ONCOLOGY LETTERS 10: , 2015

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1 3310 Long term tretment of residul or recurrent low grde endometril stroml srcom with romtse inhibitors: A report of two cses nd review of the literture HYEWON RYU, YOON SEOK CHOI, IK CHAN SONG, HWAN JUNG YUN, DEOG YEON JO, SAMYONG KIM nd HYO JIN LEE Division of Hemtology Oncology, Deprtment of Internl Medicine, Chungnm Ntionl University Hospitl, Dejeon , Republic of Kore Received October 25, 2014; Accepted August 17, 2015 DOI: /ol Abstrct. Endometril stroml srcom (ESS) occurs rrely nd ccounts for only 0.2% of ll uterine mlignncies. ESS usully expresses estrogen nd progesterone receptors, nd is regrded s hormone sensitive. Due to the rrity of these tumors, there re only few cse series on the use of romtse inhibitors in the tretment of low grde ESS. The present study reports the cses of two ptients with residul or recurrent low grde ESS who experienced long term disese free survivl following tretment with letrozole. The study lso reviews the literture with regrd to the dt on romtse inhibitors used in ptients with low grde ESS. In totl, 30 ptients with recurrent or residul low grde ESS who were treted with romtse inhibitors were identified, including the present cses. Among the 30 ptients, the overll response rte of dvnced low grde ESS to romtse inhibitors ws 77.4% (complete response, 25.8%; prtil response, 51.6%) nd the disese control rte ws 90.3%. The response rte of first line tretment ws similr to tht of second line therpy or higher (84.6 vs. 72.2%; P=0.453). Durtion of romtse inhibitor tretment rnged from 1.5 to 168 months (medin, 26.5 months). The romtse inhibitors showed miniml dverse effects. In conclusion, romtse inhibitors, prticulrly third genertion drugs, re well tolerted clss of medictions tht re effective in the tretment of dvnced low grde ESS, with fvorble toxicity profile. Correspondence to: Dr Hyo Jin Lee, Division of Hemtology- Oncology, Deprtment of Internl Medicine, Chungnm Ntionl Univeristy Hospitl, 282 Munhw ro, Jung gu, Dejeon , Republic of Kore E mil: cymed@cnu.c.kr Key words: endometril stroml srcom, romtse inhibitor, letrozole, nstrozole Introduction Uterine srcoms re uncommon tumors, ccounting for 2 3% of ll uterine neoplsms (1). Among the uterine srcoms, endometril stroml srcom (ESS) ccounts for 10% of ll tumors, representing ~0.2% of ll uterine mlignncies, with n incidence of ~2 cses per million women per yer (2). The tumors originte from the mesenchyml component of the endometrium nd re chrcterized by prolifertion of cells with endometril stroml (ES) cell differentition. ESS is divided into low nd high grde tumors ccording to cell morphology, mitotic rtes, cellulrity nd the presence of necrosis. Recently, the term 'undifferentited endometril srcom' hs been proposed for the World Helth Orgniztion clssifiction of tumors insted of the term 'high grde endometril stroml srcom' due to the bsence of originl ES components in the tumor type (3,4). The initil tretment of choice for low grde ESS is hysterectomy with bilterl slpingo oophorectomy. The role of djuvnt therpy, such s rdiotherpy, chemotherpy or hormonl tretment, is not fully estblished (5). While the prognosis of low grde ESS is fvorble, with 5 yer overll survivl of >90%, the recurrence free survivl rte is mrkedly lower t ~50% (6,7). Hormonl therpy, such s use of progestins (megestrol cette nd medroxyprogesterone