Skip to main content
Download PDF

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study

BMC Cancer volume 24, Article number: 1168 (2024) Cite this article

Abstract

Background

Tri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules.

Methods

This real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups.

Results

The median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively.

Conclusion

Our study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Peer Review reports

Introduction

Primary liver cancer (PLC) is the third leading cause of cancer mortality worldwide in 2020, of which hepatocellular carcinoma (HCC) accounting for over 70% of PLC cases [1, 2]. Given the insidious onset of HCC, almost 50% of HCC patients in China were diagnosed as locally advanced HCC with macrovascular invasion (MVI) and suffered from a poor median survival of less than 5 months if only received supportive care [3, 4].

Recently, several studies revealed that combination therapies based on the hepatic arterial infusion chemotherapy (HAIC) for borderline resectable or locally advanced HCC had potent effects on the tumor control and conversion rates in the Asia-Pacific region [5,6,7,8,9,10]. The HAIC of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) was able to achieve a 35.4% overall response rate (ORR) for advanced HCC whose ORR was 5.3% if received recommended therapy of sorafenib according to guidelines [8,9,10]. Moreover, based on HAIC, the ORR could dramatically increase to 54.3-65.9% if concurrently applied chemoradiotherapy or systemic therapies for the locally advanced HCC patients [11,12,13]. These results raised the interest of clinical practitioners to further explore the efficacy and safety of HAIC-based combination therapies.

Interestingly, our previous study found that FOLFOX-HAIC possessed the ability to enhance the efficacy of following lenvatinib plus programmed death receptor-1 (PD-1) inhibitors in treating HCC patients with portal vein tumor thrombosis (PVTT) [14], which indirectly indicated the timing of combination therapy could play a role in the treatment of HCC patient to some extent. However, whether the sequential combination therapy sacrificed the chance of tumor response for patients who received FOLFOX-HAIC monotherapy initially was still unknown yet. Moreover, due to the sequential and concurrent therapeutic patterns that have been discussed in other malignant tumors [15,16,17], it also inspired us to investigate these two therapeutic patterns in the treatment of borderline resectable or locally advanced HCC patients which was yet to be discussed in HCC. This retrospective study evaluated FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules and thus discussed this topic from the perspective of efficacy and safety.

Methods

Patients

The medical records of borderline resectable or locally advanced HCC patients from the Department of Liver Surgery in Sun Yat-sen University Cancer Center (SYSUCC) who initially received FOLFOX-HAIC monotherapy or combination of FOLFOX-HAIC plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) at the same course between March 2020 and June 2022 were retrospectively retrieved in this study. The inclusion criteria were: [1] patients were diagnosed with HCC according to clinical or pathological characteristics based on the American Association for the Study of Liver Diseases (AASLD) practice guidelines [18]; [2] borderline resectable or locally advanced HCC and unable to achieve R0 resection initially [19] defined as: (a) a solitary tumor with excessive volume; (b) tumor close contacted with the main vessel; (c) unilobar multifocal disease (either with > 3 tumors or one tumor > 3 cm) or bilobar disease; (d) high-risk of post-hepatectomy liver failure [3]. at least one measurable intra-hepatic lesion per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria; [4] initially received either FOLFOX-HAIC monotherapy (HAIC group) or FOLFOX-HAIC plus ICIs and TKIs at the same course (ConHAIC group); and [5] at least received 1–2 courses of FOLFOX-HAIC. Exclusion criteria were [1] extrahepatic metastasis [2] coexistence of other malignancies or immune-related diseases; and [3] incomplete follow-up data. The protocol complied with the ethical guidelines of the Declaration of Helsinki of the World Medical Association and was approved by the ethics committee of the Sun Yat-sen University Cancer Center (SYSUCC) (approval No. B2022-301-01). All patients provided written informed consent for HCC treatment and the use of their medical records for research purposes.

