- Email: [email protected]
Hepatocellular carcinoma recurrence after direct antiviral agent treatment: A European multicentre study
Accepted Manuscript Letter to the Editor Hepatocellular Carcinoma Recurrence after Direct Antiviral Agent Treatment: a European Multicentre Study Philippe Kolly, Oliver Waidmann, Johannes Vermehren, Christophe Moreno, Isabelle Voegeli, Thomas Berg, David Semela, Stefan Zeuzem, Jean-François Dufour PII: DOI: Reference:
S0168-8278(17)32150-5 http://dx.doi.org/10.1016/j.jhep.2017.07.007 JHEPAT 6598
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
21 March 2017 5 July 2017 6 July 2017
Please cite this article as: Kolly, P., Waidmann, O., Vermehren, J., Moreno, C., Voegeli, I., Berg, T., Semela, D., Zeuzem, S., Dufour, J-F., Hepatocellular Carcinoma Recurrence after Direct Antiviral Agent Treatment: a European Multicentre Study, Journal of Hepatology (2017), doi: http://dx.doi.org/10.1016/j.jhep.2017.07.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hepatocellular Carcinoma Recurrence after Direct Antiviral Agent Treatment: a European Multicentre Study Philippe Kolly1,2, Oliver Waidmann3, Johannes Vermehren3, Christophe Moreno4, Isabelle Voegeli1, Thomas Berg5, David Semela6, Stefan Zeuzem3, Jean-François Dufour1,2
1
Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland 2
University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
3
Department of Medicine I, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt am Main, Germany
4
Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Brussels 5
Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of
Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany 6
Division of Gastroenterology and Hepatology, Cantonal Hospital St Gallen, St Gallen, Switzerland
Corresponding author Prof. Jean-François Dufour, M.D. University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland Phone: +41 31 632 26 95 Fax: +41 31 632 97 65 E-mail: [email protected]
Conflicts of interest PK: Travel/congress cost support: Gilead OW: Grant: Medac; Consultant: Bayer, Celgene, Merck Serono, Novartis Oncology, Roche; Travel/congress cost support: Abbvie, Bayer, Celgene, Gilead, Ipsen, Medac, Merck Serono, Novartis Oncology, Teva JV: Sponsored lectures: Abbott, Abbvie, BMS, Gilead, Medtronic, Roche CM: Consulting: Abbvie, BMS, Gilead, Janssen, Merck, Intercept; Research grant: Abbvie, BMS, Gilead, Janssen, Roche, Astellas IV: None. TB: Grant: Abbvie, Roche, BMS, Gilead, Novartis, Merck/MSD, Janssen; Consultant: Abbvie, Alexion, Bayer, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, MSD/Merck, Novartis, Roche, Vertex DS: Consultant: Abbvie, Bayer, BMS, Gilead Science, Intercept, Merck; Sponsored lectures: Abbvie, Bayer, Gilead Science SZ: Consultant: Abbvie, BMS, Gilead, Janssen, Merck/MSD JFD: Advisory committees: Abbvie, Bayer, BMS, Genfit, Gilead Science, Intercept, Merck, Novartis, SillaJen; Speaking and teaching: Abbvie, Bayer, Gilead Science; Unrestricted research grant: Bayer Keywords HCC; recurrence; DAA; HCV; recurrence; multicentric
Financial support This work was partly supported by a Swiss National Foundation grant to the Swiss Hepatitis C Cohort Study and by the Swiss Foundation against Liver Cancer.
Authors’ contribution PK: study concept and design; acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analysis. OW: study concept and design, acquisition of data, critical revision of the manuscript. JV: study concept and design,
acquisition of data, critical revision of the manuscript. CM: acquisition of data, critical revision of the manuscript. IV: acquisition of data, critical revision of the manuscript. TB: acquisition of data, critical revision of the manuscript. DS: acquisition of the data, critical revision of the content, final approval. SZ: study concept and design, acquisition of data, critical revision of the manuscript. JFD: study concept and design, acquisition of data, critical revision of the manuscript, study supervision.
