Clinical Study. Oncology 2010;79: DOI: /

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1 Oncology Clinicl Study DOI: 10.59/ Received: June 24, 2010 Accepted: July 27, 2010 Published online: Mrch 1, 20 Prospective Multicenter Rndomized Phse III Study of Weekly versus Stndrd Docetxel plus Doxorubicin (D4) for First-Line Tretment of Metsttic Brest Cncer Hns-Jochim Stemmler Ndi Hrbeck c Isolde Gröll de River e Ursul Vehling Kiser f Gerhrd Ruthe g Wolfgng Abenhrdt d Almut Artmnn c Hrld Sommer b Hns-Gerd Meerpohl h Mrion Kiechle c Volker Heinemnn Deprtment of Internl Medicine III, Klinikum Grosshdern, nd b Deprtment of Gynecology nd Obstetrics, Klinikum Innenstdt, Ludwig Mximilin University of Munich, c Deprtment of Gynecology nd Obstetrics, Technische Universität München, nd d Onkologische Prxis, Munich, e Deprtment of Gynecology nd Obstetrics, Klinikum Ebersberg, Ebersberg, f Onkologische Prxis, Lndshut, g Deprtment of Gynecology nd Obstetrics, Schlossbergklinik Oberstufen, Oberstufen, nd h Deprtment of Gynecology nd Obstetrics, St.-Vincenzius-Kliniken AG, Krlsruhe, Germny Key Words Docetxel Weekly ppliction Metsttic brest cncer Combintion chemotherpy Abstrct Purpose: Previous phse II studies hve indicted gretly reduced hemtotoxicity of docetxel-bsed regimens dministered on weekly schedules. The present tril ws initited to compre the toxicity nd efficcy of weekly docetxel versus its stndrd 3-weekly ppliction in combintion with doxorubicin. Methods: Ptients previously untreted with chemotherpy for metsttic disese were recruited. Inclusion criteri were ge! 65 yers or Krnofsky Performnce Sttus of %. All ptients in the D4 study received doxorubicin (50 mg/m 2 ) on the first dy of tretment in ddition to docetxel given either t 3-weekly dose of 75 mg/m 2 every 3 weeks (q3w) or t weekly dose of 35 mg/m 2 (dys 1, 8, nd 15; q4w). Tretment ws continued until mximum of 8 cycles, uncceptble toxicity, or disese pro- gression. All ptients received stndrd corticosteroid prophylxis. Results: Since interim nlysis showed filure to rech significnt difference for the primry endpoint (hemtotoxicity, i.e. leukopeni), the study ws closed ccording to the study protocol (85 of 242 ptients). A lower-thnexpected rte of leukopeni 6 grde 3 ws observed in the stndrd rm of the D4 study compred to the weekly schedule (per-ptient nlysis: 61.9% q3w vs. 65.1% q1w; p ). Grde 3 nd grde 4 fever, dirrhe, nd infections occurred more frequently in the stndrd rm, wheres neurotoxicity nd skin/nil disorders were observed more frequently in the weekly rm. Except for fever, none of these differences reched level of significnce. Dose delys, dose reductions, nd the rte of omitted doses were incresed in the weekly rm. The overll response rte ws 44.2% in the weekly rm compred to 52.4% in the stndrd rm (p = 0.52). Time to progression ws 6.2 (q1w) versus 10.3 (q3w) months (p = H.-J.S. nd N.H. contributed eqully to this pper. Fx E-Mil krger@krger.ch 20 S. Krger AG, Bsel /10/ $26.00/0 Accessible online t: PD Dr. H.J. Stemmler, Medicl Deprtment III (Hemtology-Oncology) Klinikum Grosshdern, University of Munich Mrchioninistrsse 15, DE Munich (Germny) Tel , Fx E-Mil med.uni-muenchen.de

2 0.36), nd overll survivl ws 20.5 (q1w) versus 28.7 (q3w) months (p = 0.98). Conclusion: The present dt support the fesibility of both weekly nd 3-weekly ppliction of docetxel in combintion with doxorubicin. Nevertheless, given tht leukopeni ws similr in both rms nd the efficcy prmeters were t lest numericlly inferior with the weekly schedule, stndrd 3-weekly ppliction seems to be preferble for ptients requiring combintion chemotherpy. Copyright 20 S. Krger AG, Bsel Introduction Docetxel (Txotere ; Snofi-Aventis, Frnkfurt, Germny) is one of the most effective ntitumor gents currently vilble for the tretment of erly brest cncer s