KRANIOSPINALNA RADIOTERAPIJA U KOMBINOVANOM LEÈEWU MEDULOBLASTOMA DECE I OMLADINE
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1 RADOVI BIBLID , 131(2003) 5-6 p UDC: : KRANIOSPINALNA RADIOTERAPIJA U KOMBINOVANOM LEÈEWU MEDULOBLASTOMA DECE I OMLADINE Iva na GO LU BI ÈIÆ, Je le na BO KUN, Ma ri na NI KI TO VIÆ, Jasmina MLADENOVIÆ, Milan SARIÆ, Zoran BEKIÆ In sti tut za on ko lo gi ju i ra di o lo gi ju Sr bi je, Beograd KRATAK SADRŽAJ: Naša studija imala je za ciq evaluaciju rezultata leèewa kombinovanom terapijom (hirurgija, postoperativna kraniospinalna zraèna terapija sa hemioterapijom ili bez we) i procene faktora prognoze, u koje spadaju: vrsta hirurškog zahvata, infiltracija moždanog stabla, stepen proširenosti bolesti, postopera tivni meningitis, prisustvo šanta, uzrast, pol i vremenski interval izmeðu operativnog leèewa i zapoèiwawa radiote - rapije. U periodu od do godine leèeno je 78 pacijenata kombinovanim terapijskim pristupom, a 72 paci - jenta su bila dostupna za procenu. Kriterijumi za ukquèivawe u studiju su bili sledeæi: histopatološki potvrðe na dijagnoza, uzrast do 22 godine i prethodno odsustvo malignih bolesti. U postoperativnom periodu pacijenti su imali naèiwenu kompjuterizovanu tomografiju endokranijuma (CT), mijelografiju i citološki pregled likvora na maligne æelije. Na osnovu dobijenih podataka koristili smo operativnu klasifikaciju po Harisiadis-Èangu (Ha ri si - adis-chang) i Xen ki no vu (Jenkin) klasifikaciju prema prognoznim parametrima. Kod svih pacijenata sprovedeno je hirurško leèewe i kraniospinalna zraèna terapija, a adjuvantna hemioterapija sprovedena je kod 63 pacijen ta. Stope preživqavawa raðene su Kaplan-Majerovom (Kaplan-Meier) metodom, a statistièke razlike preživqavawa log-rank i Vil kokson (Wilcoxon) te stom. To kom pe ri o da pra æe wa od jed ne go di ne do 12 go di na (proseèno tri go di ne) dvo go diš we i pe to go diš we ukup no pre ži vqa va we i pre ži vqa va we bez zna ko va bo le sti iz no si lo je 66% i 51 %, odnosno 53% i 47%. Dijagnostikovali smo 32 recidiva. U odnosu na analizirane faktore prognoze, znaèajno boqe preživqavawe je bilo kod pacijenata kod kojih je uèiwena totalna ili suptotalna ekstirpacija tumora, kod kojih nije bilo infiltrisano moždano stablo ili kièmena moždina i koji nisu imali meningitis u postoperativnom periodu. Mlaði uzrast dece ima znaèajno lošije preživqavawe u odnosu na mlaðe adulte. Pacijenti kod kojih je radi - oterapija zapoèela u periodu od dva meseca posle hirurškog leèewa imali su boqe preživqavawe, mada nije dobijena statistièki signifikantna razlika zbog malog broja pacijenata sa odloženom radioterapijom. Grupa kod koje je sprovedena adjuvantna hemioterapija imala je boqe preživqavawe, ali nije potvrðena statistièka znaèajnost. Na osnovu ovih èiwenica potrebno je definisati grupe standardnog i visokog rizika. Hirurgija i radioterapija imaju jasno definisano mesto u okviru kombinovanog leèewa. Neophodna su daqa istraživawa antineoplastiène te ra pi je u kom bi no va nom pri stu pu, po seb no za gru pu vi so kog ri zi ka. Kquène reèi: meduloblastom, faktori prognoze, hirurgija, kraniospinalna radioterapija. UVOD Uvoðewem postoperativne kraniospinalne radio - te ra pi je, kao i po boq ša wem hi rurš kih teh ni ka u leèewu meduloblastoma (MB) znaèajno su poboqšani rezultati leèewa. Meðutim, i daqe oko polovina le èe nih bo le sni ka ima ne ga ti van is hod, naj èeš æe zbog lo kal nog re ci di va ili di se mi na ci je unu tar centralnog