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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 115-120

Outcome of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma


1 Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Departments of Surgery, College of Medicine, King Saud University; Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
3 Department of Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
4 Department of Radiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission12-Jul-2019
Date of Decision02-Sep-2019
Date of Acceptance19-Oct-2019
Date of Web Publication02-Apr-2020

Correspondence Address:
Mazen M Hassanain
Department of Surgery, College of Medicine, King Saud University, P.O. Box 25179, Riyadh 11466
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_30_19

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  Abstract 


Background and study Aims: Liver cancer, most commonly known as hepatocellular carcinoma (HCC), was ranked as the sixth most common cancer in Saudi Arabia in 2014. Management of unresectable HCC is multidisciplinary and could include radiofrequency ablation, systemic-targeted therapy, and transarterial chemoembolization (TACE). This study aimed to assess the survival outcome of patients with unresectable HCC undergoing TACE in Saudi Arabia. Patients and Methods: We retrospectively studied patients with unresectable HCC who were treated with TACE between 2004 and 2016. Patient's demographics, etiology of liver disease, Child–Turcotte–Pugh stage, computed tomography scan findings, laboratory results, details of treatment sessions, and follow-up visit data were obtained from the National Liver Disease Research Database. Results: Thirty-nine patients diagnosed with HCC underwent 103 TACE sessions at our hospital. Median overall survival time was 20 months (range 0–98). Median progression-free survival was 9 months (range 1–98). Follow-up imaging revealed progressive disease in 20 patients (54.05%), while 17 had no disease progression, and none had complete resolution. Conclusion: Our results are similar to those of previous studies that reported the benefit of TACE on survival rates of HCC patients. The correlation found between median overall survival and international normalized ratio and bilirubin level could reflect the importance of liver function deterioration effects on outcomes.

Keywords: Hepatocellular carcinoma, liver disease, Saudi Arabia, survival, transarterial chemoembolization


How to cite this article:
Helmi HA, Alharthi FF, Madkhali AA, Alsaif FA, Alshanifi AY, Hussein WS, BinKhamis SM, Alsharabi A, Hassanain MM. Outcome of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Nat Sci Med 2020;3:115-20

How to cite this URL:
Helmi HA, Alharthi FF, Madkhali AA, Alsaif FA, Alshanifi AY, Hussein WS, BinKhamis SM, Alsharabi A, Hassanain MM. Outcome of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Nat Sci Med [serial online] 2020 [cited 2020 Jun 4];3:115-20. Available from: http://www.jnsmonline.org/text.asp?2020/3/2/115/278237




  Introduction Top


Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide.[1] Liver cancer was ranked as the sixth most common cancer in Saudi Arabia in the year 2014.[2] In women, it was the ninth most common cancer in the Kingdom and the sixth most common in men.[2]

Risk factors for HCC include liver cirrhosis, chronic hepatitis B virus, exposure to toxins, and others.[3] Hepatitis C virus was described as the main risk factor for HCC in Saudi Arabia among other countries.[4] Furthermore, diabetes mellitus, which can indirectly lead to HCC through nonalcoholic fatty liver disease, is common among the population of Saudi Arabia.

Liver resection and liver transplantation are the only approaches to cure for patients with HCC. However, at the time of diagnosis, only 20%–30% of patients have resectable disease. Furthermore, due to comorbidities, patients are often inoperable.[5] Consequently, majority of patients with HCC are treated with palliative measures, which could include symptomatic therapy, radiofrequency ablation, and transarterial chemoembolization (TACE).[6],[7]

TACE is a treatment modality where chemotherapeutic agents are injected into the focus of the tumor to induce necrosis.[8] TACE has the advantage of treating patients with multifocal disease. However, potential side effects include conditions ranging from self-limiting postembolization syndrome to a life-threatening liver disease; thus, it is contraindicated in patients with advanced liver damage. Furthermore, the mortality rate and survival benefits are inconsistent throughout the literature.

Studies comparing TACE to conservative management showed that TACE is successful in reducing tumor size. However, survival rates vary, with earlier studies showing no change in mortality and more recent studies showing improved survival. In this study, we aimed to assess the survival outcome of patients with unresectable HCC undergoing TACE in the Saudi Arabian population. Furthermore, we reported patterns of tumor response to this treatment modality.


