Tumor Vascularity Does Not Predict Response to Yttrium-90 Radioembolization for Hepatic Metastases from Colorectal Cancer

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1 Originl Article 3 Tumor Vsculrity Does Not Predict Response to Yttrium-90 Rdioemboliztion for Heptic Metstses from Colorectl Cncer Alipi V. Nydenov Willim P. Hrris 2 Guy E. Johnson 3 Dniel S. Hippe 4 Siddhrth A. Pdi 5 Deprtment of Medicine, University of Wshington, Settle, Wshington, United Sttes 2 Division of Medicl Oncology, Deprtment of Medicine, University of Wshington, Settle, Wshington, United Sttes 3 Section of Interventionl Rdiology, Deprtment of Rdiology, University of Wshington, Settle, Wshington, United Sttes 4 Deprtment of Rdiology, University of Wshington, Settle, Wshington, United Sttes 5 Section of Interventionl Rdiology, Deprtment of Rdiology, Dvid Geffen School of Medicine t University of Cliforni, Los Angeles, United Sttes Address for correspondence Siddhrth A. Pdi, MD, Division of Interventionl Rdiology, Deprtment of Rdiology, Dvid Geffen School of Medicine t University of Cliforni, Los Angeles, 757 Westwood Plz, Room 225, Los Angeles, CA, 90095, United Sttes (e-mil: spdi@gmil.com). J Clin Interv Rdiol ISVIR 208;2:3 2 Abstrct Keywords rdioemboliztion locoregionl therpy liver-directed therpy The purpose of this study ws to determine whether the degree of tumor vsculrity bsed on imging hs n impct on tumor response nd survivl in ptients with metsttic colorectl cncer (mcrc) to the liver undergoing yttrium-90 rdioemboliztion. A retrospective study of 75 mcrc ptients from single-institution undergoing rdioemboliztion ws performed over 7-yer period. Tumors were ctegorized s hypo- or hypervsculr bsed on digitl subtrction ngiogrphy (DSA) nd C-rm CT during mpping ngiogrphy. Tumor response nd survivl were compred between ech group, fter undergoing rdioemboliztion. Hypervsculr tumors were present in 37 of 75 (49%) ptients ccording to DSA. Of 37 ptients who underwent C-rm CT during the procedure, 22 (59%) hd tumors clssified s hypervsculr. There were no significnt differences in tumor response rtes when vsculrity ws strtified by DSA or C-rm CT. Medin progression-free survivl (PFS) ws versus 28 dys (p = 0.4) between DSA hypervsculr nd hypovsculr cses, nd medin overll survivl (OS) ws 439 versus 342 dys (p = 0.96). When strtified by C-rm CT, medin PFS ws 33 versus 244 dys (p = 0.83) nd medin OS ws 489 versus 342 dys (p = 0.74) for hypervsculr nd hypovsculr cses, respectively. Tumor vsculrity bsed on DSA or C-rm CT does not predict imging response or survivl fter rdioemboliztion nd should not be used s criterion for selecting cndidtes for rdioemboliztion for heptic mcrc. Introduction Colorectl cncer (CRC) is the third most common cncer worldwide. Over one-hlf of ptients with CRC develop metstses (mcrc), most commonly involving the liver. 2,3 Liver metstses re the principl cuse of morbidity nd mortlity in ptients with mcrc. 4,5 Though systemic chemotherpy is the stndrd tretment for stge IV colorectl cncer, the durbility of this option is limited in the slvge setting. received July 29, 207 ccepted fter revision September 29, 207 published online December 4, 207 DOI /s ISSN Copyright 208 by Indin Society of Vsculr nd Interventionl Rdiology

2 4 Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l. Yttrium-90 ( 90 Y) rdioemboliztion hs grnered incresing interest in controlling the growth of liver CRC metstses in ptients who re not cndidtes for surgicl resection or bltion. It is most frequently used in the slvge setting where rndomized prospective trils hve shown 3-month survivl dvntge compred with stndrd chemotherpy. 6 In retrospective mtched-pir cohort comprison, 5-month survivl dvntge ws demonstrted compred with best supportive cre. 7 Despite encourging dt, there remins wide disprity in response for CRC ptients undergoing rdioemboliztion. The resons for response differences hve not been fully elucidted. Wheres bsorbed rdition dose my impct tumor response nd led to improved outcomes, 8 the ssessment of bseline chrcteristics to better strtify ptients is needed. Some erly dt with diffusion-weighted imging hve shown promise; however, mgnetic resonnce is not routinely obtined in ptients with colorectl cncer t most centers. 