cette), hs been used widely for dvnced nd recurrent ESS, s the mjority of low grde ESS express estrogen receptors (ERs) nd progesterone receptors (PRs) (8). However, progestins cn cuse edem, weight gin, vginl bleeding, hypertension nd thromboembolic problems (9). There re severl necdotl reports of low grde ESS tht responded to romtse inhibitors, prticulrly the third genertion of these drugs, with more fvorble toxicity profiles nd thus wider therpeutic index (6,9). However, due to the rrity of these tumors, there re no prospective or lrge retrospective studies on romtse inhibitor use in the tretment of low grde ESS. The present study reviewed the literture for dt on romtse inhibitor use in ptients with low grde ESS, including dt from the present study on the cses of two ptients with residul or recurrent low grde ESS who

2 RYU et l: AROMATASE INHIBITORS AND ENDOMETRIAL STROMAL SARCOMA 3311 experienced long term disese free survivl following tretment with letrozole. All ptients provided written informed consent to undergo therpy nd publish the current cse report. Cse report Ptient 1. A 51 yer old femle, who presented to Chungnm Ntionl University Hospitl (Dejeon, South Kore) with lower bdominl pin nd vginl bleeding, underwent totl bdominl hysterectomy with bilterl slpingo oophorectomy in August 2007 for presumed denomyosis. The finl histology reveled low grde ESS of the uterus. The tumor immunostining ws strongly positive for ER nd PR (ER: ++, 70%; PR: +, 40%). Positron emission tomogrphy/computed tomogrphy (CT) showed incresed glucose metbolism t the smll nodules in the prescrl spce, rectovginl spce nd right common ilic lymph node. The ptient received pllitive chemotherpy, consisting of three cycles of pclitxel (175 mg/m 2 ) nd cispltin (60 mg/m 2 ) between September nd October 2007, but showed disese progression. In lte November 2007, the ptient underwent secondry debulking surgery, including pelvic lymph node dissection, ppendectomy, prtil omentectomy nd pr ortic lymph node dissection. In December 2007, the ptient ws referred to the Deprtment of Internl Medicine for post opertive letrozole tretment, s follows. A bseline bdominopelvic CT scn reveled smll mount of scites fluid nd peritonel seeding with n incresed cncer ntigen 125 (CA 125) level of 87.7 U/ml (norml rnge, 0 35 U/ml). The ptient ws strted on letrozole t dily dose of 2.5 mg. The CA 125 level normlized fter 1 month of letrozole nd CT scn reveled complete response (CR) fter 3 months of the drug tretment. The ptient hs experienced complete response to this therpy for 80 months, with no significnt drug toxicity. Ptient 2. A 49 yer old femle, who hd known uterine myoms, visited Chungnm Ntionl University Hospitl due to vginl bleeding in August A mgnetic resonnce imging scn of the pelvis reveled two lrge heterogeneous uterine msses. The ptient underwent totl bdominl hysterectomy with bilterl slpingo oophorectomy, pelvic lymph node dissection nd pr ortic lymph node dissection for presumed uterine leiomyosrcom. Histopthologicl exmintion reveled low grde ESS with tumor emboli in the peridnexl soft tissue. An immunohistochemicl profile reveled positivity for ER (++, 80%) nd PR (++, 80%) nd the post opertive CA 125 level ws 65.8 U/ml. Between August nd November 2009, the ptient ws prescribed medroxyprogesterone cette t dily dose of 1,000 mg. The CA 125 level ws normlized fter 2 months of this tretment, with no