Treatment options in hepatocellular carcinoma today

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1 Scandinavian Journal of Surgery 100: 22 29, 2011 Treatment options in hepatocellular carcinoma today T. Livraghi 1, H. Mäkisalo 2, P.-D. Line 3 1 Interventional Radiology Department, Istituto Clinico Humanitas, Rozzano, Milano, Italy 2 Department of Surgery, Helsinki University Hospital, Helsinki, Finland 3 Department of Organ Transplantation, gastroenterology and nephrology, Oslo University Hospital, Oslo, Norway Abstract Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. As over 90% of HCCs arise in cirrhotic livers preventive methods and surveillance policies have been adopted in most countries with high prevalence of hepatitis B or C infected people. Poor prognosis of HCC has shown some improvement during the last years. Targeted therapy with radiofrequency ablation (RFA), hepatic resection (HR), liver transplantation (LT), and transcatheter arterial chemoembolisation (TACE) seems to have an influence on this development. The heterogeneity of cirrhotic patients with HCC is still a big challenge. A patient with a small tumour in a cirrhotic liver may have a worse prognosis than a patient with a large tumor in a relatively preserved liver after curative HR. The choice of the treatment modality depends on the size and the number of tumours, the stage and the cause of cirrhosis and finally on the availability of various modalities in each centre. Key words: HCC; hepatocellular carcinoma; radiofrequency ablation; percutaneous ablation procedures; percutaneous ethanol injection; intra-arterial therapy; transcatheter chemoembolization; liver resection; liver transplantation Introduction Hepatocellular carcinoma (HCC) ranks fifth among the most prevalent cancers in the world and is the third most common cause of cancer related mortality (1). There is a marked variation in occurrence of HCC among geographic regions and between men and women. The latest age-adjusted annual incidence rates per in men are 13 in Italy and 2 to 4 in the Nordic countries (2). The respective figures in females were 3 in Italy and 1 to 2 in the Nordic countries. Along with HBV vaccination and with declining Correspondence: Heikki Mäkisalo, M.D. Department of Surgery Helsinki University Hospital FI , Helsinki, Finland heikki.makisalo@hus.fi influence of HCV infections transmitted before 1990 the incidence of HCC could be expected to decline after 5 10 years in the Western Europe. Thus, the metabolic syndrome, diabetes, non-alcoholic steatohepatitis, and excessive alcohol consumption may be the main risk factors of HCC in the future. Due to HCC s grim prognosis, there has been a great research effort made in order to come up with efficient therapeutic strategies to cure this disease. Like most other solid tumours, surgery plays a fundamental role in its treatment. Surgical resection (HR), local ablation therapies, and liver transplantation (LT) are regarded as potentially curative treatment modalities depending on the size and number of tumors. It is estimated that curative treatment with either HR or radiofrequency ablation (RFA) can be offered only to 10% of all HCC patients having 3 or fewer 3 cm or smaller HCCs (3). However, with routine screening of high-risk patients more early HCC cases are going to be diagnosed allowing radical treatment.

