Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Adjuvant Radiation Therapy of Retroperitoneal Sarcoma: The Role of Intraoperative Radiotherapy (IORT)

Adjuvant Radiation Therapy of Retroperitoneal Sarcoma: The Role of Intraoperative Radiotherapy... Purpose. The pur pose is to revie w the natu ral hi story, the cl inicopathological prog nostic f actors, and t he rol e of adjuvant radiation the rapy with par ticular attention to the li mited but fav orable experience w ith IOR T. Methods. Retroperitoneal sarco mas present a continuing the rapeutic chal lenge to the onc ologist. In con trast to sarc omas of the ex tremity and supe r® cial tr unk in w hich complete rese ction pl us radiation the rapy results i n ex cellent loc al c ontrol, sarcomas of the re troperitoneum are difficult to rese ct and e ven if completely rese cted, de monstrate hig h rate s of local relapse, the pr imary pattern o f failure. Due to the prox imity of normal organs, the de livery of therapeutic d oses of adjuvant external beam radiation the rapy is problematic.T o de liver ade quate dose s (>60 Gy) of external beam to mo st pa tients woul d result in u nacceptable t oxicity. The the rapeutic dil emma is unfortunate an d bet ter strate gies are needed. O ne a ttractive approach has been to in corporate int raoperative radi ation t herapy (IORT) w ith max imal resection an d ex ternal be am radia- tion. Results and Dis cussion . A number of institutions ha ve explored t his approach with en couraging prel iminary results. Key words: retroperitoneal sarcoma, intraoperative radiation therapy (IO RT), high-dose r ate IO RT, electron beam, complications Introduction doses ( >60 Gy) of external be am r adiation w ould result i n u naccept able toxicity. The t herapeut ic Retroperitoneal s arcomas p resent a continuing ch al- dilemma is u nfortunate a nd be tter s trategies ar e lenge t o the oncolog i st. With only 1 000 cases needed. On e a ttractive approach h as been t o diagnosed p er year in the USA, t hey are a rare tu mor, incorporate in traoperative ra diation th erapy using comprising a bout 15% of all sarcomas and 40% of all 1 either el ectrons (I OERT) or hi gh-dose r ate photons primary r etroperitoneal t umors. Their rar ity impedes delivered via remote a fterloading (HD R-IORT) wi th data collection an d lim its the power of adequately maximal re section and e xternal beam r adiation.T he designed tr ials. I n co ntrast, the published d ata with purpose of this review is to overview the need for extremity sar coma i s m ore e xtensive. I t has been effective adjuvant radiation after maximal re section clearly d ocumented th at complete r esection p lus of retroperitoneal s arcomas an d to report the limited radiation t herapy can locally con trol the overwhelming but e ncouraging e xperience us ing IO RT in c ombina- majori ty of ext remity sarcoma s and s uper® c ial 2± 19 tion with conventional ex ternal beam rad iation. trunk. In t his regard, t he radiation t herapy approach c an be e ither by external b eam, br achy- Clinicopathological prognostic f actors therapy or a combination o f both, yielding lo cal control rates o f 80± 90% and 5 -year overall su rvival Achieving a gross to tal resection (GT R) of either a 7,8,16,20 of 80%. Sarcomas of the retroperitoneum ha ve primary or r ecurrent r etroperitoneal sar coma is by been a far different stor y . Due t o its remote lo cation far the most i mport ant predictive fac tor for lo cal 1,21± 24 with multiple a djacent cr itical organs, sa rcomas ar ising control and s urvival. When G TR is ac hieved, from this location pr esent as large, ad vanced stag e 5-year overall s urvival is abo ut 50% (range 35 ± 74%, tumors t hat are d ifficult t o resect wi th adequate Ta ble 1) Moreover, a fter GTR, th e microscopic margin. Th e pr oximity o f normal or gans su ch as residual d isease s tatus appears im portant as patient viscera an d n eurovascular str uctures has made th e with microscopic d isease pr esent appear to have worse 25 22 delivery of therapeutic d oses of postoperative e xternal survival and/or lo cal co ntrol compared t o those beam ir radiation pr oblematic. T o d eliver ad equate with negative re sidual.T he o utlook fo r p atients with Correspondence to: Kenneth S. Hu, MD, Attending, The Charle s and Bernice Blitman, Department of Radiation Oncology, Beth Israel Medical Ce nter, 1 0 U nion Square East, NewY ork, NY 10003, U SA.Te l: 2 12 844 -8022; F ax: 212 8 44-8086; kh u@bethisraelny.org 1357-714Xprint/136 9-1643online/00/010 011-06 2000T aylor & Francis Ltd 12 K. S. H u & L. B . H arrison Table 1. Local co ntrol and survival aft er g ross to tal r esection of r etroperitoneal sa rcomas %RT No. of Med F/U (median 5-year LR 5-year OS Tx Date patients (years) %HG dose) (actuarials %) (actuarials) % MSKCC 1982± 97 18 5* 2.3 58 NS 41 70 MSKCC 1982± 87 67 2.6 55 NS 49 74 U Fla 1970± 94 49 NS 54 NS 46 (crude) 58 MSKCC 1951± 77 47 NS NS 40 (NS) 77 40 PMH 1975± 88 45 6.3 NS 8 0 (4 0 Gy) 50 (1 0 y ear 82%) 5 5 (1 0 year 22%) Univ. Minn. 1941± 87 31 11 77 NS NS 48 Netherlands 1973± 90 29 3.2 44 45 63 35 Roswell Park 1957± 80 27 NS NS NS NS 64 MCV 1964± 82 18 NS NS 33 (NS) 56 (crude) 70 HG=high grade, L R=local recurrence, OS=ov erall survival, NS=not state d, MS KCC=Memorial Sloan-Kettering Canc er Center, P MH=Princess M argaret Ho spital, MCV=Medical Co llege of Virginia, *All pati ents prese nted w ith pr imary tumors. gross re sidual d isease is d ismal with 5-year survival o f High-grade s tatus was associated wi th worse d isease- 21,26 less than 5%. Given the importance of achieving speci® c m ortality [relative r isk (R R)=3.2, p=0.001], GTR, ag gressive su rgery m ust be pu rsued.T o o btain higher r isk for d istant m etastases (R R=5, p=0.01) a maximal en bl oc re section, i t is c ommon to resect and in creased lo cal f ailure (R R=2, p=0.01). However, 21,27 abutting or gans. In the Memorial Sloan -Kettering follow-up is sho rt wi th a median tim e of 2.3 years. Cancer C ent er ( MSK CC) seri es, J acques With median fol low-up o f 6.3 years, the data from demonstrated that that resection o f adjacent organs, Princess M argaret Ho spital (PMH) demonstrated n o primarily k idney, b owel o r p ancreas w as required in survival impact of grade. The expe rience f rom M ayo 83% of cases. Despite su ch ag gressive appr oaches, suggested that the apparent in¯ u ence o f grade o n the rate of gross total resection i s abou t 40± 50% of survival in a n earlier repor t w as lost wi th longer foll ow- 1,21,28,29 22 all patients who pr esent fo r re section. Of 500 up. patients who pre sented at MSKCC, o nly 64% of Similar co n¯ icti ng da ta exist for hi stological subty pe primary tumors an d 52% of recurrent s arcomas w ere and pr esentation, bu t no t t umor s tage. Fi ve studies grossly r esected. Among p atients presenting wi th suggest tha t histological su btype has no i mpact o n primary tumors that were re sected with grossly n ega- surviv al but fo ur of these re port that it affects the rate 21,26,30,31,34 tive margins, m edian ov erall su rv ival was 103 months of distant m e tastases. Two of these vs 18 months fo r tho se with primary tu mors in wh ich suggested that leiomyosarcoma is ass ociated with a 30,34 gross r esidua l disease r emaine d. T here w as no decrease r ate of distant m etastases, but one signi® cant difference in su rvival be tween pa tients who reports th e opposite effect of leiomyosarcoma. Lewis were u nr esecta ble and t hose w ho u nd erwent reported t hat liposarcoma had a higher r ate of local incomplete re section. recurrence (RR =2.6, p=0.01) but d id n ot im pact o n Aside f rom the extent o f resection, the prognostic disease-speci® c su rvival m ost li kely d ue to its nega- value o f other c linico pathologi ca l factors a re tive association w ith metastasis (R R=0.2, p=0.01). In controversi al. Most s tudies a nalyzing p rognosti c contrast, two studies r eport that histological s ubtype factors h ave evaluated the impact pr imarily o f grade, can im pact o n su rvival, bo th