well s metsttic brest cncer (MBC). In MBC, when compred with the gold stndrd doxorubicin, docetxel hs shown significntly superior response rte (RR; 47.8 vs. 33.3%; p = 0.008) nd trend towrds prolonged time to progression (TTP; 26 weeks vs. 21 weeks) [1]. After filure with nthrcycline-contining chemotherpy, single-gent docetxel hs demonstrted superior results when compred with mitomycin/vinblstine [RR, TTP, nd overll survivl (OS)] or methotrexte/5-fluorourcil (RR nd TTP), nd it hs shown equivlent efficcy when compred with vinorelbine/5-fluorourcil (RR, TTP, nd OS) [2 4]. When docetxel is dministered t stndrd dose of 100 mg/m 2 [every 3 weeks (q3w)], 70 90% of ptients develop grde 3/4 neutropeni [1]. Insted of dose reductions, one strtegy to reduce toxicity without growth fctor support is to pply docetxel on weekly schedule. Severl studies hve indicted tht severe hemtotoxicity (grde 3/4) could lrgely be prevented t weekly doses of less thn 40 mg/m 2 without impired efficcy in the first- or secondline setting [5 9]. Moreover, the fvorble toxicity profile of weekly scheduled docetxel ws confirmed in 2 rndomized phse II/III trils without inferior results regrding TTP or OS [10, ]. A further rtionle for weekly docetxel might be tht stndrd-dose single-gent doce - txel (100 mg/m 2 q3w) frequently needs to be djusted to 75 mg/m 2 in pretreted, unfit, or elderly ptients [12]. The reltively low rte of severe leukopeni ssocited with weekly scheduled docetxel my permit combintion with other cytotoxic gents. Txnes nd nthrcyclines re considered mong the most ctive single gents for the tretment of erly brest cncer s well s MBC. Consequently, their combined use is logicl step in the serch for highly effective chemotherpy combintions. Phse II trils which hve investigted such n nthrcycline/txne combintion given on 3-week schedule hve shown n improved RR of 46 88% without higher rte of crdiotoxicity [13 16]. The high RR were ttined in ptients with unfvorble prognostic fctors (multiple metsttic sites, viscerl involvement, nd prior exposure to djuvnt chemotherpy). However, the dose-limiting fctor in these trils ws leukopeni. Phse II trils investigting weekly scheduled nthrcycline/txne combintion proved efficient nd hd mngeble toxicity profile [17, 18]. Considering these prior experiences, the D4 study ws designed to evlute the toxicity nd efficcy of weekly docetxel/doxorubicin regimen compred to 3-weekly scheduled stndrd scheme in younger nd mediclly fit ptients with MBC. Ptients nd Methods Ptient Selection The tretment protocol ws pproved by the locl ethics committee nd ll ptients gve their written informed consent before tretment ws strted. Ptients with MBC, none of whom hd received chemotherpy for metsttic disese, were recruited for the tril. Ptients were required to hve Krnofsky Performnce Sttus (KPS) 670% nd n ge between 18 nd 65 yers. Ptients who hd received prior djuvnt nthrcyclines t cumultive dose mg/m 2 or who hd positive history of coronry hert disese with crdic dysfunction or n impired left ventriculr ejection frction (EF) were not eligible; crdic EF hd to be norml ( 6 50%). Ptients were required to hve histologiclly proven MBC, bidimensionlly mesurble disese, nd n nticipted survivl of t lest 12 weeks. Prior to study entry, heptic, renl, nd hemtologicl functions hd to be dequte [leukocyte count 63.0! 10 9 /l, pltelets 6100! 