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Introduction

Pancreatic cancer is one of the most aggressive malignancies, with only 20% of patients eligible for surgical resection at the time of diagnosis.^1–3 These patients often face prolonged hospitalization and significant postoperative challenges, among which pain control remains a major clinical concern. Poorly managed postoperative pain can stimulate catecholamine release, which may suppress natural killer cell activity—a component of innate immunity—and potentially influence anti-tumor responses.⁴ Additionally, it is associated with increased psychological distress and reduced quality of life. Despite its clinical significance, current pain management strategies after pancreatic surgery are often suboptimal, underscoring the need for more effective analgesic approaches and further investigation into their impact on postoperative outcomes.

Patient-controlled intravenous analgesia (PCIA) with opioids is widely used for postoperative pain control.^5–8 Sufentanil, a selective potent μ-receptor agonist, is widely used for its efficacy in postoperative pain management.⁹ Given the moderate to severe pain typically associated with pancreatic surgery, a potent analgesic strategy is essential. However, increasing the dosage of a single analgesic agent to achieve adequate pain relief may also elevate the risk of adverse effects, including respiratory depression, nausea, and vomiting. Dezocine, a partial μ-receptor agonist and κ-receptor antagonist, has emerged as a promising adjunct due to its analgesic and sedative effects, as well as its favorable safety profile compared to pure μ-receptor agonists.^10–12 By acting on κ-receptors in the spinal cord and brain, dezocine provides analgesic and sedative effects without the typical µ-receptor dependence, potentially reducing adverse reactions such as smooth muscle relaxation.¹⁰ Previous studies have demonstrated that dezocine offers significant postoperative antihyperalgesic and analgesic effects, with benefits lasting up to 48 hours in patients undergoing open gastrectomy.¹³

Several studies have demonstrated that dezocine, when combined with morphine, enhances postoperative analgesia and reduces opioid-related side effects, such as nausea and pruritus, making it a valuable option in anesthesia practice.^14–16 At our institution, the combination of sufentanil and dezocine has been used in PCIA for pancreatic cancer patients for several years. However, the efficacy and safety of this combination have not been thoroughly investigated. To address this gap, we conducted a propensity score-matched (PSM) study at a high-volume pancreatic center to evaluate the role of dezocine as an adjunct to sufentanil in PCIA for postoperative pain management following pancreatic surgery, which, to our knowledge, is the first study to investigate the analgesic effects of this combination in PCIA for pancreatic surgery patients.

Materials and Methods

Ethics Approval

This retrospective study was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (Ethics Approval Number: (2023) No. 48), with a waiver of patient written informed consent due to the use of de-identified, archival medical records (no active patient intervention). All patient identifiers were removed, and data were stored securely on encrypted servers accessible only to the research team, adhering to the Declaration of Helsinki (as revised in 2013).

Patients

A total of 1485 patients who underwent elective open or minimally invasive pancreatic tumor surgery and received patient-controlled intravenous analgesia (PCIA) for postoperative pain management at the Pancreas Center of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, between January 2022 and January 2023 were retrospectively enrolled. The center is one of the largest pancreatic surgery centers in Asia. Among them, 794 were male and 691 were female, with an age range of 18 to 85 years (mean age: 60.55 ± 12.55 years) and American Society of Anesthesiologists (ASA) physical status classification ranging from I to IV. Based on the PCIA regimen, patients were allocated into two groups: the sufentanil group (n = 251) and the sufentanil-dezocine combination group (n = 1234). Surgical approach (Laparotomy/Laparoscopic/Robotic) was documented based on the description of the surgical procedure in the operative notes. All operative notes were reviewed and signed off by the attending surgeon or a senior resident physician to ensure consistency in classification. To minimize confounding and selection bias, PSM was performed using a logistic regression model based on age, sex, BMI, surgical approach (laparotomy, laparoscopic, robotic), surgery type (pancreatoduodenectomy, total pancreatectomy, middle-preserving pancreatectomy, distal pancreatectomy, as different techniques may affect pain severity due to varying tissue trauma), and dexmedetomidine dose. A caliper of 0.02 and nearest-neighbor matching were applied in a 1:3 ratio using R software (v.4.3.1, The R Foundation for Statistical Computing, Vienna, Austria. http://www.r-project.org). Exclusion criteria included: (1) known allergies to study drugs; (2) inability to use patient-controlled intravenous analgesia (PCIA); (3) history of chronic pain or long-term use of analgesic medications; (4) requirement for reoperation due to postoperative bleeding or severe abdominal infection; (5) severe cardiopulmonary or hepatorenal insufficiency and (6) cognitive dysfunction.

Anesthesia Procedure

All patients fasted for 8 hours (solids) and 6 hours (clear liquids) preoperatively and were transferred to the operating room without premedication. Standard monitoring included electrocardiography (ECG), non-invasive blood pressure (BP), respiratory rate (RR), oxygen saturation (SpO₂), end-tidal carbon dioxide pressure (PetCO₂), and bispectral index (BIS). A uniform anesthetic regimen was administered to all patients, with surgeries performed by the same surgical team.