To the Editor: The introduction of direct antiviral drugs (DAAs) has revolutionized the treatment of hepatitis C virus (HCV), with sustained virologic response rates of more than 90% in most patient populations.1 However, it has been suggested that interferon-free HCV eradication may be more harmful than beneficial in a subgroup of patients. In patients with prior curative hepatocellular carcinoma (HCC) therapy, an increased tumor recurrence rate following DAA-based HCV therapy has been reported.2,3 In a Spanish multicentre study by Reig and co-workers 2, 16/58 (27.6%) patients with previously treated HCC who had received DAA treatment for hepatitis C experienced tumour recurrence, after a median follow-up of 5.7 months. In this study, patients with a short time between HCC treatment and DAA therapy (<4 months) seemed to be particularly at risk, with a recurrence rate of 41.2%. Torres et al.4 raised several methodological concerns in response to this study and published their own data from a prospective observational study of eight patients, with a median follow-up period of 12 months, which showed no HCC recurrence in any of their patients. However, in an Italian single-centre cohort, a similarly high recurrence rate of 28.8% (n=17/59 patients) at 24 weeks after DAA therapy was reported. In this study, recurrence was associated with younger age and more severe liver fibrosis.3 Based on 31 patients, Zavaglia et al.5 reported a recurrence rate of 3.1% with a median follow-up of 8 months. The authors of this study suggested that the longer time interval between HCC treatment and DAA therapy (median 19.3 months) could explain this lower recurrence rate. Using three different prospective cohorts of patients previously treated with curative therapies (including liver transplantation) for HCC, Pol reported no difference in recurrence rates between patients treated with DAAs and those who were not.6 However, this paper was criticized for methodological bias.7
Comparing 57 patients treated with interferon-based therapies and 58 patients treated with DAAs after successful treatment of their HCC, Petta et al. found recurrence rates of 3.7% and 5.2% at 6 months, and 15.2% and 26.3% at 2 years, respectively; these differences were not statistically significant.8 Several hypotheses for a possible higher recurrence rates following DAA treatment have been suggested, one of which is that the activation of regeneration mechanisms through cure of inflammation could lead to growth of precancerous lesions.9 Another hypothesis involves the liver-specific microRNA 122, which reduces tumorigenesis, angiogenesis and intrahepatic metastasis,10 and is downregulated by DAA therapy.11
The aim of this international, multicentre cohort study was to explore the incidence of HCC recurrence after DAA therapy in patients who had been previously treated for HCC. Patients were treated in five different centres in Europe: University Hospital Frankfurt, Germany; Inselspital Bern, Switzerland; Erasme Hospital Brussels, Belgium; University Hospital Leipzig, Germany; and Cantonal Hospital St Gallen, Switzerland. Patients had to meet the following criteria to be included: 1) HCC diagnosed according to the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines,12,13 by either radiological assessment or pathology; 2) Barcelona Clinic Liver Cancer (BCLC) stage 0, A or B; 3) HCC treated prior to DAA therapy with surgical resection, ablation or transarterial (chemo-)embolization (TACE/TAE); patients who had received a liver transplant were excluded; 4) radiological complete response before starting DAA treatment; 5) treatment with DAAs; and 6) radiological assessment after DAA therapy.
