Prognosis of TACE combined with sorafenib in hepatocellular carcinoma patients with microvascular invasion: A retrospective cohort study

doi:10.21203/rs.3.rs-3315160/v1

Purpose

Transcatheter arterial chemoembolization (TACE) and sorafenib each has shown therapeutic effects in patients with hepatocellular carcinoma (HCC) and microvascular invasion (MVI). The present study evaluated the feasibility of postoperative TACE combined with sorafenib in HCC patients with MVI and assessed the optimal indications for postoperative TACE treatment.

Patients and methods:

The present study included 217 HCC patients who underwent radical resection from April 2017 to April 2020 and whose postoperative pathological report showed MVI. Patients were treated with TACE, TACE plus sorafenib, of neither (control group). The primary endpoints were overall survival (OS) and disease-free survival (DFS).

Results

Patients treated with TACE plus sorafenib had higher 1-year (96.4% vs. 84.9%) and 2-year (91.6% vs. 68.9%) OS rates than patients treated with TACE alone. Median OS was significantly longer in patients treated with TACE plus sorafenib (44.6 months; 95% confidence interval [CI ] 40.81–48.4 months) than with TACE alone (39 months; 95% CI 30.2–48.3 months; (p = 0.025). Cox proportional hazard model showed that factors associated with a higher risk of death after treatment included maximum tumor diameter of tumor (hazard ratio [HR] = 6.783, p = 0.012), number of TACE sessions (HR = 0.284, p = 0.01) and liver cirrhosis (HR = 6.446, p = 0.002).

Conclusion

Compared with TACE alone, TACE plus sorafenib significantly prolonged OS in patients with HCC and MVI. Factors associated with improved prognosis included maximum tumor diameter < 7 cm and more than three TACE sessions.

hepatocellular carcinoma

microvascular invasion

transcatheter arterial chemoembolization (TACE)

vascular endothelial growth factor

sorafenib

intrahepatic metastasis

Hepatocellular carcinoma (HCC) is the sixth most common type of malignant tumor worldwide and the third most frequent cause of cancer deaths.¹ Hepatectomy is the treatment of choice for HCC, but many patients are initially diagnosed with advanced tumors, making them ineligible for hepatectomy. Survival rates are poor, with many prognostic factors being associated with survival after R0 hepatectomy. Microvascular invasion (MVI) was shown to be an important indicator of recurrence within 2 years after therapeutic hepatectomy, with adjuvant transcatheter arterial chemoembolization (TACE) showing the greatest benefit to date in patients with MVI.²

Despite the general benefits of postoperative prophylactic TACE on survival, TACE has shown benefits only in specific patient subgroups, with several patient- and treatment-related factors being associated with the survival benefits of TACE in patients with HCC and MVI. Subgroup analyses have shown that tumor diameter and number of tumor nodules are among the most important factors affecting the therapeutic effect of TACE.^3–5

Sorafenib is a multi-kinase inhibitor that inhibits tumor cell proliferation and tumor angiogenesis, thereby preventing tumor metastasis^6–8. A two arm open control phase II study in Taiwan revealed that sorafenib treatment after hepatectomy prolonged the relapse free survival time of patients by up to 8 months compared with the untreated group, as well as significantly reducing the postoperative recurrence rate in patients with HCC plus MVI.⁹ Compared with either TACE or sorafenib aloe, their combination was found to improve survival rates in HCC patients with factors associated with a high risk of recurrence.^10,11 To date, however, few studies have evaluated the benefits of combined treatment or whether this treatment would benefit all patients with HCC. The present study was therefore designed to evaluate whether postoperative TACE combined with sorafenib, administered prophylactically after hepatectomy for HCC plus MVI, can prevent early recurrence of HCC and prolong patient survival. Determination of the specific indications for TACE and sorafenib after liver resection may help formulate better treatment plans for HCC patients with MVI.

Patients

The present study included 217 patients who underwent hepatectomy for HCC plus MVI at Tianjin Medical University Cancer Institute & Hospital from April 2017 to April 2020. Patients were included if (1) they underwent standard radical resection of HCC and had no evidence of postoperative recurrence or metastasis; (2) their postoperative pathological report indicated MVI; and (3) they had not undergone neoadjuvant treatment, such as radiofrequency ablation, or adjuvant treatment prior to enrollment in this study.

The study protocol was approved by the clinical research ethics committee of the Tumor Hospital affiliated to Tianjin Medical University and conformed to the Declaration of Helsinki. The need for Informed Consent was waived by the Ethics Committee of Tianjin Medical University Cancer Hospital due to the retrospective nature of the study.

