Guiu, B , France Journal of Hepatology , 2012

1. Liver/biliary injuries following chemoembolisationof endocrine tumours and HCC :Lipiodol vs. drug-eluting beads Guiu, B , France Journal ofHepatology, 2012

2. Introduction • TACE has beenwidely used to treat hepatic malignancies including liver metastasesfrom endocrine tumours (NETs) and (HCC). • TACE has a central role in the treatment of intermediate-stage HCC and is indicated in NETs when tumoursprogress in the liver and for palliation of symptoms that fail torespond to somatostatin analogues.

3. DEB-TACE advantages • In vitro, DEBs offer simultaneous embolisation and sustained releaseof chemotherapy and provide a far more favourable drug-releaseprofile (high tumour drug retention, 70–85% decrease in plasma ). • In humans, peak drug concentrations of doxorubicinand the area under the curve were both significantlylower. • DEB-TACE has been reportedto provide 77% of complete tumour necrosis(bland embolisation 27.2%,p = 0.043).

4. No superiority • Despite undeniable pharmacological advantages, DEB-TACE didnot demonstrate its superiority to lipiodol-TACE regardingtumour response in a recent randomised phase-2 trial .

5. Aim • Bileduct or liver parenchymal injuries have been reported for manyyears in lipiodol-TACE , but very few data are availableregarding liver-specific toxicity in DEB-TACE. • This study describesand compares liver/biliary injuries encountered with TACE( DEB-TACE and lipiodol-TACE) intumours developed in cirrhotic (HCC) and non-cirrhotic ( NETs) livers.

6. Materials and Methods • Between January 2003 and June 2010 , 237 patients were screened for this study (metastatic NET = 134, HCC = 103). • After exclusion, 208 patients (n = 120 NET-group , n = 88 HCC-group) were included. • They underwent 278 (NET-group) and 198 (HCC-group) TACE sessions.(476)

7. Exclusion criteria • Unavailable liver imaging before or after TACE. • Patients who received both DEB-TACE and conventional-TACE. • Patients without clinical, biological, or histological evidence of cirrhosis in the HCC-group.

8. Imaging and liver enzymes • Liver involvement was assessed on baseline imaging data (CT or MRI)obtained within 1 month before TACE. • Baseline liver enzymes (AST, ALT, ALP, GGT, total bilirubin, prothrombin) were obtained within 3 days before the first TACE session. • The Child-Pugh score was evaluated for cirrhotic patients with HCC.

9. TACE procedure • A right femoral access→injection into the superior mesenteric artery→selective catheterisation of the proper hepatic artery→ accessory hepatic arteries. • According to the liver involvement, selective catheterisation of the artery feeding the tumours. • If stasis was not obtained, complementary embolisation was used.(bland particles or gelatin sponge )

10. TACE protocol • The TACE was classified as total, lobar, sectorialorsegmental/subsegmental. • For conventional TACE: mixture of the chemotherapeutic drug and 10-ml iodised oil. • For DEB-TACE:only doxorubicin, loaded into 1–2 vials of DC-Beads, each containing 2 ml of hydrated beads measuring 500-700 μm, 300-500 μm, or 100-300 μm, injected over at least 10 min.

11. Liver imaging and follow-up • Baseline imagingwas performed <1 month before each TACE ,follow-up imagingwas performed within 3 months after each session. • MRI: 1.5-T(T1,T2, contrast-enhanced T1), Triphasic helical CT-scans. • Serum levels of liver enzymes were recorded at the same time. • Follow-up time :2–6 weeks after each session.

12. Liver/biliary injuries definition • A total of 684 CT or MR examinations were assessed by two experienced radiologists blinded to patient information • According to previously published papers: dilated bile duct, portal vein branch narrowing, portalvenous thrombosis and biloma/liver infarct.

13. Dilated bile duct • Anincreased diameter of the bile duct reflected by unilateral linear hypodensity(on CT-scan) or hyperintensity on T2-weighted imaging (on MRI) adjacent tothe corresponding portal venous branch. • Bile duct dilatations due to directtumour invasion or the compressive effect of large tumours were excluded.

14. Portalvein branch narrowing • Adecreased diameter of the portal veinbranch with preservation of the intraluminal blood flow associated with surroundinghypodensity (on CT-scan) or hyperintensity on T2-weighted imaging(on MRI). • Portal vein branch narrowing was the consequence of periportalabnormalities (inflammatory process or collection).

