Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial

Target Article

Academic Impact of the Gut Journal

The background of this study being published in Gut, a top journal in gastroenterology, lies in the fact that it is a large-scale, multicenter randomized controlled trial (RCT) involving 1,044 patients, and it passed a rigorous international peer-review process.

According to the editor-in-chief's comments, the manuscript underwent a thorough review by five independent international experts. Strict peer reviews are not granted unless the discovered therapeutic effects are clinically justified and highly relevant.

Thus, publication in this journal suggests that the presented evidence possesses high objectivity and reliability.

Reliability Check of the Study (PICO)

The Huaier granules used in this study were a pharmaceutical preparation manufactured in China.

The administered dose was 20g per administration, three times daily, corresponding to a total preparation weight of 60g per day.

Study Design and Sample Size

Detailed Results

[Improvement in Recurrence-Free Survival Time and Overall Recurrence Rate]

In the validation by Qian Chen's research team, a comparison between the primary analysis subjects of the Huaier group (686 cases) and the control group (316 cases) showed a significant prolongation of recurrence-free survival time. The mean recurrence-free survival time in the Huaier group was 75.5 weeks, demonstrating a reduced risk of recurrence compared to 68.5 weeks in the control group (HR 0.67, 95% CI 0.55 - 0.81).

Additionally, regarding the recurrence-free survival rate at 96 weeks, the Huaier group achieved 62.39%, whereas the control group was only 49.05%. This intergroup difference was 13.34 percentage points (95% CI 6.74 - 19.94), indicating a statistically significant improvement (P=0.0001).

Furthermore, the overall recurrence rate was 37.61% (258 cases) in the Huaier group compared to 50.56% (161 cases) in the control group, demonstrating a significant recurrence suppression effect (P=0.0001).

[Impact on Overall Survival Time and Extrahepatic Recurrence Rate]

Regarding the secondary endpoint of the overall survival rate at 96 weeks, the Huaier group achieved 95.19% and the control group 91.46%, showing a significantly higher overall survival rate with an intergroup difference of 3.73 percentage points (95% CI 0.26 - 7.21) (P=0.0207). In the time-to-event analysis, the hazard ratio for death was 0.553 (95% CI 0.333 - 0.920, P=0.0226). 

The extrahepatic recurrence rate (extrahepatic metastasis rate) was significantly lower in the Huaier group than in the control group, (8.60% vs 13.61%, P=0.0149 ). In the time-to-event analysis, the hazard ratio for extrahepatic recurrence was 0.570 (95% CI 0.385 - 0.844, P=0.005), further supporting a lower incidence of extrahepatic recurrence in the Huaier group.

[Safety and Evaluation of Adverse Events]

The overall incidence of drug-related adverse events in this trial was 23.3% in the Huaier group. The most frequently observed adverse event was abnormal liver function (7.0%), but no statistically significant difference was found compared to the untreated control group (5.7%) (P=0.4405).

These results suggest that long-term oral intake of Huaier extract does not exert additional adverse effects on liver function and possesses an acceptable safety profile as a postoperative adjuvant therapy.

Source: Excerpted and created from Table 2, Chen Q, et al. Gut. 2018;67(11):2006-2016. 

Summary of Adverse Event Incidence

Source: Excerpted and created from Table 5, Chen Q, et al. Gut. 2018;67(11):2006-2016.
*1: Combined incidence of extremely low-frequency minor symptoms such as fatigue, fever, indigestion, nausea/vomiting, abdominal pain, and cough.
*2: Figures for "other complaints (rash, nail abnormalities, back pain, arthralgia, injury, hypertension, orthostatic hypotension, etc.)" in the paper. Note: The overall incidence including "all adverse events" in the Huaier group, regardless of causality, was 25.5% (175 cases).

[Key Safety Points from this Table]
Looking at the overall incidence of safety issues, there is almost no difference between the Huaier group (23.3%) and the untreated control group (22.8%), indicating an incidence rate nearly identical to having no treatment.

Furthermore, there was no statistically significant difference for "abnormal liver function," which was the most common. While fluctuations in liver function values were the most frequently observed (7.0%), this falls within the range of natural occurrences seen in the non-medicated control group (5.7%), with no statistical difference (p=0.4405).

