Cardiovasc Intervent Radiol DOI 10.1007/s00270-015-1050-2
CLINICAL INVESTIGATION
Radiofrequency Ablation for the Treatment of Hepatocellular Carcinoma in Patients with Transjugular Intrahepatic Portosystemic Shunts Jonathan K. Park • Quazi Z. Al-Tariq • Taryar M. Zaw Steven S. Raman • David S.K. Lu
•
Received: 29 May 2014 / Accepted: 21 December 2014 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2015
Abstract Purpose To assess radiofrequency (RF) ablation efficacy, as well as the patency of transjugular intrahepatic portosystemic shunts (TIPSs), in patients with hepatocellular carcinoma (HCC). Materials and Methods Retrospective database review of patients with pre-existing TIPS undergoing RF ablation of HCC was conducted over a 159-month period ending in November 2013. TIPS patency pre- and post-RF ablation was assessed by ultrasound, angiography, and/or contrastenhanced CT or MRI. Patient demographics and immediate post-RF ablation outcomes and complications were also reviewed. Results 19 patients with 21 lesions undergoing 25 RF ablation sessions were included. Child-Pugh class A, B, and C scores were seen in 1, 13, and 5 patients, respectively. Eleven patients (58 %) ultimately underwent liver transplantation. Immediate technical success was seen in all ablation sessions without residual tumor enhancement (100 %). No patients (0 %) suffered liver failure within J. K. Park (&) T. M. Zaw S. S. Raman D. S.K.Lu Department of Radiology, David Geffen School of Medicine at UCLA, 757 Westwood Plaza, Los Angeles 90024, CA, USA e-mail: [email protected] T. M. Zaw e-mail: [email protected] S. S. Raman e-mail: [email protected] D. S.K.Lu e-mail: [email protected] Q. Z. Al-Tariq Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford 94305, CA, USA e-mail: [email protected]
1 month of ablation. Pre-ablation TIPS patency was demonstrated in 22/25 sessions (88 %). Of 22 cases with patent TIPS prior to ablation, post-ablation patency was demonstrated in 22/22 (100 %) at immediate post-ablation imaging and in 21/22 (95 %) at last follow-up (1 patient was incidentally noted to have occlusion 31 months later). No immediate complications were observed. Conclusion Ablation efficacy was similar to the cited literature values for patients without TIPS. Furthermore, TIPS patency was preserved in the majority of cases. Patients with both portal hypertension and HCC are not uncommonly encountered, and a pre-existing TIPS does not appear to be a definite contraindication for RF ablation. Keywords Interventional oncology Radiofrequency ablation Transjugular intrahepatic portosystemic shunt (TIPS/TIPSS) Hepatocellular carcinoma (HCC) Portal vein hypertension Liver/hepatic
Introduction In the United States, the incidence of hepatocellular carcinoma (HCC) has almost tripled since the early 1980s. Radiofrequency (RF) ablation has emerged as a first-line therapy for small, nonresectable cases of HCC with well-established safety and efficacy profiles for selected cases [1–4]. In patients with liver cirrhosis and resultant portal hypertension, creation of a transjugular intrahepatic portosystemic shunt (TIPS) can alleviate portal hypertension sequelae including bleeding varices and refractory ascites [5]. Given that patients with cirrhosis are also at higher risk of developing HCC, TIPSs are often present in patients with HCC. Despite the benefits of TIPS in patients with
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J. K. Park et al.: RF Ablation for HCC in Patients with TIPS
significant portal hypertension, tumor growing alongside TIPS can theoretically pose a challenge to RF ablation due to the heat-sink effect [6]. This may potentially result in incomplete necrosis for lesions adjacent to blood vessels greater than 3 mm [7]. Furthermore, the effect of thermal ablation on TIPS patency is not established. While patients with portal hypertension and TIPS presenting for RF ablation of HCC are commonly encountered in clinical practice, the current literature consists of only one case report addressing the feasibility of performing RF ablation in a patient with pre-existing TIPS. Thus, the aim of our study was to assess the efficacy of RF ablation in patients with pre-existing TIPS, as well as post-procedural TIPS patency.
Materials and Methods Patients The medical center institutional review board approved the study and waived informed consent. All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. Between August 2000 and November 2013, 19 patients with 21 total lesions treated with percutaneous RF ablation for HCC were identified through a search of the hospital electronic database. Patients with TIPS placed prior to RF ablation were included in the study. One lesion was ablated 3 times, while another two lesions underwent 2 ablation sessions each, giving a total of 25 ablations. The patient population was composed of 15 men and 4 women with a mean age of 62.2 years (range 51–73). Mean period from initial RF ablation to last clinical visit was 25.5 ± 23.1 months (range 1–93). TIPS Seven of the 19 patients had Wallstent endoprostheses (Boston Scientific, Natick, MA) and 12 had Gore Viatorr endoprostheses (W.L. Gore & Associates, Flagstaff, AZ). Wallstents were placed prior to 2002, and the 12 TIPS placed after this time utilized Viatorr endoprostheses. TIPSs were performed using conventional techniques, which have previously been reported [8]. Sub-group analysis was performed for patients with tumors within 1 cm within TIPS. Data in a porcine model in a prior study indicated that 63 % of hepatic veins within 2 cm of an applicator tip had an effect on an ablation zone [9]. We thus set a more conservative and lower threshold distance to increase the likelihood that the TIPS impacted the ablation zone via heat-sink effect.
