- Email: [email protected]
Hepatocellular carcinoma
Correspondence
Hepatocellular carcinoma
2
3
Alejandro Forner and colleagues (March 31, p 1245)1 advocate for screening of hepatocellular carcinoma despite no evidence of benefit, arguing that a ”validation trial in developed regions is not feasible”. Only two randomised trials are available, both from China: one is negative, the other is positive but has several major flaws.2 From developed countries, only observational studies are available. These conclude that screening improves survival despite the raw data showing that screened patients die younger than do nonscreened patients (length time and lead time biases).3 Last, there is no agreement on the screening method because varying imaging techniques with various intervals have been used. Screening is a complex issue which necessitates a national programme to ensure minimum participation, quality controls, and evaluation of the results. None of these is currently in place in any country. Only 12% of US patients with viral cirrhosis are screened,4 which is probably because the National Cancer Institute states that: “based on fair evidence, screening would not result in a decrease in mortality from HCC…” but “would result in rare but serious side effects”.5 Patients deserve evidence-based medicine. Why can hepatologists in developed countries not do randomised trials for hepatocellular carcinoma to investigate the benefits and harms of screening, as gastroenterologists have done for colorectal cancer and urologists for prostate cancer? Recruitment is not an issue: hepatocellular carcinoma is the fifth most common cancer in the world. I declare that I have no conflicts of interest.
Alain Braillon [email protected] 27 rue Voiture, 80000 Amiens, France 1
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55.
www.thelancet.com Vol 380 August 4, 2012
4 5
Lederle FA, Pocha C. Screening for liver cancer: the rush to judgment. Ann Intern Med 2012; 156: 387–89. Braillon A. Screening for hepatocellular carcinoma: from lack of evidence to common sense. Hepatology 2010; 52: 1863–64. Braillon A. Surveillance for hepatocellular carcinoma. Ann Intern Med 2011; 155: 274–75. National Cancer Institute, US National Institutes of Health. Liver (hepatocellular) cancer screening (PDQ). http://www.cancer. gov/cancertopics/pdq/screening/ hepatocellular/HealthProfessional/page2 (accessed March 16, 2012).
The comprehensive Seminar by Alejandro Forner and colleagues1 shows that chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) and alcohol use are the main risk factors for hepatocellular carcinoma. However, several studies have shown a relatively high incidence of hepatocellular carcinoma in patients with membranous obstruction of the inferior vena cava (MOVC; table). Univariate analyses have confirmed that obstruction of the inferior vena cava is a significant predictor of hepatocellular carcinoma.2 Furthermore, Gwon and colleagues3 reported that the cumulative incidence of hepatocellular carcinoma at 1, 5, and 10 years from the initial diagnosis of MOVC was 7·3%, 13·5%, and 31·8%, respectively. The incidence of hepatocellular carcinoma in patients with MOVC seems to be similar to that in patients with HCVrelated cirrhosis (3–5% per year).1 Potential mechanisms of development of hepatocellular carcinoma in the context of MOVC have been discussed.2,4 Initially, hepatic venous hypertension and sinusoidal congestion caused by MOVC lead to centrolobular necrosis, regeneration, cirrhosis, and ultimately dysplastic hepatic nodules with malignant potential. Thus, an algorithm for the management of hepatic nodules and surveillance for hepatocellular carcinoma in these patients has been proposed.5 In conclusion, MOVC should not be neglected as a risk factor for hepatocellular carcinoma. Surveillance for hepatocellular carcinoma in patients
Country
Patients with Patients with MOVC MOVC and HCC
Gwon et al3
Korea
98
Moucari et al2
France
13*
Simson et al
South Africa
23 (23·5%) 9 (69·2%)
101
48 (47·5%) 2 (25·0%)
Rector et al
USA
8
Matsui et al4
Japan
12
3 (25·0%)
Dilawari et al
India
54
6 (11·1%)
Shrestha et al
Nepal
150*
7 (4·7%)
MOVC=membranous obstruction of the inferior vena cava. HCC=hepatocellular carcinoma. See appendix for unreferenced studies. *Inferior vena cava obstruction.
