Journal of Clinical Gastroenterology and Hepatology Open Access

Post Tace Hepatocellular Carcinoma Response Assessment by Modified Recist and Short Term Post Tace Survival

Bony George^1*, Krishnadas Devadas¹, Sandesh K¹, Jineesh V², Tharun Tom Oomen¹, Jijo Varghese¹, Arun P¹, Eldhose Elias George³ and Vijay Narayanan^{1 1}Department of Medical Gastroenterology, Government Medical College Trivandrum, India
²Department of Interventional Radiology, Sreechitrathirunnal Institute of Medical Sciences, India
³Department of Pharmacy Intern, Nirmala College of Pharmacy, India
^*Correspondence: Bony George, Department of Medical Gastroenterology, Government Medical College Trivandrum, India,

Received: 30-Mar-2022, Manuscript No. IPJCGH-22-13312; Editor assigned: 01-Apr-2022, Pre QC No. IPJCGH-22-13312 (PQ); Reviewed: 15-Apr-2022, QC No. IPJCGH-22-13312; Revised: 20-Apr-2022, Manuscript No. IPJCGH-22-13312 (R); Published: 27-Apr-2022, DOI: 10.36648/2575-7733.6.4.19

Abbreviations

(BCLC) Barcelona Clinic Liver Cancer; (cTACE) Conventional Transarterial Chemoembolization; (CR) Complete Response; (HAP) The Hepatoma Arterial-Embolization Prognostic Score; (mRECIST) Modified Response Evaluation Criteria in Solid Tumors; (PD) Progressive Disease; (PR) Partial Response; (SD) Stable Disease; (STATE) Score-Selection for Transarterial Chemoembolization Treatment

Introduction

Hepatocellular carcinoma is the most common primary malignancy of the hepatobiliary system. Approximately 7.5 Lakh new cases of HCC per year occur globally and that makes HCC the 5th common cause of cancers affecting humans. The mortality of HCC is about 0.7 million annually. HCC has been estimated to be the 3^rd common cancer related cause of death [1].

Currently, the Barcelona Clinic Liver Cancer (BCLC) system is the only staging system that accounts for tumour stage, liver function, and physical status. Recommended first-line treatment for HCC in the intermediate stage by Barcelona Clinic Liver Cancer (BCLC) tumour staging is Transarterial chemoembolization (TACE) [2]. TACE is a radio-logically guided transcatheter therapy which has both ischemic and cytotoxic effect on the tumour tissues. TACE can improve overall survival in patients with intermediate- stage HCC [3]. Different methods of TACE are there in use like conventional TACE (cTACE) and TACE with drug eluting beads (DEB-TACE). cTACE has been recommended by 3-4 RCTs for intermediate-stage HCC. However, some important limitations remain. It is due to the heterogeneity of the intermediate stage HCC population and the different types and techniques of TACE used worldwide. The wide range of liver functions of these patients and variable tumour numbers and sizes also play a part.

Many methods have been used to assess treatment efficacy. The response evaluation criteria in solid tumours (RECIST) are based on tumour shrinkage and are widely used in oncology to evaluate treatment response. Tumour response has been assumed to be a strong and valid proxy for increased survival. The Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 and updated version RECIST 1.1 cannot reliably predict the response of the treatment of patients with HCC because conventional chemotherapy plays a limited role in the treatment of these types of tumours [4,5]. Therefore, based on the concept of viable tumour (degree of enhancement/loss of enhancement after contrast injection) mRECIST criteria is widely accepted for treatment response after TACE [6,7].

Despite several advancements in the TACE technique, radiologic response evaluation, and patient selection for TACE, there is room for improvement concerning therapeutic efficacy. Various factors and scores which can predict post-TACE survival have not been extensively evaluated. In the present study, we exclusively considered conventional TACE using Epirubicin as a single treatment modality. We tried to assess modified RECIST in predicting post-TACE response. We also tried to evaluate the factors affecting post-TACE response and survival.

