MOLECULAR AND CLINICAL ONCOLOGY 7: , 2017

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1 336 Effect of intrtumorl bscess/necrosis on the outcome for hed nd neck cncer ptients treted by hypofrctionted stereotctic re irrdition using CyberKnife HIDEYA YAMAZAKI 1,2, MIKIO OGITA 3, KENGO HIMEI 4, SATOAKI NAKAMURA 1, GEN SUZUKI 1, TADAYUKI KOTSUMA 5, KEN YOSHIDA 5 nd YASUO YOSHIOKA 6 1 Deprtment of Rdiology, Grdute School of Medicl Science, Kyoto Prefecturl University of Medicine, Kyoto ; 2 CyberKnife Center, Soseiki Generl Hospitl, Kyoto ; 3 Rdiotherpy Deprtment, Fujimoto Hysuzu Hospitl, Miykonojo, Miyzki ; 4 Deprtment of Rdiology, Jpnese Red Cross Okym Hospitl, Okym ; 5 Deprtment of Rdition Oncology, Ntionl Hospitl Orgniztion Osk Ntionl Hospitl, Osk ; 6 Deprtment of Rdition Oncology, Osk University Grdute School of Medicine, Suit, Osk , Jpn Received Jnury 5, 2016; Accepted July 22, 2017 DOI: /mco Abstrct. The im of the present study ws to elucidte the effect of intrtumorl bscess/necrosis (AN) on the outcome of ptients with recurrent hed nd neck cncer (HNC) treted by stereotctic rdiotherpy. The records of 67 ptients treted with CyberKnife in four institutes between August 2000 nd July 2010 were reviewed. The frequency of AN ppered to be incresed in younger postopertive ptients with lrge ulcertive tumors. The AN + group exhibited better initil response rte compred with the AN group (64 vs. 33%, respectively; P=0.04). The 1 yer locl control rte ws 51 nd 75% in the AN + nd AN groups, respectively (P=0.01), while the respective 1-yer overll survivl rtes were 53 nd nd 71% (P=0.0004). A totl of 21 ptients (31%) experienced grde 3 toxicities, nd crotid blowout syndrome (CBOS) ws found in 11 ptients, resulting in 8 deths. A significntly lrger proportion of ptients in the AN + group developed CBOS (8/18; 44%) compred with the AN group (3/49; 6%) (P=0.001). Therefore, AN my be n importnt prognostic fctor for ptients with recurrent HNC, s well s predictor of lethl toxicity due to CBOS. Introduction Correspondence to: Dr Hidey Ymzki, Deprtment of Rdiology, Grdute School of Medicl Science, Kyoto Prefecturl University of Medicine, 465 Kjiicho Kwrmchi Hirokoji, Kmigyo ku, Kyoto , Jpn E mil: hidey10@hotmil.com Key words: hed neck cncer, reirrdition, stereotctic rdiotherpy, crotid blowout syndrome, CyberKnife, bscess necrosis The tretment of unresectble hed nd neck cncer (HNC) hs improved with the use of modern chemotherpy nd rdiotherpy (1,2). However, locoregionl filure remins mjor concern, preventing complete cure. Although slvge surgery hs the highest disese erdicting potentil, only one third of ptients re eligible (3). After surgery, chemotherpy is frequently preferred option; however, the resulting medin survivl time is <9 months (4). With the dvncement of modern rdition techniques, re irrdition using dvnced technologies, including intensity modulted rdition therpy nd/or stereotctic rdiotherpy, hs become promising therpeutic option. The imge guided stereotctic rdiotherpy system CyberKnife enbles precise dose delivery over short tretment periods (5 9). Severl institutions, including ours, hve reported on the outcome nd toxicity of re irrdition using CyberKnife hypofrctionted stereotctic body rdition therpy (SBRT) (5 10). Lethl crotid blowout syndrome (CBOS) ws previously investigted in ptients with HNC (7,9), nd the findings prompted the subsequent investigtion of predisposing fctors for CBOS (10). The presence of ulcertion nd lymph node irrdition were found to be risk fctors for CBOS, nd the