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Hepatobiliary

Hepatocellular Carcinoma: The Role of the North American GI Steering Committee Hepatobiliary Task Force and the Advent of Effective Drug Therapy

^aUniversity of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA; ^bUniversity of California at San Francisco Comprehensive Cancer Center, San Francisco, California, USA

Key Words. Hepatocellular carcinoma • Liver neoplasms • Chemoembolization • Drug therapy • Doxorubicin • Sorafenib • Bevacizumab • Erlotinib

Correspondence: Bert H. O'Neil, M.D., University of North Carolina Lineberger Comprehensive Cancer Center, 101 Manning Drive, 3009 Old Clinic Building, Chapel Hill, North Carolina 27599, USA. Telephone: 919-966-4431; Fax: 919-966-6735; e-mail: bert_oneil{at}med.unc.edu

Received August 3, 2007; accepted for publication October 18, 2007.

Disclosure: B.H.O'N. has acted as a consultant to Bayer. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

	ABSTRACT

Top Abstract Introduction Formation of the North... Therapy of Advanced HCC Conclusion Acknowledgments References

 
Hepatocellular carcinoma (HCC) is a disease that requires multidisciplinary management. There has been no widely accepted standard for systemic therapy for this disease until recently. This article briefly discusses the management of earlier stage HCC, then focuses on newer agents with promise, particularly sorafenib, a drug that appears to be the new standard of care for advanced disease.

	INTRODUCTION

Top Abstract Introduction Formation of the North... Therapy of Advanced HCC Conclusion Acknowledgments References

 
Hepatocellular carcinoma (HCC) is a major health issue worldwide, particularly in Asia and Africa, and a disease that has increased in incidence in the Western world over the past 20 years primarily as a result of the prevalence of hepatitis C virus infection [1], which predisposes patients to HCC. Management of HCC is complex, and clinicians from many disciplines including gastroenterology/hepatology, surgery, transplant surgery, interventional and conventional radiology, medical oncology, radiation oncology, and nuclear medicine must be involved in the care of patients. The different treatment options for patients with HCC have almost become too numerous to count and multidisciplinary management of HCC patients is essential to maximize the limited chance for cure and to maximize palliative outcomes for patients with incurable disease and with underlying liver dysfunction.

The Barcelona Liver Clinic (BCLC) staging system (Table 1) is one of a number of efforts to understand the prognosis for patients with HCC [2]. Other conventions include the Cancer of the Liver Italian Program score and the Chinese University Prognostic Index [3, 4], but the BCLC is used as an example. The BCLC system is conceptually useful, because it helps to integrate liver function and tumor features into a classification that is meaningful from a standpoint of treatment options (Table 1). For example, BCLC stage A patients are those suitable for surgical/ablative therapy and transplant, BCLC B patients are suitable for regional therapy such as embolization, and BCLC C patients are those best suited for systemic therapies or clinical trials. Notably, these systems lean heavily on the Child-Pugh (C-P) classification of liver disease severity (Table 2) as the means of estimating underlying liver disease severity. It is important for medical oncologists who see patients with HCC to understand these systems in general (whichever one chooses to use), as Tumor–Node–Metastasis staging is poor at determining the appropriate treatment options for a patient with HCC. Stated another way, one cannot think about treating HCC without considering that two major disease processes are almost always present in these patients: the cancer and cirrhosis of the liver with its many manifestations and complications.

	FORMATION OF THE NORTH AMERICAN HEPATOBILIARY TASK FORCE

Top Abstract Introduction Formation of the North... Therapy of Advanced HCC Conclusion Acknowledgments References

	THERAPY OF ADVANCED HCC

Top Abstract Introduction Formation of the North... Therapy of Advanced HCC Conclusion Acknowledgments References

 
The rest of this article focuses on the therapy of advanced HCC. The most effective and potentially curative therapy is liver transplantation, because it eradicates the HCC and also eliminates the precancerous cirrhotic liver; however, this option is available to a very small fraction of HCC patients whose tumors are discovered at a very early stage before there is multifocal or vascular involvement. Surgical resection can also confer long-term survival in a fraction of patients, but the number of patients with HCC considered good candidates for resection is quite low in the U.S. as a result of a high proportion of patients diagnosed with HCC who also have C-P grade B or C cirrhosis. Ablative techniques may broaden the options for selected patients with marginally resectable tumors, but all of these therapies together apply to less than a quarter of patients presenting with HCC in the West [5].