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RF Ablation RF ablation was performed under general anesthesia or conscious sedation. All procedures were performed by one of three interventionalists with 13, 11, and 5 years of ablation experience, respectively. RF ablation was performed utilizing conventional techniques, which have been reported previously [1, 10]. RF ablation devices used included multitined expandable electrodes (2.0-, 3.0-, or 3.5-cm electrodes [Boston Scientific] or 2- to 3-cm model 30/3-cm Starburst XL electrodes [Angiodynamics]), as well as internally cooled electrodes (2.0- or 3.0-cm single electrode or 2.5-cm cluster electrode [Covidien, Boulder, CO]). With all device types, tract ablation was carefully performed by simultaneously withdrawing the electrodes while applying continuous RF energy. Monitoring and guidance were performed with CT (Definition or Sensation, Siemens; or HighSpeed, GE Healthcare) and/or ultrasound (HDI 3000 or 5000, ATL). Overlapping or single ablations were done based on geometry, tumor size, as well as imaging feedback (from CT or ultrasound) during ablation. Ablations were performed with the goal of not only completely covering tumors, but also to attain safety margins of 5–10 mm around tumors when possible. Post-Ablation Follow-Up Post-treatment MRI or CT was performed within 1 month of RF ablation. CT was performed with a single-detector or multi-detector CT (Sensation 16 or 64 or Definition 64, Siemens Healthcare) and includes multi-phase liver protocol with non-enhanced, hepatic arterial, and portal venous phases. MRI was performed on a 1.5-T (Avanto, Siemens Healthcare) or 3-T scanner (Trio, Siemens Healthcare) with non-enhanced T2-weighted imaging, non-enhanced T1weighted imaging, and contrast-enhanced dynamic fat-saturated T1-weighted imaging. Representative imaging is depicted in Figs. 1, 2, 3. Clinical visit notes were reviewed for all patients to the time of last visit, or to transplantation. Disease status (disease free or HCC progression), dates of last follow-up, and dates of death (if applicable) were recorded for calculation of follow-up interval. The following clinical outcome measures were assessed, defined as follows [11]: Technical success (whether tumor was covered completely by ablation zone during or immediately following procedure) and technical efficacy (complete ablation defined by imaging follow-up at 3 months). Technical efficacy was further subdivided into primary (percentage of target tumors successfully eradicated following initial procedure) or secondary (tumors that have undergone successful repeat ablation following identification of local tumor progression). The term ‘re-treatment’ was
J. K. Park et al.: RF Ablation for HCC in Patients with TIPS
Fig. 1 Ablation probe immediately adjacent to more medial TIPS, which remained patent after procedure. Additional lateral TIPS placed in past is visualized, which occluded prior to placement of medial TIPS
Fig. 2 Doppler TIPS ultrasound in different patient 2 months after ablation demonstrates patency
reserved for describing ablation of locally progressive tumor, in cases where complete ablation was initially thought to have been achieved based upon imaging demonstrating ‘adequate’ tumor ablation. The term ‘local tumor progression’ describes appearance of tumor foci at ablation zone edge, after at least one contrast-enhanced follow-up study has documented adequate ablation and the absence of viable tissue in target tumor and surrounding ablation margin by imaging criteria. Complications, if applicable, were also noted as a portion of the patient’s follow-up. Statistical Analysis Statistical analysis was performed by our institutional statistician. Confidence interval estimates and v2 tests for
Fig. 3 Pre-ablation (A), immediate post-ablation (B), and 7-month post-ablation (C) images in same patient. A Post-contrast MRI demonstrates nodular marginal enhancement of hepatic dome lesion (arrow). B Immediate post-ablation CT demonstrates new hypodense ablation defect of lesion adjacent to TIPS (arrow). C At 7-month post-ablation CT, there is persistent contrast enhancement of TIPS lumen, indicating patency (arrow)
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proportions were performed with Stata 13 software (StataCorp, College Station, TX). Statistical significance was set at p \ 0.05.
Results Patients and Tumors Nineteen patients with 21 lesions undergoing 25 RF ablations were included. Patient demographics are summarized in Table 1. The mean maximum lesion diameter was 2.6 ± 0.7. Mean tumor distance from TIPS was 2.3 ± 1.4 cm. Seven lesions were within 1 cm of the TIPS; 1 of these lesions underwent 3 ablation sessions, and another lesion underwent 2 sessions, for a total of 10 ablations for this patient subset. Eleven patients (3/7 patients with lesions within 1 cm of TIPS, and 8/12 patients with lesions beyond 1 cm of TIPS) ultimately underwent liver transplantation. All lesions (100 %) demonstrated imaging evidence of HCC. Fourteen of 21 (67 %) lesions underwent biopsy, and 13 had biopsies demonstrating pathological evidence of HCC. 1 lesion demonstrated dysplastic tissue, but met imaging criteria for HCC. Alpha fetoprotein was also measured in patients upon initial diagnosis.
Outcomes and Follow-Up Five of 11 transplanted patients died in the follow-up period after transplant (2 from recurrent hepatitis C, 2 from multiorgan failure/sepsis, and 1 from post-operative pulmonary embolus). Of the 8 patients who did not undergo transplantation, 2 were confirmed to be alive at the time of data review, 1 died of diffuse metastatic disease (neck, intra-thoracic, abdominal, and pelvic lymphadenopathy, in addition to airway compression), and 5 were lost to follow-up. Local progression was seen in 7 patients (37 %; 95 % CI 15.2–58.5 %), with a median time of 7 months. Two of these patients went on to successful retreatment. One of the lesions was retreated at 11 and 14 months after initial treatment, with no further evidence of recurrence following the final treatment. Successful transplantation was eventually performed 20 months following initial treatment. The second of these 7 lesions demonstrating recurrence was retreated at 8 months successfully, with no residual disease out to 26 months after initial treatment. Another of the 6 lesions demonstrating local recurrence went onto successful transplantation 8 months after initial ablation. Sub-group analysis of lesions within 1 cm of TIPS is provided in Table 3. Of note, local progression rate for this subset of patients was 3/7, 43 % (95 % CI 6.2–79.5 %) TIPS Patency
Ablation Outcomes Treatment responses for all lesions are summarized in Table 2. All 11 cases showed imaging evidence of complete tumor necrosis following ablation; of these, gross pathology demonstrated complete tumor necrosis in 8/11 (72 %). The remaining 3 demonstrated 85, 80, and 60 % tumor necrosis, respectively. No patients experienced liver failure within 1 month following ablation. Table 1 Patient demographics Variable
Value (n = 19 patients)
Age in years, (range)
62.2 (range 51–73)
Male gender, number of patients (%)
15 (79 %)
Discussion
Child-Pugh class, number of patients (%) A
1 (5 %)
B
13 (69 %)
C
5 (26 %)
Cause of cirrhosis, number of patients (%) Viral hepatitis Alcohol
11 5
Non-alcoholic steatohepatitis (NASH)
2
Mixed
1
Number going onto transplantation (%)
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Pre-ablation TIPS patency was demonstrated in 22/25 ablation cases (88 %). Of the 22 cases with patent TIPS prior to ablation, post-ablation patency was demonstrated in 22/22 (100 %) on immediate post-ablation imaging and in 21/22 (95 %) at last follow-up. The only patient with subsequent TIPS occlusion was incidentally discovered 31 months after RF ablation during follow-up imaging, and did not have clinical symptoms directly related to his occluded TIPS such as increasing ascites or esophageal varices. The patient had extensive disease progression at that time. No immediate major complications following RF ablation were observed.
