The following article summary is provided by HealthDay News, abstract and discussion is available below or view the original report published in the Journal of Clinical Oncology.
Summary
Sorafenib Effect on HCC Survival Depends on Hepatitis Status
For patients with advanced unresectable hepatocellular carcinoma, the effect of sorafenib on overall survival is dependent on patients' hepatitis status, according to a meta-analysis published online Jan. 3 in the Journal of Clinical Oncology.
Richard Jackson, from the Liverpool Cancer Trials Unit in the United Kingdom, and colleagues undertook an individual patient data meta-analysis of three prospective randomized trials in which sorafenib was the control arm. Data were included for 1,643 patients with advanced unresectable hepatocellular carcinoma who received sorafenib.
The researchers found that patients who were both hepatitis B virus (HBV) negative and hepatitis C virus (HCV) positive had improved OS for sorafenib (log [hazard ratio], −0.27). In this subgroup, the median unadjusted survival was 12.6 and 10.2 months for sorafenib and other treatments, respectively. Other patient subgroups defined by HBV and HCV did not have improvement in OS. Consistent results were seen across all trials.
"There is consistent evidence that the effect of sorafenib on OS is dependent on patients' hepatitis status," the authors write. "There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib."
One author disclosed financial ties to the pharmaceutical industry; Bristol-Myers Squibb, Pfizer, and AbbVie gave access to data from studies in which they acted as sponsor.
Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials
The researchers found that patients who were both hepatitis B virus (HBV) negative and hepatitis C virus (HCV) positive had improved OS for sorafenib (log [hazard ratio], −0.27). In this subgroup, the median unadjusted survival was 12.6 and 10.2 months for sorafenib and other treatments, respectively. Other patient subgroups defined by HBV and HCV did not have improvement in OS. Consistent results were seen across all trials.
"There is consistent evidence that the effect of sorafenib on OS is dependent on patients' hepatitis status," the authors write. "There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib."
One author disclosed financial ties to the pharmaceutical industry; Bristol-Myers Squibb, Pfizer, and AbbVie gave access to data from studies in which they acted as sponsor.
Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials
Richard Jackson, Eftychia-Eirini Psarelli, Sarah Berhane, Harun Khan, and Philip Johnson
We have carried out an IPD meta-analysis of three phase III RCTs that demonstrates that the effect of sorafenib compared with other treatments for patients with aHCC cannot be considered independent of a patient’s HBV and HCV status. For patients who were HBV positive and HCV negative, there was no evidence of any positive effect on OS due to sorafenib, with the HR in this subgroup favoring the comparator, although this was not statistically significant. This patient group comprises 51% of all patients included in the analysis. There was, however, a significant positive effect of sorafenib in the group of patients who were HCV positive and HBV negative (n = 628; 22%). For all remaining patients, there was a trend supporting the use of sorafenib, but this was not statistically significant.
Our analysis extends the previous aggregate meta-analysis, which, although lacking the ability of IPD analyses to investigate treatment effects within patient subgroups, did involve additional trials to ours (the SHARP4 and Asia-Pacific region5 studies) and concluded that sorafenib might provide more survival benefits to patients positive for HCV. IPD meta-analyses are the gold standard and allow us to analyze trial data that may be more mature than the published results, ensure consistency of analytical techniques across the data sources, and further allow for the inspection of subgroup effects and treatment interactions, which would not be possible using an aggregate meta-analytical approach. Still, the results reported here represent secondary analyses of trial subgroup effects and the evidence provided is not as strong as a RCT, which specifically would look at the effect of sorafenib within each hepatitis subgroup.
The subgroup analysis of the SHARP trial showed that patients positive for HCV had a superior median OS of 14 months compared with 7.4 months in the placebo-treated group, and this benefit was also seen in terms of time to tumor progression (7.6 v 2.8 months) and disease control rate (44.2% v 29.6%).6 As noted by Bruix et al,6 the SHARP trial was not randomized relative to etiology and, therefore, the resulting subgroups were at risk for imbalance. Nonetheless, inspection of the data provided in this subgroup analysis shows that there were a significant number of patients within the HCV-positive subgroup (n = 167; 86 receiving sorafenib and 81 receiving placebo), and that the treated and the placebo groups were, in fact, well balanced with respect to region, age, sex, Child-Pugh class, macrovascular invasion/extrahepatic spread, ECOG PS, and disease stage. These observations, combined with the present detailed IPD meta-analysis and the previous aggregated meta-analysis, support the contention that the impact of sorafenib is largely confined to the patients who are HCV positive. Because the overall benefit of sorafenib in the SHARP study was only 2.8 months compared with placebo, and we found little significant overall effect of sorafenib in the analyses presented here, there is insufficient evidence to support the absolute benefit of sorafenib outside patients positive for HCV. We considered the possibility that ethnicity might be a confounding factor (because HCV and HBV are more prevalent in Western and Eastern populations, respectively), but our analysis did not support this contention. Treatment before trial entry, which may be less intense in Western (and, hence, HCV-positive) populations may also be a confounding factor, but we had insufficient data to exclude this possibility.
