Guiu, B , France Journal of Hepatology, 2012 Liver/biliary injuries following chemoembolisation of endocrine tumours and HCC : Lipiodol vs. drug-eluting beads Guiu, B , France Journal of Hepatology, 2012

Introduction TACE has been widely used to treat hepatic malignancies including liver metastases from endocrine tumours (NETs) and (HCC). TACE has a central role in the treatment of intermediate-stage HCC and is indicated in NETs when tumours progress in the liver and for palliation of symptoms that fail to respond to somatostatin analogues.

DEB-TACE advantages In vitro, DEBs offer simultaneous embolisation and sustained release of chemotherapy and provide a far more favourable drug-release profile (high tumour drug retention, 70–85% decrease in plasma ). In humans, peak drug concentrations of doxorubicin and the area under the curve were both significantly lower. DEB-TACE has been reported to provide 77% of complete tumour necrosis(bland embolisation 27.2%,p = 0.043).

No superiority Despite undeniable pharmacological advantages, DEB-TACE did not demonstrate its superiority to lipiodol-TACE regarding tumour response in a recent randomised phase-2 trial .

Aim Bile duct or liver parenchymal injuries have been reported for many years in lipiodol-TACE , but very few data are available regarding liver-specific toxicity in DEB-TACE. This study describes and compares liver/biliary injuries encountered with TACE( DEB-TACE and lipiodol-TACE) in tumours developed in cirrhotic ( HCC) and non-cirrhotic ( NETs) livers.

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)

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.

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.

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 )

TACE protocol The TACE was classified as total, lobar, sectorial or segmental/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.

Liver imaging and follow-up Baseline imaging was performed <1 month before each TACE ,follow-up imaging was 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.

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, portal venous thrombosis and biloma/liver infarct.

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

Portal vein branch narrowing Adecreased diameter of the portal vein branch with preservation of the intraluminal blood flow associated with surrounding hypodensity (on CT-scan) or hyperintensity on T2-weighted imaging (on MRI). Portal vein branch narrowing was the consequence of periportal abnormalities (inflammatory process or collection).

Portal venous thrombosis The absence of contrast enhancement of the corresponding portal vein branch. Biloma/liver infarct was defined as hypodense (on CT-scan) or hyperintense on T2-weighted imaging (on MRI) area >1 cm located in nontumoural parenchyma without evidence of enhancement at any of the vascular phases.

Statistical analysis Fischer’s exact test for categorical variables and a two-sided test or 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.

Results The characteristics of the TACE-sessions in 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)

Table 1

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).

Table 2

Dilated bile duct (Fig. 1) 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).

Portal vein narrowing (Fig. 2) 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).

Portal vein thrombosis (Fig. 3) 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 vein narrowing (empty arrow), multiple portal vein thromboses (arrowheads) and a connected biloma/liver infarct (arrow).

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 NET showing 2 cm-biloma/liver infarct of the left liver lobe (arrow) without enhancement after injection of iodine contrast material. The segmental bile duct is ruptured, responsible for portal vein narrowing (empty arrow) and in connection with the biloma/liver infarct.

A total of 17 bilomas/liver infarcts: mean size was 3. 9 ± 1 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).

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 second TACE session (in 79.3% and 87.5% of cases, respectively).

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.

Table 3

The factor of biloma/liver infarct Independently predicted 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).

Supplementary Table 3

Factors: no association In patients treated with DEB-TACE, neither treatment location nor bead type, bead size, doxorubicin dose nor complementary embolisation was significantly associated with liver/biliary injury or biloma/liver infarct (Supplementary Table 4).

Supplementary Table 4

Liver enzymes and liver/biliary injury Only ALP variation 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%.

Table 4

Dicussion We showed that the occurrence of liver/biliary injury was strongly associated (OR = 6.62) with DEB-TACE. At least one liver/biliary injury was observed after 30.4–35.7% of DEB-TACE sessions while it occurred after 4.2–7.2% of lipiodol-TACE calculated in a per-session (p <0.001).

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

The first type The first stage: Intrahepatic bile duct dilatation 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.

Loaded and unloaded DEBs Lewis reported necrosis centred on clusters of loaded DEB radiating outwards with evidence of inflammation and 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).

The second type Portal vein branch narrowing, low attenuating areas alongside the portal vein and tracking along the low-resistance connective tissue sheath of the Glisson capsule that surrounds the portal triad were suggestive of extravasated bile coming from the disruption of necrotic bile duct after TACE.

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

The fourth type Bilomas results from necrosis of the bile duct due to ischemic/chemical insult of PBP arteries Liver infarct requires concomitant arterial and portal vein occlusion Strong associations between biloma/liver infarct and both portal vein branch narrowing and thrombosis support: the preceding pathophysiological hypotheses and their probable continuum over time.

TACE sessions The vast majority of liver/biliary injuries were encountered 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)

Underlying liver Using lipiodol-TACE, also have a lower incidence of bile duct injury in patients with underlying cirrhosis Reasons: the changes observed in cirrhosis, during which the PBP becomes hypertrophiedand can act as a portoarterial shunt , resulting increased capacity for collateralisation protects the bile ducts from ischemic/chemical injury.

Hospital duration In these cases of biloma/ liver infarct, hospital duration was longer and even though management was conservative. Such complications should be considered as severe because they prolonged hospital stay to a maximum of 26 days

Liver enzymes Serum ALP level significantly increased in liver/biliary injury in our study. Biloma/liver infarct was significantly associated with an increase in the serum level of 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 external study.

Prediction of liver/biliary injury These complications were somewhat unpredictable. The use of a smaller bead size combined with high selectivity of the catheter could potentially reduce liver/biliary injuries, this combination need further investigation. (500–700μm DEBs in our study, tumour vessels﹤300μm).

Limitations This is a retrospective study This study included a relatively unusual balanced number of HCCs and NETs Our results probably need external validation, even though internal validation using bootstrapping confirmed our findings.

Conclusion The use of DEB-TACE is independently associated with liver/biliary injuries. Biloma/liver infarct is independently associated with both DEB-TACE and NETs. The absence of such associations in TACE for HCC may be explained by the hypertrophied PBP observed in cirrhosis, which may protect bile ducts against ischemic and chemical insults

Suggestion Given the unpredictability of these complications, we suggest caution when using DEB-TACE for tumours developed in the non-cirrhotic liver.

Thank you for your attention !