2 Treatment options in hepatocellular carcinoma today 23 LT has been offered to selected patients with HCC. However, up until the mid nineties, the results were disappointing with reported overall five-year survival rates ranging from 30 to 40%. In 1996, Mazzaferro and co-workers published a pivotal paper, demonstrating excellent 4-year survival data and low recurrence rates in patients with early stage, unresectable HCC (4). This led to the formation of the globally utilised Milan criteria (solitary tumour less than 5 cm or up to three nodules each less than 3 cm) for selecting HCC patients to LT. Staging systems The purpose of staging HCC tumours is to classify each case according to a certain predictable prognosis with optimal treatment. Staging is usually based on diagnostic radiological morphology. Classically, the TNM system has been utilised for classification of solid tumours and is as follows in HCC; T1: 1 nodule < 2 cm, T2: 1 nodule up to 5 cm or 3 nodules up to 3 cm, T3: one or more tumours > 5 cm, and T4: tumour extending into neighbouring organs. The significance of the liver function requires a more complex clinical classification system as a basis for therapeutic allocation. The Barcelona Clinic Liver Cancer (BCLC) staging system (Fig. 1) (5) is the only validated system which includes in addition to tumor burden patient s performance status and liver function when determining the prognosis after the treatment (6). BCLC therapeutic flow-chart BCLC therapeutic flow-chart for HCC patients (Fig. 1) and its recommendations, because endorsed by EASL (the European Association for the Study of the Liver) and AASLD (American Association for the Study of Liver Disease), are the most applied worldwide (7). The main recommendations adopted by EASL and AASLD are: a) Patients who have a single lesion can be offered surgical resection in the presence of cirrhosis with preserved liver function, normal bilirubin and hepatic vein pressure gradient < 10 mm Hg. b) LT is an effective option for patients with HCC corresponding to the Milan criteria. c) Local ablation is a safe and effective therapy for patients who cannot undergo resection, or as a bridge to transplantation. Alcohol injection and radiofrequency are equally effective for tumours < 2 cm. However, the necrotic effect of radiofrequency is more predictable in all tumour sizes. d) No recommendations can be made regarding expanding the listing criteria beyond the standard Milan criteria. e) TACE (transcatheter arterial chemoembolisation) is recommended as first line non-curative therapy for non surgical patients with large-multifocal HCC who do not have vascular invasion or extrahepatic spread. f) Systemic or selective intra-arterial chemotherapy is not recommended and should not be used as standard cure. HCC Stage 0 Okuda 1, Child A, PST 0 Stage A-C Okuda 1-2, Child A-B, PST 0-2 Stage D Okuda 3, Child C, PST >2 Very early stage (0) Single < 2 cm Carcinoma in situ Early stage (A) Single or 3 nodules < 3 cm, PST 0 Intermediate stage (B) Multinodular, PST 0 Advanced stage (C) Portal invasion N1, M1, PST 1-2 Stage D Terminal Single 3 nodules, 3 cm Portal pressure/ bilirubin increased Yes Associated diseases Portal invasion, N1, M1 No No Yes No Yes Resection Liver transplantation PEI/RFA TACE New agents Symptomatic treatment Fig. 1. The Barcelona Clinic Liver Cancer (BCLC) staging system. Modified from Llovet et al (5).

3 24 T. Livraghi, H. Mäkisalo, P.-D. Line Is the BCLC flow-chart still valid? The strictness of protocols for cancer treatment is universal and the BCLC therapeutic flow-chart is not an exception. However, heterogeneity of HCC presentations together with the variable stage of cirrhosis might require a less defined strategy. Furthermore, based on particular therapeutic experience and technical improvements and refinements, some leading centres in recent years have queried certain BCLC/ AASLD treatment allocations and proposed different strategies. In our opinion, with regard to percutaneous ablation therapies (PATs) such as percutaneous RFA or ethanol injection (PEI), and to intra-arterial therapies (IATs) such as TACE, BCLC/AASLD guidelines could currently be modified as follows. STAGE 0 tumours include carcinoma in situ or very early single tumours smaller than 2 cm in diameter. The liver disease is not worse than Child-Pugh class A cirrhosis and the patient should be fully active (performance status, PST 0). This stage is distinguished from the stage A of the lack or rarity of perinodular neoplastic invasion. Pathological specimens describe a well-differentiated nodule with indistinct margins (the so-called indistinct type) that contains bile ducts and portal veins, to which the radiological pattern well correlates showing portal blood supply without tumour staining. To be exact, in relation to the local invasiveness, the correct cut-off of very early stage should have been fixed at 1.5 cm in size. In fact pathologists, between cm, describe nodules (the so-called distinct type or small advanced type) containing zones of less differentiated tissue with more intense proliferative activity that give rise to portal microinvasion or microsatellites in 10 20% of