Adjuvant anti-PD-1 antibody for hepatocellular carcinoma with high recurrence risks after hepatectomy

doi:10.21203/rs.3.rs-2097894/v1

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Research Article

Adjuvant anti-PD-1 antibody for hepatocellular carcinoma with high recurrence risks after hepatectomy

https://doi.org/10.21203/rs.3.rs-2097894/v1

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Journal Publication

published 16 Jan, 2023

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Background and Purpose

The clinical role of postoperative adjuvant therapy in hepatocellular carcinoma (HCC) is still unclear. The purpose of our study was to explore the clinical value of postoperative adjuvant anti-programed cell death 1 antibody (PA-PD-1) on the prognosis of HCC patients with high relapse risks after surgery.

Patients and Methods

Consecutive HCC patients with high recurrence risks treated with liver resection at our center during January 2019 and March 2021 were prospectively enrolled. Baseline differences were balanced between HCC patients with (PA-PD-1 group) or without PA-PD-1 (non-PD-1 group) after hepatectomy by propensity-score matching (PSM). Between these two groups, we compared overall survival (OS) and recurrence-free survival (RFS). Independent prognostic risk factors for OS and RFS were confirmed by Cox regression analysis and subgroup analysis was also performed.

Results

47 pairs of patients with or without PD-1 treatment after hepatectomy were matched. After PSM, the 1-year and 2-year RFS were 58.4% and 44.1% in the PA-PD-1 group, and 34.0% and 21.3% in the non-PD-1 group (p = 0.008). The OS at 1-year and 2-year were 91.2% and 91.2% in the PA-PD-1 group, compared with 85.1% and 61.7% in the non-PD-1 group (p= 0.024). Multivariable analyses demonstrated that PA-PD-1 was an independent protective predictor associated with RFS and OS. Through subgroup analysis, we concluded that HCC patients with portal venous tumor thrombus (PVTT) or tumor size ≥ 5 cm significantly benefited from PA-PD-1 therapy in RFS and OS.

Conclusions

Adjuvant anti-PD-1 antibody can effectively improve the survival outcomes of HCC patients with high relapse risks after hepatectomy.

Hepatocellular carcinoma

Hepatic venous tumor thrombus

Independent prognostic factors

Overall survival

Postoperative adjuvant therapy

Portal venous tumor thrombus

Programmed cell death 1

Propensity-score matching

Recurrence

Recurrence-free survival

Hepatocellular carcinoma (HCC) makes up 75-85 percent of primary liver cancers and it is among the deadliest malignant tumors in the world(1). The established first-line therapeutic option for HCC patients is hepatectomy. However, up to 50%-70% of HCC patients undergoing radical hepatic resection experience relapse within five years(2-4), with five-year survival rates of only 30%-50%(5-7). Furthermore, patients with high relapse factors, for example, microvascular invasion (MVI), satellite nodules, multiple tumors, hepatic venous tumor thrombus (HVTT), portal venous tumor thrombus (PVTT), positive resection margin, alpha-fetoprotein (AFP) > 400 ng/mL and large tumor (especially＞5 cm) showed obviously higher recurrence rate and worse prognosis(8-10). Previous findings have revealed that the five-year survival rates for HCC patients with lymph node metastasis, HVTT, and PVTT were only 20.8 %, 6.5%, and 32.9%, respectively(11-13). Therefore, effective postoperative adjuvant therapies are certainly important to reduce recurrence and improve long-term survival.

Although adjuvant treatment after surgery is not recommended by current guidelines about HCC(14; 15), previous studies including some randomized controlled trials (RCTs) did reveal that multiple treatment modalities, such as adjuvant transarterial chemoembolization (TACE), IFN-α, and direct-acting antiviral agents for hepatitis virus-infected HCC patients, have the influence of reducing recurrence and prolonging survival(16-19). Immunotherapy has been previously explored as an adjuvant therapeutic option in HCC patients receiving radical surgery(20; 21). A randomized trial of 150 postoperative HCC patients explored the clinical effectiveness of adoptive immunotherapy in reducing the frequency of tumor recurrence and reported that patients who received lymphocyte infusion gained obviously greater recurrence-free survival (RFS) than control patients(22).