9 The presence of nonresponders in the mcrc popultion is prticulrly problemtic for severl resons. The use of rdioemboliztion in the erly stge my dely the initition of ptient's systemic chemotherpy. Furthermore, rdioemboliztion my result in short- nd long-term toxicity tht my hinder further systemic therpy nd survivl. Therefore, effective strtifiction of ptients s high- or low-likelihood responders remins n unmet need with potentil to optimize clinicl outcomes in ptients with CRC liver metstses. In minimlly embolic therpy such s rdioemboliztion, incresed tumor vsculrity should theoreticlly correlte with better response due to more effective delivery of 90 Y microspheres into trget tumors. The purpose of this study ws to determine whether tumor vsculrity predicted imging response or survivl in this setting. Methods Ptient Selection A retrospective study ws conducted t single institution by ccessing the hospitl's ptient informtion system to identify ll ptients who underwent 90 Y rdioemboliztion for heptic mcrc between Mrch 2008 nd Mrch 205. This ws collected into dtbse nd pproved by the hospitl's institutionl review bord with wiver of informed consent. All ptients were discussed in multidisciplinry liver tumor bord. This bord comprises medicl oncologists, heptobiliry surgeons, pthologists, rdition oncologists, dignostic rdiologists, nd interventionl rdiologists. Rdioemboliztion ws not offered to ptients who were cndidtes for surgicl resection or therml bltion. Ptients were considered for rdioemboliztion if they hd liver- only or liver-dominnt mcrc. Ptients hd either filed t lest one line of chemotherpy or rdioemboliztion ws performed s n djunct to first-line chemotherpy. A totl of 89 ptients were identified. Fourteen ptients were excluded for incomplete records or lck of follow-up, leving totl of 75 ptients. Prior to the procedure, ll ptients underwent bseline stging with contrst-enhnced computed tomogrphy (CT) of the chest, bdomen, nd pelvis. Timing of bdominl imging ws performed in the portl venous phse (70 0 seconds fter intrvenous contrst dministrtion). Imging ws obtined within month of the mpping ngiogrm. Rdioemboliztion Rdioemboliztion ws performed using stndrd methods with either glss (TherSphere, BTG Interntionl) or resin (SirSphere, Sirtex) microspheres. This included mpping ngiogrm with lung shunt frction determintion, 90 Y microsphere infusion, nd posttherpy Bremsstrhlung single-photon emission computed tomogrphy (SPECT)/CT. Device selection (glss vs. resin) ws bsed on multiple fctors, including opertor preference, device vilbility t the study institution t the time of the procedure, nd ptients' medicl insurnce guidelines. If necessry, prophylctic coil emboliztion of extrheptic rteries ws performed to prevent nontrget rdioemboliztion to extrheptic structures (e.g., bowel). In ll tretments, selective ctheteriztion nd infusion of the tumor-feeding rteries ws performed whenever techniclly fesible. In cses of multifocl disese in which selective rdioemboliztion ws not fesible, sequentil lobr pproch ws tken. For the mpping ngiogrm, 4 or 5F dignostic ctheter ws used to select the viscerl rtery of interest (superior mesenteric nd celic rteries). Selective ctheteriztion of the lobr heptic rteries ws performed with 2.8F coxil microctheter (Progret, Terumo Medicl Corportion). Digitl subtrction ngiogrphy (DSA) ws performed t three frmes per second (Philips) with power injection of iodinted contrst (diluted to 50 70%, depending on ptient body hbitus). Contrst injection ws optimized to mximize tissue uptke without significnt rteril reflux from the microctheter tip position. Additionl three-dimensionl (3D) imging of the bdomen ws performed using C-rm CT with contrst injection vi the microctheter