Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P19 ppsx

11 Portal Vein Embolization Prior to Resection 165 ab c Fig. 11.4 Schematic representation shows modification of the ipsilateral technique for RPVE extended to segment 4. (a) Placement of a 6-French vascular sheath into the right portal branch. An angled 5-French catheter is placed into the left portal system with coaxial placement of a micro- catheter into a segment 4 branch. Particulate embolization is performed followed by placement of coils until all the branches are occluded. (b) After segment 4 embolization is completely occluded, a 5-French reverse-curve catheter is used for RPVE. (c) After embolization of the right and seg- ment 4 portal veins are complete, the access tract is embolized with coils to prevent subcapsular hemorrhage angled 5-French catheter into the portal vein branches supplying segment 4 so that particulate embolics and coils can then be delivered. Once complete occlusion of the segment 4 embolization is achieved, a 5-French reverse-curve catheter may be needed to embolize the portal veins supplying segments 5 through 8 (i.e., right liver). After complete occlusion of the right portal venous system, the access tract is embolized with coils and/or gelfoam to diminish the risk of perihepatic bleeding at the access site. A distinct advantage of the ipsilateral approach is that the FLR is not instru- mented. However, while disadvantages do exist, they are minor. Catheterization and embolization of the right portal vein branches may be slightly more difficult due to the severe angulations between right portal branches; however, this is rarely a prob- lem when reverse-curve catheters are used. Another potential disadvantage is that some embolic material could be displaced upon catheter removal, leading to non- target embolization, although this has not occurred in our experience with more than 200 RPVEs, most of which included extension to segment 4 branches. Similarly, in our experience, ipsilateral access has not been an issue in patients with large liver tumors. 166 D.C. Madoff and R. Avritscher e c a f d b Fig. 11.5 A 72-year-old man with history of hepatitis B, cirrhosis, and hepatocellular carcinoma HCC, who had transhepatic ipsilateral RPVE with particles and coils prior to right hepatectomy. (a) Contrast-enhanced CT scan of the liver shows a hypervascular mass in the right hepatic lobe consistent with HCC (arrow). (b) Contrast-enhanced CT scan of the liver shows small left liver (FLR/TELV of 35%) with underlying cirrhosis (FLR is shaded area). (c) Anteroposterior flush por- togram shows a 6-French vascular sheath (arrowheads) in a right portal vein branch and a 5-French flush catheter (arrow) in the main portal vein. (d) Postprocedure anteroposterior flush portogram shows occlusion of the portal vein branches to segments 5–8 (black arrows) with continued patency of the vein supplying the left lobe (segments 2–4) (white arrows). (e) Contrast-enhanced CT scan of the liver performed 1 month after RPVE shows hypertrophy of the left liver (FLR/TELV of 45%) (FLR is shaded area). (f) Contrast-enhanced CT scan of the liver performed after successful right hepatectomy shows hypertrophy of the liver remnant 11 Portal Vein Embolization Prior to Resection 167 c e f a b d Fig. 11.6 A 45-year-old man with history of non-alcoholic steatohepatitis and HCC who had transhepatic ipsilateral RPVE extended to segment 4 with particles and coils prior to extended right hepatectomy. (a) Contrast-enhanced CT scan of the liver shows a heterogeneous mass in the right hepatic lobe consistent with HCC (black arrow) and small left lateral liver (shaded area) with FLR/TELV of 27%. (b) Anterior-posterior flush portogram from the ipsilateral approach shows a 6-French vascular sheath in a right portal vein branch and a 5-French flush catheter (arrow)inthe main portal vein. (c) Selective left portogram with a 5-French catheter in the left portal vein (arrow) shows the veins that supply segments 2 (s2), 3 (s3), and 4 (s4). (d) Postprocedure portogram shows complete occlusion (with particles and coils) of the portal vein branches to segments 4–8 (arrows) with continued patency of the veins supplying the left lateral