Immune checkpoint inhibitor (ICI)-based combination regimens have shown potential survival benefits in advanced HCC(23-25). Mechanically, they can play a role in enhancing human immune recognition and inhibiting tumor cell regeneration. And the duration of response to ICIs has always been long since activated T-lymphocyte can retain memories of their targets(26), making it a promising approach for postoperative adjuvant therapy in HCC, especially for HCC patients with high relapse risks after initial hepatectomy. However, to date, postoperative adjuvant treatment with anti-PD-1 antibodies for HCC has not yet been reported. Our prospective study was set up to explore the clinical benefit of postoperative adjuvant anti-PD-1 antibody (PA-PD-1) on the prognosis of HCC with high relapse risks after liver resection.

Participant Selection

Following the guidance of the Declaration of Helsinki (1964), this prospective observational study was conducted. The First Affiliated Hospital of Sun Yat-sen University's Institutional Research Ethics Committee granted ethical approval for the study. All of the enrolled participants signed informed consent. Inclusion criteria were outlined below: (1) aged 18-75 years; (2) underwent R0 resection and confirmed as HCC by postoperative pathology; (3) received radiological evaluations such as abdominal CT, or MRI to confirm no tumor relapse or residual within one month after surgery; (4) Eastern Co-operative Oncology Group (ECOG) score ≤ 1; (5) Child-Pugh A or B; (6) presence of one or more high risk for relapse: MVI, PVTT, HVTT, satellite nodules, multiple tumor nodules(> 3 nodules), AFP ＞ 400 ng/mL and maximum tumor size exceeding 5 cm(9; 17; 27). Following were the exclusion criteria: (1) known sarcomatoid HCC, combined cholangiocarcinoma and HCC or fibrolamellar HCC; (2) evidence of distant metastasis or coexistence of other malignancies on baseline imaging; (3) previously received systemic anti-cancer therapy for HCC; and (4) incomplete data. According to these criteria, patients were included and separated into two groups: (1) HCC patients undergoing hepatic resection with postoperative adjuvant anti-PD-1 antibody (PA-PD-1 group); (2) HCC patients undergoing hepatectomy without postoperative adjuvant anti-PD-1 antibody (non-PD-1 group). Data including demographic and clinical characteristics and follow-up information was collected and analyzed by two independent researchers (Yukun Sun and Shuifang Hu).

Adjuvant anti-PD-1 antibody treatment

PA-PD-1 antibody therapy was recommended according to the physician’s clinical knowledge and experience and ultimately determined by the patient. HCC patients in the PA-PD-1 group were treated with intravenous PD-1 blockade therapy at an interval of 21 days after each regimen. Patients continuously received PD-1 blockade treatment until unacceptable toxic reactions measured following the CTCAE version 5, or disease progression occurred.

Postoperative Follow-Up and Endpoints

HCC patients in the two groups received regular follow-ups after liver surgery. Postoperative surveillance visits were scheduled one month postoperatively to confirm disease-free status, every two to three months for the first two years, then every six to twelve months thereafter. Follow-up examinations were conducted using physical examination, laboratory tests (including peripheral blood test, liver function, AFP), and abdominal radiological examinations (ultrasound, contrast-enhanced CT, or MRI). RFS and overall survival (OS) were used as primary endpoints. RFS and OS were defined as the interval from the date of hepatectomy to the date of tumor relapse and the date of death due to any cause or last follow-up, respectively. The last follow-up date was based on the last hospital or outpatient visit or telephone record. Follow-up data collection was terminated on January 30, 2022.

HCC recurrences or metastases were diagnosed according to histological or cytological evidence or non-invasive examination recommended by the EASL(28). Images were independently reviewed by two senior radiologists. The final recurrent diagnosis was determined upon review all clinical data in the case of discrepancies in CT or MRI. Patients with recurrence of HCC underwent radiofrequency ablation, surgery, TACE, radiotherapy, or systemic treatment, considering tumor characteristics (location, size and number), general condition and liver function.