TACE

TACE steps included inserting a repeat hepatectomy (RH) catheter into the common hepatic artery to show the staining shadow of the tumor in the liver, followed by inserting it into the artery supplying blood to the tumor through the RH catheter, which was dependent on microcatheter superselective technology. Polyvinyl alcohol drug loaded embolic microspheres 0.7G, measuring 300–500 µm in diameter, were mixed with 40 mg epirubicin. The cobra catheter was exchanged, the catheter was introduced into the bronchial artery and 4 mg of Raltitrexed were injected. Prior to the next TACE session, the arteries supplying the same targeted tumor/tumors were fully evaluated, and chemotherapy drugs were replaced if necessary. TACE sessions were repeated once every 6 weeks.

Sorafenib

Patients were started on 400 mg/day oral sorafenib, beginning 3 days after TACE treatment. Dosages were reduced to 200 mg/day if patients experienced adverse reactions, such as nausea and vomiting, abdominal pain, diarrhea, or leucopenia, with treatment continued until unacceptable toxicity or disease progression.

Study assessment

Beginning the first month after surgery, each patient was rechecked in the outpatient department every 3 months, and regularly followed up every 4 weeks through medical records, e-mail or telephone through May 31, 2021. Follow-up examinations included assay of the tumor marker alpha-fetoprotein (AFP), abdominal color Doppler ultrasound and liver function tests. If AFP was abnormally elevated or color Doppler showed evidence of suspicious tumors, patients were further evaluated by abdominal enhanced CT or MRI. Further treatment was dependent on the time of recurrence, the location of tumor metastasis and the physical condition of the patient, and could include reoperation, radiofrequency ablation, TACE, target replacement and/or Immunotherapy.

Statistical analyses

Baseline continuous variables were compared by t-tests and categorical variables by chi square tests. Survival outcomes were determined by the Kaplan Meier method and compared by log-rank tests. Univariate analyses of variables in the three groups were compared by ANOVA, with variables statistical significant on univariate analyses (p < 0.1) entered into Cox multivariate analysis to identify independent variables affecting the prognosis. Optimal cut-off values were those corresponding to the maximum Jordan index (sensitivity + specificity − 1) calculated from receiver operating characteristics (ROC) curves. All statistical analyses were performed using R software version 3.6.1 (SPSS Inc., Chicago, IL, USA), with P values < .05 defined as statistically significant.

Patient characteristics

The study included 203 patients, 169 men and 34 women, of median age 57 years (range, 34 to 86 years). The most common cause of underlying liver disease was hepatitis B virus (HBV) infection (68.5%). Of the 203 patients, 121 were not further treated and were included in the control group, whereas 53 patients were treated with TACE alone and 29 with sorafenib plus TACE. Their baseline characteristics are shown in Table 1. Mean ages of patients in the TACE (59.9 ± 8.69 years), TACE plus sorafenib (58.9 ± 10.6 years) and control (56.4 ± 8.46 years) groups were similar (p=0.198), as were the proportion of men (p=0.379), MVI grade (p=0.773), hepatitis B surface antigen positivity (p=0.724), AFP (p=0.988) and carcinoembryonic antigen (CEA) (p=0.449) concentrations, maximum tumor diameter (p=0.510), and number of tumors (p=0.535). In addition, there were no significant differences in alanine aminotransferase (ALT) (p=0.391) and total bilirubin (Tbil) (p=0.373) concentrations, or in the proportions with liver cirrhosis (p=0.925) and those within the Milan criteria (p=0.313).