Materials and Methods

This is a prospective single centre study performed at a tertiary care University hospital in Kerala, India, over 2 years from 2019-2021 after getting approval from Institutional Ethics Committee (HEC No:06/08/2019/MCT). All patients gave written informed consent before enrolment. All patients with intermediate- stage HCC with contraindications for liver transplantation and who were fit for the TACE procedure were included in the study. Patients with extra-hepatic disease, coagulopathy and biliary obstruction and comorbid illnesses like coronary artery disease, congestive heart failure, and chronic renal failure were excluded.

TACE

All patients underwent superselective conventional TACE with Epirubicin. Both superior mesenteric and common hepatic arteriography was performed to look for overall anatomy, tumor burden, and portal vein patency. Epirubicin was mixed at a 1:1 ratio with lipiodol to form an emulsion of iodized oil (lipiodol; Guerbet, Roissy, France). It was then infused into the segmental, sub-segmental, or more peripheral-level feeding artery. This was followed by embolization with Gelfoam slurry (Upjohn, Kalamazoo, MI) until a near stasis of arterial flow was attained. The dose of lipiodol depended on the tumor size and ranged from 3–20 ml. The emulsion of lipiodol and Epirubicin was slowly injected until the accumulation of the emulsion in the tumor and the portal vein branches near the tumor was visualized. If any significant arterioportal shunt was found, embolization with Gelfoam slurry was first performed to occlude the shunt, after which the lipiodol/Epirubicin emulsion was infused and again embolization with Gelfoam slurry was performed. Embolization was performed to minimize the ischemic toxicity of the non-targeted normal liver parenchyma and to minimize vascular complications due to the repeated endovascular procedures.

Post TACE Response and Survival Analysis

Radiological assessment of treatment response was carried out 6-8 weeks after the procedure by MRI, according to mRECIST criteria. Tumor treatment response was defined as complete response (CR), based on the disappearance of all tumoral arterial enhancement in all of the target lesions, or partial response (PR) defined as at least a 30% decrease in volume of the sum of the viable target lesions. Progressive disease (PD) was defined as a 20% increase from baseline volume of the viable target lesions. Stable disease (SD) was defined as any case that did not meet the criteria for PR or PD. Patients were followed up in the outpatient setting. Objective response (OR) is taken as patients having either complete or partial response as per mRECIST criteria. Poor response (PoR) is taken as patients achieving either SD or PD. Overall survival (OS) was calculated from the time of TACE to the date of death or last follow-up.

Demographical features, medical history, clinico pathological features and biochemical factors were assessed prior to TACE. Patients were followed up to assess the prognostic significance of these factors in predicting response to TACE and short-term survival after TACE. Survival period of patients was considered as the last date when all the data were taken up for analysis.

Statistics

The data was analyzed using SPSS version 25 statistical software (SPSS, Inc, Chicago, IL, USA). Categorical and quantitative variables were expressed as frequency (percentage) and mean ± SD respectively. Chi-square test and Odds ratio with 95% CI were used to explain the association of overall response with selected variables. Multiple logistic regressions were used to find the independent risk factors of the overall response. Univariate and multivariate Cox regression analysis was carried out to find out the factors influencing the survival of Post TACE patients. For all statistical interpretations, p<0.05 was considered the threshold for statistical significance. Kaplan Meier curve was plotted to predict any significant survival benefit for TACE patients.

Results

Among 54 patients with HCC, 42 were analyzed. The mean age was 59.12 ± 8.74 years (Figure 1).

Figure 1: Consort Diagram.