General anesthesia was induced with propofol (2–2.5mg/kg), sufentanil (0.3–0.5 µg/kg), rocuronium (0.6–0.8mg/kg) or cisatracurium (0.2–0.3mg/kg), dexamethasone 5 mg, and dexmedetomidine 0.6 µg/kg. Preoxygenation with 100% oxygen was administered for at least 3 minutes via a face mask. Anesthesia was maintained with sevoflurane (3vol%, 0.8–1.3MAC), remifentanil (0.2–0.4µg/kg/min), supplemental rocuronium (1/3–1/5 of the induction dose), and intermittent sufentanil (0.4 µg/kg). Ventilation was set at a tidal volume of 8 mL/kg, with respiratory frequency adjusted to maintain PetCO₂ at 35–45 mmHg. Anesthesia depth was titrated to maintain a BIS between 40 and 60, ensuring mean arterial pressure (MAP) and heart rate (HR) remained within 20% of baseline values. Patient temperature was maintained above 36°C using infusion heaters and warming blankets. A sufentanil loading dose (0.1 µg/kg) was administered 30 minutes before the end of surgery. Intraoperative fluid balance was defined as the net change in a patient’s total body fluid volume during surgery, calculated as the difference between the total intraoperative fluids inputs and outputs. Postoperatively, patients were transferred to the post-anesthesia care unit (PACU), where residual neuromuscular blockade was reversed with neostigmine (40 µg/kg) and atropine (20 µg/kg).

Postoperative PCIA Regimen

After meeting extubation criteria, patients were extubated and connected to an Artificial Intelligence Patient-Controlled Analgesia (AI-PCA) system (Model ZZB-IB, Nantong AIPU Medical Inc., China). Patients were divided into two groups based on the PCIA solution: the sufentanil group received sufentanil (1.0 µg/mL), and the combination group received sufentanil (1.0 µg/mL) plus dezocine (2.5 mg/mL). Group allocation was guided by clinical judgment of the anesthesiologist considering factors reflected in our dataset such as patient demographics, surgical complexity, intraoperative management details.

The Acute Pain Service team prepared the PCIA solution in 100 mL normal saline bags, containing either sufentanil alone or the combination and monitored patients. If the Numerical Rating Scale (NRS) at rest was ≥4, a 2 mL bolus of PCIA solution was administered at 15-minute intervals until NRS <4. Patients were then encouraged to self-administer PCIA as needed.

The PCIA pump was set to a background infusion rate of 2 mL/h, with a 2 mL bolus dose and a 15-minute lockout interval. PCIA was maintained for 48 hours postoperatively, during which vital signs including respiratory rate, oxygen saturation, and sedation scores were closely monitored.

Outcome Measures

Demographic and intraoperative data, including surgery type, site, anesthetic drug dosages, blood loss, transfusion, and fluid balance, were recorded. Postoperative data included PCIA pump usage duration, total input, cumulative and effective press counts, rescue analgesia, and adverse events (eg, vomiting, pruritus, respiratory depression, hypotension, dizziness, delirium). We assessed Functional Activity Score (FAS) and Level of Sedation (LOS) at 1 and 2 days post-surgery. FAS (1–3 grades) quantifies pain impact on daily functions: 1=no limitation (normal coughing/limb movement despite pain); 2=mild limitation (slight difficulty/slower actions), and 3=severe limitation (struggles with basic activities). LOS (0–3 grades) evaluates consciousness via responsiveness: 0=alert (follows instructions), 1=somnolent (wakes to calls but drifts off), 2=stuporous (brief pain wakefulness), 3=comatose (no response to calls or pain). Both were graded during routine checks to guide pain management and monitor recovery. Pain intensity was evaluated using the NRS at rest (NRSR) and during coughing (NRSC) at 24, 48, and 72 hours post-surgery. The NRS ranges from 0 (no pain) to 10 (worst imaginable pain). Moderate-to-severe pain was defined as NRS ≥4. Mild pain (NRS 1–3) was also recorded in postoperative data. Adverse events were recorded based on routine clinical documentation in the hospital’s electronic medical records (EMR) and nursing care logs.

Primary endpoints were the incidence of moderate-to-severe pain at rest and during coughing within 48 hours post-surgery. Secondary endpoints included the incidence of moderate-severe pain at rest and during coughing at 24 hours and 72 hours post-surgery, LOS, FAS, and adverse events.

Statistical Analysis

Continuous variables were first assessed for normality, those with normal distribution were expressed as mean ± standard deviation (SD) and compared using independent t-tests. Skewed distributed continuous variables were presented as median (Q1, Q3) and analyzed with the Mann–Whitney U-test. Categorical variables were expressed as frequencies and percentage, and compared using Pearson’s chi-square or Fisher’s exact test. Missing data for demographic characteristics, intraoperative and postoperative data were imputed using the expectation-maximization algorithm. Univariate and multivariate logistic regression models, alongside with post-PSM analysis and inverse probability weighting (IPW) analysis were conducted to calculate odds ratios (OR) and 95% confidence intervals (CI). Analyses were performed using SAS (v.9.2, SAS Institute Inc., USA). All tests were two-sided, and statistical significance was set at the 5% level. No adjustments have been made for multiple testing.