There is evidence of genetic diversity22-25 in HCC that can be linked to specific etiologic factors22,26 and may permit identification of specific targets for therapy. The reasons for differential response to sorafenib according to etiology remain unclear. Although some in vitro data have suggested that sorafenib inhibits HCV viral replication directly, this has not been borne out in the clinical setting.7,27 There is evidence of Wnt-pathway dysregulation in about 50% of HCC cases. Of the two major activating classes (CTNNB1 and Wnt-TGFβ), the former appears to be related to HCV infection and activity is modulated by sorafenib in a xenograft model.13,24,28 HCV has also been shown to upregulate C-RAF,29 a known sorafenib target, and Braconi et al30 have shown that HCV proteins can modulate the expression of microRNAs and thereby influence the sensitivity of HCC cells to sorafenib.
Irrespective of the mechanism, our data suggest that in future trials in aHCC, particularly where sorafenib is the control arm, there should be stratification according to etiology. Etiologic differences have already been considered as factors in the interpretation of clinical trials. In the trial of adjuvant sorafenib after surgical resection or local ablation (STORM), although the overall results of the trial were negative, there was a trend for longer time to recurrence in the HCV-related cases.31
Following a proposal from the International Committee of Medical Journal Editors32, it is likely that individual patient data will become accessible to investigators unrelated to the original trial. Thus, as a condition of consideration for publication, it is proposed that authors will be required to include a description of the data-sharing plan in the submitted manuscript. Although the editors considered that “sharing data will increase confidence and trust in the conclusions drawn from clinical trials,”32(p468) our study shows how the benefits of access to completed trial data are not necessarily confined to reanalysis of the original hypothesis tested by the trial. Here, by a meta-analysis, we arrive at an answer to a question that was not considered when the trials were conceived and could not have been answered by any of the trials individually. It also illustrates the clinical benefit arising when enlightened pharmaceutical companies are prepared to share their data with an academic unit, even when the primary question does not relate to their products.
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Abstract
Purpose
Following the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib has become the standard of care for patients with advanced unresectable hepatocellular carcinoma, but the relation between survival advantage and disease etiology remains unclear. To address this, we undertook an individual patient data meta-analysis of three large prospective randomized trials in which sorafenib was the control arm.
Methods
Of a total of 3,256 patients, 1,643 (50%) who received sorafenib were available. The primary end point was overall survival (OS). A Bayesian hierarchical approach for individual patient data meta-analyses was applied using a piecewise exponential model. Results are presented in terms of hazard ratios comparing sorafenib with alternative therapies according to hepatitis C virus (HCV) or hepatitis B virus (HBV) status.
Results
Hazard ratios show improved OS for sorafenib in patients who are both HBV negative and HCV positive (log [hazard ratio], −0.27; 95% CI, −0.46 to −0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2 (8.88 to 12.2) months for “other” treatments in this subgroup. There was no evidence of improvement in OS for any other patient subgroups defined by HBV and HCV. Results were consistent across all trials with heterogeneity assessed using Cochran’s Q statistic.
Conclusion
There is consistent evidence that the effect of sorafenib on OS is dependent on patients’ hepatitis status. There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib. There was no evidence of any improvement in OS attributable to sorafenib for patients positive for HBV and negative for HCV.
Following the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib has become the standard of care for patients with advanced unresectable hepatocellular carcinoma, but the relation between survival advantage and disease etiology remains unclear. To address this, we undertook an individual patient data meta-analysis of three large prospective randomized trials in which sorafenib was the control arm.
Methods
Of a total of 3,256 patients, 1,643 (50%) who received sorafenib were available. The primary end point was overall survival (OS). A Bayesian hierarchical approach for individual patient data meta-analyses was applied using a piecewise exponential model. Results are presented in terms of hazard ratios comparing sorafenib with alternative therapies according to hepatitis C virus (HCV) or hepatitis B virus (HBV) status.
Results
Hazard ratios show improved OS for sorafenib in patients who are both HBV negative and HCV positive (log [hazard ratio], −0.27; 95% CI, −0.46 to −0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2 (8.88 to 12.2) months for “other” treatments in this subgroup. There was no evidence of improvement in OS for any other patient subgroups defined by HBV and HCV. Results were consistent across all trials with heterogeneity assessed using Cochran’s Q statistic.
Conclusion
There is consistent evidence that the effect of sorafenib on OS is dependent on patients’ hepatitis status. There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib. There was no evidence of any improvement in OS attributable to sorafenib for patients positive for HBV and negative for HCV.