Statistical Analysis

To minimize selection bias and reduce the potential impact of confounders, we used a propensity score matching (PSM) analysis, matching patients received anti-PD-1 antibody after hepatectomy with those who did not receive treatment. Baseline variables with p values＜0.2of the two groups were put into the PSM model to calculate propensity score, including age, tumor number, BCLC classification, lymph node invasion, HVTT, liver cirrhosis, PVTT, adjuvant TACE, adjuvant radiotherapy, adjuvant hepatic arterial infusion chemotherapy, and adjuvant targeted therapy. HCC patients were matched in a ratio of one to one based on logistic regression of propensity scores. Continuous normally or non-normally distributed variables were represented as means ± standard deviations or medians with interquartile ranges (IQR) and compared through the Student’s t-tests or the Mann–Whitney U-tests, respectively. Comparisons of categorical variables, expressed as frequencies (percentages), were performed through Pearson's chi-square tests or Fisher’s exact tests. RFS and OS curves were generated and compared between the non-PD-1 and PA-PD-1 groups through the Kaplan-Meier method and the log-rank test. Independent predictors for RFS and OS were confirmed by Cox regression analyses. Clinical factors with p＜0.1 in the univariate analysis were entered into multivariable analysis and considered for developing the multivariable Cox model for further screening. Subgroup analyses for clinical variables such as age (＜55 years old vs. ≥ 55 years old), sex (female vs. male), tumor size (＜5 cm vs. ＞5 cm), AFP (＜400 ng/ml vs.＞400 ng/ml), MVI (no vs. yes), and PVTT (no vs. yes) were performed through the Kaplan-Meier method and the forestplot for subgroup analyses was described with estimated hazard ratios (HRs) and 95% confidence intervals (CIs). For statistical analysis, the software of SPSS (version 26.0) was employed. With Rstudio, “survminer”, “survival”, and “forestplot” packages were used to analyze the data. Statistical tests were two-sided with significance defined as p < 0.05.

Patient Characteristics

From January 2019 to March 2021, 1001 HCC patients underwent surgery in our institution. Based on exclusion criteria, 483 patients were excluded, and 518 HCC patients with high relapse risks were included, with 51 patients undergoing PA-PA-1 treatment and 467 patients undergoing hepatectomy alone (Fig. 1). To balance the baseline differences, 94 patients were included in the two groups after 1:1 PSM. Detailed baseline and preoperative clinical characteristics of the non-PD-1 group compared with the PA-PD-1 group before and after PSM were described in Table 1. Before PSM, age, tumor number, BCLC classification, liver cirrhosis, and PVTT differed obviously between the two groups (all p＜0.05). Male patients, patients infected with hepatitis B virus, and patients with Child-Pugh A comprised the majority of patients (＞80%) in the two groups. Forty-seven pairs of HCC patients who did and did not receive anti-PD-1 antibody therapy after hepatectomy were selected from each groupafter a 1:1 PSM, with a median follow-up duration of 15.3 months. Among the 47 patients in the PA-PD-1group, 23 received Tislelizumab, 21 received Camrelizumab, two received Pembrolizumab and one received Toripalimab. Potential confounding factors were balanced in the two groups (all p > 0.05).

Recurrence-free survival and Overall survival

After PSM, the median RFS in the PA-PD-1 group was 17.67 (6.18-29.16) months, while it was 5.73 (4.31-7.15) months in the non-PA-PD-1 group. The corresponding 1-year and 2-year RFS were 58.40% and 44.13% in the PA-PD-1 group, and 34.04% and 21.28% in the non-PA-PD-1 group, respectively. In the PA-PD-1 group, the RFS was longer than in the non-PD-1 group(p= 0.008, Fig. 2a). Both groups did not reach the median OS time. The corresponding 1-year and 2-year OS were 91.29% and 91.29% in the PA-PD-1 group, and 87.23% and 61.70% in the non-PD-1 group, respectively. Between the two groups, OS showed a statistically significant difference (p = 0.024, Fig. 2b).

Univariable and Multivariable Analysis

Univariable analysis revealed that PA-PD-1 (HR=0.485; 95%CI=0.282-0.836; p =0.009), multiple tumor numbers (HR=2.493; 95%CI=1.463-4.248; p =0.001), HVTT (HR=2.605; 95%CI=1.315-5.161; p = 0.006), and AFP > 400ng/ml (HR=2.111; 95% CI=1.265-3.521; p = 0.004) were factors significantly related to RFS (Table 2). Similarly, multivariable analysis showed that PA-PD-1 (HR=0.479; 95% CI=0.276-0.832; p = 0.009), multiple tumor numbers (HR =2.058; 95% CI= 1.199-3.533; p = 0.009), HVTT (HR =2.029; 95% CI =1.353-5.545; p = 0.005), and AFP > 400ng/ml (HR=2.029; 95% CI =1.205-3.417; p = 0.008) were independent predictors of RFS (Table 2).

