rx hcc 2015 beyond guidelines

REVIEW ARTICLE

Treatment of hepatocellular carcinoma: beyond international guidelinesMassimo Colombo and Angelo Sangiovanni

Head Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano,

Via F. Sforza 35, Milan, 20122, Italy

Keywords

BCLCA staging chemoembolization

hepatic resection liver transplantation

local ablation sorafenib

Abbreviations

BCLC, score barcelona clinic liver cancer

score; HCC, hepatocellular carcinoma; HCV,

hepatitis C virus; RFA, radiofrequency

abalation; SOC, standard of care; TACE,

transarterial chemoembolization.

Correspondence

Massimo Colombo, MD

Head Division of Gastroenterology and

Hepatology, Fondazione IRCCS Ca Granda

Ospedale Maggiore Policlinico, Universita

degli Studi di Milano, Milano

Via F. Sforza 35, 20122 Milan, Italy

Tel: 39-0255035432

Fax: 39-0250320410

E-mail: [email protected]

DOI:10.1111/liv.12713

Abstract

The management of hepatocellular carcinoma (HCC) is decided according toevidence-based recommendations generated by international societies:according to these recommendations, the tumour stage, as determined by theBarcelona clinical liver cancer (BCLC) score, divides patients into five prog-nostic categories, each with a distinct treatment indication. Radical therapiessuch as hepatic resection, orthotopic liver transplantation and percutaneouslocal ablation are strongly indicated in patients with very early and early stagetumours (BCLC O and A), a choice which mainly depends on a combinationof tumour volume, status of underlying liver disease, the presence of comor-bidities and the patients age. Although radical therapies provide a survivalrate of between 50% and 75% at year five in well selected patients, tumourrecurrence is frequent following resection and ablation compared to trans-plantation (70% vs. 10% respectively), which has the additional advantage ofpreventing morbidity and mortality from portal hypertension. Generally,while radical therapies are contraindicated in patients with a large tumourburden, such as those with intermediate stage BCLC B, survival in the subsetof these patients with well compensated cirrhosis may improve from 16 to20 months, on average, following repeated treatments with transarterialchemoembolization (TACE). Survival may also improve in patients who arein poor condition or who do not respond to TACE and in those with anadvanced HCC (BCLC C) following oral therapy with the multikinase inhibi-tor sorafenib. However, because most recommendations are based on uncon-trolled studies and expert opinions rather than well designed, high poweredrandomized controlled trials, treatment criteria need to be adapted to specialgroups because real life cohorts do not match the selection criteria suggestedby the guidelines. Indeed, up to one-third of patients with early stagetumours who are unfit for radical therapy because of advanced age, the pres-ence of significant comorbidities or a strategic location of the nodule, areforced to receive palliative care. BCLC A patients with moderate portalhypertension and certain BCLC B patients could still be eligible for hepaticresection if a chance for 50% survival at 5 years is still perceived as beingcost-effective by both the patient and caregivers.

Key points

The treatment of HCC is guided by appropriatestaging of tumour disease. Because of the heteroge-neous epidemiology and clinical presentation ofHCC worldwide, there is no single universallyaccepted staging score for guidance.

In the West, the Barcelona Clinic Liver Cancer(BCLC) score is extensively used, because it is themost accurate approach for identifying the best can-

didates for radical (BCLC O & A) and palliativetreatment (BCLC B&C).

In real clinical practice, however, many patientsmay not fit the therapeutic algorithms recommendedby international societies, mainly because of the ana-tomical location of the tumour, advanced age orsevere comorbidities.

As a result, patients may be treated outside theguidelines, for example, those with an early stagetumour who receive chemoembolization (TACE)

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after being deferred from resection/ablation or aftera partial response to initial treatment with radiofre-quency.

Although multimodal treatments are a highlyeffective option to improve treatment outcome inselected patient populations, adherence to interna-tional guidelines is still the mainstay for optimizingtreatment of HCC patients.

