Abstract
Transarterial interventional therapy combined with tyrosine kinase inhibitors (TKIs) and anti-Pd-1 antibodies (triplet regimen) has shown promising results in advanced HCC. However, the clinical utility of the triplet regimen in patients with HCC and major portal vein tumor thrombosis (PVTT) remains unclear. This study compared the efficacy and safety of the triplet regimen versus transarterial interventional therapy combined with TKIs (double regimen) for such patients. Thirty-nine patients treated with the triplet regimen were retrospectively compared with 37 patients treated with the double regimen. The objective response rate (ORR), the response rate of PVTT treatment, and safety were observed; progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan‒Meier method and log-rank test. Predictors of survival were identified using multivariate analysis. Median OS and median PFS were significantly improved in the Triplet Group compared with the Double Group (482 vs. 310 days; 208 vs. 85 days). The ORR and the response rate of PVTT were significantly higher in the Triplet Group than in the Double Group (59% vs. 35%; 62% vs. 35%). There was no significant difference in the incidence of grade 3/4 adverse events between the two groups (33% vs. 21%). The most frequent grade 3/4 adverse events were thrombocytopenia (10%) in the Triplet Group and hand–foot syndrome (14%) in the Double Group. Multivariable analysis showed that treatment method and PVTT treatment response were significant predictors of OS. The triplet regimen showed superiority over the doublet regimen in improving OS and PFS and had acceptable safety in patients with HCC and major PVTT.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00262-023-03511-6.
Keywords: Hepatocellular carcinoma, Portal vein tumor thrombosis, Transarterial interventional therapy, Tyrosine kinase inhibitors, Immune checkpoint inhibitors, Immunotherapy
Introduction
Hepatocellular carcinoma (HCC) is the fourth most common malignancy and the second leading cause of tumor-related death in China [1]. Portal vein tumor thrombosis (PVTT) is present in approximately 10%-40% of patients with HCC at diagnosis and leads to a poor prognosis [2, 3] with an overall survival (OS) of 2–4 months after patients undergo supportive care [4, 5].
The combination of atezolizumab plus bevacizumab is recommended as the preferred first-line option for advanced patients with HCC, and sorafenib or lenvatinib is considered an alternative first-line treatment in the Barcelona Clinic Liver Cancer staging and treatment algorithm system [6]. However, HCC with major PVTT (Vp3/Vp4 type), as defined by the Liver Cancer Study Group of Japan [7], had only a modest survival benefit from the above first-line options, with a median OS of 6–8.8 months in a real-world setting [8–10]. The survival benefits from systemic therapy alone for a population subgroup of particularly high-risk HCC with major PVTT remain to be improved.
According to the Chinese guidelines for the treatment of liver cancer [11], surgical resection is not the first choice in most patients with HCC and major PVTT. In addition to systemic therapy, the guidelines also recommend external radiotherapy and transarterial interventional therapy, including transcatheter arterial chemoembolization (TACE) and continuous hepatic arterial infusion chemotherapy (HAIC). A meta-analysis [12] demonstrated that TACE was still safe and effective for selected patients with HCC and PVTT (median OS: 8 months; postoperative liver failure incidence: 1%). HAIC has also been used to treat HCC patients with PVTT in Japan [13] and other Asian countries [14–16], as it has been shown to yield good disease control rates and survival benefits compared with sorafenib. Transarterial interventional therapy has been combined with tyrosine kinase inhibitors in patients with HCC and PVTT in clinical practice, and the efficacy has improved to some extent compared with either of the above two therapeutic modalities [9, 17–19].
HCC exhibits immunogenic features, including the expression of the immune checkpoint molecules, programmed cell death ligand-1, and cytokine T-lymphocyte-associated protein-4, in the tumor microenvironment (TME) [20]. Immune checkpoint inhibitors (ICIs) have demonstrated encouraging antitumor activity and manageable tolerability for treating advanced HCC [21–23]. Some studies have confirmed that tyrosine kinase inhibitors synergize with anti-PD-1 antibodies and augment the efficacy of immunotherapy [24, 25]. These findings provide a scientific rationale for the improvement of tumor immunotherapy efficacy with ICIs in combination with tyrosine kinase inhibitors. Therefore, we conducted this single-center retrospective study to evaluate the efficacy and safety of transarterial interventional therapy combined with tyrosine kinase inhibitors and anti-Pd-1 antibodies (hereafter, the Triplet regimen) versus transarterial interventional therapy combined with tyrosine kinase inhibitors (hereafter, the double regimen) in the treatment of HCC with major PVTT.