associating li posarcoma 1,21,25± 23,37 histology, tumor stag e an d pre sentation sta tus. with improved su rvival. Recurrent p resentation 27,30± 33 In th e majority of these s tudies, h igh-grade status had no st atistically signi® ca nt i mpact o n sur vival 22 30 lesions app ear to confer a worse su rvival by as much in one study but d id in an other. Tu mor siz e is as 30± 70% com pare d w ith low- gr ade report ed c ons ist ently no t to in¯ u ence 21,26,27,31± 33 21,31,33,34 31,33 lesions; however, s tudies fr om s everal survival or r isk for loca l fa ilure. However, major ce nters h ave not d emonstrated any impact of T3 lesions (ba sed on th e Russell sta ging syst em) wh ich 22± 24,28 grade on s urvival. Among the studies th at invade ad jacent organs ha ve been re ported to impact 31,33 evaluate whether g r ade i mpacts o n p atterns o f negatively o n s urvival. Of 1 98 patients who wer e 28,30,34± 36 failure, four su ggest that high-grade t umors followed fo r at least 5 years, H eslin r eported tha t are ass ociated wi th an in creased in cidence o f distant patients a live at 5 years t ended t o present wi th primary metastases with three o f them sh owing n o im pact o n low- gr ade, l iposar comas i n w hich G TR w as local f ailure whil e o ne f ound tha t high-grade d esigna- achieved. tion in creased the risk f or l ocal fai lure. O n th e other hand, t wo studies sug gest tha t high-grade tum or sta tus Patterns of failure after gross total re section has no i n¯ u ence o n t he rates o f distant m etas- 1,22 tases. Lewis r eport ed r ecently an a nalysis of After G TR, pa tterns of failure s tudies i ndicate that prognostic f actors b ased o n d ata of 231 MSKCC local r elapse re presents the primary mode of failure. patients with primary d isease un dergoing G TR. However, loc al fail ure after complete re section oc curs Radiation therapy of retrop eritoneal sarcoma 13 in 41 ± 77% (Table 1). In t he largest s uch s tudy fr om bowel as well as various rad iation the rapy treatment MSKCC, lo cal f ailure alo ne as a ® rst s ite o f recur- techniques (de cubitis p osition, o blique ® elds) m ay rence o ccurred in 81% of all failures an d was a improve tole rance to modest do ses (50 ± 55 Gy) but component o f 90% of failures. Distant metastases do n ot in ge neral p ermit t herapeutic d oses. P reopera- to lung or li ver ac counted for 19% of all ® rst f ailures. tive radiation has been ad vocated to improve r esecta- Local failure alo ne c omprised a higher pr oportion o f bility and m inimize bo wel t oxicity; how ever, it s e fficacy ® rst f ailures for t hose present ing wi th recurrent disea se remains to be de monstrated an d a chieving d oses for 22,39 compared to those p resenting with primary d isease optimal c ontrol is n ot feas ible. (92% vs. 67%, respectively). I n a literature re view of 310 patients achieving g ross total resection, F ein Clinical experience wit h IORT in the t reatment showed t hat 47% recur re d l ocally while 2 1% of retroperitoneal sa rcoma developed d istant m etastases. Of 135 recurrent The ad dition of IORT to maximal r esection an d cases, 81% had a local c omponent of failure a nd EBRT re presents an attrac tive approach to delivering 37% had a di stant compone nt . Comm on l ife- more e ffective adjuvant treatment.T o d ate, there has threatening co mplications re sulting fr om l ocal r ecur- been on ly a limited e xperience with this approach renc e i nc lude s epsis, gast roint estina l bleedi ng , (Table 2). A r andomized tr ial at the NCI showed obstruction, p erforation, ® stula, bi liary obstruction signi® c antly better lo cal c ontrol with IOERT an d and o bstructive n ephropathy. Due to the high loc al post-operative EBRT 40% (6/15) vs post-operative failure r ates d espite m aximal s urgery,the role of adju- EBRT a lone 8 0% (16/20) p<0.05 at a median vant treatment b ecomes cr ucial. follow-up o f 8 years. All pat ients underwent g ross total resection a nd w ere ran domized to either EB RT Adjuvant external beam ra diation of 35± 40 Gy and 20 Gy IORT wi th misonidazole or Based on the highly s uccessful ex perience in e xtremity to 50± 55 Gy of EBRT a lone. T he I OERT a rm sarcoma, it is c lear tha t radiation de livered e ither by experienced s igni® c antly more pe ripheral n europathy external b eam r adiother apy (EBRT) or b rachy- (60% vs 5%, p<0.05), while the EBRT o nly ar m had therapy (BT) can se rve as effective adjuvant treat- a signi® can tly higher rat e of gastrointestinal com plica- 7,8,10,16,20 ment f or s arcoma. To c ontrol g r ossly tions, in cluding a higher r ate of disabling c hronic resected e xtremity s arcomas, EB RT d oses of 60± 70 enteritis [50% (10/20) vs 7%(2/15), respectively] an d 7,8,16,20 Gy or B T d oses o f 45 Gy are n eede d. ® stula [ 25% (5/20) vs 0%(0/15), respectively]. T he Combined BT (15 ± 20 Gy) plus EB RT (45 ± 50 Gy) higher i ncidence o f peripheral n europathy i n th e have also be en u sed. Achieving s uch d oses to treat IORT a rm wa s attributed to multiple f actors in cluding retroperitoneal sar comas i s p roblematic d ue to the the dose o f 20 Gy, the use o f a concomitant rad iosen- radiation t olerance o f the surrounding or gans as well sitizer w hich itse lf is n eurotoxic, an d th e use of large as the large ar eas tha t need t o be ad dressed.T e pper’ s pelvic el ectron ® elds n ear the lumbosacral pl exus. study su ggested that a post-operative E BRT d ose The M GH ex perience wi th IOERT was also f avo- greater t han >60 Gy produced be tter lo cal co ntrol rable (T able 2). Of 20 patients receiving p reopera- 83% (5/6) vs 33% (2/6) for < 50 Gy. Catton showed tive EBRT to 40± 50 Gy, 14 had a complete re section. that the addition of radiation in creased the time to Ten o f the 14 completely re sected p atients received in-® eld lo cal failu re fr om 30 to 103 months (p< 0.05), IORT t o a median do se of 15 Gy (10± 15 Gy) for especially if a dose of >35 Gy was delivered. Fein microscopic r esidual tu mor, w hile the other fo ur showed th at of 21 retroperitoneal s arcoma patien ts, received n o f urther b ecause o f extensive tu mor be ds local fai lure was 25% (2/8) vs 38% (5/13) if the dose that could n ot b e en compassed in an I ORT ® eld. A t delivere d w as <55.2 Gy vs >55.2 Gy. Cody a median fo llow-up of 3 years, only 10% (1/10) who demonstrated an incr ease in 5 -year survival r ates from underwent G TR an d I ORT f ailed lo cally. Seven of 30 to 53% in 15 patients who rec eived ad juvant radia- 10 are NED , while thr ee d eveloped m etastasis. Non e tion after GTR co mpared to 22 who had G TR alo ne; of the 10 patients undergoin g I ORT a nd G TR however, this was not s tatistically signi® c ant and a developed n europathy. One o f two patients who detailed c omparison of the treatment g roups was not received IO RT and EB RT for g ross re sidual d isease performed. Heslin s howed t hat among 5 -year developed a sensory ne uropathy af ter receiving 17.5 survivors, r adiation the rapy was the only sig ni® c ant Gy of IORT. Bowel tox icity was minimal with only a factor on un ivariate a nalysis t hat decreased loca l recur - 6% small b owel ob struction r ate. At t he same i nstitu- rence. tion in a cohort o f patients treated w ith resection an d Deliveri ng d oses g reater th an 50± 55 Gy with postoperative EB RT w ithout IORT, the 5-year local standard EBRT tec hnique i s toxi c. In the NCI trial, control an d s urvival r ates w ere b oth 54%. Thus, the 54± 55 Gy produced a 50% chronic e nteritis an d 25% addition of IORT appe ared t o improve l ocal co ntrol ® stula rate. Glenn re ported a severe e nteritis rate of and po ssibly su rvival. 