10 9 /l, hemoglobin 6 8 g/dl, bilirubin ^ 1.25 times the norml rnge, lnine minotrnsferse:sprtte minotrnsferse (ALT:AST) rtio ^ 3 times the norml rnge, nd lkline phosphtse ^ 2.5 times the norml rnge]. Ptients with bone metstses only nd/or steroid (estrogen nd/or progesterone) receptor expression without prior endocrine therpy were not eligible for the tril. Additionl exclusion criteri were ctive infections, rdiotherpy of more thn 25% of mrrow-contining bone, cliniclly overt brin metstses, previous neuropthy 6 grde II, or history of second mlignncy other thn resected bsl cell nd/or squmous cell crcinom of the skin. Ptients were not eligible for study enrolment if they were pregnnt or lctting, or if they refused effective contrception. Tretment Regimen Docetxel ws dissolved in 100 ml of 0.9% sline nd given by intrvenous (i.v.) infusion over 30 min (35 mg/m 2 weekly) or 60 min (75 mg/m 2 q3w), respectively. Doxorubicin (50 mg/m 2 ) ws dissolved in 250 ml of 0.9% sline nd infused for 60 min. D4 Combined Weekly Docetxel for MBC 205

3 Ptients in the D4 study received doxorubicin (50 mg/m 2 ) on the first dy of tretment in ddition to docetxel given either t 3-weekly dose of 75 mg/m 2 q3w or t weekly dose of 35 mg/m 2 (dys 1, 8, nd 15; q4w). Tretment ws continued until mximum of 8 cycles, uncceptble toxicity, or disese progression. All ptients received stndrd corticosteroid prophylxis, ntiemetics (routinely 5HT3 ntgonists), nd growth fctors (which were llowed t ny point) ccording to the locl stndrds. Dose Adjustments In cse of myelosuppression on the dy of the plnned tretment (leukocytes ^ 2,000/ l nd pltelets ^ 50,000/ l), further drug dministrtion ws postponed for 1 week until bone mrrow recovery occurred (leukocytes 6 2,000/ l nd pltelets 6 50,000/ l). If there ws no recovery within the dditionl rest of 1 week, the ptient ws excluded from the study. A reduced dose of ech drug ( 25%) ws pplied in cse of leukocyte count between 2,000/ l nd 3,000/ l nd pltelet count between 50,000/ l nd 100,000/ l. A full dose of docetxel nd doxorubicin ws dministered if the blood counts hd risen to leukocytes 6 3,000/ l nd pltelets 6 100,000/ l. Ptients were excluded from the tril in cse of nonhemtologicl toxicity 6 grde 3 (excluding lopeci nd nuse/vomiting). Dose reductions of 25% (for doxorubicin nd docetxel) were required in cse of hemtologicl toxicity grde 3 or 4 complicted by fever, infection, or both. Moreover, reduced dose ( 20%) ws required in cse of grde 3 dirrhe or mucositis. D t C o l l e c t i o n Drug dministrtion, KPS, nd toxicity or dverse events were recorded fter every cycle of tretment. Weekly blood counts were performed. Febrile neutropeni ws defined s fever ( 6 38 C) with grde 4 neutropeni requiring i.v. ntibiotics nd/or hospitliztion without documented infection. Fluid retention included peripherl edem nd/or pleurl nd pericrdil effusions. Toxicity ws grded ccording to the Ntionl Cncer Institute s Common Toxicity Criteri (NCI CTC 2.0) [19]. Imging studies using ultrsonogrphy, computed tomogrphy (CT), or mgnetic resonnce imging (MRI) were performed fter every 2 cycles of tretment. Crdic Surveillnce Ptients in the D4 tril underwent echocrdiogrphy prior to study entry nd then fter every second cycle. An EF 650% ws considered norml. Ptients were excluded from the study if the EF decresed to ^ 50% or decresed by 6 10% compred to the bseline vlue. Response Evlution In ll ptients, tumors were mesured by imging procedures (ultrsound, CT, or MRI) within 14 dys prior to study entry nd subsequently fter every 2 cycles of tretment. A stndrd evlution comprised of history, physicl exmintion, nd routine lbortory tests (including complete blood cell count, chemistry profile, nd electrolyte determintion) ws performed before ech tretment. Ptient response ws ssessed ccording to stndrd WHO criteri s follows: Complete response (CR) ws defined s the disppernce of ll known disese s determined by 2 observtions not less thn 4 weeks prt, while prtil response (PR) ws defined s decrese of t lest 50% in the sum of the products of the lrgest perpendiculr dimeters of ll mesurble lesions s determined by 2 observtions not less thn 4 weeks prt. Stble disese (SD), lsting t lest 6 weeks from the strt of the study (i.e. the first drug dministrtion), ws