Treatments

For patients in the HAIC group, FOLFOX-HAIC was performed every 3–4 weeks, chemotherapy agents were infused through a percutaneous microcatheter inserted and placed in the tumor feeding artery identified by repeat arteriography at each course. The following regimen was administered via hepatic artery, oxaliplatin 130 mg/m2 infusion for 2 h, D1; leucovorin 200 mg/m2 infusion for 1 h, D1; 5-fluorouracil 400 mg/m2 infusion bolus followed by 2400 mg/m2 over 24 h [10]. During the period of FOLFOX-HAIC treatment, part of patients (n = 30) detected progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs (SeqHAIC group) until convert to surgery, developed PD or intolerable toxicity. For patients in the ConHAIC group, FOLFOX-HAIC procedure was the same as that of the HAIC group. Meanwhile, patients received combined therapy of ICIs and TKIs on the first course of FOLFOX-HAIC until convert to surgery, developed PD or intolerable toxicity. TKIs were administrated on the first day of FOLFOX-HAIC and ICIs were intravenously injected on the second day after the FOLFOX-HAIC was completed. Due to the lack of solid evidence to prove the superiority among various ICIs, the choices of ICIs were mainly based on the patients’ medical insurance and economic condition. The TKIs were administrated according to the guidelines (20–21). The exact types and statistical analysis of ICIs and TKIs were listed in the Tables S1 and there was no difference between the SeqHAIC group and the ConHAIC group (p > 0.050).

Clinical endpoints

The primary clinical endpoints were progression-free survival (PFS) and overall survival (OS). For patients in ConHAIC group, the PFS was defined as the date of treatment initiation to the verified radiological progression during treatment course. For patients in SeqHAIC group, the PFS was defined as date of treatment initiation of FOLFOX-HAIC monotherapy to the verified radiological progression after sequential ICIs and TKIs systemic therapies during treatment course. The OS for both groups was defined as the date of the initiation of FOLFOX-HAIC to the date of death due to any cause. Tumor response to treatment was defined as complete response (CR), partial response (PR), stable disease (SD), or PD based on the RECIST v1.1 criteria [22]. The secondary outcomes included conversion rate, overall response rate (ORR), disease control rate (DCR), and safety. Treatment-related adverse events (TRAEs) were documented during each phase of treatment and assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0) [23].

Evaluation

All baseline data were retrieved from medical records and imaging examinations. All patients generally underwent scheduled blood test, enhanced computed tomography (CT) or magnetic resonance imaging (MRI) every 2–3 months to evaluate the efficacy and safety during the treatment. During the first 2 years of follow-up, complete blood counts, blood chemistry, tumor biomarkers and CT or MRI were repeated every 3 months. Thereafter, patients were examined every 6 months until discovered disease progression or died.

Statistical analysis

Continuous variables were analyzed by using an unpaired student’s t-test or Mann-Whitney test. Categorical variables were compared using the χ2 or Fisher’s exact test. Survival analysis was performed and compared using the Kaplan-Meier method and log-rank tests. COX regression was applied to identify the independent risk factors for PFS and OS. Univariate regression was first performed, and all variables were included in the multivariate analysis using the forward conditional method. Moreover, subgroup analysis was conducted based on the different tumor characteristics which might impact on tumor progression or survival on the basis of clinical experience of enrolled patients. All statistical analyses were performed using SPSS (version 25.0; SPSS, Inc., Chicago, United States) or R (version 4.2.1; R Foundation, Vienna, Austria). A two-sided p value < 0.050 was considered statistically significant.

Results

Demographic characteristics of the study population

The patient inclusion flowchart was presented in Fig. 1. From March 2020 and June 2022, 117 borderline resectable or locally advanced HCC patients who initially received either FOLFOX-HAIC monotherapy (n = 44), or concurrent of ICIs and TKIs (n = 73) were included, during the treatment procession 30 HCC patients converted to SeqHAIC group because of detected disease progression. The baseline characteristics of the HAIC group and the ConHAIC group were presented in the Table S2. The median cycles of FOLFOX-HAIC from initial treatment were 4 [4, 6] in HAIC group and there was no statistic difference in terms of tumor burden between the two groups (p > 0.050). In general, the cohort included 107 (91.5%) males and 10 (8.5%) females, with an average age of 55.7 years old, most of enrolled patients were hepatitis B virus (HBV) related HCC (100 cases, 85.5%) with preserved liver function. The mean measurable tumor diameter of the enrolled patients was 10.1 cm, and more than half of them suffered from PVTT (71 cases, 60.7%). In addition, as presented in the Table 1, the median cycles of FOLFOX-HAIC from initial treatment were 5 [4, 6] in SeqHAIC group and 4 [3, 4] in ConHAIC group (p > 0.050), and no significant difference was observed in the other baseline variables of the SeqHAIC group and the ConHAIC group.