22% (8/37) in pat ients receiving a dose of 54 Gy after Other im portant l imited ex periences w ith IOERT GTR, of whom se ven r equired su rgery an d on e di ed have been re ported (T able 2).The Radiation T herapy from bo wel p erforation. Tissue expa nders to displace Oncology Gr oup ( RTOG) con ducted a phase II s tudy 14 K. S. H u & L. B . H arrison Table 2. Efficacy of IO RT in the t reatment o f r etroperi toneal sar coma Med No. of F/U 5 year LR 5 year OS TX Date patients (years) %GTR %HG RT Dose (actuarial, %) (actuarial, %) Mayo Clinic 1981± 97 8 8 3 .5 8 1 62 48.6 Gy EBRT+ 41 47 15 Gy IORT NCl NS 20 100 NS 54± 5 5 Gy EBRT 80 25 8 vs [8-year] [8-year] 15 p=0.05 15 35± 4 0 Gy EBRT+ 40 20 20 Gy IORT [8-year] [8-year] MSKCC 1992± 96 3 2 2 .8 8 4 62 45 Gy EBRT+ 38 56 15 Gy IORT [4-year] [4-year DFS] Institut B ergonie 1991± 94 1 9 1 .4 7 4 74 50 Gy EBRT+ 24 60 (Grade 17 Gy IORT [2-year] [2-year DFS] 2,3) MGH 1981± 89 17 3 82 76 4 0± 5 0 Gy EBRT+ 19 64 15± 2 0 Gy IORT [59%] [4 year] [4-year DFS] RTOG NS 12 1.5 NS 40± 5 0 Gy EBRT+ 17 12.5± 2 0 Gy IORT [2 year] GTR=gross total r esection, HG =high grade, L R=local recurrence, O S=overall survival, DFS=disease fre e sur vival, NCI=National Cancer Inst itute, M GH=Massachusetts General Hospit al, NS=not st ated, M SKCC=Memorial Sloan- Kettering Can cer Ce nter, R TOG=Radiation Therapy Oncology G roup. of int raoperative radi ation f or r e trop er i tonea l gastrointestinal tox icities oc curred i n 1 4% (12/87) sarcomas. A pr eliminary analysis o f 12 patients consisting m ainly of ® stula an d pr octitis. No grade 4 treated w ith EBRT ( 45± 50.4 Gy) plus I OERT toxicities wer e r eported. (12.5± 20 Gy) demonstrated a local f ailure of 17% at The pr eliminary M emorial Sloan -Kettering Can cer a median fo llow-up of 18 months. A t the Institut Center e xperie nce u sing H DR-IORT h as been 35,36 Bergonie, 19 retroperitoneal s arcomas w ere tr eated reported an d i s also fav orable. In a prospective with IOERT af ter maximal r esection. G TR wa s protocol, 32 patients were tr eated w ith gross total achieved in 79% (15/19). The m edian I OERT d ose resection and HDR -IORT (12 ± 15 Gy) followed by was 17 Gy (15± 20 Gy) with 13/19 receiving EBRT at post-operative EB RT (4 5± 50.4 Gy). HDR-IORT w as a median d ose o f 50 Gy (30± 60 Gy). At a median delivered u sing a cable-mounted ir idium-192 s ource follow-up o f 17 months, 2 -year actuarial local fail ure into a super¯ a b afterloading a pplicator. T welve was 24% with 2-year overall su rvival of 60%. Severe patients presented with primary an d 20 with locally late complications oc curred i n 6/ 19 patients and w ere recurrent di sease. T wo -thirds of the patient (20/32) likely m ultifactorial i n o rigin w ith one ` moderate ’ had hi gh-grade d isease an d the median tu mor s ize peripheral n europathy an d o ne ili ac v essel r upture. was 203 12.53 11 cm. A t a median fol low-up o f 33 Petersen at the Mayo Clinic r eported th e largest months (r ange 1 ± 77 months), th e 4-year actuarial experience w ith IOERT in the treatment of 87 retro- local f ailure for a ll patients was 38%. Subset an alysis peritoneal sar coma w ho h ad r eceived m aximal r esec- demonstrated that local f ailure for pr imary tu mors tion a nd pr eoperative EB RT. Eighty-three per ce nt was 26% vs 46% in re current d isease ( p=0.4). Tu mor (72/87) were able to undergo G TR wi th 64% having grade d id n ot im pact o n th e rate of local f ailure (40% microscopic resid ual and 20 % had no res idual tum ors. vs 33% for h igh- and low -grade tu mors, r espectively, All pr imary t umors (43/ 87) and 77% of recurrent p=0.66). A s tatistically signi® c ant higher 4 -year tumors rec eived a preoperative EBR T do se of 45± 48.6 actuarial rate of distant m etastases was detected i n Gy. All pat ients received in traoperative ele ctron r adia- the high-grade vs low-grade tum ors (30% vs 0%, tion to a median do se o f 15 Gy. At a median follow -up p=0.05, respectively). F our-year ac tuarial disease- of 3.5 years, 23% (20/87) developed a local r ecur- free a nd o verall s urv ival were 5 5 and 4 5%, rence wi th a 3- and 5-y ear actuarial local r ecurrence respectively. Neither pr esentation s tatus nor t umor of 23 and 41% , respectively. The am ount o f residual grade im pacted o n d isease-free or ov erall su rv ival. In disease s igni® can tly affected local co ntrol with 5-year this challenging g roup of patients treated w ith an local f ailure o f 0% for n o r esidua l, 43% for aggr es sive c omb ined m o dality reg i men, 34% microscopic r esidual an d 6 3% for g ross r esidual developed co mplications, t he majority of which wer e tumors (p=0.04). Interestingly, local r elapse oc curred multifactorial in etio logy an d re solved w ith conserva- in o nly 7% (3/43) of primary tu mors tre ated with tive management. B owel obs truction wa s the most IORT, EBRT an d G TR. Fi ve-year overall s urvival after gross tot al resection wa s 49%. Grade 3 peripheral common co mplication (18%) and ® stula fo rmation neuropathy oc curred in 10 % (9/87) while g rade 3 occurred in 9%. Also n oteworthy was a 6% (2/32) Radiation therapy of retrop eritoneal sarcoma 15 incidence of femoral ne rve p alsy which wer e m ild reported or it is po ssible that follow-up is t oo s hort to and he aled with out major in tervention. make a ® rm co nclusion. T he im provement in l ocal The l ow rate of peripheral n europathy i s r eas- control w ithout a sur v ival bene® t has been suring. Bas ed on ani mal stu dies an d t he NCI rand- demonstrated for e xtremity s arcomas. Moreover, omized t rial, the main to xicity ass ociated w ith IORT given t he morbidity an d m ortality associated wi th is p eripheral n europathy. A d ose o f 20 Gy appears local f ailure, l ocal c ontrol re mains a worthy objective. to be to xic as signi® ca nt ra tes o f peripheral neu ropathy IORT s eems to be a promising n ew m odality for the developed in the NCI trial (60%), while d oses o f 15 50% of patients whose re troperitoneal sar comas m ay Gy or les s app eared to be be tter tol erated (36% ). be g ross totally resected; howev er, i ts role i n su bto- One of the potential pr oblems with IOERT is th e tally resected patien ts remains t o be d e® n ed. New dependence o n un wieldy, r igid e lectron co nes t o treat treatment ap proaches i ntegrating I ORT, possibly narrow, anatomically complex su rfaces. In ad dition, concurrently wi th new ch emotherapeutic o r o ther if the target is lar ge, abu tting el ectron ® elds m ust b e biological age nts ne ed to be inv estigated. used.T hese f actors in troduce d osimetric i nhomoge- neities tha t may underdose the target or ov erdose References adjacent n ormal tis sue. I n the NCI trial, the most 1 St orm FK, Mahvi DM. D iagnosis an d m anagement o f common s ituation ass ociated wi th the development retroperitoneal soft -tissue sarcoma. Ann Surg 1991; of clinically d ebilitating p eripheral ne uropathy was 214:2± 10. the use o f angled, abu tting ele ctron ® elds to treat 2 Ell is F. Tum or be d im plants at t he t ime of surgery, removable interstitial impl ants with ir idium-192. In: large p elvic t umors. A lthough the signi® can tly lower 2nd Inte rnational Symposium on RadiationTherapy . New rate of peripheral n europathy n oted i n the MSKCC York: Memorial Slo an-Kettering Can cer Ce nter, 1 975. series m ay be d ue to a different p atient population or 3 Gemer LS, et al. Local re currence of soft tissue s arcoma differences in s hielding t echniques, it possibly is following brachythe rapy. Int J Radiat O ncol Biol Phys related t o the type of applicator used. I n co ntrast to 1991; 2 0:587± 9 2. 4 Hilaris B, et al. Perioperative brach ytherapy and s urgery the electron c one, t he Harrison± A nderson± M ick in s oft tissue sarcomas . In: Brachyther apy O ncology . New (HAM) appl icator used i n the MSKCC s tudy is ¯ ex - York: Memorial Slo an-Kettering Can cer Ce nter, 1 982. ible e nough to conform to most t umor b eds an d can 5 Hilaris B, et al. Limb-sparing t herapy for locally be abu tted w ithout junctional d osimetric in homoge- advanced soft tissue sarco mas. Endocur Hypertherm neity. A l ow r ate of peripheral ne uropathy was also Oncol 1985; 1 :17± 2 4. 