Abstract
Background/Aims
This study aimed to study the outcome and survival of patients with large hepatocellular carcinoma (HCC) receiving drug-eluting beads (DEBs) transarterial chemoembolization (TACE). In addition, tumor morphologies were correlated with the response and survival to analyze the association of morphology with the outcome.
Methods
Patients with large HCC (>5 cm) who underwent DEB-TACE for palliation were analyzed retrospectively. Patients were assessed for objective response (OR) and overall survival (OS), which was calculated from the first session of DEB-TACE to the last follow-up/death. OR and OS were calculated for the entire study group and were compared among the subgroups consisting of solitary versus multifocal HCC, unilobar versus bilobar disease, well-defined versus ill-defined HCC, and HCC with homogeneous enhancement versus HCC with heterogeneous enhancement.
Results
Sixty-seven DEB-TACE procedures were performed in 25 patients (average: 2.7 ± 1.4 sessions per patient). The mean lesion size was 9.9 ± 4.5 cm. Of 25 patients, 13 (52%) had multifocal HCC. Unilobar disease was seen in 15 patients (60%). The mean duration of follow-up was 24.4 months. OR at 6 and 12 months were 56% and 48%, respectively, with well-defined lesions showing better OR. The median OS was 28 months (95% confidence interval, 12.3–43.6). OS rate at 12 and 24 months was 92% and 57%, respectively. OS was seen to be superior in well-defined HCC and unilobar disease.
Conclusion
In this study, DEB-TACE has shown to have a good response in patients having large/multifocal HCC with preserved liver functions. Well-defined HCC and unilobar disease have a better response and survival.
Keywords: hepatocellular carcinoma (HCC), DEB-TACE, loco-regional therapy
Abbreviations: AFP, Alpha-fetoprotein; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BCLC, Barcelona-Clinic Liver Cancer Classification; CBC, Complete blood count; CR, Complete response; CT, Computed tomography; cTACE, Conventional (Lipiodol) TACE; DEB-TACE, Drug-eluting beads TACE; HBV, Hepatitis B virus; HCC, Hepatocellular carcinoma; HCV, Hepatitis C virus; INR, International normalized ratio; MRI, Magnetic resonance imaging; mRECIST, Modified Response Evaluation Criteria in Solid Tumors; OR, Objective response; OS, Overall survival; PD, Progressive disease; PR, Partial response; SD, Stable disease; TLC, Total leucocyte count
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related deaths with gradually increasing incidence.1 Most patients present with intermediate-advanced disease that is not amenable to curative treatment, and the median survival in this group is 6–8 months.2,3 Many clinical staging systems are in place, but the Barcelona-Clinic Liver Cancer (BCLC) staging is the most widely used and validated for prognostication and treatment allocation. Transarterial chemoembolization (TACE) is recommended as standard of care for patients with unresectable HCCs without any vascular invasion or extrahepatic spread.4 Conventional TACE consists of selective intra-arterial injection of emulsion of chemotherapeutic agent with lipiodol in tumor vessels followed by embolization with gelfoam or particles, thus combining effects of cytotoxic and ischemic injury. However, because of lack of standardization of dose and unpredictable pharmacokinetics, the response is variable with impaired tolerance in patients with advanced liver dysfunction.5,6 TACE with drug-eluting beads (DEB-TACE) is a novel approach, which uses drug-loaded microspheres releasing drug into the tumor in precise and sustained manner in addition to permanent embolization.3,5 This results in less systemic toxicity and better safety profile with comparable, if not better tumor response to conventional TACE (cTACE).7
Size is an independent predictor of the response in TACE, with poorer outcome associated with larger lesions reported in many studies.8,9 The primary objective of this study was to determine the outcome (in terms of objective response [OR] rate) and survival benefit of DEB-TACE in patients with large nodular HCC. The secondary objective of the study was to look for any prognostic factors related to tumor morphology predicting the response to DEB-TACE procedure.