Hepatocellular carcinoma (HCC) is a progressivetumour whose prognosis depends on tumour stage atdiagnosis and the possibility of providing radical treat-ment (1). In the past few decades, treatment of HCC hasprogressed from a single option of surgical resection inselected patients with small tumours to an array ofchoices including orthotopic liver transplantation (LT),locoregional ablation and transarterial chemoemboliza-tion (TACE) in patients who do not meet the criteriafor resection (1). More recently, the multikinase inhibi-tor sorafenib has been validated to treat patients withadvanced HCC, for whom no therapy was previouslyavailable (2). Thanks to the development of clinicallybased staging systems such as the Barcelona clinical livercancer (BCLC) classification, which stratifies patientsaccording to tumour stage and accompanying liver dis-

ease, the life expectancy of HCC patients can be reliablypredicted and appropriate treatment can be identifiedaccording to stage (1, 3) (Table 1, Fig. 1). Not surpris-ingly, the BCLC classification has become the backboneof guidelines published by international societies tostandardize clinical practice and study designs to vali-date new treatments (1, 4). Treatment of HCC based onthe BCLC score has resulted in increased survival bypreventing treatment failures related to faulty staging ofpatients and empirical decisions. Interestingly, althougha significant number of patients with HCC do notmatch the therapeutic criteria corresponding to theirBCLC stage because of conditions from advanced age tothe anatomic localization of the hepatic tumour, thesepatients may be effectively treated outside currentguidelines.

The standard of care

Very early and early HCC (BCLC 0 and A)

Widespread screening programs for HCC and the use ofabdominal ultrasound examinations in clinical practicehave significantly increased the number of patients withchronic liver disease and a clinically silent, small HCCnodule (1). The current definition of early HCC is a

Table 1. The Barcelona clinic liver cancer staging classification for hepatocellular carcinoma

BCLC stage Performance status Tumour volume, number and invasiveness Child-Pugh Expected survival

A early 0 Single < 5 cm or three nodules

tumour 10 mmHg HVPG is a sig-nificantly predictive risk factor of early mortality frompostoperative decompensation (4). On the other hand,later mortality following resection and local ablation isinfluenced by the size and number of tumour noduleswhich are predictive of vascular tumour disseminationand the inherent risk of tumour recurrence (5, 6).Patients with nodules 2 cm, which represent 80% of alltumours detected in patients with cirrhosis followed byultrasound surveillance, have a low risk of extranodalspread (7), and are theoretically ideal candidates forsuch radical therapies as local ablation, resection andliver transplantation (LT). The final therapeutic deci-sion, however, is based on patient characteristics such asage, liver status, the presence of comorbidities, thepotential of improving underlying liver disease and thelength of the transplantation waiting list. Indeed,carefully selected patients with a tumour 2 cm andcompensated cirrhosis benefit equally from all radicaltherapies in terms of survival (>70% at 5 years), but thecosts and risks of intervention-related mortality differ.The latter is very low for percutaneous ablation, while itis 13% for resection and 10% for LT (8). Antiviralagents reduce the risk of postoperative decompensationand late onset recurrence from second primary tumoursin patients with hepatitis B or C related tumoursundergoing resection or local ablation of HCC (9, 10).In patients transplanted for end-stage hepatitis Cvirus (HCV), access to new all oral direct antiviralagents against HCV will prevent and successfully treatrecurrent HCV, which is a major cause of graft failureand early death in these patients (11).

Percutaneous local radiofrequency ablation (RFA) ismore effective than ethanol injections (PEI) in 2 and3 cm tumours because of improved prevention oftumour recurrence on the periphery of the nodule (12,13). While the efficacy of both ablative techniques issuboptimal for the treatment of tumours >3 cm because

of an increased risk of tumour recurrence (14), resectionand percutaneous ablation can be proposed to patientswith up to three nodules of 3 cm, but with less encour-aging survival rates than in patients with a single 2 cmnodule, once again because of the increased risk of post-operative recurrence (15) (Fig. 3).

The Milan criteria, i.e. the presence of a single noduleof 2 cm tumours who arein the waiting list, tumour radiofrequency ablation(RFA) or TACE is currently recommended as a bridgeto LT to prevent tumour progression and removal fromthe list or an increased risk of recurrence. However thisassumption is not evidence-based and it is debated interms of cost-effectiveness. Although per protocol sur-vival rates in transplanted patients are better than insimilar stage patients treated by resection, the benefitsto survival are less clear when calculated by intention totreat, because tumour progression in patients on the

Fig. 2. The survival of patients with an early cancer treated byresection is influenced by portal hypertension and bilirubin: bestcandidates have a solitary HCC 5 cm and ChildPugh A score withlow portal hypertension and normal bilirubin. HCC, hepatocellularcarcinoma.

