PROGNOZA JUINGOVOG (EWING) SARKOMA U ZAVISNOSTI OD PRIMEWENOG LEČEWA
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1 RADOVI BIBLID: , 134(2006) 9-10, p UDC: PROGNOZA JUINGOVOG (EWING) SARKOMA U ZAVISNOSTI OD PRIMEWENOG LEČEWA Vladan STEVANOVIĆ 1, Zoran VUKAŠINOVIĆ 1, Duško SPASOVSKI 2 1 Institut za ortopedsko-hirurške bolesti Bawica, Beograd; 2 Institut za ortopedsku hirurgiju i traumatologiju, Klinički centar Srbije, Beograd KRATAK SADRŽAJ Juingov sarkom je po broju obolelih drugi primarni maligni tumor dečjeg uzrasta. Oko 80 bolesnika se dijagnostikuje sa lokalizovanom formom bolesti, a 20 u momentu dijagnostikovawa ima prisutne i metastaze. Na posmatranom materijalu analizirana je vrsta primewenog terapijskog protokola, uticaji različitih postavqenih kriterijuma na prognozu bolesti, opšte preživqavawe i preživqavawe do pojave recidiva, odnosno metastaza. Prognostički parametri ukqučivali su uzrast, pol, lokalizaciju tumora, vrstu resekcije, vrstu primewenog hemioterapijskog protokola, odgovor na neoadjuvantnu hemioterapiju, kao i histopatološke karakteristike tumora. Utvrđeno je da se primenom široke hirurške resekcije prognoza bolesti značajno poboqšava (χ 2 =7,855; p<0,05) i da je statistički značajno različit stepen nekroze (t=2,214; p<0,05) u odnosu na ishod bolesti. Savremeno lečewe Juingovog sarkoma ukqučuje korišćewe polivalentne hemioterapije kao dopune terapije zračewem, odnosno hirurškog tretmana primarnog tumora. Bolesnici su posmatrani u periodu od završetka adjuvantne hemioterapije do posledwe kontrole, uz određivawe perioda remisije, odnosno momenta ponovne pojave osnovne bolesti, bilo u formi recidiva ili pak pojave metastaza. Najpovoqniju prognozu pokazuju lokalizacije na distalnim delovima ekstremiteta i aksijalnom skeletu. Proksimalni delovi ekstremiteta, a naročito karlični pojas, metastatska bolest i loš odgovor na hemioterapijsko lečewe povezani su sa nepovoqnijim ishodom bolesti. Prognozirawe dobrog ishoda bolesti je kod ovog patoanatomskog supstrata veoma delikatan proces. Kqučne reči: Juingova porodica tumora; prognoza ishoda bolesti; vrsta lečewa UVOD Juingov sarkom je maligni tumor koji se javqa u dečjem uzrastu. Karakterističan je po relativno kasnom postavqawu dijagnoze, a pitawe wegove terapije i daqe ostaje otvoreno. Naime, i po prevazilažewu prve prepreke u wegovom lečewu, pravovremene i tačne dijagnostike bolesti, nameće se potreba za bližim određewem zavisnosti prognoze bolesti od vrste primewenog lečewa. Takođe, ispitivawe te zavisnosti može uticati na poboqšawe indikacione odrednice pojedinačnih sastavnih delova terapijskih protokola, a sve u ciqu veće efikasnosti lečewa i obezbeđivawa što povoqnije prognoze ishoda ove teške bolesti. U lečewu Juingovog sarkoma primewuju se tri vrste terapijskih procedura. To su hemioterapija, radijaciona terapija i hirurško lečewe. Kako svaki od navedenih vidova lečewa ima svoja ograničewa i loše strane, savremeni pristup ih sa varijabilnim uspehom kombinuje u okvirima različitih terapijskih protokola. Hemioterapija Juingovog sarkoma Najranija ispitivawa adjuvantne hemioterapije u terapiji Juingovog sarkoma započeta su sredinom šezdesetih godina prošlog veka. Razvoj multimodalne terapije bolesti tokom posledwih 30 godina rezultirao je očekivawima da oko 50 bolesnika sa lokalizovanim tumorom može biti izlečeno. Ipak, čak i uz primenu najintenzivnijeg režima terapije izleči se mawe od trećine bilesnika sa metastaskom bolešću pri dijagnostikovawu [1]. Iako se lokalna i sistemska terapija mogu nezavisno razmatrati, nesumwivo je da su one međusobno zavisne, u tom smislu da sistemska hemioterapija može poboqšati stepen lokalne kontrole bolesti, a neuspeh kontrole lokalizovane bolesti obično vodi ka udaqenim recidivima bolesti. Uspešno lečewe bolesnika sa Juingovim tumorom zahteva korišćewe polivalentne hemioterapije kao dopune terapije zračewem, odnosno