Results

Patient Characteristics

Before PSM, the sufentanil group comprised 251 patients, while the combination group included 1234 patients. The sufentanil group was older (mean age 63.73 ± 13.69 years vs 59.90 ± 13.44 years, P< 0.05), had a higher proportion of pancreatoduodenectomy (PD) procedures (55.8% vs 44.8%, P< 0.05), and a greater rate of laparotomy (80.5% vs 73.9%, P < 0.05). Additionally, the sufentanil group had a lower BMI (22.25 ± 3.30 vs 22.73 ± 3.31, P < 0.05) and received a lower dexmedetomidine dosage (16.85 ± 15.75 µg vs 22.50 ± 16.32 µg, P < 0.05) compared to the combination group. No significant difference was observed in sex distribution. After PSM, the study included 247 patients in the sufentanil group and 704 in the combination group, with all baseline variables balanced between the two groups (Table 1).

Table 1 Demographic Characteristics and Perioperative Outcomes of Patients Between the Sufentanial Group and the Combination Group

Perioperative Outcomes

After PSM, no significant differences were observed in blood loss, blood transfusion volume, or total PCIA input between the two groups, despite differences before matching. The dosages of sufentanil and rocuronium bromide, as well as effective and cumulative PCIA press counts, showed no significant differences before or after PSM. However, the sufentanil group exhibited greater fluid balance difference and longer pump usage duration, which were statistically significant both before and after PSM (Table 1).

Primary Endpoint

The incidence of moderate-to-severe pain at rest and during coughing within 48 hours post-surgery is summarized in Table 2. After PSM, 19 patients (7.7%) in the sufentanil group experienced moderate-to-severe pain at rest, compared to 20 patients (2.8%) in the combination group (P < 0.05). Similarly, the incidence of pain during coughing was significantly higher in the sufentanil group (74 patients, 30.0%) than in the combination group (166 patients, 23.6%) during the same period (P < 0.05). These differences were also observed before PSM.

Table 2 Moderate-Severe Pain at Rest and During Coughing After Surgery Between the Sufentanial Group and the Combination Group

At 48 hours post-surgery, NRSR was significantly higher in the sufentanil group (1.97 ± 1.26) compared to the combination group (1.77 ± 0.91) (P= 0.018). Similarly, NRSC at 48 hours was higher in the sufentanil group (3.13 ± 1.57) than in the combination group (2.89 ± 1.17) (P= 0.022). All four analytical approaches including univariate and multivariate logistic regression analyses, post- PSM analysis and IPW analysis consistently identified sufentanil monotherapy as an independent predictor of moderate-to-severe pain, with odds ratios (ORs) and 95% confidence intervals (CIs) presented in Table 3.

Table 3 Logistic Regression Results for Moderate-Severe Pain at Rest and During Coughing After Surgery Between the Sufentanial Group and the Combination Group

Secondary Endpoints

Significant differences in the incidence of pain at rest and during coughing were observed at 24 and 72 hours post-surgery before PSM (P < 0.05). After PSM, these differences remained significant, except for pain during coughing at 72 hours (Table 2). No significant inter-group differences were noted in vomiting, hypotension, dizziness, delirium, or rescue analgesia on the first and second postoperative days, either before or after PSM. However, the functional activity scale (FAS) scores on the first and second postoperative days revealed significant differences between the two groups. Additionally, the proportion of fully alert patients on the second postoperative day was significantly higher in the combination group compared to the sufentanil group, both before and after PSM (Table 4).

Table 4 Adverse Events Between the Sufentanial Group and the Combination Group

Discussion

Pancreatic surgery is a critical intervention for pancreatic cancer, yet patients often experience prolonged postoperative pain, which can hinder physical and mental recovery. Effective pain management is therefore essential for improving patient outcomes and has garnered significant clinical attention. Opioid-based analgesia, particularly sufentanil, is widely used in patient-controlled intravenous analgesia (PCIA). However, the adverse effects of opioids, such as addiction, respiratory depression, pruritus, and sedation, have driven the search for alternative strategies to reduce opioid dosages and minimize side effects.¹⁷ Multimodal analgesia has emerged as a promising approach.¹⁸

In this propensity score-matched study, we evaluated the efficacy of combining sufentanil with dezocine in PCIA for postoperative pain management in patients undergoing pancreatic surgery. After matching, baseline characteristics and perioperative outcomes were comparable between the groups. Our findings demonstrated that the sufentanil-dezocine combination significantly reduced the incidence of moderate-to-severe pain at rest and during coughing within the first 48 hours postoperatively, without increasing the risk of clinically relevant side effects such as vomiting, hypotension, dizziness, delirium, or the need for rescue analgesia. Patients in the combination group exhibited significantly lower NRSR and NRSC at 48 hours post-surgery compared to the sufentanil group. Multivariate logistic regression analysis identified sufentanil monotherapy as an independent predictor of postoperative pain, suggesting that the addition of dezocine enhances analgesic efficacy, consistent with previous findings.¹⁶ These findings align with dezocine’s proposed mechanism: by targeting κ-receptors (which modulate pain perception) and partially activating μ-receptors (avoiding overstimulation), the combination may enhance analgesia while mitigating pure μ-agonist-related side effects. Notably, the reduction in pain during coughing–a high-pain activity critical for pancreatic surgery recovery–suggests the combination may be particularly beneficial for patients requiring early mobilization.

