- Email: [email protected]
Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus conference
HPB
DOI:10.1111/j.1477-2574.2010.00186.x
COMMENTARY
Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus conference hpb_186
321..322
Kelly W. Burak1, Melanie B. Thomas2 & Andrew X. Zhu3 1 Liver Unit, Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Canada, 2Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
Correspondence Kelly W. Burak, The University of Calgary, Liver Unit, Division of Gastroenterology, Department of Medicine, 3280 Hospital Dr NW, Calgary, Alberta, Canada, T2N 4Z6. Email: [email protected] and Andrew X. Zhu, The Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. Email: [email protected]
Despite guidelines recommending screening in all patients with cirrhosis,1 the majority of patients with hepatocellular carcinoma (HCC) in North America still present at intermediate or advanced stages when the curative options of liver transplantation (LT), surgical resection or radiofrequency ablation (RFA) are not possible. Although these patients have a poor prognosis, this Consensus Statement2 recognizes that such patients may benefit from palliative therapies including transarterial chemoembolization (TACE), transarterial radioembolization (TARE) with Yttrium-90 (90Y), external beam radiotherapy (RT), and systemic therapy with sorafenib. Selection of the appropriate therapy depends not only on the stage of the tumor (the presence and extent of vascular invasion, lymph node involvement or distant metastasis) but also on the underlying hepatic function, and the performance status of the patient. The vast majority of HCC in North America occur in the setting of a cirrhotic liver.1 It is therefore essential to manage these patients within a multidisciplinary team that recognizes the importance of the two co-existing diseases, namely the cancer and the cirrhosis, each with their own risk of mortality. Patients with Child Pugh (CP) class A cirrhosis and well preserved liver function may be candidates for any of the above mentioned therapies depending on the extent of tumor. Conversely, those with advanced decompensated liver disease (CP class C cirrhosis) are poor candidates for any therapy, regardless of the stage of their liver cancer, because they typically survive only a few months unless they are candidates for LT.1 Patients with CP class B cirrhosis have been underrepresented in randomized clinical trials
Proceedings of the Consensus Conference on Multidisciplinary Treatment of Hepatocellular Carcinoma sponsored by the American Hepato-PancreatoBiliary Association and co-sponsored by the Society of Surgical Oncology and the Society for Surgery of the Alimentary Tract and the University of Texas M. D. Anderson Cancer Center held in Orlando, FL, USA; 21 January, 2010.
HPB 2010, 12, 321–322
(RCTs) of sorafenib and TACE, making specific recommendations for this group of patients more difficult. TACE has become the standard of care for intermediate stage, unresectable patients, with large or multinodular HCC who have no extrahepatic spread and no portal vein thrombosis (PVT).1 It is important to recognize that the two RCTs which demonstrated a survival benefit of TACE over best supportive care each enrolled only 40 subjects in the TACE arms3,4 In these small studies, approximately one-third of subjects had single tumors and twothirds had multinodular HCC, and all subjects had reasonable liver function with a patent main portal vein.3,4 Subsequent, metaanalyses of RCTs have confirmed a survival advantage of TACE,5,6 with a median survival of 18 ⫾ 9.5 months.6 However, it is important not to extrapolate the benefit of TACE to patients with massive, infiltrating, bilobar tumors. Although a small study has suggested that TACE can be done safely in patients with PVT,7 the 9.5 month median survival in this series is comparable to the results of the SHARP study8 which clearly demonstrated a benefit of sorafenib therapy in subjects with vascular invasion. There is no standardized technique for performing chemoembolization, and although TACE is generally well tolerated it can result in liver failure, especially in those patients with CP class B cirrhosis or PVT, and on average 2.4% patients may die within 30 days due to complications of the procedure.6 TACE performed with doxorubicin eluting beads (DEBs) has been shown to result in lower systemic exposure to chemotherapy.9 A recent multicenter RCT demonstrated no statistically significant advantage of TACE with DEBs compared to conventional TACE, although DEBs were better tolerated in more difficult to treat patients and therefore resulted in better response rates in the subgroup of patients with CP class B cirrhosis.10 Outcomes of TARE with 90Y particles for intermediate stage HCC patients appear to be similar to TACE. A large single centre experience with TARE reported overall survival of 17.2 months for CP class A patients and 7.7 months for those with CP class B cirrhosis.11 The two technologies have not and probably will not
© 2010 International Hepato-Pancreato-Biliary Association
HPB
322
