13 Laparoscopic Liver Surgery for the Management of Hepatocellular Carcinoma 215 in itself often obviates major hemorrhage. Lastly, use of endovascular staplers are used when the remaining vascular pedicle of the tumor is identified when greater than 90% of the tumor is resected. Liberal application of staplers in a cirrhotic liver often results in deformed staplers and incomplete staple formation, hence should be averted till essential. A margin of 1 cm is considered satisfactory. However, depending on the loca- tion of the lesion (e.g., when tumor abuts major vessels), a smaller margin may be acceptable as long as the tumor does not extend to the resection margins. If the lesion is not deemed resectable or additional lesions are found, radiofrequency abla- tion of the lesion is commonly performed. The RFA probe is placed in the center of the tumor and treated as per the device protocol. Results The skepticism surrounding the advent of laparoscopic liver surgery for hepatoma had to do mainly with the fear of complications and oncological integrity. The safety on both these counts has now been demonstrated in large series. In the preliminary data from a multicenter study from Europe [18], of the 9 cirrhotic patients (Child’s A = 5; B = 4) undergoing laparoscopic liver resec- tion for hepatoma, 5 developed transient liver failure and ascites. Perioperative complications, such as bleeding, need for blood transfusion, need for portal triad clamping, and conversion to open resection, were higher in the hepatoma group as compared to patients with liver metastasis undergoing laparoscopic resection. A tumor-free margin of at least 1 cm was obtained in 70% of patients. No port site metastasis was detected and the disease-free survival was 44% at a mean follow- up of 14 months. Although this study demonstrated the feasibility of laparoscopic liver resection, it did not convince most physicians about a future role in HCC therapy. The first prospective study [19] with a reasonable follow-up included 27 Child’s A cirrhotic patients with solitary peripheral lesions up to 5 cm. The resections included 17 anatomic and 10 non-anatomic resections; the rate of conversion to open resection was 26%. Most of the conversions were required for lesions in seg- ment 6 of the liver. Postoperative complications were noted in 33%, and 15 patients had a surgical margin less than 1 cm. During a mean follow-up of 2 years 8 patients (30%) developed recurrence (includes 3 with local recurrence) and the overall and disease-free 3-year survival rates were 93 and 64%, respectively. A recent study from Italy [20] retrospectively compared laparoscopic and open liver resection for hepatoma in cirrhotic patients. Although the mean operating time was longer in the laparoscopic group, this group required significantly less blood transfusion and use of a Pringle maneuver and had reduced hospital stay and postop- erative complications compared to the open resection group. The resection margin was greater than 1 cm in 92% of the laparoscopic group. The mortality rate and 2-year survival were similar in both groups. 216 K.V. Ravindra and J.F. Buell The largest s ingle center report of laparoscopic liver resections for HCC is a ret- rospective study from Taiwan [21]. This included 116 cirrhotic patients of whom 18 were Child’s status B/C. Major resections (>2 segments) were performed in 19 patients. A hand port device was used for lesions in segments 7 and 8. Conversion to open resection was necessary in 5.2% of patients and the need for blood trans- fusion was low (6.9%). An extremely low complication rate of 6% was reported. A 5-year survival rate of 60% was reported with a complete absence of port site recurrences. An updated European multicenter study (Dagher, personal communication) included 163 resections (cirrhotic: 120; fibrosis: 11, and normal: 32). A pure laparo- scopic approach was used in 95% of cases but required a lower abdominal incision for specimen retrieval. Major resections were done in 10%. The rate of conversion to open resection and the need for blood transfusion were 9.2 and 9.8%, respec- tively. There were 2 postoperative deaths and the morbidity was detailed as liver specific in 11.6% and nonspecific in 10.4%. The mean surgical margin was 14.2 ± 10.6 mm and exceeded 5 mm in 83.4%. At a mean follow-up of 30.4 months, tumor recurrence in the liver was noted in 39.2% (local in 17% and distant 83%). A summary of the majority of reports in the literature is contained in Table 13.2. The above results strongly support the feasibility and safety of the laparoscopic technique in the surgical treatment of hepatoma of the liver in cirrhotics. Summary Laparoscopic resection of liver for hepatoma is a safe option. In centers with the necessary expertise results are equivalent to open surgery. The advantages of small incisions minimizing the incidence of ascites and adhesions are likely to increase the use of this option in the cirrhotic population (Child’s A/B). This is crucially important in those likely to need liver transplantation in the future. References 1. Mazzaferro V, Regalia E, Doci R, et al (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693–699 2. Yao FY, Ferrell L, Bass NM, et al (2001) Liver transplantation for hepatocellular carci- noma: expansion of the tumor size limits does not adversely impact survival. Hepatology 33: 1394–1403 3. Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS, et al (1999) Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 210:655–661 4. Zhou XD, Tang ZY (1998) Cryotherapy for primary liver cancer. Semin Surg Oncol 14: 171–174 5. Shiina S, Tagawa K, Niwa Y, et al (1993) Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. AJR Am J Roentgenol 160(5):1023–1028 6. Matsukawa T, Yamashita Y, Arakawa A, et al (1997) Percutaneous microwave coagulation therapy in liver tumors. A 3-year experience. Acta Radiol 38:410–415 13 Laparoscopic Liver Surgery for the Management of Hepatocellular Carcinoma 217 7. Pacella CM, Bizzarri G, Guglielmi R, et al (2001) Laser thermal ablation in the treatment of small hepatocellular carcinoma: results in 74 patients. Radiology 221:712–720 8. Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocel- lular carcinoma: Chemoembolization improves survival. Hepatology 37:429–442 9. Salem R, Lewandowski RJ, Atassi B, et al (2005) Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival. J Vasc Interv Radiol 16:1627–1639 10. Lau H, Man K, Fan ST, Yu WC, Lo CM, Wong J (1997) Evaluation of preoperative hep- atic function in patients with hepatocellular carcinoma undergoing hepatectomy. Br J Surg 84:1255–1259 11. Bryant R, Laurent A, Tayar C, et al (2008) Liver resection for hepatocellular carcinoma. Surg Oncol Clin N Am 17:607–633, ix 12. Lau WY (1997) The history of liver surgery. J R Coll Surg Edinb 42:303–309 13. Buell JF, Thomas MT, Rudich S, et al (2008) Experience with more than 500 minimally invasive hepatic procedures. Ann Surg 248:475–486 14. Koffron AJ, Auffenberg G, Kung R, Abecassis M (2007) Evaluation of 300 minimally invasive liver resections at a single institution: less is more. Ann Surg 246:385–392 15. Nguyen KT, Gamblin TC, Geller DA (2008) Laparoscopic liver resection for cancer. Future Oncol 4:661–670 16. Vauthey JN, Chaoui A, Do KA, et al (2000) Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery 127:512–519 17. Makuuchi M, Sano K (2004) The surgical approach to HCC: our progress and results in Japan. Liver Transpl 10(2 Suppl 1):S46–S52 18. Gigot JF, Glineur D, Santiago Azagra J, et al (2002) Laparoscopic liver resection for malignant liver tumors: preliminary results of a multicenter European study. Ann Surg 236:90–97 19. Cherqui D, Laurent A, Tayar C, et al (2006) Laparoscopic liver resection for peripheral hepa- tocellular carcinoma in patients with chronic liver disease: midterm results and perspectives. Ann Surg 243:499–506 20. Belli G, Fantini C, D’Agostino A, et al (2007) Laparoscopic versus open liver resection for hepatocellular carcinoma in patients with histologically proven cirrhosis: short- and middle- term results. Surg Endosc 21:2004–2011 21. Chen HY, Juan CC, Ker CG (2008) Laparoscopic liver surgery for patients with hepatocellular carcinoma. Ann Surg Oncol 15:800–806 22. Poon RT (2007) Current role of laparoscopic surgery for liver malignancies. Surg Technol Int 16:73–81 23. Buell JF, Koffron AJ, Thomas MJ, et al (2005) Laparoscopic liver resection. J Am Coll Surg 200:472–480 24. Santambrogio R, Aldrighetti L, Barabino M, et al (2009) Laparoscopic liver resections for hepatocellular carcinoma. Is it a feasible option for patients with liver cirrhosis? Langenbecks Arch Surg 394:255–264 Chapter 14 Liver Transplant for Hepatocellular Carcinoma Thomas A. Aloia, A. Osama Gaber, and R. Mark Ghobrial Keywords Liver cancer · Liver transplantation · Immunosuppression · Outcomes · Prognostic factors History of Liver Transplant for HCC From the start of liver transplantation, treatment of hepatocellular carcinoma (HCC) has played a central role. Following the unsuccessful transplant of a child with biliary atresia in 1963, the second and third attempts at liver transplantation at the University of Colorado were in adults with advanced HCC. At autopsy, both recipients were found to have micrometastatic disease [1]. As liver transplantation proceeded in an experimental environment, the high mortality procedure was fre- quently reserved for patients with advanced malignancy. In 1967, a 19-month-old child with primary liver cancer became the first liver transplant recipient to achieve prolonged survival, but recurred within 4 months and died of disseminated cancer at 400 days [2]. As the procedure and immunosuppression were refined, patient and allograft survivals improved to the point that oncologic recurrence and survival rates could be determined [3, 4]. This initial experience clearly showed that, in the immunosuppressed state fol- lowing liver transplantation, patients with advanced stage HCC had extraordinarily high recurrence rates [5]. As more experience was gained and allograft outcomes continued to improve, the non-oncologic indications for liver