/dl to 12.1 g/dl (p =.22), compred with those with the sme seline H levels who received BSC. Hemtologic Response Overll, nd s previously reported, H levels were significntly improved throughout the study in ptients receiving epoetin lf, wheres H levels slightly declined in ptients receiving BSC (p <.1, etween-group difference for the men chnge in H from seline to finl mesurement) [19]. In comprison, when strtified y seline H level, epoetin lf ptients with mild nemi (seline H >11.3 g/dl to 12.1 g/dl) mintined their H level throughout the study, wheres H declined in ptients with mild nemi receiving BSC (Fig. 2). The mjority of ptients hd seline H levels >1.5 g/dl in oth the epoetin lf group (6%) nd the BSC group (65%). In ptients with seline H levels 1.5 g/dl, epoetin lf therpy corrected H levels (Fig. 3), nd in ptients with seline H levels >1.5 g/dl, epoetin lf mintined H levels throughout the study (Fig. 4). In contrst, those receiving BSC with seline H levels 1.5 g/dl showed slight improvement in their H level, nd those with seline H levels >1.5 g/dl demonstrted decline in their H levels throughout the study. A higher proportion of ptients in the epoetin lf group, compred with the BSC group, were considered responders, correctors, nd hemtopoietic responders, regrdless of seline H level (Fig. 5). The proportion of correctors nd responders ws significntly higher for ptients receiving epoetin lf thn for those receiving BSC who hd seline H levels >9.7 g/dl to 1.5 g/dl (p =.5 for oth response ctegories), >1.5 g/dl to 11.3 g/dl (p <.1 for oth ctegories), nd >11.3 g/dl to 12.1 g/dl (p =.21 for correctors nd p =.2 for responders). In ddition, significntly higher proportion of ptients with seline H levels >9.7 The Oncologist

6 Svonije, vn Groeningen, Wormhoudt et l. 211 Percentge of Ptients H 9.7 g/dl (n = 6) H >1.5 to 11.3 g/dl (n = 98) c H >9.7 to 1.5 g/dl (n = 57) H >11.3 to 12.1 g/dl (n = 91) Figure 1. Proportion of ptients requiring trnsfusions throughout the study nd fter dy 28, strtified y seline H level. p <.1 versus BSC; p <.5 versus BSC; c p <.5 versus BSC. Arevition: BSC, est supportive cre; H, hemogloin. Epoetin lf BSC Epoetin lf BSC Ptients Trnsfused Ptients Trnsfused After Dy 28 Figure 2. H levels from seline to study completion for ptients with seline H levels >11.3 g/dl to 12.1 g/dl. Mens sed on fewer thn 1 ptients (in ech tretment group) re not displyed. Arevition: BSC, est supportive cre; H, hemogloin. H Level, g/dl Epoet in Alf BSC Dy g/dl to 1.5 g/dl (p =.4) nd >1.5 g/dl to 11.3 g/dl (p <.1) who received epoetin lf were considered hemtopoietic responders, compred with those in the BSC group with the sme seline H levels. Qulity of Life For ptients with seline H levels >1.5 g/dl, the men chnge in QOL scores from seline to lst ssessment were significntly greter with epoetin lf thn with BSC for the FACT-F scle (p =.16) nd the Anemi suscle (p =.6) (Fig. 6). The men chnges in scores from seline to lst ssessment for the CLAS energy nd overll QOL domins were lso significntly higher (p.2 for oth domins) for ptients with seline H levels >1.5 g/dl receiving epoetin lf, compred with BSC (Fig. 7). In ddition, the men chnge in the CLAS

7 212 Effect of Initil H on Epoetin Alf Efficcy H Level, g/dl Epoet inalf BSC Figure 3. H levels from seline to study completion for ptients with seline H levels 1.5 g/dl. Mens sed on fewer thn 1 ptients (in ech tretment group) re not displyed. Arevition: BSC, est supportive cre; H, hemogloin Dy Figure 4. H levels from seline to study completion for ptients with seline H levels >1.5 g/dl. Mens sed on fewer thn 1 ptients (in ech tretment group) re not displyed. Arevition: BSC, est supportive cre; H, hemogloin. H Level, g/dl Epoet inalf BSC Dy overll QOL score from seline to lst ssessment ws significntly higher (p =.2) for ptients with seline H levels 1.5 g/dl receiving epoetin lf, compred with BSC. For BSC ptients with seline H levels >1.5 g/dl, the men decline in FACT nd CLAS scores from seline to lst ssessment