A primary concern with combining dezocine and sufentanil in PCIA is the potential for excessive sedation. However, our study found no evidence of increased sedation in the combination group during the 48-hour postoperative period. While sedation levels on the first postoperative day did not differ significantly, the proportion of fully alert patients was significantly higher in the combination group on the second postoperative day. This finding suggests that dezocine may enhance patient alertness while maintaining effective analgesia–Its ability to improve alertness and reduce sedation-related complications supports its value as a “balanced” adjunct in postoperative pain management^19–21 likely due to κ-receptor activation inducing lighter sedation compared to μ-agonists.

Postoperative adverse events, such as vomiting, hypotension, and dizziness, can negatively impact patient satisfaction and prolong hospital stays.¹⁰ Our study found that the addition of dezocine to sufentanil did not exacerbate these side effects. Notably, the combination group had a significantly lower incidence of respiratory depression compared to the sufentanil group, with no significant differences in vomiting, hypotension, dizziness, or delirium. These results align with previous research^22–25 and further support the safety profile of the sufentanil-dezocine combination.

Despite these promising findings, several limitations should be acknowledged. First, the retrospective design of the study introduces potential for selection bias, although this was mitigated by propensity score matching and the uniformity of our surgical team, Sensitivity analyses using alternative matching strategies (eg inverse probability weighting, multivariate logistic regression) yielded consistent results, suggesting no major residual confounding affected our conclusions. Second, generalizability of our findings may be limited. Due to our single-center design, even though our cohort meets high-volume criteria. As emphasized in a recent review on gastric cancer surgery outcomes, institutional factors can create variability in textbook outcomes (TOs) even among high-volume centers, highlighting the need for cross-institutional validation.²⁶ Future multi-center collaborations will compare textbook outcomes across 10+ high-volume centers using a pragmatic, standardized protocol to address this gap. Third, retrospective data precluded optimization of sufentanil/dezocine dosing. Prospective dose-response studies are needed to refine postoperative pain management in high-risk surgical populations.

In conclusion, our study demonstrates that the sufentanil-dezocine combination in PCIA significantly reduces moderate-to-severe pain at rest and during coughing within the first 48 hours after pancreatic surgery, without increasing the incidence of clinically relevant adverse effects, which has not been previously reported in the context of pancreatic surgery, suggesting it as a promising and safe approach for postoperative pain management in pancreatic cancer patients. Future research should focus on optimizing dosing strategies and confirming these results in prospective, multicenter trials.

Data Sharing Statement

The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding authors.

Funding

This work was supported by the National Natural Science Foundation of China (No: T2293734).

Disclosure

The authors declare that they have no conflicts of interest in this work.

References

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Introduction

Globally, hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with increasing incidence projected over the next two decades. In China, it is the second most lethal cancer, and the long-term prognosis following curative surgery remains poor due to high recurrence rates, with 5-year recurrence rates reported at approximately 50%–70%.^1–6 Recurrence is most frequent within the first postoperative year and often appears as distant intrahepatic or extrahepatic metastases, thought to originate from undetected micrometastases present at surgery. Tumor-related features such as size, number, differentiation, microvascular invasion (MVI), and elevated alpha-fetoprotein (AFP) are major determinants of early recurrence. Conversely, factors including patient age, sex, underlying liver disease etiology, and cirrhosis are more commonly linked to late recurrence.^7–9 While transcatheter arterial chemoembolization (TACE) is commonly used in this setting, the introduction of immune checkpoint inhibitors (ICIs) offers a novel therapeutic option. Building on recent trials investigating ICIs in advanced or unresectable HCC, such as IMbrave150 and CheckMate 459, attention has shifted to their potential in earlier disease stages. However, limited data exist regarding their application following surgery, especially in patients with MVI. Moreover, the duration of ICI therapy necessary to maximize efficacy remains undefined. This study sought to compare ICI-based therapy with TACE in a real-world postoperative setting and to assess whether extended ICI treatment (≥12 months) offers added benefit in reducing recurrence.

Patients and Methods

Patients and Study Design

To evaluate the comparative efficacy of adjuvant ICI therapy versus TACE in improving RFS among HCC patients with MVI, we conducted a retrospective, multicenter cohort study enrolling patients who underwent curative-intent hepatic resection between January 1, 2017, and March 31, 2024, at Peking Union Medical College Hospital (Beijing), China-Japan Friendship Hospital (Beijing), and Sun Yat-sen University Cancer Center (Guangzhou). Inclusion criteria were: (1) complete (R0) resection; (2) age between 18 and 75 years; (3) pathologically confirmed HCC with MVI; and (4) Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤ 1. Exclusion criteria encompassed: (1) recurrent HCC following prior curative resection; (2) history of spontaneous tumor rupture with hemorrhage; (3) coexistence of other active malignancies, including those in sustained remission; (4) administration of any neoadjuvant treatment modalities for HCC, including TACE, molecular targeted therapy, immunotherapy, or radiotherapy; and (5) death from non-HCC-related causes prior to follow-up.