transplantation were expanded and, appropriately, oncologic indications were constricted [6]. In 1989, a moratorium on liver transplantation for HCC was put in place. Following this, enthusiasm waned and few guidelines directed the listing and transplantation of patients with HCC until the publication of the “Milan criteria” R.M. Ghobrial (B) Department of Surgery, Weill-Cornell Medical College, The Methodist Hospital, Houston, TX, USA 219 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_14, C Springer Science+Business Media, LLC 2011 220 T.A. Aloia et al. [7]. The Milan experience, which identified a s ubset of early HCC patients with strict tumor number (≤3) and tumor size (≤3 cm) criteria who had both excel- lent allograft and oncologic outcomes, rekindled interest in liver transplantation for malignant disease. Over the next decade the percentage of cadaveric l iver transplants for patients with HCC steadily rose, and 5-year post-transplant patient survival rates of 60% and HCC recurrence rates of less than 15% were finally achieved [8–14]. The re-expansion of liver transplantation into the HCC recipient pool was tem- porally correlated with two other shifts in liver transplantation practice. First, in Western countries with significant rates of hepatitis C virus infection and obesity, the acute rise in the incidence of HCC cases has focused the hepatology and trans- plant community on the problem of effective treatments [15, 16]. Additionally, more standardized screening recommendations have allowed diagnosis of earlier stage patients with HCC who more likely benefit from liver transplantation [17]. Second, in 2002, the United Network for Organ Sharing (UNOS) instituted the model for end-stage liver disease (MELD) waitlist rank system and created MELD exception algorithms that advantage waitlisted patients with UNOS T2-3 criteria HCC [18]. Together, these two factors have contributed to a sharp r ise in the percentage of US liver transplants performed for HCC [19]. Currently, liver transplantation stands as the best treatment modality for early- stage HCC in patients with decompensated cirrhosis, giving patients the opportunity to be free from the potentially lethal complications of both cancer and their underly- ing liver disease [11, 12, 20–22]. In settings where the number of patients with HCC and cirrhosis exceeds the availability of cadaveric liver allografts, alternative strate- gies are required. These include more liberal use of liver resection, interventional and systemic treatments, public health campaigns for organ donation awareness, and living-related liver transplantation. The Role of HCC Staging Systems in Pre-transplant Decision-Making Multiple staging systems have been proposed for the stratification of prognosis and treatment of patients with HCC. Although both the American Joint Committee on Cancer (AJCC) staging system (6th Edition) and the Pittsburg modified tumor- node-metastasis staging systems have a strong correlation with outcomes in patients with HCC, their reliance on pathological information ( i.e., microvascular invasion) limits their utility in cirrhotic pre-transplant patients. With only radiologic staging information available for most patients, US transplant programs have relied on the American Liver Tumor Study Group/UNOS staging system to determine transplant candidacy and MELD point allocation (Table 14.1). This system relies on the accu- racy of contrast-enhanced cross-sectional imaging modalities, including computed tomography (CT) and magnetic resonance imaging (MRI). Under UNOS criteria, liver masses in cirrhotic patients with vascular phase blush in the absence of gross 14 Liver Transplant for Hepatocellular Carcinoma 221 Table 14.1 Modified UNOS staging system for HCC UNOS HCC tumor stage Radiographic criteria (liver mass with vascular blush on CT, MR, or angiogram T1 Solitary, <2 cm T2 Solitary, 2–5 cm 2–3 tumors, all less than 3 cm T3 Solitary, 5–6 cm 2–3 tumors, at least one >3 cm, none greater than 5 cm, aggregate not greater than 9 cm T4a Solitary, >6 cm 2–3 tumors, any greater than 5 cm and/or aggregate greater than 9 cm >3 tumors T4b T2, T3, T4a plus gross intrahepatic portal or hepatic vein involvement American Liver Tumor Study Group [97]andYao[10], with T3 modification to account for Regional T3 MELD exception criteria. vascular invasion are eligible to be staged with this system. Many centers have added further imaging criteria, including washout of contrast on venous phase imaging and the presence of T2 signal on MRI, in order to proceed to transplant listing with an HCC indication without tissue biopsy. These noninvasive criteria have been vali- dated, obviating the need for tissue biopsy and the risk of immediate complication or tumor seeding [23–25]. Using these criteria, in the absence of complete response to neoadjuvant therapies, remarkably few patients will have a negative pathology specimen at explant. In Europe, the Barcelona Clinic Liver Cancer Staging and Treatment Approach has been popularized [26, 27]. This system uniquely integrates