be compared in a large head-to-head RCT. TARE requires two angiograms (one to calculate a shunt fraction and one to deliver the 90Y particles), has higher direct costs associated with the procedure, but unlike TACE, can be done as an outpatient without the need for hospitalization. Limited experience has suggested that 90Y TARE can be safely performed in patients with complete PVT,12 although this needs more confirmation from other groups. Survival of 10.4 months has been reported in advanced patients with vascular invasion who receive TARE,11 but RCTs comparing TARE and sorafenib are needed to determine the role of this technology in patients with PVT. TACE and TARE have also been used to downstage HCC or to keep tumors from extending beyond accepted criteria in patients awaiting transplantation. There are no RCTs demonstrating a benefit of this strategy, although it continues to enjoy popularity in some regions with long waiting times for LT. Recently, significant progress has been made in techniques to safely deliver external beam radiation to liver tumors. Patients who are not candidates for other therapies may benefit from external beam photon or proton RT and studies are underway examining its role in combination with systemic therapy or TACE. The key issues for the management of intermediate stage HCC include the adequate selection of each modality for individual patients, lack of RCTs to assess the benefits of these treatments in patients with PVT, and whether sorafenib or other newer targeted agents can be safely combined with any of these treatments to improve outcomes. Until more definitive data from RCTs are available, the clinical practice pattern will continue to be influenced by the expertise of treating physicians and institutions. The SHARP8 and Asia-Pacific13 studies have clearly established sorafenib as the new standard treatment for patients with advanced HCC. Both studies demonstrated nearly an identical mortality risk reduction for subjects receiving sorafenib compared to placebo. The patients enrolled in these studies had good performance status and CP class A cirrhosis. Despite the small retrospective studies assessing the clinical experience of sorafenib in patients with CP class B cirrhosis, further study is needed before sorafenib can be recommended for all patients with CP class B cirrhosis. Although generally well tolerated, sorafenib does come with the risk of hand-foot skin reaction, diarrhea, fatigue, and hypertension.8,13 Perhaps more important than the survival benefit of sorafenib (10.7 versus 7.9 months) demonstrated in the SHARP trial,8 is that the study renewed interest in examining the role of other systemic therapies, particularly molecularly targeted agents, in HCC. Sorafenib is now being examined in an adjuvant role to prevent recurrence following curative intent surgery or RFA and is being examined in combination with TACE, TARE and RT. For advanced HCC, sorafenib is under investigation in combination with erlotinib or doxorubicin. Furthermore, there are several phase III studies ongoing evaluating newer agents such as sunitinib, brivanib, ABT-869 in patients with advanced HCC. Further development of effective systemic therapies is met with many challenges. Understanding the mechanism of action of sor-
HPB 2010, 12, 321–322
afenib that mediates the clinical benefits and escape may provide insights for developing more effective combination strategies. In addition to angiogenesis, we need to examine agents targeting other pathways of hepatocarcinogenesis. We should be mindful about patient resources and try to select the more promising agents and regimens through vigorous phase II studies before moving on to phase III trials. Conflict of interest None declared. References 1. Bruix J, Sherman M. (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1236. 2. Schwarz RE, Abou-Alfa GK, Geschwind JF, Krishnan S, Salem R, Venook SA. (2010) Nonoperative therapies for combined modality treatment of hepatocellular cancer: a consensus statement. HPB 12:313–320. 3. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739. 4. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35:1164–1171. 5. Llovet JM, Bruix J. (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37:429–442. 6. Marelli L, Stigliano R, Triantos C, Senzolo M, Cholongitas E, Davies N, et al. (2007) Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 30:6–25. 7. Georgiades CS, Hong K, D'Angelo M, Geschwind JF. (2005) Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 16:1653–1659. 8. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390. 9. Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. (2007) Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 46:474–481. 10. Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. (2010) Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 33:41–52. 11. Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, et al. (2010) Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 138:52–64. 12. Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi B, Ryu RK, et al. (2008) Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 47:71– 81. 13. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol 10:25–34.