CBOS index, including crotid invsion of >180, ws found to be useful for risk fctor clssifiction nd determintion of indictions for re irrdition (10). As n incresed frequency of AN ws observed mong CBOS cses in n initil single institution study by our group (7), n ssessment of multi institutionl records of ptients with HNC ws conducted, focusing on AN. The im of the present study ws to investigte the role of AN in tumor control nd toxicity following re irrdition using CyberKnife SBRT in HNC ptients. Ptients nd methods Ptients. The medicl records of ptients who underwent CyberKnife SBRT (Accury; Sunnyvle, CA, USA) in four hospitls [Soseiki Generl Hospitl (Kyoto, Jpn), Osk University Hospitl (Osk, Jpn), Fujimoto Hysuzu Hospitl (Miykonojo, Jpn) nd Okym Kyokuto Hospitl

2 YAMAZAKI et l: EFFECT OF ABSCESS/NECROSIS IN HNC ON CYBERKNIFE RE-IRRADIATION OUTCOME 337 Tble I. Chrcteristics nd tretment fctors of ptients. Abscess/necrosis ( ) Abscess/necrosis (+) (n=49) (n=18) No. of ptients No. of ptients Vribles or medin (rnge) (%) or medin (rnge) (%) P vlue Age (yers) 63 (45 83) 60 (44 66) Gender Femle 11 (22) 4 (22) Mle 38 (78) 14 (78) Disese Nsophryngel cncer 32 (65) 7 (39) Orophryngel cncer 9 (18) 8 (44) Hypophryngel cncer 8 (16) 2 (11) Orl cncer 0 (0) 1 (6) Irrdited re Primry site 39 (80) 11 (61) Lymph node 10 (20) 7 (39) Lymph node lone 4 (40) 2 (29) Primry nd lymph node 6 (60) 5 (71) Ulcertion No 41 (84) 9 (50) Yes 8 (16) 9 (50) Surgicl history No 36 (73) 8 (44) 0.02 Yes 13 (27) 10 (56) Plnning trget volume (cm 3 ) 13.5 (1 339) 53 ( ) Tretment intervl (months) 17.6 ( ) 24 ( ) Response 15/16 (64) 3/3 (33) Complete/prtil response. Bold print indictes sttisticl significnce. (Okym, Jpn)] between August 2000 nd July 2010 were reviewed for inclusion in the present study. Among the ptients with HNC who received re irrdition up to the prescribed dose for residul or recurrent tumors within the irrdited re, only those who stisfied the following criteri were included: Ptients who hd undergone imging nlysis prior to SBRT to confirm the presence or bsence of AN nd hd completed course of rdicl tretment, including previous rdiotherpy t 40 Gy [biologicl equivlent 2 Gy frctions (EQD2) described in detil below], with or without chemotherpy nd surgery. Previous rdiotherpy consisted of Gy/20 62 frctions (1.2 2 Gy frctiontion), with estimted EQD2 of Gy (α/β=10). A totl of 67 ptients were considered eligible for ssessment. The ptient chrcteristics re listed in Tble I nd representtive cse of ptient with intrtumorl AN is presented in Fig. 1. The conventionl technique using liner ccelertor ws used during the first course of rdiotherpy. SBRT re irrdition ws performed using the CyberKnife system. The ptients received medin dose of 30 Gy (rnge, Gy) over medin of five dily frctions (rnge, Figure 1. Presenttion of cse with intrtumorl bscess/necrosis. A 61 yer old mn with orophryngel cncer (right lterl wll) underwent preopertive rdiotherpy t 40 Gy in 20 frctions with intr rteril chemotherpy (cispltin) followed by surgery (primry cncer nd right neck dissection) nd ws pthologiclly clssified s T3N0. A recurrent tumor ws detected t the primry site with subsequent extension to the Rouvière node 4 months lter. The ptient then received CyberKnife hypofrctionted stereotctic rdition therpy with 37 Gy dministered in 10 frctions. The ptient exhibited n intrtumorl bscess/necrosis (rrow) with ulcertion with plnning trget volume of 132 cm 3. One month fter tretment, the ptient developed crotid blowout syndrome nd succumbed within 1 dy.