defined s! 50% decrese nd! 25% increse in the sum of the products of the lrgest perpendiculr dimeters of ll mesurble lesions. Progressive disese (PD) ws 1 25% increse in the size of t lest 1 bidimensionlly or unidimensionlly mesurble lesion or the ppernce of new lesion. The occurrence of pleurl effusion ws considered sign of progression if verified by positive cytology. Study Endpoints nd Sttistics The primry study endpoint ws hemtotoxicity (leukopeni). Assuming grde 3 nd grde 4 hemtotoxicity rtes of 70 95% for the stndrd regimen nd 10 20% for the weekly regimen, the clculted smple size for the primry endpoint ws 40 ptients (20 for ech tretment rm), with sttisticl power of 80% using 5% level of significnce (Fishers s exct test). An interim nlysis ws plnned in 80 recruited ptients (40 for ech tretment rm) for the primry endpoint using 1 = nd 2 = s the levels of significnce (O Brien nd Fleming sequentil design). For the secondry endpoint (TTP) the clculted smple size ws 242 ptients, with the ssumption of the noninferiority of the weekly schedule (TTP q3w = 10.3 months nd TTP q1w = 9.3 months) (O Brien nd Fleming sequentil design). Smple sizes were clculted using NCSS/PASS 2000 softwre. Further secondry endpoints were OS nd RR. TTP ws determined by the intervl between the initition of therpy nd the first dte tht disese progression ws objectively documented. OS ws mesured from the dte of the strt of tretment to the dte of deth from ny cuse. All ptients were included in the (intent-to-tret) nlysis of TTP nd survivl. The probbilities of survivl nd TTP were estimted by Kpln-Meier nlysis, nd confidence intervls for the RR were clculted using methods for exct binominl confidence intervls [20, 21]. R e s u l t s Ptient Chrcteristics Ptients were recruited between July 2001 nd August Since the scheduled interim nlysis showed filure to rech sttisticl significnce for the primry endpoint in the finl nlysis, the D4 study ws closed before chieving its trget recruitment (85 of 242 ptients). The medin observtion time ws 18.7 months (rnge ). The ptients chrcteristics re presented in tble 1. Toxicity A summry of the hemtologicl nd nonhemtologicl toxicities is given in tble 2. A comprbly low rte of leukopeni, i.e. 6 grde 3, which ws rther similr to the one observed in the weekly rm, ws observed in the 206 Stemmler et l.

4 stndrd q3w rm of the D4 study (per-ptient nlysis: 61.9% q3w vs. 65.1% q1w; p ) even though the rte of grde 4 leukopeni ws nerly twice the number in the stndrd rm (38.1% q3w vs q1w). Fever ws more frequently observed in the 3-week regimen (21.4% q3w vs. 4.7% q1w; p = 0.03). Moreover, grde 3 nd grde 4 dirrhe nd infections occurred more frequently in the stndrd rm, wheres neurotoxicity (7.0% q1w vs. 0% q3w; p ) nd skin/nil disorders (.6% q1w vs. 0% q3w; p = 0.06) were observed more frequently in the weekly rm. Except for fever, none of these differences reched the 0.05 level of significnce. Other nonhemtologicl toxicities ( 6 grde 3) were comprble between the 2 schedules. The medin number of pplied cycles ws 6 (rnge 1 8) for the stndrd rm nd 5 (rnge 1 8) for the weekly rm. The medin durtion of tretment ws dys (rnge 1 170) for the stndrd rm nd 151 dys (rnge 1 245) for the weekly schedule. Dose reductions nd delyed nd omitted doses within cycle were required significntly more often in ptients rndomized to weekly docetxel (p! 0.001, ech). There ws significnt difference regrding the percentge of the intended drug delivered within cycle between the 2 regimens (99.2% stndrd dose vs. 78.3% weekly dose). Ef f ic c y The overll RR ws 48.2% (95% CI ), with 3 CR, 38 PR, 22 SD, nd 15 PD (intent-to-tret nlysis) ( tble 3 ). Seven ptients were not evluble. The overll RR ws comprble between the groups of stndrd or weekly scheduled docetxel (44.2% q1w vs. 52.4% q3w; p = 