Until recently, there has been no agreed upon standard therapy for the significant majority of patients whose tumors are not amenable to potentially curative therapy. One treatment that has been considered as a standard for years in localized unresectable HCC is transarterial embolization (TAE) or transarterial chemoembolization (TACE). TACE is appropriate for patients with BCLC stage B HCC, that is, those patients with reasonable liver function (C-P grade A or B) whose tumor(s) is large (i.e., >5 cm) or multifocal but does not occlude portal venous vessels and is at most minimally metastatic. TACE has been demonstrated to be an effective treatment in some, but not all, randomized studies [6]. In particular, two French studies showed no benefit in comparison with best supportive care; however, both studies used an intensive treatment schedule of repeat therapy every 6 weeks, and included a disproportionate number of patients with alcoholic cirrhosis in comparison with other studies [7, 8]. However, meta-analyses of embolization studies performed worldwide have more recently suggested that embolization confers a significant survival advantage in spite of the two negative studies mentioned before [9, 10]. One of these rigorous meta-analyses demonstrated a substantially better 2-year survival rate for the treated group compared with the control group in the combined studies (41% versus 27%; odds ratio, 0.53; 95% confidence interval, 0.32–0.89; p = .017) [9]. Based on the meta-analyses, TACE should be considered a standard of care for patients with BCLC stage B disease, as well as select BCLC stage C patients.

In spite of its widespread use, controversies surrounding TACE abound. Different strategies exist for the type of chemotherapy and how it is delivered (with or without iodized poppyseed oil, for example), type of embolic particle, and frequency of embolization, making recommendations for a specific strategy difficult. Well-powered randomized studies addressing these issues are scarce. Our own current practice is to offer TACE with polyacrylamide microspheres (Embosphere®; BioSphere Medical, Rockland, MA) following intra-arterial administration of either cisplatin (50 mg) or doxorubicin (50 mg) and mitomycin-C (10 mg) admixed with iodized poppyseed oil. Other institutions primarily use bland embolization, given a lack of strong evidence that chemotherapy adds to the effects of TAE. That said, the only studies demonstrating a survival benefit to TACE included both chemotherapy and embolic agents [9].

There are no randomized studies assessing the optimum frequency of repeated TACE. In a study by the Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire [7], embolization was repeated on a planned every-8-weeks schedule. This treatment schedule appeared to result in an unacceptable rate of serious toxicity and death from liver failure, either because of the treatment schedule or possibly the patients enrolled. A positive study by Llovet et al. [6] used a less frequent schedule of embolization: one TACE followed by a second treatment at 2 months, then every 6 months. Given these results, our own practice has been to repeat embolization to an area only after progression following initial response to TACE, or 8 or more weeks later in cases where response to initial TACE was marginal, with repeated TACE based on results of follow-up scans that are performed every 2–3 months. Response to TACE is best measured at least 8 weeks after the procedure, given the time that is required to resolve inflammation created by the procedure.

It is generally agreed that careful patient selection is necessary to avoid significant toxicity from TACE, particularly liver failure and/or necrosis leading to abscess. Specific contraindications to embolization therapy include main or ipsilateral first branch portal vein thrombosis, poorly controlled ascites, hyperbilirubinemia, and encephalopathy. Unfortunately, many patients are ineligible based on these criteria, exemplified by the previously referenced study in which 900 patients were screened to randomize 300 patients [6]. Obviously there has been a need for a therapy for the majority of patients who are not eligible for embolization therapy, as well as for those patients who initially respond to TACE but then progress. A newer and possibly less toxic alternative to TACE is the arterial administration of yttrium-90–impregnated glass or resin microspheres. Single-arm studies of glass spheres in particular have suggested good results in comparison with historical controls (mostly patients treated with TACE), but at this time randomized data are lacking in HCC, making this an investigational therapy (reviewed in [11]).