6 Karakou sis CP, et al. Feasibility of limb salvage and report ed i n r ectal c ancer p atients treated w ith survival in s oft tissue s arcomas. Cancer 1986;57:484 ± 91. HDR-IORT u sing the HAM app licator in a separate 43± 45 7 Lin dberg R, et al. Conservative surgery an d rad iation MSKCC s tudy. therapy for soft tissue sarc omas. In: Management of primary bone and soft tis sue tumors . Chicago, IL : Year Book M edical, 1 977, 28 9± 2 98. Conclusion 8 Rose nberg SA, et al. Prospective ran domized evalua - tion o f the ro le o f limb-sparing surgery, radiation In su mmary, the preponderance of the data support therapy, and ad juvant chemoimmunotherapy i n t he the hypothesis that IORT c an im prove l ocal co ntrol. treatment of adult so ft-tissue sarcomas. Surgery 1978; When co mpared t o the local r ecurrence r ates of 84:62± 9. 41± 82% after gross to tal resection witho ut IORT 9 Roy J, et al. Adjuvant endocurietherapy in the man age- (Table 1), the ® ve studies evalu ating t his modality, ment of liposarcomas of the ex tremeties. Endocur Hyper- therm Oncol 1990; 2 :29± 3 5. including a randomized tr ial, indicate tha t IORT do es 10 Sc hray MF, et al. Soft tissue sarc oma. Integration o f appear to decrease loc al f ailure to rates of 19± 41% brachytherapy, resection, and e xternal i rradiation. (Table 2). However, with the exception of the 8-year Cancer 1990; 6 6:451± 6 . follow-up o f the randomized NC I trial, follow-up o f 11 Shiu MH, et al. Control of locally advanced e xtremity most o f the other stu dies i s m odest.Th e i mportance soft tissue sarco mas by function- sa ving resection and brachytherapy. Cancer 1984; 53 :1385± 9 2. of long-term obser vation w as demonstrated by Heslin, 12 Shiu MH, et al. Brachytherapy and fun ction-saving who s howed t hat local f ailure c an co mmonly o ccur resection o f soft tissue sarco ma arising in t he limb . Int even in 5 -year surv ivors a t up to 5% per y ear. Thus, J Radiat O ncol Biol Phys 1991; 21 :1485± 9 2. close s urveillance i s r equired to con® r m th e bene® t 13 Su it HD , Russell WO, Martin RG . Management o f of IORT on l ocal control. Nev ertheless, IOR T a ppears patients wit h sarcom a of soft tissue in an extremity. Cancer 1973; 3 1:1247± 5 5. to improve l ocal con trol in o ther sites in cluding c olor- 46 14 Su it HD , Russell WO, Martin RG . Sarcoma of soft ectal, pancreatic an d g astric c ancers. tissue: clinical a nd h istopathologic p arameters and Theoretically, since lo cal re currence re presents th e response to tre atment. Cancer 1975; 3 5:1478± 83 . primary mo de of failure an d u nderlies the cause o f 15 Suit HD, et al. Preoperat ive, intraoper ative, and death in t he majority of retroperitonea l sarcoma postoperative radiation in the t reatment of primary soft tissue s arcoma. Cancer 1985; 55 :2659± 6 7. patients, it would s eem th at a survival b ene® t should 16 Suit HD, et al.Tre atment of the patie nt wit h stag e M 0 be d erived fr om th e incorporation o f IORT. Yet an soft tissue sarco ma. J Clin Oncol 1988; 6:8 54± 62 . obvious im provement in su rvival is n ot appar ent. It 17 Wi llet C, Suit H. Limited su rgery an d e xternal beam may be t hat too f ew patients treated w ith IORT ha ve irradiation in so ft tissue sarc oma. Adv Oncol 1989; been stu died as data of only 183 patients have been 5:26± 29. 16 K. S. H u & L. B . H arrison 18 Ze lefsky MJ, et al. Limb salvage in soft tissue sarcom as 33 Glenn J, et al. Results of multimodality thera py of resect- involving n eurovascular structures u sing c ombined able soft-tissue sarcomas of the retrop eritoneum. Surgery surgical rese ction an d brach ytherapy. Int J Radiat O ncol 1985; 9 7:316± 2 5. Biol Phys 1990; 1 9:913± 8 . 34 Heslin MJ, et al. Prognostic fact ors associated w ith 19 Ze lefsky MJ, et al. Combined su rgical r esection and long-term sur vival for retroperitoneal sarcom a: implica- iridium 19 2 im plantation f or locally advanced a nd recur - tions for management. J Clin Oncol 1997; 15 :2832± 9 . rent de smoid t umors. Cancer 1991; 67 :380± 4. 35 H u K, Harrison LB. Hi gh dose-rate intra operative radi a- 20 Har rison LB, et al. Long-term re sults of a prospective tion thera py (HDR-IORT) for retroperitoneal s arcomas. randomized t rial of adjuvant brachytherapy in t he In: 21st Annual Meeting of the Ame rican Brac hytherapy management of completely res ected sof t tissue s arcomas Society. San Diego, CA, 1999. of the e xtremity and supe r® cial t runk. Int J Radiat 36 A lektiar KM, et al. High dose-rate intrao perative bra chy- Oncol Biol Phys 1993; 2 7:259± 6 5. therapy (HDR-IORT) for retroperitoneal sarc omas. In 21 J aques DP, et al. Management of primary and re cur- press. rent soft -tissue sarcoma of the re troperitoneum. Ann 37 Zhang G, et al. Sarcomas of the ret roperitoneum an d Surg 1990; 21 2:51± 9. genitourinary trac t. J Urol 1989; 14 1:1107± 10 . 22 P etersen I, et al. Use of intraoperative ele ctron beam 38 T e pper JE , et al. Radiation therapy of retroperitoneal radiation the rapy in the man agement o f soft tissue soft tissue sarcom as. Int J Radiat O ncol Biol Phys 1984; sarcoma. In pre ss, 1999. 10:825± 30. 23 Catt on CN , et al. Outcome and prog nosis in re troperi- 39 Wille tt CG , et al. Intraoperative el ectron be am radia- toneal soft tissue sarc oma. Int J Radiat Oncol Bi ol Phys tion t herapy for retroperitoneal so ft tissue sarco ma. 1994; 2 9:1005± 1 0. Cancer 1991; 6 8:278± 83 . 24 v an Doorn RC, et al. Resectable re troperitoneal soft 40 Kiel KD, et al. Preliminary resul ts of protocol R TOG tissue sarco mas. The effec t of extent of resection and 85-07: phase II study of intraoperative rad iation for postoperative radiation t herapy on loc al t umor con trol. retroper itonea l sarcomas. In: 3rd I nternational Cancer 1994; 7 3:637± 4 2. Symposium of Intraoperative Radiation Therapy . Oxford: 25 Singer S, et al. Prognostic fac tors predictive o f survival Pergamon Pre ss, 1991. for truncal and retro peritoneal s oft-tissue sarcoma. Ann 41 Bu ssieres E, et al. Retroperitoneal soft tissue sarc omas: Surg 1995; 22 1:185± 9 5. a pilot stud y o f intraoperative radiatio n the rapy. J Surg 26 M cGrath P C , et al. Improved survival following Oncol 1996; 6 2:49± 5 6. complete e xcision of retroperitoneal s arcomas. Ann Surg 42 Shaw EG, et al. Peripheral ne rve and u reteral t olerance 1984; 2 00:200± 4 . to in traoperative radiatio n the rapy: clinical and dose - 27 Kilke nny JW , 3rd, Bl and KI, Copeland EM , 3 rd. Re tro- response analysis. Radiother O ncol 1990; 1 8:247± 5 5. peritoneal sa rcoma: the Un iversity of Florida e xperi- 43 Ha rrison LB, Enke rWE ,Anderson LL. High-dose-rate ence. J Am Coll Surg 1996; 1 82:329± 3 9. intraoperative ra diation t herapy for colorectal canc er. 28 Fein DA, et al. Manageme nt o f retroper itonea l Oncology (Huntingt) 1995; 9 :737± 41 ; d iscussion 7 42± 8 sarcomas: does d ose e scalation im pact on l ocoregional passim. control? Int J Radiat O ncol Biol Phys 1995; 3 1:129± 34 . 44 Ha rrison LB, Enke rWE ,Anderson LL. High-dose-rate 29 Sin delarWF , et al. Intraoperative rad iotherapy in ret ro- intraoperative ra diation t herapy for colorectal canc er. peritoneal sa rcomas. Final results of a prospective, rand- Oncology (Huntingt) 1995; 9 :679± 83 . omized, c linical tr ial. Arch Surg 1993; 1 28:402± 1 0. 45 Ha rrison LB, et al. High dose rate int raoperative rad ia- 30 Lewis JJ, et al. Retroperitoneal soft -tissue sarcoma: tion the rapy (HDR-IORT) as part of the manag ement analysis of 500 patie nts tre ated a nd follow ed a t a single strategy for locally advanced pr imary and re current institution. Ann Surg 1998; 2 28:355± 65 . rectal c ancer. Int J Radiat O ncol Bi ol Phys 1998; 31 D alton R R, et al. Management o f retroperito neal 42:325± 30. sarcomas. Surgery 1989;1 06:725± 32 ; discussion 7 32± 3 . 46 Gun derson L L, et al. Intraoperative ir radiation: current 32 Cody HSD., et al.The cont inuing c hallenge of retroperi- and f uture status. Semin O ncol 19 97; 2 4:715± 3 1. toneal sarco mas. Cancer 1981; 4 7:2147± 52 . MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Sarcoma Hindawi Publishing Corporation

Adjuvant Radiation Therapy of Retroperitoneal Sarcoma: The Role of Intraoperative Radiotherapy (IORT)

hu, Kenneth S.; Harrison, Louis C.