Fig. 3. Retrospective study of 282 consecutive patients with anHCC within Milan criteria treated in Barcelona during a 15-year per-iod: the initial tumour volume predicts survival after percutaneousablation. HCC, hepatocellular carcinoma


Colombo and Sangiovanni HCC treatment beyond guidelines

waiting list increases the risk of delisting and of tumourrecurrence after transplantation (17). Although LT is feltto be the best therapeutic option in patients with earlyHCC because it prevents the late-onset complicationsof cirrhosis, this option is limited by the limited numberof organ donations worldwide. Living donor LT hasgained popularity to compensate for donor shortage,but it is associated with high complication rates (>30%)in recipients and a small, but non-negligible, riskof donor death (0.5%) (18). In most countries, includ-ing Italy, the limited number of donor livers doesnot favour strategies to extend the oncological criteriabeyond the Milan criteria for LT in patients withHCC, since extending criteria is associated with anincreased risk of tumour recurrence and shortenedsurvival (19).

In real life, the treatment of HCC is multimodal inpatients with more than one nodule who do not reachthe end-point of a radical cure with one type of treat-ment alone. TACE has been used in combination withRFA or PEI with promising results, although thereported benefits to survival in comparison with eithertreatment alone has not been validated (20). Because theresults of liver transplantation are better than hepaticresection for tumour recurrence, LT has been used asrescue therapy in patients who are found to have micro-scopic vascular invasion during tumour resection (21).

Intermediate HCC (BCLC B)

In patients with a tumour burden exceeding the Milancriteria and in the absence of macroscopic vascular inva-sion by tumour cells and symptoms of neoplastic dis-ease, the standard of care (SOC) includes TACE. This isbased on a meta-analysis of seven studies (22) showingthat repeated treatment with TACE was associated withimproved survival of an average of 20 months inpatients with intermediate HCC (Fig. 4). HoweverTACE is limited to patients with compensated cirrhosis(ChildPugh A or B), including those with small esoph-ageal varices to minimize the risk of hepatic decompen-sation following procedure-induced liver ischaemia. Arecent expert consensus has identified absolute and rela-tive contraindications for TACE including comorbidi-ties, hepatic encephalopathy, high performance status,reduced or absent portal vein flow biliary obstructionand large/massive tumours (23). TACE is also contrain-dicated in patients with branch or portal vein thrombo-sis, since occlusion of arterial blood flow may cause liverfailure. While superselective TACE may be safely per-formed in selected patients with segmental portal veinthrombosis, a clinical benefit has not been demonstratedin this population (24). One important point is thattumour response after conventional or drug-elutingbead-TACE (DEB-TACE) should be evaluated by EASL

Fig. 4. Meta-analysis of studies of chemioembolization for intermediate hepatocellular carcinoma.

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HCC treatment beyond guidelines Colombo and Sangiovanni

or modified RECIST criteria combining assessment oftumour shrinkage and loss of viable cells (25, 26).

There is disagreement about the evidence showingincreased survival following TACE in the above men-tioned meta-analysis because the benefits in survivalwere based on two randomized studies that enrolledpatients with fairly advanced HCC. In fact, in those twostudies the 3-year predicted spontaneous survival of 8and 20 months was definitively lower than the 50% pre-dicted survival of untreated patients with an intermedi-ate HCC originally described by Llovet et al. (27).Another weakness of the meta-analysis was the lack ofstandardization of studies with TACE in relation toembolization procedures while recent developmentswith TACE including new, more effective embolizingagents (28) allow a more standardized approach. TACEwith doxorubicin-loaded (DC) beads is a new paradigm,since it can cause complete necrosis of

by many since they prevent patients from receiving life-saving treatment such as LT. Approaches to expand cri-teria for listing for LT are mostly based on tumour stagescores obtained from the explanted liver and not on pre-transplant imaging findings, which are not accurateenough to identify predictors of tumour recurrence suchas microscopic vascular invasion and tumour satellitesthat are present in patients exceeding Milan criteria(14).