hirurškog tretmana primarnog tumora. Većina bolesnika koja metastatske promene ima prilikom dijagnostikovawa bolesti dobro odgovara na hemioterapiju, kojom se pak metastatsko oboqewe uglavnom ne može u potpunosti kontrolisati, niti se može sprečiti pojava recidiva [1-6]. Savremeni hemioterapijski režimi ukqučuju VAC-doksorubicin, zračewe čitavog tela sa transplantacijom autologne kostne srži, kao i korišćewe ifosfamida i etopozida u terapiji. Dobar odgovor kod dve trećine bolesnika sa rekurentnim Juingovim sarkomom, postignut primenom režima ifosfamida (I) i etopozida (E), doveo je do studije o kombinovanoj primeni IE sa VAC-doksorubicinom. Granulocitno-monocitni faktor stimulacije kolonija (GM-CSF) ukqučen je u terapiju radi umawewa trajawa i stepena neutropenije u protokolu VAC-doksorubicin-IE. Razlog za to su febrilnost i neutropenija prouzrokovani IE kombinacijom, koji su kod više od 50 bolesnika uslovili odlagawe terapije i smaweni dozni intenzitet [7-10]. Radijaciona terapija Juingovog sarkoma Stepen lokalne kontrole bolesti zračnom terapijom kao prvog izbora lečewa varirao je od 55 do 420
2 90 [11-13]. Ovakva varijabilnost posledica je više faktora ne iskqučivo razlike u načinu primene i dozirawa, već i načina na koji se vrši evaluacija lokalnog recidiva u periodu sistemskog širewa bolesti. Poznati faktori koji zavise od tumora prilikom dijagnostikovawa ukqučuju veličinu lezije i wenu lokalizaciju. Lečewe tumora većih od 8-10 cm u prečniku i tumora centralnog (aksijalnog) skeleta, poput karličnog prstena, mawe je uspešno lokalnom kontrolom bolesti [14, 15]. Tehnika radioterapije takođe znatno utiče na lokalnu kontrolu bolesti. Najmawe zahtevni savremeni standardi tretmana podrazumevaju megavoltažnu opremu i kompjuterizovano planirawe terapije u centrima sa bogatim iskustvom lečewa ove bolesti. Skorašwe studije (Pediatric Oncology Group POG) pokazale su da za lokalnu kontrolu tumora nije od značaja to da li se zrači cela kost ili samo poqe tumorom zahvaćene kosti i okolne mekotkivne komponente tumora sa graničnom zonom od 2 cm, označeno na CT/MR pre hemioterapije. Zračna terapija se ne preporučuje bolesnicima kod kojih ne postoje znaci mikroskopski rezidualnog tumora nakon hirurške resekcije [14]. U slučajevima u kojima je za bolesnika funkcionalni deficit neprihvatqiv i u kojima se nakon hirurške resekcije dobijaju nezadovoqavajuće, kontaminirane granice, ona se još uvek primewuje na tumorima lokalizovanim na mestima gde je totalna resekcija neizvodqiva [13-15]. Hirurško lečewe Juingovog sarkoma Razvoj savremenih tehnika rekonstruktivne hirurgije proširio je indikaciono područje za hirurški pristup u kontroli primarnog tumora. Kod većeg broja bolesnika tumor se javqa u osovinskom skeletu ili na kostima gde je otežana resekcija, tako da je, istorijski gledano, mali broj wih uziman u obzir za hirurško lečewe, to jest za resekciju koja bi rezultirala lokalnom kontrolom bolesti i očuvawem funkcija ekstremiteta. Otkriveno je da inicijalni odgovor na hemioterapiju može omogućiti kompletno odstrawewe prethodno neresektabilne lezije [1, 11, 18, 27]. Premda su mnoge studije ukazale na boqe nalaze bolesnika kod kojih je primewena hirurška resekcija kao glavni metod lokalne kontrole wihove bolesti, još uvek je teško potvrditi doprinos hirurške procedure wihovom preživqavawu. Požeqno je da preduslov za vršewe hirurške resekcije budu povoqni prognostički faktori bolesnika, kakve ima tumor male veličine na distalnim lokacijama. U velikom broju slučajeva hirurški postupak je primarni modalitet lokalne kontrole bolesti. To važi i za primarne tumore na kostima, dostupne resekciji: klavikulu, telo skapule, male, dobro ograničene promene na ilijačnoj kosti, proksimalnu fibulu, tumore lokalizovane na kostima dečjih ekstremiteta, na kojima radijaciona terapija može zahvatiti jednu od većih zona rasta. Hiruršku ablaciju primarnog tumora bi