15. Portal venous thrombosis • The absence of contrast enhancement of the corresponding portalvein branch. • Biloma/liver infarct was defined as hypodense (on CT-scan)or hyperintense on T2-weighted imaging (on MRI) area >1 cm located in nontumouralparenchyma without evidence of enhancement at any of the vascularphases.

16. Statistical analysis • Fischer’s exact test for categorical variables and a two-sided testor Kruskall-Wallis test as appropriate for continuous variables. • uni- and multivariate logistic regression analyses,Stata software version 10.0, p﹤ 0.05 was considered significant.

17. Results • The characteristics of the TACE-sessionsin the NETs and the HCC are described in Table 1. • NETs: treatment locations(total) : 0.8% vs.32.9%. • NET-group and the HCC-group: dose of injected doxorubicin(p <0.001 and p = 0.003). • DEB-TACE sessions: treatment location was different for NETs vs. HCC (p = 0.043)

18. Table 1

19. Liver/biliary injuries • Liver/biliary injuries are detailed in Table 2. • A liver/biliary injury followed 17.2%(82/476) of sessions in 30.8% (64/208) of patients. • At least one liver/biliary injury: DEB-TACE: 35.7% and 30.4% lipiodol-TACE: 7.2% and 4.2% for NET (p <0.001) and HCC (p <0.001).

20. Table 2

21. Dilated bileduct (Fig. 1) B A Fig. 1. Liver/biliary injuries: bile duct dilatations. Axial CT-scan (A) before and(B) after two DEB-TACE sessions for a NET showing multiple distal bile-ductdilatations (arrows).

22. Portal vein narrowing (Fig. 2) A B Fig. 2. Liver/biliary injuries: multiple portal vein narrowings. Coronal CT-scan(A) before and (B) after one DEB-TACE session for a NET showing multiple portalvein narrowings (arrowheads) and a liver infarct of the subcapsular area of thesegment VI (arrow).

23. Portal veinthrombosis(Fig. 3) B A Fig. 3. Liver/biliary injuries: multiple portal vein thromboses. Axial CT-scan(A) before and (B) after one DEB-TACE session for a NET showing portal veinnarrowing (empty arrow), multiple portal vein thromboses (arrowheads) and aconnected biloma/liver infarct (arrow).

24. Bilomas/liver infarcts (Fig. 4) Fig. 4. Liver/biliary injury: biloma/liver infarct. Axial CT-scan (A) before and after (arterial phase (B) and portal phase (C)) one DEB-TACE session for a NETshowing 2 cm-biloma/liver infarct of the left liver lobe (arrow) without enhancement after injection of iodine contrast material. The segmental bile ductis ruptured, responsible for portal vein narrowing (empty arrow) and in connection with the biloma/liver infarct.

25. A total of 17 bilomas/liver infarcts: mean size was 3.9 ± 1.9 cm (range: 2–10). • DEB-TACE session :NETs=13 bilomas/liver infarcts, HCC=0. • Mean hospital duration was 7. 1 ± 5.6 days (range: 3–26) compared with 5 ± 2.4 days (range: 1–25) in other cases (p = 0.034).

26. Treatment • All bilomas/liver infarcts were treated conservatively: intravenous antibiotherapy, symptomatic treatment ,close clinical surveillance. • Liver/biliary injuries and bilomas/liver infarcts were mostly observed after the first or secondTACE session (in 79.3% and 87.5% of cases, respectively).

27. The factor of liver/biliary injury • By univariate logistic regression analysis: DEB-TACE and NET (significantly associated with liver/biliary injury) (Table 3). • By multivariate analysis: DEB-TACE was the only independently factor (p <0.001). • The risk of liver/biliary injury:DEB-TACE was 6.63 times greater than lipiodol-TACE. • This result was validated internally using bootstrapping.

28. Table 3

29. The factor of biloma/liver infarct • Independentlypredicted factor :DEB-TACE(p = 0.002) and NET( p= 0.04 ). • Portal vein thrombosis and portal vein branch narrowing were independently associated with biloma/liver infarct (p <0.001 and p <0.001) (Supplementary Table 3). • This was not the case for dilated bile duct (p = 0.896).

30. Supplementary Table 3

31. Factors: no association • In patients treated with DEB-TACE, neither treatment locationnor bead type, bead size, doxorubicin dose nor complementaryembolisation was significantly associated with liver/biliary injuryor biloma/liver infarct (Supplementary Table 4).