evidence of disese on bdominopelvic CT scns. However, the ptient discontinued the mediction 1 month lter due to the dverse side effects of weight gin nd hypertension. The ptient ws then strted on 2.5 mg letrozole dily. The ptient hs experienced CR for 57 months, with no dverse events. Literture review Method. For systemtic review, serch ws performed of the English lnguge literture for reports of cses of low grde ESS treted with romtse inhibitors. The systemtic review ws undertken in MEDLINE/PubMed using the key words endometril stroml srcom combined with romtse inhibitor. Seprte serches were then performed for uterine srcom, nd endometril srcom combined with romtse inhibitor. The relevnt studies were exmined nd reviewed, nd ny cited literture tht hd not been identified previously ws lso included nd evluted. Any ptients with high grde ESS were excluded. The primry outcome of this literture review ws to evlute the response rtes of ptients with low grde ESS who were treted with romtse inhibitors. The secondry outcomes included durtion of romtse inhibitor tretment. Tretment outcomes were defined s CR, prtil response (PR), stble disese (SD) or progressive disese (PD), bsed on the Response Evlution Criteri In Solid Tumors (version 1.0) (10). Durtion of romtse tretment ws defined s the intervl from the dte of initition of romtse inhibitor tretment to the dte of discontinution, mortlity or lst follow up. Sttisticl nlysis. Ctegoricl vribles were nlyzed using liner by liner ssocition. For ll nlyses, P<0.05 ws considered to indicte sttisticlly significnt difference. All sttisticl nlyses were conducted using the SPSS softwre (version 17.0; SPSS Inc., Chicgo, IL, USA). Chrcteristics nd tretment outcomes of ptients treted with romtse inhibitors. In totl, 30 ptients with recurrent or residul low grde ESS, who were treted with romtse inhibitors, including the 2 ptients of the present study (ptients 1 nd 2), were identified. Tble I shows the ptient chrcteristics nd tretment outcomes of those individuls with low grde ESS who were treted with romtse inhibitors (11 24). The ge of the ptients t the time of strting romtse inhibitor tretment rnged from 28 to 87 yers (men ge, 53 yers). The durtion of romtse inhibitor tretment rnged from 1.5 to 168 months (medin, 26.5 months). In totl, 3 ptients were dministered more thn one romtse inhibitor (ptients 5, 29 nd 30). Of the 30 ptients, 28 ptient cses hd the outcome recorded. The response rte to romtse inhibitors in the evluble ptients is listed in Tble II. The overll response rte to ll romtse inhibitors ws 77.4% nd the disese control rte ws 90.3% if ptients 5, 29 nd 30 re counted twice, once for ech tretment (n=31). A totl of 8 ptients (25.8%) experienced complete response, 16 (51.6%) experienced prtil response, 4 (12.9%) exhibited stble disese nd 3 (9.7%) experienced progressive disese. Among the romtse inhibitors, letrozole ws most widely used nd ppered to be effective (overll response rte, 85.7%). The ssocition between response rte nd the line of romtse inhibitor tretment ws lso exmined (Tble III). The overll response rte of first line romtse inhibitor tretment (11/13; 84.6%) ws slightly higher thn tht of tretment with romtse inhibitors of second line or higher (13/18; 72.2%), but the difference ws not sttisticlly significnt (P=0.453). Aromtse inhibitors pper to be well tolerted, with remrkbly low incidence of side effects. Only 2 ptients experienced side effects serious enough for discontinution of the romtse inhibitor. Ptient 5 ws treted with minoglutethimide, first genertion romtse inhibitor, nd suffered