u većini slučajeva trebalo odložiti do završetka indukcione hemioterapije. U pređašwem, tradicionalnom iskustvu, patološki prelom je bio indikacija za pristupawe amputaciji. Međutim, ipak je u ciqu zarastawa kosti pre primene radioterapije moguće bolesnika sa patološkim prelomom lečiti indukcionom hemioterapijom [2-4, 11, 18-22]. Lečewe metastatskog oblika Juingovog sarkoma Prognoza ishoda metastaske bolesti nije povoqna. Standardna terapija naizmenična primena vinkristina, doksorubicina, ciklofosfamida i ifosfamida, odnosno etopozida, zatim radijaciona terapija na svim mestima makroskopski prisutnog tumora i, u slučajevima Juingovog tumora kosti i ekstrosalnog Juingovog sarkoma, selektivna hirurška resekcija dovodi do kompletnog ili parcijalnog odgovora. Ipak, ukupni procenat izlečewa je 20. Mogućnost izlečewa bolesnika sa iskqučivo plućnim, odnosno pleuralnim metastazama, procentualno gledano, iznosi oko 30. Oboleli koji nisu podvrgnuti zračewu pluća imali su lošije prognoze ishoda bolesti od onih kojima su zračena i pluća. Stopa izlečewa od bolesti sa metastazama u kostima, odnosno u kostnoj srži, kreće se u opsegu 20-25, dok se kod oboqewa sa kombinovanim plućnim i koštanim metastazama ona spušta na 15. Intenzivnijim terapijskim procedurama, kojima je obuhvaćena visokodozna hemioterapija sa ili bez zračewa celog tela zajedno sa potporom stem ćelije, kod bolesnika sa koštanim metastazama nije postignuto poboqšawe u pogledu stepena preživqavawa bez manifestacija bolesti. S druge strane, wihov uticaj na bolesnika sa plućnim metastazama je za sada nepoznat. Transplantacija alogene stem ćelije nije povoqnije uticala na ishod bolesti od transplantacije autogene stem ćelije, a, sem toga, i tehnika wene primene bila je povezana sa višim stepenom komplikacija [23-25]. Lečewe recidiva Juingovog sarkoma Prognoze koje se odnose na bolesnike sa recidivom Juingove porodice tumora takođe su nepovoqne. Međutim, one su boqe ukoliko je do pojave recidiva došlo nakon okončawa hemioterapije, a ne na wenom početku. Odabir daqeg tretmana zavisi od više faktora, među kojima su svakako mesto recidiva, prethodno lečewe i individualno stawe bolesnika. Ifosfamid i etopozid su aktivni kod Juingove porodice tumora i wihovu primenu treba razmotriti u lečewu bolesnika koji ih nisu dobijali. Agresivniji metodi koji se u tom smislu koriste su mijeloblastni režimi. Radijaciona terapija je palijativna, a od hirurških procedura pristupa se plućnim metastazektomijama [26]. CIQ RADA Ciq rada je definisawe validnih prognostičkih faktora u okvirima parametara primewene te- 421
3 rapije Juingovog sarkoma i utvrđivawe stepena wihovog uticaja na prognozu bolesti. METOD RADA U ovoj studiji prikupqeni su podaci o 78 obolelih od Juingovog sarkoma (porodice Juingovih tumora), u periodu od do godine lečenih na Institutu za ortopedsko-hirurške bolesti Bawica u Beogradu. Dijagnoze svih bolesnika bile su patohistološki verifikovane na Institutu za patologiju Medicinskog fakulteta u Beogradu [27-30]. Lečewe bolesnika ukqučenih u ovu studiju obuhvatalo je primenu neoadjuvantne hemioterapije posle biopsije, hiruršku resekciju tumora i adjuvantnu hemioterapiju za sistemsku kontrolu bolesti, odnosno radioterapiju u slučaju kontaminiranih granica nakon hirurške resekcije. Upotreba radioterapije uz resekciju tumora za kontrolu lokalizovane bolesti napuštena je u prvoj polovini osamdesetih godina i primewivana je u onim indikacijama koje se i danas opisuju u literaturi (kontaminirane hirurške granice, neresektabilnost tumora, metastatska bolest). Hemioterapija i zračna terapija primewivani su na Odeqewu pedijatrije Instituta za onkologiju i radiologiju Kliničkog centra Srbije, prema standardnim protokolima preporučenim od strane više svetskih onkoloških centara, a na osnovu rezultata multicentričnih studija i preporuka EI-CESS (T 11; VACA, VAIA i EVAIA). Odgovor na hemioterapiju