Clinical Study. Oncology 2006;71:32 39 DOI: /

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1 Oncology Clinicl Study Oncology 2006;71:32 39 DOI: / Received: My 29, 2006 Accepted fter revision: December 9, 2006 Published online: Mrch 5, 2007 Efficcy of Consolidtion High-Dose Chemotherpy with Ifosfmide, Crbopltin nd Etoposide (HD-ICE) Followed by Autologous Peripherl Blood Stem Cell Rescue in Chemosensitive Ptients with Metsttic Soft Tissue Srcoms Mrcus Schlemmer Clemens-Mrtin Wendtner Mrtin Flk Sultn Abdel-Rhmn Thoms Licht c Jens Bumert d Christin Strk b Mrcus Hentrich f Christoph Slt Wolfgng Hiddemnn Rolf-Dieter Issels, e Deprtment of Internl Medicine III, Klinikum Grosshdern Medicl Center nd b Klinikum Innenstdt, Ludwig Mximilin University, c Deprtment of Internl Medicine III, Technicl University of Munich, d GSF Institute of Epidemiology, e KKG Hyperthermi, GSF Ntionl Reserch Center for Environment nd Helth, nd f Hospitl Hrlching, Munich, Germny Key Words High-dose chemotherpy Metstsis Soft tissue srcom Abstrct Bckground: Prognosis of ptients with metsttic soft tissue srcoms (MSTS) is poor even fter response to doxorubicin-bsed chemotherpy. We report phse II dt of highdose chemotherpy nd peripherl blood stem cell (PBSC) rescue in ptients with MSTS responding to AI-G chemotherpy. Ptients nd Methods: From 1997 to 2002, 55 ptients with MSTS were prospectively treted with 4 cycles of AI-G (doxorubicin 75 mg/m 2, ifosfmide 6 g/m 2 with G-CSF support). Responders received 2 further cycles of AI-G with collection of PBSCs. High-dose chemotherpy consisted of ifosfmide 12 g/m 2, crbopltin 1.2 g/m 2 nd etoposide 1.2 g/m 2 (HD-ICE) followed by reinfusion of PBSCs. Results: Twenty-one of 55 ptients (38%) were ssessed s responders (3 complete response, 18 prtil response). All but 2 p- tients refusing tretment received high-dose chemotherpy with PBSC rescue leding to grde IV hemtologic toxicity without severe infections in ll ptients. No toxic deth occurred. After medin follow-up time of 30 months, the medin progression-free time ws 12 months nd survivl time ws 22 months for the entire group. By intent-totret nlysis the probbility of 5-yer progression-free survivl ws significntly higher for ptients llocted to HD-ICE compred to ptients receiving second-line chemotherpy fter filure of AI-G (14 vs. 3%; p = 0.003). The estimted 5- yer overll survivl between the 2 groups ws different (27% vs. not reched) but did not rech significnce (p = 0.08). Conclusion: HD-ICE is fesible nd promising in ptients with chemosensitive MSTS. A rndomized phse III tril is wrrnted to further define the role of HD-ICE s consolidtion tretment in these ptients. Copyright 2006 S. Krger AG, Bsel Fx E-Mil krger@krger.ch S. Krger AG, Bsel /06/ $23.50/0 Accessible online t: Mrcus Schlemmer, MD Medizinische Klinik und Poliklinik III Grosshdern Mrchioninistrsse 15, DE München (Germny) Tel , Fx E-Mil Mrcus.Schlemmer@med.uni-muenchen.de

2 Introduction Ptients with metsttic soft tissue srcoms (MSTS) hve poor prognosis with response rtes to doxorubicin-bsed chemotherpy between 23 nd 45% nd medin overll survivl (OS) of bout months [1 4]. As single gents, doxorubicin, ifosfmide nd dcrbzine were shown to be most ctive in soft tissue srcoms (STS) with n overll response rte between 15 nd 28% [5 8]. For the combintion of doxorubicin nd ifosfmide, dose-dependent ctivities were shown [9, 10]. In phse II tril of the EORTC Soft Tissue nd Bone Srcom Group using doxorubicin 75 mg/m 2 nd ifosfmide 5 g/m 2, response rte of 45% ws reched leding to medin survivl of 15 months [1]. This promising result could not be confirmed in phse III tril with response rte of only 23% nd medin OS of 13 months [2]. The most recent EORTC tril in MSTS rndomizes between doxorubicin 75 mg/m 2 nd dose-intensified combintion (doxorubicin 75 mg/m 2 nd ifosfmide 10 g/m 2 ) to nswer the question whether combintion chemotherpy provides survivl dvntge over single-gent