For patients with advanced disease (BCLC stage C) not amenable to embolization or having failed embolization, the de facto standard of care has been systemic doxorubicin for many years. This is based on a large number of single-arm efficacy trials with wide variation in reported response rates (reviewed in [12]). There has never been an adequately powered study of doxorubicin against best supportive care to support the routine use of this relatively toxic drug, but a large multinational study of doxorubicin compared with the antifolate drug nolatrexed revealed a very disappointing 2% overall response rate and a median survival time of approximately 6 months for the doxorubicin arm, although that was actually slightly better than that seen with the experimental agent nolatrexed [13]. Based on this result, the consensus opinion has been that it is not necessary to use doxorubicin as the control arm in a study of a new systemic agent.

Combination chemotherapy appeared promising in two phase II studies of cisplatin, interferon, doxorubicin, and 5-fluorouracil (PIAF) [14, 15] and was notable for a small, but significant, number of pathologic complete remissions discovered after tumor downstaging (patients were all deemed unresectable as a criterion for entering the study) allowed surgical resection. The "downstaging" issue was interesting, but may apply only to patients with hepatitis B–related HCC, as most patients with hepatitis C–related HCC have cirrhosis that constitutes a contraindication to surgery in spite of tumor downsizing. Subsequently, PIAF was found to be no better than single-agent doxorubicin in a randomized controlled trial [16]. In that study, performed in China, 188 patients were randomized to receive either doxorubicin (60 mg/m² every 3 weeks) or PIAF (every 4 weeks). While the response rate for PIAF was double that for doxorubicin (21% versus 10%), the overall survival (OS) duration was not significantly longer (8.6 versus 6.8 months; p = .83).

With that background in mind, the multitargeted tyrosine kinase inhibitor sorafenib was studied in HCC on the basis of tumor responses and stable disease seen during the early development of the drug [17]. Sorafenib was initially designed and developed as an inhibitor of the c-Raf and B-Raf kinases (Fig. 1), encoded by oncogenes known to be mutated frequently in several tumor types, including melanoma and colorectal cancer [18]. In addition to inhibition of RAF kinase activity, sorafenib is also known to affect the functioning of several other tyrosine kinases. The kinase family that is inhibited by sorafenib that has seemed to be most relevant to the efficacy of sorafenib to date has been the vascular endothelial growth factor receptor (VEGFR) family. This fact has been demonstrated most convincingly in renal cell carcinoma, an often highly vascular tumor that is nearly always driven by VEGF secretion caused by loss of inhibition of hypoxia-inducible factor 1-alpha that results from inactivation of the von Hippel-Lindau tumor suppressor [19]. At present, it is unknown whether sorafenib-related activities other than VEGFR-1 or VEGFR-2 inhibition are clinically relevant.

View larger version (21K): [in this window] [in a new window]   Figure 1. Simplified diagram of signaling between cell surface receptor tyrosine kinases (e.g., EGFR, IGFR), the Ras pathway, and the Raf/MEK/ERK pathway. Potential targeting points are shown in yellow (to the left). Abbreviations: EGFR, epidermal growth factor receptor; ERK, extracellular signal–related kinase; FTI, farnesyltransferase inhibitors; IGFR, insulin-like growth factor receptor; KI, kinase inhibitor; MEK, mitogen-activated protein kinase–extracellular signal-related kinase kinase; PI3K, phosphoinositide-3-kinase pathway; RTK, receptor tyrosinekinase.