Table 1. Patient baseline demographic and clinical characteristics

Characteristics	Control group	TACE		Sorafenib + TACE		P
	N=121	N=53		N=29
Age(years)	59.9 (±8.69)		58.9 (±10.6)		56.4 (±8.46)	0.198
Gender						0.379
Male，n (%)	97 (80.2%)	47 (88.7%)		25 (86.2%)
Female，n (%)	24 (19.8%)	6 (11.3%)		4 (13.8%)7(11.3%) (11.3%) (13.8%)
MVI						0.773
I，n (%)	93 (76.9%)	42 (79.2%)		24 (82.8%)
II，n (%)	28 (23.1%)	11 (20.8%)		5 (17.2%)
Positive for HBsAg						0.724
Yes, n (%)	84 (69.4%)	37 (69.8%)		18 (62.1%)
No, n (%)	37 (30.6%)	16 (30.2%)		11 (37.9%)
AFP (ng/ml)						0.988
>400, n (%)	42 (34.7%)	19 (35.8%)		10 (34.5%)
<400, n (%)	79 (65.3%)	34 (64.2%)		19 (65.5%)
CEA (ng/ml)						0.449
>5, n (%)	15 (12.4%)	6 (11.3%)		1 (3.45%)
<5, n (%)	106 (87.6%)	47 (88.7%)		28 (96.6%)
Tumor diameter (cm)						0.510
<5, n (%)	43 (35.5%)	17 (32.1%)		13 (44.8%)
>5, n (%)	78 (64.5%)	36 (67.9%)		16 (55.2%)
Tumor number						0.535
single, n (%)	104 (86.0%)	48 (90.6%)		24 (82.8%)
multiple, n (%)	17 (14.0%)	5 (9.43%)		5 (17.2%)
Tbil (μmol/L)						0.373
<17.1, n (%)	102 (84.3%)	40 (75.5%)		23 (79.3%)
>17.1, n (%)	19 (15.7%)	13 (24.5%)		6 (20.7%)
Exceed Milan Criteria						0.313
Yes, n (%)	87 (71.9%)	39 (73.6%)		17 (58.6%)
No, n (%)	34 (28.1%)	14 (26.4%)		12 (41.4%)
Liver cirrhosis						0.925
No, n (%)	58 (47.9%)	24 (45.3%)		13 (44.8%)
Yes, n (%)	63 (52.1%)	29 (54.7%)		16 (55.2%)
ALT (U/L) )						0.391
<40, n (%)	88 (72.7%)	42 (79.2%)		19 (65.5%)
>40, n (%)	33 (27.3%)	11 (20.8%)		10 (34.5%)

Abbreviations: MVI, microvascular invasion; AFP, α-fetoprotein; CEA, carcinoembryonic antigen; ALT, alanine aminotransferase; HBsAg, hepatitis B virus surface antigen; Tbil, total bilirubin. Values are shown as mean ± standard deviation or n (%)

Survival outcomes

Of the 203 patients, 80 died and 123 survived. The median OS of patients in the control, TACE alone and TACE plus sorafenib groups were 28.5 months (95% CI 21.5-35.3 months), 39 months (95% CI 30.2-48.3 months) and 44.6 months (95% CI 40.81-48.4 months), respectively, and their median DFS were 17.2 months (95% CI 13.2-21.3 months), 25.4 months (95% CI 17.7-33.1 months) and 30.1 months (95% CI 25.2-38.7 months), respectively. Survival was significantly longer in the TACE plus sorafenib group than in the other two groups. The 3-year OS and DFS rates in the TACE plus sorafenib group were 40.1% and 78.5%, respectively (Table 2).

Table 2. Survival rates and median survival duration in different groups

Variables	LR	LR+TACE	LR+TACE+Sorafenib
Median DFS
Time (95% CI), months	17.2 (13.2~21.3)	25.4 (17.7～33.1)	30.1 (25.2~38.7)
DFS，%
1-year	62.0%	64.1%	85.8%
2-year	28.6%	51.6%	54.1%
3-year	12.3%	27.3%	40.1%
Median OS
Time (95% CI), months	28.5 (21.5~35.3)	39 (30.2~48.3)	44.6 (40.81~48.4)
OS, %
1-year	82.6%	84.9%	96.4%
2-year	57.2%	68.9%	91.6%
3-year	36.3%	62.0%	78.5%

Abbreviations: HR, hazard ratio; CI, confidence interval; OS, overall Survival; DFS, disease free survival; LR, liver resection; TACE transcatheter arterial chemoembolization

Comparison between the TACE and control groups

OS rate was significantly higher in the TACE than in the control group. Eighteen patients (34.0%) in the TACE group died, with their 1-year and 2-year OS rates being 84.9% and 68.9%, respectively, and their median OS being 39 months (95 %CI 30.2~48.3 months). Fifty-nine patients (48.8%) in the control group died, with their 1-year and 2-year OS rates being 82.6% and 57.2%, respectively, and their median OS being 28.5 months (95%CI 21.5~35.3 months), Postoperative survival time was significantly longer in the TACE than in the control group (p=0.00043, Fig. 1A).