doxorubicin. As the use of hemtopoietic growth fctors llows sfe escltion of dose, severl regimes hve been tested in ptients with metsttic disese. These trils included smll numbers of ptients with vriety of bone srcoms nd STS [11 14]. Furthermore, high-dose chemotherpy with utologous peripherl blood stem cell rescue (PBSCR) ws performed in 18 ptients with STS receiving doxorubicin nd esclted doses of ifosfmide. The overll response rte ws 50%, but OS ws only 13 months [15]. In nother series including 27 ptients treted with epirubicin nd ifosfmide, the overll response rte ws 38% [16]. A French protocol used etoposide, cispltin nd ifosfmide in 30 ptients with MSTS nd while observing high renl toxicity, progression-free survivl (PFS) ws 21% t 5 yers [17]. In order to better define the role of similr regimen including ifosfmide, crbopltin nd etoposide (ICE) with respect to both toxicity nd efficcy, we performed phse II tril in ptients with MSTS responding to doxorubicin/ifosfmide induction chemotherpy supported by G-CSF (AI-G). Ptients nd Methods Ptients Eligibility Ptients between 18 nd 60 yers with histologiclly confirmed chemonive MSTS of grde II nd III with mesurble disese were eligible for this phse II tril. Ptients were required to hve good performnce sttus (grde 0 2 ccording to WHO) nd norml orgn functions. Bseline eligibility criteri were norml blood counts (WBC 1 4,000/ l, pltelet count 1 100,000/ l) nd dequte renl (serum cretinine! 1.5 mg/dl) nd liver (serum bilirubin! 1.5 mg/dl) function tests. Ptients with history of ctive crdic disese, including myocrdil infrction nd congestive hert disese, were excluded from the study. Further exclusion criteri included histology of mlignnt mesotheliom, nonmesenchyml chondrosrcom, neuroblstom, chordom, Kposi s srcom nd gstrointestinl stroml tumor, s well s history of nother mlignncy, centrl nervous system involvement nd prior rdiotherpy on prmeter lesions. The study ws performed ccording to the guidelines estblished by the Helsinki Declrtion. The protocol ws pproved by the Ethics Committee of the Ludwig Mximilin University, Germny (No. 93/97). Written informed consent ws obtined from ll ptients enrolled onto this study. Tre t m e n t Induction chemotherpy consisted of doxorubicin 75 mg/m 2 s 30 min infusion on dy 1 nd ifosfmide 1.5 g/m 2 s 120 min infusion on dys 1 4 (AI-G). Twenty-four hours fter the end of chemotherpy, G-CSF ws given subcutneously t dose of 5 g/kg body weight/dy until neutrophil counts exceeded 3,000/ l. AI-G cycles were repeted on dy 22. After 4 cycles, responding ptients received 2 further cycles of AI-G chemotherpy with n incresed dose of G-CSF (10 g/kg body weight/dy). If more thn 10 CD34 cells/ l were found in peripherl blood, leukpheresis ws performed to hrvest t lest 2! 10 6 CD34 cells/kg body weight for utologous stem cell trnsplnttion. The intervl between the end of induction therpy or surgery nd the strt of high-dose chemotherpy ws 4 weeks ccording to protocol. Highdose chemotherpy consisted of ifosfmide 2 g/m 2 (1 h infusion) from dy 8 until dy 3, crbopltin 200 mg/m 2 (1 h infusion) from dy 8 until dy 3 nd etoposide 200 mg/m 2 (22 h infusion) from dy 8 until dy 3 (HD-ICE). This resulted in totl doses of 12 g/m 2 ifosfmide, 1,200 mg/m 2 crbopltin nd 1,200 mg/m 2 etoposide. After 2 dys without chemotherpy, ptients received t lest 2! 10 6 CD34 cells/kg body weight vi centrl venous ctheter on dy 0. G-CSF (5 g/kg body weight) ws given subcutneously from dy 1 until recovery of neutrophils. Stging Procedures nd Tretment Evlution At enrollment, physicl exmintion, full lbortory nlysis of blood prmeters, cretinine clernce nd crdic ultrsound were performed. Additionlly, contrst-enhnced CT scn of chest nd bdomen nd, if needed, MRI of the site of disese were performed. During induction tretment, blood counts, physicl exmintion nd toxicity ssessment were performed fter ech cycle of AI-G chemotherpy. After 4 cycles, ll ptients were evluted for