IMAGING THE BIOLOGICAL EFFECT OF DOSE IN THE LIVER NORMAL TISSUE
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1 8/5/2 IMAGING THE BIOLOGICAL EFFECT OF DOSE IN THE LIVER NORMAL TISSUE Yue Cao, Ph.D. Departmets of Radiatio Ocology ad Radiology Uiversity of Michiga Ackowledgemets James Balter, Ph.D. Edgar Be-Josef, MD Thomas L. Cheevert, Ph.D. Mary Feg, MD Isaac R Fracis, MD Kirk Frey, MD, Ph.D. Tim Johsoo, Ph.D. Ted S. Lawrece, MD,Ph.D. Da Normolle, Ph.D. Charlie Pa, MD Joel F. Platt, MD Zhou She, MA Radall Te Hake, Ph.D. Hesheg Wag, Ph.D. Database group NIH/NCI 3 P CA59827 NIH/NINDS/NCI RONS64973 NIH/NCI RO CA32834 Normal Liver Toxicity RILD is a limitig factor for high dose RT of itrahepatic cacers Cliical complicatios usually preset 2-6 weeks after the completio of therapy, with devastatig outcomes Radiatio-iduced tissue toxicity is a complex, dyamic ad progressive process Idividual sesitivity to radiatio limits the utility of existig NTCP models Determiatio of specific risks versus beefits of treatmet should be a itegral part of cliical decisio makig for each patiet Fuctioal Imagig A valuable tool for evaluatio of ormal tissue toxicity Temporal chages i ormal tissue from pre to durig ad to post RT Spatially-resolved volumetric distributio of fuctio of subuits Idividual sesitivity to dose pre-rt dysfuctio of the live or fuctioal reserve Early assessmet ad predictio of potetial radiatio risks ad cliical outcomes Re-optimizatio of idividual patiets treatmet plas ad early itervetio ivolvig tissue/orga protectio Cao 2
2 8/5/2 Liver Fuctioal Imagig Hepatic perfusio imagig (DCE MR ad CT) Arterial ad portal veous perfusio Histopathology of RILD is veous occlusio 99mTc HIDA SPECT 25 ml/g/mi 45 ml/g/mi 25 ml/g/mi Eovist MRI 99mTc galactosyl serum albumi (GSA) scitigraphy or SPECT Hepatocyte bidig via the asialoglycoprotei receptor (Scheider, Surg cli N Am 24) ml/g/mi ml/g/mi ml/g/mi 8F-Deoxy-Galactose (FDGal) PET Total perfusio High uptake i Arterial tumor cells perfusio Portal vei perfusio Respose i ormal liver to dose (Hoyer, ESTRO 2) Liver Fuctioal Imagig Hepatic perfusio imagig (MR ad CT) Arterial ad portal veous perfusio Histopathology of RILD is veous occlusio 99mTc HIDA SPECT/CT Eovist MRI 99mTc galactosyl serum albumi (GSA) scitigraphy or SPECT Hepatocyte bidig via the asialoglycoprotei receptor (Scheider, Surg cli N Am 24) 8F-Deoxy-Galactose (FDGal) PET High uptake CT Hepatic Extractio i tumor cells Fractio Respose i ormal liver to dose (Hoyer, ESTRO 2) Liver Fuctioal Imagig Hepatic perfusio imagig (MR ad CT) Arterial ad portal veous perfusio Regeeratio Histopathology Kubo, of J RILD Surg is Res veous 22occlusio 99mTc HIDA SPECT Eovist MRI 99mTc galactosyl serum albumi (GSA) scitigraphy or SPECT GSA plaar image Hepatocyte prior bidig to right via the asialoglycoprotei GSA plaar image receptor 2 weeks after portal vei embolizatio (Scheider, Surg cli N Am 24) right portal vei embolizatio 8F-Deoxy-Galactose (FDGal) PET High uptake i tumor cells Respose i ormal liver to dose (Hoyer, ESTRO 2) Liver Fuctioal Imagig Hepatic perfusio imagig (MR ad CT) Arterial ad portal veous perfusio Histopathology of RILD is veous occlusio 99mTc HIDA SPECT Eovist MRI 99mTc galactosyl serum albumi (GSA) scitigraphy or SPECT Hepatocyte bidig via the asialoglycoprotei receptor (Scheider, Surg cli N Am 24) 8F-Deoxy-Galactose (FDGal) PET High uptake i tumor cells Dose respose i ormal liver (Hoyer, ESTRO 2) Cao 2 2
3 Fp after 3 Fx (ml/g/mi) Fp moth after RT (ml/g/mi) 8/5/2 Hypotheses Chages i portal veous perfusio ad/or hepatobiliary fuctio durig the early course of RT are potetially a biomarker for liver dysfuctio after irradiatio Perfusio ad/or hepatobiliary fuctio biomarkers may allow us to select patiets who are susceptible to liver ijury prior to cliical symptoms ad therefore to modify treatmet Assessmet of Idividual ad spatial sesitivity to doses by fuctioal imagig durig the course of therapy allow us to adapt treatmet pla to miimize local tissue damage ad thereby to prevet from orga ijury Liver Fuctioal Imagig at UM Prospective perfusio CT/MRI ad HIDA SPECT protocols Patiets with itrahepatic cacers ad treated with RT Patiets at high risk for liver ijury Large tumor volume Primary cacers, e.g., HCC with or without cirrhosis previous treatmets, e.g., TACE, RFA, resectio, or RT DCE CT/MRI ad HIDA SPECT Pre-treatmet, mid-course (5-6%), ad post RT ( ad 2 moths after treatmet completio) DCE MRI covers the whole liver Overall liver fuctio assessmet Idocyaie gree (ICG) clearace or retetio: the best established test for overall liver fuctio Veous Perfusio Dysfuctio Dose Effect o Veous Perfusio After 45 Gy (durig RT) Oe moth after RT Prior to RT 4Gy 3Gy 2Gy Gy 7 ml/g/mi ml/g/mi After 45 Gy 3 fx of.5 Gy/fx twice daily Cao Y et al, Medical Physics ml/g/mi per GY 2.5 ml/g/mi per GY 25 y = -.6x R = R =.77 p<. 2 p< dose at the time of sca (cgy) dose at the ed of RT (cgy) Note: () time depedet slopes time depedet respose (2) Idividual variatio -- idividual sesitivity Cao 2 3
