Introduction

Liver cancer is one of the most prevalent and deadly malignancies worldwide, with hepatocellular carcinoma (HCC) accounting for the majority of cases.1,2 Despite advances in diagnosis and treatment, most patients are diagnosed at advanced stages and face limited therapeutic options and poor survival outcomes.3 Tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, have become standard systemic therapies for advanced HCC since 2007, contributing to improved survival; however, their overall response rates remain low, and their use is frequently complicated by adverse events.4

One of the most common and clinically significant adverse effects of TKI therapy is diarrhea, with reported incidences as high as 43–51% among HCC patients treated with sorafenib.4 TKI-induced diarrhea can cause dehydration and electrolyte imbalances, which may necessitate dose reduction or discontinuation of anticancer therapy, ultimately compromising clinical outcomes.5–9 The underlying mechanisms are multifactorial and incompletely understood, involving gastrointestinal mucosal injury, pancreatic exocrine dysfunction, increased chloride secretion, colonic crypt loss, and alterations in the intestinal microbiota.10–14 Current management strategies for TKI-induced diarrhea-including dietary modifications and antidiarrheal medications such as loperamide and montmorillonite powder-are often inadequate and fail to address the underlying pathophysiology or associated systemic symptoms.5 As a result, optimizing the management of this complication remains a pressing clinical challenge.

However, despite the significant clinical need, high-quality research on the efficacy of Traditional Chinese Medicine (TCM) interventions-particularly for TKI-induced diarrhea in this specific patient population-is still limited. Few randomized controlled trials have rigorously evaluated the impact of classical TCM formulas or their modifications on this specific patient population. TCM offers a holistic approach to gastrointestinal disorders and has shown promise in alleviating diarrhea, improving digestive function, and enhancing patient quality of life. Classical formulas such as Sishen Pill, indicated for diarrhea due to spleen-kidney Yang deficiency, have demonstrated the ability to protect the intestinal barrier, regulate gut flora, and ameliorate mucosal injury.15–19 Likewise, Sijunzi Decoction is reported to strengthen the spleen, promote liver repair, maintain intestinal microecological balance, and improve immunity in liver cancer patients.20–24 Compared to Western medicine, which primarily provides symptomatic relief, TCM treatments may offer multi-targeted benefits, including modulation of gastrointestinal function and systemic symptoms.

Clinically, HCC patients on TKI therapy frequently present with symptoms consistent with spleen-kidney Yang deficiency, such as pallor, fatigue, poor appetite, and increased stool frequency. The modified Sishen decoction, which combines Sishen Pill and Sijunzi Decoction, is designed to warm and tonify the spleen and kidney, consolidate and astringe to stop diarrhea, and improve gastrointestinal function. Therefore, this randomized controlled trial (RCT) was conducted to evaluate the clinical efficacy and safety of modified Sishen decoction in the treatment of TKI-induced diarrhea and related systemic symptoms in patients with primary liver cancer.

MethodsStudy Design and Setting

This single-blind, randomized controlled trial was conducted in the Department of Traditional Chinese Medicine at the Minhang Branch of Fudan University Cancer Hospital between May 2025 and November 2025. The study protocol was developed in accordance with the Declaration of Helsinki,25 approved by the The study was approved by Medical Ethics Committee of Minhang Branch of Fudan University Cancer Hospital ([2025] Ethics No. [011]). Written informed consent was obtained from all participants prior to enrollment.

Participants

Participants were eligible if they met the following criteria: (1) Diagnosis of HCC in accordance with the “Primary Liver Cancer Diagnosis and Treatment Guidelines 2017” issued by the National Health and Family Planning Commission; (2) treatment with TKIs for at least two weeks; (3) development of diarrhea following TKI administration, defined according to Western medicine criteria:26 watery, loose, or sticky purulent stools, and a significant increase in stool frequency compared to baseline; (4) diagnosis of diarrhea with spleen-kidney Yang deficiency based on TCM criteria:27 primary symptom of loose or watery stools occurring more frequently than normal; secondary symptoms include diarrhea with undigested food, abdominal distension, poor appetite, lassitude, cold limbs, and waist/knee pain. Additional TCM findings included pale tongue with white or slippery coating, and a thin or weak pulse. Patients were required to present at least two secondary symptoms in combination with tongue and pulse findings; (5) Expected survival of at least two months; (6) age between 18 and 75 years; (7) provision of signed informed consent.