response ccording to WHO criteri by contrst-enhnced CT scns, MRI, or both, bsed on the extent of the disese defined t presenttion [18]. Two independent investigtors reviewed the files nd films of ll responding ptients. Toxicity ws evluted ccording to the Common Toxicity Criteri [19]. Before the strt of high-dose chemotherpy, possible infections were excluded nd serologicl blood tests were tken. During follow-up, stging ws repeted every 3 months in the first yer nd every 6 months therefter. The durtion of response ws mesured from the strt of induction tretment to the dte of documented progression; the du- High-Dose Chemotherpy in Chemosensitive STS Oncology 2006;71:

3 Tble 1. Ptients chrcteristics Chrcteristics Sex Mle 34 Femle 21 Age t entry yers yers 29 Site of metstses Lung 24 Lung nd liver 7 Lung nd lymph node 4 Lung, liver nd bone 2 Liver 4 Liver nd bone 2 Lymph node 8 Bone 4 Prior tretment None 16 Surgery lone 24 Surgery plus rdition 15 Rdition lone 0 Ptients Tble 2. Histologic dignoses nd grdes Cell type Ptients grde 2 grde 3 totl % Leiomyosrcom Liposrcom Rhbdomyosrcom PNET MFH Synovil srcom Hemngiopericytom Other PNET = Primitive neuroectoderml tumor; MFH = mlignnt fibrous histiocytom. rtion of complete response (CR) ws clculted from the moment CR ws documented to the first evidence of progression. PFS ws mesured from the dte of tretment strt to documented progression. Survivl ws clculted from the time of tretment strt to the dte of deth. The primry endpoint ws PFS. Secondry endpoints were response to induction chemotherpy nd OS. S t t i s t i c s OS nd PFS were estimted ccording to the method of Kpln nd Meier [20]. The 95% confidence intervls (CIs) of the Kpln- Meier estimtes were clculted with Greenwood s vrinces [21]. The endpoints for cturil nlysis were PFS nd OS. The comprison of survivl prmeters in responding versus nonresponding ptients ws performed using the log-rnk test [22]. For ll tests, p! 0.05 ws considered to be sttisticlly significnt. This protocol ws designed s multicenter, nonrndomized, controlled single rm phse II study with PFS s primry endpoint. Smple size estimtion for ptients with MSTS ws performed for the improvement in PFS from 12 to 24 months by the log-rnk test. The estimted response rte ws 34% (23 45%). In cse of 5.5 yers of recruitment nd 5-yer follow-up, the required number ws estimted s 53 ptients ( = 5%, = 20%). R e s u l t s Ptients Chrcteristics Between April 1997 nd December 2002, 55 ptients with MSTS were treted ccording to the protocol. The study popultion consisted of 34 mle nd 21 femle ptients with medin ge of 40.5 yers (rnge yers). Detils re shown in tbles 1, 2. Fesibility nd Toxicity of Induction Chemotherpy (AI-G) Forty-six ptients (84%) received 4 induction chemotherpy cycles (AI-G) ccording to the study protocol. One ptient refused further tretment fter 1 cycle, 6 ptients progressed fter 2 cycles nd 2 ptients fter 3 cycles. The medin number of induction chemotherpy cycles given ws 4 (rnge 1 4). Before high-dose chemotherpy, 21 ptients were found eligible for PBSCR, 2 ptients refused PBSCR. During induction chemotherpy, nonhemtologic toxicity ws minly mild, while no severe side effects (grde 3 nd 4) were seen. The most frequent side effects were lopeci (grde 2) which ws observed in ll ptients, nd nuse (grde 1) which ws seen in the mjority of ptients (70%). Hemtologic toxicity ws significnt in terms of leukopeni (30% grde 3 nd 15% grde 4) nd thrombocytopeni which occurred in lmost every ptient during the induction tretment, but did not differ from previously published dt for doxorubicin/ifosfmide chemotherpy combined with G- CSF [1]. Response to Induction Therpy (AI-G), Stem Cell Collection nd Surgery All ptients were evluted fter 4 cycles of AI-G chemotherpy. An objective response ws observed in 21 (38%) of the 55 ptients, including 3 CR nd 18 prtil responses (PR). No chnge ws observed in 20 ptients 34 Oncology 2006;71:32 39 Schlemmer et l.