the cases (usually within 10 mm of the nodule). Increasing the diameter, the rate of microinvasion increases proportionally, i.e % in nodules 2 5 cm and up to 60 80% above 5 cm of size (8, 9). When feasible, HR is considered the treatment of choice in patients who are not candidates for LT. This statement was not based on randomized controlled trials (RCTs) vs other options, but on the oncological assumption that HR is the more suitable option for obtaining complete tumour ablation with safety margins around it. This statement was established in spite of several cohort studies comparing HR and PATs that failed to demonstrate better results in favour of HR (10 13). Now some RCTs are available, all revealing that OS rates in patients with early HCC are similar after PAT (principally RFA) and HR (14 16). In very early HCC, due to the smaller tumour size, RFA should probably offer even better overall survival (OS) because of its higher local efficacy than in early HCC. Are the safety margins around the tumour more safe with HR than RFA when treating very early tumours? Aiming to a safety margin RFA obtained a sustained complete response in 97.2% of 218 cases (17). According to the histopathological study of Sasaki only one case of very early HCC out of 100 cases presented a microsatellite more than 10 mm distant (18). Of course, the best way to determine whether RFA is more effective than HR for very early stage would obviously be by direct comparison in a RCT. However, the results in the studies reviewed above indicate that the difference between the two approaches is fairly small, and the sample size required to ensure meaningful results is quite large. For this reason a trial of this sort is probably not feasible. To give shape to such a trial a recent Markov model analysis was applied (19). Its conclusion was that RFA followed by HR for the few cases of initial local treatment failure was nearly identical to HR regarding OS, even with the best scenario for HR and the worst scenario for RFA. Albeit under an equivalent OS, RFA offers lower complication rate, negligible perioperative mortality, lower ablation of nonneoplastic tissue, and lower costs by reducing treatment times, hospital stay, material used, and need for blood transfusions. All the studies comparing RFA to PEI were in favour of RFA, in terms of shortness of treatment, local efficacy, OS and disease free survival, while the only initial advantage of PEI was the relatively lower complications rate (20 21). When the learning curve was over and the risk conditions were known, the complications and mortality rates compared with those of PEI. However, PEI remains recommended in cases contraindicated for RFA and, of course, where RFA is not available. In summary, referring to points a and c of AASLD recommendations, there are good reasons to suggest that RFA should replace HR as therapeutic gold standard for patients with very early HCC. Furthermore, RFA is preferable to PEI also in HCC < 2 cm in that it can obtain higher local efficacy in cases presenting perinodular invasiveness. However, RFA is comparable to HR only in centres with a high experience of the procedure. The long learning-curve of RFA is much more difficult to achieve in countries with low prevalence of HCC. Stage A tumours are early single tumours or 3 nodules smaller than 3 cm in diameter, Child-Pugh class is A or B, and PST 0. Although demonstrating comparable OS when comparing HR to PAT (10 13), these cohort studies were flawed by critical drawbacks in baseline characteristics between the groups, particularly regarding the better liver function for HR patients. Severe fibrosis is not only associated with earlier liver failure but also with a higher risk of multicentric carcinogenesis strongly influencing the final outcomes. Some of these studies compared OS according to the number and to the diameter of the nodules as well. Multiplicity resulted a favourable factor for patients treated with RFA, probably because of the higher loss of nonneoplastic tissue after HR that could anticipate the liver decompensation. The efficacy of RFA is known to be size dependent. After PATs, OS of patients with nodules < 3 cm in diameter was higher than that of carriers of nodules with a diameter 3 5 cm. Why did the RCTs demonstrate that OS rates in patients with early HCC are similar after PAT (principally RFA) and HR, even with nodules > 3 cm (14 16)? In fact, it would be reasonable to expect better OS rates among patients sub-