The recurrence rate was significantly lower in the TACE than in the control group (p=0.00072, Fig. 1B). Ninety-eight patients (81%) in the control group experienced early recurrence, with the 1-year and 2-year recurrence rates being 38% and 71.4%, respectively, and the median DFS being 17.2 months (95%CI 13.2~21.3 months). In comparison, 32 patients (60.4%) treated with TACE alone had early recurrence, with the 1-year and 2-year recurrence rates being 35.9% and 48.4%, respectively, and the median DFS being 25.4 months (95%CI 17.7~33.1 months).

Comparison between the TACE and TACE +Sorafenib group

OS was significantly longer in the TACE plus sorafenib than in the TACE group (p=0.0013, Fig. 1C). Three patients (10.3%) in the TACE plus sorafenib group, with patients in this group having a median OS of 44.6 months (95% CI 40.81-48.4 months) and 1-year and 2-year OS rates of 96.4% and 91.6% respectively. In comparison, 18 patients (34.0%) in the TACE group died, with patients in this group having a median OS of 39 months (95%CI 30.2-48.3 months) and 1-year and 2-year OS rates of 84.9% and 68.9%, respectively.

DFS was also significantly longer in the TACE plus sorafenib than in the TACE group (p=0.0016, Fig. 1D). Twelve 12 (41.4%%) in the TACE plus sorafenib group experienced tumor recurrence, with 1-year and 2-year recurrence rates of 14.2% and 36.9%, respectively, and a median DFS of 30.1 months (95% CI 25.2-38.7 months). In comparison, 32 patients (60.4%) experienced recurrence in the TACE group, with 1-year and 2-year recurrence rates of 35.9% and 48.4%, respectively, and a median DFS in this group of 25.4 months (95% CI 17.7~33.1 months).

Factors Associated with Patient Survival

Cox multivariate regression analysis showed that tumor diameter ≥ 5 cm (HR 3.4197, 95% CI 1.885~6.203), and AFP ≥ 400 µg/ml (HR 2.6927, 95% CI 1.716~4.226, p=0.0000187) were factors significantly prognostic of reduced OS (Table 3).

Table 3. Univariate and multivariate analyses of factors affecting overall survival (OS)

	Univariate Cox P	HR	95% CI	P
Sex male/female	0.239
Age Per year	0.00313	2.0127 1	1.265-3.201	0.34624
Tumor maximal diameter (cm) >5/<5	0.0000519	3.4197 1	1.885～6.203	0.00146
Exceed Milan Criteria No/Yes	0.000738	2.8826 1	1.559～5.331	0.18271
TACE Yes/No	0.000638	0.4182 1	0.2536～0.6898	0.01163
Sorafenib Yes/No	0.00412	0.1847 1	0.05824~0.5856	0.04594
MVI M1/M2	0.342
Tumor number Single/multiple	0.141
cirrhosis Yes/No	0.285
AFP (ng/ml) >400<400	0.0000165	2.6927 1	1.716～4.226	0.0000187
ALT(U/L) >40/<40	0.287
Positive for HBsAg Yes/No	0.0782
CEA (ng/ml) >5<5	0.699
TBIL (µmol/l) >17.1/ <17.1	0.719

Abbreviations: HR, hazard ratio; CI, confidence interval; MVI, microvascular invasion; AFP, α-fetoprotein; CEA, carcinoembryonic antigen; ALT, alanine aminotransferase; HBsAg, hepatitis B virus surface antigen; Tbil, total bilirubin; TACE, transcatheter arterial chemoembolization

Factors prognostic of reduced DFS included tumor maximum diameter ≥ 5cm (HR 3.8645, 95% CI 2.125~7.029, p=0.0019), hepatitis B positivity (HR 1.668, 95% CI 1.005~2.769, p=0.0355), and AFP ≥ 400 µg/ml (HR 2.835, 95% CI 1.813~4.433, p=0.000014) (Table 4).

Table 4. Univariate and multivariate analyses of factors predictive of disease-free survival (DFS)

	Univariate Cox P		HR	95% CI	P
Sex male/female	0.599
Age Per year	0.00102		2.1816 1	1.370～3.474	0.3469
Tumor maximal diameter (cm) >5/<5		0.0000095	3.8645 1	2.125～7.029	0.0019
Exceed Milan Criteria No/Yes	0.000125		3.3427 1	1.804～6.193	0.3564
TACE Yes/No	0.00101		0.4318 1	0.262～0.712	0. 0608
Sorafenib Yes/No	0.00469		0.1891 1	0.060～0.600	0.0336
MVI M1/M2	0.227
Tumor number Single/multiple	0.129
cirrhosis Yes/No	0.394
AFP (ng/ml) >400<400	0.0000049		2.835 1	1.813～4.433	0.000014
ALT(U/L) >40/<40	0.541
Positive for HBsAg Yes/No	0.0478		1.668 1	1.005~2.769	0.0355
CEA (ng/ml) >5<5	0.71
TBIL (µmol/l) >17.1/ <17.1	0.953