Treatment and Data Collection

For patients anticipated to undergo extensive hepatectomy, preoperative evaluation of hepatic functional reserve was performed using the indocyanine green (ICG) retention test at 15 minutes. Surgical procedures were standardized across centers in accordance with established protocols previously described in the literature.¹⁰

Postoperative follow-up was routinely conducted 4 to 8 weeks after hepatic resection. For patients with MVI, adjuvant therapy was recommended contingent upon satisfactory general health and absence of contraindications. Given the lack of universally accepted adjuvant standards for MVI-positive HCC, treatment decisions were made based on multidisciplinary clinical evaluation, institutional practice patterns, and physician consensus. Regimen selection followed consistent clinical principles across centers and reflected contemporary real-world management of high-risk HCC. All adjuvant therapies, when applied, were initiated within 4 to 8 weeks following surgery.

Adjuvant TACE was initiated within 4–6 weeks post-resection, involving femoral artery catheterization and infusion of chemotherapeutic agents, as per institutional protocols.

Frequently employed targeted agents included lenvatinib,¹¹ apatinib,¹² donafenib, regorafenib,¹³ bevacizumab,¹⁴ administered once daily with dosage adjusted according to body weight or manufacturer guidelines. Immunotherapeutic agents commonly utilized in the adjuvant setting included sintilimab,¹⁵ carrelizumab,¹⁶ atezolizumab,¹⁴ tislelizumab.¹⁷ Prior to initiation, patients underwent thorough pre-treatment screening comprising blood panels, thyroid function assessment, electrocardiography, and chest CT imaging to ensure eligibility. ICIs were administered intravenously every three weeks in accordance with recommended dosing protocols. Vital signs were closely monitored during infusion and for at least 1hour post-infusion to promptly detect and manage any infusion-related reactions. Although the intended duration of adjuvant ICI therapy was 24 months, actual treatment durations varied in clinical practice. Some patients discontinued treatment within the first few months due to adverse events, financial burden, or poor adherence, even in the absence of tumor recurrence. To reduce immortal time bias in survival comparisons, patients who received ICI therapy for less than 6 months or experienced disease recurrence within 6 months were excluded from the duration-based survival analysis.

Follow-Up

Postoperative surveillance was rigorously implemented. All patients were scheduled for monthly follow-up visits during the first three months after hepatic resection, followed by assessments every three months for the subsequent two years, and semiannually thereafter. Each follow-up visits included evaluation of serum tumor markers, abdominal ultrasonography, and contrast-enhanced abdominal CT or MRI. Additional investigations, such as chest CT, bone scan, or positron emission tomography–CT (PET-CT), were performed when distant metastasis was clinically suspected. Follow-up was continued until patient death or loss to follow-up. The endpoint of the follow-up was September 20, 2024. Treatment of recurrence was personalized according to tumor profile, organ function, and patient status. The primary endpoint was RFS, as it reflects the direct effect of adjuvant therapy on preventing early relapse, particularly relevant in MVI-positive patients. OS was designated as a secondary endpoint, acknowledging the variability introduced by post-recurrence treatment heterogeneity. Of the 319 patients who received postoperative adjuvant therapy, 30 (9.4%) were lost to follow-up. Among the 80 patients under routine surveillance who did not receive adjuvant treatment, 9 (11.2%) were lost to follow-up. These individuals were not excluded from the analysis; instead, the time of their last documented follow-up was incorporated as censored observations in the survival analysis. This censoring strategy, implemented via the Kaplan–Meier method, ensured the inclusion of all available patient data and upheld the statistical robustness and validity of survival estimations.

Statistical Analysis

Continuous variables were summarized as mean ± standard deviation or median with interquartile range (IQR), and compared using Student’s t test or Mann–Whitney U-test, as appropriate. Categorical variables were compared using Pearson’s chi-square or Fisher’s exact test. To adjust for baseline differences between the TACE and immunotherapy groups, 1:1 PSM was performed using a nearest-neighbor algorithm (caliper = 0.2, no replacement). Covariates included AFP grade, HBV DNA, tumor differentiation, surgical margin, tumor number and size, satellite nodules, tumor embolus, MVI, and liver cirrhosis, selected based on clinical relevance and potential influence on treatment assignment. RFS and OS were estimated by Kaplan–Meier analysis and compared using Log rank tests; Cox regression identified independent predictors. Variables with P < 0.05 in univariate analysis, as well as clinically relevant covariates, were entered into the multivariate Cox regression model. To reduce immortal time bias, a 6-month landmark analysis excluded patients with recurrence or death before this point. Analyses were conducted using R (v4.3.1), with p < 0.05 considered significant.

Results

Patient Characteristics

From January 2017 to March 2024, a total of 1526 HCC patients from the three aforementioned centers were initially enrolled. All patients underwent curative liver resection, and postoperative pathology confirmed the diagnosis of HCC. Among them, 1,048 patients without MVI, 46 patients who received neoadjuvant therapy, 23 patients diagnosed with concurrent malignancies, and 10 patients who died from non-HCC-related causes were excluded. Ultimately, 399 patients were included in the final analysis (Figure 1). Among these patients, 132 received TACE alone, 58 received TACE combined with targeted therapy, 68 received TACE combined with targeted immunotherapy, 21 received targeted therapy combined with immunotherapy, 40 received only immunotherapy, and the remaining 80 patients did not receive any form of postoperative adjuvant therapy. Among the 319 patients who received postoperative adjuvant therapy, 30 were lost to follow-up, and among the 80 patients under active monitoring, 9 were lost to follow-up.