PA-PD-1 treatment (HR= 0.303; 95% CI= 0.101-0.908; p = 0.033), tumor size > 5cm (HR =3.453; 95% CI =1.027-11.612; p = 0.045), and HVTT (HR= 2.709; 95% CI =1.086-6.757; p = 0.033) were significantly related with OS in the univariate analysis. Multivariable analysis revealed that PA-PD-1 treatment (HR =0.297; 95% CI= 0.095-0.922; p = 0.036) was a predictor of OS.

Subgroup Analysis

Subgroup analyses stratified by different clinical variables were performed to further explore the efficacy of the PA-PD-1 for HCC patients after surgery.

The PA-PD-1 group consistently achieved longer RFS than the non-PA-PD-1 group in the subgroups of < 55 years (HR= 0.51, 95% CI=0.27-0.96; Fig. 3a), male (HR = 0.54, 95% CI= 0.32-0.92), tumor size ≥ 5 cm (HR = 0.41, 95% CI=0.23-0.73), no HVTT (HR= 0.45, 95% CI =0.26-0.79), PVTT presence (HR= 0.40, 95% CI= 0.18-0.88), no MVI (HR= 0.38, 95% CI =0.15-0.93), no tumor satellites (HR =0.55, 95% CI =0.31-0.96), no liver cirrhosis (HR= 0.53, 95% CI= 0.28-0.98), Child-Pugh A (HR =0.50, 95% CI =0.29-0.84), no HCV infection (HR= 0.51, 95% CI=0.29-0.86), no lymph node invasion (HR =0.55, 95% CI =0.33-0.93), and AFP < 400 ng/ml (HR=0.41, 95% CI =0.2-0.84).

In addition, patients obviously benefited from PA-PD-1 in OS if they had age ≥ 55 years (HR= 0.18, 95% CI= 0.04-0.78; Fig. 3b), male (HR =0.37, 95% CI =0.16-0.86), tumor size ≥ 5 cm (HR= 0.21, 95% CI= 0.09-0.49), tumor number > 3 (HR =0.24, 95% CI =0.06-0.89), BCLC stage A and B (HR =0.25, 95% CI =0.07-0.93), no HVTT (HR= 0.25, 95% CI =0.1-0.64), PVTT presence (HR= 0.15, 95% CI= 0.04-0.5), no tumor satellites (HR= 0.36, 95% CI= 0.14-0.94), no liver cirrhosis (HR =0.36, 95% CI =0.14-0.95), Child-Pugh A (HR =0.38, 95% CI =0.17-0.89), no lymph node invasion (HR= 0.37, 95% CI= 0.16-0.85), and AFP < 400ng/ml (HR =0.18, 95% CI =0.05-0.67).

Recently, PD-1 inhibitors have been developed as postoperative adjuvant treatment in some cancers due to their ability to boost patients’ immune systems; for instance, pembrolizumab has been approved for melanoma and renal-cell carcinoma based on conclusions from the KEYNOTE-716 study (NCT03553836) and phase III KEYNOTE-564 study (NCT03142334), respectively(29; 30). However, clinical evidence of PA-PD-1 therapy for HCC is still lacking, although many clinical trials exploring the efficacy of PA-PD-1 treatment are currently ongoing, such as durvalumab (NCT03847428), pembrolizumab (NCT03867084), atezolizumab (NCT04102098), and nivolumab (NCT03383458).