Table: Incidence of hepatocellular carcinoma in patients with membranous obstruction of the inferior vena cava
with MOVC should be recommended to improve these patients’ survival. We declare that we have no conflicts of interest.
See Online for appendix
Weirong Ren, Xingshun Qi, Jia Jia, Man Yang, *Guohong Han [email protected] Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, China 1 2
3
4
5
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Moucari R, Rautou PE, Cazals-Hatem D, et al. Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors. Gut 2008; 57: 828–35. Gwon D 2nd, Ko GY, Yoon HK, et al. Hepatocellular carcinoma associated with membranous obstruction of the inferior vena cava: incidence, characteristics, and risk factors and clinical efficacy of TACE. Radiology 2010; 254: 617–26. Matsui S, Ichida T, Watanabe M, et al. Clinical features and etiology of hepatocellular carcinoma arising in patients with membranous obstruction of the inferior vena cava: in reference to hepatitis viral infection. J Gastroenterol Hepatol 2000; 15: 1205–11. Plessier A, Rautou PE, Valla DC. Management of hepatic vascular diseases. J Hepatol 2012; 56: S25–38.
Alejandro Forner and colleagues1 provide an update of the available evidence for image-guided transcatheter treatment of hepatocellular carcinoma. They conclude that transarterial chemoembolisation is the only option that has shown survival benefit in hepatocellular carcinoma. Forner and colleagues state that, although radioembolisation with yttrium90-labelled (⁹⁰Y-labelled) spheres has much potential, a randomised controlled trial to define its role in
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
469
Correspondence
clinical practice is lacking. This latter statement is incorrect. ⁹⁰Y radioembolisation involves transarterial administration of minimally embolic microspheres loaded with the β-emitting isotope ⁹⁰Y, which deliver selective internal radiation to the tumour. ⁹⁰Y radioembolisation is increasingly used in clinical practice for treatment of hepatocellular carcinoma.2 The largest prospective study to date included 291 patients.3 Median survival for the 83 patients with intermediate-stage disease, as classified by the Barcelona Clinic Liver Cancer staging system, was 17·2 months (95% CI 13·5–29·6). This result is similar to that of transarterial chemoembolisation. Therefore we have started a multicentre randomised controlled trial (TRACE; ClinicalTrials.gov reference NCT01381211) in which patients with intermediate-stage hepatocellular carcinoma are randomly assigned to either ⁹⁰Y radioembolisation or transarterial chemoembolisation. 140 patients will be included. Structural follow-up for 2 years after treatment will be done with MRI every 3 months to assess tumour response. The primary outcome is time to progression, and secondary outcome variables are overall survival, tumour response, toxic effects and adverse events, quality of life, and cost-effectiveness. Recruitment of patients has now started in the first two European centres. We declare that we have no conflicts of interest. See Online for appendix
*Maurice A A J van den Bosch, Luc Defreyne [email protected] University Medical Center, 3584 CX Utrecht, Netherlands (MAAJvdB); and Ghent University Hospital, Ghent, Belgium (LD) 1 2
3
470
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Vente MA, Wondergem M, Van der Tweel I, et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol 2009; 19: 951–59. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010; 138: 52–64.