  Patients and Methods Top


In our retrospective cohort study, we collected data from the Liver Disease Research Database on all consecutive patients diagnosed with unresectable HCC between 2004 and 2016 who had been treated with TACE. Included patients fulfilled the following inclusion criteria: patients with calculated Child's A or B liver function score and <50% involvement of liver by HCC. The exclusion criteria included patients with extra hepatic disease, coagulopathy, biliary obstruction, severe comorbid illnesses like coronary artery disease, congestive heart failure, and chronic renal failure; a previous history of encephalopathy or upper gastrointestinal bleeding in the last 6 months. In addition, we excluded patients with resectable disease and those who were candidates for liver transplantation. Institutional review board approval was obtained prior to data collection. Informed consent was waived as the majority of data were collected from hospital records with no patient interaction. However, patient confidentiality was maintained throughout the study.

HCC was diagnosed based on the criteria set by the American Association for the Study of the Liver. Multiple staging systems were used in the database including Child–Turcotte–Pugh stage, Barcelona clinic liver cancer (BCLC) staging system,[9] and Okuda staging.[10] Patient's demographics, risks factors for liver disease, biochemical, and radiological markers, as well as number and time of treatment were obtained. Furthermore, prognostic scoring systems, hepatoma arterial-embolization prognostic (HAP) score,[11] and albumin-bilirubin (ALBI) grade[12] were calculated from the existing data.

The primary outcome measures were overall survival and progression-free survival (PFS). Survival was measured in months with overall survival defined as the number of months between the first TACE and the date of death for deceased patients and date of last follow-up for patients who remained alive. PFS was defined as the duration in months between the first TACE and the date of last computed tomography (CT) showing stable or responsive disease.

Therapeutic effect of TACE on HCC lesions was evaluated on the basis of the modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessment for HCC criteria.[13] Patients were followed up within 3 months of their TACE sessions at the outpatient clinic. Follow-up assessments included serum biochemistry, serum alpha-fetoprotein (AFP) level, and CT.

Statistical analysis was performed using JMP 10.0 statistical software (SAS Institute Inc, Cary, NC, USA). Survival was assessed by Kaplan–Meier method. Log-rank and linear regression statistical tests were used to correlate survival with prognostic factors. Paired Student's t-test was used to compare continuous variables.


  Results Top


Between September 2004 and February 2016, 39 patients who were diagnosed with HCC underwent TACE at King Khalid University Hospital. Overall, 103 TACE sessions were conducted on 25 males, and 14 females. The average age was 63.4 (range 27–85) years. Patients were investigated before the initiation of therapy. [Table 1] shows the baseline patient and disease characteristics.
Table 1: Patient demographics and disease-related variables

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Follow-up visits

The majority of patients (12/35; 30.77%) underwent 2 TACE procedures, while 9 patients (23.08%) underwent the procedure once. Of the remaining patients, 8 (20.51%), 5 (12.82%), 4 (10.26%), and 1 (0.03) patient had the procedure 3, 4, 5, and 6 times, respectively. Patients were followed up in the clinic after each TACE procedure with new set of laboratory tests and CT imaging. [Table 2] compares the blood test results of patients between initial visit and the visit following the last TACE procedure. Change in pre-TACE versus post-TACE serum albumin, bilirubin, and international normalized ratio (INR) were significant with P = 0.005, 0.024, and 0.004, respectively. The difference in AFP level was not statistically significant. Post-TACE Child–Pugh score remained unchanged in 18 patients.
Table 2: Comparison between laboratory values before and after, transarterial chemoembolization

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mRECIST was used to measure the radiological response of the tumor to therapy. Among the patients who underwent CT scan following TACE interventions, 20 (54.05%) had progressive disease and 17 showed no disease progression. No patients had complete resolution. Median PFS time was 9 (range 1–98) months.

Survival

During the follow-up period, 22 patients died, and in 17 patients, death was not documented; however, a number of patients were lost to follow-up. Median overall survival time was 20 months; the survival rate at 1-, 2-, and 3-year survival rate was 69.2%, 41%, and 23%, respectively [Figure 1] and [Figure 2].
Figure 1: Overall survival curve (months)

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Figure 2: Progression-free survival curve (months

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Univariate analysis showed that INR and bilirubin levels were significantly correlated with overall survival with a P = 0.0271 and 0.033, respectively. While age, gender, average tumor size, number of lesions, lobe affected, performance status, Child Score, Okuda stage, BCLC score, HAP score, ALBI grade, number of TACE sessions, portal vein thrombosis (PVT), AFP level, or albumin level were not significantly correlated with overall survival. Multivariate analysis did not reveal any correlation between overall survival and any of the previously mentioned variables.