Materials and methods
Study design and patients
This retrospective study was approved by the institutional review board of Fujian Cancer Hospital (K202001001) and conformed to the standards of the Declaration of Helsinki. All patients provided written informed consent.
HCC was diagnosed according to the guidelines of the American Association for the Study of Liver Disease [26]. The inclusion criteria were as follows: age, 18–75 years; Eastern Cooperative Oncology Group (ECOG) performance status, 0–2; life expectancy of 2 months or more; naïve HCC or intrahepatic recurrent HCC with major PVTT after curative hepatectomy or ablation therapy; Child‒Pugh class A or B7; at least 1 measurable lesion; adequate organ function (i.e., white blood cell count ≥ 3.5 × 109/L; platelet count ≥ 75 × 109/L; aspartate transaminase and alanine transaminase ≤ 5 times or less of the upper limit of the normal; and serum creatinine ≤ 2.0 mg/dL). The exclusion criteria were as follows: serious medical comorbidities, including severe dysfunction of the heart and lung; currently having other malignancies in addition to HCC; undergoing additional local treatments (i.e., external beam radiotherapy, iodine 125 seed implantation, or ablation therapy) or systemic treatment during the study; having undergone local or systemic therapy for targeted lesions before enrollment in the study; and lacking regular follow-up data.
By searching the Hospital Information System in our hospital between January 1, 2019, and March 15, 2022, we identified 123 consecutive patients with HCC and major PVTT who underwent either double-regimen therapy or triplet-regimen therapy. The collection of follow-up data ended on June 15, 2022. A total of 47 patients were excluded. Finally, a total of 76 patients were enrolled in the study, including 39 patients in the Triplet Group and 37 patients in the Double Group (Fig. 1). Before the initiation of therapy, one of the physicians on our multidisciplinary team introduced two different therapeutic options for the patients. The final treatment choice was generally made by the patients, who were informed of the advantages and disadvantages of the two options, including treatment outcomes, treatment-related complications, and costs. All patients provided written informed consent prior to treatment. The available tyrosine kinase inhibitors and anti-Pd-1 antibodies in our hospital were sorafenib (Bayer, Germany), lenvatinib (Beacon Pharmaceuticals Ltd., Japan), apatinib (Jiangsu Hengrui Medicine Co., Ltd., People’s Republic of China), sindilizumab, camrelizumab, tislelizumab, and pembrolizumab.
Fig. 1.
Patient selection flowchart. CT computed tomography, DCR disease control disease, Double Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors regimen group, HCC hepatocellular carcinoma, MRI magnetic resonance imaging, PFS progression-free survival, OR overall response, OS overall survival, PVTT portal vein tumor thrombosis, Triplet Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors and anti-Pd-1antibodies regimen group
Transarterial interventional procedures
The HAIC and TACE procedures were performed by experienced oncology radiologists. Briefly, the HAIC procedure was performed using temporary catheter placement in all cases. A tip of the coaxial microcatheter was positioned in the targeted artery based on the distribution of the tumor within the liver. HAIC consisted of an infusion of oxaliplatin (100 mg/m2 for 4 h), followed by an infusion of raltitrexed (3 mg/m2 for 1 h), which were repeated using an interval of 3 weeks. HAIC therapy was preferred for patients with a significant arterioportal shunt or a complete portal vein obstruction without abundant compensatory collateral vessels. The TACE procedure was as follows. After successful selective catheterization of the tumor supplying artery, an emulsion of epirubicin and lipiodol or 100–300 μm CalliSphere Microspheres loaded with epirubicin was administered into the feeding artery under fluoroscopic guidance until there was complete disappearance or remarkable decrease of the tumor stain.