© 2010 International Hepato-Pancreato-Biliary Association
DOI:10.1111/j.1477-2574.2010.00186.x
COMMENTARY
Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus conference hpb_186
321..322
Kelly W. Burak1, Melanie B. Thomas2 & Andrew X. Zhu3 1 Liver Unit, Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Canada, 2Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
Correspondence Kelly W. Burak, The University of Calgary, Liver Unit, Division of Gastroenterology, Department of Medicine, 3280 Hospital Dr NW, Calgary, Alberta, Canada, T2N 4Z6. Email: [email protected] and Andrew X. Zhu, The Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. Email: [email protected]
Despite guidelines recommending screening in all patients with cirrhosis,1 the majority of patients with hepatocellular carcinoma (HCC) in North America still present at intermediate or advanced stages when the curative options of liver transplantation (LT), surgical resection or radiofrequency ablation (RFA) are not possible. Although these patients have a poor prognosis, this Consensus Statement2 recognizes that such patients may benefit from palliative therapies including transarterial chemoembolization (TACE), transarterial radioembolization (TARE) with Yttrium-90 (90Y), external beam radiotherapy (RT), and systemic therapy with sorafenib. Selection of the appropriate therapy depends not only on the stage of the tumor (the presence and extent of vascular invasion, lymph node involvement or distant metastasis) but also on the underlying hepatic function, and the performance status of the patient. The vast majority of HCC in North America occur in the setting of a cirrhotic liver.1 It is therefore essential to manage these patients within a multidisciplinary team that recognizes the importance of the two co-existing diseases, namely the cancer and the cirrhosis, each with their own risk of mortality. Patients with Child Pugh (CP) class A cirrhosis and well preserved liver function may be candidates for any of the above mentioned therapies depending on the extent of tumor. Conversely, those with advanced decompensated liver disease (CP class C cirrhosis) are poor candidates for any therapy, regardless of the stage of their liver cancer, because they typically survive only a few months unless they are candidates for LT.1 Patients with CP class B cirrhosis have been underrepresented in randomized clinical trials
Proceedings of the Consensus Conference on Multidisciplinary Treatment of Hepatocellular Carcinoma sponsored by the American Hepato-PancreatoBiliary Association and co-sponsored by the Society of Surgical Oncology and the Society for Surgery of the Alimentary Tract and the University of Texas M. D. Anderson Cancer Center held in Orlando, FL, USA; 21 January, 2010.
HPB 2010, 12, 321–322
(RCTs) of sorafenib and TACE, making specific recommendations for this group of patients more difficult. TACE has become the standard of care for intermediate stage, unresectable patients, with large or multinodular HCC who have no extrahepatic spread and no portal vein thrombosis (PVT).1 It is important to recognize that the two RCTs which demonstrated a survival benefit of TACE over best supportive care each enrolled only 40 subjects in the TACE arms3,4 In these small studies, approximately one-third of subjects had single tumors and twothirds had multinodular HCC, and all subjects had reasonable liver function with a patent main portal vein.3,4 Subsequent, metaanalyses of RCTs have confirmed a survival advantage of TACE,5,6 with a median survival of 18 ⫾ 9.5 months.6 However, it is important not to extrapolate the benefit of TACE to patients with massive, infiltrating, bilobar tumors. Although a small study has suggested that TACE can be done safely in patients with PVT,7 the 9.5 month median survival in this series is comparable to the results of the SHARP study8 which clearly demonstrated a benefit of sorafenib therapy in subjects with vascular invasion. There is no standardized technique for performing chemoembolization, and although TACE is generally well tolerated it can result in liver failure, especially in those patients with CP class B cirrhosis or PVT, and on average 2.4% patients may die within 30 days due to complications of the procedure.6 TACE performed with doxorubicin eluting beads (DEBs) has been shown to result in lower systemic exposure to chemotherapy.9 A recent multicenter RCT demonstrated no statistically significant advantage of TACE with DEBs compared to conventional TACE, although DEBs were better tolerated in more difficult to treat patients and therefore resulted in better response rates in the subgroup of patients with CP class B cirrhosis.10 Outcomes of TARE with 90Y particles for intermediate stage HCC patients appear to be similar to TACE. A large single centre experience with TARE reported overall survival of 17.2 months for CP class A patients and 7.7 months for those with CP class B cirrhosis.11 The two technologies have not and probably will not
© 2010 International Hepato-Pancreato-Biliary Association
HPB
322