Materials and methods
This is a single-center retrospective study for which the institutional review board and ethical committee approval was obtained, and the requirement of informed consent was waived off. The hospital data were searched for patients with large HCC (>5 cm; Figure 1) who had undergone DEB-TACE as a palliative therapy from January 2011 to December 2017. Patients were included for analysis according to the inclusion criteria.
Figure 1.
Contrast-enhanced arterial phase axial and coronal CT images (a, b) show a large enhancing and well-defined HCC measuring 18.7 cm × 17.1 cm × 13.0 cm. Digital subtraction celiac angiogram (c) shows multiple arterial feeders supplying the HCC, which were selective cannulated and DEB-TACE was performed.
The inclusion criteria were as follows: patients having large size HCC (single tumor nodule >5 cm or multifocal with dominant nodule >5 cm) with ECOG Performance Status 0 or 1 and Child-Pugh class/score A or B 7.
The exclusion criteria were as follows: diffusely infiltrative HCC, main portal vein thrombosis, ascites, extrahepatic metastatic disease, and patients having advanced cirrhosis (Child-Pugh class/score B 8/9 or C). Patients who either received additional conventional TACE or radiation therapy or transarterial radioembolization before or after DEB-TACE were also excluded.
Preprocedure evaluation
The diagnosis of HCC was based on imaging, either by dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) as per the American Association for the Study of Liver Disease guidelines. All studies included precontrast, late arterial, portal venous, and delayed phases. Tumor margins were classified as either well marginated with sharp borders or ill-defined with partially obscured margins. Tumor enhancement was subjectively evaluated and divided into two groups: homogeneous enhancement and heterogeneous enhancement. Homogeneous enhancement was defined as >50% cross-sectional area enhancement on a single reference image at the largest tumor diameter, whereas heterogeneous enhancement was defined as HCC with <50% enhancement with predominant areas of nonenhancement or necrosis.
The diagnosis in patients with atypical imaging findings and elevated alpha-fetoprotein (AFP) were confirmed by fine-needle aspiration/biopsy of the lesion. The stage of HCC was assessed according to the BCLC classification. Baseline laboratory investigations such as serum AFP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, albumin, hemoglobin, total leucocyte count, and platelets were recorded before the procedure, preferably within a week.
DEB-TACE procedure
The procedure was performed through right femoral arterial access using standard angiographic technique. Celiac angiogram (and superior mesenteric arteriogram if required) was obtained to assess arterial anatomy and vascular supply to the tumor (Figure 1). The segmental/subsegmental artery supplying the tumor was selectively cannulated and embolized with DEBs (11 sessions were performed with DC beads of sizes 100–300 μm and 300–500 μm and 56 sessions with hepaspheres of size 30–60 μm and 50–100 μm) loaded with 50–75 mg of doxorubicin and mixed with nonionic iodinated contrast media in a ratio of 1:4. The beads mixed with contrast were injected slowly (1 ml/min), and after every aliquot, 2–4 ml of saline was also injected slowly to clear the DEB from the catheter and feeding arteries before the next aliquot of DEB. Initially, smaller DEBs (DC beads 100–300 μm or hepaspheres 30–60 μm) were injected to reach the distal bed of the HCC, and if the HCC continued to take up the beads because of the large size/vascularity, then another vial of larger beads (DC beads 300–500 μm or hepaspheres 50–100 μm) were injected in the peripheral arterial supply to the HCC for completion.
Extrahepatic collateral blood supply was always looked for and embolized. The end point of embolization was stasis of contrast in the feeding arteries or administration of 150 mg of doxorubicin, whichever was earlier. Even after injecting maximum dose of DEB with doxorubicin if incomplete/partial embolization was noted, then the residual lesion was treated in the next session of TACE. The volume of DEB taken up by the HCC depended on the vascularity and vessel caliber supplying the HCC.
Post-treatment assessment and follow-up
Technical success was defined as the ability to cannulate the segmental arteries supplying the tumor and injection of chemotherapeutic drug-loaded beads till the desired end point.