Figure 1 Patients flow chart. Abbreviations: MVI, microvascular invasion; HCC, hepatocellular carcinoma; TACE, transcatheter arterial chemoembolization; ICI, immune checkpoint inhibitor.

A total of 129 patients received adjuvant immunotherapy following curative hepatic resection. Among them, 40 received tislelizumab (anti–PD-1), 24 received camrelizumab (anti–PD-1), 21 received sintilimab (anti–PD-1), 11 received atezolizumab (anti–PD-L1), 10 received cadonilimab (a bispecific PD-1/CTLA-4 antibody), 10 received toripalimab (anti–PD-1), 7 received envafolimab (anti–PD-L1), and 6 received pembrolizumab (anti–PD-1). To minimize immortal time bias in the treatment duration analysis, 45 patients were excluded due to tumor recurrence occurring between 2 and 6 months postoperatively or receipt of immunotherapy for fewer than 6 months. The remaining 84 patients were included in the final analysis: 46 received adjuvant immunotherapy for less than 12 months, and 38 received it for 12 months or longer (Figure 1).

Before matching, the TACE and immunotherapy groups were largely comparable in baseline demographics and disease characteristics, except for differences in age, HBV DNA, and AFP levels. After 1:1 propensity score matching, 108 patients were included in each group (Figure 1), with no significant differences observed in baseline characteristics. A summary of baseline characteristics before and after matching is presented in Table 1.

Table 1 Baseline Characteristics of HCC Patients in the TACE and Immunotherapy Groups Before and After PSM

Treatment and Efficacy

During a median follow-up of 18 months (IQR 10–29 months), recurrence or metastasis occurred in 44 patients (34.1%) in the immunotherapy cohort and 86 patients (65.2%) in the TACE cohort. The predominant recurrence sites were the liver, lungs, and bones.

The median RFS was significantly longer in the immunotherapy cohort at 35 months (95% CI, 19–NA), compared with 16 months (95% CI, 10.8–27) in the TACE cohort (HR = 0.50, 95% CI, 0.34–0.72; p = 0.00015; Figure 2a). RFS rates at 12, 24, and 36 months were 75.4%, 53.1%, and 49.6% in the immunotherapy group, versus 54.5%, 42.8%, and 25.9% in the TACE group. Mortality was lower in the immunotherapy cohort (5.4%, 7 patients) compared to the TACE cohort (17.4%, 23 patients). Median overall survival (OS) was not reached in either group, but OS was significantly improved with immunotherapy (HR = 0.34, 95% CI, 0.14–0.80; p = 0.0096; Figure 2b). OS rates at 12, 24, and 36 months were 100.0%, 93.6%, and 86.9% in the immunotherapy cohort, versus 88.6%, 82.8%, and 81.0% in the TACE cohort. After PSM, the RFS benefit associated with immunotherapy remained statistically significant (HR = 0.54, 95% CI, 0.36–0.82; p = 0.0042; Figure 2c), while the OS difference was no longer statistically significant (HR = 0.43, 95% CI, 0.18–1.40; p = 0.060; Figure 2d).

Figure 2 Kaplan-Meier survival curves comparing the adjuvant ICI cohort and the TACE cohort: (a) RFS and (b) OS before PSM; (c) RFS and (d) OS after PSM. Abbreviations: HR, hazard ratio; CI, confidence interval.

Univariate and Multivariate Analyses of RFS and OS

Univariate and multivariate Cox regression analyses identified several independent predictors of poor prognosis (Table 2). For RFS, an advanced CNLC stage was significantly associated with shorter survival. For OS, a resection margin of less than 0.5 cm was identified as independent adverse prognostic factors.

Table 2 Univariate and Multivariate Analysis for RFS and OS of HCC Patients

Adverse Events (AE) in the Immunotherapy Cohort

Among the 129 patients who received immunotherapy, 55 patients (42.6%) experienced at least one treatment-related AE. Grade 1–2 AEs occurred in 51 patients (39.5%), while 13 patients (10.1%) experienced grade 3–4 events. No grade 5 AEs were reported (Supplementary Table 1). The most frequent AEs (any grade) were rash (9.3%), elevated AST (8.5%), ALT (7.8%), thrombocytopenia (7.0%), hypoalbuminemia (6.2%), and hypothyroidism (6.2%). Most events were grade 1–2 in severity. The most common grade 3–4 AEs included rash (5.4%), hypothyroidism (4.7%), and hypertension (3.9%). Other observed toxicities such as increased bilirubin (3.9%), elevated creatinine (3.9%), leukopenia (3.1%), mouth ulcers (3.1%), and fatigue (1.6%) were generally mild and manageable. No treatment-related deaths were observed.

Efficacy of Immunotherapy Duration on Survival Outcomes and AEs

To minimize immortal time bias, we excluded patients with recurrence-free survival less than 6 months and those who received ICI therapy for fewer than 6 months. Among the remaining cohort, patients who received adjuvant ICI therapy for 12 months or longer demonstrated significantly better RFS compared to those treated for less than 12 months (HR: 0.46, 95% CI: 0.21–0.99, p = 0.041; Figure 3a). A similar trend toward improved overall survival was observed, although the difference did not reach statistical significance (HR: 0.19, 95% CI: 0.02–1.59, p = 0.086; Figure 3b).