nervnog sistema (CNS), što ukazuje na neophodnost daqih istraživawa faktora prognoze, kao i do dat nih mo da li te ta an ti ne o pla stiè ne te ra - pi je [1, 2]. Shod no to me, mul ti cen triè ni ran do mi - zovani istraživaèki projekti pod rukovodstvom Meðunarodnog društva za deèju onkologiju (In ter na - ti o nal So ci ety of Pe di a tric On co logy SI OP) u Evro pi i Grupe za izuèavawe raka kod dece (Chil dren s Can cer Study Gro up CCSG) u Sje di we nim Ame riè kim Državama daju smernice za daqa istraživawa u pravcu definisawa faktora prognoze u ciqu odreðivawa grupe pacijenata sa visokim rizikom (nepovoqnim prognoznim parametrima) i grupe sa standardnim rizikom (povoqnim prognoznim parametrima) [3, 4]. Preciznim definisawem grupa stvaraju se uslo vi za da qe una pre ðe we te ra pij skih mo da li te ta, a ti me i re zultata le èewa. S ob zirom na to da razvojem di jag no stiè kih pro ce du ra, kao i te ra pij skih modaliteta dolazi do poboqšawa rezultata leèewa dece sa MB, savremena istraživawa poseban znaèaj pri da ju kva li te tu ži vo ta le èe ne de ce i te ra pij - skim se kve la ma [4 6]. CIQ RADA Naša studija je imala za ciq evaluaciju rezultata leèewa kombinovanom terapijom (hirurgija, posto - perativna kraniospinalna zraèna terapija sa hemioterapijom ili bez we) i procene faktora prognoze (vrsta hirurškog zahvata, infiltracija moždanog sta bla, ste pen pro ši re no sti bo le sti, po sto pe ra - tiv ni me nin gi tis, pri su stvo šan ta, uz rast, pol i vremenski interval izmeðu operativnog leèewa i zapoèiwawa radioterapije). METOD RADA U pe riodu od do go dine u In stitutu za on - kologiju i radiologiju Srbije leèeno je 78 pacijenata sa MB uz rasta od jedne do 22 go dine (proseèno 8,6 go di- 226
2 TABELA 1. Karakteristike ispitivane grupe. TABLE 1. Patients characteristics. Broj pacijenata No of patients 78 Muški/ženski pol Male/Female (ratio) 51/27 (1.89:1) Medijana, uzrast (godine) Median age (years, range) 8.6 (1-22) * Stadijumi * Stage T1 0 (0%) T2 24 (30.8%) T3a 33 (42.3%) T3b 18 (23%) T4 3 (3.9%) Mx 15 (19.2%) M0 41 (52.6%) M1 16 (20.5%) M2 0 (0%) M3 6 (7.7%) M4 0 (0%) Mijelografija Myelography Da Yes 40 (51.3%) Ne No 38 (48.7%) Pozitivna Positive 6 (7.7%) Negativna Negative 34 (92.3%) **CSF citologija **CSF citology Da Yes 61 (78.2%) Ne No 17 (21.8%) Pozitivna Positive 20 (25.6%) Negativna Negative 41 (74.4%) Meningitis Meningitis Da Yes 5 (6.4%) Ne No 73 (93.6%) Šant Shunt ***VP 12 (15.4%) ****VA 23 (29.5%) * Harisiadis-Èeng klasifikacija; ** cerebrospinalna teènost; *** ventrikuloperitonealni; **** ventrikuloatrijalni * Harisiadis-Chang classification; ** Cerebrospinal fluid; *** ventriculoperitoneal; **** ventriculoatrial na) postoperativnom karniospinalnom radioterapijom. Daqa procena je uraðena u 72 pa cijenta. Naj veæi broj pacijenata operisan je u Institutu za neurohirurgiju Klinièkog centra Srbije. Kriterijumi za ukquèivawe u studiju bili su: histopatološki potvrðena dijagnoza, uzrast do 22 godine i prethodno odsustvo malignih bolesti. Karakteristike grupe prikazane su u ta beli 1. Kod svih pa cijenata le èewe je za poèeto operativnim tretmanom. Totalna ekstirpacija tumora uèiwena je kod 29 pacijenata (37,2%), suptotalna ekstirpacija kod osam (10,3%), a maksimalna redukcija kod 41 bolesnika (52,5%). U okviru postoperativne procene ra ðen je CT endokranijuma, mijelografija i citološki pregled likvora na maligne æelije. Na osnovu svih dobijenih podataka koristili smo operativnu klasifikaciju po