Cumulative disease-free survival rates were calculated by the Kaplan–Meier method using two different time frames: 1) time from HCC treatment to time of first radiological assessment showing a recurrence or last radiological assessment showing no recurrence; 2) time from start of DAA therapy to time of first radiological assessment showing a recurrence or last radiological assessment showing no recurrence. Cox proportional hazard regressions were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Recurrence rates were compared between groups of patients using Pearson’s chi-squared test. The local ethics committee of each centre approved the protocol. All analyses were conducted using R version 3.3.2.14 A p value of less than 0.05 was considered to be statistically significant. A total of 79 nonconsecutive patients met all inclusion criteria. 11 patients were excluded due to incomplete data. 12 patients were excluded because the time-frame between HCC treatment and last radiological assessment before the therapy with DAA was considered too short (< 30 days). 8 patients were excluded because they had previous recurrence before DAA treatment, despite showing complete radiological response at the moment of starting DAA. 1 patient treated with a combination of pegylated interferon was excluded. A total of 47 were retained for the study. Demographic and clinical characteristics are summarized in Supplementary Table 1. Seventy-six percent of patients were men and the median (range) age was 60 (48–78) years. Most patients were cirrhotic (85.1%), of whom 80.0% were classified Child–Pugh A. Most patients were BCLC stage A (82.6%). More than 95% of patients had received a DAA combination including sofosbuvir. The mean followup times were 21.5 months after HCC treatment and 9.6 months after DAA therapy.
HCC cumulative disease-free rates were 96%, 81% and 58% at 6, 12 and 24 months, respectively, after HCC treatment, and 77% and 58% at 6 and 12 months, respectively, after DAA therapy (Figure 1). There was no statistically significant difference in recurrence rate between the resection (35.3%), ablation (52.4%) and TACE/TAE (33.3%) groups (p = 0.470). Anti-HBc positive serology (p = 0.321), hepatitis C genotype (p = 0.954) and Child–Pugh score (p = 0.432) showed no timedependent association with HCC recurrence after HCC treatment. In patients with a longer time frame between HCC treatment and DAA treatment were at a reduced risk of HCC recurrence (HR 0.894, 95% CI 0.827–0.965, p = 0.004). Age was also linked with a reduced risk of HCC recurrence (HR 0.933, 95% CI 0.871–0.999 , p = 0.048).
In this study we found a HCC disease-free survival rate of 77% at 6 months after HCV therapy. This is in line with the findings reported by Reig et al.2 and Conti et al.3 When taking HCC treatment as the starting point of the survival analysis, diseasefree survival rates of 96%, 81%, and 58% were observed at 6, 12 and 24 months, respectively. Recently, Cabibbo et al. published a meta-analysis of 11 studies evaluating the HCC recurrences in HCV-untreated patients 15. Patients in the retained studies for this meta-analysis had an early HCC and a complete response after surgical resection or ablation, as the patients in our study. The meta-analysis obtained recurrence actuarial probability of 7.4%, 20% and 47% at 6 months, 1 year and 2 years, respectively. In our cohort, patients did not show higher recurrence rates than those reported in this meta-analysis. Thus, we hypothesize that the high rates of HCC recurrence reported shortly after DAA therapy, which was also found in our study when the starting point of the analysis was DAA therapy, may be explained by selection bias with regard to inclusion criteria and individual disease history.
In this study, the time between HCC treatment and the start of DAA therapy was a significant time-dependent predictor for recurrence. Based on our data, we cannot conclude whether this effect is linked to the DAA therapy or whether it is due to satellite tumour cells that are not identified by radiologic imaging before the start of HCV therapy. However, early tumour recurrence shortly after HCC resection has also been reported previously.16 The inclusion of patients treated with TACE/TAE has been criticized in the past because of the palliative treatment intention. However, in the study by Reig and coworkers, none of the patients treated by TACE/TAE showed early HCC recurrence2. Therefore, we specifically included patients who underwent TACE/TAE to keep the inclusion criteria in line with these previous studies. Interestingly, our data also showed not higher recurrence rates in this specific subpopulation. There is a continuing debate on the methodology of the studies reporting HCC recurrence after DAA therapy, as all of these studies included only few patients, had short observation periods, and lacked a proper comparison arm. To avoid selection bias, we believe that it is important to consider the optimal starting point of the survival analysis. There is still a strong need for randomized controlled trials on this subject, in particular to establish whether patients should wait a certain minimum amount of time before DAA treatment is started.