11 (58 %)
RF ablation is a first-line therapy for small HCC with favorable survival outcomes compared to surgical resection [12–16]. Hepatic cirrhosis and resultant portal hypertension are frequently also present in the setting of HCC. Although placement of TIPS can alleviate sequelae of portal hypertension, in a cirrhotic, a tumor may grow in any location, including alongside a TIPS. Thus, clinical scenarios will arise where treatment for HCC must be directed in close proximity to TIPS.
J. K. Park et al.: RF Ablation for HCC in Patients with TIPS Table 2 Ablation outcomes and TIPS patency Procedural outcomes Variable
Value
Immediate technical success, number of ablation sessions (%)
25 (100 %)
Primary technical efficacy rate, number (%)
13 (68 %)
Lesions with primary technical efficacy, successful retreatment, or eventual transplant, number (%) Local progression rate, number (%)
16 (76 %) 7 (37 %; 95 % CI 15.2–58.5 %); median time 7 months
Survival in patients not undergoing transplantation 1 year
100 %
2 year
80 %
3 year
67 %
Lesions within 1 cm of TIPS, number (%)
7 (33 %; 95 % CI 13.2–53.5 %)
Table 3 Ablation outcomes and TIPS patency for lesions within 1 cm of TIPS Procedural outcomes Variable
Value
Number of lesions within 1 cm of TIPS; number of total ablation sessions
7; 10
Immediate technical success, number of ablation sessions (%)
10 (100 %)
Primary technical efficacy rate, number (%)
2 (29 %)
Local progression rate, number (%)
3 (43 %; 95 % CI 6.2–79.5 %), p = 0.78
Lesions with primary technical efficacy, successful retreatment, or eventual transplant, number (%)
4 (57 %)
Patients ultimately undergoing transplantation
3 (43 %)
Pre-ablation TIPS patency, number (%)
7 (100 %)
Post-ablation patency in cases with patent TIPS prior to ablation Immediate, number (%)
7 (100 %)
Delayed, number (%)
6 (86 %)
Our study indicates that RF ablation for HCC may be safe and effective in patients with TIPS. All cases demonstrated immediate technical success without evidence of initial residual tumor enhancement (100 %). The local progression rate in our study was 7/19 (37 %; 95 % CI 15.2–58.5 %), with a median time of 7 months. While the sample size for number of lesions within 1 cm of TIPS was relatively small (n = 7), local progression rate (3/7, 43 %; 95 % CI 6.2–79.5 %) was relatively similar to the literature values for RF ablation of HCC (2–18 %, and 18–39 % for small HCC B3 cm and intermediate HCC 3–5 cm, respectively [16]). Survival at 1, 2, and 3 years for patients not undergoing eventual transplantation in our study was 100, 80, and 67 %, respectively (compared to the literature values of 77–100, 62–87, and 53–80 %, respectively [16]). Although our sample size of this subset of 8 patients was relatively small, survival values were comparable to those cited in other studies, suggesting that ablation efficacy is preserved even in patients presenting with previously placed TIPS. Furthermore, when considering these values it
should be taken into account that patients undergoing TIPS tend to be particularly unhealthy at baseline due to their severe underlying hepatic dysfunction. We performed further sub-group analysis for lesions directly adjacent to (within 1 cm of) TIPS stents, as we believe it is of fundamental importance to evaluate the effect of the stent-graft on lesions of proximity. When comparing the subgroup with lesions directly adjacent to TIPS with all total cases, local progression rate was comparable (43 vs. 37 %, p = 0.78), respectively. However, comparison between the subgroup with lesions adjacent to TIPS and the group containing all cases is limited by the small patient population. TIPS patency was also preserved both immediately and in the delayed period in the majority of patients following RF ablation for HCC (100 and 95 %, respectively), even in cases where the ablation zone was directly within 1 cm of a TIPS stent-graft (7/21 cases, 33 %; 95 % CI 13.2–53.5 %). The only patient with subsequent TIPS occlusion (his TIPS was within 1 cm of the ablation zone) was incidentally
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J. K. Park et al.: RF Ablation for HCC in Patients with TIPS
discovered 31 months during follow-up imaging, and did not have clinical symptoms directly related to his occluded TIPS such as increasing ascites. Seven patients had Wallstent and 12 had Gore Viatorr endoprostheses. Covered stents such as the Viatorr show improved patency compared to bare metal stents, and are now the standard material used for TIPS procedures [8]. In our study, the currently commercially available TIPS stents did not seem to increase the risk for occlusion or following RF ablation. These findings are encouraging for the use of RF ablation for HCC in patients with severe portal hypertension who have had TIPS placed previously. While RF ablation is likely performed at multiple centers in the setting of preexisting TIPS, to date there is only one case report addressing the feasibility of performing RF ablation in this scenario [6]. A high proportion of patients with HCC have underlying cirrhosis, and will not uncommonly have TIPS placed for portal hypertension. In contrast to this case report, we did not employ any measures such as the Pringle maneuver to temporarily occlude the TIPS to reduce any potential heat-sink effect. Several studies have evaluated other locoregional therapies of HCC in the setting of an underlying TIPS. Mixed results have been described following transarterial chemoembolization (TACE) for patients with TIPS and HCC. One study by Kohi et al,. found that the incidence of hepatobiliary severe adverse events following TACE was nearly twice as high in patients with TIPS than without [17]. Another report by Tesdal et al. reported that TACE and percutaneous ethanol injection were beneficial in HCC patients treated with TIPS, with the caveat that liver function be adequate (the patient who died of liver failure was Child-Pugh Class C). In contrast, in our cohort of patients treated with RF ablation with TIPS, none suffered death from exacerbation of hepatic dysfunction related to the ablation procedure. Selective TACE has also been reported to be safe and effective for the palliative treatment of HCC in patients with TIPS, while late tumor stage was a poor prognostic factor for patient survival [18]. The utilization of Yttrium-90 radioembolization for HCC in patients with TIPS has also been reported [5]; 50 % of patients went onto liver transplantation, comparable to our study (11/19, 58 %, p = 0.67). In addition, one case report has been published reporting the use of irreversible electroporation (IRE) performed for HCC adjacent to a TIPS stent-graft with full ablation and complete preservation of TIPS flow [19]. An additional study of IRE adjacent to the hepatic veins in an animal model demonstrated some instances of acute venous narrowing without thrombi formation at any time points [20]. While IRE is a novel ablation technique that could eventually present as a potential improvement to the current
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status of tumor ablation, its precise role in HCC treatment has yet to be validated [21]. As such, it has been stated that an HCC adjacent to a TIPS should not be considered a contraindication for conventional ablative therapy [21], a statement this is corroborated by our results. Our experiences expand upon these prior brief reports and indicate that pre-existing TIPS should not deter the use of locoregional therapies for HCC, specifically RF ablation. The data presented in our study support the efficacy and safety of RF ablation for HCC in a patient population with severe underlying hepatic dysfunction in addition to tumor burden. However, several important limitations should be considered for our retrospective study of a relatively small sample size from a single institution. 11/19 patients in our study (57.9 %) underwent eventual liver transplantation. The large percentage of patients receiving this additional therapy may introduce bias to the long-term ablation efficacy and calculated mean survival rates. Furthermore, 5 of the 11 transplanted patients died in the follow-up period after transplant (2 from recurrent hepatitis C, 2 from multiorgan failure/sepsis, and 1 from post-operative pulmonary embolus); thus, patient deaths in the time period following RF ablation occurred for reasons in addition to local disease progression, further confounding survival data. An additional limitation is that not all lesions (7/21 total lesions, 10/25 ablation sessions) were directly adjacent (within 1 cm) to TIPS stent-grafts; however, the aim of our study was to establish ablation efficacy and safety for lesions both abutting and more remote to TIPS, as both scenarios are likely to be encountered in clinical practice. In conclusion, our study demonstrated that the survival and response rates of RF ablation in this small sample are similar to reports for larger studies of RF ablation for HCC. A high rate of TIPS patency at immediate and delayed time points following RF ablation for HCC was also seen. While patients with both portal hypertension and HCC are commonly encountered in clinical practice, we conclude that a pre-existing TIPS does not appear to be a contraindication for RF ablation. While the number of RF ablation cases performed in patients with TIPS is limited, future studies with larger groups of patients would be beneficial to further elucidate factors predicting outcomes and response of RF ablation in patients with HCC and preexisting TIPS. Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Lu DS, Yu NC, Raman SS et al (2005) Percutaneous radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. Hepatology 41:1130–1137
J. K. Park et al.: RF Ablation for HCC in Patients with TIPS 2. Lau WY, Leung TW, Yu SC, Ho SK (2003) Percutaneous local ablative therapy for hepatocellular carcinoma: a review and look into the future. Ann Surg 237:171–179 3. Lencioni R, Cioni D, Bartolozzi C (2001) Percutaneous radiofrequency thermal ablation of liver malignancies: techniques, indications, imaging findings, and clinical results. Abdom Imaging 26:345–360 4. Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS (1999) Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 210:655–661 5. Donahue LA, Kulik L, Baker T et al (2013) Yttrium-90 radioembolization for the treatment of unresectable hepatocellular carcinoma in patients with transjugular intrahepatic portosystemic shunts. J Vasc Interv Radiol 24:74–80 6. Pua U, Punamiya S (2012) Transjugular intrahepatic portosystemic shunt occlusion via modified pringle maneuver for radiofrequency ablation of nearby tumor. J Vasc Interv Radiol 23:563–565 7. Lu DS, Raman SS, Limanond P et al (2003) Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. J Vasc Interv Radiol 14:1267–1274 8. Otal P, Smayra T, Bureau C et al (2002) Preliminary results of a new expanded-polytetrafluoroethylene-covered stent-graft for transjugular intrahepatic portosystemic shunt procedures. AJR Am J Roentgenol 178:141–147 9. Frericks BB, Ritz JP, Albrecht T et al (2008) Influence of intrahepatic vessels on volume and shape of percutaneous thermal ablation zones: in vivo evaluation in a porcine model. Invest Radiol 43:211–218 10. Kim YJ, Raman SS, Yu NC, Busuttil RW, Tong M, Lu DS (2008) Radiofrequency ablation of hepatocellular carcinoma: can subcapsular tumors be safely ablated? AJR Am J Roentgenol 190: 1029–1034 11. Ahmed M, Solbiati L, Brace C et al (2014) Image-guided tumor ablation: standardization of terminology and reporting criteria—a ten year update. Radiology 273(1):241–260 12. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC (2004) Radiofrequency ablation improves prognosis compared with ethanol