clinical tumor stag- ing, degree of cirrhotic complications as measured by the Child-Turcotte-Pugh (CTP) score, portal pressure measurement, performance status, and comorbidities to assign various treatments to HCC patients. In this algorithm, liver transplantation is reserved for Conventional Milan Criteria (CMC) HCC patients with preserved performance status and cirrhosis with portal hypertension. HCC patients trans- planted under this algorithm are reported to have 5-year post-transplant survivals of 60–70%. Despite advances in radiologic staging there continues to be a considerable difference between preoperative clinical staging and postoperative tumor staging. Exclusive of histopathologic variables such as vascular invasion and tumor differen- tiation, the simple measurements of tumor number and maximal tumor dimension that make up the foundation of UNOS, Conventional Milan Criteria (CMC), and University of California at San Francisco (UCSF) criteria can lead to pathologi- cal upstaging in as many as 30% of recipients [14, 22, 28–32]. Predictably, patient 222 T.A. Aloia et al. and oncologic outcomes post-transplant correlate more closely with the patholog- ical stage of disease. For example, one European study identified 39 patients with HCC pathologically staged between CMC and within UCSF criteria. These patients demonstrated similar and favorable survival compared to pathologically staged CMC patients; however, survival for the 44 patients who were clinically staged prior to transplant between CMC and UCSF criteria experienced a 5-year survival rate of only 48%. This example highlights the importance of precise preoperative liver imaging and clinical staging prior to liver transplantation. The Clinical Significance of Serum Alpha-Fetoprotein Serum alpha-fetoprotein (AFP) measurement is commonly used as a screening tool for HCC in patients with cirrhosis and a staging tool in patients with suspected or proven HCC. In general, the test has little accuracy. Most patients with early-stage HCC do not have elevated AFP levels. Rarely, patients with negative radiographic metastatic survey will have AFP levels above 200 ng/mL, raising the suspicion of occult metastases. Although some studies report a correlation between elevated pre- transplant AFP, poor tumor differentiation, and post-transplant recurrence [33, 34], in the absence of radiographic evidence for vascular invasion or metastatic disease, AFP elevation should not be a contraindication to transplantation. In practical terms for liver transplantation, the AFP level is useful in only two settings. First, under UNOS guidelines patients with macronodular cirrhosis (that makes radiographic differentiation between dysplastic nodules and early HCC dif- ficult) who also have an AFP level >500 in the absence of radiographic evidence for liver malignancy may receive additional MELD exception points. Second, in patients with early T-stage HCC and an elevated or rising AFP level, complete metastatic survey including bone scan is advisable and should be repeated every 3 months while on the transplant waitlist. Pre- and Post-transplant Metastasis Screening As HCC is most likely to metastasize to lung and bone, traditional metastasis screen- ing consists of chest CT and bone scan with either nuclear isotope or magnetic resonance. A shared experience that bone metastases are rare in UNOS T1 and T2 patients has lead to UNOS no longer requiring metastatic survey of the skeleton as a criteria for liver transplant listing with HCC MELD exception. For patients with either elevated AFP and/or UNOS T3 stage disease, bone survey remains a pru- dent staging study. While on the waitlist, restaging with chest and liver imaging is typically repeated every 3 months. Of HCC patients who recur following liver transplant, 90% will do so within 2 years of the transplant procedure [35–39]. Therefore, radiological and biochemical 14 Liver Transplant for Hepatocellular Carcinoma 223 staging during this critical period is performed every 3 months. Thereafter, restaging intervals can reasonably be lengthened to 6–12 month intervals. Neoadjuvant Therapies As liver transplant waitlist times have increased and interventional radiology tech- niques have improved, many liver transplant teams have employed neoadjuvant therapies in an effort to decrease waitlist dropout and to potentially reduce the rate of post-transplant recurrence [40, 41]. These include transarterial chemoembolization (TACE), percutaneous ethanol injection, radiofrequency ablation (RFA), cryoabla- tion, and more recently, radioembolization with yttrium-90, microwave ablation, and systemic chemotherapy. TACE Given its wide therapeutic window in cirrhotic patients and relatively simple deliv- ery, the most frequently used neoadjuvant therapy in waitlisted HCC patients has been TACE. The chemotherapeutic agent is typically doxorubicin or cisplatin, and the embolic agent is variable, typically consisting of gelfoam, polyvinyl alcohol, embospheres, or glass beads. Lipiodol is also frequently added as a radiographic marker. Multiple