4 (37%) nd 14 (25%) progressed during induction therpy ( tble 3 ). All 21 ptients with chemosensitive tumors received 2 dditionl cycles of AI-G followed by peripherl blood stem cell pheresis. Collection of peripherl blood stem cells ws chieved for these ptients with hrvest efficiency of t lest 2! 10 6 CD34 cells/kg body weight. During mobiliztion chemotherpy, none of the ptients progressed. Before high-dose chemotherpy (HD-ICE), 4 ptients underwent surgery. One ptient hd rdicl (R0) resection of his lung metstses. In 2 ptients R0 surgery of their primry tumor could be obtined, nd in 1 ptient R1 resection of the primry tumor ws chieved. Before the strt of HD-ICE, 6 ptients hd no evidence of disese, 8 ptients hd only distnt disese with no evidence of disese t the primry tumor site nd 7 ptients entered high-dose chemotherpy with persistent disese t locl nd distnt sites. Toxicity nd Fesibility of High-Dose Chemotherpy (HD-ICE) Of 21 ptients responding to AI-G (3 CR nd 18 PR), 19 ptients received high-dose chemotherpy with PBSCR while 34 ptients were not eligible for high-dose chemotherpy. Two ptients being eligible for HD-ICE refused this tretment. HD-ICE s conditioning regimen ws fesible nd no deth due to therpy occurred. The medin number of infused mononucler CD34 cells ws 6! 10 6 /kg body weight (rnge 2 12! 10 6 ). After HD-ICE chemotherpy, ll ptients experienced grde 3 or 4 neutropeni nd thrombocytopeni ( tble 4 ). The mximum nemi seen in the tril ws of grde 3, s ptients received pcked red cells before the hemoglobin decresed below 7.5 g/dl. The medin number of trnsfused pcked red cell units during high-dose chemotherpy ws 2 (rnge 0 4). The medin durtion of grde 4 neutropeni nd thrombocytopeni ws 9.3 (7 14) nd 6.9 dys (3 17), respectively. Due to severe thrombocytopeni (grde 4), 11 ptients required medin of 2 pltelet trnsfusions (rnge 1 5). Four ptients suffered from severe pneumoni, which resolved fter combined ntibiotic tretment. Other infectious complictions were mild, only fever of unknown origin with medin durtion of 3.5 dys (0 12) ws observed. Mucositis ws severe (grde 3) in 6 ptients requiring infusion of morphine. Heptotoxicity with elevtion of bilirubin 1 3! N, most likely due to drug toxicity, ws observed in 1 ptient on dy 1 fter PBSCR, resolving spontneously. At medin of 13 dys fter PBSCR, ptients were dischrged from hospitl. Up to now, with medin follow-up of 30 months, no lte toxicity like myelodysplsi, leukemi or solid tumors were seen. Tble 3. Rdiogrphic response to induction chemotherpy Rdiogrphic response Ptients % CR 3 6 PR No chnge Progressive disese Totl Tble 4. Mximl toxicity during high-dose chemotherpy (HD- ICE; n = 18) Ptients with CTC grde toxicity Leukopeni Neutropeni Thrombopeni Anemi Infection Mucositis Nuse Nephrotoxicity Heptotoxicity Neurotoxicity Crdiotoxicity One ptient refused further therpy fter dy 1 of HD-ICE. This ptient ws excluded from the toxicity evlution. CTC = Common Toxicity Criteri. Relpse nd Survivl After medin follow-up time of 30 months, the medin time to progression for the entire study group of 55 ptients ws 12 months (95% CI 8 15). The 2- nd 5-yer PFS rte estimted ccording to Kpln-Meier ws 18% (95% CI 8 28) nd 7% (95% CI 0 8), respectively ( fig. 1 ). In n intent-to-tret nlysis including ll 21 ptients responding to AI-G induction therpy, the 2-yer PFS for ptients llocted to HD-ICE (n = 21) ws 32% (95% CI 12 52) compred to 9% (95% CI 0 18) in ptients being treted with second-line chemotherpy fter filure of AI-G induction (p = ). The medin PFS for ptients in the high-dose group ws 16 months in contrst to the conventionl tretment rm with medin PFS of only 7 months ( fig. 2 ). The difference in probbility of 5-yer PFS in the high-dose group (n = 21) with 14% (95% CI 5 47) compred to the stndrd tretment rm (n = 34) High-Dose Chemotherpy in Chemosensitive STS Oncology 2006;71:

