Trans-Arterial Chemoembolization for the Treatment of Hepatocellular Carcinoma: A Single Tertiary Care Institute Experience

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INTRODUCTION
Hepatocellular carcinoma (HCC) is a serious and a major global health issue with about 500,000 new cases identified yearly, making it the most prevalent and the 5 th most frequent primary liver cancer 1,2 .It represents between 70%-90% of all cases of primary liver cancer 3 .In Asian countries, the prevalence ranges between 0.3% and 1.6% 4 .Chronic viral hepatitis or cirrhosis, environmental contaminants, secondary viral infections such as hepatitis B(HBV) and C (HCV) and alcoholic or fatty liver conditions, lifestyle aspects including smoking, alcohol intake, and dietary habits, metabolic conditions like diabetes and high body mass index, and genetic and hereditary issues are the most common causes 3,5 .Despite diagnostic, and therapeutic advancements, HCC continues to pose significant diagnostic and treatment limitations 5,6 .
"The Barcelona Clinic Liver Cancer (BCLC) staging system" considers tumor characteristics, performance status and liver function for evidencebased treatment selections 7 .Hepatic resection, radio-frequency ablation (RFA) and liver transplantation are recommended for early stage HCC BCLC (stage A).Nevertheless, due to specific situations, these modalities cannot always be utilized for all HCC patients.Loco-regional treatment (LRT) is a bridging technique for patients on the transplant queue 8,9 .Trans-arterial chemo embolization (TACE) is a therapeutic approach that involves the selective delivery of chemotherapeutic agents and embolic materials directly into the tumor-feeding arteries, leading to the dual effect of tumor necrosis and arterial occlusion.It is the most frequently used treatment in patients with BCLC stage B, which includes multi-nodular tumors with Child-Pugh (A or B) stage and good performance status and is not susceptible to resection.Arterial neoangiogenesis is the hallmark of HCC or hepatoma.These aggressive liver tumors rely heavily on the development of an extensive blood supply to sustain their rapid growth and progression.TACE blocks tumor blood flow, inhibits tumor growth and produces significant findings in terms of tumor response, which is about 50% 9,10 .This means that about half of the patients treated with TACE experience a significant reduction in tumor size or stabilization of the disease, leading to improved clinical outcomes.These findings highlight the considerable impact of TACE in managing HCC and its potential as a curative or palliative treatment modality.The radiological and clinical response of TACE in the treatment of HCC has been a subject of significant interest and research.Assessing tumor response to TACE is crucial for determining treatment efficacy and future therapy. 11To assess response to LRT, a "modified response evaluation criterion in solid tumours (mRECIST) are a set of published rules used to assess tumor burden in order to provide an objective assessment of response to therapy with targeted agents for hepatocellular carcinoma (HCC).It considers the extent of viable contrast-enhancing regions within the tumor 9,10,12 .Although there is a validated relationship between HCC enhancement patterns and image results, these findings are closely associated with tumor differentiation, which plays a crucial role in understanding the aggressiveness and prognosis of HCC 11,13,14 However there is a data scarcity of this region and the therapy outcomes remain diverse.Considering this, the present study is conducted to determine the radiological and clinical response of HCC patients who underwent TACE.

TACE Technique:
Prior to the TACE procedure, written informed consent was obtained.Once the aseptic measures were taken, a local anaesthesia was administered and the common right femoral artery was punctured.A 6Fr vascular sheath was then placed, and the celiac and superior mesenteric arteries were surveyed angiographically.The next step was to perform a common hepatic angiography to determine the tumor's blood supply.After that, a microcatheter was cautiously and selectively inserted into the artery that was feeding the tumor.Doxorubicin 50mg, the chemotherapy agent mixed with lipiodol was injected.Additional embolisation was performed with PVA particles (100-350 microns).The interventional radiologist determined the correct amount of the chemotherapeutic and embolic agents based on the several factors like size and number of tumors, the tumor arterial blood supply, the degree of liver impairment, and renal function.For those who had adequate hepatic function reserve (Child-Pugh A or Child-Pugh B < 8) and a residual viable tumor, repeat TACE treatments were planned at 6 to 8weeks intervals after the initial treatment.However, those patients who showed no evidence of residual viable disease (i.e., with CR according to mRECIST), imaging follow-up was recommended every 2 to 3 months.

Radiological Characteristics:
The pre-and post-TACE triphasic abdominal CT scans were performed, and tumor characteristics were recorded as reported by experienced radiologists.The HCC attenuation in each phase was classified as arterially enhancing with washout in porto-venous and delayed phases tumor and heterogeneously enhancing with washout in portal venous and delayed phases.The pattern of enhancement is classified as residual tumor enhancement or no residual tumor enhancement.Tumor size was compared pre-and post TACE.