Harisiadis-Èangu (Harisiadis-Chang) i Xenkinovu (Jenkin) klasifikaciju prema prognoznim parametrima. Kod 72 od 78 pacijenata sprovedena je postoperativna kraniospinalna zraèna terapija. U zavisnosti od velièine tumora, karaktera hirurške intervencije i uzrasta bolesnika, kraniospinalna radioterapija je planirana sa tumorskom dozom od 30 do 40 Gy X fotonima energije 10 MeV. Pr - vi ciklus kraniospinalne tehnike je aplikovan na predeo kranijuma i proksimalne cervikalne kième do èetvrtog cervikalnog pršqena iz dva suprotna paralelna poqa, a preostali deo vertebralnog kanala do drugog sakralnog pršqena je zraèen iz jednog/dva direktna poqa takoðe X fotonima. Procena dubinske doze za direktno vertebralno poqe je obraèunavana na nivou predwe ivice sedmog cervikalnog pršqena i petog lumbalnog pršqena. U drugom aktu kraniospinalne tehnike zraèen je iz dva suprotna paralelna poqa predeo zadwe lobawske jame (boost) do zom od 15 do 20 Gy. Radioterapija je zapoèeta dana (proseèno 36 dana) posle hirurškog tretmana. Samo 13 pacijenata je zapoèelo zraèni tretman u periodu dužem od 60 dana posle hirurgije. Adjuvantna hemioterapija je sprovedena kod 63 bolesnika (80,7%). Najveæi broj bolesnika (46; 73%) leèen je po pro tokolu SIOP I (Vincristine, CCNU). Stope preživqavawa raðene su Kaplan-Majerovom (Kaplan-Meier) metodom, a statistièke razlike preživqavawa log-rank i Vilkokson (Wilcoxon) te stom. REZULTATI Za našu ispitivanu grupu tokom perioda posmatrawa od jed ne go dine do 12 go dina (proseèno tri go dine) dvogodišwe i petogodišwe ukupno preživqa - vawe iznosilo je 66% i 51%, a preživqavawe bez znakova bolesti 53% i 47%. Verovatnoæa desetogodišweg ukupnog preživqavawa iznosila je 45%, a preživqavawa bez znakova bolesti 43% (Grafikoni 1a i 1b). Di jag no sti ko va li smo 32 re ci di va. Anali - zirajuæi faktore prognoze, primetili smo da je znaèajno boqe preživqavawe kod pacijenata gde moždano stablo nije bilo infiltrisano tumorom (p=0,0023) (Gra fi kon 2). Pa ci jen ti sa po zi tiv nim mi je lo grafskim nalazom imali su znaèajno lošije preživqavawe u odnosu na grupu sa negativnom mijelografi - jom (p=0,0116). Od 40 bolesnika kod šest je utvr ðena po zi tiv na mi je lo gra fi ja i ni je dan od le èe nih ni je preživeo dve go dine. Kod 61 bo lesnika je od dve do èe ti ri ne de qe po sle ope ra ci je ra ðen ci to loš ki pre gled li kvo ra na ma lig ne æe li je. Na laz je bio pozitivan kod 20 bolesnika, pokazujuæi maligne æeli - je u gru pa ma ili po je di naè no. Ni je po tvr ðe na sta ti - stiè ka zna èaj nost u od no su na pri su stvo ma lig nih æelija u cerebrospinalnoj teènosti (CSF) (p=0,8207) niti u od nosu na pri sustvo, niti na tip si stema za 227
3 GRAFIKON 3. Verovatnoæa ukupnog preživqavawa u odnosu na meningitis. GRAPH 3. Overall survival according to meningitis. GRAFIKON 1. Verovatnoæa petogodišweg i desetogodišweg uku - pnog preživqavawa (1a) i preživqavawa bez znakova bo lesti (1b). GRAPH 1. Five and ten years overall survival (1a) and five and ten years desease free survival (1b). de ri va ci ju li kvo ra (ven tri ku lo a tri jal ni ili ventri ku lo pe ri to ne al ni šant) (p=0,5307 i p=0,7119). Sig ni fi kant no lo ši je pre ži vqa va we je kod pa ci - je na ta sa me nin gi ti som u po sto pe ra tiv nom pe ri o du, odnosno nijedan pacijent nije živeo duže od dve godi ne (p=0,0134) (Grafikon 3). De ca uz rasta do tri godine imala su znaèajno lošije preživqavawe u odnosu na grupu dece starije od 16 godina (p=0,0473). Iako postoji viša