Fig. 1
figure 1

Patient disposition. HCC, hepatocellular carcinoma; FOLFOX-HAIC, HAIC of infusion fluorouracil, leucovorin, and oxaliplatin; ICIs, immune checkpoint inhibitors; TKIs, tyrosine kinase inhibitors; PD, progressive disease

Full size image
Table 1 Clinicopathological characteristics of patients by different treatment groups
Full size table

Progression-free and overall survival

As of September 1st, 2023, for the overall population, the median follow-up was 18.9 months (95% confidence interval [95% CI], 17.54–20.26 months). As shown in the Fig.S1, the median PFS for all patients was 5.8 months (95% CI, 3.21–8.39 months), and a total of 43 (36.8%) deaths were observed, the median OS was 27.33 months (95% CI, 21.64–33.02 months). The HAIC group demonstrated obvious disadvantage in both PFS (hazard ratio [HR], 10.821; 95% CI, 5.914–19.800; p < 0.001) and OS (HR, 2.119; 95% CI, 1.137–3.950; p = 0.018) compared to the ConHAIC group (Fig.S2A-B). For the 44 patients who initiated with the FOLFOX-HAIC monotherapy (HAIC group), only 4 patients did not develop PD, 10 patients combined with TKIs only sequentially when developed PD during the follow-up period. After excluded 14 patients who did not meet eligibility criteria, the rest 30 patients were finally included into the SeqHAIC group for further analysis. Notably, no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups (Fig. 2A-B). In detail, the median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months). At the data cut-off, 13 (43.3%) and 18 (24.7%) patients died in the SeqHAIC and ConHAIC groups, respectively. The median PFS was 11.6 months (95% CI, 9.34–13.87 months) in the SeqHAIC group and 19.37 months (95% CI, 12.90–25.84 months) in the ConHAIC group, respectively (Fig. 2A). Additionally, the 6-, 12-, 18- and 24-month PFS rates were 83.3%, 40.0%, 16.7% and 3.3%, respectively, in the SeqHAIC group and 53.4%, 37.0%, 13.7% and 2.7% in the ConHAIC group, respectively (Fig. 2A). A total of 25 patients in the ConHAIC group who developed PD or unacceptable toxicity during the follow-up period, appropriate second-line treatments were recommended according to the multi-discipline team (MDT). In detail, 6 patients switched to second-line TKIs monotherapy, 15 patients received combined therapy of ICIs and TKIs, and 4 patients lost follow-up. The median OS of the SeqHAIC group was 27.33 months (95% CI, 18.60-36.06 months), and the median OS of the ConHAIC group was not reached at the data cut-off (Fig. 2B). The 6-, 12-, 18- and 24-month OS rates were comparable between the two groups, 100%, 73.3%, 53.3% and 36.7%, and 87.7%, 74.0%, 38.4% and 13.7% in the SeqHAIC and ConHAIC groups, respectively (Fig. 2B).

Fig. 2
figure 2

Kaplan–Meier curves for progression-free survival (A) and overall survival (B) of patients in the SeqHAIC group (n = 30) and the ConHAIC group (n = 73). HR, hazard ratio; CI, confidence interval

Full size image

Response and conversion to resection

The tumor responses were presented in the Fig. 3A and the Table S3. There was no significant difference between the two groups regarding tumor responses, the ORRs and DCRs were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively (Fig. 3A; p > 0.050). However, for the 44 patients who received the FOLFOX-HAIC monotherapy, the ORR and DCR were 25% and 43.2% before enrolled in the SeqHAIC group, respectively (11 patients achieved PR and no patients achieved CR). The best response for intra-hepatic target lesions according to the RECIST v1.1 criteria was also shown in the Fig. 3B. 2 patients in the SeqHAIC group and 6 patients in the ConHAIC group suffered from extrahepatic metastasis in the case of stable controlling of the intra-hepatic lesions, respectively (6.7% vs. 8.2%, p = 1.000 Fig. 3B). In addition, 3 (10.0%) and 9 (12.3%) patients in the SeqHAIC and the ConHAIC groups had received surgical resection, respectively (Fig. 3B). At the data cut-off, 3 and 5 patients in the SeqHAIC and the ConHAIC groups who converted to hepatectomy experienced an intra-hepatic recurrence but all of them remained alive after receiving subsequent therapies.