We have carried out an IPD meta-analysis of three phase III RCTs that demonstrates that the effect of sorafenib compared with other treatments for patients with aHCC cannot be considered independent of a patient’s HBV and HCV status. For patients who were HBV positive and HCV negative, there was no evidence of any positive effect on OS due to sorafenib, with the HR in this subgroup favoring the comparator, although this was not statistically significant. This patient group comprises 51% of all patients included in the analysis. There was, however, a significant positive effect of sorafenib in the group of patients who were HCV positive and HBV negative (n = 628; 22%). For all remaining patients, there was a trend supporting the use of sorafenib, but this was not statistically significant.
Our analysis extends the previous aggregate meta-analysis, which, although lacking the ability of IPD analyses to investigate treatment effects within patient subgroups, did involve additional trials to ours (the SHARP4 and Asia-Pacific region5 studies) and concluded that sorafenib might provide more survival benefits to patients positive for HCV. IPD meta-analyses are the gold standard and allow us to analyze trial data that may be more mature than the published results, ensure consistency of analytical techniques across the data sources, and further allow for the inspection of subgroup effects and treatment interactions, which would not be possible using an aggregate meta-analytical approach. Still, the results reported here represent secondary analyses of trial subgroup effects and the evidence provided is not as strong as a RCT, which specifically would look at the effect of sorafenib within each hepatitis subgroup.
The subgroup analysis of the SHARP trial showed that patients positive for HCV had a superior median OS of 14 months compared with 7.4 months in the placebo-treated group, and this benefit was also seen in terms of time to tumor progression (7.6 v 2.8 months) and disease control rate (44.2% v 29.6%).6 As noted by Bruix et al,6 the SHARP trial was not randomized relative to etiology and, therefore, the resulting subgroups were at risk for imbalance. Nonetheless, inspection of the data provided in this subgroup analysis shows that there were a significant number of patients within the HCV-positive subgroup (n = 167; 86 receiving sorafenib and 81 receiving placebo), and that the treated and the placebo groups were, in fact, well balanced with respect to region, age, sex, Child-Pugh class, macrovascular invasion/extrahepatic spread, ECOG PS, and disease stage. These observations, combined with the present detailed IPD meta-analysis and the previous aggregated meta-analysis, support the contention that the impact of sorafenib is largely confined to the patients who are HCV positive. Because the overall benefit of sorafenib in the SHARP study was only 2.8 months compared with placebo, and we found little significant overall effect of sorafenib in the analyses presented here, there is insufficient evidence to support the absolute benefit of sorafenib outside patients positive for HCV. We considered the possibility that ethnicity might be a confounding factor (because HCV and HBV are more prevalent in Western and Eastern populations, respectively), but our analysis did not support this contention. Treatment before trial entry, which may be less intense in Western (and, hence, HCV-positive) populations may also be a confounding factor, but we had insufficient data to exclude this possibility.
There is evidence of genetic diversity22-25 in HCC that can be linked to specific etiologic factors22,26 and may permit identification of specific targets for therapy. The reasons for differential response to sorafenib according to etiology remain unclear. Although some in vitro data have suggested that sorafenib inhibits HCV viral replication directly, this has not been borne out in the clinical setting.7,27 There is evidence of Wnt-pathway dysregulation in about 50% of HCC cases. Of the two major activating classes (CTNNB1 and Wnt-TGFβ), the former appears to be related to HCV infection and activity is modulated by sorafenib in a xenograft model.13,24,28 HCV has also been shown to upregulate C-RAF,29 a known sorafenib target, and Braconi et al30 have shown that HCV proteins can modulate the expression of microRNAs and thereby influence the sensitivity of HCC cells to sorafenib.
Irrespective of the mechanism, our data suggest that in future trials in aHCC, particularly where sorafenib is the control arm, there should be stratification according to etiology. Etiologic differences have already been considered as factors in the interpretation of clinical trials. In the trial of adjuvant sorafenib after surgical resection or local ablation (STORM), although the overall results of the trial were negative, there was a trend for longer time to recurrence in the HCV-related cases.31
Following a proposal from the International Committee of Medical Journal Editors32, it is likely that individual patient data will become accessible to investigators unrelated to the original trial. Thus, as a condition of consideration for publication, it is proposed that authors will be required to include a description of the data-sharing plan in the submitted manuscript. Although the editors considered that “sharing data will increase confidence and trust in the conclusions drawn from clinical trials,”32(p468) our study shows how the benefits of access to completed trial data are not necessarily confined to reanalysis of the original hypothesis tested by the trial. Here, by a meta-analysis, we arrive at an answer to a question that was not considered when the trials were conceived and could not have been answered by any of the trials individually. It also illustrates the clinical benefit arising when enlightened pharmaceutical companies are prepared to share their data with an academic unit, even when the primary question does not relate to their products.
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