Abbreviations: HR, hazard ratio; CI, confidence interval; MVI, microvascular invasion; AFP, α-fetoprotein; CEA, carcinoembryonic antigen; ALT, alanine aminotransferase; HBsAg, hepatitis B virus surface antigen; Tbil, total bilirubin; TACE, transcatheter arterial chemoembolization

Factors Associated with Survival of patients in TACE group

Table 5 shows that the three predictors of OS in the TACE group, tumor diameter, TACE frequency, and liver cirrhosis, are independent risk factors affecting the prognosis of TACE treatment. Tumor diameter ≥ 5cm (HR 6.783, 95% CI 1.511~30.445, p=0.012) and liver cirrhosis (HR 6.446, 95% CI 1.993~20.847, p=0.002) were risk factors, whereas and ≥ 3 TACE sessions was a protective factor (HR 0.284, 95%CI 0.109~0.742, P=0.01).

Table 5. Multivariate analysis of factors affecting prognosis in patients undergoing TACE

	Multivariate analysis
	HR	95% CI	P
Tumor diameter (≥5/<5 cm)	6.783	1.511~30.445	0.012
TACE sessions (≥3/<3)	0.284	0.109~0.742	0.01
Liver cirrhosis (Yes/No)	6.446	1.993~20.847	0.002

Abbreviations: HR, hazard ratio; CI, confidence interval.

Cut-off value of tumor diameter

Tumor diameter is an independent risk factor that affects patient prognosis and survival after surgery. To evaluate the specific impact of tumor diameter on patient prognosis, ROC curves were drawn and the areas under the curve (AUC) were used to evaluate the predictive ability of these indicators on OS rate. The AUC for the association between tumor diameter and OS in the TACE group was 0.752 (95% CI 0.639~0.864, p=0.001), with the maximum value of the Jordan index being 0.466, The optimal cut-off point of tumor diameter predicting OS was 6.75 cm, which had a sensitivity of 81.0% and a specificity of 65.6% in predicting OS (Fig. 2).

MVI is an indicator of early metastasis of HCC, being observed in 15%~57.1% after resection.¹² At present, TACE is the first choice of adjuvant treatment for patients with postoperative MVI, and has been shown to significantly improve prognosis.^13,14 Prophylactic TACE treatment after R0 operation for HCC with MVI can effectively reduce the early recurrence rate and prolong patient OS. For example, a multicenter study involving 1517 patients compared the differences between short-term and long-term survivors of HCC patients with MVI, finding that TACE and wide surgical margins were independently prognostic of long-term survival. However, the choice of extended surgical margins is dependent on preoperative prediction of MVI, which is particularly difficult, making postoperative TACE of great significance.

The present study compared clinical outcomes in patients treated with TACE or liver resection alone. Both OS (P=0.00043) and DFS (P=0.00072) rates were significantly higher in patients treated with TACE than in patients who underwent liver resection alone, confirming that postoperative preventive TACE treatment of patients HCC and MVI could significantly prolong OS and reduce tumor recurrence.

Sorafenib is not only effective in the treatment of advanced HCC, but can reduce the risk of early recurrence, especially in patients with factors indicating a high-risk of metastasis and recurrence.¹⁶ High-risk factors include large sized and multinodular tumors ¹¹, as well as MVI positivity soon after surgery.¹⁷ Repeated adjuvant TACE treatment can enhance the secretion of vascular endothelial growth factor (VEGF),¹⁸ increasing the density of microvessels in the liver and increasing the risk of residual cancer cell metastasis in the microvessels.^19,20 Sorafenib targets VEGF receptor, thereby effectively inhibiting tumor angiogenesis. This, in turn, not only significantly prolongs the time to disease progression, but also prolongs OS. Sorafenib combined with TACE inhibits angiogenesis and eliminates the adverse effects of a hypoxic microenvironment. To date, this combination has achieved good results in patients with BCLC-C stage HCC,^21,22 and has been shown effective in HCC patients with early diffuse recurrence (EDR) and portal vein tumor thrombosis (PVTT).^23,24 Similarly, the present study showed that the combination of TACE and sorafenib had a greater than expected effect in the adjuvant treatment of HCC patients with MVI. The 1-year and 2-year recurrence rates were 14.2% and 36.9%, respectively, in the TACE plus sorafenib group, compared with 35.9% and 48.4%, respectively, in the TACE group. Median DFS (30.1 vs. 25.4 months, p=0.0016) and median OS (44.6 vs. 39 months, p=0.0013) were significantly lower in the TACE plus sorafenib than in the TACE alone group, indicating that the combination was more effective as adjuvant treatment than TACE alone in patients with HCC and MVI.