3 3312 Tble I. Chrcteristics nd tretment outcomes of low grde ESS ptients treted with AIs. Ptient Age, Systemic therpy Response Durtion of no. (ref) yers prior to AI ER/PR AI to AI AI, months Sttus b 1 51 PC +/+ Letrozole CR 77+ NED /+ Letrozole CR 55+ NED 3 (11) 58 Tmoxifen, MA +/+ Letrozole PR 9 AWD 4 (12) 47 +/+ Aminoglutethimide CR 168+ NED 5 (12) 40 Tmoxifen +/+ Aminoglutethimide PR 39 Letrozole CR 43+ NED 6 (13) 76 +/+ Letrozole PR 36+ AWD 7 (14) 51 BEP, DG +/+ Anstrozole with MA PR 24+ AWD 8 (6) 63 MPA +/+ Letrozole PR 37+ AWD 9 (6) 69 +/+ Letrozole PR 9+ AWD 10 (6) 42 +/+ Letrozole PR 10+ AWD 11 (6) 69 +/+ Letrozole PD n AWD 12 (6) 47 Tmoxifen +/+ Letrozole PR 3+ AWD 13 (15) 56 +/+ Letrozole CR 24+ AWD 14 (16) 61 Tmoxifen, etoposide, n ns n n AWD progestin 15 (16) 65 Etoposide n ns n n AWD 16 (17) 48 +/+ Letrozole PR 39+ AWD 17 (18) 41 Goserelin +/+ Anstrozole CR 108+ AWD 18 (19) 49 MA n Letrozole PR 29+ NED 19 (20) 87 n Letrozole PD n AWD 20 (20) 53 n Letrozole PR 4+ AWD 21 (20) 47 MA -/ Letrozole PR 6+ AWD 22 (21) n +/+ Letrozole CR 88 n 23 (21) n MA +/+ Letrozole PR 124 c n 24 (21) n n Letrozole PR 53 n 25 (22) 59 +/+ Letrozole CR 24+ NED 26 (23) 53 MPA +/+ Anstrozole PR 9 AWD 27 (24) 28 MA +/ Anstrozole SD 70+ AWD 28 (24) 37 MA +/+ Anstrozole SD n AWD 29 (24) 42 MA?/+ Anstrozole PD 1.5 AWD Exemestne PR (24) 44 MA n Anstrozole SD 16 AWD Letrozole SD 10+ Estimted ge t the time of strting romtse inhibitor tretment. b Ptient's sttus when the cse ws reported. c Includes durtion of response to megesterol. Letrozole ws dministered t 2.5 mg dily; minoglutethimide ws dministered t 500 mg four times dy; nstrozole ws dministered t 1 mg dily; nd exemestne ws dministered t 25 mg dily. Ptient 4: Initil minoglutethimide ws discontinued ccording to the ptient's decision following the chievement of CR. Low grde ESS recurrence ws observed, nd following luteinizing hormone relesing hormone nlog use, the initil tretment ws restrted nd CR ws chieved once gin. Ptient 5: Aminoglutethimide ws discontinued due to tretment side effects (stheni nd dirrhe) fter 39 months of PR nd then letrozole ws strted, resulting in CR. Ptient 7 ws dignosed with ESS with sex cord stroml component t the time of hysterectomy. Ptient 18 underwent n nterior exentertion with negtive mrgins, resulting in CR. Ptient 21 ws dignosed with mix of low grde ESS nd undifferentited srcom. Ptient 26 underwent complete resection of the recurrent tumor following PR to nstrozole tretment for 9 months nd subsequently remined progression free for 16 months. AI, romtse inhibitor; ER, estrogen receptor; PR, progesterone receptor; CR, complete response; PR, prtil response; SD, stble disese; PD, progression; NED, no evidence of disese; AWD, live with disese; PC, pclitxel nd cispltin regimen; BEP, bleomycin, etoposide nd cispltin regimen; DG, docetxel nd gemcitbine regimen; MPA, medroxyprogesterone cette; MA, megestrol cette; n, not vilble; ns, not specified;, second tretment. from stheni nd dirrhe. However, the ptient showed CR without side effects over long period once prescribed letrozole, third genertion romtse inhibitor. Ptient 26, who ws treted with nstrozole for 9 months, experienced rthritis with joint dysfunction nd discontinued use of the drug.