Fig. 3
figure 3

Barplot for tumor responses rates based on RECIST v1.1 in the SeqHAIC group (n = 30) and the ConHAIC group (n = 73) (A) and (B) Waterfall plot for tumor size changes of intrahepatic target lesions. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

Full size image

Subgroup and prognostic analysis

Given patients in the SeqHAIC group tended to suffer from larger tumor size (10.5 cm ± 3.2 vs. 9.9 cm ± 3.0, p = 0.542) while patients in the ConHAIC group had more PVTT (46.7% vs. 67.1%, p = 0.053; Table 1), hierarchical subgroup analysis in terms of PFS and OS was further conducted (Fig. 4A-B). After stratification, concurrent FOLFOX-HAIC plus ICIs and TKIs was able to postpone tumor progression for unresectable HCC patients with tumor size smaller than 10 cm (HR, 0.25; 95% CI, 0.08–0.78; p = 0.017). No significant difference was observed in both PFS and OS across different tumor numbers, PVTT status and alpha-fetoprotein (AFP) levels in either the SeqHAIC or the ConHAIC group (p > 0.050; Fig. 4A-B). Additionally, univariate and multivariate COX analysis was presented in Table 2. After the multivariate COX regression analysis, escalated C-reaction protein (CRP) levels (HR, 3.86; 95% CI, 1.71–8.73; p = 0.001) for borderline resectable or locally advanced HCC patients were identified as independently risk prognostic factors for PFS (Table 2).

Fig. 4
figure 4

Forest plots of (A) progression-free survival and (B) overall survival in terms of interested subgroups for the SeqHAIC and the ConHAIC groups. HR, hazard ratio; CI, confidence interval; PVTT, portal vein tumor thrombosis; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; ALBI, Grade Albumin-Bilirubin grade; HBV, Hepatitis B virus infection

Full size image
Table 2 The COX regression analysis for progression free survival and overall survival
Full size table

Toxicity events

Overall, no patient died because of TRAEs during the follow-up period and there was no significant difference between the SeqHAIC and ConHAIC groups in the types of severe (i.e., grade 3/4) TRAEs (46.7% vs. 61.6%, p = 0.163; Table 3). The most common TRAEs were albumin decrease (100.0%) and the elevation of total bilirubin (80.6%), while patients in the ConHAIC group underwent significantly more frequent hand-foot-skin reaction (10.0% vs. 28.8%, p = 0.041) and hypertension (3.3% vs. 21.9%, p = 0.044) than those of the SeqHAIC group (Table 3).

Table 3 Treatment-related adverse events for the study population
Full size table

Discussion

It has been controversial for a long time, whether subject to the most potent therapeutic options directly or gradually for locally advanced HCC patients who were expected to have a chance to receive curative resection theoretically. The present study preliminarily explored the efficacy and safety of these two treatment patterns in treating borderline resectable or locally advanced HCC patients. The results revealed that FOLFOX-HAIC-based sequential or concurrent systemic ICIs and TKIs possessed comparable long-term prognosis and tolerability for locally advanced HCC patients, which first provided evidence regarding the timing and sequencing of locoregional and systemic therapies in the treatment of locally advanced HCC patients.

With decades of development across the world, HAIC became a promising locoregional therapy with 27.6-31.5% responsive rates for locally advanced HCC [9, 24, 25]. By placing the catheter to the tumor feeding arterial under digital subtraction angiography (DSA), high concentrations of chemotherapy antigens were able to pump into tumor tissue directly and attenuated the damages towards liver parenchyma [26, 27]. Since Qin et al.. proved the safety and efficacy of FOLFOX4 regimen as systemic therapy for advanced HCC patients [28, 29], the locoregional control rate of HAIC was further improved via applying FOLFOX regimen on HAIC [9]. Li et al.. reported that response rate of FOLFOX-HAIC peaked to 45.9% for large HCC patients who not suitable for resection [7]. Therefore, FOLFOX-HAIC was supposed to be a promising therapy in controlling locally advanced HCC, which has been recommended in some guidelines [6, 21].