The analysis of risk factors affecting the prognosis of HCC patients with MVI can be used to assess the possible effects of postoperative preventive TACE. Maximum tumor diameter was shown to be closely related to the prognosis of HCC patients with MVI.^25-27 The present study confirmed the negative correlation between the maximum tumor diameter and poor prognosis. In addition, hepatitis B positivity and AFP 400 µg/ml were found to be prognostic of DFS, and AFP≥400 µg/ml to be prognostic of OS. Patients with these factors should therefore be more frequently monitored and be considered for more active treatment measures.

Multivariate analysis found that tumor diameter ≥n5 cm, liver cirrhosis, and ≥ 3 TACE sessions were independently associated with survival after treatment. Subgroup analysis showed that ≥ 3 TACE sessions could significantly prolong survival of patients with maximum tumor diameter <5 cm. A previous study involving 695 patients found that tumor diameter >5 cm and MVI were indications of the need for early postoperative TACE treatment,²⁸ with survival times significantly longer than those of patients who underwent surgery alone. To further assess the impact of tumor diameter on patient prognosis, an ROC curve was drawn to test the impact of tumor diameter on survival after TACE treatment. The optimal tumor diameter cut-off point predicting survival was calculated to be 6.75 cm, suggesting that TACE is effective in treating tumors <7 cm in diameter. Patients with larger tumors may be insensitive to TACE because of the presence in these patients of greater numbers of unrecognized microscopic metastases⁵ or the greater vascular density of larger tumors. Thus, the ability of TACE to reactivate and aggravate vascular invasion in larger tumors may be greater than its ability to block blood supply. Alternatively, the residual liver volume after resection of huge tumors is small, resulting in a poor postoperative liver load capacity, with postoperative recurrence usually associated with potential liver diseases, such as liver cirrhosis or active hepatitis.^29,30 The patient may die due to poor liver function. Treatment guidelines suggest that HCC patients with MVI receive at least three sessions of TACE, with patients found to have progressive disease after TACE treatment not recommended to continue TACE. Liver cirrhosis is reflective of reduced liver tolerance, with postoperative TACE not being poorly tolerated, but may exacerbate damage to liver function and suppress the immune system³¹.

The present study had several limitations. First, it was a single center retrospective analysis, which may result in subjective selection bias. Second, relatively few patients received TACE plus sorafenib, and their follow-up time was relatively short. In subgroup analysis, most patients had solitary HCC nodules, with fewer having multinodular HCC. Prospective, large-scale multicenter studies are needed to determine the efficacy of TACE combined with sorafenib for HCC patients with MVI.

The present study shows that TACE combined with sorafenib is an excellent postoperative adjuvant treatment for patients with HCC, especially those with MVI and tumor diameter <7 cm. Moreover, three or more TACE sessions may achieve better effects. Further studies are needed to determine the optimal indications for TACE plus sorafenib in patients with HCC.

HCC hepatocellular carcinoma

MVI microvascular invasion

PVTT portal vein tumor thrombus

VEGF vascular endothelial growth factor

TACE transcatheter arterial chemoembolization

AFP alpha fetoprotein

TBIL total bilirubin

CEA carcinoembryonic antigen

ALT alanine transaminase

HBsAg Hepatitis B surface antigen

EDR early diffuse recurrence

BCLC-C Barcelona Clinic Liver Cancer phase C

OS overall survival

DFS disease free survival

Ethical approval and consent to participate

The study methodologies conformed to the standards set by the Declaration of Helsinki. Ethics approval was obtained from the Ethics Committee of Tianjin Medical University Cancer Hospital. The participants provided their written informed consent to participate in this study.

Consent for publication

Not applicable

Availability of data and materials

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Competing interests

The authors report no conflicts of interest in this work.

Funding

Not applicable

Authors' contributions

QL designed the study. QL and QZ conducted the study. TS and SL collected data, QZ and YZ performed the statistical analyses and interpreted the data, YL beautified images, QZ and HZ writing the manuscript. All authors read and approved the final manuscript.