Moreover, all reported symptoms were minor, and no severe adverse reactions forcing the discontinuation of administration were confirmed.

Potential Application in Veterinary Medicine 

[How to Utilize in Clinical Practice]

The first-line treatment for hepatocellular carcinoma in dogs and cats is surgical resection, but postoperative adjuvant therapies to suppress micrometastasis and recurrence have not yet been established in veterinary medicine.

The approach demonstrated in this study—modulating innate immunity and inhibiting tumor angiogenesis (inhibition of VEGF expression) by Huaier extract—serves as a crucial rationale when considering new options for postoperative management in veterinary medicine.

In particular, the evidence that it prolonged recurrence-free survival time and achieved improved overall survival rates without using cytotoxic anticancer drugs could contribute to the development of scientific options for cases where standard chemotherapy is difficult to choose due to old age or complications.

[Comparison with Existing Treatments and Challenges of High-Dose Oral Administration]

A critically important clinical fact in this study is that a large oral dose of 20g per intake, three times a day (total 60g/day), was administered to humans. When simply extrapolating this to dogs and cats of typical body weight, one faces practical clinical challenges. For example, assuming a human weight of 60kg, the daily dose is 1g/kg. Therefore, a 10kg dog would need to be given 10g/day (3.3g per intake), and a 4kg cat would need 4g/day (1.3g per intake) of powder every day. This is a massive administration volume for dogs and cats, and considering the unique flavor and bitterness of Huaier extract, there is a high risk of decreased appetite.

Furthermore, in cases already accompanied by anorexia, maintaining an oral administration regimen of three times a day over a long period (up to 96 weeks) raises concerns about reducing treatment continuity, including the owner's living environment. In addition, administering large amounts of polysaccharide substances daily to the gastrointestinal tracts of dogs and cats, which are closer to carnivores, carries the potential for gastrointestinal disorders such as indigestion, loose stools, and diarrhea.

[Study Limitations and Critical Appraisal]

It has been noted that many of the human subjects in this study were Hepatitis B virus (HBV) carriers. Therefore, it has been suggested that the results might have been obtained through the antiviral response of the Huaier extract.

Unlike humans, hepatocellular carcinoma in dogs and cats occurs spontaneously without a background of viral hepatitis, so it is necessary to carefully assess whether equivalent immunomodulatory effects can be obtained. Furthermore, this trial was an open-label study lacking a placebo control (blank-controlled trial), and blinding was impossible due to the distinct flavor. Therefore, considering these species differences in background factors and the possibility of bias, it is required to critically appraise the relationship with individual prognostic factors in dogs and cats rather than directly applying the evidence.

Mini-Glossary for Readers

• TLR4 (Toll-like Receptor 4): A receptor in innate immunity that recognizes pathogen-associated molecular patterns. When activated, it induces the production of inflammatory cytokines.
• NF-κB: An important transcription factor involved in the regulation of immune and inflammatory responses, as well as in the processes of cell proliferation and apoptosis.
• MAPK (Mitogen-Activated Protein Kinase): An intracellular signal transduction factor that transmits extracellular stimuli into the nucleus and regulates various physiological functions such as cell proliferation, differentiation, and survival.
• Proteoglycan: A general term for glycoconjugates in which numerous sugar chains are covalently bonded to a core protein, playing diverse physiological roles in vivo.
• BCLC Stage: Abbreviation for Barcelona Clinic Liver Cancer staging. A staging system that comprehensively evaluates the progression, liver function, and general condition in human hepatocellular carcinoma.
• Child-Pugh Classification: An index for evaluating the severity and hepatic reserve of liver cirrhosis. It is scored based on items such as serum bilirubin and albumin.
• Transcatheter Arterial Chemoembolization (TACE): A treatment method in which a catheter is advanced into an artery supplying a hepatocellular carcinoma, and anticancer drugs and embolic agents are injected to necrose the tumor.
  
  
  
  Link to the full article：https://doi.org/10.1136/gutjnl-2018-315983