Of the 42 patients analysed, 34 patients (81%) had diabetes mellitus, 21(50%) had hypertension, and 22(52.45%) had dyslipidemia. Predominant etiology for HCC was NASH (52.4%), alcohol (30.95%), HBV (19.04%) and HCV (11.9%). 26.2% (11/42) had combined etiologies-4 patients (HCV+NASH), 3 patients (NASH+ethanol), 2 patients (NASH+AIH) and 2 patients (HBV+ ethanol). 59.5% were Child A and 40.5% were Child B. 71.4% of patients had MELD <15. 40.5% of patients had prior de-compensations in the form of ascites, upper GI bleed. 81% were in BCLC B stage, and the rest were in BCLC A.

Sub-Classification of BCLC

Using Bolondi sub-classification, 27 patients (64.3%) were of B1 and B2 subtypes, and 15 patients (35.7%) were of B3 and B4 subtypes. 20 patients (47.6%) were of HAP A and B, and 22 patients (52.4%) were of HAP C and D. 28 patients (66.7%) had a STATE score of ≥ 18 and 14 patients (33.3%) had a STATE score of <18. Considering the performance status of the patients, 34 patients (81%) had ECOG performance status of 0 and 8 patients (19%) had performance status of 1. 88.1% lesions were in the right lobe. 54.8% of patients who underwent TACE had a single lesion. 1-3 lesions were present in 40.5% and >3 lesions were present in 4.8% of patients. In 76.2% of patients, the size of the largest lesion was <5 cm. Detailed information about clinic pathological features, biochemical indices, and lesion characteristics mentioned in (Table 1).

Table 1: Baseline characteristics of the study population.

Clinical response after c TACE

Objective response was obtained in 73.8% of the patients who underwent TACE and poor response in 26.2% (Table 2).

Table 2: Response distribution of the population Post TACE response by mRECIST.

Comprehensive Analysis of Factors Influencing Objective Response

Univariate and multivariate analysis was performed to find out the predictive factors affecting clinical response. On univariate analysis Child A populations had significant objective response {[Odds ratio 6.52 (95% CI) (1.40-30.31), p=0.011]. HAP A, B patients had better objective response compared to HAP C, D patients { Odds ratio 15.83 (1.79-139.92), p=0.003} (Tables 3 and 4).

Table 3: Association of objective response with selected variables.

Table 4: Independent predictors of Post TACE response by modified RECIST among patients with hepatocellular carcinoma (Multiple Logistic regression).

Factors associated with overall survival with p<0.05 were further analyzed by multivariate model. On multivariate cox regression analysis, only HAP staging was found to have significance in the objective response. Relative to HAP C and D, HAP A and B patients had 2.76 times chances of getting objective response {(Odds 15.83, 1.79-139.92, p=0.013)}

Overall Survival Analysis

Prognostic variables affecting the survival of patients after TACE: Higher ART score post TACE was found to have an HR of 1.29 (1.08-1.54), p=0.004 for mortality. CTP score increase after TACE, had an HR of 1.40 (1.13-1.74), p=0.002, for mortality. Objective response by mRECIST had an impact on survival, with patients getting no response having higher mortality with an HR of 1.08(1.01-1.1.6), p=0.02. Post TACE de-compensation had a significant effect on survival with an HR of 6.23 (1.78- 21.77), p=0.004. CHILD B patients had a poor survival compared to CHILD A patients, HR 5.75 (1.97-16.78), p=0.001. Patients with a MELD score of ≥ 15 at the time of TACE had higher mortality, HR 3.96 (1.49-10.54), p=0.006. Bolondi stages B3, B4 had poor survival compared to stage B1, B2, HR 4.19 (1.55- 11.3), p=0.005. STATE score <18 had a poor survival response than with a score of >18 with HR 4.31 (1.65-11.26), p=0.003. Patients with a single lesion had a better survival compared to multiple lesions (Tables 5 and 6).

Table 5: Prognostic variables affecting the survival of patients with TACE treatment (Univariate Cox regression Analysis).

Table 6: Independent Prognostic variables affecting the survival of patients with TACE treatment.