32. Supplementary Table 4

33. Liver enzymes and liver/biliary injury • Only ALPvariation was significantly associated with liver/biliary injury(p = 0.033). • AST, ALT, ALP, and GGT variations were associated with biloma/liver infarcts (p = 0.005,p = 0.005, p = 0.012, p = 0.006) .(Table 4) • ALP variation : prediction of liver/biliary injury: sensitivity = 60.3% , specificity = 69.2%. prediction of biloma/liver infarct: sensitivity =76.9% , specificity=82.5%.

34. Table 4

35. Dicussion • We showed that the occurrence of liver/biliary injury wasstrongly associated (OR = 6.62) with DEB-TACE. • At least one liver/biliaryinjury was observed after 30.4–35.7% of DEB-TACE sessions whileit occurred after 4.2–7.2% of lipiodol-TACE calculated in aper-session(p <0.001).

36. The four types of liver/biliary injuries we described here probablyreflect liver damage that occurs gradually over time.

37. The first type • The first stage: Intrahepaticbile ductdilatation is the most common • The second stage:necrosis of the bile duct (result from damage to the peribiliary plexus PBP). • This damage can be due to embolisation or chemical insult of the vessel walls caused by the high concentration of doxorubicin of DEBs.

38. Loaded and unloadedDEBs • Lewis reported necrosis centred on clustersof loaded DEB radiating outwards with evidence of inflammationand fibrosis, while unloaded DEBs did not. • In our study ,the dose of doxorubicin in DEB-TACE was significantly higher than that in lipiodol-TACE. • It is possible of a periportal inflammatory process related to the effect of high concentrations of chemotherapic agents (especially doxorubicin, vesicant effect).

39. The second type • Portal vein branchnarrowing, lowattenuatingareas alongside the portal vein and tracking along thelow-resistance connective tissue sheath of the Glisson capsulethat surrounds the portal triad were suggestive of extravasatedbile coming from the disruption of necrotic bile duct after TACE.

40. The third type • Portal venous thrombosis : ①result from the collection of extravasated fluid in theGlisson capsule, which can gradually compress and compromisethe adjacent portal vein branches . ② related to an additional inflammatory process due to chemical vasculitisof the PBP.

41. The fourth type • Bilomas results fromnecrosis of the bile duct due to ischemic/chemical insult of PBParteries • Liver infarct requires concomitant arterial andportal vein occlusion • Strong associations between biloma/liver infarct and both portal vein branch narrowing and thrombosissupport: the preceding pathophysiological hypotheses and theirprobablecontinuum over time.

42. TACE sessions • The vast majority of liver/biliary injuries wereencountered after the first or second TACE and thus were not related to repeated TACE procedures alone. • Associated with biloma/liver infarct: DEB-TACE: OR = 9.78 NETs: OR = 8.13(non-cirrhotic)

43. Underlying liver • Using lipiodol-TACE, also have a lower incidence of bile duct injury inpatients with underlying cirrhosis • Reasons: the changesobserved in cirrhosis, during which the PBP becomes hypertrophiedand can act as a portoarterial shunt , resultingincreased capacity for collateralisation protects the bile ductsfrom ischemic/chemical injury.

44. Hospital duration • In these cases of biloma/liver infarct, hospital duration was longer and even though managementwas conservative. • Such complications should be consideredas severe because they prolonged hospital stay to amaximum of 26 days

45. Liver enzymes • Serum ALP level significantlyincreased in liver/biliary injury in our study. • Biloma/liver infarctwas significantly associated with an increase in the serum levelof several liver enzymes (ALP, GGT, AST, and ALT). • Despite excellent prediction ability of biloma/liver infarct in our series, needs to be validated in an externalstudy.

46. Prediction of liver/biliary injury • These complications were somewhatunpredictable. • The use of a smaller beadsize combined with high selectivity of the catheter could potentially reduce liver/biliary injuries, this combinationneed further investigation. (500–700μm DEBs in our study, tumour vessels﹤300μm).

47. Limitations • This is a retrospective study • This study included a relatively unusualbalanced number of HCCs and NETs • Our results probablyneed external validation, even thoughinternal validation using bootstrapping confirmed our findings.

48. Conclusion • The use of DEB-TACE is independently associatedwith liver/biliary injuries. • Biloma/liver infarctis independently associated with both DEB-TACE andNETs. • The absence ofsuch associations in TACE for HCC may be explained by thehypertrophied PBP observed in cirrhosis, which may protect bileducts against ischemic and chemical insults

49. Suggestion • Given the unpredictabilityof these complications, we suggest caution when usingDEB-TACE for tumours developed in the non-cirrhotic liver.

50. Thank you for your attention !