stopa preživqavawa dece ženskog po la u od nosu na muš ki pol, ni je do bijena sta - ti stiè ki zna èaj na raz li ka (p=0,2386). GRAFIKON 4. Verovatnoæa petogodišweg i desetogodišweg ukupnog preživqavawa u odnosu na vrstu operacije. GRAPH 4. Five and ten years overall survival according to the extent of tumor removal. Ana li zi ra ju æi re zul ta te le èe wa, sig ni fi kant no boqe preživqavawe je kod pacijenata kod kojih je uèi we na to tal na ili sup to tal na eks tir pa ci ja tu mo - ra (p=0,0022) (Grafikon 4). Pacijenti kod kojih je zraèna terapija zapoèeta u periodu dva meseca posle hirurškog leèewa imali su boqe preživqavawe posebno u prvih pet godina, da bi se u kasnijem pe riodu posmatrawa ono smawivalo, tako da nije dobijena sta ti stiè ki zna èaj na raz li ka (p=0,02231) (Grafi- GRAFIKON 2. Verovatnoæa petogodišweg i desetogodišweg uk upnog preživqavawa u odnosu na Harisiadis-Èang klasifikaciju. GRAPH 2. Five and ten years overall survival according to Harisiadis - Chang classification. GRAFIKON 5. Verovatnoæa petogodišweg i desetogodišweg uku - pnog preživqavawa. GRAPH 5. Five and ten years overall survival according to start ra diotherapy after surgery. 228
4 kon 5). Ta koðe se mora uze ti u ob zir da je od loženu ra di o te ra pi ju imao ma li broj bo le sni ka (18%). Pacijenti kod kojih je sprovedena adjuvantna hemiote - ra pi ja ima li su bo qe pre ži vqa va we, ali ni je do bi - je na sta ti stiè ki zna èaj na raz li ka (p=0,1113). DISKUSIJA Re zul ta ti le èe wa ob ja vqe ni od še zde se tih go di na 20. veka do danas pokazuju napredak pedijatrijske neuroonkologije. Istraživawe sprovedeno u Velikoj Britaniji u pe riodu od do go dine u ko je je bio ukqu èen 491 pa cijent uz rasta do 15 go dina sa di - jagnozom meduloblastoma donosi podatak o petogo - dišwem ukup nom pre živqavawu od 18%, da bi sledeæa studija, sprovedena u periodu od do godine, u koju je bilo ukquèeno 214 pacijenata, dala podatak o petogodišwem ukupnom preživqavawu od 27%, dok sledeæa, sprovedena na 154 bolesnika, objavquje petogodišwe ukupno preživqavawe od 38% [1]. U savremenim serijama petogodišwe ukupno preživqavawe pokazuje porast i iznosi 40-55% [1, 7]. Aca de mic Me di cal Cen ter i The Net her lands Center Institute objavquju podatke studije u koju je bilo ukquèeno 80 pacijenata u periodu od do godine, i to petogodišwe ukupno preživqavawe (OS) i preživqavawe bez znakova bolesti (DFS) 66 %, od nosno 64% [8]. Istraživawe In ter na ti o nal Soci ety of Pa e di a tric On co logy (SIOP) u Evro pi u pe riodu od do go dine ko je je obuhvatilo 286 pa cijenata iz 15 zemaqa kao rezultat iznosi petogodišwi DFS od 48%, a u istom pe riodu istraživawe sprovedeno u SAD pod rukovodstvom Chil dren s Cancer Study Group (CCSG), u saradwi sa Ra di a tion Therapy On co logy Gro up (RTOG), u ko ju je bilo ukqu èeno 234 is pi ta ni ka, iz no si pe to go diš wi DFS od 57% [9]. SI OP II istraživawe, ko je je obuhvatilo 364 pa - cijenta, otvoreno godine u saradwi sa Ger man So ci ety of Pe di a tric On co logy (GPO), da je po datak o pe - togodišwem DFS od 58,9% [3]. U na šoj grupi ukup no petogodišwe preživqavawe iznosi 51%, a petogo - dišwe preživqavawe bez znakova bolesti 47%. Koristeæi operativnu klasifikaciju po Harisiadis-Èengu, SIOP u svom pr vom istraživawu ob javquje petogodišwe preživqavawe bez znakova bole - sti od 64% za sta dijume T 1 i T 2 u grupi od 113 pa cijenata, u od nosu na 38% za sta dijume T 3 i T 4 grupe od 163 pacijenta [1, 3]. Kanadska