A retrospective study on combination therapy with ifosfamide, adriamycin and cisplatin for progressive or recurrent uterine sarcoma

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1 MOLECULAR AND CLINICAL ONCOLOGY 2: , 2014 A retrospective study on combintion therpy with ifosfmide, drimycin nd cispltin for progressive or recurrent uterine srcom WATARU YAMAGAMI, NOBUYUKI SUSUMU, TOMOMI NINOMIYA, MICHIKO KUWAHATA, AYA TAKIGAWA, HIROYUKI NOMURA, FUMIO KATAOKA, EIICHIRO TOMINAGA, KOUJI BANNO, HIROSHI TSUDA nd DAISUKE AOKI Deprtment of Obstetrics nd Gynecology, School of Medicine, Keio University, Shinjuku, Tokyo , Jpn Received Jnury 15, 2014; Accepted Mrch 20, 2014 DOI: /mco Abstrct. There is currently insufficient evidence to recommend specific chemotherpeutic regimen s stndrd tretment for uterine srcoms. In this study, we investigted the toxicity nd effectiveness of ifosfmide, drimycin nd cispltin (IAP therpy) in ptients with progressive nd recurrent uterine srcom. A totl of 11 ptients with progressive or recurrent uterine srcom contining leiomyosrcom (LMS), undifferentited endometril srcom (UES) or denosrcom, who were dignosed t our institution, were retrospectively investigted. We recorded the dverse events, response rte nd progression free survivl in these cses. The histologicl types included LMS (54.5%), denosrcom (27.3%) nd UES (18.2%). Grde 3 leukopeni or neutropeni were observed in ll the cses, febrile neutropeni developed in 45.5% of the ptients nd grde 4 thrombocytopeni developed in 3 cses (27.3%). With IAP therpy, the response rte ws 36.4% nd the disese control rte ws 90.9%. Therefore, IAP therpy my be vible option s chemotherpy for uterine srcom. Introduction Uterine srcoms re extremely rre, non-epithelil mlignnt uterine tumors. Uterine srcoms ccount for 8% of ll mlignnt tumors of the corpus uteri nd the most common histologicl types re crcinosrcom (CS), leiomyosrcom (LMS) nd endometril stroml srcom (ESS), in decresing order of frequency (1). In Jpn, it ws reported tht the most common histologicl types re CS (46%), LMS (36%) nd ESS (13%) (2). CS is mlignnt tumor consisting of n epithelil nd nonepithelil component, which minly ffects postmenopusl Correspondence to: Dr Wtru Ymgmi, Deprtment of Obstetrics nd Gynecology, School of Medicine, Keio University, 35 Shinnomchi, Shinjuku, Tokyo , Jpn E-mil: gmi@z8.keio.jp Key words: chemotherpy, drimycin, ifosfmide, cispltin, uterine srcom women. A combintion tumor theory suggested tht the mjority of CSs originte from single cell nd differentite into epithelioid-like nd stroml-like components, wheres they re considered to exhibit cellulr chrcteristics nd progression similr to those of poorly differentited endometrioid denocrcinom (3). Therefore, CSs tend to be treted in ccordnce with the tretment for epithelil endometril cncer. However, LMS nd ESS possess totlly different properties compred to epithelil endometril cncer. LMS nd ESS re mlignnt tumors tht re minly encountered during the perimenopusl period. Uterine leiomyoms my exhibit mlignnt trnsformtion to LMS in % of the cses (4). These tumors re dignosed bsed on the number of mitoses, degree of cellulr typi nd presence of cogultion necrosis. ESS my be clssified s low- or high grde, bsed on the number of mitoses. However, these srcoms re currently considered s different types of tumors. High grde ESS, in prticulr, is referred to s undifferentited endometril srcom (UES). Totl hysterectomy nd bilterl slpingo-oophorectomy (BSO) re currently considered the first choice for the tretment of uterine srcoms, lthough consensus hs not been reched regrding retroperitonel lymphdenectomy (5,6). However, these tumors cnnot be sufficiently controlled by surgicl tretment lone, since number of ptients develop progression nd recurrence of uterine srcom. As LMS often develops distnt hemtogenous metstses to the lungs nd the liver, chemotherpy is commonly required s systemic tretment. However, there is insufficient evidence to recommend specific chemotherpeutic regimen s stndrd tretment for uterine srcoms, s these re rre tumors nd the number of reported cses is limited. We dministered combintion of ifosfmide (IFM), drimycin (ADM) nd cispltin (CDDP) (IAP therpy) to ptients with progressive nd recurrent uterine srcoms nd retrospectively investigted tretment effectiveness nd toxicity. Ptients nd methods Ptients. We investigted 11 ptients who were dignosed with uterine srcom nd treted with IAP between 1990 nd 2010 t the Keio University Hospitl, Tokyo, Jpn.