REFERENCES 1. Pawlotsky, J.-M. New Hepatitis C Therapies: The Toolbox, Strategies, and Challenges. Gastroenterology 146, 1176–1192 (2014). 2. Reig, M. et al. Unexpected high rate of early tumor recurrence in patients with HCVrelated HCC undergoing interferon-free therapy. J. Hepatol. 65, 719–726 (2016). 3. Conti, F. et al. Early occurrence and recurrence of hepatocellular carcinoma in HCVrelated cirrhosis treated with direct-acting antivirals. J. Hepatol. 65, 727–733 (2016). 4. Torres, H. A., Vauthey, J.-N., Economides, M. P., Mahale, P. & Kaseb, A. Hepatocellular carcinoma recurrence after treatment with direct-acting antivirals: First, do no harm by withdrawing treatment. J. Hepatol. 65, 862–864 (2016). 5. Zavaglia, C. et al. Is the risk of neoplastic recurrence increased after prescribing directacting antivirals for HCV patients whose HCC was previously cured? J. Hepatol. 66, 236– 237 (2017). 6. Pol, S. Lack of evidence of an effect of Direct Acting Antivirals on the recurrence of hepatocellular carcinoma. J. Hepatol. (2016). 7. Kolly, P. & Dufour, J.-F. A strong message is needed to address the issue of HCC recurrence after DAA therapy. J. Hepatol. 65, 1268–1269 (2016). 8. Petta, S. et al. Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon. Aliment. Pharmacol. Ther. 45, 160–168 (2017). 9. Kozbial, K. et al. Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment. J. Hepatol. 65, 856–858 (2016). 10.
Tsai, W.-C. et al. MicroRNA-122, a tumor suppressor microRNA that regulates
intrahepatic metastasis of hepatocellular carcinoma. Hepatology 49, 1571–1582 (2009).
11.
Waring, J. F. et al. Serum miR-122 may serve as a biomarker for response to direct
acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR-122 in HCV-infected subjects. J. Viral Hepat. 23, 96–104 (2016). 12.
Bruix, J. & Sherman, M. Management of hepatocellular carcinoma: an update.
Hepatology 53, 1020–1022 (2011). 13.
EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma.
J. Hepatol. 56, 908–943 (2012). 14.
R Core Team. R: A language and environment for statistical computing. (R
Foundation for Statistical Computing, 2016). 15.
Cabibbo, G. et al. A meta-analysis of single HCV-untreated arm of studies evaluating
outcomes after curative treatments of HCV-related hepatocellular carcinoma. Liver Int. (2017). 16.
Imamura, H. et al. Risk factors contributing to early and late phase intrahepatic
recurrence of hepatocellular carcinoma after hepatectomy. J. Hepatol. 38, 200–207 (2003).
FIGURE LEGEND Figure 1. Disease-free survival curves of patients treated with DAAs after potentially curative HCC treatment. Left, disease-free survival curve with HCC treatment as the starting point showing disease-free rates of 96%, 81% and 58% at 6, 12 and 24 months, respectively. Right, disease-free survival curve with the start of DAA therapy as the starting point showing disease-free rates of 77% and 58% at 6 and 12 months, respectively.
Table 1. Demographic and clinical characteristics of the patients.