Furthermore, the number of TACE procedures (P = 0.0009), PVT (P = 0.013), serum albumin (P = 0.025), serum bilirubin (P = 0.002), child score (P = 0.0322), Okuda score (P <0.001), and ALBI grade (P = 0.0003) were correlated with PFS. In fact, patients with Child B had a median progression-free time of 5 months compared to 12 months for Child A patients. Patients who were staged by Okuda system as Stage 1 and 2 had similar median progression-free time of 10 months, but one patient with Stage 3 had immediate disease progression. Patients' age and gender, average size of tumor, number of lesions, lobe affected, performance status, BCLC score, HAP score, AFP level, and INR did not significantly affect PFS.

[Table 3] shows results of the multivariate analysis, where OKUDA score was the only variable significantly correlated with PFS.
Table 3: Results of multivariant analysis for progression-free survival

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  Discussion Top


In this study, the median overall survival time was 20 months, and the survival rate correlated significantly with INR and bilirubin level, reflecting the importance of liver function deterioration on patients' outcomes. Median PFS time was 9 months and significant correlation was noted with number of TACE treatments, PVT, serum albumin, bilirubin levels, ALBI grade, Child score, and Okuda score was found.[7],[14]

Although resection and transplantation are the mainstay of treatment for patients with HCC, different modalities have been considered in the nonsurgical candidates, whether due to their functional status or tumor resectability, including TACE. Our institute is one of the earliest centers to implement this approach in the country. However, due to the lack of audit of the results from the Middle East, the outcome of this type of therapeutic procedure is under-reported. However, a study conducted at our institute consisting of 15 patients who underwent TACE between 2004 and 2005 was published.[15] Although survival was not one of the measurable outcomes of that study, results revealed better CT responses using the World Health Organization (WHO) criteria with no patients showing progressive disease at follow-up imaging, while the majority (40%) showed no change.[15] In the current study, however, 39 patients were included and mRECIST was used for tumor responsiveness at follow-up CT scan.

Survival following TACE has been variable, with numbers ranging between 17.1 ± 3.4 months in one study[16] to 34 months in another.[17] The first study was associated with higher mortality rates, high AFP levels, and model for end-stage liver disease score, while patients who demonstrated reduction in the size of lesions had lower mortality rates.[16] The second study, including 8510 patients from various countries, reported a median survival of 34 months, that was correlated with the degree of liver damage, AFP level, tumor size, number of TACE procedures, and portal vein invasion.[17] The relatively shorter median survival time and lack of statistically significant variables in our study could be attributed to the small sample size. Furthermore, patient selection might have contributed, as this treatment modality has only been recently introduced in the region.

When comparing TACE to other treatment modalities, many randomized clinical trials (RCT) exist in the literature, with early studies showing no survival benefits.[18],[19] The first RCT to report survival benefit of TACE compared to symptomatic therapy was in 2003 and involved 80 patients that were randomized. They reported a favorable 1-, 2-, and 3-year survival rate in patients who received TACE. The survival benefit remained significant in multivariate analysis.[20] Later that year, a systematic review of 14 RCTs was published by the Barcelona group, which further supported the survival benefits of TACE in patients with unresectable HCC.[14] Furthermore, that review suggested that patient selection might play a role in the beneficial effect of TACE on survival and that the ideal target population included patients with well-preserved liver function and multinodular HCC in the absence of vascular invasion.[14]

Several biochemical markers of liver function have been correlated with liver disease and prognosis.[21] In fact, some of these markers have been implicated in the development of prognostic scores, including HAP and ALBI.[11],[12] In univariate analysis, we report that serum bilirubin level and INR were correlated with overall survival, while serum bilirubin, serum albumin, and ALBI grade were correlated with PFS. However, none of the previously mentioned correlations were maintained in multivariate analysis. HAP score was developed in 2013 as a prognostic indicator for patients with HCC undergoing TACE.[11] It has been a valuable tool in predicting survival, with scores of C and D being indicative of poor prognosis.[11] In a multicenter study, they reported a median overall survival of 52 months in patients with HAP A score undergoing TACE, that was reduced to only 9 months in patients with HAP D.[22] Median overall survival in our population based on HAP score is shown in [Table 4]. Although nearly half of our patients had a combined HAP score of C or D (36.8% and 10.5%, respectively), we did not find a significant correlation with overall survival or PFS. Multiple factors could have played a role, including the small sample size, normal distribution of patients among the HAP score groups, low number of patients in each of HAP A and D groups, or the small difference in median overall survival between HAP B and C scores.
Table 4: Distribution and median overall survival of patients based on the hepatoma arterial-embolization prognostic score