2 592 YAMAGAMI et l: IAP THERAPY FOR UTERINE SARCOMA Totl hysterectomy nd BSO or tumorectomy were performed in our hospitl. The pthologicl dignosis in ll the cses ws LMS, UES or denosrcom. The medin follow-up period ws 298 dys (rnge, 36-2,757 dys). Remission induction chemotherpy ws performed in ll the cses, s 8 of the ptients hd progressive disese (PD) nd 3 ptients hd recurrent disese. This study ws pproved by the Keio University School of Medicine Ethics Committee (pprovl no ) nd ll the ptients provided informed consent. Tretment pln. The tretment schedule ws bsed on cse report of uterine srcom tht ws treted with IAP (7,8). The dministrtion ws every 3 weeks s follows: IFM 1.5 g body on dys 1 5, mesn 900 mg/body on dys 1 5, ADM 50 mg m 2 on dy 1 nd CDDP 50 mg m 2 on dy 1, intrvenously. Grnulocyte colony-stimulting fctor (G CSF) ws used ccording to the criteri of the Americn Society of Clinicl Oncology. This tretment schedule ws repeted every 3 weeks until disese progression or until discontinution due to dverse events. Evlution of response nd toxicity. The dverse events were ssessed ccording to the Common Terminology Criteri for Adverse Events, version 4.0, bsed on the interviews nd blood tests conducted once week or more frequently fter ech cycle. The subsequent cycle ws initited fter the dverse events were resolved. As regrds hemtotoxicity, if ptients presented with grde 4 leukopeni or neutropeni for >7 dys, grde 3-4 thrombocytopeni, or febrile neutropeni, we considered reducing the dose or withdrwing drugs for the subsequent cycle. We ssessed the overll response rte of 11 cses who hd received remission induction therpy nd hd evluble lesions in ccordnce with the World Helth Orgniztion evlution criteri nd recorded the progression-free survivl. The tumors were mesured by computed tomogrphy fter every 2 cycles. After the product of the two longest perpendiculr dimeters ws clculted, the response ws ssessed s follows: complete response (CR), complete disppernce of ll known lesions for minimum of 4 weeks; prtil response (PR), >50% reduction in the sum of the length x width of ech mesurble lesion for minimum of 4 weeks; PD, >25% increse in the sum of the products of ll mesurble lesions or ppernce of ny new lesions; no chnge (NC), ny outcome tht did not qulify s response or progression. Sttisticl nlysis. SPSS softwre, version 20 (IBM-SPSS Softwre, Chicgo, IL, USA) ws used for sttisticl nlysis, using Fisher's exct test. P<0.05 ws considered to indicte sttisticlly significnt difference. Kpln-Meier curves were used for the estimtion of progression free survivl nd were compred with stndrd log-rnk tests. Results Clinicopthologicl chrcteristics. The clinicopthologicl chrcteristics of the 11 cses who underwent IAP therpy re presented in Tbles Ⅰ nd Ⅱ. The medin ge t IAP therpy ws 50 yers (rnge, yers). The primry tumor sites Tble I. Clinicopthologicl chrcteristics of the 11 cses. Chrcteristics No. Age (yers) < Origin Uterus 10 Retroperitoneum 1 Histologicl type Leiomyosrcom 6 Adenosrcom 3 Undifferentited endometril srcom 2 Stge (FIGO 1988) I 4 II 0 III 1 IV 5 Other 1 Type of disese Progressive 6 Recurrent 5 Initil tretment Surgery 11 Chemotherpy 0 Type of surgery Hysterectomy + BSO (USO) 7 Other 4 Chemotherpy prior to IAP None 9 CYVADIC b 1 DOC + GEM 1 Ifosfmide, drimycin nd cispltin. b Cyclophosphmide, vincristine, drimycin nd dcrbzine. FIGO, Interntionl Federtion of Gynecology nd Obstetrics; BSO, bilterl slpingo-oophorectomy; USO, unilterl slpingo-oophorectomy; DOC, docetxel; GEM, gemcitbine. were the uterus (10 cses, 90.9%) or the retroperitoneum (1 cse, 9.1%). The histologicl types were LMS (6 cses, 54.5%), denosrcom (3 cses, 27.3%) nd UES (high grde ESS; 2 cses, 18.2%). Tretment. A totl of 2 cses (18.2%) hd received pretretment; 1 cse hd received cyclophosphmide, vincristine, ADM nd dcrbzine (DTIC) (CYVADIC therpy) nd 1 cse hd received docetxel (DOC) + gemcitbine (GEM). The medin number of cycles of IAP therpy ws 6 (rnge, 1-8 cycles). In 72.7% of the cses, dose reduction ws required. Among cses who received >6 cycles, in prticulr, 71.4% required dose reduction. The chemotherpy ws interrupted fter 1 to 2 cycles for the ptients who requested tretment discontinution due to intolerble dverse events. Adverse events. The dverse events of IAP therpy re summrized in Tble Ⅲ. Hemtotoxicity, prticulrly grde 3