Total n = 47 Age, years, median (range)
60 (48–78)
Sex Male
36 (76.6)
Female
11 (23.4)
1
40 (85.1)
Cirrhosis
Child–Pugh A
32 (80.0)
B
8 (20.0) 2
Anti-HBc positive
20 (50.0)
HCV genotype 1
25 (53.2)
2
4 (8.5)
3
15 (31.9)
4
3 (6.4) 2
BCLC 0
4 (8.7)
A
38 (82.6)
B
4 (8.7)
Treatment Resection
17 (36.2)
Ablation
21 (44.7)
TACE/TAE
9 (19.1) 3
Alcohol consumption
3 (9.1)
Diabetes mellitus
7 (18.4)
DAA combination SOF-LDV
9 (19.1)
SOF-RBV
8 (17.0)
SOF-DAC
7 (14.9)
SOF-SMV
6 (12.8)
SOF-DAC-RBV
9 (19.1)
SOF-LDV-RBV
4 (8.5)
SOF-SMV-RBV
2 (4.3)
Other
2 (4.3)
Data are presented as n (%) of patients unless otherwise stated 1
Child–Pugh score was calculated in cirrhotic patients only
2
Value is missing for some patients (7 for anti-HBc and 1 for BCLC)
3
More than 30 g/day for men, 20 g/day for women
Anti-HBc, hepatitis B core antibodies; HCV, hepatitis C virus; BCLC, Barcelona Clinic Liver Cancer; DAA, direct antiviral agent; SOF, sofosbuvir; LDV, ledipasvir; DAC, daclatasvir; RBV, ribavirin; SMV, simeprevir;
S0168-8278(17)32150-5 http://dx.doi.org/10.1016/j.jhep.2017.07.007 JHEPAT 6598
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
21 March 2017 5 July 2017 6 July 2017
Please cite this article as: Kolly, P., Waidmann, O., Vermehren, J., Moreno, C., Voegeli, I., Berg, T., Semela, D., Zeuzem, S., Dufour, J-F., Hepatocellular Carcinoma Recurrence after Direct Antiviral Agent Treatment: a European Multicentre Study, Journal of Hepatology (2017), doi: http://dx.doi.org/10.1016/j.jhep.2017.07.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hepatocellular Carcinoma Recurrence after Direct Antiviral Agent Treatment: a European Multicentre Study Philippe Kolly1,2, Oliver Waidmann3, Johannes Vermehren3, Christophe Moreno4, Isabelle Voegeli1, Thomas Berg5, David Semela6, Stefan Zeuzem3, Jean-François Dufour1,2
1
Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland 2
University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
3
Department of Medicine I, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt am Main, Germany
4
Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Brussels 5
Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of
Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany 6
Division of Gastroenterology and Hepatology, Cantonal Hospital St Gallen, St Gallen, Switzerland
Corresponding author Prof. Jean-François Dufour, M.D. University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland Phone: +41 31 632 26 95 Fax: +41 31 632 97 65 E-mail: [email protected]
Conflicts of interest PK: Travel/congress cost support: Gilead OW: Grant: Medac; Consultant: Bayer, Celgene, Merck Serono, Novartis Oncology, Roche; Travel/congress cost support: Abbvie, Bayer, Celgene, Gilead, Ipsen, Medac, Merck Serono, Novartis Oncology, Teva JV: Sponsored lectures: Abbott, Abbvie, BMS, Gilead, Medtronic, Roche CM: Consulting: Abbvie, BMS, Gilead, Janssen, Merck, Intercept; Research grant: Abbvie, BMS, Gilead, Janssen, Roche, Astellas IV: None. TB: Grant: Abbvie, Roche, BMS, Gilead, Novartis, Merck/MSD, Janssen; Consultant: Abbvie, Alexion, Bayer, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, MSD/Merck, Novartis, Roche, Vertex DS: Consultant: Abbvie, Bayer, BMS, Gilead Science, Intercept, Merck; Sponsored lectures: Abbvie, Bayer, Gilead Science SZ: Consultant: Abbvie, BMS, Gilead, Janssen, Merck/MSD JFD: Advisory committees: Abbvie, Bayer, BMS, Genfit, Gilead Science, Intercept, Merck, Novartis, SillaJen; Speaking and teaching: Abbvie, Bayer, Gilead Science; Unrestricted research grant: Bayer Keywords HCC; recurrence; DAA; HCV; recurrence; multicentric
Financial support This work was partly supported by a Swiss National Foundation grant to the Swiss Hepatitis C Cohort Study and by the Swiss Foundation against Liver Cancer.