Sarcoma , Volume 4 – Jan 1, 2000
Download PDF
7 pages

Loading next page...
 
/lp/hindawi-publishing-corporation/adjuvant-radiation-therapy-of-retroperitoneal-sarcoma-the-role-of-PBCIvOtV3i

References (50)

Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2000 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
1357-714X
eISSN
1369-1643
DOI
10.1155/s1357714x00000037
Publisher site
See Article on Publisher Site

Abstract

Purpose. The pur pose is to revie w the natu ral hi story, the cl inicopathological prog nostic f actors, and t he rol e of adjuvant radiation the rapy with par ticular attention to the li mited but fav orable experience w ith IOR T. Methods. Retroperitoneal sarco mas present a continuing the rapeutic chal lenge to the onc ologist. In con trast to sarc omas of the ex tremity and supe r® cial tr unk in w hich complete rese ction pl us radiation the rapy results i n ex cellent loc al c ontrol, sarcomas of the re troperitoneum are difficult to rese ct and e ven if completely rese cted, de monstrate hig h rate s of local relapse, the pr imary pattern o f failure. Due to the prox imity of normal organs, the de livery of therapeutic d oses of adjuvant external beam radiation the rapy is problematic.T o de liver ade quate dose s (>60 Gy) of external beam to mo st pa tients woul d result in u nacceptable t oxicity. The the rapeutic dil emma is unfortunate an d bet ter strate gies are needed. O ne a ttractive approach has been to in corporate int raoperative radi ation t herapy (IORT) w ith max imal resection an d ex ternal be am radia- tion. Results and Dis cussion . A number of institutions ha ve explored t his approach with en couraging prel iminary results. Key words: retroperitoneal sarcoma, intraoperative radiation therapy (IO RT), high-dose r ate IO RT, electron beam, complications Introduction doses ( >60 Gy) of external be am r adiation w ould result i n u naccept able toxicity. The t herapeut ic Retroperitoneal s arcomas p resent a continuing ch al- dilemma is u nfortunate a nd be tter s trategies ar e lenge t o the oncolog i st. With only 1 000 cases needed. On e a ttractive approach h as been t o diagnosed p er year in the USA, t hey are a rare tu mor, incorporate in traoperative ra diation th erapy using comprising a bout 15% of all sarcomas and 40% of all 1 either el ectrons (I OERT) or hi gh-dose r ate photons primary r etroperitoneal t umors. Their rar ity impedes delivered via remote a fterloading (HD R-IORT) wi th data collection an d lim its the power of adequately maximal re section and e xternal beam r adiation.T he designed tr ials. I n co ntrast, the published d ata with purpose of this review is to overview the need for extremity sar coma i s m ore e xtensive. I t has been effective adjuvant radiation after maximal re section clearly d ocumented th at complete r esection p lus of retroperitoneal s arcomas an d to report the limited radiation t herapy can locally con trol the overwhelming but e ncouraging e xperience us ing IO RT in c ombina- majori ty of ext remity sarcoma s and s uper® c ial 2± 19 tion with conventional ex ternal beam rad iation. trunk. In t his regard, t he radiation t herapy approach c an be e ither by external b eam, br achy- Clinicopathological prognostic f actors therapy or a combination o f both, yielding lo cal control rates o f 80± 90% and 5 -year overall su rvival Achieving a gross to tal resection (GT R) of either a 7,8,16,20 of 80%. Sarcomas of the retroperitoneum ha ve primary or r ecurrent r etroperitoneal sar coma is by been a far different stor y . Due t o its remote lo cation far the most i mport ant predictive fac tor for lo cal 1,21± 24 with multiple a djacent cr itical organs, sa rcomas ar ising control and s urvival. When G TR is ac hieved, from this location pr esent as large, ad vanced stag e 5-year overall s urvival is abo ut 50% (range 35 ± 74%, tumors t hat are d ifficult t o resect wi th adequate Ta ble 1) Moreover, a fter GTR, th e microscopic margin. Th e pr oximity o f normal or gans su ch as residual d isease s tatus appears im portant as patient viscera an d n eurovascular str uctures has made th e with microscopic d isease pr esent appear to have worse 25 22 delivery of therapeutic d oses of postoperative e xternal survival and/or lo cal co ntrol compared t o those beam ir radiation pr oblematic. T o d eliver ad equate with negative re sidual.T he o utlook fo r p atients with Correspondence to: Kenneth S. Hu, MD, Attending, The Charle s and Bernice Blitman, Department of Radiation Oncology, Beth Israel Medical Ce nter, 1 0 U nion Square East, NewY ork, NY 10003, U SA.Te l: 2 12 844 -8022; F ax: 212 8 44-8086; kh u@bethisraelny.org 1357-714Xprint/136 9-1643online/00/010 011-06 2000T aylor & Francis Ltd 12 K. S. H u & L. B . H arrison Table 1. Local co ntrol and survival aft er g ross to tal r esection of r etroperitoneal sa rcomas %RT No. of Med F/U (median 5-year LR 5-year OS Tx Date patients (years) %HG dose) (actuarials %) (actuarials) % MSKCC 1982± 97 18 5* 2.3 58 NS 41 70 MSKCC 1982± 87 67 2.6 55 NS 49 74 U Fla 1970± 94 49 NS 54 NS 46 (crude) 58 MSKCC 1951± 77 47 NS NS 40 (NS) 77 40 PMH 1975± 88 45 6.3 NS 8 0 (4 0 Gy) 50 (1 0 y ear 82%) 5 5 (1 0 year 22%) Univ. Minn. 1941± 87 31 11 77 NS NS 48 Netherlands 1973± 90 29 3.2 44 45 63 35 Roswell Park 1957± 80 27 NS NS NS NS 64 MCV 1964± 82 18 NS NS 33 (NS) 56 (crude) 70 HG=high grade, L R=local recurrence, OS=ov erall survival, NS=not state d, MS KCC=Memorial Sloan-Kettering Canc er Center, P MH=Princess M argaret Ho spital, MCV=Medical Co llege of Virginia, *All pati ents prese nted w ith pr imary tumors. gross re sidual d isease is d ismal with 5-year survival o f High-grade s tatus was associated wi th worse d isease- 21,26 less than 5%. Given the importance of achieving speci® c m ortality [relative r isk (R R)=3.2, p=0.001], GTR, ag gressive su rgery m ust be pu rsued.T o o btain higher r isk for d istant m etastases (R R=5, p=0.01) a maximal en bl oc re section, i t is c ommon to resect and in creased lo cal f ailure (R R=2, p=0.01). However, 21,27 abutting or gans. In the Memorial Sloan -Kettering follow-up is sho rt wi th a median tim e of 2.3 years. Cancer C ent er ( MSK CC) seri es, J acques With median fol low-up o f 6.3 years, the data from demonstrated that that resection o f adjacent organs, Princess M argaret Ho spital (PMH) demonstrated n o primarily k idney, b owel o r p ancreas w as required in survival impact of grade. The expe rience f rom M ayo 83% of cases. Despite su ch ag gressive appr oaches, suggested that the apparent in¯ u ence o f grade o n the rate of gross total resection i s abou t 40± 50% of survival in a n earlier repor t w as lost wi th longer foll ow- 1,21,28,29 22 all patients who pr esent fo r re section. Of 500 up. patients who pre sented at MSKCC, o nly 64% of Similar co n¯ icti ng da ta exist for hi stological subty pe primary tumors an d 52% of recurrent s arcomas w ere and pr esentation, bu t no t t umor s tage. Fi ve studies grossly r esected. Among p atients presenting wi th suggest tha t histological su btype has no i mpact o n primary tumors that were re sected with grossly n ega- surviv al but fo ur of these re port that it affects the rate 21,26,30,31,34 tive margins, m edian ov erall su rv ival was 103 months of distant m e tastases. Two of these vs 18 months fo r tho se with primary tu mors in wh ich suggested that leiomyosarcoma is ass ociated with a 30,34 gross r esidua l disease r emaine d. T here w as no decrease r ate of distant m etastases, but one signi® cant difference in su rvival be tween pa tients who reports th e opposite effect of leiomyosarcoma. Lewis were u nr esecta ble and t hose w ho u nd erwent reported t hat liposarcoma had a higher r ate of local incomplete re section. recurrence (RR =2.6, p=0.01) but d id n ot im pact o n Aside f rom the extent o f resection, the prognostic disease-speci® c su rvival m ost li kely d ue to its nega- value o f other c linico pathologi ca l factors a re tive association w ith metastasis (R R=0.2, p=0.01). In controversi al. Most s tudies a nalyzing p rognosti