positioned within the lobr heptic rtery. Imging ws cquired over 5-second timefrme with contrst injection occurring both prior to nd during imge cquisition. This llowed for enhncement to be identified both in the rteril nd prenchyml phses. For glss microsphere dosimetry, n intended dose of 20 gry to the trget perfused tissue ws delivered. For resin microsphere dosimetry, ctivity ws clculted bsed on the body-surfce re formul, ccording to the pckge insert. Evlution of Tumor Imging Chrcteristics Rdiologists blinded to ptient informtion nd outcome dt reviewed imging nd ctegorized ech tumor s hypo- or hypervsculr ccording to bseline contrst-enhnced CT (portl venous phse), 2 C-rm CT obtined during mpping ngiogrphy, nd 3 DSA during the mpping procedure. On bseline CT nd C-rm CT, if the tumor enhnced to greter degree thn the surrounding heptic prenchym, it ws ctegorized s hypervsculr. Peripherl hypervsculrity (with centrl hypoenhncement) ws ctegorized s hypervsculr. Conversely, if the tumor enhnced less thn the surrounding prenchym, it ws ctegorized s hypovsculr ( Fig. ). Likewise, for DSA, tumors

3 Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l. 5 Fig. C-rm CT during mpping ngiogrm with contrst injection from the left heptic rtery demonstrting () tumor hypovsculrity nd (b) tumor hypervsculrity. were ctegorized s hypo- or hypervsculr bsed on the degree of vsculrity reltive to the surrounding heptic prenchym ( Fig. 2). Ptient Follow-up nd Response Evlution Follow-up visits nd imging (portl venous phse contrst-enhnced CT) took plce month following rdioemboliztion nd every 3 months therefter. Toxicity ws ssessed ccording to Common Terminology Criteri for Adverse Events (CTCAE), version Tumor response ws ctegorized s complete response, prtil response, stble disese, or progressive disese, ccording to Response Evlution Criteri in Solid Tumors (RECIST) criteri version.. Sttisticl Anlysis Ctegoricl vribles were summrized s number (percentge) nd continuous vribles s men (interqurtile rnge [IQR]) or medin (rnge). Ctegoricl vribles were compred between vsculrity groups using Fisher's exct test nd continuous vribles were compred between groups using the Mnn-Whitney test. Overll survivl (OS) nd progression-free survivl (PFS) were ssessed using Kpln-Meier curves. Index tumor progression ws ssessed using the cumultive incidence curve to ccount for the competing risk of deth. 2 Medin OS, PFS, nd timeto- progression were estimted from these curves for ech vsculrity group. Event rtes were compred between Fig. 2 Digitl subtrction ngiogrm during mpping ngiogrm with contrst injection from the right heptic rtery demonstrting () tumor hypovsculrity nd (b) tumor hypervsculrity.

4 6 Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l. vsculrity group using Cox proportionl-hzrd models (survivl nd progression-free survivl) nd the fine-gry proportion subdistribution hzrd model (index tumor progression). 3 Hzrd rtios (HRs) were used to summrize differences in event rtes between the vsculrity groups; 95% confidence intervls (CIs) were used to ssess the extent of the potentil differences between vsculrity groups. All sttisticl clcultions were conducted with the sttisticl computing lnguge R (version 3..; R Foundtion for Sttisticl Computing). Throughout, two-sided tests nd CIs were used, with sttisticl significnce defined s p < Results Seventy-five ptients with mcrc treted with rdioemboliztion were included. Ptients ge rnged from 29 to 8 yers (medin, 57), nd 55% of the ptient popultion ws femle ( Tble ). The colon ws the primry site of mlignncy in 79% of ptients nd rectum in 2% of ptients; metsttic disese ws dignosed t the sme time s the primry tumor in 73%. KRAS muttion ws identified in 63%. The medin follow-up time fter tretment ws 375 dys (IQR: dys). Of the 75 ptients treted, 37 (49%) hd hypervsculr tumors determined by DSA. Thirty-seven ptients hd C-rm CT imging during mpping ngiogrphy, of which 22 (59%) were clssified s hypervsculr nd 5 (4%) hypovsculr. Ptients who did