nakon biopsije kontrolisan je kliničkim pregledom (smawewe veličine tumorske mase) i dostupnim, objektivnim metodima primewivanim i preoperativno (CT ili MRI odgovarajuće regije). Kada je to bilo moguće, kao parametar odgovora na neoadjuvantnu terapiju određivan je stepen nekroze tumora nakon hirurške resekcije. Evidentirani su parametri primewenog lečewa (karakteristike hirurških granica nakon resekcije, neoadjuvantna i adjuvantna hemioterapija u tretmanu sistemske bolesti, stepen nekroze nakon neoadjuvantne hemioterapije), kao i relevantni kliničko-dijagnostički parametri dobijeni nakon toga što je lečewe završeno i dijagnoza patohistološki potvrđena praćewem stawa bolesnika. Određeni su parametri na osnovu kojih se može govoriti o povoqnoj ili nepovoqnoj prognozi bolesti, a zatim je izvršena analiza uticaja na prognozu bolesti onih parametara vezanih za način primewenog lečewa Juingovog sarkoma. Za prognostičke kriterijume su na bazi referentne literature uzeti: uzrast i pol bolesnika, veličina tumora, lokalizacija tumora u muskuloskeletnom sistemu, karakteristike kliničkog pregleda, vrsta hirurške resekcije, metastaska bolest prilikom dijagnostikovawa, primewen režim hemioterapije i odgovor na neoadjuvantnu hemioterapiju, kao i histopatološke karakteristike i biološko ponašawe tumora. Na osnovu toga su za parametre nepovoqne prognoze ishoda bolesti definisani: muški pol, starost obolelih iznad 12 godina, febrilno stawe u kliničkom nalazu, ubrza- na sedimentacija, patološki prelom i pojava metastaza (na kostnom ili plućnom tkivu) prilikom dijagnostikovawa Juingovog sarkoma, lokalizacija tumora u aksijalnom skeletu (kičmenom stubu, karlici), lokalizacija tumora u proksimalnom delu dugih kostiju, tip hirurške resekcije (intraleziona, marginalna), odgovor tumora na hemioterapiju (stepen nekroze tumora ispod 90 nakon neoadjuvantne hemioterapije), pojava recidiva ili metastaza nakon završenog lečewa. Izvršena je analiza uticaja ovako definisanih terapijskih parametara na prognozu ishoda bolesti. Materijal je obrađen standardnim statističkim metodima, korišteni su χ 2 -test, Studentov t-test, korelacija i logistička regresiona analiza kao metod kojim je testiran značaj odabranih epidemioloških i kliničkih faktora na prognozu bolesti. TABELA 1. Trajawe remisije bolesti kod obolelih od Juingovog sarkoma (meseci). TABLE 1. Remission period in patients with Ewing s sarcoma (months). Maksimum Maximum Sredwa vrednost Mean value Standardna devijacija Standard deviation Broj bolesnika Number of patients (33.3) TABELA 2. Trajawe posmatrawa obolelih od Juingovog sarkoma bez manifestacija bolesti. TABLE 2. Follow-up period in patients with Ewing s sarcoma without manifestations of disease. Maksimum Maximum Sredwa vrednost Mean value Standardna devijacija Standard deviation Broj bolesnika Number of patients REZULTATI Kod 26 od 78 bolesnika sa Juingovim sarkomom (33) došlo je do pojave recidiva bolesti u prosečnom periodu od 22,8 meseci (Tabela 1), dok se kod 52 wih (66,7) recidivi bolesti od završetka terapije do posledwe kontrole nisu javili u prosečnom periodu od 54,5 meseci (Tabela 2). Maksimalno praćewe bez manifestacija osnovne bolesti trajalo je 189 meseci. Vrsta hirurške resekcije (marginalna, široka ili radikalna), primewena kao rezultat tehnika limb salvage ili amputacione hirurgije, pokazala se kao dobar prognostički faktor ishoda bolesti (Tabela 3). Statističkom analizom potvrđeno je da se u zavisnosti od vrste izvršene resekcije prognoza bolesti značajno razlikuje (χ 2 =7,855; p<0,05). Ukup (66.7) 422