ws greter thn in the overll BSC group (men chnges in QOL scores in the overll BSC group were 4.1 points for FACT-F, 1.91 points for the Anemi suscle, 3.69 points for FACT-An, 6.9 mm for CLAS energy, 5.3 mm for CLAS ctivity, nd 7.3 mm for CLAS overll QOL [19]) (Fig. 6 nd Fig. 7). In ddition, ptients with seline H levels 1.5 g/dl receiving epoetin lf demonstrted greter improvement in QOL thn the entire epoetin lf group (men chnges in QOL scores in the overll epoetin lf group were 4.36 points for FACT-F, 3.93 points for the Anemi suscle, 3.98 points for FACT-An, 6.2 mm for CLAS energy, 4.4 mm for CLAS ctivity, nd 5.3 mm for CLAS overll QOL [19]). The Oncologist

8 Svonije, vn Groeningen, Wormhoudt et l. 213 Percentge of Ptients c H 9.7 g/dl (n = 6) H >1.5 to 11.3 g/dl (n = 98) Epoetinlf BSC Epoetinlf BSC Epoetinlf d H >9.7 to 1.5 g/dl (n = 57) H >11.3 to 12.1 g/dl (n = 91) d BSC 64.7 Figure 5. Proportion of ptients with hemtopoietic responses strtified y seline H level. Responder, ptient with 2.- g/dl increse in H from seline unrelted to trnsfusion; corrector, ptient who chieved n H level >12. g/dl unrelted to trnsfusion; hemtopoietic responder, ptient who chieved 2.-g/dl increse in H nd/or n H level >12. g/dl unrelted to trnsfusion. p <.1; p <.1; c p <.5; d p <.5. Arevitions: BSC, est supportive cre; H, hemogloin. Correctors Responders Hemtopoietic Responders Figure 6. Men chnge in FACT-G, FACT-F, FACT-An Anemi suscle, nd FACT- An scores from seline to lst ssessment y study group (epoetin lf vs. BSC) nd strtified y seline H level. p =.16 versus BSC; p =.6 versus BSC.Arevitions: BSC, est supportive cre; FACT-G, Functionl Assessment of Cncer Therpy-Generl; FACT-F, FACT-Ftigue; FACT-An, FACT-Anemi; H, hemogloin; QOL, qulity of life. Men Chnge in FACT Score (points) Epoetin lf H 1.5 g/dl (n = 5 53) Epoetin lf H >1.5 g/dl (n = 1 12) BSC H 1.5 g/dl (n = 22 23) BSC H >1.5 g/dl (n = 39 4) FACT-G FACT-F FACT-An FACT-An Anemi Suscle

9 214 Effect of Initil H on Epoetin Alf Efficcy Men Chnge in CLAS Score (mm) Epoetin lf H 1.5 g/dl (n = 53) Epoetin lf H >1.5 g/dl (n = 96) BSC H 1.5 g/dl (n = 22) BSC H >1.5 g/dl (n = 39) Figure 7. Men chnge in CLAS scores from seline to lst ssessment y study group (epoetin lf vs. BSC) nd strtified y seline H level. p <.5 versus BSC. Arevitions: BSC, est supportive cre; CLAS, Cncer Liner Anlogue Scle; H, hemogloin EnergyL evel Ailityto Do DilyActivties i Oerll v QOL Discussion The positive effects of erly intervention with epoetin lf on trnsfusion requirements, hemtopoietic response, nd QOL in ptients with chemotherpy-relted nemi, regrdless of seline H level, were shown in the originl nlysis of the full dt from this study, which hs een pulished previously [19]. The results of this suset nlysis support those of the overll study nd indicte tht, even t higher seline H levels, epoetin lf therpy results in significnt reduction in the proportion of ptients requiring trnsfusions, while improving or mintining H levels nd QOL. These results re consistent with those of other studies evluting the effect of erly epoetin lf therpy on H vlues nd QOL in ptients with solid tumors [16, 17] nd hemtologic mlignncies [18]. Current clinicl guidelines recommend epoetin therpy for ptients with moderte nemi (H <1. g/dl or <11. g/dl), ut leve tretment of ptients with mild nemi to the discretion of the treting physicin [14, 15]. However, two retrospective nlyses of epoetin lf therpy in ptients with cncer receiving chemotherpy with or without rdition therpy hve shown tht the gretest incrementl improvement in QOL occurs when H increses from 11. g/dl to 12. g/dl [1, 23]. These dt indicte tht erlier tretment with epoetin lf to mintin H, rther thn to correct estlished nemi, my e eneficil in optimizing QOL in ptients receiving chemotherpy. In the current study, ptients with seline H levels >1.5 g/dl nd 1.5 g/dl receiving epoetin lf experienced improvements in QOL. In contrst, ptients with seline H levels >1.5 g/dl receiving BSC experienced greter decline