Authors’ contribution PK: study concept and design; acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analysis. OW: study concept and design, acquisition of data, critical revision of the manuscript. JV: study concept and design,
acquisition of data, critical revision of the manuscript. CM: acquisition of data, critical revision of the manuscript. IV: acquisition of data, critical revision of the manuscript. TB: acquisition of data, critical revision of the manuscript. DS: acquisition of the data, critical revision of the content, final approval. SZ: study concept and design, acquisition of data, critical revision of the manuscript. JFD: study concept and design, acquisition of data, critical revision of the manuscript, study supervision.
To the Editor: The introduction of direct antiviral drugs (DAAs) has revolutionized the treatment of hepatitis C virus (HCV), with sustained virologic response rates of more than 90% in most patient populations.1 However, it has been suggested that interferon-free HCV eradication may be more harmful than beneficial in a subgroup of patients. In patients with prior curative hepatocellular carcinoma (HCC) therapy, an increased tumor recurrence rate following DAA-based HCV therapy has been reported.2,3 In a Spanish multicentre study by Reig and co-workers 2, 16/58 (27.6%) patients with previously treated HCC who had received DAA treatment for hepatitis C experienced tumour recurrence, after a median follow-up of 5.7 months. In this study, patients with a short time between HCC treatment and DAA therapy (<4 months) seemed to be particularly at risk, with a recurrence rate of 41.2%. Torres et al.4 raised several methodological concerns in response to this study and published their own data from a prospective observational study of eight patients, with a median follow-up period of 12 months, which showed no HCC recurrence in any of their patients. However, in an Italian single-centre cohort, a similarly high recurrence rate of 28.8% (n=17/59 patients) at 24 weeks after DAA therapy was reported. In this study, recurrence was associated with younger age and more severe liver fibrosis.3 Based on 31 patients, Zavaglia et al.5 reported a recurrence rate of 3.1% with a median follow-up of 8 months. The authors of this study suggested that the longer time interval between HCC treatment and DAA therapy (median 19.3 months) could explain this lower recurrence rate. Using three different prospective cohorts of patients previously treated with curative therapies (including liver transplantation) for HCC, Pol reported no difference in recurrence rates between patients treated with DAAs and those who were not.6 However, this paper was criticized for methodological bias.7
Comparing 57 patients treated with interferon-based therapies and 58 patients treated with DAAs after successful treatment of their HCC, Petta et al. found recurrence rates of 3.7% and 5.2% at 6 months, and 15.2% and 26.3% at 2 years, respectively; these differences were not statistically significant.8 Several hypotheses for a possible higher recurrence rates following DAA treatment have been suggested, one of which is that the activation of regeneration mechanisms through cure of inflammation could lead to growth of precancerous lesions.9 Another hypothesis involves the liver-specific microRNA 122, which reduces tumorigenesis, angiogenesis and intrahepatic metastasis,10 and is downregulated by DAA therapy.11
The aim of this international, multicentre cohort study was to explore the incidence of HCC recurrence after DAA therapy in patients who had been previously treated for HCC. Patients were treated in five different centres in Europe: University Hospital Frankfurt, Germany; Inselspital Bern, Switzerland; Erasme Hospital Brussels, Belgium; University Hospital Leipzig, Germany; and Cantonal Hospital St Gallen, Switzerland. Patients had to meet the following criteria to be included: 1) HCC diagnosed according to the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines,12,13 by either radiological assessment or pathology; 2) Barcelona Clinic Liver Cancer (BCLC) stage 0, A or B; 3) HCC treated prior to DAA therapy with surgical resection, ablation or transarterial (chemo-)embolization (TACE/TAE); patients who had received a liver transplant were excluded; 4) radiological complete response before starting DAA treatment; 5) treatment with DAAs; and 6) radiological assessment after DAA therapy.