Systemic therapy administration
Briefly, the patients received oral lenvatinib (12 mg/day for bodyweight ≥ 60 kg or 8 mg/day for bodyweight < 60 kg), sorafenib (400 mg twice daily), or apatinib (500 mg, once daily in the double group; 250 mg, once daily in the triplet group), and the patients continuously received tyrosine kinase inhibitors with no breaks before or after repetitive transarterial interventional therapy. The doses of the tyrosine kinase inhibitors could be adjusted, or they could be discontinued according to the grade of the adverse event based on routine clinical practice. All patients in the triplet group received 200 mg of anti-Pd-1 antibodies intravenously every 3 weeks. The systemic therapies started 5–7 days after the first transarterial interventional therapy and were provided continually until the progression of the disease, an unbearable toxicity occurred or patient refusal.
Follow-up and repeated transarterial interventional therapy
All involved patients in the study underwent regular follow-ups in our hospital. Each follow-up session consisted of a detailed history and physical examination, laboratory tests, upper abdominal contrast-enhanced three-phase dynamic spiral CT or MRI scan, and chest CT plain scan. Laboratory tests included routine analysis of blood, measurement of the a-fetoprotein level, hepatic function, renal function, electrolytes, thyroid gland function, and prothrombin time. All patient follow-ups were conducted at a 4–6-week interval after the previous TACE or after two cycles of HAIC therapy. HAIC would continue until disease progression, unbearable adverse events, or patient refusal with a maximum of 6 consecutive cycles. Repeated TACE was performed as deemed clinically necessary if the follow-up images showed intrahepatic viable tumor tissue, and liver function was adequate to allow for another TACE session. The interchange of TACE and HAIC was considered during the whole treatment process under special conditions. TACE could be switched to HAIC if the tumor-feeding arteries became significantly slim with remarkably decreasing tumor staining after TACE and systemic therapy or if a severe arteriovenous fistula was confirmed at the last TACE procedure. HAIC could be switched to TACE if the intrahepatic small, disseminated lesions disappeared with a tendency for the massive remnant lesion to shrink (when they would then be eligible for embolization).
Assessments
The tumor response was defined as the best response across all time points. Assessment of the tumor response was performed independently by two experienced physicians in interventional oncology according to both the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and modified RECIST (mRECIST). We measured the largest diameters of the tumor thrombus and compared them with the basal values to assess the PVTT treatment response according to RECIST, version 1.1. Any inconsistency in the assessment results was resolved by consensus. The patients were followed up every 2 months during systemic maintenance treatment. The objective response rate (ORR) was defined as the percentage of patients who achieved complete response or partial response, and the disease control rate (DCR) was defined as the percentage of patients who achieved complete response, partial response, or stable disease.
OS was calculated as the time from the initiation of interventional therapy until death or the last follow-up. Progression-free survival (PFS) was defined as the time from the date of the first treatment to radiologic tumor progression, death, or the last follow-up.
Adverse events related to transarterial interventional therapy and systemic therapy were graded by using the National Cancer Institute Common Terminology Criteria version 4.0. Adverse events that occurred within 4 weeks after transarterial interventional therapy were recorded. In addition, liver function (including measurement of serum total bilirubin level, albumin level, and prothrombin time) and routine blood tests performed 4 weeks after the last transarterial interventional therapy session were used to evaluate treatment toxicity to the liver and bone marrow. Symptoms of postembolization syndrome (i.e., abdominal pain, fever without any infection focus, nausea, and vomiting) were expected, and therefore, were not documented separately [19].
Statistical analyses
Continuous variables are presented as the mean ± standard deviation or as the median and range, and they were compared using Student’s t test. Categorical variables are presented as frequencies, and percentages and were compared using χ2 or Fisher’s exact test. The Wilcoxon signed-rank test was used to determine the difference in liver function and routine blood test values before and after treatment. Survival curves were generated by the Kaplan‒Meier method and compared by the log-rank test. The Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for survival analysis. Univariate analyses were performed with the log-rank test. Variables with a P value ≤ 0.10 in the univariate analysis were entered into a multivariate analysis. Multivariate analysis was performed with a Cox proportional hazard regression model. A two-sided P value < 0.05 indicated statistical significance. All statistical analyses were performed using SPSS v.26.0 software (IBM Corp, Armonk, NY, USA).