in QOL thn BSC ptients with seline H levels 1.5 g/dl nd thn the overll BSC popultion. On ll the QOL scles evluted, the enefit of epoetin lf reltive to BSC ws sustntil in ptients with seline H levels 1.5 g/dl; however, the difference etween groups ws gretest in ptients with seline H levels >1.5 g/dl. These dt show tht initition of epoetin lf therpy t n H level >1.5 g/ dl prevents the decrese in H nd the ssocited decline in QOL tht ws oserved in the BSC group. This oservtion dds further support to erly intervention with epoetin lf to negte or meliorte the effects of nemi on QOL in this setting. For the suset of ptients with men seline H levels 1.5 g/dl, only the CLAS overll QOL scores were significntly different etween the epoetin lf nd BSC groups. These findings my reflect the reltively low numer of ptients in these susets, nd further study is wrrnted to dequtely ssess the mening of these results. In generl, ptients with chemotherpy-relted nemi hve significntly impired QOL reltive to the norml popultion [2]. In one study compring popultion normtive dt with QOL dt from rndomized, doule-lind tril of epoetin lf (15 U/kg to 3 U/kg dministered s.c. TIW) in ptients with cncer nd nemi receiving che- The Oncologist

10 Svonije, vn Groeningen, Wormhoudt et l. 215 motherpy, the QOL of ptients with cncer nd nemi ws significntly lower thn tht of the norml popultion [2]. However, nemi in ptients receiving chemotherpy continues to e indequtely mnged, despite its high prevlence in this popultion [11, 22]. For exmple, in the ECAS, 67% of 13,628 ptients with hemtologic mlignncies nd solid tumors were nemic t some point during the 6-month survey [11]. Anemi ws reported most frequently in ptients receiving chemotherpy (75%) [11]. However, only 38.9% of ptients received tretment for their nemi [11]. Anemi tretment ws initited t men H level of 9.7 g/dl; one third of the ptients who received epoetin lf (48/1,217) nd one hlf of the ptients who received trnsfusion (562/1,67) did not receive nemi tretment until their H level ws <9. g/dl, level much lower thn currently recommended y evidence-sed guidelines for the tretment of chemotherpy-relted nemi [11, 14, 15]. Previous studies of epoetin lf dministered once weekly (QW) or TIW to ptients with cncer nd moderte nemi hve shown significnt correltion etween n H increse nd improved QOL [1, 3, 8, 1, 24]. In ddition, recent open-lel studies in ptients with rest cncer [25, 26] or hemtologic mlignncies [18] hve shown tht QW epoetin lf in ptients with cncer nd mild nemi (men seline H >11. g/dl) mintins H level nd prevents QOL deteriortion during chemotherpy. The results of this suset nlysis support these findings nd show tht epoetin lf initited t n H level >1.5 g/dl to 12.1 g/dl reduces lood trnsfusion requirements while incresing H levels nd improving QOL in ptients undergoing chemotherpy. These findings suggest tht nemi cn e prevented y inititing epoetin lf therpy t n H level <12. g/dl nd support the tretment of mild nemi with epoetin lf in this ptient popultion. Epoetin lf ws well tolerted in the primry prospective tril from which this H sunlysis ws derived; its dverse event profile ws mrkedly similr to tht oserved in the BSC group (primrily consisting of gstrointestinl complints, ftigue, nd fever) nd likely reflected the concomitnt dministrtion of chemotherpy [19]. The epoetin References 1 Crwford J, Cell D, Cleelnd CS et l. Reltionship etween chnges in hemogloin level nd qulity of life during chemotherpy in nemic cncer ptients receiving epoetin lf therpy. Cncer 22;95: Cell D, Zgri MJ, Vndoros C et l. Epoetin lf tretment results in cliniclly significnt improvements in qulity of life in nemic cncer ptients when referenced to the generl popultion. J Clin Oncol 23;21: Littlewood TJ, Bjett E, Nortier JW et l. Effects of epoetin lf on hemtologic prmeters nd qulity of life in cncer ptients receiving nonpltinum chemotherpy: results of rndomized, doule-lind, plceo-controlled tril. J Clin Oncol 21;19: lf nd BSC groups lso hd similr