Surgeons at the University of California, San Fran-cisco (UCSF) developed criteria based on explant histol-ogy, and were the first to propose expanded criteria forlisting that were then prospectively validated by radio-logical imaging in clinical practice (37,41). Listing fortransplantation based on UCSF criteria, which include 1nodule 6.5 cm, or 23 nodules 4.5 cm to reach a totaltumour diameter 8 cm, resulted in a comparable 5-year recurrence-free probability (90% and 94%) inpatients within and outside Milan criteria, while the riskof pretreatment tumour understaging was similar forpatients within the Milan (20%) and UCSF (29%) crite-ria (41). Another expanded set of criteria were devel-oped in Pamplona including 1 nodule 6 cm, or 23nodules each 5 cm. This approach resulted in recur-rence free survival rates of 70% in a small group of 47patients. However, this study was limited by the lack ofseparate analysis of the outcomes in patients exceedingthe Milan criteria (42). A more complex approach byRoayaie et al. (43) was the use of a multimodal neoadju-vant treatment protocol with systemic chemotherapywith doxorubicin and chemoembolisation that wasapplied to 80 patients with 1 or more nodules of57 cm. Survival was significantly better in patients withtumours between 5 and 7 cm than >7 cm tumours(55% vs. 34%, P = 0.024), but it was poorer thanthat reported for historical controls listed according tothe Milan criteria (9). Knetenen et al. compared 19patients with HCC meeting the Milan criteria with 21patients meeting the expanded criteria (1 nodule

severe portal hypertension and multiple hepatic lesionsas long as they are carefully selected in relation to theseverity of contraindications (52,56). The Italian societyfor the study of the liver (AISF) has suggested thatpatients with portal hypertension, hyperbilirubinemia,or multinodular tumours should be evaluated by anexpert multidisciplinary team to weigh the options ofsurgical treatment against the risk of postoperativedecompensation (57). In a recent randomized con-trolled trial comparing hepatectomy vs. TACE forresectable multiple HCCs exceeding the Milan criteria,1-, 2- and 3- year overall survival was 76%, 63% and51%, respectively, for the resected patients, comparedwith 52%, 35% and 18% for the TACE group(P < 0.001) (58).

BCLA A patients not suitable for hepatic resectioncan be considered for RFA. In the grey zone of tumours>3 cm that have an increased risk of satellite nodules,techniques to enlarge the ablation field or combinationtherapy with other modalities such as TACE, should beconsidered. Survival benefits provided by combinationtherapy with RFA plus TACE, compared to RFA alonein HCCs between 3 and 5 cm, was demonstrated in aRCT in Japan (59) and a consensus-based clinicalpractice manual of the Japanese Society of Hepatologyrecommends RFA combined with TACE for HCC>3 cm. (60). The recent availability of the microwavetechnique ensures larger areas of tumour necrosisthereby modifying these recommendations; however,this approach needs to be validated.

Chemoembolization of HCC is a viable treatmentoption to overcome the risks of morbidity during thetreatment of patients with severe portal hypertension. Atpresent, TACE is used to treat patients with early HCCin whom surgical or ablative therapies are not applicablefor technical reasons and/or the presence of comorbidi-ties. The results of DEB-TACE using doxorubicin-loaded beads rather than the conventional doxorubicinLipiodol (Guerbet, Genoa, Italy) emulsion, haveshown an overall favourable toxicity profile and potentantitumour activity. However, while initial studiesreported response rates ranging from 13.3% to 80.7%(61), a phase III RCT (PRECISION V) failed to showthat DB-TACE was better than conventional TACE (30).DEB-TACE has been confirmed as a user friendly, effec-tive technique in a recent international study (62) where173 patients who were not suitable for curative treat-ment (41% Child-Pugh B) achieved a 5-year overall sur-vival of 22.5%, with better responses in Child-Pugh Athan in Child-Pugh B patients (29.4 vs. 12.8%).

The infusion of radioactive substances such asIodine-131-labelled Lipiodol or microspheres contain-ing Yttrium-90 into the hepatic artery (TARE) is analternative approach to treat both unresectable interme-diate and advanced stage tumours. In a feasibility trial,Salem et al. (63) reported a response rate of 57% basedon EASL criteria and an overall time to tumour progres-sion of 7.9 months with an acceptable rate of side

effects, including fatigue (57%), pain (23%) and nau-sea/vomiting (20%) and a 30-day mortality rate of 3%.In a phase II trial, 52 patients with intermediate toadvanced HCC treated for a median follow-up of36 months, showed a median time to progression of11 months with no significant difference betweenpatients with portal vein thrombosis and those without(7 vs. 13 months), while the median overall survival was15 months (95% confidence interval, 1218 months).