On multivariate cox regression analysis, 3 factors were found to be significant predictors of mortality on post TACE survival. These were the number of lesions at the time of TACE, ECOG PS at the time of TACE, and post TACE de-compensations. Patients with post TACE de-compensation had a poorer survival than those with no de-compensation after TACE with HR 4.18 (1.14- 15.27), p=0.030. Patients with Grade 1 ECOG performance status at the time of TACE had a poorer survival as compared to ECOG 0, HR 4.08 (1.39-11.97), p=0.010. For patients undergoing TACE, those with a single lesion had a better survival than those with more than 3 lesions, HR 9 (1.49-54.56), p=0.017 (Table 7).

Table 7: Mean Survival duration among mRECIST response patients.

Overall survival was calculated from the date of TACE to death of the patient or till the date of study closure. Of all the patients analysed, 18 (42.9%) of patients died during the study interval. 5 out of 23 patients who had a complete response, died. Among them, one patient died due to the recurrence of colorectal carcinoma, which had been previously treated, and another had a gastric artery embolism while he underwent a second TACE for recurrence after an initial CR. 5 out of 7 (71%) patients with PD after TACE died during the study period. 5 out of 8 patients with PR and 3 out of 4 patients with SD died. 52.4% had post TACE de-compensation, like worsening of ascites, upper GI bleed and hepatic encephalopathy. 81% had post TACE syndrome and all the patients improved after conservative medical management and observation.

Mean survival for patients with mRECIST CR, PR, SD and PD was 27.94 months, 18.72 months, 19.33 months and 10.43 months respectively. Patients with objective response had a survival of 25.64 months, and patients with poor response had a survival of 13.10 months (P=0.001) (Figure 2).

Figure 2: Kaplan Meier Curve showing the survival with Post TACE response by modified RECIST among patients with objective and poor response.

Discussion

Hepatocellular carcinoma is one of the leading causes of cancer. Globally, it is the 3^rd most common cause of death among cancers. TACE is a recommended modality of treatment for patients with good performance status and intermediate stage HCC who cannot undergo resection/Radiofrequency ablation/ liver transplantation. mRECIST is the imaging criteria accepted globally for assessing response evaluation of the lesions which underwent TACE.

Our study is one of the largest studies from a single center. We analyzed patients undergoing conventional TACE using Epirubicin as a single treatment modality for intermediate stage HCC over 2 years. During the COVID-19 pandemic.

Using mRECIST, 54.8% of the patients achieved a complete response, 19% achieved a partial response, 9.5% had stable disease and 16.7% had progressive disease, in our study. Considering complete response and partial response as objective response, 73.8% of the patients who underwent TACE had objective response. This was similar to the response seen in the study by M. Elkadeem et al. [8], where complete response (CR) occurred in 25(40.3%) patients, partial response (PR) in 15(24.2%) patients, stable disease (SD) in 2(3.2%) patients, and progressive disease (PD) in 20 (32.3%) patients. 64.5% had an overall response in the quoted study whereas our patients had an OR in 73.8%. The study by M Elkadeem et al had more advanced patients than in our study and patients with portal vein thrombosis were also considered.

We found that HAP staging significantly predicted objective response on multivariate cox regression analysis. The results obtained corroborate the finding obtained by L Kadalayil et al. [9] which found that HAP A and B patients had significantly better TACE response and overall survival.

42.9% of patients in our study died. 8/11 (72.7%) patients with poor response died as against only 10/31(32.2%) of patients with objective response. A meta-analysis done by N. Haywood [10] showed that the median survival of patients following TACE was significantly greater in those having response than in those with nonresponse (20.8 months versus 14.9 months, p=0.011). Survival outcomes also significantly varied among the four mRECIST categories (p=0.0003): complete (21.4 months), partial (20.8 months), stable disease (16.8 months) and progressive disease (7.73 months). In the meta-analysis, only progressive disease demonstrated significantly worse survival when compared to complete response. Multivariable analysis showed that progressive disease, increasing total tumor diameter, and non-Child-Pugh class A were independent predictors of post-TACE mortality. We also found that patients with OR had significantly higher survival than patients with PoR (25.64 months vs 13.1 months). Most of the patients in the PD group survived less than 1-year post TACE. The study done by Gillimore et al. [11] also supports the findings in the present study where survival was significantly longer in responders than in patients with a poor response (20.8 months versus 14.9 months, p=0.011). The significant survival difference between patients with objective response and poor response after TACE shows that objective response after TACE is having a significant survival advantage in intermediate HCC patients.