lobe (segments 2 and 3) (shaded area). (e) Contrast-enhanced CT scan performed 4 weeks after PVE shows hypertrophy of the left lateral liver (FLR/TELV now 39%, a degree of hypertrophy of 12%) with rounded margins (shaded area). Coil within segment 4 (arrowhead) is seen. (f) Contrast-enhanced CT scan of the liver performed after successful extended right hepatectomy shows hypertrophy of the liver remnant 168 D.C. Madoff and R. Avritscher Additional PVE Approaches PVE Followed by Bland Transarterial Embolization Other approaches have been used for PVE. The thought of combining PVE and TAE for complete portal venous and hepatic arterial occlusion has been reported in patients with biliary tract cancer and colorectal metastases who had inadequate hypertrophy after PVE alone [91, 92]. Nagino and colleagues [91] described a patient that required an extended left hepatectomy but the FLR volume (i.e., right posterior liver) did not increase 51 days after PVE. After TAE, the FLR volume increased from 485 cm 3 before PVE to 685 cm 3 after PVE, an addition of 215 cm 3 . Another patient required a right hepatectomy, but no significant volume change was seen after PVE (pre-PVE: 643 cm 3 and post-PVE: 649 cm 3 ). After TAE, the left liver volume enlarged to 789 cm 3 , an increase of 140 cm 3 . Both patients underwent successful and uneventful resection after the staged procedures. However, there are potential drawbacks. As both arterial and portal systems are deprived of blood, the potential for hepatic infarction exists such that only half the target segments were treated with TAE, superselectively. While this approach was effective, the disad- vantage is that two separate procedures are needed, performed at different times, leading to considerably longer waiting periods. During these waiting periods, tumor progression could occur to the degree that the tumors become unresectable. Sequential Arterial Embolization and PVE In 2004, Aoki and colleagues [72] described their experience with the use of sequen- tial transcatheter arterial chemoembolization followed within 2 weeks by PVE in 17 patients with HCC (Fig. 11.7). Their justification for this approach was as fol- lows: (1) The livers of most patients with HCC are compromised by underlying liver disease such that the liver’s regenerative capability after hepatic resection is weakened, making it hard to predict if adequate FLR hypertrophy can be achieved after PVE. (2) Since most HCCs are hypervascular and supplied largely by arte- rial blood flow, termination of portal flow induces compensatory augmentation in arterial blood flow (i.e., “arterialization of the liver”) in the embolized segments that may lead to rapid tumor progression after PVE. (3) Arterioportal shunts often found in cirrhotic livers and HCC may limit the effects of PVE. To this end, sequen- tial chemoembolization and PVE were used to prevent tumor progression during the time between the PVE and planned hepatectomy and to strengthen the effect of PVE by embolizing arterioportal shunts with chemoembolization. As a result, the researchers found that the combined procedures were safe, induced sufficient FLR hypertrophy within 2 weeks, and caused no worsening of the basal hepatic func- tional reserve or increase in tumor progression. Importantly, when the explanted livers were evaluated, tumor necrosis was profound but without substantial injury to the non-cancerous liver, and they therefore encourage the aggressive application of this treatment strategy in patients with large HCC and chronically injured livers. 11 Portal Vein Embolization Prior to Resection 169 b d a c f e Fig. 11.7 A 71-year-old man with history of liver steatosis, fibrosis, and HCC, who underwent sequential transcatheter arterial chemoembolization followed 1 month later by RPVE prior to a right hepatectomy. (a) A single image from pre-PVE contrast-enhanced CT scan shows a large hypervascular mass in the right hepatic lobe (arrow) and a small left liver (shaded area)witha FLR/TELV of 27%. (b) Celiac arteriogram performed during chemoembolization shows a hyper- vascular mass with iodized oil uptake in the right hepatic lobe (arrows). (c) Contrast-enhanced CT shows iodized oil uptake in the HCC (arrow). (d) Anterior-posterior flush portogram from the ipsilateral approach shows a 6-French vascular sheath in a right portal vein branch and a 5-French flush catheter (white arrows) in the main portal vein. Persistent iodized oil uptake in the right hep- atic mass is seen (black arrows). (e) Postembolization portogram shows complete occlusion of all branches to right portal vein (black arrows). The left portal vein remains patent (white arrow). (f) Contrast-enhanced CT scan of the liver after RPVE shows complete necrosis of the right liver mass (black arrow), hypertrophy of the left liver (shaded area), and massive atrophy of the right liver (arrowheads). The FLR/TELV increased to 56%. The patient underwent uncomplicated right hepatectomy 170 D.C. Madoff and R. Avritscher More recently, a French group reported on the use of PVE in 36 patients with HCC and chronic liver disease prior to right hepatectomy [93]. In their study, 18 patients underwent chemoembolization followed 3–4 weeks later by PVE and the remaining 18 patients underwent PVE alone. Although PVE was well tolerated in all patients, the mean increase in percentage FLR volume was significantly higher for patients in the combined chemoembolization and PVE group than those who under- went PVE alone (P = 0.022). The incidence of complete tumor necrosis (83%:15/18 vs. 6%: 1/18; P <0.001) and 5-year disease-free survival rate (37% vs. 19%; P = 0.041) were also significantly greater in patients who underwent chemoem- bolization and PVE. Given t he risks of hepatic infarction, the authors recommended that the two procedures should be separated by at least 3 weeks to reduce procedure- related morbidity. However, similar to Nagino’s TAE/PVE approach, the downside of the combined approach is that two separate procedures and an increased waiting times are required. PVE with Transjugular Access In 2003, a pilot study of performing PVE by means of the transjugular route was described [94]. This technique was tried because of the vast experience gained during the preceding decade with transjugular intrahepatic portosystemic shunts (TIPS). Under sonographic guidance, the right internal jugular vein was accessed, and then with fluoroscopy, a right or left portal branch was punctured from a right, middle, or left hepatic vein. A catheter was placed near the portal bifurcation and used to perform right PVE with a mixture of n-butyl-2-cyanoacrylate (NBCA) and iodized oil. All 15 procedures were technically successful without any serious complications. FLR hypertrophy was deemed sufficient and right hepatectomy was performed in 12 (80%) patients. While this approach appears safe and effective, the series was small, and further studies will be needed before this approach becomes widespread. For RPVE in patients with cirrhosis, this may be an attractive alterna- tive; however, the technical feasibility of RPVE extended to segment 4 has not yet been explored. Extent of Embolization The optimal extent of PVE is presently a subject of much debate. Currently, sev- eral groups who utilize PVE to prepare patients for extended right hepatectomy occlude only branches of the right portal vein and leave the segment 4 portal veins patent even though segment 4 will be resected [11, 71, 95]. While FLR hypertrophy does occur, full diversion of portal flow to segments 2, 3 ± 1 ensures the maxi- mal stimulus for FLR hypertrophy [12, 13]. Further, incomplete embolization of the liver to be resected will also lead to segment 4 hypertrophy. Segment 4 hypertro- phy is undesirable for an extended right hepatectomy due to increased morbidity associated with a larger area of intraoperative parenchymal transection across this hypertrophic segment [12]. Nagino and colleagues [13] first showed that a greater 11 Portal Vein Embolization Prior to Resection 171 left lateral bisegment hypertrophy occurs after RPVE + 4 (50% increase in FLR volume) t han after only RPVE (31% increase, P<0.0005) [34]. Recent studies have corroborated Nagino’s findings and without any increase in PVE-associated com- plications [96]. Because segment 4 embolization has shown to be of benefit, the ipsilateral approach for RPVE + 4 has been further refined and this has led to improved