Cumulative disease-free survival rates were calculated by the Kaplan–Meier method using two different time frames: 1) time from HCC treatment to time of first radiological assessment showing a recurrence or last radiological assessment showing no recurrence; 2) time from start of DAA therapy to time of first radiological assessment showing a recurrence or last radiological assessment showing no recurrence. Cox proportional hazard regressions were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Recurrence rates were compared between groups of patients using Pearson’s chi-squared test. The local ethics committee of each centre approved the protocol. All analyses were conducted using R version 3.3.2.14 A p value of less than 0.05 was considered to be statistically significant. A total of 79 nonconsecutive patients met all inclusion criteria. 11 patients were excluded due to incomplete data. 12 patients were excluded because the time-frame between HCC treatment and last radiological assessment before the therapy with DAA was considered too short (< 30 days). 8 patients were excluded because they had previous recurrence before DAA treatment, despite showing complete radiological response at the moment of starting DAA. 1 patient treated with a combination of pegylated interferon was excluded. A total of 47 were retained for the study. Demographic and clinical characteristics are summarized in Supplementary Table 1. Seventy-six percent of patients were men and the median (range) age was 60 (48–78) years. Most patients were cirrhotic (85.1%), of whom 80.0% were classified Child–Pugh A. Most patients were BCLC stage A (82.6%). More than 95% of patients had received a DAA combination including sofosbuvir. The mean followup times were 21.5 months after HCC treatment and 9.6 months after DAA therapy.
HCC cumulative disease-free rates were 96%, 81% and 58% at 6, 12 and 24 months, respectively, after HCC treatment, and 77% and 58% at 6 and 12 months, respectively, after DAA therapy (Figure 1). There was no statistically significant difference in recurrence rate between the resection (35.3%), ablation (52.4%) and TACE/TAE (33.3%) groups (p = 0.470). Anti-HBc positive serology (p = 0.321), hepatitis C genotype (p = 0.954) and Child–Pugh score (p = 0.432) showed no timedependent association with HCC recurrence after HCC treatment. In patients with a longer time frame between HCC treatment and DAA treatment were at a reduced risk of HCC recurrence (HR 0.894, 95% CI 0.827–0.965, p = 0.004). Age was also linked with a reduced risk of HCC recurrence (HR 0.933, 95% CI 0.871–0.999 , p = 0.048).
In this study we found a HCC disease-free survival rate of 77% at 6 months after HCV therapy. This is in line with the findings reported by Reig et al.2 and Conti et al.3 When taking HCC treatment as the starting point of the survival analysis, diseasefree survival rates of 96%, 81%, and 58% were observed at 6, 12 and 24 months, respectively. Recently, Cabibbo et al. published a meta-analysis of 11 studies evaluating the HCC recurrences in HCV-untreated patients 15. Patients in the retained studies for this meta-analysis had an early HCC and a complete response after surgical resection or ablation, as the patients in our study. The meta-analysis obtained recurrence actuarial probability of 7.4%, 20% and 47% at 6 months, 1 year and 2 years, respectively. In our cohort, patients did not show higher recurrence rates than those reported in this meta-analysis. Thus, we hypothesize that the high rates of HCC recurrence reported shortly after DAA therapy, which was also found in our study when the starting point of the analysis was DAA therapy, may be explained by selection bias with regard to inclusion criteria and individual disease history.
In this study, the time between HCC treatment and the start of DAA therapy was a significant time-dependent predictor for recurrence. Based on our data, we cannot conclude whether this effect is linked to the DAA therapy or whether it is due to satellite tumour cells that are not identified by radiologic imaging before the start of HCV therapy. However, early tumour recurrence shortly after HCC resection has also been reported previously.16 The inclusion of patients treated with TACE/TAE has been criticized in the past because of the palliative treatment intention. However, in the study by Reig and coworkers, none of the patients treated by TACE/TAE showed early HCC recurrence2. Therefore, we specifically included patients who underwent TACE/TAE to keep the inclusion criteria in line with these previous studies. Interestingly, our data also showed not higher recurrence rates in this specific subpopulation. There is a continuing debate on the methodology of the studies reporting HCC recurrence after DAA therapy, as all of these studies included only few patients, had short observation periods, and lacked a proper comparison arm. To avoid selection bias, we believe that it is important to consider the optimal starting point of the survival analysis. There is still a strong need for randomized controlled trials on this subject, in particular to establish whether patients should wait a certain minimum amount of time before DAA treatment is started.