In their Seminar on hepatocellular carcinoma,1 Alejandro Forner and colleagues question the conclusions of our Cochrane systematic review.2 We could not identify evidence to show that transarterial (chemo)embolisation (TAE/TACE) has a beneficial effect on survival in patients with unresectable hepatocellular carcinoma. Using trial sequential analyses, we also showed that additional patients might be needed to reach firm evidence to accept or refute the superiority of TAE/TACE over no intervention.2 Our systematic review has substantial methodological advantages over earlier attempts to summarise TAE/TACE trials.3 These advantages include assessment of trial quality on the basis of empirical evidence, adequate statistics for time-toevent data (ie, hazard ratios), and trial sequential analyses.2 In Llovet and Bruix’s meta-analysis,3 assessments of trial quality were not based on empirical evidence. Furthermore, the two highlighted positive trials4,5 have methodological shortcomings, including a high risk of selection bias,5 risks associated with early stopping,4 and baseline imbalances.4 Accordingly, all positive conclusions1,3 have been based on a low number of events and few trials with low risk of bias. Forner and colleagues question our inclusion of several randomised trials and our choice of a 10% relative risk reduction. However, exclusion of such “ineligible” trials only reinforces our conclusions that we lack any support for TAE/TACE (appendix). Furthermore, the only intervention effect one can hope for is a more modest effect than a 10% relative risk reduction (appendix). We therefore continue to advocate for more efforts to investigate the benefits and harms of TACE through adequately powered and biasprotected trials. Such trials could give Forner and colleagues a needed reality check. RSO and JW declare that they have no conflicts of interest. CG is co-ordinating editor of The Cochrane Hepato-Biliary Group.
*Roberto S Oliveri, Jørn Wetterslev, Christian Gluud [email protected] Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research (RSO, JW, CG) and Department of Clinical Immunology (RSO), Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark 1 2
3
4
5
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011; 3: CD004787. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429–42. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359: 1734–39. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164–71.
Authors’ reply In answer to Alain Braillon, we openly exposed the limited scientific evidence to support screening for hepatocellular carcinoma and commented on the challenges a controlled trial would face. An Australia survey1 showed that 99% of patients refused to enter a screening versus no screening trial. Even if up to 5% accepted, such a proportion would not be representative and results would be questioned by those wanting highlevel evidence. The bulk of available information suggests that screening is beneficial. Thus, having to select between not recommending screening because of an absence of proof and recommending screening because of expert critical analysis, all practice guidelines by scientific associations recommend screening patients at high enough risk of hepatocellular carcinoma, but only if treatment were possible if diagnosed.2,3 Weirong Ren and colleagues state that membranous obstruction of the inferior vena cava (MOVC) should be included in the risk factors. This rare entity has a higher prevalence in Asia www.thelancet.com Vol 380 August 4, 2012
Hepatocellular carcinoma
2
3
Alejandro Forner and colleagues (March 31, p 1245)1 advocate for screening of hepatocellular carcinoma despite no evidence of benefit, arguing that a ”validation trial in developed regions is not feasible”. Only two randomised trials are available, both from China: one is negative, the other is positive but has several major flaws.2 From developed countries, only observational studies are available. These conclude that screening improves survival despite the raw data showing that screened patients die younger than do nonscreened patients (length time and lead time biases).3 Last, there is no agreement on the screening method because varying imaging techniques with various intervals have been used. Screening is a complex issue which necessitates a national programme to ensure minimum participation, quality controls, and evaluation of the results. None of these is currently in place in any country. Only 12% of US patients with viral cirrhosis are screened,4 which is probably because the National Cancer Institute states that: “based on fair evidence, screening would not result in a decrease in mortality from HCC…” but “would result in rare but serious side effects”.5 Patients deserve evidence-based medicine. Why can hepatologists in developed countries not do randomised trials for hepatocellular carcinoma to investigate the benefits and harms of screening, as gastroenterologists have done for colorectal cancer and urologists for prostate cancer? Recruitment is not an issue: hepatocellular carcinoma is the fifth most common cancer in the world. I declare that I have no conflicts of interest.
Alain Braillon [email protected] 27 rue Voiture, 80000 Amiens, France 1
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55.
www.thelancet.com Vol 380 August 4, 2012
4 5
Lederle FA, Pocha C. Screening for liver cancer: the rush to judgment. Ann Intern Med 2012; 156: 387–89. Braillon A. Screening for hepatocellular carcinoma: from lack of evidence to common sense. Hepatology 2010; 52: 1863–64. Braillon A. Surveillance for hepatocellular carcinoma. Ann Intern Med 2011; 155: 274–75. National Cancer Institute, US National Institutes of Health. Liver (hepatocellular) cancer screening (PDQ). http://www.cancer. gov/cancertopics/pdq/screening/ hepatocellular/HealthProfessional/page2 (accessed March 16, 2012).