not hve C-rm CT were either due to lck of this technology in one of the ngiogrphy suites, or due to significnt respirtory motion in which C-rm CT could not be performed. Although they were not vilble in ll ptients, C-rm CT imges were vilble in similr frction of ptients with hypervsculr tumors per DSA s ptients with hypovsculr tumors (49% vs. 50%, p > 0.99). Of the 37 ptients with both DSA nd C-rm CT imges, there ws concordnce of imging hypervsculrity in 29 (78%). Tumor vsculrity ws lso exmined on bseline contrst-enhnced CT. By CT, only 5 of 75 (7%) ptients' tumors were clssified s hypervsculr, ll of which were concordnt with DSA nd C-rm CT. Becuse of the limited smple size of tumors clssified s hypervsculr by CT, these clssifictions by bseline CT were not nlyzed further. Grouped ccording to vsculrity, bseline ptient chrcteristics re shown in Tble, nd bseline tumor chrcteristics re shown in Tble 2. There were no significnt differences in bseline ptient chrcteristics between ptients who hd hyper- or hypovsculr tumors ( Tble ), with the exception of the site of the primry tumor. The only tumor or tretment chrcteristic tht differed significntly between hypo- nd hypervsculr tumors ws the 90 Y device used ( Tble 2), where hypervsculr tumors were more likely to be treted using glss microspheres thn hypovsculr tumors bsed on DSA nd C-rm CT. After tretment, most clinicl complictions nd biochemicl toxicities were uncommon, nd not significntly different between the different groups of ptients ( Tble 3). Of the 68 ptients with imging follow-up, 5.9% hd complete response by RECIST criteri. Though rtes of complete response were higher in the hypovsculr groups by DSA nd C-rm CT, these differences did not rech sttisticl significnce ( Tble 4). There were no significnt differences in OS (medin: 439 vs. 342 dys, p = 0.96), PFS (medin: versus 28 dys, p = 0.4), or heptic time-to-progression (medin: 33 vs. 244 dys, p = 0.83) between DSA hyper- nd hypovsculr tumors ( Fig. 3). The ssocited HRs re summrized in Tble 5. Results were not meningfully chnged fter djusting for the 90 Y device used. Similrly, there were no significnt differences in OS (medin: 489 vs. 342 dys, p = 0.74), PFS (medin: 00 vs. 52 dys, p = 0.62), or heptic time-to-progression (medin: 23 vs. 273 dys, p = 0.42) between C-rm CT hyper- nd hypovsculr tumors ( Fig. 4). The ssocited HRs re summrized in Tble 6. Discussion Growing evidence suggests tht 90 Y rdioemboliztion in ddition to chemotherpy my be superior to chemotherpy lone for refrctory liver mcrc. 6,4 6 However, subset of ptients my experience toxicity or my fil to chieve heptic tumorl stbility or response. According to recently published phse III tril, lthough ddition of rdioemboliztion to fluorourcil (5FU) incresed the proportion of ptients with stble disese from 35 to 76% nd resulted in prtil response in 0% of ptients (compred with 0% in the 5FU-only group), there were still 0% of ptients with disese progression fter rdioemboliztion. 6 Similrly, prospective studies hve reported tht between 4.8 nd 37% of ptients hve progressive disese despite rdioemboliztion, nd retrospective studies hve reported s high s 23% progressive disese bsed on rdiogrphic response. 7 Therefore, it is resonble to conclude tht there is sizeble portion of ptients who do not benefit from rdioemboliztion, nd it remins n open question how this cohort cn be identified priori. Severl fctors hve been ssocited with poor outcomes fter rdioemboliztion. Two groups hve reported tht more thn 3 prior lines of chemotherpy re ssocited with poor response to rdioemboliztion. 8,9 It is uncler whether this is result of the effect of prior chemotherpy on the susceptibility of tumor tissue to rdiotherpy, or if multiple prior lines of chemotherpy re simply mrker of ggressive tumors. Documented predictors of dverse outcomes fter rdioemboliztion include lrge heptic burden of disese, extrheptic disese, nd lymph node involvement. 7,8,20,2 Additionl fctors ssocited with dverse outcomes fter rdioemboliztion include elevted bseline tumor mrkers nd rectl primry mcrc. 8,20 Though multiple prognostic fctors re likely required to identify pproprite ptients for rdioemboliztion, our study exmines the potentil utility of rdiogrphic mesures of tumor vsculrity to ugment ptient selection. This study demonstrtes tht tumor vsculrity, s mesured by C-rm CT nd DSA, does not correlte with tumor response or survivl. These dt suggest tht lthough