Given the potent response rate of FOLFOX-HAIC for locally advanced HCC patients, a series of FOLFOX-HAIC-based combination therapies were carried out by clinical practicians and validated for efficacy. When combined with TKIs, FOLFOX-HAIC plus sorafenib increased 13.7% of DCR compared to FOLFOX-HAIC alone for patients with advanced HCC [30], which preliminarily proved the feasibility of FOLFOX-HAIC-based combinations patterns. Furthermore, as evaluated the HAIC plus ICIs, Wu et al.. revealed that HAIC combined with ICIs had a superior response of PVTT compared to HAIC alone and was correlated to reduced risk of progression or death [31]. Based on the above practice, the FOLFOX-HAIC combined with ICIs and TKIs which was supposed to be the strongest therapeutic patterns for locally advanced HCC patients was reasonable to explore from a multi-center level [32, 33]. The ORRs were able to reach 37–42.5% for FOLFOX-HAIC plus ICIs and TKIs in treatment of intermediate and advanced HCC patients, which was similar to the current study [32, 33]. Therefore, it was believed that FOLFOX-HAIC combined with ICIs and TKIs could be further developed in the future. However, in order to deeply understand the mechanisms behind triple therapy, the roles of locoregional and systemic therapies should be further depicted from different perspectives.

Inspired by Fu et al.. who described the inductive role of FOLFOX-HAIC in treating HCC patients with PVTT with triple therapy [14], the sequence of locoregional and systemic therapies for locally advanced HCC has attracted attention in the clinical practice. The induction therapy of FOLFOX-HAIC and ICIs plus TKIs in the initial period of treatment and then dual maintenance therapy of ICIs and TKIs demonstrated significantly superior disease control rates and long-term prognosis to the systemic therapy alone for HCC patients with PVTT [14]. Oxaliplatin-induced multidrug regimen was reported to induce high levels of necrosis and apoptosis in tumor tissue and release antigens which enhanced the effectiveness of following immune therapy [34, 35]. In the current study, the FOLFOX-HAIC-based combination therapy achieved extremely high ORRs of almost 50%, which obviously higher than systemic combination therapies from other studies for locally advanced HCC patients [36, 37]. Meanwhile, in our clinical practice, as the triplet treatment has a potent efficacy on tumor control, on the other hand, patients also suffer from significantly higher adverse effects. In this study, we compared sequential and concurrent FOLFOX-HAIC plus systemic therapies, and the results indicated that FOLFOX-HAIC sequential ICIs and TKIs did not compromise the efficacy for locally advanced HCC patients, nevertheless, the occurrence of TRAEs was able to significantly decrease which have patients had better compliance and quality of life. In addition, the SeqHAIC group consisted mostly of patients who were resistant to FOLFOX-HAIC monotherapy, but the patients in ConHAIC group were not necessarily refractory to it, which might be the reason of the ConHAIC group seemed to have longer PFS in Kaplan-Meier curve.

Subgroup analysis in the current study revealed that locally advanced HCC patients with tumors less than 10 cm might benefit from FOLFOX-HAIC plus ICIs and TKIs in terms of PFS, while patients with huge tumors failed to demonstrate benefits regardless of sequential or concurrent systemic therapies combined with FOLFOX-HAIC, suggesting that smaller tumors were more likely to be controlled by concurrent FOLFOX-HAIC plus ICIs and TKIs in the short term, but this advantage was not demonstrated in larger tumors. In the multivariate analysis, higher CRP were found to be predictive variables for long-term prognosis, which was similar to other studies [38,39,40].

With comparable tumor control rate and long-term prognosis, concurrent FOLFOX-HAIC plus ICIs and TKIs significantly increased the incidence of TRAEs. A higher incidence of hand-foot-skin reaction and hypertension was observed in the ConHAIC group, which might be due to direct cytotoxicity to hepatocytes and hematopoietic cells by concurrent FOLFOX-HAIC plus ICIs and TKIs. And the FOLFOX-HAIC sequenced by ICIs and TKIs were able to screen patients who sensitive to FOLFOX-HAIC monotherapy and cloud save money and energies for the subsequent systemic therapies in the future. Moreover, in the ConHAIC group, patients received an average of 3.6 times of FOLFOX-HAIC, while patients in the SeqHAIC group underwent 4.9 times on average, which suggested that the sequential strategy enabled the patients to tolerate the side effects of FOLFOX-HAIC better and thus received more treatment courses which were expected to have more durable tumor control. Majority of the TRAEs were generally controllable and did not aggravate the disease, and the abnormal liver function indicators could be recovered between two cycles of HAIC treatment with corresponding supporting medications.