c contrast, two studies r eport that histological s ubtype factors h ave evaluated the impact pr imarily o f grade, can im pact o n su rvival, bo th associating li posarcoma 1,21,25± 23,37 histology, tumor stag e an d pre sentation sta tus. with improved su rvival. Recurrent p resentation 27,30± 33 In th e majority of these s tudies, h igh-grade status had no st atistically signi® ca nt i mpact o n sur vival 22 30 lesions app ear to confer a worse su rvival by as much in one study but d id in an other. Tu mor siz e is as 30± 70% com pare d w ith low- gr ade report ed c ons ist ently no t to in¯ u ence 21,26,27,31± 33 21,31,33,34 31,33 lesions; however, s tudies fr om s everal survival or r isk for loca l fa ilure. However, major ce nters h ave not d emonstrated any impact of T3 lesions (ba sed on th e Russell sta ging syst em) wh ich 22± 24,28 grade on s urvival. Among the studies th at invade ad jacent organs ha ve been re ported to impact 31,33 evaluate whether g r ade i mpacts o n p atterns o f negatively o n s urvival. Of 1 98 patients who wer e 28,30,34± 36 failure, four su ggest that high-grade t umors followed fo r at least 5 years, H eslin r eported tha t are ass ociated wi th an in creased in cidence o f distant patients a live at 5 years t ended t o present wi th primary metastases with three o f them sh owing n o im pact o n low- gr ade, l iposar comas i n w hich G TR w as local f ailure whil e o ne f ound tha t high-grade d esigna- achieved. tion in creased the risk f or l ocal fai lure. O n th e other hand, t wo studies sug gest tha t high-grade tum or sta tus Patterns of failure after gross total re section has no i n¯ u ence o n t he rates o f distant m etas- 1,22 tases. Lewis r eport ed r ecently an a nalysis of After G TR, pa tterns of failure s tudies i ndicate that prognostic f actors b ased o n d ata of 231 MSKCC local r elapse re presents the primary mode of failure. patients with primary d isease un dergoing G TR. However, loc al fail ure after complete re section oc curs Radiation therapy of retrop eritoneal sarcoma 13 in 41 ± 77% (Table 1). In t he largest s uch s tudy fr om bowel as well as various rad iation the rapy treatment MSKCC, lo cal f ailure alo ne as a ® rst s ite o f recur- techniques (de cubitis p osition, o blique ® elds) m ay rence o ccurred in 81% of all failures an d was a improve tole rance to modest do ses (50 ± 55 Gy) but component o f 90% of failures. Distant metastases do n ot in ge neral p ermit t herapeutic d oses. P reopera- to lung or li ver ac counted for 19% of all ® rst f ailures. tive radiation has been ad vocated to improve r esecta- Local failure alo ne c omprised a higher pr oportion o f bility and m inimize bo wel t oxicity; how ever, it s e fficacy ® rst f ailures for t hose present ing wi th recurrent disea se remains to be de monstrated an d a chieving d oses for 22,39 compared to those p resenting with primary d isease optimal c ontrol is n ot feas ible. (92% vs. 67%, respectively). I n a literature re view of 310 patients achieving g ross total resection, F ein Clinical experience wit h IORT in the t reatment showed t hat 47% recur re d l ocally while 2 1% of retroperitoneal sa rcoma developed d istant m etastases. Of 135 recurrent The ad dition of IORT to maximal r esection an d cases, 81% had a local c omponent of failure a nd EBRT re presents an attrac tive approach to delivering 37% had a di stant compone nt . Comm on l ife- more e ffective adjuvant treatment.T o d ate, there has threatening co mplications re sulting fr om l ocal r ecur- been on ly a limited e xperience with this approach renc e i nc lude s epsis, gast roint estina l bleedi ng , (Table 2). A r andomized tr ial at the NCI showed obstruction, p erforation, ® stula, bi liary obstruction signi® c antly better lo cal c ontrol with IOERT an d and o bstructive n ephropathy. Due to the high loc al post-operative EBRT 40% (6/15) vs post-operative failure r ates d espite m aximal s urgery,the role of adju- EBRT a lone 8 0% (16/20) p<0.05 at a median vant treatment b ecomes cr ucial. follow-up o f 8 years. All pat ients underwent g ross total resection a nd w ere ran domized to either EB RT Adjuvant external beam ra diation of 35± 40 Gy and 20 Gy IORT wi th misonidazole or Based on the highly s uccessful ex perience in e xtremity to 50± 55 Gy of EBRT a lone. T he I OERT a rm sarcoma, it is c lear tha t radiation de livered e ither by experienced s igni® c antly more pe ripheral n europathy external b eam r adiother apy (EBRT) or b rachy- (60% vs 5%, p<0.05), while the EBRT o nly ar m had therapy (BT) can se rve as effective adjuvant treat- a signi® can tly higher rat e of gastrointestinal com plica- 7,8,10,16,20 ment f or s arcoma. To c ontrol g r ossly tions, in cluding a higher r ate of disabling c hronic resected e xtremity s arcomas, EB RT d oses of 60± 70 enteritis [50% (10/20) vs 7%(2/15), respectively] an d 7,8,16,20 Gy or B T d oses o f 45 Gy are n eede d. ® stula [ 25% (5/20) vs 0%(0/15), respectively]. T he Combined BT (15 ± 20 Gy) plus EB RT (45 ± 50 Gy) higher i ncidence o f peripheral n europathy i n th e have also be en u sed. Achieving s uch d oses to treat IORT a rm wa s attributed to multiple f actors in cluding retroperitoneal sar comas i s p roblematic d ue to the the dose o f 20 Gy, the use o f a concomitant rad iosen- radiation t olerance o f the surrounding or gans as well sitizer w hich itse lf is n eurotoxic, an d th e use of large as the large ar eas tha t need t o be ad dressed.T e pper’ s pelvic el ectron ® elds n ear the lumbosacral pl exus. study su ggested that a post-operative E BRT d ose The M GH ex perience wi th IOERT was also f avo- greater t han >60 Gy produced be tter lo cal co ntrol rable (T able 2). Of 20 patients receiving p reopera- 83% (5/6) vs 33% (2/6) for < 50 Gy. Catton showed tive EBRT to 40± 50 Gy, 14 had a complete re section. that the addition of radiation in creased the time to Ten o f the 14 completely re sected p atients received in-® eld lo cal failu re fr om 30 to 103 months (p< 0.05), IORT t o a median do se of 15 Gy (10± 15 Gy) for especially if a dose of >35 Gy was delivered. Fein microscopic r esidual tu mor, w hile the other fo ur showed th at of 21 retroperitoneal s arcoma patien ts, received n o f urther b ecause o f extensive tu mor be ds local fai lure was 25% (2/8) vs 38% (5/13) if the dose that could n ot b e en compassed in an I ORT ® eld. A t delivere d w as <55.2 Gy vs >55.2 Gy. Cody a median fo llow-up of 3 years, only 10% (1/10) who demonstrated an incr ease in 5 -year survival r ates from underwent G TR an d I ORT f ailed lo cally. Seven of 30 to 53% in 15 patients who rec eived ad juvant radia- 10 are NED , while thr ee d eveloped m etastasis. Non e tion after GTR co mpared to 22 who had G TR alo ne; of the 10 patients undergoin g I ORT a nd G TR however, this was not s tatistically signi® c ant and a developed n europathy. One o f two patients who detailed c omparison of the treatment g roups was not received IO RT and EB RT for g ross re sidual d isease performed. Heslin s howed t hat among 5 -year developed a sensory ne uropathy af ter receiving 17.5 survivors, r adiation the rapy was the only sig ni® c ant Gy of IORT. Bowel tox icity was minimal with only a factor on un ivariate a nalysis t hat decreased loca l recur - 6% small b owel ob struction r ate. At t he same i nstitu- rence. tion in a cohort o f patients treated w ith resection an d Deliveri ng d oses g reater th an 50± 55 Gy with postoperative EB RT w ithout IORT, the 5-year local standard EBRT tec hnique i s toxi c. In the NCI trial, control an d s urvival r ates w ere b oth 54%. Thus, the 54± 55 Gy produced a 50% chronic e nteritis an d 25% addition of IORT appe ared t o improve l ocal co ntrol ® stula rate. Glenn re ported a severe e nteritis rate of and po ssibly su rvival. 