5 PFS Time (months) OS Time (months) Fig. 1. PFS in the entire cohort of 55 ptients. Fig. 3. OS in the entire cohort of 55 ptients. PFS Time (months) Responder,n=21 Nonresponder,n=34 p < OS Responder,n=21 Nonresponder,n=34 p = Time (months) Fig. 2. PFS in ptients responding to AI-G induction nd being llocted to HD-ICE (n = 21) versus ptients receiving conventionl second-line chemotherpy fter filure to induction tretment (no HD-ICE; n = 34; intent-to-tret nlysis). Fig. 4. OS in ptients responding to AI-G induction nd being llocted to HD-ICE (n = 21) versus ptients receiving conventionl second-line chemotherpy fter filure to induction tretment (no HD-ICE; n = 34; intent-to-tret nlysis). with 3% (95% CI 0 9) ws sttisticlly significnt (p = 0.003). One ptient with neurofibrosrcom nd lung metstses being in PR fter induction chemotherpy refusing HD-ICE died fter 39 months due to progression of the lung metstsis, nother being in CR fter induction therpy nd lso refusing HD-ICE, died 13 months fter the strt of the study due to progressive disese. At present, 7 of the 21 responding ptients re live. The 5- yer estimted OS rte of ll ptients is 12% with medin OS time of 22 months ( fig. 3 ). The probbility of OS ws not higher for ptients responding (CR, PR) to induction chemotherpy compred to nonresponders. In n in- 36 Oncology 2006;71:32 39 Schlemmer et l.

6 tent-to-tret nlysis, the medin OS for the ptients being llocted to high-dose chemotherpy (n = 21) ws 24 months versus 18 months for nonresponders to AI-G induction. There ws no sttisticl difference in OS between ptients with stble nd progressive disese (p = 0.14). The estimted 4-yer OS rte ws 27% (95% CI 7 47) for the high-dose group nd 5% (95% CI 0 11) for the conventionl tretment rm. Estimted 5-yer OS in the 2 groups did not rech the level of significnce (p = 0.08; fig. 4 ). Discussion The objective of the present study ws to investigte efficcy in terms of OS nd PFS fter HD-ICE nd PB- SCR given s consolidtion therpy in chemosensitive ptients with MSTS. Therefore, HD-ICE ws tested in well-defined subgroup of ptients experiencing CR or PR to AI-G chemotherpy. The design of our study is similr to previously conducted study in 30 ptients with dvnced STS receiving high-dose chemotherpy consisting of ifosfmide, etoposide nd cispltin (VIC) [17]. The uthors reported renl toxicity of grde 1 in 43% nd grde 2 or higher in 20% of the ptients using the VIC regimen. Replcing cispltin by crbopltin in our HD- ICE regimen ws fvorble with no grde 2 nephrotoxicity observed. The hemtologic toxicity of the HD-ICE regime ws comprble to the VIC protocol in terms of durtion of plsi nd number of required trnsfusions. The OS rte in our present series t 2 nd 5 yers is 40 nd 12%, respectively, compred to the reported OS nd PFS rtes t 5 yers fter high-dose chemotherpy bsed on the VIC regimen, i.e. 23 nd 21%, respectively. In ddition, the percentge of ptients with CR before highdose chemotherpy ws higher in the former series (27%) compred to our study popultion (6%). This is of mjor importnce since the percentge of long-term survivors mong ptients with metststic or dvnced STS chieving CR fter conventionl chemotherpy is predictor of survivl rtes in given series of ptients [4, 12, 17, 23]. In lrge series of the EORTC Soft Tissue nd Bone Srcom Group including 2,185 ptients with defined firstline chemotherpy, performnce sttus of 0, femle gender nd grde I histology were independent prmeters correlting to 5-yer survivl besides chievement of CR