There are potential limitations in the current study. First of all, given the retrospective nature of present study, the selection bias was inevitable. To further discuss this topic, a large-volume and prospective design is needed in the future. Second, in most of population in current study, HBV was the major reason that developed HCC. Whether the survival benefit of different treatment sequencing patterns apply in the absence of HBV has yet to be determined. Finally, in the present study, the types of TKIs and ICIs were comparable between two groups. However, due to the retrospective nature of current study, it was hard to identify the associations between dose of TKIs and the toxicities which we also curious. We hope this question could be answered in prospective in the future.

Conclusion

In conclusion, our study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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.

    Article  PubMed  Google Scholar 

  2. Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, Li X, Wang L, Wang L, Liu Y, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;394:1145–58.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.

    Article  PubMed  Google Scholar 

  4. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, Kelley RK, Galle PR, Mazzaferro V, Salem R, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76:681–93.

    Article  PubMed  Google Scholar 

  5. Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, Toyoda H, Imai Y, Hiraoka A, Ikeda M, et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer. 2021;10:181–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sun J, Guo R, Bi X, Wu M, Tang Z, Lau WY, Zheng S, Wang X, Yu J, Chen X, et al. Guidelines for diagnosis and Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus in China (2021 Edition). Liver Cancer. 2022;11(4):315–28.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Li Q-J, He M-K, Chen H-W, Fang W-Q, Zhou Y-M, Xu L, Wei W, Zhang Y-J, Guo Y, Guo R-P, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial. J Clin Oncol. 2022;40:150–60.

    Article  CAS  PubMed  Google Scholar 

  8. Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, Zhang Z, Zheng L, Deng H, Li S, et al. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018;69:60–9.

    Article  PubMed  Google Scholar 

  9. Ning Lyu X, Wang J-B, Li J-F, Lai Q-F, Chen S-L, Li H-J, Deng M, He L-W, Mu, Zhao M. Arterial chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1). J Clin Oncol. 2022;40:468–80.

    Article  PubMed  Google Scholar 

  10. He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5:953–60.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, Gavin A, Visser O, Bray F. Lenvatinib, toripalimab plus hepatic arterial infusion chemotherapy in patients with high-risk advanced hepatocellular carcinoma: a biomolecular exploratory, phase II trial. Eur J Cancer. 2022;174:68–77.

    Article  Google Scholar 

  12. Dongming Liu H, Mu C, Liu W, Zhang Y, Cui Q, Wu X, Zhu F, Fang W, Zhang W, Xing, et al. Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): a prospective, single-arm phase II trial. J Clin Oncol. 2022;40:4073.

    Article  Google Scholar 

  13. Zhang J, Zhang X, Mu H, Yu G, Xing W, Wang L, Zhang T. Surgical conversion for initially unresectable locally advanced hepatocellular carcinoma using a triple combination of angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy: a retrospective study. Front Oncol. 2021;11:729–64.

    Google Scholar 

  14. Fu Y, Peng W, Zhang W, Yang Z, Hu Z, Pang Y, Hu D, Chen J, Wang J, Zhou Z, et al. Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis. J Gastroenterol. 2023;58(4):413–24.

    Article  CAS  PubMed  Google Scholar 

  15. Huang H, Feng YL, Wan T, Zhang YN, Cao XP, Huang YW, Xiong Y, Huang X, Zheng M, Li YF, et al. Effectiveness of sequential chemoradiation vs concurrent chemoradiation or Radiation alone in Adjuvant Treatment after Hysterectomy for Cervical Cancer: the STARS phase 3 Randomized Clinical Trial. JAMA Oncol. 2021;7(3):361–9.

    Article  PubMed  Google Scholar 

  16. Verma V, Moreno AC, Haque W, Fang P, Lin SH. Sequential Versus Concurrent Chemoradiation Therapy by Surgical Margin Status in Resected Non-small Cell Lung Cancer. J Natl Compr Canc Netw. 2018;16(5):508–16.

    Article  PubMed  Google Scholar 

  17. Wang Y, Liu S, Yang Z, Algazi AP, Lomeli SH, Wang Y, Othus M, Hong A, Wang X, Randolph CE, et al. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. Cancer Cell. 2021;39(10):1375–e13876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, Murad MH, Marrero JA. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358–80.