Results
Patient characteristics
A total of 76 patients were included in this study (Triplet Group, n = 39; Double Group, n = 37). Detailed baseline patient characteristics are shown in Supplementary Table 1. The baseline characteristics between the Triplet Group and Double Group were well balanced. The median follow-up duration was 532 days (range: 78–1106 days) in the Triplet Group and 839 days (range: 175–974 days) in the Double Group. In total, 16 (41%) of the 39 patients in the Triplet Group and 32 (86%) of the 37 patients in the Double Group died during the follow-up period. Thirty-four (87%) patients in the Triplet Group and 29 (78%) patients in the Double Group underwent ≥ 2 sessions of TACE or HAIC, with a mean of 3.6 (range: 1–8) and 2.8 (range: 1–6) procedures per patient, respectively. Twenty (51%), 14 (36%), and 5 (13%) patients in the Triplet Group versus 16 (43%), 18 (49%), and 3 (8%) patients in the Double Group underwent HAIC, TACE, or an interchange of both treatments, respectively. The proportions of three different treatment modalities between the two groups were not different (P = 0.57). The patients underwent first-line tyrosine kinase inhibitor treatment, including the use of apatinib (n = 13, 33%), lenvatinib (n = 14, 36%), and sorafenib (n = 12, 31%) for 39 patients in the Triplet Group, and the use of apatinib (n = 18, 49%), lenvatinib (n = 5, 14%), and sorafenib (n = 14, 38%) for 37 patients in the Double Group. There was no difference in the proportions of different tyrosine kinase inhibitors between the two groups (P = 0.08). The mean ± standard deviation of the duration of tyrosine kinase inhibitor treatment was 231 days ± 218 in the Triplet Group and 163 days ± 187 in the Double Group (P = 0.15). The median cycle number of anti-Pd-1 antibody treatment was 6 (range: 1–50). Camrelizumab, tislelizumab, sintilimab, and pembrolizumab were administered to 14 patients (36%), 12 patients (31%), 12 patients (31%), and 1 patient (3%), respectively. After disease progression or discontinuation of the study treatment, twenty-three (59%) patients in the Triplet Group and 20 (54%) patients in the Double Group experienced late-line systemic therapy or/and other local therapies (P = 0.67) based on a consensus decision made by two experienced physicians.
Tumor response
According to RECIST, version 1.1, the patients in the Triplet Group had a higher objective response rate than those in the Double Group (46% [n = 18] vs. 19% [n = 7]; P = 0.01). Based on the mRECIST criteria, the ORR was higher in the Triplet Group than in the Double Group (59% [n = 23] vs. 35% [n = 13], P = 0.04). For the DCR, there was only an increasing trend in the Triplet Group compared with the Double Group (82% [n = 32] vs. 65% [n = 24], P = 0.09) according to either of the two above evaluation criteria (Table 1). The response rate of PVTT was 62% [n = 24] in the Triplet Group versus 35% [n = 13] in the Double Group by RECIST 1.1 (P = 0.02) (Supplementary Table 2).
Table 1.
Tumor response
| Variable | RECIST, version 1.1 | mRECIST | ||||
|---|---|---|---|---|---|---|
| Triplet Group (n = 39) | Double Group (n = 37) | P value | Triplet Group (n = 39) | Double Group (n = 37) | P value | |
| Best response | – | – | 0.03 | – | – | 0.19 |
| Complete response | 0 | 0 | – | 3 (8) | 1 (3) | – |
| Partial response | 18 (46) | 7 (19) | – | 20 (51) | 12 (32) | – |
| Stable disease | 14 (36) | 17 (46) | – | 9 (23) | 11 (29) | – |
| Progressive disease | 7 (18) | 13 (35) | – | 7 (18) | 13 (35) | – |
| Objective response | 18 (46) | 7 (19) | 0.01 | 23 (59) | 13 (35) | 0.04 |
| Disease control | 32 (82) | 24 (65) | 0.09 | 32 (82) | 24 (65) | 0.09 |
Unless otherwise indicated, data are numbers of patients, and data in parentheses are percentages. Double Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors regimen group, mRECIST modified response evaluation criteria in solid tumors, RECIST response evaluation criteria in solid tumors, Triplet Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors and anti-Pd-1antibodies regimen group
Survival
The patients in the Triplet Group had a longer median PFS of 208 days (95% CI 160, 256) compared with the median PFS of 85 days (95% CI 63, 107) in the Double Group (HR = 0.44 [95% CI 0.27, 0.75]; log-rank test P = 0.002). After stratification by portal vein invasion grade, the patients with Vp3 achieved a longer median PFS (235 days [95% CI 113, 357] versus 84 days [95% CI 54, 114]; HR = 0.35 [95% CI 0.16, 0.77]; log-rank test P = 0.007), and the patients with Vp4 had a PFS extension trend (169 days [95% CI 100, 238] versus 89 days [95% CI 54, 124]; HR = 0.60 [95% CI 0.30, 1.20]; log-rank test P = 0.14) in the triple group than in the double group (Fig. 2a–c).