As we know, this is the first prospective study to explore the effect of PA-PD-1 therapy, demonstrating that HCC patients with high recurrence risks after hepatectomy had obviously improved OS and RFS in the PA-PD-1 group compared with the non-PD-1 group. With 1:1 PSM, the two groups were well balanced for potential clinical variables affecting tumor relapse, such as tumor size, number, MVI, BCLC stage, AFP, and HVTT. Therefore, the significant reduction in the risk of recurrence is attributable to PA-PD-1 therapy. Furthermore, univariable and multivariable analyses revealed that PA-PD-1 treatment was an independent predictor of both RFS and OS. This finding suggests that PA-PD-1 could be a promising therapy for HCC patients with high risk of relapse after hepatectomy. In accordance with the present results, a phase II prospective multicenter trial reported at the 2021 ASCO Annual Meeting showed that the 1-y RFS was 76.7% and the median RFS was 26 months (95% CI 23.9 to 28.1 months) for HCC patients received nivolumab after liver resection, which greatly improved postoperative quality of life(31). Patients in this multicenter study had a more favorable RFS than those in our study (76.5% vs 58.40%), partly because the HCC patients in our study had at least one of the recurrence risk factors, meaning they were more susceptible to tumor recurrence. In fact, subgroup analysis of the phase 2 clinical trial also demonstrated that patients with an immunosuppressive tumor microenvironment had worse RFS, which further indicates the importance of postoperative immunotherapy for HCC patients with high relapse factors after hepatectomy (31).

The tumor relapse rate within five years after hepatic resection for HCC is as high as 50-70%, which is related to the possible existence of small dissemination or multicentric occurrence before surgery(3; 32; 33). The relapse of HCC is classified as early relapse (within two years) and late relapse (after two years) based on the time to recurrence after hepatectomy. Intrahepatic tumor metastasis is related to the aggressiveness of the primary cancer and is the primary reason for early recurrence (34). Because of the short duration of treatment and follow-up, we only provide data on early recurrence and overall survival in the first two years. Our multivariable analyses showed that multiple tumor numbers (≥ 3), HVTT, and AFP > 400ng/ml were other factors significantly related to RFS, indicating that these factors affect early recurrence. Previous studies reported that early tumor recurrence is more likely to occur with the characteristics of tumor pathology, such as poor cell differentiation, multiple tumors, large tumor size, MVI, and satellite lesions(35-37). We are presently unable to arrive at conclusions about the predictive factors for late recurrence because of the short follow-up duration, but previous literature has reported on them. A multicenter retrospective study of 734 HCC patients after curative hepatectomy demonstrated that sex of male, cirrhosis, multiple tumors, satellite nodules, tumor size exceeding 5 cm, and MVI were independent predictors of late relapse(10). Regardless of whether HCC patients with high-risk factors of early or late relapse would benefit more from immunotherapy, our subgroup analysis suggested that PA-PD-1 significantly improved RFS and OS for patients with PVTT or tumor size ≥ 5 cm.

There are several limitations. First, the observational, non-randomized study has its inherent flaws, and it is difficult to completely avoid selection bias, although PSM was applied. Moreover, the number of patients is insufficient (47 patients in each group after PSM) and the follow-up period was short. Thus, research with more patients and longer follow-ups are needed to verify. our results.

PA-PD-1 is a potentially new and effective intervention in improving survival outcomes for HCC patients with high relapse factors after hepatectomy. Further randomized controlled trials investigating its efficacy and safety are required to confirm the finding and to better understand the value of postoperative adjuvant PD-1 in patients with HCC.

AFP: alpha-fetoprotein; CIs: confidence intervals; HCC: hepatocellular carcinoma; HRs: hazard ratios; HVTT: hepatic venous tumor thrombus; MVI: microvascular invasion; RFS: recurrence-free survival; TACE: transarterial chemoembolization; OS: overall survival; PA-PD-1: postoperative adjuvant anti-programed cell death 1 antibody; PSM: propensity-score matching; PVTT: portal venous tumor thrombus.

Author Contributions

Zhenwei Peng, Shunli Shen, Jian Wu conceived and designed this study; Material acquisition, data collection, analysis, and interpretation were carried out by Wei Chen, Shuifang Hu, Yukun Sun and Zhenwei Peng. The initial draft of the artical was written by Wei Chen, Shuifang Hu, and Yukun Sun. And Zhenwei Peng revised it. Final approval of the manuscript was obtained from all authors.

Conflict of Interest

Wei Chen, Shuifang Hu, Yukun Sun, Jian Wu, Shunli Shen and Zhenwei Peng declare that they do not have any conflict of interests.