22% (8/37) in pat ients receiving a dose of 54 Gy after Other im portant l imited ex periences w ith IOERT GTR, of whom se ven r equired su rgery an d on e di ed have been re ported (T able 2).The Radiation T herapy from bo wel p erforation. Tissue expa nders to displace Oncology Gr oup ( RTOG) con ducted a phase II s tudy 14 K. S. H u & L. B . H arrison Table 2. Efficacy of IO RT in the t reatment o f r etroperi toneal sar coma Med No. of F/U 5 year LR 5 year OS TX Date patients (years) %GTR %HG RT Dose (actuarial, %) (actuarial, %) Mayo Clinic 1981± 97 8 8 3 .5 8 1 62 48.6 Gy EBRT+ 41 47 15 Gy IORT NCl NS 20 100 NS 54± 5 5 Gy EBRT 80 25 8 vs [8-year] [8-year] 15 p=0.05 15 35± 4 0 Gy EBRT+ 40 20 20 Gy IORT [8-year] [8-year] MSKCC 1992± 96 3 2 2 .8 8 4 62 45 Gy EBRT+ 38 56 15 Gy IORT [4-year] [4-year DFS] Institut B ergonie 1991± 94 1 9 1 .4 7 4 74 50 Gy EBRT+ 24 60 (Grade 17 Gy IORT [2-year] [2-year DFS] 2,3) MGH 1981± 89 17 3 82 76 4 0± 5 0 Gy EBRT+ 19 64 15± 2 0 Gy IORT [59%] [4 year] [4-year DFS] RTOG NS 12 1.5 NS 40± 5 0 Gy EBRT+ 17 12.5± 2 0 Gy IORT [2 year] GTR=gross total r esection, HG =high grade, L R=local recurrence, O S=overall survival, DFS=disease fre e sur vival, NCI=National Cancer Inst itute, M GH=Massachusetts General Hospit al, NS=not st ated, M SKCC=Memorial Sloan- Kettering Can cer Ce nter, R TOG=Radiation Therapy Oncology G roup. of int raoperative radi ation f or r e trop er i tonea l gastrointestinal tox icities oc curred i n 1 4% (12/87) sarcomas. A pr eliminary analysis o f 12 patients consisting m ainly of ® stula an d pr octitis. No grade 4 treated w ith EBRT ( 45± 50.4 Gy) plus I OERT toxicities wer e r eported. (12.5± 20 Gy) demonstrated a local f ailure of 17% at The pr eliminary M emorial Sloan -Kettering Can cer a median fo llow-up of 18 months. A t the Institut Center e xperie nce u sing H DR-IORT h as been 35,36 Bergonie, 19 retroperitoneal s arcomas w ere tr eated reported an d i s also fav orable. In a prospective with IOERT af ter maximal r esection. G TR wa s protocol, 32 patients were tr eated w ith gross total achieved in 79% (15/19). The m edian I OERT d ose resection and HDR -IORT (12 ± 15 Gy) followed by was 17 Gy (15± 20 Gy) with 13/19 receiving EBRT at post-operative EB RT (4 5± 50.4 Gy). HDR-IORT w as a median d ose o f 50 Gy (30± 60 Gy). At a median delivered u sing a cable-mounted ir idium-192 s ource follow-up o f 17 months, 2 -year actuarial local fail ure into a super¯ a b afterloading a pplicator. T welve was 24% with 2-year overall su rvival of 60%. Severe patients presented with primary an d 20 with locally late complications oc curred i n 6/ 19 patients and w ere recurrent di sease. T wo -thirds of the patient (20/32) likely m ultifactorial i n o rigin w ith one ` moderate ’ had hi gh-grade d isease an d the median tu mor s ize peripheral n europathy an d o ne ili ac v essel r upture. was 203 12.53 11 cm. A t a median fol low-up o f 33 Petersen at the Mayo Clinic r eported th e largest months (r ange 1 ± 77 months), th e 4-year actuarial experience w ith IOERT in the treatment of 87 retro- local f ailure for a ll patients was 38%. Subset an alysis peritoneal sar coma w ho h ad r eceived m aximal r esec- demonstrated that local f ailure for pr imary tu mors tion a nd pr eoperative EB RT. Eighty-three per ce nt was 26% vs 46% in re current d isease ( p=0.4). Tu mor (72/87) were able to undergo G TR wi th 64% having grade d id n ot im pact o n th e rate of local f ailure (40% microscopic resid ual and 20 % had no res idual tum ors. vs 33% for h igh- and low -grade tu mors, r espectively, All pr imary t umors (43/ 87) and 77% of recurrent p=0.66). A s tatistically signi® c ant higher 4 -year tumors rec eived a preoperative EBR T do se of 45± 48.6 actuarial rate of distant m etastases was detected i n Gy. All pat ients received in traoperative ele ctron r adia- the high-grade vs low-grade tum ors (30% vs 0%, tion to a median do se o f 15 Gy. At a median follow -up p=0.05, respectively). F our-year ac tuarial disease- of 3.5 years, 23% (20/87) developed a local r ecur- free a nd o verall s urv ival were 5 5 and 4 5%, rence wi th a 3- and 5-y ear actuarial local r ecurrence respectively. Neither pr esentation s tatus nor t umor of 23 and 41% , respectively. The am ount o f residual grade im pacted o n d isease-free or ov erall su rv ival. In disease s igni® can tly affected local co ntrol with 5-year this challenging g roup of patients treated w ith an local f ailure o f 0% for n o r esidua l, 43% for aggr es sive c omb ined m o dality reg i men, 34% microscopic r esidual an d 6 3% for g ross r esidual developed co mplications, t he majority of which wer e tumors (p=0.04). Interestingly, local r elapse oc curred multifactorial in etio logy an d re solved w ith conserva- in o nly 7% (3/43) of primary tu mors tre ated with tive management. B owel obs truction wa s the most IORT, EBRT an d G TR. Fi ve-year overall s urvival after gross tot al resection wa s 49%. Grade 3 peripheral common co mplication (18%) and ® stula fo rmation neuropathy oc curred in 10 % (9/87) while g rade 3 occurred in 9%. Also n oteworthy was a 6% (2/32) Radiation therapy of retrop eritoneal sarcoma 15 incidence of femoral ne rve p alsy which wer e m ild reported or it is po ssible that follow-up is t oo s hort to and he aled with out major in tervention. make a ® rm co nclusion. T he im provement in l ocal The l ow rate of peripheral n europathy i s r eas- control w ithout a sur v ival bene® t has been suring. Bas ed on ani mal stu dies an d t he NCI rand- demonstrated for e xtremity s arcomas. Moreover, omized t rial, the main to xicity ass ociated w ith IORT given t he morbidity an d m ortality associated wi th is p eripheral n europathy. A d ose o f 20 Gy appears local f ailure, l ocal c ontrol re mains a worthy objective. to be to xic as signi® ca nt ra tes o f peripheral neu ropathy IORT s eems to be a promising n ew m odality for the developed in the NCI trial (60%), while d oses o f 15 50% of patients whose re troperitoneal sar comas m ay Gy or les s app eared to be be tter tol erated (36% ). be g ross totally resected; howev er, i ts role i n su bto- One of the potential pr oblems with IOERT is th e tally resected patien ts remains t o be d e® n ed. New dependence o n un wieldy, r igid e lectron co nes t o treat treatment ap proaches i ntegrating I ORT, possibly narrow, anatomically complex su rfaces. In ad dition, concurrently wi th new ch emotherapeutic o r o ther if the target is lar ge, abu tting el ectron ® elds m ust b e biological age nts ne ed to be inv estigated. used.T hese f actors in troduce d osimetric i nhomoge- neities tha t may underdose the target or ov erdose References adjacent n ormal tis sue. I n the NCI trial, the most 1 St orm FK, Mahvi DM. D iagnosis an d m anagement o f common s ituation ass ociated wi th the development retroperitoneal soft -tissue sarcoma. Ann Surg 1991; of clinically d ebilitating p eripheral ne uropathy was 214:2± 10. the use o f angled, abu tting ele ctron ® elds to treat 2 Ell is F. Tum or be d im plants at t he t ime of surgery, removable interstitial impl ants with ir idium-192. In: large p elvic t umors. A lthough the signi® can tly lower 2nd Inte rnational Symposium on RadiationTherapy . New rate of peripheral n europathy n oted i n the MSKCC York: Memorial Slo an-Kettering Can cer Ce nter, 1 975. series m ay be d ue to a different p atient population or 3 Gemer LS, et al. Local re currence of soft tissue s arcoma differences in s hielding t echniques, it possibly is following brachythe rapy. Int J Radiat O ncol Biol Phys related t o the type of applicator used. I n co ntrast to 1991; 2 0:587± 9 2. 4 Hilaris B, et al. Perioperative brach ytherapy and s urgery the electron c one, t he Harrison± A nderson± M ick in s oft tissue sarcomas . In: Brachyther apy O ncology . New (HAM) appl icator used i n the MSKCC s tudy is ¯ ex - York: Memorial Slo an-Kettering Can cer Ce nter, 1 982. ible e nough to conform to most t umor b eds an d can 5 Hilaris B, et al. Limb-sparing t herapy for locally be abu tted w ithout junctional d osimetric in homoge- advanced soft tissue sarco mas. Endocur Hypertherm neity. A l ow r ate of peripheral ne uropathy was also Oncol 1985; 1 :17± 2 4. 