The study done by Farina M et al. [12] showed survival to be associated with Child-Pugh (CP) class (p=0.038), MELD score (p=0.028), maximum AFP value (p=0.0002) and response after first TACE (p=0.006), on univariate analysis. We found that ART score (p=0.0040), change in CTP score post-TACE (p=0.002), post-TACE de-compensations (p=0.004), prior de-compensation at the time of TACE (p=0.008), CHILD stage at the time of TACE (p=0.001), MELD score at the time of TACE (p=0.006), Bolondi stage (p=0.005), STATE score (p=0.003), ECOG performance status at the time of TACE (p=0.002) and the number of lesions for TACE significantly affected post-TACE survival (p=0.0090) on univariate Cox regression analysis. AFP level did not predict survival in our study. The finding in our study is contrary to the results obtained by M. Elkadeem et al. [8] where de-compensation at the time of TACE and after TACE did not predict the survival of patients. Our result on uni/multivariate analysis showed that de-compensation in TACE patients significantly affects survival. Severity of underlying liver disease could be an important factor in determining survival.

The results also support the studies done by M. Elkadeem et al. [8] and F. Trevisani et al. [13] that radiological response after TACE is inadequate as a sole variable to determine the prognosis in patients with HCC who undergo regional therapy. Similar to both these studies mRECIST response had significant involvement in the survival on univariate analysis. But, it did not independently predict survival.

On multivariate Cox regression analysis, the factors independently predicting survival were the number of lesions, ECOG PS at the time of TACE and post TACE de-compensations. Patients who decompensated after TACE had a poorer survival than those who had no de-compensations after TACE, (HR 4.18, p=0.03). A recent study by Pipa-Muñiz et al. [14] also mentioned that the worst survival outcome is for patients with post TACE de-compensation. Patients with normal performance status at the time of TACE had significantly better survival than the patients with poorer performance status with HR 4.08, p=0. 010. The finding from our study corroborates the study done by X. Wu et al. [15] where patients with higher performance status had poor survival. Patients undergoing TACE for a single lesion had better survival than those having multiple lesions (HR 9, p=0. 017). The study done by Sawhney et al. [16] also found that patients with a lesser number of lesions had better post TACE survival. The results obtained from the present study did not substantiate the findings from the previous studies by Dhanasekaran et al. [17] where CHILD and MELD stages significantly predicted survival.

The strength of our study is that most of the studies done previously were retrospective studies. We prospectively analyzed all the patients who underwent TACE for post TACE de-compensation, mRECIST response, and survival during the study interval. Most studies previously had analyzed different treatment methods like DEB TACE, selective and super selective TACE. Here in this study, we analyzed patients undergoing super selective TACE with Epirubicin as a single treatment modality. Our study is one of the largest single tertiary care center studies from South India, where patients were monitored over 2 years.

Conclusion

In conclusion, TACE has a significant survival advantage in intermediate stage HCC when they achieve objective response as per mRECIST. Proper selection of patients is important for achieving objective response and survival.

Aknowledgement

The author would like to thank the staff and members of the Gastroenterology department of Government Medical College, Thrivananthapuram. Also I would like to thank Dr. Nithin A, Dr. Swetha Sattanathan, Dr. Asif N Iqbal, Dr. Antony George, Dr. David Mathew, Dr. Athul Hareendran, Dr. Sreejaya S, and Dr. Premalatha N

Disclosure of Funding

None

Conflict of Interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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