grupa iznosi podatke o petogodišwem preživqavawu bez znakova bolesti za grupe T 1 i T 2 od 69% i T 3a i T 3b od 30% [10]. Go tovo iste rezultate objavquju Xenkin i saradnici: za T 1 i T 2 87%, a za T 3a i T 3b 45% [11]. Na ši rezultati od - govaraju objavqenim rezultatima. Ha ri si a dis-èeng in fil tra ci ju mo žda nog sta bla klasifikuju kao T 3b [12]. Istraživaèki projekat SIOP I kao jedan od prognoznih parametara navodi za hva æe nost mo žda nog sta bla, da bi veæ u sle de æem projektu SI OP II jedan od kriterijuma za podelu pacijenata u grupe niskog, odnosno visokog rizika bilo odsudstvo, odnosno prisustvo tumorske mase u mo žda nom sta blu. UKCCSG/SIOP PNET STUDY III, pre ma istom kri te ri ju mu, pa ci jen te de li na ni sko - ri ziè ne i vi so ko ri ziè ne [1, 9, 13]. Ol den bur ger (Olden bur ger) i sa rad ni ci [8] iz no se po dat ke o in fil - traciji moždanog stabla kod 29 od 80 pacijenata, a Ol brajt (Albright) i sa radnici [14] kod 38% u grupi od 141 ispitanog pacijenta. Naši rezultati potvr - ðu ju da po sto ji vi so ko sta ti stiè ki zna èaj na raz li ka u preživqavawu u korist pacijenata kod kojih možda no sta blo ni je in fil tri sa no tu mo rom. Leptomeningelna diseminacija je nepovoqan prognozni parametar u podeli na grupe niskog, odnosno visokog rizika. Mijelografija se smatra opšteprihvaæenom dijagnostièkom procedurom, dok se cito - loški pregled likvora na maligne æelije ne može koristiti kao pouzdana dijagnostika leptomeningelne diseminacije. UKCCSG/SIOP PNET STUDY III kao oba - veznu proceduru ukquèivawa u studiju navodi postoperativnu mijelografiju s obzirom na to da je u seriji od 364 pa cijenta istraživaèkog projekta SIOP II mi jelografija uèiwena kod 140, a pozitivan nalaz bio prisutan kod 15 pacijenata (10%) [13]. Treba istaæi da je u istoj studiji najveæi broj pacijenata sa leptomeningelnom diseminacijom bio asimptomatski. Xenkin i saradnici [11] pri kazuju da je u grupi od 72 pa - cijenta mijelografija naèiwena kod 15, a pozitivan nalaz bio prisutan kod dva pa cijenta (13%). O Rajli (O Reilly) i sa radnici [15] u gru pi od 47 pa cijenata po - zitivnu mijelografiju dijagnostikuju kod devet bolesnika (19%). Harisiadis i Èeng u posmatranoj grupi od 58 ispitanika navode podatak da je 15 imalo spinalnu diseminaciju i ukazuju na wihovo znaèajno lošije preživqavawe [12]. Grupa iz Kanade objavquje da je petogodišwe preživqavawe bez znakova bolesti 0% za pacijente sa leptomeningelnom diseminacijom [10]. Rezultati naše studije odgovaraju objavqenim rezultatima u literaturi. Meningitis u postoperativnom periodu je još jedan ne povoqan fak tor prognoze [10]. Isto je po tvrðe no u na šoj stu di ji. Mo ra se na gla si ti da me nin gi - tis u postoperativnom periodu znaèajno odlaže sprovoðewe kraniospinalne zraène terapije, a rezultat je lošije preživqavawe [11]. S ob zirom na to da je hi rurgija osnov ni te rapijski mo da li tet, ste pen re duk ci je tu mor ske ma se je od izuzetnog znaèaja za prognozu. Veæ istraživaèki projekat SIOP I kao prognostièki znaèajan faktor na vo di ka rak ter hi rurš kog za hva ta [1]. Sle de æi projekti kao osnovni prognozni parametar u defi - ni sa wu gru pa sa ni skim, od no sno vi so kim ri zi kom na vo de ka rak ter hi rur gi je. Gru pi ni skog ri zi ka pri pa da ju pa ci jen ti kod ko jih je uèi we na to tal na ili sup to tal na eks tir pa ci ja tu mo ra, a gru pi vi so - kog ri zi ka pa ci jen ti kod ko jih je uèi we na re duk ci ja tu mor ske ma se [9, 13]. Xen kin i sa rad ni ci ob ja vqu ju da je u grupi od 72 pacijenta totalna ekstirpacija uèiwena kod 28 (39 %), suptotalna ekstirpacija kod 22 (31%), a parcijalna resekcija ili biopsija kod 24 (31%) pa cijenta [11]. Grupa iz Ka nade u gru pi od