4 no 56,5 (13 od 23 bolesnika sa širokim tipom resekcije) učiwenih širokih hirurških resekcija koje su dovele do povoqnog ishoda bolesti ukazuju na to da se najboqi rezultati u lečewu postižu upravo tim tipom intervencije. Neoadjuvantna i adjuvantna hemioterapija korištene su u kontroli sistemske bolesti (Tabela 4). Na 74 bolenika primewena je hemioterapija, pri čemu je za 27,0 wih postojala nepovoqna prognoza bolesti u slučaju primene neoadjuvantne i adjuvantne hemioterapije, a za 54,0 nepovoqna predviđawa odnosila su se samo na primenu neoadjuvantne hemioterapije nakon biopsije lezije. Nije uočena statistički značajnija razlika prognoza bolesti u odnosu na vrstu primewene hemioterapije. Analizom dobijenih podataka utvrđeno je da je veći broj bolesnika imao lošu prognozu bolesti. Međutim, radioterapija se ne može posmatrati kao izolovani prognostički faktor, budući da je upotreba bila ograničena na neresektabilne lezije, tumore sa kontaminiranim granicama nakon resekcije, recidive tumora i metastaske promene (Tabela 5). Nije zabeležena statistički značajna razlika prognoza bolesti u zavisnosti od vrste primewene zračne terapije. DISKUSIJA U našem istraživawu najzastupqeniji tip hirurške resekcije bila je široka resekcija, postignuta kod 54,8 bolesnika. Ređe se pristupalo marginalnoj (30,9) i radikalnoj proceduri (14,3). Intralezionih hirurških resekcija nije bilo. Multivarijaciona analiza u radu Karija (Carrie) i saradnika pokazala je da je niži uzrast pri dijagnostikovawu udružen sa poboqšanim petogodišwim preživqavawem bolesnika. Ahmad i sarad- TABELA 3. Prognoza bolesti obolelih od Juingovog sarkoma u zavisnosti od tipa hirurške resekcije tumora. TABLE 3. Prognosis in relation to the type of surgical resection in patients with Ewing s sarcoma. Tip hirurške resekcije Type of surgical resection Marginalna Marginal Široka Wide Radikalna Radical χ 2 =7.885; p<0.05 TABELA 5. Prognoza bolesti obolelih od Juingovog sarkoma u zavisnisti od vrste primewene radioterapije. TABLE 5. Prognosis in relation to the type of radiotherapy in patients with Ewing s sarcoma. Radioterapija Radiotherapy Preoperaciona i postoperaciona Preoperative and postoperative Preoperaciona Preoperative Postoperaciona Postoperative p>0.05 Povoqna Favorable Povoqna Favorable Prognoza Prognosis Nepovoqna Unfavorable Prognoza Prognosis Nepovoqna Unfavorable TABELA 4. Prognoza bolesti obolelih od Juingovog sarkoma u zavisnisti od vrste primewene hemioterapije. TABLE 4. Prognosis in relation to the type of chemotherapy in patients with Ewing s sarcoma. Vrsta hemioterapije Type of chemotherapy Neoadjuvantna i adjuvantna Neoadjuvant and adjuvant Neoadjuvantna Neoadjuvant p>0.05 Povoqna Favorable Prognoza Prognosis Nepovoqna Unfavorable
5 nici su došli do zakqučka da su bolesnici kod kojih je izvršena široka hirurška resekcija imali povoqniju prognozu od onih kod kojih se nije pristupilo hirurškom lečewu, te je predloženo da hiruršku resekciju treba razmotriti za sve bolesnike sa ekstraskeletnim Juingovim sarkomom. Veličina tumora i prisustvo metastaza na početku bolesti nisu se u wihovoj studiji iskazali kao značajni prognostički faktori [27]. Ozaki (Ozaki) sa saradnicima [28] je na Univerzitetu Vestfališe Vilhelms u Munsteru ispitao značaj kontaminiranosti granica nakon hirurške resekcije u lokalnoj kontroli Juingovog sarkoma. Hirurške granice bile su distribuirane po sledećem principu: radikalna hirurška resekcija 11,9 bolesnika, široka resekcija 60,7, marginalna resekcija 15,9 i intraleziona procedura 11,5 bolesnika. Rezultati su pokazali da je stepen lokalnog ili kombinovanog recidiva (uz metastaze) nakon hirurške resekcije bio statistički značajno niži od onih slučajeva u kojima se u lokalnoj kontroli pribegavalo iskqučivo radioterapiji. Stepen lokalnog ili kombinovanog recidiva nakon kompletne resekcije (radikalna ili široka resekcija), upoređen sa onim nakon izvršene inkompletne resekcije (marginalne ili intralezione procedure), bio je niži. Desetogodišwe preživqavawe bolesnika sa određenim tipom hirurških granica bilo je u sledećem odnosu: radikalna resekcija 58 bolesnika, široka resekcija 65, marginalna resekcija 61, intraleziona resekcija 71 bolesnika (bez statističkog značaja). Navedeni