be compared in a large head-to-head RCT. TARE requires two angiograms (one to calculate a shunt fraction and one to deliver the 90Y particles), has higher direct costs associated with the procedure, but unlike TACE, can be done as an outpatient without the need for hospitalization. Limited experience has suggested that 90Y TARE can be safely performed in patients with complete PVT,12 although this needs more confirmation from other groups. Survival of 10.4 months has been reported in advanced patients with vascular invasion who receive TARE,11 but RCTs comparing TARE and sorafenib are needed to determine the role of this technology in patients with PVT. TACE and TARE have also been used to downstage HCC or to keep tumors from extending beyond accepted criteria in patients awaiting transplantation. There are no RCTs demonstrating a benefit of this strategy, although it continues to enjoy popularity in some regions with long waiting times for LT. Recently, significant progress has been made in techniques to safely deliver external beam radiation to liver tumors. Patients who are not candidates for other therapies may benefit from external beam photon or proton RT and studies are underway examining its role in combination with systemic therapy or TACE. The key issues for the management of intermediate stage HCC include the adequate selection of each modality for individual patients, lack of RCTs to assess the benefits of these treatments in patients with PVT, and whether sorafenib or other newer targeted agents can be safely combined with any of these treatments to improve outcomes. Until more definitive data from RCTs are available, the clinical practice pattern will continue to be influenced by the expertise of treating physicians and institutions. The SHARP8 and Asia-Pacific13 studies have clearly established sorafenib as the new standard treatment for patients with advanced HCC. Both studies demonstrated nearly an identical mortality risk reduction for subjects receiving sorafenib compared to placebo. The patients enrolled in these studies had good performance status and CP class A cirrhosis. Despite the small retrospective studies assessing the clinical experience of sorafenib in patients with CP class B cirrhosis, further study is needed before sorafenib can be recommended for all patients with CP class B cirrhosis. Although generally well tolerated, sorafenib does come with the risk of hand-foot skin reaction, diarrhea, fatigue, and hypertension.8,13 Perhaps more important than the survival benefit of sorafenib (10.7 versus 7.9 months) demonstrated in the SHARP trial,8 is that the study renewed interest in examining the role of other systemic therapies, particularly molecularly targeted agents, in HCC. Sorafenib is now being examined in an adjuvant role to prevent recurrence following curative intent surgery or RFA and is being examined in combination with TACE, TARE and RT. For advanced HCC, sorafenib is under investigation in combination with erlotinib or doxorubicin. Furthermore, there are several phase III studies ongoing evaluating newer agents such as sunitinib, brivanib, ABT-869 in patients with advanced HCC. Further development of effective systemic therapies is met with many challenges. Understanding the mechanism of action of sor-
HPB 2010, 12, 321–322
afenib that mediates the clinical benefits and escape may provide insights for developing more effective combination strategies. In addition to angiogenesis, we need to examine agents targeting other pathways of hepatocarcinogenesis. We should be mindful about patient resources and try to select the more promising agents and regimens through vigorous phase II studies before moving on to phase III trials. Conflict of interest None declared. References 1. Bruix J, Sherman M. (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1236. 2. Schwarz RE, Abou-Alfa GK, Geschwind JF, Krishnan S, Salem R, Venook SA. (2010) Nonoperative therapies for combined modality treatment of hepatocellular cancer: a consensus statement. HPB 12:313–320. 3. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739. 4. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35:1164–1171. 5. Llovet JM, Bruix J. (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37:429–442. 6. Marelli L, Stigliano R, Triantos C, Senzolo M, Cholongitas E, Davies N, et al. (2007) Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 30:6–25. 7. Georgiades CS, Hong K, D'Angelo M, Geschwind JF. (2005) Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 16:1653–1659. 8. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390. 9. Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. (2007) Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 46:474–481. 10. Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. (2010) Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 33:41–52. 11. Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, et al. (2010) Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 138:52–64. 12. Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi B, Ryu RK, et al. (2008) Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 47:71– 81. 13. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol 10:25–34.
© 2010 International Hepato-Pancreato-Biliary Association