FLR hypertrophy and operative outcomes [88]. Lastly, left PVE is rarely needed due to consistently large volumes of the right posterior liver (i.e., segments 6/7) [12, 69, 70]. Another potential benefit of RPVE + 4, from an oncological standpoint, is that the entire tumor-bearing liver is systematically embolized (i.e., RPVE for right hep- atectomy and RPVE + 4 for extended right hepatectomy) to reduce the risk of tumor growth that may result from increased portal blood flow and hepatotrophic factors. A recent M.D. Anderson study evaluated 112 patients where the entire tumor-bearing liver was systematically embolized and found no increase in the median tumor size during the waiting period [67]. However, tumor growth within the non-embolized liver has been discussed upon analysis of a very limited number of patients with primary and secondary liver tumors after RPVE alone (although no comparison to pre-PVE tumor growth rate was made so the true effect of PVE on tumor growth could not be proven) [97, 98]. Furthermore, liver hypertrophy occurs quickly in patients with normal liver, and thus resection can be undertaken in most patients with multiple colorectal metastases within 3–4 weeks of PVE. Embolic Agents Many embolic materials have been used for PVE, with no remarkable differences reported in the degree or rate of hypertrophy. These agents include, but are not lim- ited to, fibrin glue, n-butyl cyanoacrylate (NBCA) mixed with ethiodized oil, gelatin sponge, thrombin, metallic coils, spherical and non-spherical microparticles (e.g., PVA particles and tris-acryl gelatin microspheres), and absolute alcohol. Choosing a particular embolic agent is at the operator  s discretion, and the decision is based on the extent of the embolization and surgery, their preference for a particular catheter and approach, and their experience with a specific agent. In the early experiences with PVE, gelatin sponge was widely used as an embolic agent. However, portal recanalization was frequently observed 2 weeks after the pro- cedure [10, 21, 54] and when compared with other embolic agents, gelatin sponge seemed less efficient at 4 weeks in terms of hypertrophy. Also, fibrin glue com- bined with ethiodized oil is a commonly used mixture for PVE. This mixture usually induces <75% portal occlusion at 2 weeks and <25% portal occlusion at 4 weeks [10, 54]. Some authors prefer NBCA mixed with ethiodized oil because the mixture leads to fast, reliable hypertrophy and minimizes the delay between PVE and definitive resection. NBCA ensures portal vein occlusion that persists beyond 4 weeks. Since polymerization time can be modulated by varying the lipiodol volume added to the NBCA, distal and proximal branches can be aggressively embolized. Typically, 172 D.C. Madoff and R. Avritscher NBCA is mixed with lipiodol at a ratio of 1:1 to 1:3. Because it is a liquid, NBCA can be quickly delivered throughout the entire right portal system, which greatly decreases procedure time. In terms of effectiveness, de Baere and colleagues [54] reported that NBCA embolization l ed to a 90% increase in liver volume after 30 days and Denys and colleagues [99] found it helpful in inducing hypertrophy in patients with underlying cirrhosis or advanced fibrosis. However, there are a few drawbacks of NBCA embolization. For instance, the NBCA injections have to be precise because of the increased risk of non-target embolization, thus requiring a highly experienced operator. In addition, NBCA induces an inflammatory process that may make hepatectomy more difficult [54]. NBCA can be difficult to use in patients with reduced hepatopetal flow, as is commonly seen in patients with chronic hepatic disease. These altered flow dynamics have been associated with increased risk of procedural complications [85]. Lastly, while this agent may be straightforward when the anatomy is favorable (e.g., the anterior and posterior sector portal veins originating from a right por- tal vein), this agent may not be the best alternative in situations where variant anatomy is present or when multiple segment 4 veins are to be embolized (i.e., multiple microcatheters are needed leading to considerable expense; increased risk of non-target embolization