    Article  PubMed  Google Scholar 

  19. Hermanek P, Wittekind C. Residual tumor (R) classification and prognosis. Semin Surg Oncol. 1994;10(1):12–20.

    Article  CAS  PubMed  Google Scholar 

  20. Vogel A, Martinelli E, ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice guidelines. Ann Oncol. 2021;32(6):801–5.

    Article  CAS  PubMed  Google Scholar 

  21. Zhou J, Sun H, Wang Z, Cong W, Wang J, Zeng M, Zhou W, Bie P, Liu L, Wen T et al. Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition). Liver Cancer. 2020; 9(6):682–720.

  22. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

    Article  CAS  PubMed  Google Scholar 

  23. National Cancer Institute. common terminology criteria for adverse events, version 5.0. [ Jun;2020 ]; https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf

  24. Tomokazu Kawaoka H, Aikata H, Hyogo R, Morio K, Morio M, Hatooka T, Fukuhara T, Kobayashi N, Naeshiro D, Miyaki, et al. Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma. J Dig Dis. 2015;16(9):505–12.

    Article  PubMed  Google Scholar 

  25. Choi JH, Chung WJ, Bae SH, Song DS, Song MJ, Kim YS, Yim HJ, Jung YK, Suh SJ, Park JY, et al. Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. Cancer Chemother Pharmacol. 2018;82(3):469–78.

    Article  CAS  PubMed  Google Scholar 

  26. He MK, Liang RB, Zhao Y, Xu YJ, Chen HW, Zhou YM, Lai ZC, Xu L, Wei W, Zhang YJ, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xu YJ, Lai ZC, He MK, Bu XY, Chen HW, Zhou YM, Xu L, Wei W, Zhang YJ, Chen MS, et al. Toripalimab Combined with hepatic arterial infusion Chemotherapy Versus Lenvatinib for Advanced Hepatocellular Carcinoma. Technol Cancer Res Treat. 2021;20:15330338211063848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shukui Qin Y, Bai HY, Lim S, Thongprasert Y, Chao J, Fan T-S, Yang V, Bhudhisawasdi WK, Kang Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013;31(28):3501–8.

    Article  PubMed  Google Scholar 

  29. Qin S, Cheng Y, Liang J, Shen L, Bai Y, Li J, Fan J, Liang L, Zhang Y, Wu G, et al. Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study. Oncologist. 2014;19(11):1169–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liang RB, Zhao Y, He MK, Wen DS, Bu XY, Huang YX, Lai ZC, Xu YJ, Kan A, Wei W, et al. Hepatic Arterial Infusion Chemotherapy of Oxaliplatin, Fluorouracil, and Leucovorin with or without Sorafenib as initial treatment for Advanced Hepatocellular Carcinoma. Front Oncol. 2021;11:619461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wu JS, Hong TC, Wu HT, Lin YJ, Chang TT, Wang CT, Liu WC, Hsieh MT, Wu IC, Chen PJ, et al. Hepatic arterial infusion chemotherapy and immune checkpoint inhibitors, alone or in combination, in advanced hepatocellular carcinoma with macrovascular invasion: a single-centre experience in Taiwan. J Gastrointest Oncol. 2023;14(2):849–62.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Pan Y, Zhu X, Liu J, Zhong J, Zhang W, Shen S, Jin R, Liu H, Ye F, Hu K, China Liver Cancer Study Group Young Investigators (CLEAP). Systemic therapy with or without transcatheter intra-arterial therapies for unresectable hepatocellular carcinoma: a real-world, multi-center study. Front Immunol. 2023;14:1138355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zang M, Hu X, Yuan G, Li R, Li W, Pang H, Li Q, Chen J. Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: a retrospective study. Int Immunopharmacol. 2023;125, (Part A):111019.

  34. Correale P, Cusi MG, Del Vecchio MT, Aquino A, Prete SP, Tsang KY, Micheli L, Nencini C, La Placa M, Montagnani F, et al. Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. J Immunol. 2015;175(2):820–8.

    Article  Google Scholar 

  35. Wang X, Li M, Ren K, Xia C, Li J, Yu Q, Qiu Y, Lu Z, Long Y, Zhang Z, et al. On-Demand autophagy Cascade amplification nanoparticles precisely enhanced Oxaliplatin-Induced Cancer Immunotherapy. Adv Mater. 2020;32(32):e2002160.