Fig. 2.
Progression-free survival in the total study population (a), in the subgroup population of Vp3 patients (b), in the subgroup of Vp4 patients (c)
The patients in the Triplet Group had a longer OS (median, 482 days [95% CI 279, 684]) than those in the Double Group (median, 310 days [95% CI 258, 361]; log-rank test P = 0.007). Compared with the double group, the findings of the Cox proportional hazards model further supported the longer OS in the triplet group (HR = 0.45 [95% CI 0.25, 0.82]; P = 0.009). After stratification by portal vein invasion grade, the patients with Vp3 (median OS: 768 days [95% CI not applicable, not applicable] vs. 334 days [95% CI 260, 408]; HR = 0.46 [95% CI 0.18, 1.17]; log-rank test P = 0.09) and the patients with Vp4 (median OS: 477 days [95% CI 393, 560] vs. 282 days [95% CI 191, 373]; HR = 0.47 [95% CI 0.21, 1.03]; log-rank test P = 0.05) in the triplet group demonstrated a trend of OS improvement compared with those in the double group (Fig. 3a–c). The univariate analyses revealed that PVTT type (Vp3 vs. Vp4), treatment method (triplet vs. double), and PVTT treatment response (response vs. nonresponse) were associated with OS (Table 2; P = 0.10, P = 0.007, P = 0.01, respectively). Based on these findings, the above three factors were included in the multivariate analysis. The multivariate analysis found that the treatment method (P = 0.046) and PVTT treatment response (P = 0.04) were identified as two independent prognostic factors for OS (Table 2). The univariate and multivariate analyses of prognostic factors for PFS are presented in Supplementary Table 3. The results demonstrated that the treatment method was the only independent prognostic factor for PFS (P = 0.03).
Fig. 3.
Overall survival in the total study population (a), in the subgroup population of Vp3 patients (b), in the subgroup of Vp4 patients (c)
Table 2.
Univariate and multivariate analyses of prognosis factor for OS
| Univariate Analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|
| Factor | No. of Patients (n = 76) | Median OS (Days) | P value* | HR (95% CI) | P value |
| AFP (ng/mL) | 0.44 | ||||
| ≤ 400 | 23 | 323 (242, 403) | – | ||
| > 400 | 53 | 425 (269, 581) | – | ||
| ECOG performance | 0.14 | ||||
| 0–1 | 70 | 412 (289, 535) | – | ||
| 2 | 6 | 219 ( 53,385) | – | ||
| Tumor size (cm) | 0.38 | ||||
| ≤ 10 | 30 | 477 (279, 675) | – | ||
| > 10 | 46 | 323 (291, 355) | – | ||
| PVTT type | 0.10 | ||||
| Vp3 | 34 | 341 (113, 568) | – | ||
| Vp4 | 42 | 351 (197, 504) | – | ||
| Child–Pugh class | 0.60 | ||||
| A | 59 | 351 (233, 469) | – | ||
| B | 17 | 293 (106, 480) | – | ||
| No. of tumors | 0.58 | ||||
| ≤ 3 | 36 | 465 (24, 906) | – | ||
| > 3 | 40 | 334 (301, 367) | – | ||
| Treat method | 0.007 | 0.53 (0.29, 0.99) | 0.046 | ||
| Triplet regimen | 39 | 482 (279, 685) | – | ||
| Double regimen | 37 | 310 (258, 361) | – | ||
| Age | 0.12 | ||||
| ≤ 45 | 27 | 310 (252, 368) | – | ||
| > 45 | 49 | 465 (285, 642) | – | ||
| PVTT response | 0.01 | 0.54 (0.29, 0.98) | 0.04 | ||
| Response | 37 | 417 (259,6 95) | |||
| Nonresponse | 39 | 310 (205, 414) | |||
| Extrahepatic metastasis | 0.14 | ||||
| Absent | 54 | 341 (301,381) | – | ||
| Present | 22 | 779 (41,1517) | – | ||
Data in parentheses are 95% CIs. AFP α-Fetoprotein level, Double Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors regimen group, ECOG Eastern Cooperation Oncology Group, Nonresponse refers to stable disease and progression disease, PVTT portal vein tumor thrombosis, Response refers to complete response and partial response, Triplet Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors and anti-Pd-1antibodies regimen group