Figure 3 Survival outcomes of patients receiving adjuvant ICI therapy for ≥12 months versus <12 months: (a) RFS and (b) OS. Abbreviations: HR, hazard ratio; CI, confidence interval.

Among the 129 patients who received ICI-based adjuvant therapy, 68 received TACE combined with targeted immunotherapy, 21 received targeted immunotherapy, and 40 received immunotherapy alone. To account for the potential influence of different treatment regimens on survival outcomes, we conducted a subgroup analysis focusing on the largest group—patients who received postoperative TACE combined with targeted immunotherapy. After excluding those with a DFS less than 6 months and those who received immunotherapy for less than 6 months, we reevaluated RFS and OS. The analysis showed that patients who received ICIs for 12 months or longer had significantly improved RFS compared to those treated for less than 12 months (HR: 0.29, 95% CI: 0.11–0.79, p = 0.011; Figure 4a). While a longer OS was also observed in patients treated for 12 months or more, this difference was not statistically significant (HR: 0.19, 95% CI: 0.02–1.61, p = 0.089; Figure 4b).

Figure 4 Survival outcomes in the subgroup receiving TACE combined with targeted immunotherapy, stratified by ICI treatment duration (≥12 months vs <12 months): (a) RFS and (b) OS. Abbreviations: HR, hazard ratio; CI, confidence interval.

Among patients who received adjuvant immunotherapy, no significant differences were observed in the total number of adverse events between those treated for ≥12 months and those treated for <12 months (84.8% vs 89.5%, p >0.999; Supplementary Table 2). Similarly, the occurrence of grade 3–4 adverse events did not differ significantly between the two groups (26.1% vs 15.9%, p = 0.149; Supplementary Table 2). When comparing specific adverse events, no individual AE type showed a statistically significant difference between the two groups. However, numerically higher rates of hypertension and thrombocytopenia were noted in the ≥12-month treatment group, suggesting a trend toward increased incidence of some events with prolonged immunotherapy. Overall, extended treatment duration was not associated with a significantly increased risk of severe toxicity.

Discussion

Adjuvant therapies such as TACE, targeted agents, and immunotherapy have been associated with improved RFS and OS in HCC patients after curative resection.^18–20 However, the optimal duration of adjuvant immunotherapy for HCC patients with high-risk recurrence factors remains undefined, and real-world evidence on this topic is lacking. Although certain guidelines recommend that adjuvant immunotherapy should not exceed one year, they do not specify a minimum or preferred treatment duration.^21,22 In our study, compared to TACE alone, immunotherapy—either as monotherapy or in combination with TACE or targeted agents—was associated with a significant reduction in recurrence and improvement in OS among HCC patients with MVI who underwent R0 resection. After PSM, the benefit in RFS remained statistically significant, while the difference in overall survival was attenuated and no longer reached statistical significance. Importantly, ICI-based adjuvant therapies did not lead to a significant increase in AEs, with most AEs being grade 1–2, indicating good safety and tolerability. Among patients receiving adjuvant ICIs, a treatment duration of 12 months or longer was associated with significantly improved RFS compared to shorter durations. While a numerically favorable trend in OS was noted in the longer-duration group, the difference was not statistically significant. Therefore, no definitive conclusion regarding OS benefit can be drawn based on the current data, and this observation should be interpreted with caution. Furthermore, the total number of AEs and the incidence of grade 3–4 AEs were not significantly increased with longer treatment durations. Nevertheless, given the limited sample size of our study, larger and more comprehensive trials are needed to validate the safety and efficacy of postoperative adjuvant ICI therapy in this setting.

The clinical efficacy of ICIs was initially established in the advanced or unresectable HCC setting, as demonstrated by trials such as CheckMate 459²³ and IMbrave150.⁷ These studies showed that ICIs enhance antitumor immunity and may eradicate disseminated tumor cells. Extending this principle to earlier disease stages, adjuvant therapy aims to eliminate residual micrometastases and reduce distant recurrence, a major cause of treatment failure in MVI-positive patients. Indeed, several recent trials have tested this hypothesis. IMbrave050 reported an early RFS benefit with atezolizumab plus bevacizumab, though its updated analysis raised concerns about durability.²⁴ In contrast, a Phase II randomized controlled trial investigating adjuvant sintilimab showed a significant improvement in RFS among HCC patients with MVI,¹⁹ aligning with our findings and underscoring that high-risk populations may derive the greatest benefit. Retrospective studies have also suggested that adjuvant ICIs may improve prognosis among patients at high risk of recurrence.^25,26