incidences of hypertension nd thromoemolism s well s similr medin survivl times. The fvorle sfety profile of erlier tretment with epoetin lf oserved in the current study is in contrst to two recent studies, one reported y Henke et l. [27] nd the other y Leylnd-Jones et l. [28], which reported n dverse effect on mortlity with erythropoietic therpy in ptients with cncer nd mild nemi. However, these previous studies involved the use of erythropoietic therpy eyond the correction of nemi nd to higher H levels thn currently recommended (i.e., to H >12. g/dl), nd other confounding fctors my hve contriuted to these results, including the permission of rpid H increses nd differences in seline chrcteristics etween tretment groups. More recently, met-nlysis ws pulished in which survivl outcomes were ssessed for 2,85 ptients with cncer who prticipted in 19 rndomized trils (studies of Henke et l. [27] nd Leylnd-Jones et l. [28] not included yet) of recominnt humn erythropoietin (epoetin lf or epoetin et) versus no erythropoietic therpy [29]. The pooled survivl hzrd rtios of.84 (using undjusted dt from one study) nd.81 (sed on djusted dt), the ltter of which ws sttisticlly significnt, fvored erythropoietic therpy nd suggested tht treting or preventing nemi with erythropoietin my improve overll survivl in the cncer popultion. The results of the current nlysis nd other studies indicte tht further investigtion into the effects of erythropoietic therpy on H nd QOL in ptients with cncer nd mild nemi re wrrnted. Until then, treting ptients to n H level of 12. g/dl is cliniclly pproprite to optimize QOL outcomes. Acknowledgment This study ws supported y grnt from Ortho Biotech, division of Jnssen-Cilg B.V., Tilurg, The Netherlnds. Disclosure of Potentil Conflicts of Interest Lrs W. Wormhoudt is n employee of Ortho Biotech nd indictes finncil interest. 4 Dmmcco F, Cstoldi G, Rödjer S. Efficcy of epoetin lf in the tretment of nemi of multiple myelom. Br J Hemtol 21;113: Aels R. Erythropoietin for nemi in cncer ptients. Eur J Cncer 1993;29A(suppl 2):S2 S8. 6 Ptrick DL, Ggnon DD, Zgri MJ et l. Assessing the clinicl significnce of helth-relted qulity of life (HrQOL) improvements in nemic cncer ptients receiving epoetin lf. Eur J Cncer 23;39: Demetri GD, Kris M, Wde J et l. Qulity-of-life enefit in chemotherpy ptients treted with epoetin lf is independent of disese response or tumor type: results from prospective community oncology study. J Clin Oncol 1998;16:

11 216 Effect of Initil H on Epoetin Alf Efficcy 8 Grilove JL, Cleelnd CS, Livingston RB et l. Clinicl evlution of once-weekly dosing of epoetin lf in chemotherpy ptients: improvements in hemogloin nd qulity of life re similr to three-times-weekly dosing. J Clin Oncol 21;19: Glspy J, Bukowski R, Steinerg D et l. Impct of therpy with epoetin lf on clinicl outcomes in ptients with nonmyeloid mlignncies during cncer chemotherpy in community oncology prctice. J Clin Oncol 1997;15: Fllowfield L, Ggnon D, Zgri M et l. Multivrite regression nlyses of dt from rndomised, doule-lind, plceo-controlled study confirm qulity of life enefit of epoetin lf in ptients receiving non-pltinum chemotherpy. Br J Cncer 22;87: Ludwig H, Vn Belle S, Brrett-Lee P et l. The Europen Cncer Anemi Survey (ECAS): lrge, multintionl, prospective survey defining the prevlence, incidence, nd tretment of nemi in cncer ptients. Eur J Cncer 24;4: Groopmn JE, Itri LM. Chemotherpy-induced nemi in dults: incidence nd tretment. J Ntl Cncer Inst 1999;91: Silerstein PT, Witzig TE, Slon JA et l. Weekly erythropoietin for ptients with chemotherpy induced nemi: rndomized, plceo-controlled tril in the North Centrl Cncer Tretment Group. Proc Am Soc Clin Oncol 22;21: Rizzo JD, Lichtin AE, Woolf SH et l. Use of epoetin in ptients with cncer: evidence-sed clinicl prctice guidelines of the Americn Society of Clinicl Oncology nd the Americn Society of Hemtology. J Clin Oncol 22;2: Rodgers GM, Cell D, Chnn-Khn A et l. Cncer nd tretmentrelted nemi. Ntionl Comprehensive