*Log-rank test was used
Safety
All adverse events related to systemic treatment and local therapy within 4 weeks after transarterial interventional therapy are shown in Table 3. The overall incidence of any grade of any adverse event was similar between the two groups (80% [n = 31] in the Triplet Group vs. 68% [n = 25] in the Double Group, P = 0.30). There was no difference in the incidence of grade 3–4 adverse events between the two groups (33% [n = 13] in the triplet group vs. 21% [n = 8] in the double group, P = 0.31). The most frequent grade 3–4 adverse events were thrombocytopenia (n = 4 [10%]) in the Triplet Group and hand–foot syndrome (n = 5 [14%]) in the Double Group. No treatment-related deaths occurred in the two groups. In the triple group, eight patients (21%) experienced any grade, and 3 (8%) experienced grade 3–4 adverse events related to anti-Pd-1 antibody treatment. The most frequent adverse event related to anti-Pd-1 antibody treatment was hypothyroidism (n = 4 [10%]). Additionally, we observed liver function and routine blood test changes 4 weeks after the last transarterial intervention treatment in the two groups (Supplementary Table 4). All liver function test values obtained 4 weeks after the treatment were not different compared with the baseline values (P > 0.05); however, the leukocyte count in the routine blood tests was decreased compared with baseline values after the last transarterial interventional treatment, both in the Triplet Group ([6.5 ± 2.5] × 109 / L vs. [5.3 ± 1.9] × 109 / L; P = 0.003) and in the Double Group ([7.5 ± 2.7] × 109 / L vs. [6.4 ± 3.0] × 109 / L; P = 0.02).
Table 3.
Adverse events
| Events (%) | Triplet Group (n = 39) | Double Group (n = 37) | ||
|---|---|---|---|---|
| Any Grade | Grade 3–4 | Any Grade | Grade 3–4 | |
| Adverse events related to transarterial interventional therapy and TKIs | ||||
| Any adverse event | *31 (80) | †13 (33) | *25 (68) | †8 (21) |
| Plural effusion | 5 (13) | 0 | 3 (8) | 0 |
| Leukocytopenia | 14 (36) | 3 (7) | 6 (16) | 1 (3) |
| Thrombocytopenia | 14 (36) | 4 (10) | 11 (30) | 3 (8) |
| Diarrhea | 5 (13) | 0 | 2 (5) | 2 (5) |
| Liver abscess | 1 (3) | 1 (3) | 0 | 0 |
| Digestive ulcer | 2 (5) | 0 | 0 | 0 |
| Upper gastrointestinal tract bleeding | 5 (13) | 3 (7) | 1 (3) | 0 |
| Hand–foot syndrome | 10 (25) | 3 (7) | 11 (30) | 5 (14) |
| Fatigue | 8 (21) | 1 (3) | 5 (14) | 2 (5) |
| Hypertension | 9 (23) | 2 (5) | 7 (19) | 2 (5) |
| Gingival bleeding | 2 (5) | 0 | 3 (8) | 0 |
| Oral ulcer | 2 (5) | 1 (3) | 2 (5) | 1 (3) |
| Proteinuria | 1 (3) | 0 | 1 (3) | 1 (3) |
| Adverse events related anti-Pd-1 antibodies treatment | ||||
| Any adverse event | 8 (21) | 3 (8) | NA | NA |
| Hypothyroidism | 4 (10) | 0 | NA | NA |
| Suppurative tonsillitis | 1 (3) | 0 | NA | NA |
| Intestinal infection | 1 (3) | 1 (3) | NA | NA |
| Hepatitis | 1 (3) | 1 (3) | NA | NA |
| Rash | 2 (5) | 1 (5) | NA | NA |
Data are numbers of patients, and data in parentheses are percentages. Double Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors regimen group, NA not applicable, TKIs tyrosine kinase inhibitors, Triplet Group refers to transarterial interventional therapy combined with tyrosine kinase inhibitors and anti-Pd-1antibodies regimen group