Acknowledgement

Not applicable

Sung H, Ferlay J, Siegel RL, 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(3):209-249. doi:10.3322/caac.21660
Jeong J, Park JG, Seo KI, et al. Microvascular invasion may be the determining factor in selecting TACE as the initial treatment in patients with hepatocellular carcinoma. Medicine (Baltimore). 2021;100(27):e26584. doi:10.1097/md.0000000000026584
Chen ZH, Zhang XP, Zhou TF, et al. Adjuvant transarterial chemoembolization improves survival outcomes in hepatocellular carcinoma with microvascular invasion: A systematic review and meta-analysis. Eur J Surg Oncol. 2019;45(11):2188-2196. doi:10.1016/j.ejso.2019.06.031
Wang H, Du PC, Wu MC, Cong WM. Postoperative adjuvant transarterial chemoembolization for multinodular hepatocellular carcinoma within the Barcelona Clinic Liver Cancer early stage and microvascular invasion. Hepatobiliary Surg Nutr. 2018;7(6):418-428. doi:10.21037/hbsn.2018.09.05
Liu S, Li H, Guo L, et al. Tumor size affects efficacy of adjuvant transarterial chemoembolization in patients with hepatocellular carcinoma and microvascular invasion. Oncologist. 2019;24(4):513-520. doi:10.1634/theoncologist.2018-0305
Gu W, Tong Z. Sorafenib in the treatment of patients with hepatocellular carcinoma (HCC) and microvascular infiltration: a systematic review and meta-analysis. J Int Med Res. 2020;48(8):300060520946872. doi:10.1177/0300060520946872
Huang Y, Zhang Z, Zhou Y, Yang J, Hu K, Wang Z. Should we apply sorafenib in hepatocellular carcinoma patients with microvascular invasion after curative hepatectomy? Onco Targets Ther. 2019;12:541-548. doi:10.2147/ott.S187357
Yang J, Liang H, Hu K, et al. The effects of several postoperative adjuvant therapies for hepatocellular carcinoma patients with microvascular invasion after curative resection: a systematic review and meta-analysis. Cancer Cell Int. 2021;21(1):92. doi:10.1186/s12935-021-01790-6
Wang SN, Chuang SC, Lee KT. Efficacy of sorafenib as adjuvant therapy to prevent early recurrence of hepatocellular carcinoma after curative surgery: A pilot study. Hepatol Res. 2014;44(5):523-531. doi:10.1111/hepr.12159
Kimura Y, Kaneko R, Yano Y, et al. The prognosis of hepatocellular carcinoma treated with sorafenib in combination with TACE. Asian Pac J Cancer Prev. 2020;21(6):1797-1805. doi:10.31557/apjcp.2020.21.6.1797
Aktas G, Kus T, Emin Kalender M, et al. Sorafenib with TACE improves the survival of hepatocellular carcinoma patients with more than 10 cm tumor: a single-center retrospective study. J BUON. 2017;22(1):150-156.
Rodríguez-Perálvarez M, Luong TV, Andreana L, Meyer T, Dhillon AP, Burroughs AK. A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability. Ann Surg Oncol. 2013;20(1):325-339. doi:10.1245/s10434-012-2513-1
Li SR, Bu LL, Cai L. Cuproptosis: lipoylated TCA cycle proteins-mediated novel cell death pathway. Signal Transduct Target Ther. 2022;7(1):158. doi:10.1038/s41392-022-01014-x
Li KY, Zhang SM, Shi CX, Tang KL, Huang JZ. Effect of prophylactic transcatheter arterial chemoembolization on hepatocellular carcinoma with microvascular invasion after R0 resection. A case-control study. Sao Paulo Med J. 2020;138(1):60-63. doi:10.1590/1516-3180.2019.0042.R1.05072019
Jiang X, Yan Q, Xie L, et al. Construction and validation of a ferroptosis-related prognostic model for gastric cancer. J Oncol. 2021;2021:6635526. doi:10.155/2021/6635526
Chen W, Ma T, Zhang J, et al. A systematic review and meta-analysis of adjuvant transarterial chemoembolization after curative resection for patients with hepatocellular carcinoma. HPB (Oxford). 2020;22(6):795-808. doi:10.1016/j.hpb.2019.12.013
Zhang XP, Chai ZT, Gao YZ, et al. Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis. HPB (Oxford). 2019;21(12):1687-1696. doi:10.1016/j.hpb.2019.04.014
Lin W, Wang H, Zhong M, et al. Effect and molecular mechanisms of Jiedu recipe on hypoxia-iInduced angiogenesis after taranscatheter arterial chemoembolization in hepatocellular carcinoma. Evid Based Complement Alternat Med. 2021;2021:6529376. doi:10.1155/2021/6529376