    Article  PubMed  Google Scholar 

  36. Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, et al. Phase ib study of Lenvatinib Plus Pembrolizumab in patients with Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020;38(26):2960–70.

    Article  PubMed  PubMed Central  Google Scholar 

  37. D’Alessio A, Fulgenzi CAM, Nishida N, Schönlein M, von Felden J, Schulze K, Wege H, Gaillard VE, Saeed A, Wietharn B, et al. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and child-pugh A and B cirrhosis: a real-world study. Hepatology. 2022;76(4):1000–12.

    Article  PubMed  Google Scholar 

  38. Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, Himmelsbach V, Schulze K, von Felden J, Fründt TW, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol. 2022;76(2):353–63.

    Article  CAS  PubMed  Google Scholar 

  39. Guan R, Mei J, Lin W, Deng M, Li S, Guo R. Is the CRAFITY score a superior predictor of prognosis and adverse events in hepatocellular carcinoma patients treated with locoregional-immunotherapy? Hepatol Int. 2023;17(5):1279–88.

    Article  PubMed  Google Scholar 

  40. Li Q, Wei Y, Zhang T, Che F, Yao S, Wang C, Shi D, Tang H, Song B. Predictive models and early postoperative recurrence evaluation for hepatocellular carcinoma based on gadoxetic acid-enhanced MR imaging. Insights Imaging. 2023;14(1):4.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the patients and their families, as well as the investigators and personnel for their significant contribution.

Funding

This work is funded by the National Natural Science Foundation of China (No. 82103566).

Author information

Authors and Affiliations

  1. Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of China

    Liyang Sun, Zhiwen Hu, Wa Xie, Zhenyun Yang, Huilan Zeng, Yaojun Zhang, Minshan Chen, Dandan Hu, Zhongguo Zhou & Yangxun Pan

  2. Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Liyang Sun, Zhiwen Hu, Wa Xie, Zhenyun Yang, Huilan Zeng, Yaojun Zhang, Minshan Chen, Dandan Hu, Zhongguo Zhou & Yangxun Pan

  3. Guangdong Provnvial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Liyang Sun, Zhiwen Hu, Wa Xie, Zhenyun Yang, Huilan Zeng, Yaojun Zhang, Minshan Chen, Dandan Hu, Zhongguo Zhou & Yangxun Pan

Authors
  1. Liyang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiwen Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wa Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenyun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huilan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yaojun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Minshan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dandan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhongguo Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yangxun Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LS: conceptualization, methodology, software, formal analysis, writing—original draft; ZH: methodology, software, formal analysis; WX: software, data curation, revise; ZY: conceptualization, software, resources, data curation; HZ: resources, investigation; YZ: supervision, data curation; MC: conceptualization, project administration, supervision; DH: resources, funding acquisition, investigation; ZZ: conceptualization, project administration, supervision; YP: conceptualization, methodology, project administration, supervision, writing—review & editing.

Corresponding authors

Correspondence to Dandan Hu, Zhongguo Zhou or Yangxun Pan.

Ethics declarations

Ethics approval and consent to participate

The protocol complied with the ethical guidelines of the Declaration of Helsinki of the World Medical Association and was approved by the ethics committee of the Sun Yat-sen University Cancer Center (SYSUCC) (approval No. B2022-301-01). All patients provided written informed consent for HCC treatment and the use of their medical records for research purposes.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12885_2024_12940_MOESM1_ESM.pdf

Supplementary Material 1: Figure S1 Kaplan–Meier curves for progression-free survival (A) and overall survival (B) of patients in the HAIC and the ConHAIC groups (n = 117). Kaplan–Meier curves for progression-free survival (C) and overall survival (D) of patients in the SeqHAIC and the ConHAIC groups (n = 103). HR, hazard ratio; CI, confidence interval.

Supplementary Material 2

Supplementary Material 3

Supplementary Material 4

12885_2024_12940_MOESM5_ESM.tif

Supplementary Material 5: Figure S2 Kaplan–Meier curves for progression-free survival (A) and overall survival (B) of patients in the HAIC group (n = 44) and the ConHAIC group (n = 73). HR, hazard ratio; CI, confidence interval

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, L., Hu, Z., Xie, W. et al. Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study. BMC Cancer 24, 1168 (2024). https://doi.org/10.1186/s12885-024-12940-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-024-12940-0

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us