5 Tble Ptient chrcteristics by vsculrity Vrible All (n = 75) Vsculrity by DSA Hypervsculr (n = 37) Hypovsculr (n = 38) p Vlue b Vsculrity by C-rm CT Hypervsculr (n = 22) Hypovsculr (n = 5) Sex Mle 34 (45.3) 5 (40.5) 9 (50.0) (3.8) 9 (60.0) 0. Femle 4 (54.7) 22 (59.5) 9 (50.0) 5 (68.2) 6 (40.0) Age (y) 57 (29 8) 57 (30 8) 58 (29 75) (35 72) 55 (30 75) > 0.99 ECOG score 0 39 (52.0) 20 (54.0) 9 (50.0) > (40.9) 0 (66.7) (4.3) 5 (40.5) 6 (42.) 0 (45.5) 4 (26.7) 2 5 (6.7) 2 (5.4) 3 (7.9) 3 (3.6) (6.7) Primry tumor site c Colon 57 (79.2) 3 (86.) 26 (72.2) (90.9) 5 (38.5) Timing of heptic metsttis dignosis c Rectum 5 (20.8) 5 (3.9) 0 (27.8) 2 (9.) 8 (6.5) Metchronous with primry Synchronous with primry 20 (27.4) 7 (9.4) 3 (35.) (8.2) 5 (35.7) (72.6) 29 (80.6) 24 (64.9) 8 (8.8) 9 (64.3) KRAS muttion Wild type 8 (36.7) 9 (37.5) 9 (36.0) > (44.4) 4 (36.4) 0.72 sttus c Mutnt 3 (63.3) 5 (62.5) 6 (64.0) 0 (55.6) 7 (63.6) Crcinoembryonic 32.6 (.2,658) 32.6 (.2,658) 28.2 (.5 993) (.8 694) 8.8 ( ) 0.4 ntigen c Bilirubin 0.7 (0.3.9) 0.7 (0.3.9) 0.6 (0.3.5) (0.3.5) 0.7 (0.4.3) 0.73 Albumin 3.7 (. 4.5) 3.8 (. 4.5) 3.6 ( ) (. 4.5) 3.5 ( ) 0.36 Abbrevitions: CT, computed tomogrphy; DSA, digitl subtrction ngiogrphy; ECOG, Estern Coopertive Oncology Group. Vlues re no. (%) or medin (rnge). b Fisher s exct test or the Mnn-Whitney test. c Ptients with missing vlues for primry tumor site (n = 3), timing of dignosis (n = 2), KRAS sttus (n = 26), or crcinoembryonic ntigen (n = 23) were excluded. p Vlue b Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l. 7

6 Tble 2 Tumor nd tretment chrcteristics by vsculrity Vrible All (n = 75) Vsculrity by ngiogrphy Hypervsculr (n = 37) Hypovsculr (n = 38) p Vlue b Vsculrity by C-rm CT Hypervsculr (n = 22) Hypovsculr (n = 5) No. of tumors 5 (6.7) 2 (5.4) 3 (7.9) 0.3 (4.5) (6.7) (4.7) 9 (24.3) 2 (5.3) 6 (27.3) (6.7) (3.3) 5 (3.5) 5 (3.2) 4 (8.2) 2 (3.3) (65.3) 2 (56.8) 28 (73.7) (50.0) (73.3) Tumor distribution Bilobr 62 (82.7) 29 (78.4) 33 (86.8) (8.8) 3 (86.7) > 0.99 Long xis tumor (lrgest) dimension (mm) Unilobr 3 (7.3) 8 (2.6) 5 (3.2) 4 (8.2) 2 (3.3) 44 (4 40) 48 (5 30) 40 (4 40) (23 30) 34 (4 9) 0.6 Infiltrtive tumor 8 (0.7) 5 (3.5) 3 (7.9) (3.6) 2 (3.3) > 0.99 Tumor burden > 50% 7 (9.3) 2 (5.4) 5 (3.2) (9.) 2 (3.3) > 0.99 Portl vein thrombus 4 (5.3) 2 (5.4) 2 (5.3) > (9.) (6.7) > 0.99 Definite extrheptic spred 3 (7.3) 5 (3.5) 8 (2.) (22.7) 5 (33.3) 0.7 Prior liver tretment Resection 9 (25.3) (29.7) 8 (2.) (27.3) 2 (3.3) 0.43 Abltion 6 (2.3) 9 (24.3) 7 (8.4) 0.58 (4.5) 4 (26.7) 0.4 Chemoemboliztion (.3) (2.7) 0 (0.0) (0.0) 0 (0.0) > 0.99 Externl bem rdition p Vlue b 2 (2.7) (2.7) (2.6) > 0.99 (4.5) (6.7) > 0.99 Prior lines of chemotherpy b 0 (.4) 0 (0.0) (2.6) (0.0) (6.7) (33.8) 3 (36.) 2 (3.6) 0 (45.5) 4 (26.7) 2 28 (37.8) 2 (33.3) 6 (42.) 8 (36.4) 7 (46.7) (27.0) (30.6) 9 (23.7) 4 (8.2) 3 (20.0) Lung shunt frction (%) 3. (.0 2.4) 3.0 (.0 2.4) 3.2 (.2 9.8) (.0 2.4) 3.2 ( ) Y device infused Resin 43 (57.3) 5 (40.5) 28 (73.7) (8.2) 8 (53.3) Glss 32 (42.7) 22 (59.5) 0 (26.3) 8 (8.8) 7 (46.7) Loction of 90 Y infusions Right lobe only 7 (9.3) (2.7) 6 (5.8) (3.6) 3 (20.0) 0.50 Left lobe only 3 (4.3) 8 (48.6) 3 (34.2) 2 (54.5) 5 (33.3) Both lobes 37 (49.3) 8 (48.6) 9 (50.0) 7 (3.8) 7 (46.7) Abbrevition: CT, computed tomogrphy. Vlues re no. (%) or medin (rnge). b Fisher s exct test or the Mnn-Whitney test. c Ptients with missing vlues for prior chemotherpy (n = ), chemotherpy fter 90 Y (n = 4), or ntingiogenic gent fter 90 Y (n = 6) were excluded. 8 Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l.