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injection for hepatocellular carcinoma B4 cm. Gastroenterology 127:1714–1723 Livraghi T, Meloni F, Di Stasi M et al (2008) Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 47:82–89 N’Kontchou G, Mahamoudi A, Aout M et al (2009) Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology 50:1475–1483 Shiina S, Teratani T, Obi S et al (2005) A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129:122–130 Cho YK, Rhim H, Noh S (2011) Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a systematic review. J Gastroenterol Hepatol 26:1354–1360 Kohi MP, Fidelman N, Naeger DM, LaBerge JM, Gordon RL, Kerlan RK Jr (2013) Hepatotoxicity after transarterial chemoembolization and transjugular intrahepatic portosystemic shunt: do two rights make a wrong? J Vasc Interv Radiol 24:68–73 Kang JW, Kim JH, Ko GY, Gwon DI, Yoon HK, Sung KB (2012) Transarterial chemoembolization for hepatocellular carcinoma after transjugular intrahepatic portosystemic shunt. Acta Radiol 53:545–550 Niessen C, Jung EM, Wohlgemuth WA et al (2013) Irreversible electroporation of a hepatocellular carcinoma lesion adjacent to a transjugular intrahepatic portosystemic shunt stent graft. Korean J Radiol 14:797–800 Lee YJ, Lu DS, Osuagwu F, Lassman C (2012) Irreversible electroporation in porcine liver: short- and long-term effect on the hepatic veins and adjacent tissue by CT with pathological correlation. Invest Radiol 47:671–675 Pua U (2014) RE: Irreversible Electroporation of a Hepatocellular Carcinoma Lesion Adjacent to a Transjugular Intrahepatic Portosystemic Shunt Stent Graft. Korean J Radiol 15:181–182
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CLINICAL INVESTIGATION
Radiofrequency Ablation for the Treatment of Hepatocellular Carcinoma in Patients with Transjugular Intrahepatic Portosystemic Shunts Jonathan K. Park • Quazi Z. Al-Tariq • Taryar M. Zaw Steven S. Raman • David S.K. Lu
•
Received: 29 May 2014 / Accepted: 21 December 2014 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2015
Abstract Purpose To assess radiofrequency (RF) ablation efficacy, as well as the patency of transjugular intrahepatic portosystemic shunts (TIPSs), in patients with hepatocellular carcinoma (HCC). Materials and Methods Retrospective database review of patients with pre-existing TIPS undergoing RF ablation of HCC was conducted over a 159-month period ending in November 2013. TIPS patency pre- and post-RF ablation was assessed by ultrasound, angiography, and/or contrastenhanced CT or MRI. Patient demographics and immediate post-RF ablation outcomes and complications were also reviewed. Results 19 patients with 21 lesions undergoing 25 RF ablation sessions were included. Child-Pugh class A, B, and C scores were seen in 1, 13, and 5 patients, respectively. Eleven patients (58 %) ultimately underwent liver transplantation. Immediate technical success was seen in all ablation sessions without residual tumor enhancement (100 %). No patients (0 %) suffered liver failure within J. K. Park (&) T. M. Zaw S. S. Raman D. S.K.Lu Department of Radiology, David Geffen School of Medicine at UCLA, 757 Westwood Plaza, Los Angeles 90024, CA, USA e-mail: [email protected] T. M. Zaw e-mail: [email protected] S. S. Raman e-mail: [email protected] D. S.K.Lu e-mail: [email protected] Q. Z. Al-Tariq Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford 94305, CA, USA e-mail: [email protected]
1 month of ablation. Pre-ablation TIPS patency was demonstrated in 22/25 sessions (88 %). Of 22 cases with patent TIPS prior to ablation, post-ablation patency was demonstrated in 22/22 (100 %) at immediate post-ablation imaging and in 21/22 (95 %) at last follow-up (1 patient was incidentally noted to have occlusion 31 months later). No immediate complications were observed. Conclusion Ablation efficacy was similar to the cited literature values for patients without TIPS. Furthermore, TIPS patency was preserved in the majority of cases. Patients with both portal hypertension and HCC are not uncommonly encountered, and a pre-existing TIPS does not appear to be a definite contraindication for RF ablation. Keywords Interventional oncology Radiofrequency ablation Transjugular intrahepatic portosystemic shunt (TIPS/TIPSS) Hepatocellular carcinoma (HCC) Portal vein hypertension Liver/hepatic
Introduction In the United States, the incidence of hepatocellular carcinoma (HCC) has almost tripled since the early 1980s. Radiofrequency (RF) ablation has emerged as a first-line therapy for small, nonresectable cases of HCC with well-established safety and efficacy profiles for selected cases [1–4]. In patients with liver cirrhosis and resultant portal hypertension, creation of a transjugular intrahepatic portosystemic shunt (TIPS) can alleviate portal hypertension sequelae including bleeding varices and refractory ascites [5]. Given that patients with cirrhosis are also at higher risk of developing HCC, TIPSs are often present in patients with HCC. Despite the benefits of TIPS in patients with
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J. K. Park et al.: RF Ablation for HCC in Patients with TIPS
significant portal hypertension, tumor growing alongside TIPS can theoretically pose a challenge to RF ablation due to the heat-sink effect [6]. This may potentially result in incomplete necrosis for lesions adjacent to blood vessels greater than 3 mm [7]. Furthermore, the effect of thermal ablation on TIPS patency is not established. While patients with portal hypertension and TIPS presenting for RF ablation of HCC are commonly encountered in clinical practice, the current literature consists of only one case report addressing the feasibility of performing RF ablation in a patient with pre-existing TIPS. Thus, the aim of our study was to assess the efficacy of RF ablation in patients with pre-existing TIPS, as well as post-procedural TIPS patency.