*For any grade events, the incidence of any adverse event was not significantly different between the two groups (P = 0.30)
†For grade 3–4 events, the incidence of any adverse event was not significantly different between the two groups (P = 0.31)
Discussion
Based on the poor prognosis of patients with HCC and major PVTT, novel or optimized therapies are urgently needed to meet further treatment desires of such high-risk patients in real clinical practice [2, 5]. This retrospective study showed the promising efficacy of triplet-regimen treatment for patients with HCC and major PVTT in clinical settings. The main findings of this study are as follows: first, the triplet regimen significantly prolonged OS (482 vs. 310 days, log-rank test P < 0.05) and PFS (208 vs. 85 days, log-rank test P < 0.05) in the overall cohort. Second, the triplet regimen could also increase the ORR (59% vs. 35%, P < 0.05) in contrast with that from the double regimen; the response rate of PVTT in the Triplet Group was higher than that in the Double Group (62% vs. 35%, P = 0.02). Third, the treatment method and PVTT treatment response were independent prognostic factors for OS (P = 0.046, P = 0.04, respectively); the treatment method was also the only independent prognostic factor affecting PFS (P = 0.03). Finally, the addition of anti-Pd-1 antibodies to the double regimen did not increase the incidence of adverse events (33% in the triple group vs. 21% in the double group, P > 0.05). Our study provided concrete evidence to support the administration of the triplet regimen in patients with HCC and major PVTT. The underlying reasons for the satisfactory efficacy of the triplet regimen in our study may be as follows. First, TACE or HAIC can cause necrosis or apoptosis of tumor cells, release tumor antigens, and stimulate host immune responses [27]. Second, in addition to inhibiting angiogenesis, tyrosine kinase inhibitors can play a role in TME immunomodulation, including normalizing immature tumor blood vessels to facilitate drug delivery, reducing the recruitment of immunosuppressive cells and cytokines, and increasing the enrichment of immune effector cells in the TME [28–30]. Third, anti-Pd-1 antibodies can stimulate the host immune responses that trigger long-lived tumor destruction. Therefore, we speculate that triplet-regimen therapy may produce a potential synergistic effect and thus optimize antitumor efficacy. Additionally, the PVTT itself also benefited significantly from the triplet-regimen therapy in our study. The PVTT shrinkage or disappearance helps increase the hepatic blood supply from the portal vein, inhibit the deterioration of liver function, and improve the tolerance of patients to triplet-regimen therapy [19].
A few studies [31–34] have reported survival improvement by using triplet-regimen therapy for patients with advanced or unresectable HCC. There was great heterogeneity of the included patients in these studies. For example, the prognosis of patients with extrahepatic metastases was greatly different from that of patients with Vp1/Vp2 type PVTT. Additionally, these studies were designed as one-arm studies. Both of these factors could bias the results and weaken the conclusion of those studies. Unlike the above studies [31–34], our study mainly focused on advanced patients who had HCC and major PVTT and used a controlled design including a Triplet Group and Double Group. Therefore, the value of anti-Pd-1 antibodies in the triplet regimen could be better disclosed in our study.