Cncer Network Clinicl Prctice Guidelines in Oncology v Aville t http//: org. Acessed July 14, Grote TH, Cstillo R, Fishkin E et l. Effects of erly intervention with epoetin lf in ptients with smll cell lung cncer. Lung Cncer 23;41: S Milroy R, Scgliotti G, vn den Berg PM et l. Erly intervention with epoetin lf mintins hemogloin in dvnced non-smll-cell lung cncer ptients. Lung Cncer 23;41:S Strus DJ, Test M, Riggs SA et l. Erly tretment with epoetin lf improves nemi, qulity of life (QOL), nd productivity in ptients (pts) with hemtologic mlignncies nd mild nemi during chemotherpy (CT). Blood 23;12: Svonije JH, vn Groeningen CJ, vn Bochove A et l. Effects of erly intervention with epoetin lf on trnsfusion requirement, hemogloin level nd survivl during pltinum-sed chemotherpy: results of multicenter rndomised controlled tril. Eur J Cncer 25;41: Yellen SB, Cell DF, Wester K et l. Mesuring ftigue nd other nemirelted symptoms with the Functionl Assessment of Cncer Therpy (FACT) mesurement system. J Pin Symptom Mnge 1997;13: Cell D. The Functionl Assessment of Cncer Therpy-Anemi (FACT- An) Scle: new tool for the ssessment of outcomes in cncer nemi nd ftigue. Semin Hemtol 1997;34(suppl 2): Cell D, Wester KA. Qulity of life nd tretment vlue in the mngement of hemtologic mlignncies. Semin Oncol 1999;26(suppl 14) Shsh D, Cremieux P, Hrrison L. Reltionship etween hemogloin levels nd qulity of life during rdition therpy plus concomitnt or sequentil chemotherpy in ptients with cncer nd nemi treted with epoetin lf. J Ntl Compr Cncer Netw 24;2: Witzig TE, Silerstein PT, Loprinzi CL et l. Phse III, rndomized, doule-lind study of epoetin lf compred with plceo in nemic ptients receiving chemotherpy. J Clin Oncol 25;23: Chng J, Couture F, Young S et l. Weekly epoetin lf mintins hemogloin, improves qulity of life, nd reduces trnsfusion in rest cncer ptients receiving chemotherpy. J Clin Oncol 25;23: Hudis CA, Vogel CL, Grlow JR et l. Weekly epoetin lf during djuvnt chemotherpy for rest cncer: effect on hemogloin levels nd qulity of life. Clin Brest Cncer 25;6: Henke M, Lszig R, Rue C et l. Erythropoietin to tret hed nd neck cncer ptients with nemi undergoing rdiotherpy: rndomised, doule-lind, plceo-controlled tril. Lncet 23;362: Leylnd-Jones B, Semiglzov V, Pwlicki M et l. Mintining norml hemogloin levels with epoetin lf in minly nonnemic ptients with metsttic rest cncer receiving first-line chemotherpy: survivl study. J Clin Oncol 25;23: Bohlius J, Lngensiepen S, Schwrzer G et l. Recominnt humn erythropoietin nd overll survivl in cncer ptients: results of comprehensive met-nlysis. J Ntl Cncer Inst 25;97: Additionl Reding Svonije JH, vn Groeningen CJ, vn Bochove A et l. Effects of erly intervention with epoetin lf on trnsfusion requirement, hemogloin level nd survivl during pltinum-sed chemotherpy: results of multicenter rndomised controlled tril. Eur J Cncer 25;41: Hudis CA, Vogel CL, Grlow JR et l. Weekly epoetin lf during djuvnt chemotherpy for rest cncer: effect on hemogloin levels nd qulity of life. Clin Brest Cncer 25;6: Chng J, Couture F, Young S et l. Weekly epoetin lf mintins hemogloin, improves qulity of life, nd reduces trnsfusion in rest cncer ptients receiving chemotherpy. J Clin Oncol 25;23: Grote TH, Cstillo R, Fishkin E et l. Effects of erly intervention with epoetin lf in ptients with smll cell lung cncer. Lung Cncer 23;41: S Strus DJ, Test M, Riggs SA et l. Erly tretment with epoetin lf improves nemi, qulity of life, nd productivity in ptients with hemtologic mlignncies nd mild nemi during chemotherpy. Blood 23;12:497. The CME ctivity for this rticle consists of mteril from oth Erly Intervention with Epoetin Alf During Pltinum-Bsed Chemotherpy: An Anlysis of the Results of Multicenter, Rndomized, Controlled Tril Bsed on Initil Hemogloin Levels nd Erly Intervention with Epoetin Alf During Pltinum-Bsed Chemotherpy: An Anlysis of Qulity-of-Life Results of Multicenter, Rndomized, Controlled Tril Compred with Popultion Normtive Dt. The Oncologist