4 Fp moth after RT mea Fp post RT(Fp>2) 8/5/2 Idividual Sesitivity to Radiatio Y-itercept or low dose regio: reperfusio Slope: reductio i perfusio caused by uit dose X-itercept: critical dose resultig i udetectable veous perfusio Idividual patiet y = -.423x R 2 = dose at the ed of RT (cgy) Cao, et al, It J Rad Oc Biol Phys, 28 Idividual Sesitivity to Radiatio Pts Slope ml/( g mi) per Gy X-itercept Dose (Gy) Fp= NA NA Liver Fuctioal Volume Pts Slope ml/( g mi) per Gy X-itercept Dose (Gy) Fp= LV% Fp= FLV% Fp> NA NA NA % % % % % % % % % % % Substatially Reduced Veous Perfusio 3 Fuctioal volume Overall Liver Fuctio vs Fuctioal Subuits Overall liver fuctio (ICG clearace) F it 3 N w P it N w ( D it it a ) Veous perfusio at a subuit of fuctioal liver (>critical value) it R 2 =.89 P< T/2 ICG post RT (mi) t Cao 2 4
5 mea D at the ed of RT 8/5/2 Mea Liver Dose vs Liver Fuctioal Reserve R 2 =. NS T/2 ICG post RT (mi) Volumetric MRI Perfusio 7 patiets i this aalysis 7 mets, 7 HCC, ad 3 cholagio 6 with previous treatmets (TACE, RFA, SBRT or resectio) Tx: 5 by SBRT, 2 by fractioated RT Imagig ad liver fuctio tests Pre RT, 5%-6% plaed doses, ad 2 moths after RT Doses biologically corrected (LQ model w / =2.5) for differet fractioal sizes Liver fuctio pre RT assessed by ICG clearace 5 pts: T /2 > mi (high risk) pts: T /2 raged from 3.7 to 7 mi (ormal or close to ormal) Mea of Portal Veous Perfusio of Subuits ad Overall Liver Fuctio Chages i Veous Perfusio after RT hyperperfusio r=.72, p<.x Gy Gy 2 Gy 5 Gy 4 Gy Pre RT Oe moth post RT Cao 2 5
6 VOI activity Activity 8/5/2 Idividual Respose Fuctio hyperperfusio Cholagio treated by Fx RT met treated by Fx RT Hypoperfusio pre RT ad Reperfusio after RT Four patiets: Overall Hypoperfusio Mea perfusio i the liver < 6 ml/(g mi) Three patiets: Overall ad regioal recovery After RT, except i the highest-dose regios 8 Pre RT Oe moth after RT HCC treated with Fx RT Summary 99mTc-HIDA SPECT/CT i the Liver Veous perfusio imagig could be a biomarker for local liver fuctio.3.2 HEF liver Blood.3.2 ImpResp fit There are large variatios i dose resposes of portal veous perfusio across idividual patiets ad over lobes, segmets or regios. Excretio rate Time (mi) Time (mi) Sigificat hyperperfusio was observed. The potetial relevace for ormal tissue sparig/regeeratio is worthy of further ivestigatio 99mTc-HIDA is a established aget for assessmet of hepatobiliary fuctio usig SPECT. hepatic extractio fractio (HEF) bile excretio rate Cao 2 6
7 Effect o H EF (% ) effect o k (%) 8/5/2 Hepatobiliary Fuctio Dose Effects o HEF ad Bile Excretio Rate Phys Dose B io D o se 2 Phys Dose BioDose 5 Do s e (cgy) 5 Dose( cgy) Tx Plaig CT Co-registered CT pre RT (SPECT/CT) Co-registered CT m postrt (SPECT/CT) HEF prert HEF m postrt Every Gy causes a reductio:.87% i HEF whe the dose is greater tha ~5 Gy.76% i bile excretio rate Summary Fuctioal ad metabolic imagig is emergig as a promisig tool for risk maagemet, particularly for patiets at high-risk for liver ijury Dose-respose of liver measured by fuctioal imagig may deped upo treatmet regimes Fuctioal/metabolic imagig aget uptake may deped upo ezyme levels i the liver Summary Our uderstadig of the histopathology ad biologic processes of radiatio-iduced tissue/orga toxicity is quite limited Fuctioal ad molecular imagig are potetial biomarkers for early assessmet ad predictio of radiatio-iduced tissue/orga toxicity Cliical trials with adequate edpoits are warrated to establish the value of these methods Whether other hepatic fuctioal/metabolic imagig provides ay discrimiatory iformatio beyod portal veous perfusio has yet to be demostrated. Cao 2 7
8 8/5/2 Hyperperfusio after liver irradiatio Regeeratio? Kubo, J Surg Res 22 Regeeratio CT Hepatic Extractio Fractio GSA plaar image prior to right portal vei embolizatio GSA plaar image 2 weeks after right portal vei embolizatio Dose-Respose of Portal Veous Perfusio Cao 2 8
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