Materials and Methods Patients The medical center institutional review board approved the study and waived informed consent. All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. Between August 2000 and November 2013, 19 patients with 21 total lesions treated with percutaneous RF ablation for HCC were identified through a search of the hospital electronic database. Patients with TIPS placed prior to RF ablation were included in the study. One lesion was ablated 3 times, while another two lesions underwent 2 ablation sessions each, giving a total of 25 ablations. The patient population was composed of 15 men and 4 women with a mean age of 62.2 years (range 51–73). Mean period from initial RF ablation to last clinical visit was 25.5 ± 23.1 months (range 1–93). TIPS Seven of the 19 patients had Wallstent endoprostheses (Boston Scientific, Natick, MA) and 12 had Gore Viatorr endoprostheses (W.L. Gore & Associates, Flagstaff, AZ). Wallstents were placed prior to 2002, and the 12 TIPS placed after this time utilized Viatorr endoprostheses. TIPSs were performed using conventional techniques, which have previously been reported [8]. Sub-group analysis was performed for patients with tumors within 1 cm within TIPS. Data in a porcine model in a prior study indicated that 63 % of hepatic veins within 2 cm of an applicator tip had an effect on an ablation zone [9]. We thus set a more conservative and lower threshold distance to increase the likelihood that the TIPS impacted the ablation zone via heat-sink effect.
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RF Ablation RF ablation was performed under general anesthesia or conscious sedation. All procedures were performed by one of three interventionalists with 13, 11, and 5 years of ablation experience, respectively. RF ablation was performed utilizing conventional techniques, which have been reported previously [1, 10]. RF ablation devices used included multitined expandable electrodes (2.0-, 3.0-, or 3.5-cm electrodes [Boston Scientific] or 2- to 3-cm model 30/3-cm Starburst XL electrodes [Angiodynamics]), as well as internally cooled electrodes (2.0- or 3.0-cm single electrode or 2.5-cm cluster electrode [Covidien, Boulder, CO]). With all device types, tract ablation was carefully performed by simultaneously withdrawing the electrodes while applying continuous RF energy. Monitoring and guidance were performed with CT (Definition or Sensation, Siemens; or HighSpeed, GE Healthcare) and/or ultrasound (HDI 3000 or 5000, ATL). Overlapping or single ablations were done based on geometry, tumor size, as well as imaging feedback (from CT or ultrasound) during ablation. Ablations were performed with the goal of not only completely covering tumors, but also to attain safety margins of 5–10 mm around tumors when possible. Post-Ablation Follow-Up Post-treatment MRI or CT was performed within 1 month of RF ablation. CT was performed with a single-detector or multi-detector CT (Sensation 16 or 64 or Definition 64, Siemens Healthcare) and includes multi-phase liver protocol with non-enhanced, hepatic arterial, and portal venous phases. MRI was performed on a 1.5-T (Avanto, Siemens Healthcare) or 3-T scanner (Trio, Siemens Healthcare) with non-enhanced T2-weighted imaging, non-enhanced T1weighted imaging, and contrast-enhanced dynamic fat-saturated T1-weighted imaging. Representative imaging is depicted in Figs. 1, 2, 3. Clinical visit notes were reviewed for all patients to the time of last visit, or to transplantation. Disease status (disease free or HCC progression), dates of last follow-up, and dates of death (if applicable) were recorded for calculation of follow-up interval. The following clinical outcome measures were assessed, defined as follows [11]: Technical success (whether tumor was covered completely by ablation zone during or immediately following procedure) and technical efficacy (complete ablation defined by imaging follow-up at 3 months). Technical efficacy was further subdivided into primary (percentage of target tumors successfully eradicated following initial procedure) or secondary (tumors that have undergone successful repeat ablation following identification of local tumor progression). The term ‘re-treatment’ was
J. K. Park et al.: RF Ablation for HCC in Patients with TIPS
Fig. 1 Ablation probe immediately adjacent to more medial TIPS, which remained patent after procedure. Additional lateral TIPS placed in past is visualized, which occluded prior to placement of medial TIPS
Fig. 2 Doppler TIPS ultrasound in different patient 2 months after ablation demonstrates patency
reserved for describing ablation of locally progressive tumor, in cases where complete ablation was initially thought to have been achieved based upon imaging demonstrating ‘adequate’ tumor ablation. The term ‘local tumor progression’ describes appearance of tumor foci at ablation zone edge, after at least one contrast-enhanced follow-up study has documented adequate ablation and the absence of viable tissue in target tumor and surrounding ablation margin by imaging criteria. Complications, if applicable, were also noted as a portion of the patient’s follow-up. Statistical Analysis Statistical analysis was performed by our institutional statistician. Confidence interval estimates and v2 tests for
Fig. 3 Pre-ablation (A), immediate post-ablation (B), and 7-month post-ablation (C) images in same patient. A Post-contrast MRI demonstrates nodular marginal enhancement of hepatic dome lesion (arrow). B Immediate post-ablation CT demonstrates new hypodense ablation defect of lesion adjacent to TIPS (arrow). C At 7-month post-ablation CT, there is persistent contrast enhancement of TIPS lumen, indicating patency (arrow)
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J. K. Park et al.: RF Ablation for HCC in Patients with TIPS
proportions were performed with Stata 13 software (StataCorp, College Station, TX). Statistical significance was set at p \ 0.05.
