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Llovet JP, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390. (Reprinted with permission from the Massachusetts Medical Society)

Abstract

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  2. Abstract
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Background: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results: At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P < 0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P < 0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443 http://clinicaltrials.gov.)

Comment

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Effective treatment for hepatocellular carcinoma (HCC) is desperately needed because it is a deadly disease whose worldwide annual incidence matches its prevalence and is the fifth leading cause of cancer death worldwide.1 The mainstay of management of HCC is early diagnosis with the hope of applying curative therapy. It is estimated that with the application of current surveillance modalities, 30%-40% of cases could be diagnosed early enough for curative treatments.2

Given the limited efficacy of adjuvant and palliative treatment options to date, there has been an extensive effort to identify other agents useful for the management of HCC. Systemic chemotherapy has largely been disappointing in terms of palliation or cure. Cytotoxic chemotherapy has been shown to provide no survival benefit possibly due to study design with inadequate endpoints to determine efficacy and/or intrinsic or acquired tumor resistance.3 The cytotoxic agent that has been the most investigated is doxorubicin (adriamycin). A systematic review published in 1997 found only 10 randomized clinical trials evaluating chemotherapy for HCC, nine of which involved doxorubicin.4 The only study that compared doxorubicin to no treatment showed no benefit.4 In the other studies, doxorubicin was not shown to be better than any of the other agents tested with the exception of 5-fluorouracil monotherapy, which showed an improved median survival of 14 versus 6 weeks for doxorubicin.4 Nevertheless, doxorubicin has continued to be used as a control arm in more recent studies with published median survival times between 3.7 and 8.8 months with no clear survival benefit.3 A meta-analysis of seven randomized controlled trials comparing tamoxifen to placebo failed to show a difference in 1-year survival (23% versus 22%).5

Sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals) is a small-molecule inhibitor that has been shown by in vitro and xenograft studies of HCC to affect cell proliferation and angiogenesis.6 This agent is a serine/threonine kinase inhibitor that blocks wild-type and mutant B-rat sarcoma activated factor (Raf) B-Raf and C-Raf, thus inhibiting cell proliferation. It also is a tyrosine kinase inhibitor that has activity against the vascular endothelial growth factor receptors VEGFR2 and VEGFR3, and the platelet-derived growth factor receptor (PDGFR) involved in angiogenesis.6

A total of 602 patients with advanced-stage hepatocellular carcinoma who were not candidates for, or who had disease progression after locoregional therapy, were enrolled in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial.7 Almost all patients (97%) had Child class A cirrhosis, 38% had evidence of macrovascular invasion, and 51% had extrahepatic spread with the most common sites being lymph nodes and lung. The 1-year survival for the sorafenib group was 44% and 33% for the placebo group. The median survival for the sorafenib group was 10.7 months from enrollment compared to 7.9 months for those who received placebo. The survival benefit appeared to be correlated to a 2.7-month delay in radiologic progression (5.5 months for the sorafenib group versus 2.8 months for the placebo group). Radiologic progression was defined as a 20% increase of the sum of the longest diameter of the tumors without previous partial or complete response. Partial and complete responses were defined as a 30% decrease in the sum of the tumor diameters or complete disappearance, respectively. There was no difference between treatment groups in the modest partial response rates (2% versus 1%) and there were no complete responses in the study. This phase 3 clinical trial was stopped early at its second interim analysis because of the evidence for a survival benefit associated with sorafenib therapy and has been subsequently approved by the U.S. Food and Drug Administration. The SHARP study therefore represents a clear paradigm shift in the role of chemotherapy for HCC; the most recent American Association for the Study of Liver Diseases practice guidelines for the management of hepatocellular carcinoma, published in 2005, advise against systemic chemotherapy as a standard of care.8 Sorafenib should be offered as treatment for patients with advanced HCC and Child class A cirrhosis and should be considered the reference standard in trials for patients with advanced HCC and Child class A cirrhosis.