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AFP level has been shown as strongly correlated with survival in patients with HCC treated with TACE.[16] Generally, AFP level >400 ng/mL is associated with poor prognosis.[11] One study further correlated the reduction in AFP level between the pretreatment level and serum level 1 month following treatment, with overall survival.[23] Patients with decreased AFP level of >50% following TACE were considered to be AFP-responders and had a median overall survival of 35 months, while nonresponders had a median overall survival of 13 months.[23] However, our analysis revealed no significant correlation between AFP and overall survival or PFS. Furthermore, the increase in the mean AFP level before and after TACE was not statistically significant. This could be attributed to the fact that most of our patients (53.8%) had a normal baseline AFP level and only 9 patients (23%) had a baseline AFP level higher than 400 ng/mL. This speculation can be supported by a study that reported a significant difference in overall survival among AFP-negative patients undergoing TACE compared to AFP-positive patients, using a cutoff AFP >20 ng/mL.[24]

The presence of PVT is common among HCC patients. Increased risk of liver ischemia, compilations of portal hypertension and aggressive tumor features associated with PVT, have made PVT a poor prognostic factor for HCC patients and often considered a contraindication to TACE.[25],[26] Despite these findings, many studies involving such patients have shown survival benefits.[25],[27] In fact, the previous cohort study involving 8510 patients not only correlated PVT with survival but also examined the degree of thrombosis.[17] A study involving 17 patients with unresectable HCC and lobar/branch PVT reported a median overall survival of 10 months, with a significant correlation with response of the tumor on imaging, presence of ascites, and Child score.[25] However, this previous study excluded patients with complete PVT.[25] In our study, PVT, present in two patients, did not affect the overall survival but was correlated with PFS. One patient developed progression almost immediately following TACE while the other progressed within 7 months of the treatment. Both patients had partial occlusion of the main portal vein.

Several staging systems have been developed for HCC, including BCLC,[9] Cancer of the Liver Italian Program,[28] Okuda score,[10] and less commonly used the Chinese University Prognostic Index (CUPI),[29] and the Japan Integrated Staging,[30] and the Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire.[31] Over the years, studies have compared the effectiveness of these staging systems in predicting prognosis; however, none of these previous studies were specific to HCC patients undergoing TACE. [Table 5] represents detailed results of these previous studies, with the most significant predictors being BCLC[32],[33] and CUPI.[34],[35] Although only BCLC and Okuda scores were tested in our study, neither BCLC nor Okuda score were significantly correlated with overall survival. However, Okuda score was correlated with PFS and was the only variable that statistically significant association with PFS in multivariate analysis. While only one patient had an Okuda score of III, the remaining 36 patients were equally divided among Okuda I and II. Although Okuda score is frequently associated with prognosis, it has not been proven superior when compared to other prognostic staging systems.[32],[33],[34],[35],[36]
Table 5: Detailed results of studies comparing various staging systems

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The potential limitations of this study should be considered. In this study, data were collected over a 10-year period from a single institute. During this period, the use of TACE in patients with HCC could have changed. Furthermore, patients enrolled in our study were treated by various physicians, each with their own training, experiences, and approaches, which could have led to inconsistency in treatment and outcome. For example, there were lack of standardization in the number of treatment sessions, follow-up duration, and follow-up imaging. Small sample size as well as missing data could have contributed to the lack of significance reported. The criteria for patient selection could have played a role in this regard; patients in our study had the diagnosis of unresectable HCC, while other studies tended to enroll patients who ultimately received liver transplantation. There is considerable limitation in retrospective cohort studies compared to RCTs or case–control studies.


  Conclusion Top


We presented similar results to previous studies in support of the benefit of TACE on survival rates in patients with unresectable HCC. The correlation found between median overall survival and markers of liver function, including INR and bilirubin level, may reflect the importance of the effect of liver function deterioration on survival. Many staging systems have been developed to predict the outcome of such patients. Although less widely used, OKUDA score was correlated with PFS in our population.

Acknowledgments

This work was supported by the College of Medicine Research Center, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia. The authors would like to thank the Liver Disease Research Center at King Saud University, Riyadh for their support and contributions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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