7 Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l. 9 Tble 3 Short-term clinicl nd biochemicl toxicity by vsculrity Clinicl toxicity All (n = 74) Vsculrity by DSA b Hyper (n = 37) Hypo (n = 37) p Vlue c Vsculrity by C-rm CT b Hyper (n = 22) Hypo (n = 4) p Vlue c Ftigue 45 (60.8) 24 (64.9) 2 (56.8) (63.6) 9 (64.3) > 0.99 Pin 2 (6.2) 6 (6.2) 6 (6.2) > (3.6) 4 (28.6) 0.39 Postemboliztion syndrome 0 (3.5) 5 (3.5) 5 (3.5) > (9.) (7.) > 0.99 Hospitl redmission within 30 d 6 (8.3) 3 (8.3) 3 (8.3) > (4.3) 2 (4.3) > 0.99 Ulcer 5 (6.8) (2.7) 4 (0.8) (0.0) 0 (0.0) > 0.99 Ascites 4 (5.4) 3 (8.) (2.7) (9.) 0 (0.0) 0.5 Liver filure 3 (4.0) 3 (8.) 0 (0.0) (9.) 0 (0.0) 0.5 Deth (.4) (2.7) 0 (0.0) > 0.99 (4.5) 0 (0.0) > 0.99 Encephlopthy 0 (0.0) 0 (0.0) 0 (0.0) > (0.0) 0 (0.0) > 0.99 Bilom 0 (0.0) 0 (0.0) 0 (0.0) > (0.0) 0 (0.0) > 0.99 Abscess 0 (0.0) 0 (0.0) 0 (0.0) > (0.0) 0 (0.0) > 0.99 Biochemicl toxicity All DSA Hyper DSA Hypo CT Hyper CT Hypo (CTCAE grde 3) (n = 70) (n = 35) (n = 35) p Vlue c (n = 2) (n = 4) p Vlue c Any biochemicl toxicity 5 (7.2) 3 (8.6) 2 (5.9) > (0.0) 0 (0.0) 0.50 Hypolbuminemi 4 (5.7) 2 (5.7) 2 (5.7) > (9.5) 0 (0.0) 0.5 Incresed totl bilirubin 2 (2.9) 2 (5.7) 0 (0.0) (0.0) 0 (0.0) 0.50 Leukopeni (.4) (2.9) 0 (0.0) > (0.0) 0 (0.0) > 0.99 Incresed AST (.4) (2.9) 0 (0.0) > 0.99 (4.8) 0 (0.0) > 0.99 Incresed ALT 0 (0.0) 0 (0.0) 0 (0.0) > (0.0) 0 (0.0) > 0.99 Abbrevitions: AST, sprtte minotrnsferse; ALT, lnine trnsminse; CT, computed tomogrphy; CTCAE, Common Terminology Criteri for Adverse Events; DSA, digitl subtrction ngiogrphy. Ptients with insufficient follow-up to ssess clinicl toxicity (n = ), hospitl redmission (n = 3), or biochemicl toxicity (n = 5) were excluded. b Vlues re no. (%). c Fisher s exct test. biomrkers for high-likelihood rdioemboliztion-responders remin in need, rdiogrphic mesures of tumor vsculrity re unlikely to be of use for this purpose. Though these results re unexpected, they hve potentilly importnt consequences for ptient selection for rdioemboliztion. There re severl possible explntions for the results in this study. There is extensive literture to suggest tht tissue oxygen is rdiosensitizer nd tht hypoxi is rdioprotective First, hypoxi is known to occur in mny solid tumors nd locl hypoxi tht my promote tumor ngiogenesis. 