0.52). Moreover, there ws numericl but not significnt difference with regrd to TTP (6.2 months q1w vs months q3w; p = 0.36) nd OS (20.5 months q1w vs months q3w; p = 0.98) ( tble 4 ; fig. 1 ). A summry of the response nd survivl dt is given in tbles 3 nd 4 nd in figure 1. Discussion Numerous phse II studies hve shown considerbly reduced hemtotoxicity, but stble efficcy, of weekly scheduled docetxel in the first- or second-line setting of MBC [5 9]. These dt hve been confirmed in 2 rndomized phse II/III trils by River et l. [10] nd Tbernero et l. []. This rther low rte of severe leukopeni ssocited with weekly scheduled docetxel my permit its combintion with nthrcyclines. Both gents re Tble 1. Ptient chrcteristics Chrcteristics D4 (n = 85) q1 w q3w Ptients Age, yers Medin Rnge KPS, % Medin Rnge Estrogen nd progesterone receptor sttus Positive Negtive Unknown Menopusl sttus Premenopusl Postmenopusl HER-2 sttus Positive (IHC 3+ or 2+ nd FISH+) Negtive (IHC 0 or 1+ or 2+ nd FISH ) Unknown Mesurble disese sites Lung Liver Lymph nodes Skin Skeleton Disese sites per ptient, n Prior tretment Adjuvnt chemotherpy (including nthrcyclines) Adjuvnt hormonl therpy considered mong the most ctive single gents for the tretment of MBC. Consequently, their combined use is logicl step in the serch for highly effective chemotherpy combintions. Previous phse II trils investigted 3-week scheduled nthrcycline/txne regimen with impressive high RR of 46 88% [13 16]. However, the dose-limiting fctor in these trils ws leukopeni, leding to the initition of phse II trils investigting weekly nthrcycline/txne combintion. Such studies hve demonstrted efficcy with mngeble toxicity profile [17, 18]. Gmucci et l. [17] reported considerbly low rte of 6grde 3 neutropeni of 16% of ptients who received first-line weekly epirubicin (25 mg/m 2 ) nd docetxel (25 mg/m 2 ) for MBC. The regimen ws quite effective, with n RR of D4 Combined Weekly Docetxel for MBC 207

5 Tble 2. Toxicity profile (per-ptient nlysis): hemtologicl nd nonhemtologicl toxicity by NCI CTC grde A (q3w), % B (q1w), % p vlue (fter dichotomiztion / 3) Hemtologicl toxicity Anemi >0.05 Leukopeni >0.05 Thrombocytopeni >0.05 Nonhemtologicl toxicity Alopeci >0.05 AP >0.05 Arrhythmis >0.05 Bilirubin >0.05 Constiption >0.05 Cretinine >0.05 Dirrhe >0.05 Fever Fluid retention >0.05 Gstrointestinl symptoms >0.05 GGT >0.05 Infections >0.05 Mucositis >0.05 Musculoskeletl disorders >0.05 Nuse nd vomiting >0.05 Neurotoxicity >0.05 Edem >0.05 Pin >0.05 Skin nd nil disorders >0.05 Tble 3. Efficcy: RR (intent-to-tret nlysis) D4 CR PR SD PD Not evluble RR, % 95% CI, % p All ptients (n = 85) q1w group (n = 43) q3w group (n = 42) RR q1w versus q3w. 60% nd medin OS of 25 months. Moreover, Perez- Mng et l. [18] reported on phse II study which investigted combintion of doxorubicin (50 mg/m 2 q4w) nd weekly scheduled docetxel (36 mg/m 2 dys 1, 8, nd 15; q4w) for loclly dvnced or metsttic brest cncer (first line). A consistently low rte of severe neutropeni ( 6 grde 3) ws reported (! 10% febrile neutropeni) nd RR were considerbly high mong loclly dvnced nd metstsized ptients, i.e. 93 nd 64%, respectively. Lcking rndomized dt, the D4 study ws designed to evlute the toxicity nd efficcy of weekly docetxel/ doxorubicin regimen compred to the 3-weekly stndrd scheme in younger nd mediclly fit MBC ptients. In brief, in the primry sfety endpoint of the D4 study significnt difference ws not reched. The ssumption of mrkedly reduced hemtotoxicity within the weekly schedule ws not verified. Surprisingly, the rte of leukopeni ( 6 grde 3) ws rther low in the stndrd rm, wheres it ws not reduced t ll in the weekly rm (61.9% q3w vs. 65.1% q1w; p ). Since the primry endpoint ws not reched, the D4 study ws closed fter n interim nlysis ccording to the study protocol (85 of Stemmler et l.