5 pacijenata navodi da je totalna ekstirpacija uèiwena kod 38 bolesnika (35%). Postoji znaèajna razlika u preživqavawu prema vrsti operativnog zahvata, tako da je petogodišwe preživqavawe bez znakova bolesti za grupu sa totalnom ekstirpacijom 81%, za grupu sa suptotalnom ekstirpacijom 47%, za grupu sa parcijalnom resekcijom 42%, a za grupu sa biopsijom 33% [10]. Ha risiadis i Èeng u gru pi od 59 pacijenata objavquju petogodišwe ukupno preži - vqavawe od 25% za gru pu kod koje je uèiwena par cijalna re sekcija ili bi opsija, a 44% za gru pu kod ko je je uèi we na to tal na ili sup to tal na eks tir pa ci ja tumora [12]. U na šoj gru pi zna èajno je bo qe pre živqavawe pacijenata kod kojih je uèiwena totalna ili suptotalna ekstirpacija tumora u odnosu na grupu kod koje je uèiwena parcijalna resekcija, što je u skla du sa po da ci ma iz li te ra tu re. Jedan od zakquèaka istraživawa SIOP II jeste da je sprovedena radioterapija redukovanim dozama udružena sa lošijim ishodom posebno zbog odlagawa radioterapije sprovoðewem preradijacione hemioterapije, te se stoga javqa interesovawe za istraživawe vremenskog intervala izmeðu operativnog i zraènog tretmana [1]. UKCCSG/SIOP PNET STUDY III kao prognozni parametar ukquèuje vreme proteklo od operacije do poèetka radioterapije [13]. Plouman (Plowman) i saradnici [7, 16] smatraju da duže od lagawe kraniospinalne zraène terapije daje vrlo èesto recidive, kao i da odlagawe radioterapije, zbog primene hemioterapije ili drugih razloga, kompromitu - je leèewe. Grupa autora iz Misurija slaže se u oceni da se pri li kom pri me ne po sto pe ra tiv ne he mi o te rapi je mo ra iz be æi od la ga we ra di o te ra pij skog tretmana [17]. Oldenburger i saradnici objavquju da je znaèajan faktor prognoze vremenski interval izme - ðu operativnog i zraènog tretmana, a kao granièni period uzimaju interval od dva meseca. U grupi od 80 pacijenata vremenski interval kraæi od dva meseca bio je kod 56 pa cijenata, a kod 24 du ži. Pe togodišwe ukupno preživqavawe za prvu grupu iznosi - lo je 75%, a za drugu 46% [8]. U na šoj studiji, iako postoji boqe preživqavawe pacijenata kod kojih je zraèna terapija zapoèeta u periodu kraæem od dva meseca po sprovedenom operativnom leèewu, nije do bi je na sta ti stiè ki zna èaj na raz li ka ve ro vat no zbog ma log bro ja pa ci je na ta kod ko jih je zraè ni tretman za poèet u pe riodu du žem od dva me seca po spro - vedenom operativnom leèewu. ZA KQU ÈAK Naši rezultati potvrðuju potrebu podele dece i omladine sa meduloblastomom zadwe lobawske jame, u zavisnosti od faktora prognoze, na grupu visokog i grupu standardnog rizika. Ova podela trebalo bi da bude osnova za dizajnirawe konvencionalne terapije (hirurgija i postoperativna radioterapija) u grupi bolesnika standardnog rizika. Za grupu bolesnika visokog rizika neophodna je intenzivnija terapija, te bi buduæi istraživaèki rad trebalo da bude usmeren u pravcu definisawa novih terapijskih modaliteta (efektivne hemioterapije, genske terapije, jediwewa aktivnih u anti-angiogenezi tumora itd.). LITERATURA 1. Bloom GJH. Tu mors of the Cen tral Ner vous Sys tem. In: Voute AP, Barret A, Bloom GJH(eds.): Can cer in Chil dren (second ed.). Springer-Verlag, Berlin, 1986; Heideman LR, Packer JR, Albright AL, Free