REFERENCES 1. Pawlotsky, J.-M. New Hepatitis C Therapies: The Toolbox, Strategies, and Challenges. Gastroenterology 146, 1176–1192 (2014). 2. Reig, M. et al. Unexpected high rate of early tumor recurrence in patients with HCVrelated HCC undergoing interferon-free therapy. J. Hepatol. 65, 719–726 (2016). 3. Conti, F. et al. Early occurrence and recurrence of hepatocellular carcinoma in HCVrelated cirrhosis treated with direct-acting antivirals. J. Hepatol. 65, 727–733 (2016). 4. Torres, H. A., Vauthey, J.-N., Economides, M. P., Mahale, P. & Kaseb, A. Hepatocellular carcinoma recurrence after treatment with direct-acting antivirals: First, do no harm by withdrawing treatment. J. Hepatol. 65, 862–864 (2016). 5. Zavaglia, C. et al. Is the risk of neoplastic recurrence increased after prescribing directacting antivirals for HCV patients whose HCC was previously cured? J. Hepatol. 66, 236– 237 (2017). 6. Pol, S. Lack of evidence of an effect of Direct Acting Antivirals on the recurrence of hepatocellular carcinoma. J. Hepatol. (2016). 7. Kolly, P. & Dufour, J.-F. A strong message is needed to address the issue of HCC recurrence after DAA therapy. J. Hepatol. 65, 1268–1269 (2016). 8. Petta, S. et al. Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon. Aliment. Pharmacol. Ther. 45, 160–168 (2017). 9. Kozbial, K. et al. Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment. J. Hepatol. 65, 856–858 (2016). 10.
Tsai, W.-C. et al. MicroRNA-122, a tumor suppressor microRNA that regulates
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FIGURE LEGEND Figure 1. Disease-free survival curves of patients treated with DAAs after potentially curative HCC treatment. Left, disease-free survival curve with HCC treatment as the starting point showing disease-free rates of 96%, 81% and 58% at 6, 12 and 24 months, respectively. Right, disease-free survival curve with the start of DAA therapy as the starting point showing disease-free rates of 77% and 58% at 6 and 12 months, respectively.
Table 1. Demographic and clinical characteristics of the patients.
Total n = 47 Age, years, median (range)
60 (48–78)
Sex Male
36 (76.6)
Female
11 (23.4)
1
40 (85.1)
Cirrhosis
Child–Pugh A
32 (80.0)
B
8 (20.0) 2
Anti-HBc positive
20 (50.0)
HCV genotype 1
25 (53.2)
2
4 (8.5)
3
15 (31.9)
4
3 (6.4) 2
BCLC 0
4 (8.7)
A
38 (82.6)
B
4 (8.7)
Treatment Resection
17 (36.2)
Ablation
21 (44.7)
TACE/TAE
9 (19.1) 3
Alcohol consumption
3 (9.1)
Diabetes mellitus
7 (18.4)
DAA combination SOF-LDV
9 (19.1)
SOF-RBV
8 (17.0)
SOF-DAC
7 (14.9)
SOF-SMV
6 (12.8)
SOF-DAC-RBV
9 (19.1)
SOF-LDV-RBV
4 (8.5)
SOF-SMV-RBV
2 (4.3)
Other
2 (4.3)
Data are presented as n (%) of patients unless otherwise stated 1
Child–Pugh score was calculated in cirrhotic patients only
2
Value is missing for some patients (7 for anti-HBc and 1 for BCLC)
3
More than 30 g/day for men, 20 g/day for women
Anti-HBc, hepatitis B core antibodies; HCV, hepatitis C virus; BCLC, Barcelona Clinic Liver Cancer; DAA, direct antiviral agent; SOF, sofosbuvir; LDV, ledipasvir; DAC, daclatasvir; RBV, ribavirin; SMV, simeprevir;