Post TACE Tumor Response:
Patients were evaluated at 6weeks of post TACE period by contrast CT scan of abdomen with triphasic protocol and then followed up every 2 to 3months, depended on individual tumor response until they reached the endpoints, which included death or survival.The tumor response was measured based on the modified RECIST (mRECIST) standards 12 with two categories of response: complete response (CR) and partial response (PR) obtained at first follow-up visit.

Statistical Analysis:
The retrieved data was analysed SPSS version 21.Quantitative variables were presented as mean and standard deviation, medians and interquartile ranges, or both.Numbers and percentages were used for categorical variables.The Chi square test or Fisher exact was used to determine the association between categorical variables, and numerical data differences were calculated using the student independent t test.A paired sample t-test was used to see the pre-and post-mean differences.Survival analysis was done using the Kaplan-Meier curve.Statistical significance was set at 5% with a 95% confidence interval.p value 0.05 was considered significant,

RESULTS
The details of the study patients (n=118) are summarised in Table-1.The mean age of the study patients was 49.42±10.74years [median (IQR) 50.00 (16.25)].Nearly two-thirds of the study participants were male.Viral hepatitis caused by HCV was observed in 81 (68.64%) patients and HBV in 37 (31.36%)patients.Those who had coexisting illnesses were 53 (44.92),where hypertension was documented in 41 (34.75%), and diabetes mellitus in 38 (32.10%).Majority patients were grouped into Child-Pugh stage A, whereas 75.42% of the patients were in stage B based on "The Barcelona Clinic Liver Cancer (BCLC) staging system."All patients had multiple tumors.The HCC diameter was 3.99±0.90cm, with 83 (70.30%) having a tumor size >3 cm.Tumors were located in more than half of the patients in right lobe of the liver.On the other hand, one-fourth of the patients had portal vein tumor thrombus.The study patients were divided into two tumor response categories.Of the total 118 patients, 51.70% showed complete response to TACE, while 48.3% had partial response (PR).Patient background, laboratory, and tumor characteristics, as well as the outcome of both tumor response categories, are presented abridged in Table-1.Age, sex, viral hepatitis infection, and co-morbid conditions showed no intergroup differences.Child-Pugh stage and BCLC were significantly associated with tumor response.Laboratory parameters including total bilirubin, albumin, and AFP showed a significant mean inter group differences (p<0.001).Those who responded completely had a mean tumor (3.00±1.00vs.5.00±1.00p<0.001) compared to the partial responders.Those with smaller ( 3cm) tumor sizes had a higher rate of complete response than those with larger (>3cm) ones did not [(26(42.60%)vs. 9(15.80%)],and the association was statistically significant (P<=0.001).Patients were followed, and at the endpoint, no mortality was noted in those who responded completely.Tumor size was assessed using a CT scan of the abdomen with a triphasic protocol, and the results were compared pre-and post-6-weeks TACE as shown in Fig- 1.A paired sample t-test was run to ascertain whether there was a statistically significant mean difference before and after TACE.There was a significant mean difference in tumor size (3.27±0.90 vs. 3.99±1.02,p<0.0001).The paired mean difference was 0.72 (95% CI [0.62-0.82]).Arterially enhancing with washout in portovenous and delayed phases tumor appearance before TACE was documented in 90 (76.30%), followed by heterogeneously enhancing with washout in portal venous and delayed phases in 28 (23.70%).Post-TACE, no residual enhancement was documented in more than half of the patients.A high proportion of patients showed no residual enhancement of tumor in arterial phase, as given in Fig- 2 and Fig- 3.
The average duration of patient survival was 12.55 months (95% confidence interval: 11.90-13.19), with a median survival of 14.00 months (95% confidence interval: 12.36-15.64).Tumor response yielded no statistics because all cases were censored in CR.The computed mean [(12.68,95% 11.99-13.37 vs. 11.63,95% 10.42-12.83)]duration for the absence of PPVT was greater compared to the presence (p=0.414).Overall, the estimated mean duration for tumor size 3 was greater than that for tumour size >3 (12.42 Vs.12.22) but the difference was statistically nonsignificant (p=0.138).Likewise, BCLC (stage B) had an estimated mean survival time greater than that of BCLC C, and the difference was statistically nonsignificant (p=0.414).On the contrary, Child-Pugh score A had an estimated mean survival time greater than that of score B, and the difference was statistically significant (p<0.001) as shown in Fig- 4.