Results Patients and Tumors Nineteen patients with 21 lesions undergoing 25 RF ablations were included. Patient demographics are summarized in Table 1. The mean maximum lesion diameter was 2.6 ± 0.7. Mean tumor distance from TIPS was 2.3 ± 1.4 cm. Seven lesions were within 1 cm of the TIPS; 1 of these lesions underwent 3 ablation sessions, and another lesion underwent 2 sessions, for a total of 10 ablations for this patient subset. Eleven patients (3/7 patients with lesions within 1 cm of TIPS, and 8/12 patients with lesions beyond 1 cm of TIPS) ultimately underwent liver transplantation. All lesions (100 %) demonstrated imaging evidence of HCC. Fourteen of 21 (67 %) lesions underwent biopsy, and 13 had biopsies demonstrating pathological evidence of HCC. 1 lesion demonstrated dysplastic tissue, but met imaging criteria for HCC. Alpha fetoprotein was also measured in patients upon initial diagnosis.
Outcomes and Follow-Up Five of 11 transplanted patients died in the follow-up period after transplant (2 from recurrent hepatitis C, 2 from multiorgan failure/sepsis, and 1 from post-operative pulmonary embolus). Of the 8 patients who did not undergo transplantation, 2 were confirmed to be alive at the time of data review, 1 died of diffuse metastatic disease (neck, intra-thoracic, abdominal, and pelvic lymphadenopathy, in addition to airway compression), and 5 were lost to follow-up. Local progression was seen in 7 patients (37 %; 95 % CI 15.2–58.5 %), with a median time of 7 months. Two of these patients went on to successful retreatment. One of the lesions was retreated at 11 and 14 months after initial treatment, with no further evidence of recurrence following the final treatment. Successful transplantation was eventually performed 20 months following initial treatment. The second of these 7 lesions demonstrating recurrence was retreated at 8 months successfully, with no residual disease out to 26 months after initial treatment. Another of the 6 lesions demonstrating local recurrence went onto successful transplantation 8 months after initial ablation. Sub-group analysis of lesions within 1 cm of TIPS is provided in Table 3. Of note, local progression rate for this subset of patients was 3/7, 43 % (95 % CI 6.2–79.5 %) TIPS Patency
Ablation Outcomes Treatment responses for all lesions are summarized in Table 2. All 11 cases showed imaging evidence of complete tumor necrosis following ablation; of these, gross pathology demonstrated complete tumor necrosis in 8/11 (72 %). The remaining 3 demonstrated 85, 80, and 60 % tumor necrosis, respectively. No patients experienced liver failure within 1 month following ablation. Table 1 Patient demographics Variable
Value (n = 19 patients)
Age in years, (range)
62.2 (range 51–73)
Male gender, number of patients (%)
15 (79 %)
Discussion
Child-Pugh class, number of patients (%) A
1 (5 %)
B
13 (69 %)
C
5 (26 %)
Cause of cirrhosis, number of patients (%) Viral hepatitis Alcohol
11 5
Non-alcoholic steatohepatitis (NASH)
2
Mixed
1
Number going onto transplantation (%)
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Pre-ablation TIPS patency was demonstrated in 22/25 ablation cases (88 %). Of the 22 cases with patent TIPS prior to ablation, post-ablation patency was demonstrated in 22/22 (100 %) on immediate post-ablation imaging and in 21/22 (95 %) at last follow-up. The only patient with subsequent TIPS occlusion was incidentally discovered 31 months after RF ablation during follow-up imaging, and did not have clinical symptoms directly related to his occluded TIPS such as increasing ascites or esophageal varices. The patient had extensive disease progression at that time. No immediate major complications following RF ablation were observed.
11 (58 %)
RF ablation is a first-line therapy for small HCC with favorable survival outcomes compared to surgical resection [12–16]. Hepatic cirrhosis and resultant portal hypertension are frequently also present in the setting of HCC. Although placement of TIPS can alleviate sequelae of portal hypertension, in a cirrhotic, a tumor may grow in any location, including alongside a TIPS. Thus, clinical scenarios will arise where treatment for HCC must be directed in close proximity to TIPS.
J. K. Park et al.: RF Ablation for HCC in Patients with TIPS Table 2 Ablation outcomes and TIPS patency Procedural outcomes Variable
Value
Immediate technical success, number of ablation sessions (%)
25 (100 %)
Primary technical efficacy rate, number (%)
13 (68 %)
Lesions with primary technical efficacy, successful retreatment, or eventual transplant, number (%) Local progression rate, number (%)
16 (76 %) 7 (37 %; 95 % CI 15.2–58.5 %); median time 7 months
Survival in patients not undergoing transplantation 1 year
100 %
2 year
80 %
3 year
67 %
Lesions within 1 cm of TIPS, number (%)
7 (33 %; 95 % CI 13.2–53.5 %)
Table 3 Ablation outcomes and TIPS patency for lesions within 1 cm of TIPS Procedural outcomes Variable
Value
Number of lesions within 1 cm of TIPS; number of total ablation sessions
7; 10
Immediate technical success, number of ablation sessions (%)
10 (100 %)
Primary technical efficacy rate, number (%)
2 (29 %)
Local progression rate, number (%)
3 (43 %; 95 % CI 6.2–79.5 %), p = 0.78
Lesions with primary technical efficacy, successful retreatment, or eventual transplant, number (%)
4 (57 %)
Patients ultimately undergoing transplantation
3 (43 %)
Pre-ablation TIPS patency, number (%)
7 (100 %)
Post-ablation patency in cases with patent TIPS prior to ablation Immediate, number (%)
7 (100 %)
Delayed, number (%)
6 (86 %)
Our study indicates that RF ablation for HCC may be safe and effective in patients with TIPS. All cases demonstrated immediate technical success without evidence of initial residual tumor enhancement (100 %). The local progression rate in our study was 7/19 (37 %; 95 % CI 15.2–58.5 %), with a median time of 7 months. While the sample size for number of lesions within 1 cm of TIPS was relatively small (n = 7), local progression rate (3/7, 43 %; 95 % CI 6.2–79.5 %) was relatively similar to the literature values for RF ablation of HCC (2–18 %, and 18–39 % for small HCC B3 cm and intermediate HCC 3–5 cm, respectively [16]). Survival at 1, 2, and 3 years for patients not undergoing eventual transplantation in our study was 100, 80, and 67 %, respectively (compared to the literature values of 77–100, 62–87, and 53–80 %, respectively [16]). Although our sample size of this subset of 8 patients was relatively small, survival values were comparable to those cited in other studies, suggesting that ablation efficacy is preserved even in patients presenting with previously placed TIPS. Furthermore, when considering these values it