3 338 Tble II. Anlysis of prognostic fctors. Vribles No. of ptients 1-y LC (%) P vlue MST (months) 1 y OS (%) P vlue Age (yers) < Sex Mle Femle PTV (cm 3 ) > Abscess/necrosis (AN) Yes <0.001 No Ulcertion Yes <0.001 No Primry cncer type NPC <0.001 Others Tretment intervl (months) > Prescribed dose (EQD2), Gy > Surgicl history Yes No Intervl between CyberKnife stereotctic body rdition therpy nd prior rdition therpy. Bold print indictes sttisticl significnce. 1 y LC, one-yer locl control; MST, medin survivl time; OS, overll survivl; NPC, nsophrygel cncer; EQD2, biologiclly effective dose in 2 Gy frctions; PTV, plnning trget volume. A B C Figure 2. Effect of intrtumorl AN on the outcome for ptients with hed nd neck cncer. Solid line, AN cses; broken line, AN + cses. (A) Locl control rte, (B) overll survivl rte nd (C) CBOS-free survivl rte depending on the presence of AN. AN, bscess/necrosis; CBOS, crotid blowout syndrome. 1 8 frctions) tht were prescribed t D90, D95, or mrginl dose. D90 (D95) ws defined s minimum dose covering 90% (95%) of the plnning trget volume (PTV). The mrginl dose prescription ws defined s the percentge (mximum dose, 100%) of the isodose curve covering the PTV. None of the ptients received chemotherpy. All irrdited lesions were locted inside res previously subjected to high dose irrdition. Prior to SBRT, the presence of AN ws confirmed

4 YAMAZAKI et l: EFFECT OF ABSCESS/NECROSIS IN HNC ON CYBERKNIFE RE-IRRADIATION OUTCOME 339 by imging nlysis, such s computed tomogrphy (CT) nd/or mgnetic resonnce imging (MRI), contrst-enhnced if required. AN ws identified s focl re of low density with surrounding rim of high density nd/or enhncement on CT, or focl re of high signl intensity on T2 weighted imges, or focl re of low signl intensity on T1 weighted imges with surrounding rim of enhncement on MRI (11). These interprettions were mde by t lest one dignostic rdiologist nd one rdition oncologist. The presence of mucosl ulcertion of the upper erodigestive trct ws determined by visul inspection (fibroscopy if required) nd/or imging nlysis (CT nd/or MRI). EQD2 ws clculted using the liner qudrtic model s follows: EQD2=prescription dose x (α/β+dose per frction)/(α/β+2), where α/β = 10 for tumors nd 3 for orgns t risk. In principle, follow up by physicl exmintion ws performed t intervls of t lest 1 month for the first yer nd t intervls of 3 6 months therefter. Exmintion with imging methods, such s CT nd/or MRI nd/or ultrsonogrphy, ws performed fter 3 nd 6 months, 1, 1.5 nd 2 yers, nd t 1 yer intervls therefter, or when locl or lymph node recurrence ws suspected. Initil response ws ssessed using the Response Evlution Criteri in Solid Tumors version 4.0 ( html). Written informed consent ws obtined from the ptients for the publiction of their dt nd ccompnying imges. Sttisticl nlysis. All sttisticl nlyses were performed using Sttview 5.0 sttisticl softwre (SAS Institute, Inc., Cry, NC, USA). The percentge vlues were nlyzed using the χ 2 test, nd vlues were compred using Mnn Whitney U test. Cumultive incidences were estimted by the Kpln Meier method. The durtions were clculted from the first dy of CyberKnife SBRT. Vribles tht hd P vlues <0.05 were further tested by multivrite nlysis using Cox proportionl hzrds model. The cut-off vlue ws set t the verge or medin vlue of ech vrible if not otherwise stted. All nlyses used significnce level of P<0.05. Results AN is ssocited with poor prognosis of ptients with recurrent HNC following SBRT. The medin follow up time for the surviving ptients fter SBRT ws 17 months (rnge, months). As shown in Tble I, the frequency of AN ws significntly incresed in ptients who received surgery, nd those who hd lrge, ulcertive tumors; furthermore, the medin ge in the AN + group ws significntly lower compred with tht in the AN - group. Thus, younger, postopertive ptients with lrge ulcertive tumors tended to exhibit AN. In prticulr, AN exhibited strong correltion with ulcertion (P=0.001; Tble I). The AN - group exhibited better initil response rte (15 complete responses + 16 prtil responses = 64%) compred with the AN + group (3 complete responses + 3 prtil responses = 33%) (P=0.04). The locl control (LC) rte in the AN + group ws 51%, which ws significntly lower compred with tht in the AN - group (75%; P=0.01). The medin survivl time nd 1 yer survivl rtes for the AN + nd AN - groups were 13.6 vs months (P<0.001) nd 53 vs. 71% (P=0.0004), respectively (Tble II Tble III. Risk fctors for CBOS. Fctors No CBOS CBOS % Crotid invsion 180 AN 20 - (0) AN (50) Crotid invsion >180 AN 26 3 (10) AN (44) Percentge represents CBOS/(no. CBOS+CBOS). AN, bscess/necrosis; CBOS, crotid blowout syndrome. nd Fig. 2). PTV, ulcertion, primry site (nsophrynx or other) nd prescribed dose were sttisticlly significnt predisposing fctors for reduced overll survivl (OS) ccording to the