6 Karakou sis CP, et al. Feasibility of limb salvage and report ed i n r ectal c ancer p atients treated w ith survival in s oft tissue s arcomas. Cancer 1986;57:484 ± 91. HDR-IORT u sing the HAM app licator in a separate 43± 45 7 Lin dberg R, et al. Conservative surgery an d rad iation MSKCC s tudy. therapy for soft tissue sarc omas. In: Management of primary bone and soft tis sue tumors . Chicago, IL : Year Book M edical, 1 977, 28 9± 2 98. Conclusion 8 Rose nberg SA, et al. Prospective ran domized evalua - tion o f the ro le o f limb-sparing surgery, radiation In su mmary, the preponderance of the data support therapy, and ad juvant chemoimmunotherapy i n t he the hypothesis that IORT c an im prove l ocal co ntrol. treatment of adult so ft-tissue sarcomas. Surgery 1978; When co mpared t o the local r ecurrence r ates of 84:62± 9. 41± 82% after gross to tal resection witho ut IORT 9 Roy J, et al. Adjuvant endocurietherapy in the man age- (Table 1), the ® ve studies evalu ating t his modality, ment of liposarcomas of the ex tremeties. Endocur Hyper- therm Oncol 1990; 2 :29± 3 5. including a randomized tr ial, indicate tha t IORT do es 10 Sc hray MF, et al. Soft tissue sarc oma. Integration o f appear to decrease loc al f ailure to rates of 19± 41% brachytherapy, resection, and e xternal i rradiation. (Table 2). However, with the exception of the 8-year Cancer 1990; 6 6:451± 6 . follow-up o f the randomized NC I trial, follow-up o f 11 Shiu MH, et al. Control of locally advanced e xtremity most o f the other stu dies i s m odest.Th e i mportance soft tissue sarco mas by function- sa ving resection and brachytherapy. Cancer 1984; 53 :1385± 9 2. of long-term obser vation w as demonstrated by Heslin, 12 Shiu MH, et al. Brachytherapy and fun ction-saving who s howed t hat local f ailure c an co mmonly o ccur resection o f soft tissue sarco ma arising in t he limb . Int even in 5 -year surv ivors a t up to 5% per y ear. Thus, J Radiat O ncol Biol Phys 1991; 21 :1485± 9 2. close s urveillance i s r equired to con® r m th e bene® t 13 Su it HD , Russell WO, Martin RG . Management o f of IORT on l ocal control. Nev ertheless, IOR T a ppears patients wit h sarcom a of soft tissue in an extremity. Cancer 1973; 3 1:1247± 5 5. to improve l ocal con trol in o ther sites in cluding c olor- 46 14 Su it HD , Russell WO, Martin RG . Sarcoma of soft ectal, pancreatic an d g astric c ancers. tissue: clinical a nd h istopathologic p arameters and Theoretically, since lo cal re currence re presents th e response to tre atment. Cancer 1975; 3 5:1478± 83 . primary mo de of failure an d u nderlies the cause o f 15 Suit HD, et al. Preoperat ive, intraoper ative, and death in t he majority of retroperitonea l sarcoma postoperative radiation in the t reatment of primary soft tissue s arcoma. Cancer 1985; 55 :2659± 6 7. patients, it would s eem th at a survival b ene® t should 16 Suit HD, et al.Tre atment of the patie nt wit h stag e M 0 be d erived fr om th e incorporation o f IORT. Yet an soft tissue sarco ma. J Clin Oncol 1988; 6:8 54± 62 . obvious im provement in su rvival is n ot appar ent. It 17 Wi llet C, Suit H. Limited su rgery an d e xternal beam may be t hat too f ew patients treated w ith IORT ha ve irradiation in so ft tissue sarc oma. Adv Oncol 1989; been stu died as data of only 183 patients have been 5:26± 29. 16 K. S. H u & L. B . H arrison 18 Ze lefsky MJ, et al. Limb salvage in soft tissue sarcom as 33 Glenn J, et al. Results of multimodality thera py of resect- involving n eurovascular structures u sing c ombined able soft-tissue sarcomas of the retrop eritoneum. Surgery surgical rese ction an d brach ytherapy. Int J Radiat O ncol 1985; 9 7:316± 2 5. Biol Phys 1990; 1 9:913± 8 . 34 Heslin MJ, et al. Prognostic fact ors associated w ith 19 Ze lefsky MJ, et al. Combined su rgical r esection and long-term sur vival for retroperitoneal sarcom a: implica- iridium 19 2 im plantation f or locally advanced a nd recur - tions for management. J Clin Oncol 1997; 15 :2832± 9 . rent de smoid t umors. Cancer 1991; 67 :380± 4. 35 H u K, Harrison LB. Hi gh dose-rate intra operative radi a- 20 Har rison LB, et al. Long-term re sults of a prospective tion thera py (HDR-IORT) for retroperitoneal s arcomas. randomized t rial of adjuvant brachytherapy in t he In: 21st Annual Meeting of the Ame rican Brac hytherapy management of completely res ected sof t tissue s arcomas Society. San Diego, CA, 1999. of the e xtremity and supe r® cial t runk. Int J Radiat 36 A lektiar KM, et al. High dose-rate intrao perative bra chy- Oncol Biol Phys 1993; 2 7:259± 6 5. therapy (HDR-IORT) for retroperitoneal sarc omas. In 21 J aques DP, et al. Management of primary and re cur- press. rent soft -tissue sarcoma of the re troperitoneum. Ann 37 Zhang G, et al. Sarcomas of the ret roperitoneum an d Surg 1990; 21 2:51± 9. genitourinary trac t. J Urol 1989; 14 1:1107± 10 . 22 P etersen I, et al. Use of intraoperative ele ctron beam 38 T e pper JE , et al. Radiation therapy of retroperitoneal radiation the rapy in the man agement o f soft tissue soft tissue sarcom as. Int J Radiat O ncol Biol Phys 1984; sarcoma. In pre ss, 1999. 10:825± 30. 23 Catt on CN , et al. Outcome and prog nosis in re troperi- 39 Wille tt CG , et al. Intraoperative el ectron be am radia- toneal soft tissue sarc oma. Int J Radiat Oncol Bi ol Phys tion t herapy for retroperitoneal so ft tissue sarco ma. 1994; 2 9:1005± 1 0. Cancer 1991; 6 8:278± 83 . 24 v an Doorn RC, et al. Resectable re troperitoneal soft 40 Kiel KD, et al. Preliminary resul ts of protocol R TOG tissue sarco mas. The effec t of extent of resection and 85-07: phase II study of intraoperative rad iation for postoperative radiation t herapy on loc al t umor con trol. retroper itonea l sarcomas. In: 3rd I nternational Cancer 1994; 7 3:637± 4 2. Symposium of Intraoperative Radiation Therapy . Oxford: 25 Singer S, et al. Prognostic fac tors predictive o f survival Pergamon Pre ss, 1991. for truncal and retro peritoneal s oft-tissue sarcoma. Ann 41 Bu ssieres E, et al. Retroperitoneal soft tissue sarc omas: Surg 1995; 22 1:185± 9 5. a pilot stud y o f intraoperative radiatio n the rapy. J Surg 26 M cGrath P C , et al. Improved survival following Oncol 1996; 6 2:49± 5 6. complete e xcision of retroperitoneal s arcomas. Ann Surg 42 Shaw EG, et al. Peripheral ne rve and u reteral t olerance 1984; 2 00:200± 4 . to in traoperative radiatio n the rapy: clinical and dose - 27 Kilke nny JW , 3rd, Bl and KI, Copeland EM , 3 rd. Re tro- response analysis. Radiother O ncol 1990; 1 8:247± 5 5. peritoneal sa rcoma: the Un iversity of Florida e xperi- 43 Ha rrison LB, Enke rWE ,Anderson LL. High-dose-rate ence. J Am Coll Surg 1996; 1 82:329± 3 9. intraoperative ra diation t herapy for colorectal canc er. 28 Fein DA, et al. Manageme nt o f retroper itonea l Oncology (Huntingt) 1995; 9 :737± 41 ; d iscussion 7 42± 8 sarcomas: does d ose e scalation im pact on l ocoregional passim. control? Int J Radiat O ncol Biol Phys 1995; 3 1:129± 34 . 44 Ha rrison LB, Enke rWE ,Anderson LL. High-dose-rate 29 Sin delarWF , et al. Intraoperative rad iotherapy in ret ro- intraoperative ra diation t herapy for colorectal canc er. peritoneal sa rcomas. Final results of a prospective, rand- Oncology (Huntingt) 1995; 9 :679± 83 . omized, c linical tr ial. Arch Surg 1993; 1 28:402± 1 0. 45 Ha rrison LB, et al. High dose rate int raoperative rad ia- 30 Lewis JJ, et al. Retroperitoneal soft -tissue sarcoma: tion the rapy (HDR-IORT) as part of the manag ement analysis of 500 patie nts tre ated a nd follow ed a t a single strategy for locally advanced pr imary and re current institution. Ann Surg 1998; 2 28:355± 65 . rectal c ancer. Int J Radiat O ncol Bi ol Phys 1998; 31 D alton R R, et al. Management o f retroperito neal 42:325± 30. sarcomas. Surgery 1989;1 06:725± 32 ; discussion 7 32± 3 . 46 Gun derson L L, et al. Intraoperative ir radiation: current 32 Cody HSD., et al.The cont inuing c hallenge of retroperi- and f uture status. Semin O ncol 19 97; 2 4:715± 3 1. toneal sarco mas. Cancer 1981; 4 7:2147± 52 . MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

Sarcoma – Hindawi Publishing Corporation

Published: Jan 1, 2000

There are no references for this article.