fter first-line chemotherpy [24]. In our study, grde I tumors were excluded by definition of high-risk criteri while most of the ptients presented t n initil performnce sttus of 1. Furthermore, the mjority of our ptients were mle. Also, the bsence of liver metstses ws shown to be ssocited with longer survivl times in multivrite nlysis [24]. Our study comprised 12 ptients with heptic metstses explining n dverse survivl outcome. The CR rte of 6% fter AI-G induction ws low nd in our study 7 ptients re live, 3 without evidence of disese t 37, 47 nd 84 months, nd 4 ptients with disese t 22, 30, 37 nd 43 months. One ptient who did not qulify for high-dose chemotherpy due to lck of response to AI-G chemotherpy is live. This ptient ws formlly dignosed s hving gstrointestinl stroml srcom which hs menwhile been reclssified s gstrointestinl stroml tumor nd is now responding to tretment with imtinib. The present study ws negtive for its primry endpoint, i.e. PFS could not be prolonged from 12 to 24 months. For the entire study popultion PFS ws only 12 months in ccordnce with previous reports nd ptients in the high-dose group showed only slight improvement in PFS with 16 months. Compring ptients hving received high-dose chemotherpy with those hving received best second-line chemotherpy lthough this non-rndomized phse II study ws not powered to nswer this question sufficiently revels tht OS does not seem to be improved by high-dose chemotherpy. Only PFS, which is vlid endpoint for phse II studies [25] ws better for those ptients receiving high-dose chemotherpy. It hs to be stressed tht it remins to be demonstrted in phse III tril whether high-dose chemotherpy is ble to improve survivl of those ptients who re in CR before high-dose chemotherpy. High-dose therpy hs been evluted more extensively in peditric ptients with Ewing s srcoms, rhbdomyosrcoms nd osteosrcoms. Also, in this ptient group severl studies conclude tht high-dose chemotherpy does not significntly improve tretment outcome compred to conventionl relpse therpy [26, 27]. Trnsplnttion-relted side effects nd the thret of secondry mlignnt neoplsm fter high-dose chemotherpy my complicte the future course of ptients who re currently viewed s progression-free survivors [28]. Histologicl subtypes which might benefit from dose-intensified chemotherpy should be selected for high-dose chemotherpy strtegies. Ptients with peripherl primitive neuroectoderml tumors were found to hve superior PFS to ptients with other histologicl srcom subtypes [29]. The concept of tndem high-dose chemotherpy, estblished for other tumor entities, should lso be further studied for STS fter High-Dose Chemotherpy in Chemosensitive STS Oncology 2006;71:

7 first pilot studies hve proved the fesibility of this pproch in srcoms [30, 31]. Our dt rise the question whether high-dose chemotherpy nd PBSCR or the intensified dose of ifosfmide (12 g/m 2 ) in the ICE regime is responsible for the long-term survivl of these ptients. As lrge number of phse II trils showed only limited ctivity of severl new gents in STS [32, 33], possible pproch is to increse the CR rte to conventionl chemotherpy by esclting the dose of drugs ctive ginst STS. The dosge of ifosfmide in our AI-G regimen ws suboptiml with 6 g/m 2. Menwhile numerous trils hve suggested dose-response reltionship for ifosfmide [2, 34]. In previous tril it ws shown tht multiple cycles of dose-intensive therpy with high-dose ifosfmide cn be dministered sfely, resulting in CR rtes bove 20% [15]. It is n open question whether the dose intensity of ifosfmide in our HD-ICE regimen lone wrrnts n dvntge for ptients with metsttic STS. 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