4 RYU et l: AROMATASE INHIBITORS AND ENDOMETRIAL STROMAL SARCOMA 3313 Tble II. Response rte to AI in evluble ptients with low grde endometril stroml srcom. AI Best All, n (%) Aminoglutethimide Letrozole Anstrozole Exemestne response (n=31) (n=2) (n=21) (n=7) (n=1) CR 8 (25.8) PR 16 (51.6) SD 4 (12.9) 1 3 PD 3 (9.7) 2 1 Counting ptients 5, 29 nd 30 twice, once for ech tretment. AI, romtse inhibitor; CR, complete response; PR, prtil response; SD, stble disese; PD, progressive disese. Tble III. Response rte to first line (n=13) nd second line or higher (n=18) AIs in evluble ptients with low grde endometril stroml srcom. AI Best First line, Second line or response n (%) higher, n (%) P vlue CR 5 (38.5) 3 (16.7) PR 6 (46.2) 10 (55.6) SD 0 (0.0) 4 (22.2) PD 2 (15.4) 1 (5.6) P vlue ws clculted by comprison of the four groups using liner by liner ssocitions. CR, complete response; PR, prtil response; SD, stble disese; PD, progressive disese. Discussion ESSs re rre tumors tht occur predominntly in premenopusl nd perimenopusl women (25 27). ESSs re indolent tumors nd hve long disese free intervls in the bsence of specific therpies, such s estrogen contining hormone replcement therpy or tmoxifen. The prognosis for low grde ESS is extremely good, with 5 yer survivl rte of >90% (6). However, 40 50% of those individuls with low grde ESS develop recurrent disese, which often occurs yers fter the initil dignosis (17,18). ESS resembles proliferting endometril strom histologiclly, typiclly expressing ERs nd PRs, nd is regrded s hormone sensitive. Aromtse inhibitors, progesterone nd gondotropin relesing hormone gonists hve ll been suggested s uterine srcom tretments. Progestins re the most widely used gents for the tretment of dvnced nd recurrent ESS (8). Progestins inhibit estrogen medited growth fctors, downregulte the ER nd increse estrogen metbolism nd clernce, thereby decresing the effects of estrogen on ER positive cells. Although progestins re n effective mediction, they lso exhibit vrious dverse side effects, including weight gin, depression nd thromboembolic events (9). Aromtse inhibitors hve been used in the tretment of brest cncer nd re potentil tretment for ESS. Aromtse inhibitors decrese levels of estrogen by peripherlly inhibiting estrogen synthesis. First genertion (minoglutethimide) nd second genertion (formestn nd fdrozole) romtse inhibitors were non specific non steroidl romtse inhibitors, which exhibited serious side effects due to the inhibition of minerlocorticoid nd glucocorticoid synthesis (9). The third genertion non steroidl romtse inhibitors exemestne nd letrozole, nd the steroidl romtse inhibitor nstrozole, exhibit miniml effects on the drenl glnds nd cn be orlly dministered. Severl cse studies hve been published with regrd to the efficcy of the romtse inhibitors minoglutethimide, letrozole, nstrozole nd exemestne in the tretment of dvnced low grde ESS (20,27). However, no systemic systemtic reviews or prospective studies on romtse inhibitor tretment for ESS hve been published. In the literture review of romtse inhibitor tretment in ptients with low grde ESS in the present study, the overll response rte ws 77.4% nd the disese control rte ws 90.3%. Additionlly, romtse inhibitors showed similr tumor responses in the second line or higher tretment setting compred with first line therpy. Furthermore, romtse inhibitors, prticulrly third genertion letrozole, which is the most widely used romtse inihibitor, re well tolerted during long term tretment. Together, these dt suggest tht romtse inhibitors re effective for the tretment of low grde ESS nd exhibit fvorble toxicity profile. The present study reports the cses of two ptients with residul or recurrent low grde ESS who experienced long term disese free survivl following tretment with letrozole. Aromtse inhibitors, prticulrly the third genertion drugs, re well tolerted clss of medictions tht re effective for the tretment of ESS with miniml dverse effects nd thus higher therpeutic window. However, given the rrity of these tumors, dt from lrge, prospective rndomized trils re lcking. To ddress these issues, lrge, multicenter, prospective tril is required. References 1. Olh KS, Gee H, Blunt S, Dunn JA, Kelly K nd Chn KK: Retrospective nlysis of 318 cses of uterine srcom. Eur J Cncer 27: , 1991.

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