3 MOLECULAR AND CLINICAL ONCOLOGY 2: , Tble Ⅱ. Clinicopthologicl nd tretment detils of the 11 cses. Age Age t t IAP No. Recurrence dignosis therpy Histologicl Disese Prior of fter PFS (yers) (yers) type sttus Initil tretment chemotherpy cycles Effectiveness IAP therpy (dys) Leiomyosrcom Recurrent ATH + BSO CYVADIC b 8 SD Yes 1, Adenosrcom Recurrent ATH + BSO - 2 SD No Leiomyosrcom Recurrent Tumorectomy + BSO - 3 CR Yes Leiomyosrcom Progressive Tumorectomy - 8 SD Yes ESS, high grde Progressive Virchow LN biopsy - 1 SD Yes Adenosrcom Progressive ATH + BSO + PLN SD Yes 44 OMT + tumorectomy ESS, high grde Progressive ATH + BSO - 2 SD Unknown Leiomyosrcom Progressive ATH + BSO + PLN - 8 PD Yes 25 + tumorectomy Adenosrcom Progressive ATH + tumorectomy - 6 PR Yes Leiomyosrcom Progressive ATH + BSO DOC + GEM 6 CR No Leiomyosrcom Progressive Tumorectomy - 6 CR Yes 1,539 Ifosfmide, drimycin nd cispltin. b Cyclophosphmide, vincristine, drimycin nd dcrbzine. PFS, progression-free survivl; ESS, entometril stroml srcom; ATH, bdominl totl hysterectomy; BSO, bilterl slpingo-oophorectomy; LN, lymph node; PLN, pelvic lymphdenectomy; OMT, omentectomy; DOC, docetxel; GEM, gemcitbine; SD, stble disese; CR, complete response; PD, progressive disese; PR, prtil response. leukopeni or neutropeni, developed in ll the cses during the first cycle. Febrile neutropeni developed in 45.5% of the cses nd resolved with dministrtion of ntibiotics nd G-CSF. Grde 4 thrombopeni developed in 3 cses (27.3%), one of which required pltelet trnsfusion. Non-hemtologicl dverse events other thn norexi, nuse nd vomiting were not reported. Hemorrhgic cystitis or crdiotoxicity, which re dverse events chrcteristic of IFM nd ADM, were lso not reported. Effectiveness. The therpeutic effects of remission induction chemotherpy re presented in Fig. 1. The sum of CR + PR ws 36.4% (95% CI: %) nd tht of CR + PR + NC ws 90.9% (95% CI: %). The medin progression-free survivl ws 307 dys (95% CI: dys). Discussion Although severl chemotherpeutic options for uterine srcom were previously suggested, the number of lrge scle studies on uterine srcoms is limited, s this type of tumor is reltively rre. The overll rte of response to single gent chemotherpy is presented in Tble Ⅳ. The response rte for ADM, IFM nd gemcitbine (GEM) ws 25.0, 17.0 nd 21.0%, respectively (9-11); these re considered to be the key drugs in the tretment of uterine srcom. However, the response rte with pclitxel nd CDDP ws 9.0 nd 3.0%, respectively (12,13); thus, these drugs re considered to be less effective. The efficiency of multi gent chemotherpy for uterine srcom is summrized in Tble Ⅴ. Omur et l (9) investigted the efficiency of ADM + DTIC therpy nd reported tht, mong 66 cses with mesurble lesions of uterine srcom, 16 (24.2%) chieved remission (CR + PR). Specificlly, the response rte ws 30.0% (6/20) in cses with LMS. Tble Ⅲ. Adverse events following IAP therpy. Adverse events Grde N % Hemtologicl Leukopeni Neutropeni Febrile neutropeni Thrombocytopeni Non-hemtologicl Ifosfmide, drimycin nd cispltin. Sutton et l (14) investigted ADM + IFM therpy in 33 ptients with LMS. As regrds dverse events, grde >3 neutropeni developed in 17 cses (48.6%), of which 2 developed febrile neutropeni. Grde 3 thrombocytopeni ws observed in 2 cses nd nephrotoxicity in 1 cse. There were 2 reported deths due to the development of severe dverse events, specificlly sepsis nd crdiotoxicity. CR ws chieved in 1 cse nd PR in 9 cses. The overll response rte ws 30.3% nd the disese control rte (CR + PR + SD) ws 82.0%. Piver et l (15) investigted CYVADIC therpy in 26 ptients with intrpelvic srcom. As regrds dverse events, neurotoxicity ws observed in 8 cses (30.7%), including 6 mild to-moderte nd 2 severe cses. No ptient developed crdiotoxicity. However, sepsis developed in 4 cses (15.3%) nd 1 ptient succumbed to the complictions. The effectiveness ws determined in 10 uterine srcom cses. The overll response rte nd disese control rte were 20.0 nd 60.0%, respectively.