Based on a response seen in an HCC patient during phase I evaluation of sorafenib [17] and the preclinical rationale detailed above, a large multinational phase II trial in patients with HCC was undertaken [24]. The study included patients with advanced or metastatic HCC and C-P grade A or B cirrhosis. The fraction of patients receiving any prior therapy, such as embolization, was not detailed. C-P grade B cirrhosis can entail significant hyperbilirubinemia, but cutoff values for bilirubin were not detailed in the manuscript. Over a quarter of the patients enrolled had C-P grade B liver disease. Dosing of sorafenib was 400 mg orally twice a day continuously, the same as the established dose for renal cell cancer. That study included several interesting correlative studies such as pharmacokinetics, measures of tumor necrosis (by imaging), a measure of baseline phosphorylated ERK expression, and pharmacogenomics.

Sorafenib was well tolerated in this group of patients, with no grade 4 toxicities reported; fatigue, diarrhea, and rash were the most frequently reported grade 3 toxicities, none occurring in even 10% of enrolled patients. In spite of a nominal radiographic response rate of 3%, the median OS time was 9.2 months (compared with <6 months expected for doxorubicin treatment in a roughly similar population). Tumor necrosis was noted in a subset of patients, with several patients' tumors demonstrating necrosis in spite of a size increase. The correlation of this finding with more important outcomes, such as OS, is at present unknown.

These encouraging phase II findings led to the initiation of an international phase III trial, the Sorafenib HCC Assessment Randomized Protocol (SHARP), which was presented at the 2007 Annual Meeting of the American Society of Clinical Oncology (ASCO) [25]. In contrast to the phase II study, the SHARP trial almost exclusively enrolled patients with C-P grade A cirrhosis, a requirement that resulted in exclusion of a large fraction of patients (approximately one third of the patients who were evaluated at participating centers) with advanced HCC. The SHARP trial was designed to demonstrate a 40% longer OS duration for sorafenib plus best supportive care compared with placebo plus best supportive care. The target population was patients with advanced or metastatic disease who could have previously been treated with locoregional therapy, although the numbers of patients treated with ablation versus embolization was not reported. Seventy percent of patients enrolled had portal vein thrombosis, signifying a relatively poor prognosis, albeit within the context of C-P class A status. Sorafenib was dosed continuously at 400 mg orally twice daily. The drug appeared to be very well tolerated, with very few grade 3 or 4 toxicities. As in the phase II experience, rash (in this case mostly a variant of hand–foot syndrome) and diarrhea were the most frequent adverse effects of the drug. Also similar to the phase II study was a very low rate of outright radiographic response: only 2.3% of patients experienced a partial response. Again, in spite of this very low response rate, patients treated with sorafenib experienced a significantly longer OS (a primary endpoint) and time to progression (TTP) compared with patients receiving placebo. The median survival for placebo-treated patients was approximately 8.0 months, whereas sorafenib-treated patients survived 10.8 months (p = .00058). TTP was similarly longer with sorafenib.

A second notable primary endpoint was time to symptomatic progression (TTSP) based on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 [26] instrument. This endpoint uses a questionnaire with eight questions to evaluate symptomatology. Use of this endpoint allowed patients to be treated beyond radiographic progression; however, on final analysis, TTSP was not significantly better for patients treated with sorafenib than for patients treated with placebo. Continuing sorafenib beyond radiographic progression therefore cannot be recommended. The authors of the study reasonably concluded that the SHARP trial demonstrated sorafenib to be the new standard of care for the treatment of locally advanced or metastatic HCC. It is important to note that patients enrolled in that study had excellent baseline prognoses compared with other studies (as evidenced by the 8-month median survival time for placebo-treated patients), with nearly all patients having C-P grade A cirrhosis, and that these results cannot at this time be extrapolated to patients with more severe liver disease.