Acknowledgments

Not applicable.

Informed Consent in Studies with Human Subjects

All enrolled participants provided written informed consent for data collection and analysis.

Ethical Approval:

The study was conducted under the guidance of the Declaration of Helsinki (1964) and was approved by the institutional research ethics committee of the First Affiliated Hospital of Sun Yat-sen University.

Funding:

This study was supported by the National Natural Science Foundation of China (No. 82072029), the National high level talents special support plan- “Ten thousand plan”-Young top-notch talent support program (No. 2019).

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.
Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235:373–82.
Lee SY, Konstantinidis IT, Eaton AA, Gönen M, Kingham TP, et al. Predicting recurrence patterns after resection of hepatocellular cancer. HPB (Oxford). 2014;16:943–53.
Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg. 2015;261:947–55.
Lang H, Sotiropoulos GC, Brokalaki EI, Schmitz KJ, Bertona C, et al. Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers. J Am Coll Surg. 2007;205:27–36.
Altekruse SF, McGlynn KA, Dickie LA, Kleiner DE. Hepatocellular carcinoma confirmation, treatment, and survival in surveillance, epidemiology, and end results registries, 1992–2008. Hepatology. 2012;55:476–82.
Lee JG, Kang CM, Park JS, Kim KS, Yoon DS, et al. The actual five-year survival rate of hepatocellular carcinoma patients after curative resection. Yonsei Med J. 2006;47:105–12.
Shinkawa H, Tanaka S, Takemura S, Amano R, Kimura K, et al. Nomograms predicting extra- and early intrahepatic recurrence after hepatic resection of hepatocellular carcinoma. Surgery. 2021;169:922–8.
Tung-Ping Poon R, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000;232:10–24.
Xu XF, Xing H, Han J, Li ZL, Lau WY, et al. Risk Factors, Patterns, and Outcomes of Late Recurrence After Liver Resection for Hepatocellular Carcinoma: A Multicenter Study From China. JAMA Surg. 2019;154:209–17.
Amini N, Ejaz A, Spolverato G, Maithel SK, Kim Y, Pawlik TM. Management of lymph nodes during resection of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: a systematic review. J Gastrointest Surg. 2014;18:2136–48.
Chen ZH, Zhang XP, Feng S, Feng JK, Chai ZT, et al. Liver resection versus intensity-modulated radiation therapy for treatment of hepatocellular carcinoma with hepatic vein tumor thrombus: a propensity score matching analysis. Hepatobiliary Surg Nutr. 2021;10:646–60.
Kokudo T, Hasegawa K, Matsuyama Y, Takayama T, Izumi N, et al. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol. 2016;65:938–43.
Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80.
European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. 2018. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 69:182–236.
Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg. 2007;245:831–42.
Wang Z, Ren Z, Chen Y, Hu J, Yang G, et al. Adjuvant Transarterial Chemoembolization for HBV-Related Hepatocellular Carcinoma After Resection: A Randomized Controlled Study. Clin Cancer Res. 2018;24:2074–81.
Wei W, Jian PE, Li SH, Guo ZX, Zhang YF, et al. Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety. Cancer Commun (Lond). 2018;38:61.
Yin J, Li N, Han Y, Xue J, Deng Y, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol. 2013;31:3647–55.
Hui D, Qiang L, Jian W, Ti Z, Da-Lu K. A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis. 2009;41:36–41.
Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015;148:1383–91.e6.
Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356:802–7.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–502.
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–52.
Qin S, Ren Z, Meng Z, Chen Z, Chai X, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21:571–80.
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.
Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–7.
2018. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 69:182–236.
Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399:1718–29.
Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021;385:683–94.
Kudo M, Ueshima K, Nakahira S, Nishida N, Ida H, et al. Adjuvant nivolumab for hepatocellular carcinoma (HCC) after surgical resection (SR) or radiofrequency ablation (NIVOLVE): A phase 2 prospective multicenter single-arm trial and exploratory biomarker analysis. J Clin Oncol. 2021;39:4070-.
Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.
Poon RT, Fan ST, Ng IO, Wong J. Significance of resection margin in hepatectomy for hepatocellular carcinoma: A critical reappraisal. Ann Surg. 2000;231:544–51.
Zhu XD, Li KS, Sun HC. Adjuvant therapies after curative treatments for hepatocellular carcinoma: Current status and prospects. Genes Dis. 2020;7:359–69.
Shimoda M, Tago K, Shiraki T, Mori S, Kato M, et al. Risk Factors for Early Recurrence of Single Lesion Hepatocellular Carcinoma After Curative Resection. World J Surg. 2016;40:2466–71.
Lee HY, Rhim H, Lee MW, Kim YS, Choi D, et al. Early diffuse recurrence of hepatocellular carcinoma after percutaneous radiofrequency ablation: analysis of risk factors. Eur Radiol. 2013;23:190–7.
Huang L, Li J, Yan J, Cao J, Liu C, et al. Early recurrence after curative resection in oligonodular hepatocellular carcinoma. Hepatogastroenterology. 2013;60:28–31.