Exclusion criteria were as follows: (1) Use of antibiotics within the past month; (2) history or risk of bowel perforation, active gastrointestinal bleeding, absorption dysfunction, or inability to take oral medications for unexplained reasons; (3) diagnosis of diabetes mellitus; (4) obesity (BMI ≥ 28 kg/m2); (5) severe hepatic dysfunction (serum total bilirubin ≥ 2× upper limit of normal [ULN], alanine aminotransferase ≥ 3× ULN, or ascites > 3 cm) or renal dysfunction (serum creatinine > 200 μmol/L), or other major organ dysfunction. (6) severe dehydration, bacterial enteritis, dysentery, or other systemic diseases such as malnutrition; (7) receipt of concurrent radiation therapy or chemotherapy. (8) determination by the investigator that the patient was unsuitable for study participation.

Randomization and Blinding

Eligible participants (N=60) were randomly assigned in a 1:1 ratio to the TCM group or the Western medicine (WM) group. Randomization was performed using a computer-generated random number table with block randomization (SAS version 9.4; SAS Institute Inc., Cary, NC, USA), overseen by an independent statistician not otherwise involved in the study. The allocation sequence was concealed with password protection. Participants were blinded to the group allocation. Both TCM and WM interventions were encapsulated in identical capsules to maintain blinding.

Pattern differentiation (spleen–kidney Yang deficiency) was independently evaluated by two senior TCM physicians using prespecified criteria. Inclusion required agreement by both physicians; in this cohort, no discordant classifications occurred at screening. All participants completed baseline demographic and clinical assessments, including diarrhea severity grading (NCI CTCAE v4.0) and a TCM symptom scale for spleen-kidney Yang deficiency.27 Study data were collected using standardized case report forms and entered into a dedicated electronic database.

InterventionsTCM Group

Participants received a modified Sishen decoction, prepared by the Minhang Branch of Fudan University Cancer Hospital Pharmacy, consisting of Nutmeg (9g), Psoralea (24g), Fructus Schisandrae (12g), Evodia Rutaecarpa (6g), Radix Codonopsis (15g), Rhizoma Atractylodis Macrocephalae (9g), Poria (9g), and Liquorice (6g). The herbal ingredients were ground into powder and packed into capsules (3g per capsule). Participants took one capsule orally, three times daily for seven days.

WM Group

Participants received montmorillonite powder (Hainan Xiansheng Pharmaceutical Co., Ltd)., encapsulated identically (3g per capsule), administered orally, three times daily for seven days. Montmorillonite was selected as the control because it is commonly used as symptomatic management for TKI-associated diarrhea in Chinese clinical practice and is included in relevant Chinese expert consensus recommendations.28,29

Concomitant use of other antidiarrheal medications was not permitted during the study. Use of medications required for other comorbidities was allowed, with details recorded (drug name, daily dose, indication, start/stop dates).

Outcome Measures

The primary outcome was the severity of diarrhea, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0): Grade 1: Increase of <4 stools/day over baseline, mild symptoms. Grade 2: Increase of 4–6 stools/day over baseline, requiring minimal intervention. Grade 3: Increase of ≥7 stools/day over baseline, incontinence, hospitalization required, limitation of self-care activities. Grade 4: Life-threatening consequences, urgent intervention indicated.

Secondary outcomes included assessment of TCM symptoms using a validated quantitative scale for spleen-kidney Yang deficiency-type diarrhea, as per the “Guiding Principles for Clinical Research of New Chinese Medicine”.27 The clinical efficacy index was calculated as: (pre-treatment score − post-treatment score) / pre-treatment score × 100% (nimodipine method). Adverse events were actively assessed daily during the 7-day intervention, with specific evaluation for dehydration and electrolyte disturbance; laboratory tests were repeated at the end of treatment (Day 8).

Efficacy was categorized as follows: (1) Clinical cure: Symptom reduction ≥95%, near or complete resolution. (2) Significant improvement: Symptom reduction ≥70%. (3) Effective: Symptom reduction ≥30%. (4) Ineffective: Symptom reduction <30% or worsening of symptoms. The incidence and severity of all adverse events (AEs) were recorded. Laboratory assessments (urinalysis, liver and kidney function tests, electrocardiogram) were performed before and after the intervention. AEs were graded according to NCI CTCAE v3.0.

Sample Size Calculation

Sample size was estimated using PASS 11 software (NCSS, Kaysville, Utah, USA).30 The assumed distribution of outcomes in the control group (effective/moderately effective/ineffective: 10%/75%/15%) was derived from a pilot dataset collected at our center prior to study initiation in HCC patients with TKI-induced diarrhea receiving routine symptomatic management with montmorillonite. We planned for an expected odds ratio of 2.0 for the intervention versus control in the ordinal outcome. The pilot dataset was not part of the randomized trial and was used only for planning purposes. For a comparison of two ordinal categorical variables, a minimum of 23 patients per group was required. To account for a potential 20% dropout rate, 29 patients per group were enrolled.