autori [28] su zakqučili da kod bolesnika sa Juingovim sarkomom hirurška terapija doprinosi pouzdanosti lokalne kontrole bolesti. Uz terapijski režim sa intenzivnom hemioterapijom i radioterapijom, kompletna resekcija tumora uspešno umawuje rizik od pojave lokalnog recidiva. Histološki odgovor na preoperativnu hemioterapiju i veličina primarnog tumora najvažniji su klinički faktori u pokazivawu ishoda hirurškog lečewa nemetastatskog Juingovog sarkoma. Ove indikatore treba koristiti u otkrivawu bolesnika kojima preti visok rizik pojave metastaza, pošto bi oni mogli biti podvrgnuti intenzivnijem ili novom terapijskom režimu. Stepen nekroze nakon neoadjuvantne hemioterapije u našoj studiji iskazao je vrednosti od 5 do 100, a prosečna wegova vrednost iznosila je 54,35. U studiji Vundera (Wunder) i saradnika [29] histološki odgovor na hemioterapiju stepenovan je na sledeći način: gradus I tumor nekroza od 50 ili mawe; gradus II nekroza veća od 50, ali mawa od 90; gradus III nekroza u opsegu 90-99; gradus IV 100 nekroza tumora. I u toj studiji je primećena povezanost rizika pojave recidiva sa karakterom hirurških granica. U našoj studiji smo definisali veći broj parametara udruženih sa nepovoqnom prognozom ishoda bolesti. O Konor (O Connor), Bači (Bacci), Rosito (Rosito), Oberlin (Oberlin), Koteril (Cotterill), Paulusen (Paulussen), Piči (Picci) [10, 27, 30] dokazali su da na prognozu nemetastatskog Juingovog sarkoma utiču različita klinička i hematološka obeležja. Sva ta obeležja nužno treba uzeti u obzir pri grupisawu bolesnika prema riziku pojave recidiva. Kod hirurški tretiranih bolesnika najznačajniji prognostički faktor je hemioterapijom indukovana nekroza. Ustanovqeni su mnogi parametari udruženi sa lošom prognozom: muški pol, starost iznad 12 godina, febrilnost, anemija, visok nivo laktata dehidrogenaze, aksijalna lokalizacija, radijaciona terapija za lokalnu kontrolu bolesti, tip hemioterapijskog protokola i visok procenat hemioterapijom indukovane nekroze. 66,7 bolesnika obuhvaćenih našim istraživawem bilo je bez znakova osnovne bolesti na posledwoj kontroli, a do pojave recidiva, odnosno metastatske bolesti došlo je kod 33,3 obolelih. Ni kod jednog bolesnika nije zapažena pojava sekundarnog maligniteta nakon završetka lečewa Juingovog sarkoma. Prosečan period posmatrawa bolesnika u istraživawu Bačija i saradnika [22] trajao je devet godina. U toj studiji je 43 bolesnika sa lokalizovanom bolešću, tretiranih adjuvantnom i neoadjuvantnom hemioterapijom, konstantno bilo bez znakova bolesti, a 53 je razvilo metastatsku bolest, odnosno lokalni recidiv, dok je kod 2 došlo do pojave sekundarnog maligniteta. Kod 24 obolelih metastaze, odnosno lokalni recidiv, pojavili su se tri godine po početku terapije. Do pojave recidiva nakon završenog lečewa došlo je kod 33,3 obolelih od Juingovog sarkoma obuhvaćenih našom studijom. Shodno vrsti terapije, boqi rezultati postignuti su hirurškim tretmanom i hemioterapijom sa četiri leka (vinkristin, ciklofosfamid, adriamicin, daktinomicin) nego lečewem primarnog tumora radioterapijom i hemioterapijom sa samo tri leka. Takođe, Aparačo (Aparacio) i saradnici su godine u retrospektivnoj analizi 116 obolelih od Juingovog sarkoma ustanovili da je prosečno vreme za pojavu recidiva iznosilo 24 meseca. Petogodišwi period preživqavawa procewen je na 37,4, a desetogodišwi na 33,3. Oboleli podvrgnuti hirurškom lečewu imali su boqu stopu preživqavawa od onih koji nisu operisani. I u ovoj se studiji potvrdilo da su povišeni nivoi LDH, hipoalbuminemija i metastaze prilikom dijagnostikovawa nezavisni prognostički faktori. Preživqavawe obolelih sa ekstraosalnom lokalizacijom tumora u našoj studiji je u proseku iznosilo 16,6 meseci. Ahmad i saradnici su godine u retrospektivnoj studiji analizirali 24 obolela od Juingovog sarkoma. Oni su za svakog bolesnika dokumentovali podatke o anatomskoj lokalizaciji i veličini tumora, uzrastu obolelog, hirurškim granicama i režimu primewene hemioterapije ili dozi primewenog zračewa. Stopa petogodišweg preživqavawa bolesnika u wihovoj studiji iznosila je 61. Multivarijantnom regresionom analizom utvrđeno je da je niži uzrast prilikom dijagnostikovawa bolesti udružen sa boqim petogodišwim preživqavawem. Takođe, kod bolesnika na kojima je izvršena široka resekcija ispoqena je viša stopa 424