The utility of sorafenib in HCC is highly encouraging from a standpoint of being able to broaden the use of targeted therapies beyond a few malignancies. One of the most interesting questions raised by these results is whether the benefit of sorafenib is primarily a result of inhibition of Raf, as was predicted in preclinical studies, or whether it is secondary to inhibition of the VEGF pathway, as would seem to be the case in renal cell carcinoma, or if some unexplained effect on the progression of cirrhosis may also be important. One of the correlates to the phase II study described earlier provided a tantalizing early clue: a subset of patients with available biopsies was studied for ERK phosphorylation, a potential marker of Raf downstream activity. Raf directly phosphorylates MEK, which subsequently can phosphorylate ERK. In this case, patients whose tumors were more highly phosphorylated-ERK positive by immunohistochemistry (high defined as 2–4+ staining versus 0–1+) experienced a significantly longer TTP. Unfortunately, however, without a control arm we are only left to wonder whether this finding represents a prognostic as opposed to a predictive feature, and further study should certainly be conducted.

Partial answers to the Raf versus VEGF question may also come from the performance of other agents that do not target the Raf/MEK/ERK pathway. Phase II studies have now been conducted with several alternative VEGF pathway inhibitors, including bevacizumab and sunitinib. Two single-agent bevacizumab studies and two combination (with capecitabine plus oxaliplatin and gemcitabine plus oxaliplatin, respectively) studies have already been reported [27–30]. Preliminarily, bevacizumab alone appears to have some activity, but the data are too immature to fully evaluate its potential. The studies of bevacizumab and chemotherapy had relatively few responses, but median survival times appeared similar to that seen with sorafenib in the much larger phase II study. Perhaps the most interesting combination thus far that could potentially challenge sorafenib's brand new spot atop the hill in HCC is the combination of erlotinib and bevacizumab [31]. Erlotinib alone appeared to have modest activity (but again, infrequent responses) in an already-published phase II study, with a median survival time of 13 months [32]. In a phase II trial presented at ASCO 2007, the erlotinib–bevacizumab combination resulted in a very interesting 20% radiographic response rate and a preliminary but highly encouraging estimated OS duration of 19 months. This early survival estimate will likely fall with longer patient follow-up. A phase III study of this combination against sorafenib is under consideration within the Hepatobiliary Task Force. A summary of planned randomized trials is presented in Table 3.

	CONCLUSION

Top Abstract Introduction Formation of the North... Therapy of Advanced HCC Conclusion Acknowledgments References

 
In summary, treatment of HCC has finally entered the targeted therapy age with the findings of the SHARP phase III trial. Sorafenib can be considered standard of care for patients with advanced and metastatic HCC who are not candidates for curative or locoregional therapies such as TACE, but at present only patients with good liver function have been rigorously studied. Sorafenib is under consideration for approval for this indication by the U.S. Food and Drug Administration and European regulatory agencies. Clinicians who see patients with HCC will need to become familiar with indications for TACE and have a good understanding of measures of liver function. Consultation with a hepatologist familiar with cirrhotic patients and HCC is certainly encouraged for medical oncologists who have not cared for many HCC patients. What should we do with a patient with C-P grade B cirrhosis and advanced HCC? The appropriate answer for now is enrollment in properly designed clinical trials. That said, the small amount of data available from the phase II study of sorafenib suggests that sorafenib is at least safe for a good group of C-P grade B patients, and in the absence of an available study, it would seem reasonable to consider sorafenib. Studies of sorafenib post- or peri-TACE are also under way, with a randomized study of TACE with or without post-TACE sorafenib enrolling. Other questions to be addressed in the near future are what combinations with sorafenib might further improve survival in advanced disease, and whether sorafenib might provide benefit in the adjuvant setting for those patients treated with resection or ablative therapy. Groups like the Intergroup Hepatobiliary Task Force will be at the forefront of turning many of these questions into answers in the coming years.

	ACKNOWLEDGMENTS

Top Abstract Introduction Formation of the North... Therapy of Advanced HCC Conclusion Acknowledgments References

 
B.H.O'N. is supported by National Institutes of Health 5K23CA118431–02.

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Top Abstract Introduction Formation of the North... Therapy of Advanced HCC Conclusion Acknowledgments References

 

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