26 Therefore, there my not necessrily be direct or predictble reltionship between tumor's vsculrity nd the prtil pressure of oxygen (PO 2 ) in the tumor tissue. 27 Indeed, if vsculrity vries in concert with tissue metbolism, there my be no overll reltion between vsculrity nd PO 2 s demnd my exceed supply. There is gret Tble 4 Best response mesured by RECIST criteri Vrible All (n = 68) Vsculrity by ngiogrphy b Hyper (n = 37) Hypo (n = 3) p Vlue c Vsculrity by C-rm CT b Hyper (n = 22) Hypo (n = 2) Best response CR 4 (5.9) (2.7) 3 (9.7) 0.55 (4.5) 2 (6.7) 0.74 PR 22 (32.4) 4 (37.8) 8 (25.8) 7 (3.8) 4 (33.3) SD 23 (33.8) 2 (32.4) (35.5) 8 (36.4) 3 (25.0) PD 9 (27.9) 0 (27.0) 9 (29.0) 6 (27.3) 3 (25.0) p Vlue c Abbrevitions: CR, complete response; CT, computed tomogrphy; PR, prtil response; PD, progression of disese; RECIST, Response Evlution Criteri in Solid Tumors; SD, stble disese. Ptients with insufficient imging follow up (n = 7) were excluded. b Vlues re no. (%). c Fisher s exct test.

8 0 Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l. 00 VA (N=38) VA+ (N=37) VA (N=38) VA+ (N=37) Overll Survivl, % Progression-Free Survivl, % # t Risk VA+: VA : Time, months # t Risk VA+: VA : Time, months Fig. 3 Kpln-Meier curves showing overll survivl (left pnel) nd progression-free survivl (right pnel) for ptients with hyper- nd hypovsculr lesions by DSA. Tick mrks indicte censoring times. VA, vsculrity by ngiogrphy. Tble 5 Differences in survivl nd progression between vsculrity groups defined by DSA Event incidence Event No. Hyper (n = 37) Hypo (n = 38) HR (95% CI) p Vlue Deth (86.5) 30 (78.9) 0.99 ( ) 0.96 Deth or overll tumor progression (94.6) 34 (89.5).22 ( ) 0.4 Index tumor progression (6.) 22 (68.8) 0.94 ( ) 0.83 Abbrevitions: CI, confidence intervl; DSA, digitl subtrction ngiogrphy; HR, hzrd rtio. HR > indictes hypervsculr group is t higher risk thn hypovsculr group. Vlues re no. (%); ptients with insufficient imging follow-up (n = 7) were excluded. 00 VC (N=5) VC+ (N=22) VC (N=5) VC+ (N=22) Overll Survivl, % Progression-Free Survivl, % # t Risk VC+: VC : Time, months # t Risk VC+: VC : Time, months Fig. 4 Kpln-Meier curves showing overll survivl (left pnel) nd progression-free survivl (right pnel) for ptients with hyper- nd hypovsculr lesions by C-rm CT. Tick mrks indicte censoring times. VC, vsculrity by c-crm CT.