Table 1. Baseline demographic and clinical characteristics of Non-PD-1 Group Compared with PA-PD-1 Group Before and After PSM.

Parameters

Before PSM

After PSM

Non-PD-1 Group(n=467)

PA-PD-1 Group(n=51)

Non-PD-1 Group(n=47)

PA-PD-1 Group(n=47)

Age(years)

Mean (SD)

54.54 ± 11.93

49.51 ± 12.02

0.009

50.81±13.02

49.26±12.23

0.553

Sex

Female

Male

47 (10.1%)

420 (89.9%)

2 (3.9%)

49 (96.1%)

0.241

6(12.8%)

41(87.2%)

2(4.3%)

45(95.7%)

0.267

Tumor Number

＞3

328(70.2%)

52(11.1%)

6(1.3%)

81(17.3%)

28(54.9%)

7(13.7%)

2(3.9%)

14(27.5%)

0.022

23(48.9%)

5(10.6%)

2(4.3%)

17(36.2%)

26(55.3%)

7(14.9%)

2(4.3%)

12(25.5%)

0.382

BCLC classification

13(2.8%)

252(54%)

91(19.3%)

111(23.8%)

0(0%)

14(27.5%)

15(29.4%)

22(43.1%)

＜0.001

3(6.4%)

12(25.5%)

11(23.4%)

21(44.7%)

0(0.0%)

14(29.8%)

19(40.4%)

0.987

Maximum tumor size (mm)

72.94 ± 36.87

77.09 ± 32.66

0.229

76.54 ±43.69

79.15±32.21

0.621

Microvascular invasion

Yes

291(62.3%)

176(37.7%)

32(62.7%)

19(37.3%)

1.000

31(66.0%)

16(34.0%)

28(59.6%)

19(40.4)

0.522

Tumor satellites

Yes

56(12%)

411(88%)

6(11.8%)

45(88.2%)

1.000

10(21.3%)

37(78.7%)

5(10.6%)

42(89.4%)

0.159

Lymph node invasion

Yes

4(0.9%)

463(99.1%)

2(3.9%)

49(96.1%)

0.110

2(4.3%)

45(95.7%)

1(2.1%)

46(97.9%)

1.000

HVTT

Yes

26(5.6%)

441(94.4%)

7(13.7%)

44(86.3%)

0.050

6(12.8%)

41(87.2%)

6(12.8%)

41(87.2%)

1.000

Liver cirrhosis

Yes

180(38.5%)

287(61.5%)

10(19.6%)

41(80.4%)

0.008

18(38.3%)

29(61.7%)

10(21.3%)

37(78.7%)

0.071

PVTT

Yes

96(20.6%)

371(79.4%)

20(39.2%)

31(60.8%)

0.003

18(38.3%)

29(61.7%%)

17(36.2%)

30(63.8%)

0.5

Child-Pugh grade

444(95.1%)

23(23%)

48(94.1%)

3(5.9%)

1.000

44(93.6%)

3(6.4%)

44(93.6%)

3(6.4%)

1.000

HbsAg positive

Yes

383(82%)

84(18%)

44(86.3%)

7(13.7%)

0.448

40(85.1%)

7(14.9%)

41(87.2%)

6(12.8%)

0.765

HCV-Ab positive

Yes

12(2.6%)

455(94.7%)

1(2%)

50(98%)

1.000

4(8.5%)

43(91.5%)

1(2.1%)

46(97.9%)

0.358

AFP

AFP＞400ng/ml

AFP＜400ng/ml

157(33.6%)

310(66.4%)

19(37.3%)

32(62.7%)

0.603

19(40.4%)

28(59.6%)

18(38.3%)

29(61.7%)

0.833

Note: The bold text means P<0.05.