Given the heterogeneity of HCC and the lack ofhigh level evidence-based data favouring one treatmentover the other, the decision-making process in hepato-oncology remains flawed. While the international sci-entific societies EASL-EORTC and AASLD have builttheir treatment algorithms on the stage of BCLC,defined by tumour burden, liver impairment and per-formance status, it should be acknowledged that bydefault these guidelines disregard clinical variables inthe field which could influence the decision-makingprocess. In two studies performed in Italy, up to 40%of patients with HCC were in fact treated outside rec-ommended guidelines (64,65) because of tumour char-acteristics/location or comorbidities making it difficultto classify patients according to international recom-mendations. Until a personalized algorithm based ongenetic predictors of tumour aggressiveness can bedeveloped, the decision-making process for HCC iswell suited to the regret theory model, which postulatesthat treatment choices may be influenced by the deci-sion-makers anticipation that certain outcomes will beassociated with high regret, which he/she would like toavoid or minimize (55), leaving some renowned HCCreferral centres to question the accuracy of BCLC/AASLD treatment allocations. In fact, internationalguidelines for HCC are not consistently applied in ourcentre either, or in other academic hospitals in Italy, asign that the caregivers expertise and desire to treatoften goes beyond guidelines. In our centre, where2005 AALSD recommendations have been the SOC forthe treatment of HCC, 29% of 227 patients consecu-tively treated in the last 5 years, did not receive a SOCtreatment, including 21% of the best prognosis BCLCA patients, who ultimately did not receive radical treat-ment (66). While adjuvant treatment is awaited toimprove the outcome of patients who undergo radicaltherapies, a multinational, placebo-controlled random-ized trial including more than 1000 patients with earlyHCC treated with limited hepatic resection or localradio frequency ablation (STORM trial: http://clinical-trials.gov.com, NCT00692770) failed to demonstrateany adjuvant property of sorafenib in preventing earlyrecurrence of HCC (33.4 vs. 33.8 months) and reduc-ing mortality at 5 years (25% in both groups) (67). Inparticular, 30% of the patients had to discontinue so-rafenib in the first 3 months of treatment due toadverse effects. Previous studies with interferon, tradi-tional chemotherapy and neo-adjuvant immunother-apy, missed the target as well.



Conclusions

In the last decades, management of HCC has signifi-cantly improved thanks to numerous breakthroughs instandardized therapeutic algorithms. A better under-standing of the natural history of the disease was instru-mental in the development of evidence-based stagingsystems which improve patient selection and treatment.At present, while treatment of HCC patients is based onindividual evaluation of a patient to guide the decision-making process, half of the patients referred to a tertiarycentre will have an early tumour fulfilling the criteria forradical therapy with resection, local ablation or trans-plantation. At the same time, one-third of the patientswill have an intermediate HCC, which can benefit fromtreatment with TACE in the presence of compensatedcirrhosis (ChildPugh status A or B) and the absence ofportal vein complications such as thrombosis or largeesophageal varices. In the remaining patients withadvanced HCC, sorafenib is a SOC option as long as cir-rhosis is well compensated (ChildPugh A) and a radio-logical or a clinical response can be achieved in the first2 months of treatment. Because of the extended survivalin patients when tumours are detected early, surveil-lance of patients with chronic liver disease to obtain anearly diagnosis is the only practical approach to improveboth access to and the outcome of HCC treatment.Nevertheless, there is also a substantial hope of obtain-ing clinical benefits in the many patients with moreadvanced tumour disease if a multidisciplinaryapproach is taken combining different treatment modal-ities. However, adopting therapeutic algorithms beyondthe recommendations inevitably results in lower survivalbenefits compared to a guideline driven treatment ofHCC.

Acknowledgements

Conflict of interest: Massimo Colombo: Grant andresearch support: BMS, Gilead Science. Advisory com-mittees: Merck, Roche, Novartis, Bayer, BMS, GileadScience, Tibotec, Vertex, Janssen Cilag, Achillion, Lund-beck, GSK, GenSpera, AbbVie, AlfaWasserman, Jen-nerex Speaking and teaching: Tibotec, Roche, Novartis,Bayer, BMS, Gilead Science, Vertex, Merck, Janssen,Sanofi. Angelo Sangiovanni: Bayer.

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