Statistical Analysis

Descriptive statistics were computed for baseline characteristics. Continuous variables with normal distribution were summarized as mean ± standard deviation and compared using independent-samples t-tests. Non-normally distributed data were analyzed using the Mann–Whitney U-test. Categorical variables were compared using the chi-square test. Ordinal data were compared using rank-sum tests. Repeated measures of diarrhea grade were analyzed using generalized estimating equations (GEE) for an ordinal outcome with a cumulative logit link (proportional odds model) and an exchangeable working correlation matrix. The model included fixed effects for group (TCM vs WM), time (baseline/day 3/day 5/day 8), and the group × time interaction. With the TCM group as the reference, odds ratios (ORs) for WM vs TCM were interpreted as the relative odds of being in a higher (worse) diarrhea grade; thus, OR > 1 indicates a higher likelihood of more severe diarrhea in the WM group compared with the TCM group at the specified time point. Pre-specified baseline covariates were adjusted for in the model (age, sex, BMI, BCLC stage, ECOG PS, and type of TKI). Baseline values were incorporated into the time effect and were not entered as separate covariates. All statistical tests were two-sided, and a p-value <0.05 was considered statistically significant.

ResultsDemographic and Baseline Clinical Characteristics

A total of 63 patients with primary liver cancer were screened for eligibility between May 2025 and November 2025 in the Department of Traditional Chinese Medicine at the Minhang Branch of Fudan University Cancer Hospital. Three patients declined participation, resulting in 60 patients who were randomized equally to the TCM group (n=30) and the WM group (n=30). All participants completed the study and were included in the final analysis (Figure 1).

Figure 1 Expermental flow chart.

Baseline demographic and clinical characteristics were comparable between the two groups (all P > 0.05). No significant differences were observed in gender distribution, age, body mass index (BMI), Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group Performance Status (ECOG PS), type of tyrosine kinase inhibitor, diarrhea severity, or baseline TCM symptom scores (all P>0.05, Tables 1 and 2).

Table 1 Baseline Demographic and Clinical Characteristics

Table 2 Baseline TCM Symptom Scores

Primary Outcomes

Analysis using GEE revealed that the main effect between groups was not statistically significant (P = 0.073), whereas the main effect of time (P = 0.007) and the interaction between group and time (P = 0.007) were significant. From Day 5 onward, the TCM group exhibited a significantly greater reduction in diarrhea severity compared to the WM group [Day 5: odds ratio (OR) = 4.053, 95% CI: 1.265–12.987, P = 0.019; Day 8: OR = 4.746, 95% CI: 1.495–15.051, P = 0.008; Table 3]. Following treatment, the proportion of patients with grade 2/3 diarrhea in the TCM group decreased from 73.33% at baseline to 6.67%, while in the WM group, the proportion decreased to 30% (Table 4).

Table 3 Diarrhea Severity at Each Time Point

Table 4 Distribution of Diarrhea Grades Before and After Intervention

Secondary Outcomes

Within-group analyses demonstrated significant improvements in multiple TCM symptoms in the TCM group after intervention, including stool diarrhea, bowel sounds, diarrhea with undigested food, abdominal distension, poor appetite, lassitude, fatigue, and cold limbs (all P < 0.05). In the WM group, significant improvements were observed only in stool diarrhea and abdominal distension (Table 5). Because individual symptom items were scored on discrete ordinal scales, some post-treatment item scores showed minimal variability.

Table 5 Change in TCM Symptom Scores Within Groups

Between-group comparisons post-treatment revealed significantly lower symptom scores in the TCM group for stool diarrhea, diarrhea with undigested food, abdominal distension, poor appetite, lassitude, fatigue, and cold limbs (all P < 0.05). The total TCM symptom score was also significantly reduced in the TCM group compared to the WM group (6.57±2.47 vs. 9.17±2.00, P < 0.001) (Table 5). The overall effective rate (clinical cure + effective + significant improvement) was 90% in the TCM group, significantly higher than the 20% observed in the WM group (Table 6).

Table 6 Efficacy Assessment of TCM Symptom Group

Correlation Between Western and TCM Outcomes

Spearman correlation analysis showed a positive association between CTCAE diarrhea grade and total TCM syndrome score at baseline and post-treatment in both groups (TCM group: baseline r=0.414, P=0.023; post-treatment r=0.411, P=0.024; WM group: baseline r=0.736, P<0.001; post-treatment r=0.582, P=0.001; Table S1).