Abbreviations: AFP, alpha-fetoprotein; HCV, hepatitis C virus; HVTT: hepatic venous tumor thrombus; PSM, propensity-score matching; PA-PD-1: adjuvant anti-PD-1; PVTT: portal venous tumor thrombus; SD, Standard Deviation.

Table 2. Univariate and Multivariate Analysis of RFS and OS for HCC with high risk factors after PSM.

Parameter				RFS								OS
		Univariate					Multivariate				Univariate					Multivariate
	HR		95% CI		P	HR		95% CI	P	HR			95% CI	P	HR		95% CI	P
Age, ≥55 vs ＜55	0.729		0.426-1.249		0.250					0.851			0.379-1.912	0.696
Sex, male vs female	0.941		0.376-2.354		0.897					0.730			0.219-2.435	0.608
Maximum tumor size, ＞5cm vs ＜5cm	1.109		0.603-2.038		0.739					3.453			1.027-11.612	0.045	2.961		0.820-10.693	0.097
Number of lesions, ＞3 vs 1/2/3	2.493		1.463-4.248		0.001	2.058		1.199-3.533	0.009	1.516			0.687-3.345	0.303
BCLC classification, C vs 0/A/B	1.476		0.888-2.452		0.133					2.107			0.966-4.595	0.061	1.337		0.526-3.301	0.542
Lymph node invasion, yes vs no	1.041		0.253-4.281		0.956					2.530			0.590-10.843	0.211
HVTT, yes vs no	2.605		1.315-5.161		0.006	2.739		1.353-5.545	0.005	2.709			1.086-6.757	0.033	1.805		0.601-5.424	0.293
PVTT, yes vs no	1.296		0.772-2.176		0.326					1.306			0.599-2.850	0.502
MVI, yes vs no	1.379		0.799-2.378		0.248					0.971			0.432-2.185	0.944
Tumor satellites, yes vs no	1.492		0.775-2.872		0.231					2.352			0.986-5.612	0.054	1.279		0.468-3.497	0.632
Liver cirrhosis, yes vs no	1.325		0.774-2.269		0.305					0.882			0.382-2.037	0.769
Child-pugh classification, B vs A	1.286		0.513-3.223		0.592					0.977			0.230-4.146	0.975
HbsAg, positive vs negative	1.108		0.526-2.335		0.787					0.636			0.240-1.687	0.363
HCV-Ab, positive vs negative	1.473		0.532-4.080		0.456					2.786			0.834-9.302	0.096	2.333		0.661-8.236	0.188
AFP, ＞400ng/ml vs ＜400ng/ml	2.111		1.265-3.521		0.004	2.029		1.205-3.417	0.008	1.936			0.895-4.191	0.093	1.259		0.539-2.941	0.594
Adjuvant PD-1 antibody, yes vs no	0.485		0.282-0.836		0.009	0.479		0.276-0.832	0.009	0.303			0.101-0.908	0.033	0.297		0.095-0.922	0.036

Note: The bold text means P<0.05.

Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval; HCC, hepatocellular carcinoma; HR, hazard ratio; HCV, hepatitis C virus; HVTT: hepatic venous tumor thrombus; MVI, microvascular invasion; PSM, propensity-score matching; PA-PD-1: adjuvant anti-PD-1; OS: overall survival; PVTT: portal venous tumor thrombus; RFS, recurrence-free survival; Standard Deviation.

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Journal Publication

published 16 Jan, 2023

Read the published version in Hepatology International →

Editorial decision: Major Revisions Needed
09 Oct, 2022
Reviewers agreed at journal
25 Sep, 2022
Reviewers invited by journal
25 Sep, 2022
Editor assigned by journal
24 Sep, 2022
First submitted to journal
23 Sep, 2022

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Adjuvant anti-PD-1 antibody for hepatocellular carcinoma with high recurrence risks after hepatectomy

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