4 594 YAMAGAMI et l: IAP THERAPY FOR UTERINE SARCOMA Tble Ⅳ. Overll rte of response to single-gent chemotherpy. Agents Dose nd regimen Response rte (%) First uthor Refs. ADM 60 mg/m 2 dy 1 25 Omur (9) Etoposide 100 mg/m 2 dy Slyton (19) CDDP 50 mg/m 2 dy 1 3 Thigpen (13) Ifosfmide 1.5 g/m 2 dy Sutton (10) Pclitxel 175 mg/m 2 dy 1 9 Sutton (12) Gemcitbine 50 mg/m 2 dy 1, 8 nd Look (11) Liposoml doxorubicin 50 mg/m 2 dy 1 14 Sutton (20) Topotecn 1.5 mg/m 2 dy Miller (21) Trbectedin 1.5 mg/m 2 dy 1 10 Monk (22) ADM, drimycin; CDDP, cispltin. Tble Ⅴ. Overll rte of response to multi-gent chemotherpy. Agents Dose nd regimen Cses Response rte (%) Disese control rte (%) First uthor Refs. ADM + DTIC ADM 60 mg/m 2 dy Omur (9) DTIC 250 mg/m 2 dys 1-5 IFM + ADM IFM 5 g/m 2 dy Sutton (14) ADM 50 mg/m 2 dy 3 CYVADIC CPA 400 mg/m 2 dy Piver (15) Vicristine 1 mg/m 2 dys 1-5 ADM 40 mg/m 2 dy 2 DTIC 200 mg/m 2 dys 1-5 GEM + DOC GEM 900 mg/m 2 dy Hensley (16,17) DOC 100 mg/m 2 dys 1 nd 8 MAID Mesn 1.5 g/m 2 dys Perl (18) IFM 1.5 g/m 2 dys 1-3 ADM 15 mg/m 2 dys 1-3 DTIC 250 mg/m 2 dys 1-5 IAP IFM 1.5 g/body dys Present study ADM 50 mg/m 2 dy 1 CDDP 50 mg/m 2 dy 1 ADM, drimycin; CPA, cyclophosphmide; GEM, gemcitbine; DTIC, dcrbzine; DOC, docetxel; IFM, ifosfmide; CDDP, cispltin. Figure 1. Therpeutic effects of remission induction chemotherpy. (A) The overll response rte ws 36.4% nd the disese control rte, including NC, ws 90.9%. (B) The medin progression-free survivl ws 307 dys (95% CI: dys). NC, no chnge; CR, complete response; PR, prtil response; PD, progressive disese.

5 MOLECULAR AND CLINICAL ONCOLOGY 2: , Hensley et l (16,17) investigted docetxel (DOC) + GEM therpy in 42 ptients with uterine LMS. The dverse events were grde 3 neutropeni in 17.0%, grde 3 nemi in 24.0% nd grde thrombocytopeni in 14.5% of the cses. Grde 3 llergic rections nd grde 4 pulmonry toxicity developed in ll the ptients. As regrds effectiveness, the overll response rte ws 35.8% nd the disese control rte ws 62.0%. Perl et l (18) investigted MAID therpy in 23 ptients with gynecologicl srcom, including uterine LMS nd denosrcom. The overll response rte ws 33.3% nd the disese control rte ws 50.0%. The number of studies on IAP therpy for uterine srcom is currently limited. Ymwki et l (6) reported tht IAP ws effective in cse with progressive UES. Ymguchi et l (23) lso reported tht the rte of PR with IAP therpy for uterine srcoms ws 40.0% in the first line nd 9.1% in the second line chemotherpy setting. In this study, IAP therpy chieved n overll response rte of 36.4% nd disese control rte, including NC, of 90.9%. Our results were comprble to those of IFM + ADM or DOC + GEM therpy. The dverse events recorded in the present study were minly hemtologicl, with grde 3 leukopeni nd neutropeni in ll the cses. However, these dverse events were mngeble with dose reduction nd G-CSF dministrtion for severe hemtotoxicity. Only one ptient experienced severe thrombocytopeni requiring pltelet trnsfusion. The medin number of dministered cycles ws 6. There were no severe non-hemtologicl complictions or tretment-relted deths in the present study. In conclusion, tking into considertion the bovementioned findings, IAP therpy my be fesible chemotherpeutic option for progressive or recurrent uterine srcom. Acknowledgements The uthors would like to thnk Ms. Keiko Abe nd Ms. Tomomi Nod for their secretril ssistnce. References 1. 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