univrite nlysis (Tble II). There were sttisticlly significnt differences in LC nd OS rtes between the AN + nd AN groups (Tble II, Fig. 2), indicting poor prognosis for ptients with AN. Toxicity. A totl of 21 ptients (31%) experienced grde 3 dverse effects. Among them, CBOS ws found in 11 ptients nd resulted in 8 deths, wheres the 3 remining ptients recovered following intervention. All ftl dverse effects were due to CBOS. A totl of 44% (8/18) of ptients in the AN + group nd 6% (3/49) of ptients in the AN - group developed CBOS (P=0.001). The AN + group exhibited lower CBOS-free survivl rtio (65% t 1 yer) compred with the AN - group (98% t 1 yer; P<0.0001; Fig. 2C). In ddition, mong ptients with crotid invsion t 180, only AN + recurrent orl cncer ptients exhibited CBOS, wheres mong ptients with crotid invsion t >180, 44% of AN + nd 10% of AN - ptients developed CBOS (P<0.01; Tble III). Other grde 3 rdition-induced dverse effects included 2 cses of mucositis requiring percutneous endoscopic gstrostomy, 2 cses of lterl lobe necrosis (grde 4 in 1 cse), 5 cses of fistuls nd 1 cse ech of bone necrosis, soft tissue necrosis, visul disturbnce nd ulcertion. Discussion To the best of our knowledge, the present study ws the first to investigte AN s prognostic fctor in ptients with recurrent HNC following re irrdition using SBRT. Low density res on CT nd/or wter intensity res on MRI, which my indicte centrl necrosis in the lymph node nd/or ring enhncement in contrst enhnced imges (10,11), re occsionlly encountered in routine clinicl exmintion. However, it remins elusive whether these findings ffect the outcome nd/or dverse effects of SBRT in ptients with recurrent HNC. The presence of AN hs been identified s fctor ssocited with the inflmmtory nd/or infection process, which wekens the rteril wlls nd my result in CBOS. In ddition, hypoxic tumor environment indictes rdioresistnt nd infiltrtive nture, which my be ssocited with worse prognosis. Certin studies hve indicted tht centrl necrosis in lymph nodes is indictive of mlignncy

5 340 nd poor prognosis with extrcpsulr extension (12,13). However, ptients with humn ppillom virus infection hve been found to hve better prognosis compred with ptients without this infection, nd their lymph node metstses frequently disply cystic chnges (14). In the present study, the detiled morphology of AN, such s wll thickness nd smoothness, could not be ssessed due to the heterogeneous methods of imge collection (CT nd MRI, with or without contrst enhncement, with the use of different imge cquisition techniques nd conditions); however, imge interprettion for dignostic purposes should be performed in future studies nd the results of the present study should be interpretted with cution. Ptients with ftl CBOS who exhibited AN were encountered in our previous study (7). CBOS is one of the most devstting complictions of HNC nd minly occurs fs postopertive compliction, prticulrly in ptients with history of rdiotherpy nd/or when the tumor compromises the vsculr xis (7 10,15 17). McDonld et l (16) hve reported tht CBOS following re irrdition is rre [41/1,554 (2.6%)] nd often ftl (75%) event. Zoumln et l (12) reported tht 15 of 33 tretment relted deths (40%) were ssocited with CBOS in cohort of 166 ptients (overll mortlity rte, 9%). Similrly, we lso previously reported tht CBOS occurred in 8.4% of cses mong 381 HNC ptients treted with 484 re-irrdition sessions t seven Jpnese CyberKnife institutions, nd 69% of the cses were ftl (10). In ddition, the presence of ulcertion in ssocition with crotid invsion t >180 ws n importnt risk fctor for CBOS (11). The present study identified AN s n dditionl risk fctor for CBOS in ptients with recurrent HNC fter SBRT. The present study hd severl limittions. Due to the retrospective nture of the study nd inclusion of only smll number of ptients with short follow up period, selectionnd physicin bsed bises my exist. Therefore, the results of the present study should be confirmed in prospective tril with lrger number of ptients with longer follow up periods. In ddition, there were severl confounding fctors exhibiting correltion with AN, such s ge, postopertive sttus, tumor volume nd ulcertion. Therefore, lthough AN ws not found to be n independent risk fctor, it should be tken into considertion when determining ptient's eligibility for re irrdition using SBRT. In conclusion, younger postopertive ptients with lrge nd ulcertive tumors tended to exhibit AN. Thus, AN is n importnt prognostic fctor for HNC ptients following reirrdition using CyberKnife, s well s predictor of ftl CBOS. References 1. Mzeron R, To Y, Lusinchi A nd Bourhis J: Current concepts of mngement in rdiotherpy for hed nd neck squmous cell cncer. Orl Oncol 45: , Vokes EE, Weichselbum RR, Lippmn SM nd Hong WK: Hed nd neck cncer. 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