Safety

No participants experienced dehydration, electrolyte imbalance, or other diarrhea-related complications during the 7-day intervention. Post-treatment laboratory indices, including WBC, total bilirubin (TB), AST, ALT, creatinine, blood urea nitrogen (BUN), platelets (PLT), and hemoglobin (Hb), were graded according to CTCAE criteria and are presented relative to the hospital laboratory upper limit of normal. The distributions of CTCAE laboratory abnormality grades were comparable between groups for all reported parameters (all P > 0.05; Table 7). Clinically meaningful abnormalities (CTCAE grade ≥ 3) were uncommon and showed no group difference, and no clinically meaningful new safety signals attributable to the study interventions were observed during the trial. No patients in either group required TKI dose reduction, interruption, or discontinuation due to diarrhea during the 7-day intervention period.

Table 7 Laboratory Abnormalities (Post-Treatment) Graded by CTCAE

Discussion

This randomized controlled trial showed that modified Sishen decoction improved TKI-induced diarrhea more than montmorillonite powder among patients with HCC. The between-group difference emerged from Day 5 and remained significant at Day 8, and the distribution of CTCAE grades shifted toward grade 0–1 more strongly in the modified Sishen decoction group. In parallel, patients receiving modified Sishen decoction showed a greater reduction in the total TCM symptom score, with improvements in systemic symptoms including fatigue and poor appetite. No dehydration, electrolyte imbalance, or treatment-related serious adverse events were observed during the 7-day intervention, and laboratory abnormalities were comparable between groups. These findings are clinically relevant because diarrhea during TKI therapy can lead to dose reduction or treatment interruption, which may compromise delivery of anticancer treatment.5–9

The pathophysiology of TKI-induced diarrhea is complex, involving gastrointestinal mucosal injury, altered secretion of water and electrolytes, immune dysregulation, and changes in the intestinal microbiota.10–14 Montmorillonite powder, the control intervention in this study, acts mainly through luminal adsorption and can reduce stool liquidity. Consistent with this symptomatic mechanism, diarrhea grade improved over time in the montmorillonite group, but the improvement was smaller than that observed with modified Sishen decoction.5–9

Interpretation and clinical context. Supportive care for treatment-related diarrhea varies across settings. In China, montmorillonite is commonly used in routine practice and is included in Chinese expert consensus recommendations, often alongside loperamide.28 We selected montmorillonite as a pragmatic comparator reflecting local practice and our center’s pilot data used for sample size planning. At the same time, international practice frequently uses loperamide as first-line therapy for treatment-related diarrhea, which limits direct generalization of our results to settings where loperamide is the default comparator.5 Accordingly, our data support the clinical benefit of modified Sishen decoction relative to montmorillonite in this setting, but do not define its comparative effectiveness versus loperamide or other standard antidiarrheal regimens.

Safety considerations are relevant in HCC. Many patients have underlying hepatic dysfunction, and loperamide undergoes extensive first-pass metabolism. Although loperamide is generally safe when used appropriately, clinically significant toxicity has been reported in the setting of misuse or supratherapeutic dosing, including cardiotoxicity that may require monitoring and active management.31 These considerations influenced our choice of a minimally absorbed comparator for a short-term trial; however, they do not replace the need for direct comparative trials against internationally used first-line agents.

In this randomized controlled trial, modified Sishen Decoction was associated with greater improvement in CTCAE diarrhea grade over time and with a larger reduction in TCM syndrome scores compared with the control intervention, without new safety concerns during the study period. These findings suggest that the formula may be a useful supportive-care option for managing TKI-associated diarrhea in patients with primary liver cancer, particularly when symptom burden is accompanied by a spleen–kidney Yang deficiency pattern. In addition, there was a significant positive correlation between the CTCAE diarrhea grade and the total TCM syndrome score at both baseline and post-treatment. This finding supports the integrated interpretation of Chinese and Western medicine indicators in oncology supportive care. The CTCAE grading provides a standardized measure of local gastrointestinal toxicity, while the TCM syndrome score captures the broader, systemic functional status. The correlation of these two indicators suggests that TKI-induced diarrhea may be associated with a systemic state of spleen-kidney Yang deficiency. Previous studies have also established that combining standardized clinical indices with TCM syndrome patterns could improve the accuracy and clinical value of patient evaluations.32 This dual-evaluation approach provides a holistic view of patient recovery and treatment tolerability.