9 Tumor Vsculrity Does Not Predict Response to 90 Y Rdioemboliztion for Heptic Metstses from CRC Nydenov et l. Tble 6 Differences in survivl nd progression between vsculrity groups defined by C-rm CT Event incidence Event No. Hyper (n = 22) Hypo (n = 5) HR (95% CI) p Vlue Deth 37 7 (77.3) (73.3) 0.88 ( ) 0.74 Deth or overll tumor progression (90.9) 4 (93.3).9 ( ) 0.62 Index tumor progression 34 3 (59.) 7 (58.3).44 ( ) 0.42 Abbrevitions: CI, confidence intervl; HR, hzrd rtio. HR > indictes hypervsculr group is t higher risk thn hypovsculr group. Vlues re no. (%); ptients with insufficient imging follow up were excluded. interest in the development of technology for imging tumor hypoxi. 28 Understnding the PO 2 within trget tumors my help with ptient selection or dose plnning for rdioemboliztion. Wheres rdioembolic prticles my be more effectively delivered to hypervsculr tumors, such tumors my be inherently more ggressive. Alterntively, dditionl unidentified components in the tumorl strom nd microenvironment my ffect both vsculrity nd susceptibility to rdition. Limittions to this study exist. This is retrospective study, nd therefore both ptient selection nd rdioemboliztion device is nonuniform for the ptient cohort. Second, though the ssessment of vsculrity ws performed by consensus of physicins who were blinded to the results, no stndrdized criteri currently exist for the scoring of tumor vsculrity. Additionlly, becuse CT imges re cquired over n instnt, the ppernce of the vsculrity of the tumor could be ffected by the timing of the cquisition reltive to the contrst mteril injection. Nevertheless, the CT protocol used reflects reltively conventionl method for portl venous phse timing, generlizble to other ptient popultions. Third, it is possible tht hypervsculr tumors my exhibit more ggressive behvior compred with hypovsculr tumors. In tht scenrio, rdioemboliztion could be more effective t treting (ggressive) hypervsculr tumors thn t treting (less ggressive) hypovsculr tumors, leding to similr outcomes in two tumor popultions tht might behve differently without tretment. Conclusion In summry, this study concludes tht rdiogrphic mesures of tumor vsculrity correlte poorly with outcome fter 90 Y rdioemboliztion. Therefore, the degree of vsculrity of tumor should not impct cndidcy for rdioemboliztion given current evidence. Finncil Disclosures AVN: None WPH: Consultnt for NeoTherm nd Hlozyme SAP: Consultnt for BTG Interntionl DSH: None GEJ: None Conflict of Interest There is no conflict of interest for ny uthors. Note This reserch did not receive ny specific grnt from funding gencies in the public, commercil, or not-for-profit sectors. References Ferly J, Shin HR, Bry F, Formn D, Mthers C, Prkin DM. Estimtes of worldwide burden of cncer in 2008: GLOBOCAN Int J Cncer 200;27(2): Fong Y, Kemeny N, Pty P, Blumgrt LH, Cohen AM. Tretment of colorectl cncer: heptic metstsis. Semin Surg Oncol 996;2(04): Steele G Jr, Rvikumr TS. Resection of heptic metstses from colorectl cncer. Biologic perspective. Ann Surg 989;20(02): Helling TS, Mrtin M. Cuse of deth from liver metstses in colorectl cncer. Ann Surg Oncol 204;2(02): Wgner JS, Adson MA, Vn Heerden JA, Adson MH, Ilstrup DM. The nturl history of heptic metstses from colorectl cncer. A comprison with resective tretment. Ann Surg 984;99(05): Hendlisz A, Vn den Eynde M, Peeters M, et l. Phse III tril compring protrcted intrvenous fluorourcil infusion lone or with yttrium-90 resin microspheres rdioemboliztion for liver-limited metsttic colorectl cncer refrctory to stndrd chemotherpy. J Clin Oncol 200;28(23): Seidensticker R, Denecke T, Krus P, et l. Mtched-pir comprison of rdioemboliztion plus best supportive cre versus best supportive cre lone for chemotherpy refrctory liver-dominnt colorectl metstses. Crdiovsc Intervent Rdiol 202;35(05): Willowson KP, Hyes AR, Chn DLH, et l. Clinicl nd imging-bsed prognostic fctors in rdioembolistion of liver metstses from colorectl cncer: retrospective explortory nlysis. EJNMMI Res 207;7(0):46 9 Schmeel FC, Simon B, Luetkens JA, et l. Prognostic vlue of pretretment diffusion-weighted mgnetic resonnce imging for outcome prediction of colorectl cncer liver metstses undergoing 90Y-microsphere rdioemboliztion. J Cncer Res Clin Oncol 207;43(08): Ntionl Cncer Institute. Common Terminology Criteri for Adverse Events v4.0. NCI, NIH, DHHS. My 29, NIH publiction Eisenhuer EA, Thersse P, Bogerts J, et l. New response evlution criteri in solid tumours: revised RECIST guideline (version.). Eur J Cncer 2009;45(02): Gooley TA, Leisenring W, Crowley J, Storer BE. Estimtion of filure probbilities in the presence of competing risks: new representtions of old estimtors. Stt Med 999;8(06): Fine JP, Gry RJ. A proportionl hzrds model for the subdistribution of competing risk. J Am Stt Assoc 999;94:

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