The comprehensive Seminar by Alejandro Forner and colleagues1 shows that chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) and alcohol use are the main risk factors for hepatocellular carcinoma. However, several studies have shown a relatively high incidence of hepatocellular carcinoma in patients with membranous obstruction of the inferior vena cava (MOVC; table). Univariate analyses have confirmed that obstruction of the inferior vena cava is a significant predictor of hepatocellular carcinoma.2 Furthermore, Gwon and colleagues3 reported that the cumulative incidence of hepatocellular carcinoma at 1, 5, and 10 years from the initial diagnosis of MOVC was 7·3%, 13·5%, and 31·8%, respectively. The incidence of hepatocellular carcinoma in patients with MOVC seems to be similar to that in patients with HCVrelated cirrhosis (3–5% per year).1 Potential mechanisms of development of hepatocellular carcinoma in the context of MOVC have been discussed.2,4 Initially, hepatic venous hypertension and sinusoidal congestion caused by MOVC lead to centrolobular necrosis, regeneration, cirrhosis, and ultimately dysplastic hepatic nodules with malignant potential. Thus, an algorithm for the management of hepatic nodules and surveillance for hepatocellular carcinoma in these patients has been proposed.5 In conclusion, MOVC should not be neglected as a risk factor for hepatocellular carcinoma. Surveillance for hepatocellular carcinoma in patients
Country
Patients with Patients with MOVC MOVC and HCC
Gwon et al3
Korea
98
Moucari et al2
France
13*
Simson et al
South Africa
23 (23·5%) 9 (69·2%)
101
48 (47·5%) 2 (25·0%)
Rector et al
USA
8
Matsui et al4
Japan
12
3 (25·0%)
Dilawari et al
India
54
6 (11·1%)
Shrestha et al
Nepal
150*
7 (4·7%)
MOVC=membranous obstruction of the inferior vena cava. HCC=hepatocellular carcinoma. See appendix for unreferenced studies. *Inferior vena cava obstruction.
Table: Incidence of hepatocellular carcinoma in patients with membranous obstruction of the inferior vena cava
with MOVC should be recommended to improve these patients’ survival. We declare that we have no conflicts of interest.
See Online for appendix
Weirong Ren, Xingshun Qi, Jia Jia, Man Yang, *Guohong Han [email protected] Department of Liver Diseases and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, China 1 2
3
4
5
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Moucari R, Rautou PE, Cazals-Hatem D, et al. Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors. Gut 2008; 57: 828–35. Gwon D 2nd, Ko GY, Yoon HK, et al. Hepatocellular carcinoma associated with membranous obstruction of the inferior vena cava: incidence, characteristics, and risk factors and clinical efficacy of TACE. Radiology 2010; 254: 617–26. Matsui S, Ichida T, Watanabe M, et al. Clinical features and etiology of hepatocellular carcinoma arising in patients with membranous obstruction of the inferior vena cava: in reference to hepatitis viral infection. J Gastroenterol Hepatol 2000; 15: 1205–11. Plessier A, Rautou PE, Valla DC. Management of hepatic vascular diseases. J Hepatol 2012; 56: S25–38.