Mechanistic interpretation is limited in this trial. This study evaluated clinical efficacy and safety and did not measure biomarkers related to intestinal barrier function, inflammatory mediators, fecal microbiota, or enteric nervous system activity. Therefore, the mechanisms underlying the observed clinical benefits cannot be determined from the present data. Prior experimental studies have reported that components related to Sishen Pill may have pharmacological activities relevant to intestinal inflammation and mucosal protection.15–19 Because these endpoints were not assessed here, this evidence should be considered supportive background rather than an explanation of our clinical findings, and should be verified in future translational studies that incorporate prespecified biomarkers.

Importantly, the improvements observed in both diarrhea severity and broader symptom domains (eg, appetite, fatigue, and cold limbs) may have practical implications for supportive oncology care, as better symptom control could contribute to improved tolerability of ongoing anticancer therapy. Future studies should validate these findings in larger, multicenter cohorts, evaluate formulation-related factors (eg, capsule versus decoction), and integrate objective biomarker assessments to clarify potential biological pathways.

From a clinical standpoint, these findings suggest that modified Sishen decoction may represent a potential supportive-care option for patients with TKI-induced diarrhea in settings where montmorillonite is commonly used, particularly when diarrhea is accompanied by a spleen–kidney Yang deficiency pattern. By addressing both the gastrointestinal and systemic dimensions of TKI-induced toxicity, the decoction could support more consistent TKI dosing, improve patient comfort, and potentially enhance adherence to anticancer therapy. However, while montmorillonite powder serves as a rational comparator within the Chinese healthcare context, it is necessary to acknowledge that loperamide is widely recommended in international guidelines as a first-line agent for managing TKI- or chemotherapy-induced diarrhea.5 The absence of a loperamide arm in this study represents a limitation, and future trials should include this and other internationally recognized agents to better contextualize the place of modified Sishen decoction in global practice.

Several limitations should be considered when interpreting these results. First, the single-center design and sample size (N=60), which may limit generalizability to other populations, TKI regimens, and supportive-care standards. Multicenter trials with larger sample sizes and internationally relevant comparators are warranted. Second, the short duration of the intervention (7 days) precludes the assessment of long-term outcomes, such as sustained diarrhea control, patient adherence, or the impact on cancer progression and overall survival. In routine supportive care in China, symptomatic antidiarrheal therapy for TKI-associated diarrhea commonly includes montmorillonite (smectite) and loperamide, consistent with Chinese expert consensus recommendations.28 Given that many patients with HCC have varying degrees of hepatic impairment and loperamide undergoes extensive first-pass hepatic metabolism, we chose montmorillonite as a pragmatic comparator reflecting local standard practice. Nevertheless, because loperamide is frequently recommended as a first-line agent in international guidance for treatment-related diarrhea, we acknowledge that the choice of comparator may limit the generalizability of our findings, and future multicenter trials should include a loperamide arm. Because the herbal intervention was administered as capsules to maintain blinding, its pharmacokinetic and bioavailability profile may differ from that of a traditional water decoction. This could influence effectiveness and should be evaluated in future comparative formulation studies. Finally, while our study provides strong clinical evidence, the underlying mechanistic hypotheses remain speculative in the absence of direct biomarker or laboratory analyses. Future research should address these limitations by incorporating comprehensive mechanistic assessments, including measurements of intestinal permeability, inflammatory mediators, and microbiome composition, as well as conducting larger-scale, multicenter, and longer-term clinical trials to confirm these findings and clarify the precise pathways through which this compound formula exerts its benefits.

Conclusion

In conclusion, this study shows that modified Sishen decoction provides significant and clinically meaningful benefits for the management of TKI-induced diarrhea and associated systemic symptoms in HCC patients. In this trial, modified Sishen decoction demonstrated superior symptom improvement compared with montmorillonite powder and was well tolerated. Therefore, modified Sishen decoction may be an alternative or add-on option for patients with an inadequate response to montmorillonite powder. However, further studies comparing modified Sishen decoction with other standard antidiarrheal treatments (eg, loperamide) and in multicenter, larger-sample trials are needed to better define its role in supportive care and to explore underlying mechanisms.

Clinical Trial Registration

The trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry (ChiCTR1900023194).

Data Sharing Statement

All data generated or analysed during this study are included in this published article.

Ethics Approval and Consent to Participate

The study was approved by Medical Ethics Committee of Minhang Branch of Fudan University Cancer Hospital ([2025] Ethics No. [011]). All participants were informed about the study protocol and provided written informed consent to participate in the study. I confirm that all methods were performed in accordance with the relevant guidelines. All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The study was supported by 2025MHZ144, 22Y11921200, 82374540.

Disclosure

The authors declare that they have no competing interests in this work.

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