should be taken into account that patients undergoing TIPS tend to be particularly unhealthy at baseline due to their severe underlying hepatic dysfunction. We performed further sub-group analysis for lesions directly adjacent to (within 1 cm of) TIPS stents, as we believe it is of fundamental importance to evaluate the effect of the stent-graft on lesions of proximity. When comparing the subgroup with lesions directly adjacent to TIPS with all total cases, local progression rate was comparable (43 vs. 37 %, p = 0.78), respectively. However, comparison between the subgroup with lesions adjacent to TIPS and the group containing all cases is limited by the small patient population. TIPS patency was also preserved both immediately and in the delayed period in the majority of patients following RF ablation for HCC (100 and 95 %, respectively), even in cases where the ablation zone was directly within 1 cm of a TIPS stent-graft (7/21 cases, 33 %; 95 % CI 13.2–53.5 %). The only patient with subsequent TIPS occlusion (his TIPS was within 1 cm of the ablation zone) was incidentally
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discovered 31 months during follow-up imaging, and did not have clinical symptoms directly related to his occluded TIPS such as increasing ascites. Seven patients had Wallstent and 12 had Gore Viatorr endoprostheses. Covered stents such as the Viatorr show improved patency compared to bare metal stents, and are now the standard material used for TIPS procedures [8]. In our study, the currently commercially available TIPS stents did not seem to increase the risk for occlusion or following RF ablation. These findings are encouraging for the use of RF ablation for HCC in patients with severe portal hypertension who have had TIPS placed previously. While RF ablation is likely performed at multiple centers in the setting of preexisting TIPS, to date there is only one case report addressing the feasibility of performing RF ablation in this scenario [6]. A high proportion of patients with HCC have underlying cirrhosis, and will not uncommonly have TIPS placed for portal hypertension. In contrast to this case report, we did not employ any measures such as the Pringle maneuver to temporarily occlude the TIPS to reduce any potential heat-sink effect. Several studies have evaluated other locoregional therapies of HCC in the setting of an underlying TIPS. Mixed results have been described following transarterial chemoembolization (TACE) for patients with TIPS and HCC. One study by Kohi et al,. found that the incidence of hepatobiliary severe adverse events following TACE was nearly twice as high in patients with TIPS than without [17]. Another report by Tesdal et al. reported that TACE and percutaneous ethanol injection were beneficial in HCC patients treated with TIPS, with the caveat that liver function be adequate (the patient who died of liver failure was Child-Pugh Class C). In contrast, in our cohort of patients treated with RF ablation with TIPS, none suffered death from exacerbation of hepatic dysfunction related to the ablation procedure. Selective TACE has also been reported to be safe and effective for the palliative treatment of HCC in patients with TIPS, while late tumor stage was a poor prognostic factor for patient survival [18]. The utilization of Yttrium-90 radioembolization for HCC in patients with TIPS has also been reported [5]; 50 % of patients went onto liver transplantation, comparable to our study (11/19, 58 %, p = 0.67). In addition, one case report has been published reporting the use of irreversible electroporation (IRE) performed for HCC adjacent to a TIPS stent-graft with full ablation and complete preservation of TIPS flow [19]. An additional study of IRE adjacent to the hepatic veins in an animal model demonstrated some instances of acute venous narrowing without thrombi formation at any time points [20]. While IRE is a novel ablation technique that could eventually present as a potential improvement to the current
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status of tumor ablation, its precise role in HCC treatment has yet to be validated [21]. As such, it has been stated that an HCC adjacent to a TIPS should not be considered a contraindication for conventional ablative therapy [21], a statement this is corroborated by our results. Our experiences expand upon these prior brief reports and indicate that pre-existing TIPS should not deter the use of locoregional therapies for HCC, specifically RF ablation. The data presented in our study support the efficacy and safety of RF ablation for HCC in a patient population with severe underlying hepatic dysfunction in addition to tumor burden. However, several important limitations should be considered for our retrospective study of a relatively small sample size from a single institution. 11/19 patients in our study (57.9 %) underwent eventual liver transplantation. The large percentage of patients receiving this additional therapy may introduce bias to the long-term ablation efficacy and calculated mean survival rates. Furthermore, 5 of the 11 transplanted patients died in the follow-up period after transplant (2 from recurrent hepatitis C, 2 from multiorgan failure/sepsis, and 1 from post-operative pulmonary embolus); thus, patient deaths in the time period following RF ablation occurred for reasons in addition to local disease progression, further confounding survival data. An additional limitation is that not all lesions (7/21 total lesions, 10/25 ablation sessions) were directly adjacent (within 1 cm) to TIPS stent-grafts; however, the aim of our study was to establish ablation efficacy and safety for lesions both abutting and more remote to TIPS, as both scenarios are likely to be encountered in clinical practice. In conclusion, our study demonstrated that the survival and response rates of RF ablation in this small sample are similar to reports for larger studies of RF ablation for HCC. A high rate of TIPS patency at immediate and delayed time points following RF ablation for HCC was also seen. While patients with both portal hypertension and HCC are commonly encountered in clinical practice, we conclude that a pre-existing TIPS does not appear to be a contraindication for RF ablation. While the number of RF ablation cases performed in patients with TIPS is limited, future studies with larger groups of patients would be beneficial to further elucidate factors predicting outcomes and response of RF ablation in patients with HCC and preexisting TIPS. Conflict of interest of interest.
The authors declare that they have no conflict
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