DISCUSSION
TACE is the preferred loco-regional treatment for intermediate-stage HCC, according to the clinical guidelines.Multimodal therapies based on TACE have been shown to be more efficient than conservative management.To evaluate the efficacy, it is crucial to perform post-TACE radiological response analysis, utilizing the modified RECIST principle, which recommends one-dimensional evaluation of the longest remaining tumor dimension and the RECIST numerical criteria of response 12,15 .The measurement of residual viable tumor tissue after TACE to determine personal responses is a proxy indication of the survival rate.
Our findings revealed that a CR was achieved in 51.70% of patients.A study conducted by Lee, S. W., et al 9 reported radiological CR in 60% of the study patients.A similar study in Italy with a single HCC undertaking TACE reported a 64% CR rate and 26% PR 16 .The variation could be attributed to the tumour size, inclusion criteria, selectivity of technique, and expertise of the treating consultant.Most clinico-laboratory variables had no effect on the CR.However, a smaller Child-Pugh grade was found to have significant impact on TACE response in the study.This association has been shown frequently in studies 10,17,18 , and it may be associated to the aggressive therapy regimen that patients with a better functional liver status were able to tolerate as compared to that utilised in the wake of advanced disease.Patient with larger tumors ( 3 cm) had a significantly higher percentage of CR compared to those with smaller tumors (<3 cm) (42.60% vs 57.40%).TACE is the treatment of choice for large tumors and neoadjuvant chemoembolization to reduce the size of the tumor for liver transplant or resection 19 .Previous studies suggest that small tumors are more likely to achieve CR, unlike our study findings 16,20 .The plausible explanation for these differences, where larger tumors had a higher percentage of CR, could be attributed to differences in the patient population, tumor characteristics, or therapy protocols.It is also possible that the sample size or methodology of the earlier studies was not robust enough to detect the effect of tumor size on TACE response.
In our study, those with no partial portal vein tumor thrombus (PVTT) had a high radiological complete response.TACE paired with radiation has demonstrated greater efficacy in patients with HCC and PVTT by maintaining portal blood flow, preventing the loss of liver function, and preventing intra-vascular tumour progression 19 .The presence of PVTT poses a therapeutic challenge, and its presence may compromise the candidature for TACE due to the risk of liver function deterioration and hepatic infarction.However, selective, or superselective TACE procedures can still be performed safely in some cases.
To further understand what factors, influence HCC responsiveness, the study divided HCC lesions into two groups based on radiological appearance and found that 76.30% of tumors were arterially enhancing with washout in the porto-venous and delayed phases, while 23.70% were heterogeneously enhancing with washout in the portal venous and delayed phases.More than half of the patients had no residual enhancement after TACE.In arterial phase, a large number of patients had no residual tumor enhancement as found by Zhang Wie et al 10 , found that lesions with strong arterial phase enhancement had a higher probability of nearcomplete necrosis compared to those with mild to moderate enhancement (37%).Considering enhancement and margin factors may help determine TACE outcomes, and examining both variables before treatment may be beneficial.The findings imply that the application of enhancement and margin factors may aid in determining the probability of TACE outcome, and henceforth it may be beneficial to examine both variables concurrently before subjecting patients to surgical procedures.The absence of PPVT and tumor size 3 had a longer mean duration than the presence and larger size.BCLC (B) had a greater estimated mean survival time than BCLC (C), while Child-Pugh score A had a greater estimated mean survival time than score B, with a significant difference.CR had no statistics for tumor response, but TACE-induced radiological tumor response predicted overall survival, and no mortality was observed in those who achieved CR.The study's findings are consistent with those of other studies regarding smaller tumors, Child-Pugh score, and BCLC staging on cumulative survival 9,16,20 .TACE is an effective therapy for unresectable HCC, including BCLC-C and Child-Pugh-B stages, and can improve survival and responsiveness without affecting liver function 19,21 .The study has limitations such as a retrospective design, selection and reporting biases, small sample size, grouping of radiological response into two categories only, and lack of characterization of tumor margin shape.Prospective studies with more cases and covariates are needed to improve the findings.

CONCLUSION
Based on this study's findings, it can be concluded that over 50% of the patients achieved a complete response to TACE.Factors such as BCLC B stage, Child-Pugh class A, and small tumor size positively influenced the response to TACE during the early stages of HCC.Additionally, tumors exhibiting arterial enhancement and washout in the portovenous and delayed phases were found to be more susceptible to TACE treatment.The use of CT imaging could aid in refining the criteria for selecting TACE as a treatment option, thereby enhancing overall outcomes and patient survival.It is important to consider an individual's risk profile, co-morbid conditions, and potential benefits when deciding to pursue TACE as a therapeutic approach, with the goal of improving survival rates while minimizing adverse events.