6 Fig. 1. TTP nd OS in the D4 study. mo = Months. Proportion of TTP nd survivl D4: medin OS q3w 28.7 mo q1w 20.5 mo p = 0.98 D4: medin TTP q3w 10.3 mo q1w 6.2 mo p = ,080 1,260 1,440 Time (dys) Tble 4. Efficcy: TTP nd OS D4 q3w q1w p vlue medin rnge medin rnge (log-rnk test) TTP, months OS, months Tble 5. Toxicity profile: dose modifictions All q3w q1w p vlue (n = 432) (n = 236) (n = 196) Cycles Dose reductions 130 (30.09) 55 (23.31) 75 (38.27) <0.001 Delyed doses 86 (19.91) 25 (10.59) 61 (31.12) <0.001 Omitted doses 43 (9.95) 0 43 (21.94) <0.001 Percentge of intended drug delivery <0.001 R eductions within cycle; dt given s n (%). ptients). The presumption of gretly reduced hemtotoxicity in the weekly rm ws bsed on the studies of Perez-Mng et l. [17] nd Gmucci et l. [18]. Both investigted weekly scheduled nthrcycline/txne combintion which hs shown reduced rte of leukopeni. Thus, we cnnot provide vluble explntion for the reltively high numbers of grde 3 nd 4 leukopeni in the weekly docetxel rm observed in our study. With regrd to nonhemtologicl toxicities, i.e. skin nd nil disorders, the known sequele of weekly dministered docetxel were incresed in ptients who were rndomized to the weekly schedule (.6% q1w vs. 0% q3w; p = 0.06). Moreover, even more surprisingly, the rte of reduced, delyed, or omitted doses within cycle ws significntly higher mong ptients receiving weekly docetxel s follows: 38.3 versus 23.3%, 31.1 versus 10.6%, nd 21.9 versus 0%, respectively (q1w vs. q3w; p! 0.001, ech). Therefore, the percentge of the intended drug delivered within cycle ws gretly reduced in the weekly rm (77.3% q1w vs. 90.3% q3w) ( tble 5 ). It is suspected tht this lesser dose contributed to mesurble loss of efficcy even though none of the differences in RR, TTP, nd OS reched the level of significnce. The RR ws 44.2% in the weekly rm compred to 52.4% under the stndrd regimen (p = 0.52). Moreover, the medin TTP nd OS were numericlly inferior in ptients who received the weekly schedule. TTP ws 6.2 (q1w) versus 10.3 (q3w) months (p = 0.36), nd OS ws 20.5 (q1w) versus 28.7 (q3w) months (p = 0.98). A finl sttement regrding efficcy is restricted by the limittion tht the clculted smple size for the secondry endpoints (TTP nd OS) ws not reched in the D4 study. Moreover, imblnces regrding the cumultive nthrcycline dose between both study rms my contribute to bis regrding the efficcy prmeters (50 mg/m 2 doxorubicin pplied q3w in the stndrd rm vs. q4w in the weekly rm ). Nevertheless, the study ws ter- D4 Combined Weekly Docetxel for MBC 209

7 minted fter the interim nlysis due to filure to rech sttisticl significnce in the primry endpoint (leukopeni). The striking trend towrds n improved TTP nd OS within the stndrd rm of the D4 study (q3w vs. q1w: TTP 10.3 vs. 6.2 months nd OS 28.7 vs months) my be t lest prtilly explined by the bove mentioned limittions. In conclusion, the dt of the D4 study hve surprisingly but unmistkbly shown tht leukopeni could not be prevented by weekly schedule of docetxel/nthrcycline combintion despite phse II dt indicting gretly reduced hemtotoxicity in fvor of the weekly dministrtion of docetxel. In view of the t lest numericlly reduced efficcy in the weekly rm s well s the substntilly incresed nonhemtologicl side effects, this pproch seems not to merit further investigtion. 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