Many agents under investigation for the treatment of advanced HCC target growth factors, their receptors, or downstream pathways that have been implicated in HCC development.9, 10 These include derangements in the regulation of signal transduction pathways involved cell proliferation (Ras/Raf/MEK/ERK pathway) apoptosis and protein synthesis (PI3/AKT/mTOR pathway).11 Angiogenesis also plays an important role in tumorigenesis because HCC is highly vascular.

The results of the SHARP trial offer hope for patients with HCC, although some caution is warranted in clinical application of these data. It should be noted that there was no difference in symptomatic progression or quality of life between the two study arms. A total of 80% of those taking sorafenib experienced a treatment-related adverse event compared to 52% of those taking placebo; the majority of these were mild to moderate in degree of severity. The two most common severe (grade 3, interfering with daily function) adverse events were diarrhea and hand foot skin reaction (HFSR). In the sorafenib group, 8% experienced grade 3 diarrhea versus 2% of the placebo group. HFSR is characterized by tender blisters/ulcerations on the palms or soles. Eight percent of patients taking sorafenib experienced grade 3 HFSR versus 1% of those taking placebo, which is comparable to other clinical trials.12 Despite the increased number of adverse events in the sorafenib arm, the rate of discontinuation of the study drug was nearly the same for both groups (38% versus 37%), although only 76% of the sorafenib group versus 94% of the placebo group received 80% of the planned daily dose.

It is not clear whether the results of the SHARP trial can be extrapolated to all patients with HCC, because most patients enrolled in the study had Child class A cirrhosis. This study primarily included European patients, which limited the applicability to other demographics, but a recent abstract of a phase 3 trial of sorafenib versus placebo in Asian patients reported a similar increase in survival (6.2 versus 4.1 months).13 Another factor which may limit widespread use is cost; the average wholesale price of sorafenib is approximately $5400 per month. Nevertheless, the dramatic results of the SHARP trial open a range of new therapeutic options for HCC, using sorafenib as an adjunctive therapy for HCC in addition to locoregional therapies or in combination with other systemic treatments.

Several such trials are currently under way, as listed on the National Institutes of Health website http://clinicaltrials.gov, that are studying sorafenib as an adjunct to curative therapy and transarterial chemoembolization, sorafenib in combination cytotoxic chemotherapy (gemcitabine, 5-fluorouracil, doxorubicin), and sorafenib in combination or compared to another targeted therapeutic (bevacizumab, sunitinib, mapatumumab). Mapatumumab is a monoclonal antibody that activates tumor necrosis factor–related apoptosis-inducing ligand receptor 1, a mediator of apoptosis. This agent has been studied in a phase 1 trial for solid tumors and a safety trial in HCC has been initiated.13 Sunitinib, another multikinase inhibitor approved for the treatment of renal cell carcinoma, is now currently in phase 1 and 2 trials for the treatment of HCC. In an uncontrolled phase 2 study, 46 patients with unresectable HCC treated every 2 weeks with bevicizumab, a monoclonal antibody directed against vascular endothelial growth factor, had a median survival of 12.4 months and a 1-year survival of 53%.15 A phase 2 trial assessing the safety of erlotinib, a small-molecule tyrosine kinase inhibitor of the epidermal growth factor receptor, for patients with unresectable HCC, reported a 10.75-month median survival from time of diagnosis and 6.25 months from the start of treatment.16

In summary, sorafenib is the first targeted therapeutic proven to show a survival benefit for the treatment of advanced HCC via favorable effects on both proliferation and angiogenesis. Additional studies are awaited on the role of this agent in patients with advanced liver disease and as an adjunctive therapy in combination with other modalities. Sorafenib and the newer targeted agents represent the future of HCC therapy, which will likely require single or multiple agents targeted at the multiple carcinogenic pathways involved. Hopefully, this glimmer of hope will develop into a major advance in the treatment of unresectable HCC.

References

  1. Top of page
  2. Abstract
  3. Comment
  4. References