4 Treatment options in hepatocellular carcinoma today 25 mitted to HR, which is seemingly the only method capable of ensuring complete ablation of nodules accompanied by peritumoral microinvasion. The equivalent outcome probably reflects the compensatory effects of certain advantages of RFA, i.e. less destruction of normal tissue and lower morbidity rate, with respect to the higher local efficacy of HR. In summary, there are good reasons suggesting that RFA should be coupled with HR as therapeutic gold standard for selected patients with early HCC, i.e. with Child-Pugh class B, or with multiple tumours. With regards to the size, in single nodules > 3 cm HR remains the first option, while in nodules 2 3 cm a peer discussion is advisable, according to individual clinical parameters (age, site, associated diseases, risk conditions) and to the operator s expertise. Of course, when the patient is considered inoperable, RFA can be indicated also in huge tumours, even in combination with other procedures (13,22). Stage B tumours are intermediate, multinodular tumours, and the patients have either Child A or B cirrhosis and are of PST 0. It is worth emphasizing that the intermediate stage includes a very wide range of tumoural presentations, i.e. from four small to dozens (or uncountable) tumours of various sizes occupying a large part of the liver. Such a variety of possibilities makes it difficult to compare the trials concerning the IAT results. Of note, the survival improvement after conventional TACE (ctace) seems to be marginal, as one meta-analysis did not find a significant OS difference between treatment versus supportive care alone (23). Unlike some earlier RCTs were in favour of ctace a more recent RCT was not able to demonstrate an improvement in OS after ctace versus inactive treatments (24). The key clinical problem is whether all patients with intermediate stage should receive ctace or only a subgroup of them. To date, ctace has been considered the standard option for patients with intermediate stage, even though several important issues remain to be clarified, including what is the best chemotherapeutic drug (doxorubicin, cisplatin, mitomycin, etc), what is its best dosage, what is the best embolisation agent (gelatin sponge, autologous blood clots, polyvinyl alcohol particles, etc), what is the efficacy of Lipiodol, and what is the optimum time interval for re-treatment (scheduled or on demand ). However, the evidence of an additive antitumoural effect with consequent higher efficacy and better OS of ctace versus ctae is unavailable, suggesting that ischemia might be the more important factor inducing tumour response after ctace. For this reason IAT is a continuous work in progress field. To improve the modest, if any, therapeutic efficacy of ctace and to reduce its induced ischemic damage to the non-neoplastic tissue and its systemic toxicity, some new techniques were recently proposed. TAE with small spherical embolic particles (25) and TACE with nonresorbable hydrogel drug-eluting beads (DEB) capable of being loaded with anthracyclin derivates such as doxorubicin, seem to offer such advantages. Another possibility is offered by advancements in microcatheter technology, which facilitates ultraselective catheterization of nodule feeders and the overflow of Lipiodol into the portal vein, a factor associated with lower local recurrence (26). The multikinase inhibitor sorafenib has antiangiogenic and antiproliferative properties and is the first agent to demonstrate a statistically significant improvement in OS (27). Sorafenib is now considered as standard care of patients with advanced HCC in many centres to patients having Child A cirrhosis and good performance status. Sorafenib is also used in an adjuvant setting after surgery or RFA (STORM trial) and combined with TACE (SPACE trial, phase II, trials.gov). Referring to point e of AASLD recommendations, ctace is no longer regarded as the standard treatment of intermediate stage, being comparable to ctae. However, new selective techniques, such as TAE with small particles, TACE with DEB or ultraselective TACE seem to be more effective obtaining a not negligible rate of complete responses, and avoiding the damage of nonneoplastic tissue. In advanced HCC with preserved liver function sorafenib may be considered as a palliative treatment. Operative options are still needed in HCC Despite emphasizing the role of ablative treatment of potentially curable HCC, HR and LT remain as the basic treatment modalities in certain indications. Liver resection. It is reasonable that with surveillance programs RFA is the mainstay in areas with a high prevalence of HCC associated to viral hepatitis. Elsewhere most of tumours are found in a symptomatic phase and quite often in a non-cirrhotic liver as well. In these cases HR can still be regarded as the gold standard when feasible. Without aggressive treatment of these patients with the best supportive care the median survival is less than 1 year (28). As a result of advances in surgical techniques and peri-operative management the hospital mortality after HR is practically zero and morbidity less than 20% when resecting livers of healthy or Child A cirrhotic patients in experienced centres (29). Similar 5-year survival has been seen regardless the patient had cirrhosis or not but disease-free survival is decreased in cirrhotic patients (30). Tolerance to HR depends, however, on the degree of impaired liver function and portal hypertension. If the patient has significant portal hypertension 5-year survival is only 25% compared to 74% in patients without portal hypertension and with normal bilirubin level (31). One of the advantages of HR over RFA suggested has been a better contol of micrometastases with anatomic resections. A large Japanese study on patients with a single HCC showed an improved disease-free survival after an anatomical subsegmentectomy than after non-anatomical minor hepatectomy but only when the tumour size was between 2 cm and 5 cm (32). In congruence, in the consensus statement for the treatment of HCC the Japanese Society of Hepatology (JSH) preserved HR to tumours more than 3 cm in diameter and 3 or less in number in patients with Child A cirrhosis (33). HR was also