To date, studies concerning triplet regimens consisting of sorafenib, lenvatinib, or apatinib with interventional therapy and anti-PD-1 antibodies versus double regimens for advanced HCC have been published [35–37], and their conclusions consistently support that triplet regimens have better efficacy than double regimens and can bring significant survival benefits to patients with advanced HCC, similar to the conclusions obtained in our study. However, our study builds on these previous studies [35–37] to further answer the question of whether triplet regimens can benefit patients with HCC and major PVTT. Importantly, in addition to the treatment method affecting PFS and OS, our study also indicated that PVTT treatment response was an independent prognostic factor for OS. Our findings were similar to those reported in Tsai et al. [38]. They reported that vascular responders to anti-Pd-1 antibodies had a significantly longer survival than did nonresponders (11.1 vs. 3.9 months, P < 0.05).
Despite some recent breakthroughs in the systemic treatment of advanced HCC, especially anti-vascular endothelial growth factor-targeted therapy combined with ICIs, the survival benefits in patients with major PVTT remain unsatisfactory. The updated data of the IMbrave150 study showed that the median OS of patients with HCC and macrovascular invasion was only 14.2 months [39], which was inferior to that (approximately 16 months) achieved in the Triplet Group in our study. Until now, anti-Pd-1 antibodies alone have not been adequately studied in multiple phase 3 clinical trials in the setting of HCC with major PVTT because clinical trials have largely excluded such patients. Few studies have examined the value of anti-PD-1 antibodies in the treatment of patients with HCC and major PVTT with a triple regimen. Therefore, our study is valuable because it indicates that the triplet regimen can provide significant survival benefits in such patients.
Most of the adverse events related to either the triplet regimen or the double regimen were easily manageable, and there were more adverse events with grade 1 and 2 severity. Our results were similar to the results of previous studies that used a triplet regimen or double regimen for advanced HCC [35–37]. Notably, the toxicity profile of the triplet regimen was similar to that of the double regimen, indicating that the addition of anti-PD-1 antibodies to the double regimen did not introduce a new safety profile.
The current study has several limitations. First, this was a retrospective study, and the determination of two different treatment methods in patients depended on the attending physician’s preference and the option of the patients. This nonrandomized enrollment was bound to introduce selection bias, but the bias was limited by obtaining balanced baseline characteristics between the two groups. Second, the sample size in the study was limited, especially in the subgroup of patients with Vp3 or Vp4, which weakened the robustness of our analyses. Third, due to the nature of retrospective studies, there is inevitable heterogeneity in the treatment protocols, such as inconsistency in the transarterial interventional therapy and the diversity in the tyrosine kinase and immune checkpoint inhibitors that were used. Therefore, a sufficiently powered, prospective randomized controlled trial with a large sample size is warranted to validate our findings. Nonetheless, we do not believe that these limitations impact the main findings of the study.
In conclusion, transarterial interventional therapy combined with tyrosine kinase inhibitors and anti-Pd-1 antibodies yielded a promising outcome and manageable adverse events in patients with HCC and major PVTT. Compared with the double-regimen treatment, the patients seemed to significantly benefit from the triple-regimen treatment, acquiring a longer PFS and OS. However, a large-scale study is required to further confirm these findings.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors acknowledge Huining Nian, Department of Interventional Oncology, Fujian Cancer Hospital, for her support in part of the statistical work and manuscript reading. The authors also thank Yan Zhou for providing statistical consulting services from the Section of Follow-up, Fujian Cancer Hospital.
Abbreviations
- CI
Confidence interval
- DCR
Disease control rate
- ECOG
Eastern cooperative oncology group
- HAIC
Hepatic arterial infusion chemotherapy
- HCC
Hepatocellular carcinoma
- HRs
Hazard ratios
- ICIs
Immune checkpoint inhibitors
- mRECIST
Modified RECIST
- ORR
Objective response rate
- OS
Overall survival
- PFS
Progression-free survival
- PVTT
Portal vein tumor thrombosis
- RECIST
Response evaluation criteria in solid tumors
- TACE
Transcatheter arterial chemoembolization
- TME
Tumor microenvironment
Author contributions
WY initiated the study concept, coordinated the entire study, and wrote the manuscript. WL, KZ, SC, and XW collected and helped interpret the clinical data. All authors approved the final version of the article, including the authorship list.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest
All authors declare that there are no conflicts of interest.
Ethical approval
This study was approved by the Institutional Review Board of Fujian Cancer Hospital (K202001001).
Consent to participate
All patients provided written informed consent.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.