Alejandro Forner and colleagues1 provide an update of the available evidence for image-guided transcatheter treatment of hepatocellular carcinoma. They conclude that transarterial chemoembolisation is the only option that has shown survival benefit in hepatocellular carcinoma. Forner and colleagues state that, although radioembolisation with yttrium90-labelled (⁹⁰Y-labelled) spheres has much potential, a randomised controlled trial to define its role in
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
469
Correspondence
clinical practice is lacking. This latter statement is incorrect. ⁹⁰Y radioembolisation involves transarterial administration of minimally embolic microspheres loaded with the β-emitting isotope ⁹⁰Y, which deliver selective internal radiation to the tumour. ⁹⁰Y radioembolisation is increasingly used in clinical practice for treatment of hepatocellular carcinoma.2 The largest prospective study to date included 291 patients.3 Median survival for the 83 patients with intermediate-stage disease, as classified by the Barcelona Clinic Liver Cancer staging system, was 17·2 months (95% CI 13·5–29·6). This result is similar to that of transarterial chemoembolisation. Therefore we have started a multicentre randomised controlled trial (TRACE; ClinicalTrials.gov reference NCT01381211) in which patients with intermediate-stage hepatocellular carcinoma are randomly assigned to either ⁹⁰Y radioembolisation or transarterial chemoembolisation. 140 patients will be included. Structural follow-up for 2 years after treatment will be done with MRI every 3 months to assess tumour response. The primary outcome is time to progression, and secondary outcome variables are overall survival, tumour response, toxic effects and adverse events, quality of life, and cost-effectiveness. Recruitment of patients has now started in the first two European centres. We declare that we have no conflicts of interest. See Online for appendix
*Maurice A A J van den Bosch, Luc Defreyne [email protected] University Medical Center, 3584 CX Utrecht, Netherlands (MAAJvdB); and Ghent University Hospital, Ghent, Belgium (LD) 1 2
3
470
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Vente MA, Wondergem M, Van der Tweel I, et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol 2009; 19: 951–59. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010; 138: 52–64.
In their Seminar on hepatocellular carcinoma,1 Alejandro Forner and colleagues question the conclusions of our Cochrane systematic review.2 We could not identify evidence to show that transarterial (chemo)embolisation (TAE/TACE) has a beneficial effect on survival in patients with unresectable hepatocellular carcinoma. Using trial sequential analyses, we also showed that additional patients might be needed to reach firm evidence to accept or refute the superiority of TAE/TACE over no intervention.2 Our systematic review has substantial methodological advantages over earlier attempts to summarise TAE/TACE trials.3 These advantages include assessment of trial quality on the basis of empirical evidence, adequate statistics for time-toevent data (ie, hazard ratios), and trial sequential analyses.2 In Llovet and Bruix’s meta-analysis,3 assessments of trial quality were not based on empirical evidence. Furthermore, the two highlighted positive trials4,5 have methodological shortcomings, including a high risk of selection bias,5 risks associated with early stopping,4 and baseline imbalances.4 Accordingly, all positive conclusions1,3 have been based on a low number of events and few trials with low risk of bias. Forner and colleagues question our inclusion of several randomised trials and our choice of a 10% relative risk reduction. However, exclusion of such “ineligible” trials only reinforces our conclusions that we lack any support for TAE/TACE (appendix). Furthermore, the only intervention effect one can hope for is a more modest effect than a 10% relative risk reduction (appendix). We therefore continue to advocate for more efforts to investigate the benefits and harms of TACE through adequately powered and biasprotected trials. Such trials could give Forner and colleagues a needed reality check. RSO and JW declare that they have no conflicts of interest. CG is co-ordinating editor of The Cochrane Hepato-Biliary Group.
*Roberto S Oliveri, Jørn Wetterslev, Christian Gluud [email protected] Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research (RSO, JW, CG) and Department of Clinical Immunology (RSO), Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark 1 2
3
4
5
Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379: 1245–55. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2011; 3: CD004787. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429–42. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359: 1734–39. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164–71.
Authors’ reply In answer to Alain Braillon, we openly exposed the limited scientific evidence to support screening for hepatocellular carcinoma and commented on the challenges a controlled trial would face. An Australia survey1 showed that 99% of patients refused to enter a screening versus no screening trial. Even if up to 5% accepted, such a proportion would not be representative and results would be questioned by those wanting highlevel evidence. The bulk of available information suggests that screening is beneficial. Thus, having to select between not recommending screening because of an absence of proof and recommending screening because of expert critical analysis, all practice guidelines by scientific associations recommend screening patients at high enough risk of hepatocellular carcinoma, but only if treatment were possible if diagnosed.2,3 Weirong Ren and colleagues state that membranous obstruction of the inferior vena cava (MOVC) should be included in the risk factors. This rare entity has a higher prevalence in Asia www.thelancet.com Vol 380 August 4, 2012