STORM: Sorafenib as Adjuvant Therapy for HCC (2015)

“Adjuvant sorafenib did not improve recurrence-free survival, time to recurrence, or overall survival after surgical resection or local ablation in patients with hepatocellular carcinoma. The safety profile of sorafenib was consistent with previous reports.”

— The STORM Investigators

1. Publication Details

  • Trial Title: Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.
  • Citation: Bruix J, Takayama T, Mazzaferro V, et al; for the STORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344-1354. doi:10.1016/S1470-2045(15)00198-9.
  • Published: October 1, 2015, in The Lancet Oncology.
  • Author: Jordi Bruix, M.D.
  • Funding: Bayer HealthCare Pharmaceuticals.

2. Keywords

Hepatocellular Carcinoma (HCC), Adjuvant Therapy, Sorafenib, Recurrence-Free Survival, Liver Cancer, Resection, Ablation.

3. The Clinical Question

In patients who have undergone potentially curative resection or ablation for hepatocellular carcinoma (HCC) (Population), does adjuvant therapy with sorafenib (Intervention) compared to placebo (Comparison) improve recurrence-free survival (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Hepatocellular carcinoma (HCC) has a very high rate of recurrence even after potentially curative treatments like surgical resection or local ablation, with 5-year recurrence rates exceeding 70%. Sorafenib, a multikinase inhibitor, was the standard of care for advanced, unresectable HCC.
  • Knowledge Gap: There was no effective, established adjuvant therapy to reduce the high risk of recurrence after curative-intent treatment for HCC. It was unknown if sorafenib, being effective in the advanced setting, could prevent or delay recurrence when used in the adjuvant setting.
  • Proposed Hypothesis: The authors hypothesized that adjuvant sorafenib would improve recurrence-free survival compared with placebo in patients with HCC after curative resection or ablation.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, double-blind, placebo-controlled, phase 3 trial.
  • Setting: 154 centers in 28 countries across North America, Europe, and the Asia-Pacific region.
  • Trial Period: Enrollment from August 2010 to June 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with a complete radiological response after surgical resection or radiofrequency ablation (RFA) for HCC, with an intermediate or high risk of recurrence.
    • Exclusion Criteria: Previous systemic therapy for HCC, Child-Pugh score >7, or significant cardiovascular disease.
  • Intervention: Sorafenib 400 mg orally twice daily.
  • Control: Matching placebo orally twice daily.
  • Management Common to Both Groups: Treatment was continued for a maximum of 4 years or until disease recurrence or unacceptable toxicity. All patients underwent regular imaging surveillance for recurrence.
  • Power and Sample Size: The trial was powered to detect a hazard ratio of 0.79 for recurrence-free survival, requiring 1100 patients.
  • Outcomes:
    • Primary Outcome: Recurrence-free survival (RFS).
    • Secondary Outcomes: Overall survival (OS) and time to recurrence.

6. Key Results

  • Enrollment and Baseline: 1114 patients were randomized (556 to sorafenib, 558 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the median recurrence-free survival between the sorafenib and placebo groups (33.3 months vs 33.7 months; P=0.26).
  • Secondary Outcomes: There were no significant differences in the median time to recurrence or in overall survival between the two groups.
  • Adverse Events: Grade 3 or 4 adverse events were significantly more common in the sorafenib group (50% vs 14%), with hand-foot skin reaction and diarrhea being the most frequent.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using the log-rank test.
  • Primary Outcome Analysis: Time to recurrence or death was compared between the two groups using a Kaplan-Meier analysis.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for recurrence-free survival with sorafenib: 0.94 (95% CI, 0.78 to 1.13; P=0.26).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR): An HR of 0.94 suggests a 6% lower hazard of recurrence or death with sorafenib, but this was not statistically significant.
    • Confidence Interval (CI): The 95% CI widely crosses 1.0, indicating no significant difference between the groups.
    • P-value: The p-value of 0.26 confirms the lack of a statistically significant difference.
  • Clinical Impact Measures: Not applicable as no benefit was shown for the primary outcome.
  • Subgroup Analyses: No significant benefit for sorafenib was found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, international, multicenter, double-blind, placebo-controlled phase 3 trial, representing the highest level of evidence.
  • Generalizability: The inclusion of a large number of centers worldwide with a diverse patient population increases the applicability of the findings.
  • Clinically Relevant Question: The trial addressed a major unmet need in the management of HCC.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The findings are specific to sorafenib and do not necessarily apply to other systemic therapies, such as immunotherapy, which have since been developed.
  • Other: A high rate of dose reductions and discontinuations due to toxicity was observed in the sorafenib arm, which may have attenuated any potential effect.

10. Conclusion of the Authors

“Adjuvant sorafenib is not recommended for patients with hepatocellular carcinoma after resection or ablation. The development of effective adjuvant treatments remains an important unmet medical need.”

11. To Summarize

  • Impact on Current Practice: This was a definitive “negative” trial that clearly established that sorafenib, despite its efficacy in advanced disease, should not be used in the adjuvant setting for HCC. It prevented the widespread adoption of an ineffective and toxic therapy and highlighted the different biology of micrometastatic disease compared to established tumors.
  • Specific Recommendations:
    • Patient Selection: For adult patients who have undergone curative-intent resection or ablation for HCC.
    • Actionable Intervention: Do not administer adjuvant sorafenib. The standard of care remains surveillance.
    • Expected Benefit: No benefit was demonstrated; use of sorafenib leads to significant toxicity.
  • What This Trial Does NOT Mean: This trial does not diminish the role of sorafenib (or other tyrosine kinase inhibitors) in the treatment of advanced, unresectable HCC.
  • Implementation Caveats: The findings provide a strong evidence-based recommendation against a specific off-label practice.

12. Context and Related Studies

  • Building on Previous Evidence: The STORM trial was designed to test the logical next step for a drug proven effective in advanced cancer—its use in the adjuvant setting to prevent recurrence.
  • Influence on Subsequent Research: As a large and robust negative trial, STORM has been a crucial benchmark. It has tempered enthusiasm for using targeted therapies in the adjuvant setting without a strong biological rationale. The field of adjuvant therapy for HCC has now shifted to investigating immunotherapy agents, with recent trials like IMbrave050 showing the first positive results for an adjuvant strategy (atezolizumab-bevacizumab).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Why do drugs effective in advanced HCC fail in the adjuvant setting? Are there specific molecular subtypes of HCC that might respond to adjuvant targeted therapy?
  • Future Directions: The development of effective adjuvant therapy for HCC is a major focus of oncology research, with the current emphasis being on immune checkpoint inhibitors and combination therapies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing a major unmet clinical need with a biologically plausible intervention.
  • Methods: The study’s design was of the highest quality: a large, international, multicenter, double-blind, placebo-controlled phase 3 RCT.
  • Results: The trial had a clear and definitive negative result for its primary endpoint of recurrence-free survival, with no signal of benefit in any secondary outcome or subgroup.
  • Conclusions and Applicability: The authors’ conclusion is a direct and unambiguous interpretation of the data. The results are highly applicable globally and have definitively established that adjuvant sorafenib is not indicated for patients with resected HCC.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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