Although several studies have investigated the safety and efficacy of adjuvant immunotherapy for HCC, the optimal duration of treatment has not been thoroughly explored. Given that treatment duration may critically influence patient outcomes, there is an urgent need for dedicated clinical trials addressing this issue. However, research specifically focused on treatment duration remains scarce. A prospective, multicenter cohort study evaluated the impact of adjuvant ICI treatment duration on RFS and OS in HCC patients at high risk of recurrence.²⁷ The results suggested that patients receiving adjuvant ICI therapy for more than six months tended to achieve better RFS and OS compared to those treated for six months or less, although the differences did not reach statistical significance. Despite the absence of a positive finding, the study indicated that six months of adjuvant ICI therapy might be insufficient and that extended treatment duration could potentially yield greater clinical benefits. Importantly, the design of ongoing Phase III randomized trials also reflects this rationale. Major studies such as CheckMate-9DX, KEYNOTE-937, JUPITER-04, SHR-1210-III-325, EMERALD-2, and DaDaLi have all adopted a 12-month adjuvant ICI regimen as the standard duration,²⁷ underscoring the clinical plausibility of our chosen cutoff. Nevertheless, the optimal duration of adjuvant immunotherapy remains an unresolved issue, not only in HCC but also in other malignancies such as non-small cell lung cancer^28,29 and melanoma, where prolonged ICI therapy has shown improved outcomes in certain settings. Our findings suggest that extending ICI therapy beyond 12 months may confer additional benefits for high-risk HCC patients; however, this hypothesis requires validation in prospective randomized studies. Future research should focus on defining the optimal duration of adjuvant immunotherapy, identifying predictive biomarkers for treatment benefit, and developing combination strategies tailored to individual recurrence risk profiles.

As a retrospective study, our analysis is inevitably subject to inherent biases. We acknowledge that comparisons based on treatment duration are vulnerable to immortal time bias, as longer-lived patients may be more likely to receive prolonged therapy. To mitigate this issue, we excluded patients who experienced recurrence or death within 6 months after surgery and those who received ICI therapy for less than 6 months. By restricting the analysis to patients who survived at least 6 months and initiated ICI treatment early, the impact of immortal time bias was reduced, although residual confounding remains possible. We also recognize that analyses involving secondary endpoints and subgroup comparisons may increase the risk of type I error. Another limitation is that the majority of ICIs used in our cohort were PD-1 inhibitors, with only a minority of patients treated with a bispecific PD-1/CTLA-4 antibody. Consequently, the efficacy and safety of other classes of immunotherapeutic agents, such as PD-L1 inhibitors, CTLA-4 inhibitors, and dual-targeting antibodies, were not assessed and warrant further investigation. Moreover, the heterogeneity of treatment regimens within our cohort may have influenced the outcomes. In addition, most patients in our study had HBV-related HCC, reflecting the epidemiological profile of HBV-endemic regions. Therefore, the generalizability of our findings to populations with HCV-related, alcohol-related, or non-viral HCC remains uncertain. Taken together, these limitations indicate that our conclusions should be interpreted with caution. Nonetheless, our findings provide important insights into the potential inadequacy of immunotherapy durations shorter than one year in high-risk HCC patients and highlight the need for prospective, standardized studies across diverse patient populations to confirm these observations.

Conclusions

This retrospective cohort study suggests that adjuvant ICI therapy following curative resection may improve RFS in HCC patients at high risk of recurrence compared to TACE. Notably, our findings indicate that a treatment duration of 12 months or longer is associated with improved RFS in patients with MVI. However, no statistically significant improvement in OS was observed with longer treatment duration. These results highlight the need to reconsider adjuvant immunotherapy strategies in this population, and underscore the importance of prospective, randomized, and large-scale clinical trials to determine the optimal duration of adjuvant ICI therapy for HCC.

Abbreviations

HCC, Hepatocellular carcinoma; MVI, Microvascular invasion; ICI, Immune checkpoint inhibitor; TACE, Transcatheter arterial chemoembolization; RFS, Recurrence-free survival; OS, Overall survival; PSM, Propensity score matching; AFP, Alpha-fetoprotein; HAIC, Hepatic arterial infusion chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; CT, Computed tomography; MRI, Magnetic resonance imaging; ICG, Indocyanine green; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; CNLC, China Liver Cancer staging system; BCLC, Barcelona Clinic Liver Cancer staging; PET-CT, Positron emission tomography-computed tomography; HR, Hazard ratio; CI, Confidence interval; AE, Adverse event; PD-1, Programmed death-1; PD-L1, Programmed death-ligand 1; CTLA-4, Cytotoxic T-lymphocyte-associated protein 4.

Data Sharing Statement

All data supporting the results of the study can be found in the article. Further inquiries can be directed to the corresponding author.

Statement of Ethics

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Peking Union Medical College Hospital (Approval No. I-23PJ964). Informed consent was obtained from all individual participants included in the study.

Acknowledgments

Xiaokun Chen, Jiali Xing, and Baoluhe Zhang are co-first authors for this study. We thank all the patients and the medical staff.

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

This work was supported by the National Natural Science Foundation of China (81972698); the CAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-01-014); Changzhou Xi Tai Hu development foundation for frontier cell- therapeutic technology (2024-P-019); the 2024 PhD Short-term Academic Visiting Program of Peking Union Medical College; the Start-up Fund from the Department of Liver Surgery, Peking Union Medical College Hospital; the Central high-level hospital clinical research special key cultivation project (2022-PUMCH-C-047); and 2021 Liver Cancer Diagnosis and Treatment Exchange Fund of Hubei Chen Xiaoping Science and Technology Development Foundation (CXPJJH1200009-01).

Disclosure

The authors have no conflicts of interest to declare in this work.

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