6 preživqavawa nego kod nepodrvgnutih hirurškoj terapiji. S tim u skladu, Ahmad i saradnici zakqučili su da su uzrast i hirurški tretman važni prognostički faktori u terapiji ekstraskeletnog Juingovog sarkoma, kao i to da lečewe hirurškom resekcijom treba razmatrati u svim slučajevima ekstraosalne forme ovog tumora. ZAKQUČAK Hirurška resekcija kao metod izbora u kontroli lokalizovane bolesti od izuzetne je važnosti u terapiji Juingovog sarkoma. Statističkom analizom je potvrđeno da se u odnosu na vrstu resekcije prognoza značajno razlikuje (χ 2 =7,855; p<0,05). Najboqi rezultati postizani su resekcijom širokog tipa, to jest u 55,0 učiwenih širokih hirurških resekcija ishod bolesti bio je povoqan. Odgovor tumora na preoperativnu, odnosno indukcionu hemioterapiju daje bitne nagoveštaje o ishodu bolesti. Naša analiza je pokazala da je statistički značajna zavisnost stepena nekroze od prognoze bolesti kao obeležja posmatrawa (t=2,214; p<0,05). Logistička regresija postavqena prema dobrom, odnosno lošem ishodu bolesti kao obeležju posmatrawa, pruža odgovore na pitawa o mogućnosti i pouzdanosti predviđawa ishoda na osnovu znawa o lokalizaciji tumora (generalnog), uputnoj dijagnozi i stepenu hirurške resekcije nakon biopsije. u 68,42 slučajeva se na osnovu ova tri poznata kriterijuma može dati pouzdana prognozu. Nijedan od predloženih parametara nije sam po sebi dovoqno značajan da ima prediktorsku ulogu, ali u interakciji sa ostalima daje veoma kvalitetan prognostički indeks. Od ukupnog broja loših ishoda 84,62 wih moglo se unapred prognozirati, a od ukupnog broja dobrih ishoda prognozirano je tačno 33,33. Prognozirawe dobrog ishoda ovog patoanatomskog supstrata veoma je delikatan proces. LITERATURA 1. Paulussen M, Ahrens S, et al. On behalf of European Intergroup Cooperative Ewing sarcoma Studies. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. Ann Oncol 1998; 9(3): Horowitz ME. Ewing s sarcoma: Current status of diagnosis and treatment. Oncol 1989; 3: Horowitz ME, Tsokos MG, DeLaney TF. Ewing s Sarcoma. CA Cancer J Clin 1992; 42(5): Donaldson S, Shuster J, Andreozzi C. The Pediatric Oncology Group (POG) experience in Ewing s sarcoma of bone. Med Pediatr Oncol 1989; 17: Kissane JM, Askin FB, Foulkes M, et al. Ewing s sarcoma of bone: clinicopathologic aspects of 303 cases from the Intergroup Ewing s Sarcoma Study. Hum Pathol 1983; 14: Wilkins RM, Prithcard DJ, Burgert EO, et al. Ewing s sarcoma of bone: Experience with 140 patients. Cancer 1986; 58: Meyers PA, Krailo MD, Ladanyi M, et al. High dose melphalan, etoposide, total body irradiation and autologous stem cell reconstitution as consolidation therapy for high risk Ewing s sarcoma does not improve prognosis. J Clin Oncol 2001; 19(11): Womer RB, Daller RT, Fenton JG, et al. Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing s sarcomas and soft tissue sarcomas in children. Eur J Canc 2000; 36(1): Womer RB, Daller RT, Fenton JG, et al. Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatmen of Ewing s sarcoma and soft tissue sarcomas in children. Eur J Canc 2000; 36(1): Oberlin O, Deley MC, Bui BN, et al. French Society of Paediatric Oncology: Prognostic factors in localized Ewing s tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 2001; 85(11): Horowitz M.E, Neff J.R, Kun L.E. Ewing s sarcoma: Radiotherapy versus surgery for local control. Pediatr Clin North Am 1991; 38: Sailer SL. The Role of Radiation Therapy in Localized Ewing s Sarcoma. Semin Radiat Oncol 1997; 7(3): Dunst J, Jurgens H, sauer R, et al. Radiation therapy in Ewing s sarcoma: an update of the CESS 86 trial. Int J Rad Oncol 1995; 32(4): Paulussen M, Ahrens S, Braun-Munzinger G. [EICESS 92 (European Intergroup Cooperative Ewing s Sarcoma Study) preliminary results]. Klin Padiatr 1999; 211(4): Jurgens H, Gadner H, Gobel U, et al. Update of the Cooperative Ewing s sarcoma Studies (CESS) of the German Society of Pediatric Oncology (GPO). Med Pediatr Oncol 1989; 17: Malawer M.M, Henshaw R.M, Shmookler B.M. Principles of orthopaedic oncology. In: Dee R, Editor. Principles of orthopaedic practice. New York: McGraw Hill; p Sanders J, Glader B, Cairo M, et al. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 1997; 99(1): Scully SP, Temple HT, O Keefe RJ, et al. Role of surgical resection in pelvic Ewing s sarcoma. J Clin Oncol 1995; 13(9): Terek RM, Brien EW, Marcove RC, et al. Treatment of femoral Ewing s sarcoma. Cancer 1996; 78(1): Ayob KS, Fiorenza F, Grimer RJ, et al. Extensibile endoprotheses of the humerus after resection of bone tumors. J Bone Joint Surg 1999; 81(3): Scully SP, Temple HT, O Keefe RJ, et al. Role of surgical resection in pelvic Ewing s sarcoma. J Clin Oncol 1995; 13: Bacci G, Toni A, Avella M, et al. Long term results in 144 localized Ewing s sarcoma patients treated with combined therapy. Cancer 1989; 63: Cangir A, Vietti TJ, Gehan EA, et al. Ewing s sarcoma metastatic at dignosis: results and comparisons of two intergroup Ewing s sarcoma studies. Cancer 1990; 66(5): Pinkerton CR, Bataillard A, Guillo S, et al. Treatment strategies for metastatic Ewing s sarcoma. Eur J Canc 2001; 37(11): Paulussen M, Ahrens S, Craft AW, et al. Ewing s tumors with primary lung metastases: survivals analysis of 114 (European Intergroup) Cooperative Ewing s Sarcoma Studies patients. J Clin Oncol 1998; 16(9): Hayes FA, Thompson EI, Kumar M, et al. 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7 EWING S SARCOMA IN CHILDREN: PROGNOSIS IN RELATION TO THE METHOD OF TREATMENT Vladan STEVANOVIĆ 1, Zoran VUKAŠINOVIĆ 1, Duško SPASOVSKI 2 1 Institute of Orthopedic Surgery Banjica, Belgrade; 2 Institute of Orthopedic Surgery and Traumatology, Clinical Center of Serbia, Belgrade ABSTRACT Ewing s tumor of bone is the second primary malignant bone tumor. Localized lesion is found in nearly 80 of cases and metastatic lesions are present in 20 at the time of diagnosis. Treatment protocols were analyzed, prognostic parameters were evaluated, and overall survival as well as survival until relapse of disease was studied. Prognostic features included age and sex, localization of tumor, type of applied surgical resection and treatment protocol, and presence of necrosis after neoadjuvant therapy as well as morphological characteristics of the tumor. Wide surgical resection (χ 2 =7.855; p<0.05), and tumor necrosis (χ 2 =7.855; p<0.05) were verified to be significant parameters for the outcome. Multimodal chemotherapy with local radiation and/or surgical resection is the best mode of modern treatment. Follow-up included the period from the completion of therapy to final control, with remission period defined by development of recurrence or metastatic lesions. Localization on distal parts of the extremities and axial skeleton is good prognostic feature, while localization on proximal parts of the extremities and pelvic girdle, presence of metastatic disease and low index of postchemotherapeutic necrosis, are associated with poor outcome. In Ewing s sarcoma, prognosis of good outcome is definitely very delicate process. Key words: Ewing s tumor family; disease outcome; method of treatment Vladan STEVANOVIĆ Institut za ortopedsko-hirurške bolesti Banjica Mihajla Avramovića 28, Beograd Tel.: vladanbg@beotel.yu * Rukopis je dostavqen Uredništv u godine. 426
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