to the FLR). Absolute ethanol is another effective embolic agent for PVE. Osagawara and colleagues [100] demonstrated near doubling of the left liver volume within 4 weeks for patients with chronic hepatic disease and HCC who underwent PVE with this agent. Unfortunately, the most pronounced changes in liver function tests of all PVE embolic agents and poor patient tolerance are seen with absolute ethanol. Recently, the use of particulate agents for PVE had been proposed [40, 54, 59, 101]. In the first clinical report in a single patient, no recanalization of the right portal vein was observed 5 weeks after PVE with PVA particles alone [ 101]. Later, Madoff and colleagues [87, 88] showed that a combination of particles (e.g., polyvinyl alcohol particles (PVA) and tris-acryl gelatin microspheres) and coils is safe and effective for PVE. Particles are safe, cause little periportal reaction, and generate durable portal vein occlusion, especially when used in combination with coils [59, 88]. In 2003, results from the first 26 patients who had PVE with non-spherical PVA particles ranging in size from 300 to 1000 μm and coils were reported; the mean FLR/TELV increased 7.8% (pre-PVE FLR/TELV, 17.6%; post- PVE FLR/TELV, 25.4%), and the mean absolute FLR increase was 47% [87]. The subsequent development of spherical particulate embolics has led to even f ur- ther refinements in technique for PVE by using a stepwise infusion of very small (100–300 μm) tris-acryl microspheres followed by larger spheres (up to 700 μm) [88]. This type of distal embolization is thought to limit development of collateral circulation that may potentially reduce hypertrophy due to the improved targeting of distal portal vein branches (i.e., non-spherical particles tend to clump and therefore do not always reach the targeted size vessel). Metallic coils are then used proxi- mally to block venous inflow and further reduce the possibility of recanalization. This approach was used for RPVE + 4 and led to an absolute increase in FLR vol- ume of 69.0%, an FLR/TELV increase of 9.7%, and a subsequent resection rate of 86% that was a significant improvement over their previously reported method. 11 Portal Vein Embolization Prior to Resection 173 Complications of PVE As with all transhepatic procedures, complications include subcapsular hematoma, hemoperitoneum, hemobilia, pseudoaneurysm, arteriovenous fistula, arterioportal shunts, portal vein thrombosis, transient liver failure, pneumothorax, and sepsis [85, 102]. Kodama and colleagues [102] compared the complication rate between the ipsilateral and contralateral approaches in 47 patients, who underwent PVE. They found that in 11 patients who underwent contralateral PVE, 2 (18.1%) experi- enced complications, and in 36 patients who underwent ipsilateral PVE, 5 (13.9%) experienced complications. This difference was not statistically significant. The rate of technical complications associated with percutaneous PVE using either approach was 14.9%. The patients in the study developed the following complications: two pneumothoraces, two subcapsular hematomas, one inadvertent arterial puncture, one pseudoaneurysm (in a patient who also had a subcapsular hematoma), one hemobilia, and one portal vein thrombosis. Complications more specific to percu- taneous PVE included portal vein thrombosis and portal hypertension resulting in esophageal variceal hemorrhage. However, the authors emphasized that given the potential for injury to the FLR when using the contralateral approach, the ipsilateral approach should be tried first. Di Stefano and colleagues [85] conducted a study of 188 patients who underwent PVE using the contralateral approach. They reported that only one patient experi- enced a major complication (complete portal vein thrombosis) directly related to the contralateral approach that precluded the planned surgical resection. Two other patients experienced inadvertent migration of embolic material into the FLR requir- ing intervention; one needed a portoportal graft during hepatic resection because of portal vein thrombosis. On CT imaging, another 10 patients were found to have embolic material in non-targeted portal venous branches. Ribero and colleagues [67] recently studied 112 patients who underwent PVE with the ipsilateral approach. In this study, only one patient had non-targeted embolization to the FLR. However, the overall complication rate was 8.9%, which was not substantially different than the rate reported by Di Stefano and colleagues. If one takes into account the fact that Di Stefano and colleagues considered clini- cally occult incidental CT findings in their complication rate, the studies reported remarkably similar numbers. Further, the study by Ribero and colleagues found no difference in the complication rate whether right PVE was extended to segment 4 or not. Outcomes Following PVE and Hepatectomy for HCC In patients who developed HCC in the setting of chronic liver disease (e.g., chronic hepatitis, fibrosis, or cirrhosis), the increase in non-embolized liver volumes after PVE varies (range, 28–46%), and hypertrophy after PVE may take more than 4 weeks because of slower regeneration rates [45]. The degree of parenchymal fibro- sis is thought to limit regeneration, possibly as a result of reduced portal blood flow 174 D.C. Madoff and R. Avritscher [75]. However, a study by Denys and colleagues [99], in which 40 patients with HCC in the setting of advanced liver fibrosis and cirrhosis, found that only two factors sig- nificantly affected hypertrophy: a lower degree of fibrosis, as indicated by a Knodell histological score [103] of <F4, and a pre-PVE lower functional liver ratio as defined by the ratio between the left liver (i.e., FLR) and the total liver volume minus tumor volume. Factors that did not correlate with improved hypertrophy included age, sex, history of diabetes, and prior chemoembolization. In addition, numerous studies have been performed that evaluated liver regeneration and the degree of hypertro- phy after preoperative PVE in patients with and without underlying liver disease (Table 11.1)[104–106]. Rates of hepatectomy after PVE in patients with HCC are reported to be approximately 70%; series that report a very high rate of hepatectomy after PVE (over 90%) are either very small (<15 patients) or include patients who under- went less extensive PVE (e.g., embolization of only the right anterior or right posterior sector). Furthermore, in patients with HCC and chronic liver disease, hep- atectomy outcomes, including the number and severity of complications and the incidence of postoperative liver failure and death, are better with PVE than without [26, 45, 71, 75, 107, 108]. Good outcomes following major hepatectomy after PVE in patients with HCC are regularly reported. In 2000, Azoulay and colleagues [75] reported long-term outcomes after resection of three or more liver segments for Table 11.1 Future liver remnant (FLR) hypertrophy after portal vein embolization in patients with and without underlying liver disease FLR (%) Author (year) Baseline liver PVE (n) Pre Post DH (%) Abdalla, 2002 [5]Normal 1818258 Aoki, 2004 [72] ICGR 15 <10% ICGR 15 >10% 8 9 40 51 11 Azoulay, 2000 [75] Mild or moderate fibrosis Cirrhosis 3 7 36 52 16 Cotroneo, 2009 [104] Normal Cirrhosis 24 7 23 31 33 40 10 9 Farges, 2003 [71] Normal Cirrhosis 13 14 31 35 47 44 16 9 Ogata, 2006 [93] Cirrhosis (PVE) Cirrhosis (TACE/PVE) 18 18 29 30 37 42 8 12 Ribero, 2007 [67] Normal, fibrosis, Cirrhosis 112 – – 9–11 Sugawara, 2002 [105] Cirrhosis 40 35 48 13 Vauthey, 2000 [3] Normal 12 26 36 10 Wakabayashi, 2002 [106] Normal Hepatitis 17 26 27 33 36 40 9 7 PVE = portal vein embolization, (n) = number of patients, DH = degree of hypertrophy, TACE = transcatheter arterial chemoembolization, and ICGR 15 = indocyanine green retention at 15 min . Madoff and R. Avritscher e c a f d b Fig. 11.5 A 72-year-old man with history of hepatitis B, cirrhosis, and hepatocellular carcinoma HCC, who had transhepatic ipsilateral RPVE with particles and. livers and HCC may limit the effects of PVE. To this end, sequen- tial chemoembolization and PVE were used to prevent tumor progression during the time between the PVE and planned hepatectomy and. spherical and non-spherical microparticles (e.g., PVA particles and tris-acryl gelatin microspheres), and absolute alcohol. Choosing a particular embolic agent is at the operator  s discretion, and