publications report large experiences with TACE in the pre- transplant setting [37, 40–48]. Although TACE has been shown to lengthen survival in patients with unresectable and nontransplantable bulky disease [49], it has been difficult to show a benefit in early-stage patients awaiting transplant, either in terms of reducing waitlist dropout rates or in post-transplant survival. Based on a review of the published outcomes data, the opinion that TACE has no role in the neoadjuvant treatment of pre-transplant HCC patients was recently proposed [50]. This opinion contrasted with a shared experience among many cen- ters that TACE, while rarely curative, is frequently able to maintain a stable disease pattern during prolonged wait times and is frequently associated with significant tumoral necrosis in explanted liver pathology analyses. One explanation for the inability of many studies to prove a TACE benefit is that, like most other chemotherapies, there is a finite therapeutic window for TACE in patients with HCC. Also similar to systemic chemotherapy for most solid tumors, only a small percentage of patients achieve a complete response (i.e., cure), with most patients’ responses distributed equally between progression, stable disease, and partial response. This pattern would predict a finite interval in which TACE would have maximal benefit. This hypothesis is supported by a recent analysis of the reported literature indicating that centers reporting outcomes in the setting of median waitlist times between 4 and 9 months showed a benefit to neoadjuvant TACE, while programs with shorter (<4 mo) and longer (>9 mo) median waitlist times found no benefit from TACE [51]. These data s uggest that HCC patients 224 T.A. Aloia et al. listed at programs with waitlist times between 4 and 9 months should be offered neoadjuvant TACE therapy. HCC Tumor Ablation Following TACE, ablation treatments are the second most frequently used neoadjuvant therapy in patients with transplantable HCC. The most experience is with radiofrequency ablation and to a lesser extent cryoablation. Their application can be limited by anatomic tumor characteristics (location, size over 3 cm, and tumor number) and the condition of t he cirrhotic liver. However, those patients who are candidates for ablative treatments typically benefit from this approach. Liver explant data suggest that individually treated tumors, particularly those less than 3 cm, frequently have extensive necrosis [52, 53]. Like TACE, radiofrequency abla- tion does appear to have a finite therapeutic window with patients recurring at the ablation site or elsewhere in the liver within 6 months [54]. The complication rates tend to be higher for ablation than for TACE, but in general, this modality is well tolerated in CTP class A patients with low to mid MELD scores. More recently, microwave ablation has been proposed as a novel ablative modality, but not enough clinical experience has been gained to comment on the utility of this therapy for HCC patients awaiting transplant. Radioembolization with Y-90 Following the large experience with transarterial chemotherapy delivery to HCC patients, the use of radioembolization as a neoadjuvant therapy for patients with HCC has gained favor. Two products are available for this application. Unlike TACE, which is most effectively given in a selective application to the artery directly feeding the liver tumor, yttrium-90 (Y-90) particles are generally directed either to one hemi-liver or to the whole liver. Given the broader dispersion, pretreatment testing with nuclear colloid scan to rule out hepatopulmonary shunts and arteri- ogram to identify and embolize accessory hepatic arteries to extrahepatic structures is mandatory. Selected centers have report excellent short-term results in nontransplantable HCC patients [55], as well as a smaller subset of patients awaiting transplant [56, 57]. Typically, patients who have received this therapy prior to transplant yield a liver explant specimen with significant tumor necrosis. Although it has not been determined whether there is a post-transplant survival advantage for neoadjuvant Y-90 over TACE, radiotherapy is appealing for patients with multifocal HCC where a broader dispersion of therapeutic agent is likely to achieve a more durable tumor effect. Caution is required in patients with advanced cirrhosis, in whom the radiation hepatitis induced by the therapy can lead to early and/or delayed liver failure. . open resection and the need for blood transfusion were 9.2 and 9.8%, respec- tively. There were 2 postoperative deaths and the morbidity was detailed as liver specific in 11.6% and nonspecific. injection therapy for hepatocellular carcinoma: results in 146 patients. AJR Am J Roentgenol 160(5):1023–1028 6. Matsukawa T, Yamashita Y, Arakawa A, et al (1997) Percutaneous microwave coagulation therapy. months and died of disseminated cancer at 400 days [2]. As the procedure and immunosuppression were refined, patient and allograft survivals improved to the point that oncologic recurrence and survival