5 26 T. Livraghi, H. Mäkisalo, P.-D. Line A B C D Fig. 2. A and B represent a large hepatocellular carcinoma (HCC) with a good prognosis after right lobectomy. C and D: Child B cirrhosis with a 3 cm HCC and a suspected satellite nodus less than 1 cm in the right lobe. Liver transplantation was the only option available for the patient. regarded as an alternative to RFA in smaller tumours. Significant risk factors for early recurrence are tumour rupture, venous invasion and cirrhosis, whereas viral replication in viral hepatitis and multiple tumours increase the risk for late recurrence (34,35). Controversy exists related to the surgical margin as HCC seldom recurs to the resection surface (36,37). Nevertheless, it is highly recommended that the tumour should not be exposed during the surgery. Vascular invasion is a prognostic indicator of HCC despite the treatment modality and its risk is high in tumours more than 5 cm in diameter (38). Neither HR nor LT are usually recommended when vascular invasion has been established. However, when feasible HR is the only alternative of a large HCC without proven dissemination (Fig. 2). Liver transplantation. Excellent results after LT using Milan criteria from the study by Mazzaferro have been reproduced multiple times by other researchers, and the results seem to be robust and valid across different populations and etiologic backgrounds (39). However, only a minority of HCC patients can be treated with LT due to the scarcity of organs available for transplantation and increasing waiting times in most countries. Selection criteria. Independently of TNM stage, the presence of vascular invasion is a determining parameter for aggressive disease and recurrence following LT or HR, but this factor can only be assessed on histology and is thus not available for preoperative evaluation (40). TNM stage 2 (T2) comprises the Milan criteria. The prognosis of patients exceeding these limitations is more unpredictable, and the Milan criteria can in this sense be viewed as a surrogate marker for absence of vascular invasion. Another prognostic factor of significance is alpha-fetoprotein (AFP). AFP level higher than 400 µg/l is a sign of either aggressive and/or advanced disease (40). The problem in a population setting, however, is that AFP levels are not sensitive and specific enough to be of true staging value, whereas it can be of significance in the judgement of an individual patient (40). In a cohort study of multiple centres, the impact of staging on post explant pathology (diameter of largest tumour, number of nodules and vascular invasion) survival was explored and correlated to post transplant survival and recurrence (41). The results

6 Treatment options in hepatocellular carcinoma today 27 show that the diameter of the largest tumour is a more important predictor for survival and recurrence than the number of nodules (Fig. 2). Furthermore, a subgroup of patients where the sum of the diameter of the largest tumour and the total number of nodules were equal to seven, ( up to seven criteria), displayed a survival benefit that was not significantly different from those within the Milan criteria. Another approach to tumour morphologic criteria has been total tumour volume (TTV). This has the advantage of excluding the number of nodules which are of less significance than size. TTV of less than 115 cm 3 has proven to provide similar results as the Milan criteria (35, 42). Transplantation beyond the Milan criteria. The concept of limiting transplantation to BCLC A patients is inherently linked to the scarcity of liver grafts available. Due to the unpredictable availability, different waiting times and local or national guidelines of the LT indications with respect to tumour size and stages vary. In general, the outcome after LT for HCC should ideally be comparable to transplantation for benign indications. If transplants are performed outside the established criteria, this should not lead to extended waiting times or exclusion of other patients. In countries where the Model for End-Stage Liver Disease (MELD) is used for liver allocation, HCC patients within the Milan criteria are granted extra points to ensure access to transplantation within reasonable time. In the Asian countries, the availability of deceased donor grafts is very low or absent. Hence, the majority of grafts are derived from a living donor. In living donation, the question of excluding other recipients from the access to LT becomes irrelevant. Living donation enables the waiting times to be short and might also encourage transplantation of patients on extended criteria. In Scandinavia, LT for HCC comprises 7.9% of all transplants performed, reflecting a low incidence of the disease. Concomitantly, the waiting times in the Nordic countries are in international comparison