Persano G, Cantone N, Pani E, Ciardini E, Noccioli B. Heterotopic pancreas in the gastrointestinal tract in children: a single-center experience and a review of the literature. Ital J Pediatr. 2019;45(1):142. doi:10.1186/s13052-019-0738-3
Lauwers GY, Terris B, Balis UJ, et al; International Cooperative Study Group on Hepatocellular Carcinoma. Prognostic histologic indicators of curatively resected hepatocellular carcinomas: a multi-institutional analysis of 425 patients with definition of a histologic prognostic index. Am J Surg Pathol. 2002;26(1):25-34. doi:10.1097/00000478-200201000-00003
Patidar Y, Chandel K, Condati NK, Srinivasan SV, Mukund A, Sarin SK. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE in patients with BCLC Stage C hepatocellular Carcinoma - a retrospective study. J Clin Exp Hepatol. 2022;12(3):745-754. doi:10.1016/j.jceh.2021.12.009
Liu KC, Hao YH, Lv WF, et al. Transarterial chemoembolization combined with sorafenib in patients with BCLC stage C hepatocellular carcinoma. Drug Des Devel Ther. 2020;14:3461-3468. doi:10.2147/dddt.S248850
Yao W, Xue M, Lu M, et al. Diffuse recurrence of hepatocellular carcinoma after liver resection: Transarterial chemoembolization (TACE) combined with sorafenib versus TACE monotherapy. Front Oncol. 2020;10:574668. doi:10.3389/fonc.2020.574668
Yuan J, Yin X, Tang B, et al. Transarterial chemoembolization (TACE) combined with sorafenib in ireatment of HBV background hepatocellular carcinoma with portal vein tumor thrombus: A propensity score matching study. Biomed Res Int. 2019;2019:2141859. doi:10.1155/2019/2141859
Wei W, Jian PE, Li SH, 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). Oct 10 2018;38(1):61. doi:10.1186/s40880-018-0331-y
Qi YP, Zhong JH, Liang ZY, et al. Adjuvant transarterial chemoembolization for patients with hepatocellular carcinoma involving microvascular invasion. Am J Surg. 2019;217(4):739-744. doi:10.1016/j.amjsurg.2018.07.054
Okamura Y, Sugiura T, Ito T, et al. The predictors of microscopic vessel invasion differ between primary hepatocellular carcinoma and hepatocellular carcinoma with a treatment history. World J Surg. 2018;42(11):3694-3704. doi:10.1007/s00268-018-4658-y
Wang L, Ke Q, Lin K, et al. Not all hepatocellular carcinoma patients with microvascular invasion after R0 resection could be benefited from prophylactic transarterial chemoembolization: A propensity score matching study. Cancer Manag Res. 2020;12:3815-3825. doi:10.2147/cmar.S251605
Yang Y, Dang Z, Lu P, et al. Impact of pathological response after preoperative transcatheter arterial chemoembolization (TACE) on incidences of microvascular invasion and early tumor recurrence in hepatocellular carcinoma: a multicenter propensity score matching analysis. Hepatobiliary Surg Nutr. 2022;11(3):386-399. doi:10.21037/hbsn-20-700
Lei Z, Li J, Wu D, et al. Nomogram for preoperative estimation of microvascular invasion risk in hepatitis B virus-related hepatocellular carcinoma within the Milan criteria. JAMA Surg. 2016;151(4):356-363. doi:10.1001/jamasurg.2015.4257
Jin YJ, Lee JW, Lee OH, et al. Transarterial chemoembolization versus surgery/radiofrequency ablation for recurrent hepatocellular carcinoma with or without microvascular invasion. J Gastroenterol Hepatol. 2014;29(5):1056-1064. doi:10.1111/jgh.12507

No competing interests reported.

Prognosis of TACE combined with sorafenib in hepatocellular carcinoma patients with microvascular invasion: A retrospective cohort study

Status:

Version 1

Abstract

Purpose

Patients and methods:

Results

Conclusion

Figures

Introduction

Materials and methods

Patients

TACE

Sorafenib

Study assessment

Statistical analyses

Results

Patient characteristics

Survival outcomes

Comparison between the TACE and control groups

Comparison between the TACE and TACE +Sorafenib group

Factors Associated with Patient Survival

Factors Associated with Survival of patients in TACE group

Cut-off value of tumor diameter

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1