man RC, Rorke BL. Tu - mors of the Cen tral Nrvous Sys tem. In: Pizzo A.Ph, Poplack GD, (eds.): Prin ci ples and Prac tice of Pe di at ric On col ogy. JB Lippincott Com pany, Phil a del phia, 1989; Bailey CC, Gnecow A, Wellek S, Jones M. et al. Prospective Ran - dom ised Trial of Che mo ther apy Given Be fore Ra dio ther apy in Child hood Medulloblastoma. In ter na tional So ci ety of Pe di at ric Oncology (SIOP) and the (German Society of Pediatric Oncology (GPO): SIOP II. Med ical and Pediatric On cology 1995; 25(3): Lanzkowsky PH. Cen tral Ner vous Sys tem Ma lig nan cies. In: Lanzkowsky Ph: Man ual of Pe di at ric He ma tol ogy and On col ogy (sec.ed.). Chur chill Living stone, New York, 1995; Cohen HB, Packer JR. Tumors of the Cen tral Ner vous System. In: D Angio G, Sinniah D, Meadows TA (eds.): Practical Pe diatric Oncology, The practice of the Cancer Center, The Children s Hos pital Philadelphia. Edward Ar nold; a di vision of Hodder and Stoughton, London, 1992; Golubièiæ I. Late treatment related mor bidity of radiotherapy in children and ad olescents treated for brain tu mors. PhD The sis, Medical Faculty, University of Belgrade, Plowman PN. Tu mors of the Cen tral Ner vous Sys tem. In: Plow - man PN, Pinkerton CR (eds.): Pediatric On cology Clinical Prac tice and Con tro ver sies. Chap man and Hall Med i cal, Lon don, 1992; Oldenburger F, Burgers JMV, De Kraker J, Gon zales D et al. Medulloblastoma in chil dren: The Am ster dam Ex pe ri ence. The Eu ro pean Jour nal of Can cer The Eu ro pean Can cer Con fer ence (Meeting Ab stract) 1995; 31A(5):A SIOP/GPO. SIOP II Trial of sandwich chemotherapy for the treatment of medulloblastoma in children, Draft protocol, Danjoux E C, Jenkin D, McLaughlin J, Grimard L et al. Childhood Medulloblastoma in On tario, : Pop ulation-based Re - sults. Med i cal and Pe di at ric On col ogy 1996; 26(1): Jenkin D, Goddard K, Armstrong D, Becker L (eds.). Posterior fossa medulloblastoma in child hood: Treatment re sults and pro - posal for a new staging system. IJ Ra diation On cology-biology-physics 1990; 19(2): Harisiadis L, Chang HC. Medulloblastoma in children: A cor relation be tween staging and re sults of treat ment. Radiation On cology-bi ol ogy-phys ics 1977; 2(9): Medulloblastoma Trial Committee. UKCCSG/SIOP: PNET STUDY III, Draft Pro tocol, Albright A L, Wisoff J H, Zeltzer P M, Deutsch M et al. Cur rent neurosurgical treatment of medulloblastoma in children. A re port from the Children s Can cer Study Group. Pediatr Neurocsi 1989; 15(6): O Reilly G, Hay ward R D, Harkness W F. Myelography in the as - sessment of chil dren with medduloblastoma. Br. J. Neurosurg 1993; 7(2): Attard-Montaldo S, Plowman N, Breatnach F, Saha V, Eden O B. Is there a danger in delaying radiotherapy in childhood medulloblastoma. Br. J. Radiol. 1993; 66(789): Mosijczuk A D, Nigro M A, Thomas P R, Burger P C (eds). Preradiation chemotherapy in ad vanced medulloblastoma. A Pe diatric On cology Group pi lot study. Can cer 1993; 72(9):