short, particularly in Norway, Finland and Sweden, and somewhat longer in Denmark (43). Apparently this fact might have an impact on the LT indications. The overall five-year survival for LT for HCC in the Nordic countries is 57.4%, indicating that a proportion transplants are most likely done on extended criteria (43). Is this an acceptable outcome in LT? The survival data from registries like the Nordic Liver Transplant Registry (NLTR) or the European Liver Transplant Registry (ELTR) indicate that LTs in cases with the actual 5 year survival of about 50%, such as relt for hepatitis C are still performed (43, 44). Transplantation on extended criteria does, however, raise certain issues of concern. Patients with more advanced disease have an increased risk of dropout on the waiting list, particularly when the waiting times exceed more than 100 days (31). Conversely, very short waiting times might preclude the natural selection process and lead to transplantation of poor candidates that have a very high likelihood of recurrence and short post transplant survival (45). This might be of particular relevance in living donor transplantation, and increased recurrence rates compared to whole graft deceased donor grafts have been reported in the literature (46). Strategies such as neoadjuvant treatment or downstaging to improve outcome in extended criteria transplantation have been suggested. Neoadjuvant treatments are given prior to the transplant procedure in order to improve post transplant outcome, whereas downstaging is a term describing lowering the patients morphological stage. Bridging, on the other hand, is a related strategy to keep patients that qualify for transplantation able to stay on the waiting list for an extended time, i.e. preventing them from dropping out (45). In all these instances, locoregional therapies RFA or TACE can be utilised (47). There are data available, suggesting that the rate of dropouts might be reduced by adopting bridging strategies for T2 tumours where the waiting times exceed 6 months (45). Furthermore, some studies suggest that the response to TACE or RFA as downstaging modalities can be utilised as a selection criteria for transplantation in patients outside Milan (48). It has been proposed that a proper response to downstaging should be evaluated by both radiology (Milan criteria) and reduction in AFP levels (47). Conventional Recist criteria appears to be poorly adapted for evaluating the response to TACE and RFA, and new, modified criteria (mrecist modified Recist) have been proposed (49). Another attempt to improve survival after LT in HCC is to modify the immunosuppressive regimen. Immunosuppression is in itself associated with an increased risk of malignancy and might facilitate tumour growth and metastasis. Anti-proliferative agents, like the m-tor inhibitor rapamycin, could possibly offer an oncological benefit, particularly in patients outside the Milan criteria (50). A large randomised study comparing conventional immunosuppression to rapamycin that might give a better answer to this question is underway (51). Hepatic resection or liver transplantation? The excellent results after LT using the Milan criteria in HCC patients are impaired with the scarcity of organs as the dropout rate may be up to 30% because of progression of the disease during the waiting time (28). HR has been estimated to yield similar results as LT on the intention-to-treat- basis (52). However, fiveyear disease-free survival even after curative HR of small HCCs has been only 22 36% (30, 53) and on long-term the recurrence may be regarded as almost universal. Thus the best long-term result of a multifocal HCC could be reached with LT. Nevertheless, LT may have a significant role in the treatment of HCC only in countries of low prevalence of HCC leaving both RFA and HR as the treatments of choice in the high prevalence areas. With a close follow-up recurrent tumours should be treated actively with RFA. In addition, there is an evidence that the results of a salvage LT after HR are not inferior to primary LTs (54). According to Poon et al. almost 80% of patients primarily treated with curative HR could later be

7 28 T. Livraghi, H. Mäkisalo, P.-D. Line treated with LT (30). A rapid recurrence after HR refers to a metastatic disease and late recurrences to metachronic tumours with a better prognosis after LT (34). In fact, early recurrence within one year could be regarded as a contraindication to LT. Conclusion During the last years the major influence on the prognosis of HCC in developed countries has been achieved by surveillance, early diagnosis, and multidisciplinary treatment of the disease. After detecting the tumour a targeted therapy with RFA, HR, TACE, or LT or with their combinations gives the patient the best chance for survival. Neoadjuvant therapy and downstaging strategies as well as novel immunosuppressive regimens might be of relevance, but further studies are needed to validate these measures in liver transplantation for HCC. REFERENCES 01. Rampone B, Schiavone B, Martino A, et al: Current management strategy of hepatocellular carcinoma. 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