6 POSTOPERATIVE CRANIOSPINAL RADIOTHERAPY OF MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS Ivana GOLUBIÈIÆ, Jelena BOKUN, Marina NIKITOVIÆ, Jasmina MLADENOVIÆ, Milan SARIÆ, Zoran BEKIÆ Institute of Oncology and Radiology of Serbia, Belgrade PURPOSE The aim of this study was: 1. to eval uate treat ment results of com bined therapy (surgery, postoperative craniospinal radiotherapy with or without chemotherapy) and 2. to assess fac tors affecting prog nosis (extend of tumor removal, involve ment of the brain stem, extent of dis ease, postoperative meningitis, shunt placement, age, sex and time interval from surgery to start of postoperative radiotherapy). PATIENTS AND METHODS During the period , 78 patients with medulloblastoma, aged 1-22 years (median 8.6 years), were treated with combined modality therapy and 72 of them were evaluable for the study endpoints. Entry criteria were histologically proven diagnosis, age under 22 years, and no history of previous malig nant disease. The main char - acteristics of the group are shown in Table 1. Twenty-nine patients (37.2%) have total, 8 (10.3%) near total and 41 (52.5%) partial removal. Seventy-two of 78 patients were treated with cura tive intent and received post op er a tive craniospinal irra di a tion. Radio ther apy started days after surgery (median 36 days). Only 13 patients started radio ther apy after 60 days fol low ing sur gery. Adjuvant che mo ther apy was applied in 63 (80.7%) patients. The majority of them (46; 73%) received chemotherapy with CCNU and Vincristine. The sur vival rates were cal culated with the Kaplan-Meier method and the differences in survival were ana lyzed using the Wilcoxon test and log-rank test. RESULTS The follow-up period ranged from 1-12 years (median 3 years). Five-year overall sur vival (OS) was 51% and dis ease-free survival (DFS) 47% (Graph 1). Dur ing fol low-up 32 relapses occurred. Patients hav - ing no brain stem infiltration had sig nificantly better sur vival (p=0.0023) (Graph 2). Patients with positive myelographic find ings had sig nificantly poorer sur vival compared to dose with negative myelographic find ings (p=0.0116). Significantly poorer sur vival was found in patients with men in gi tis devel op ing in the post op er a tive period, with no patient liv ing longer than two years (p=0.0134) (Graph 3). By anal ysis of OS and DFS in rela tion to pres ence of the malig nant cells in liquor, sta tis ti cally sig nif i cant dif fer ence, i. e. pos i - tive CSF cytology was not obtained, which was of sta tistical importance for sur vival (p=0.8207). Neither shunt place ment nor shunt type showed any impact on sur vival (p= and , respec tively). Children younger than three years had sig nificantly poorer survival compared to those older than 16 years (p=0.0473). Although there was a better sur vival rate in females than in males this was not statistically significant (p=0.2386). The anal ysis results of treat ment showed that sig nificantly better survival occurred in patients in whom total or subtotal tumor removal was possible (p=0.0022) (Graph 4). Patients who started radiotherapy within two months after surgery have better survival, but again this was not sta tistically significant, probably due to the small number of patients receiving delayed radiotherapy (p=0.2231) (Graph 5). CONCLUSION Based on this fac tors stan dard and high risk group could be defined. Com bined che mo ther apy should to be inves ti gated par tic u larly for high risk sub group. Future research should be done to define new ther a peu tic modal i ties (gene ther apy, com pounds active in tumor antiangiogenesis etc). Key words: medulloblastoma, prognostic fac tors, craniospinal radiother apy, sur gery. Ivana GOLUBIÈIÆ In sti tut za on ko lo gi ju i ra di o lo gi ju Sr bi je Pa ste ro va 14, Be o grad Tel: ; lo kal 137 Faks: * Rukopis je dostavqen Uredništvu godine. 231
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