Laboratory parameters including complete blood count, international normalized ratio, Liver function tests (LFT), and, in some cases, serum LDH were done on Day 1 or 2 after the procedure in all patients. Investigations were repeated if required.
During the follow-up, laboratory parameters including serum AFP, AST, ALT, bilirubin, albumin, and complete hemogram along with a multiphasic contrast-enhanced CT or a dynamic MRI were performed (Figure 2).
Figure 2.
Serial contrast-enhanced arterial phase axial CT images (a–d). Panel (a) shows stable disease with <20% necrosis after one session of DEB-TACE, Panel (b) shows partial response after 2 sessions of DEB-TACE, Panel (c) shows complete response after five sessions of DEB-TACE, and Panel (d) shows persistence complete response at 60-month follow-up imaging.
The imaging assessment for response was done at 1 month and depending on the response, further at 3 months interval using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Repeat session was planned according to the imaging findings at follow-up. All patient had at least 12-month follow-up. The mean duration of follow-up was 24.4 months with maximum of 78 months (Figure 2).
Outcome measures
The primary outcomes were assessed by OR (using mRECIST criteria), which is defined as having either a CR or a PR. Overall survival (OS) was calculated from the date of first session to the death or last follow-up. OR and OS were calculated for the entire group and were compared among various subgroups based on imaging morphology, consisting of solitary versus multifocal HCC, unilobar versus bilobar HCC, well-defined versus ill-defined HCC, and tumor enhancement of <50% versus tumor enhancement >50%.
The safety was assessed in the form of incidence of treatment-related common and serious adverse events occurring within 4 weeks of procedure as per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Statistical analysis
Categorical variables were presented in number and percentage, and continuous variables were presented as mean ± SD. Qualitative variables were compared using the chi-square test/Fisher's exact test. Kaplan–Meier survival curve was used to find out OS, and the log-rank test was used for comparison. A P value of <0.05 was considered statistically significant. The data were entered in MS EXCEL spreadsheet, and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0.
Results
Baseline characteristics
The study included 25 patients of large size HCC who underwent DEB-TACE based on the inclusion and exclusion criteria. The mean age of patients in this group was 61.2 ± 10.9 years, and the majority were male. The most common etiology of chronic liver disease was hepatitis B virus (Table 1).
Table 1.
Baseline Characteristic of Patients (n = 25).
| Variable | Baseline (mean ± SD) |
|---|---|
| Age (years) | 61.2 ± 10.9 |
| Sex | |
| Male | 20 (80%) |
| Female | 5 (20%) |
| Etiology of cirrhosis | |
| HCV | 4 (16%) |
| HBV | 10 (4%) |
| Ethanol | 3 (12%) |
| NASH | 3 (12%) |
| Crypto | 5 (20%) |
| Child-Pugh class | |
| A | 17 (68%) |
| B | 8 (32%) |
| Average number of sessions | 2.7 ± 1.4 |
| Tumor multiplicity | |
| Solitary | 12 (48%) |
| Multifocal | 13 (52%) |
| Mean tumor diameter (cm) | |
| Solitary | 9.9 ± 4.5 |
| Multifocal | 7.2 ± 2.2 |
| Tumor distribution | |
| Unilobar | 15 (60%) |
| Bilobar | 10 (40%) |
| Tumor margins | |
| Well defined | 15 (60%) |
| Ill defined | 10 (40%) |
| Tumor enhancement | |
| <50% | 13 |
| >50% | 12 |
| MELD score | 10.1 ± 3.1 |
| AFP (ng/ml) | 13,075 ± 45,575 (median = 36.3) |
| Serum bilirubin (mg/dl) | 1.35 ± 0.78 |
| AST (IU/L) | 60.4 ± 23 |
| ALT (IU/L) | 45.4 ± 23 |
| Serum albumin (g/dl) | 3.2 ± 0.25 |
| INR | 1.2 ± 0.21 |
| Platelets (×109/L) | 166 ± 82 |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AFP, alpha-fetoprotein; HCV, hepatitis C virus; HBV, hepatitis B virus; INR, international normalized ratio; MELD, Model of End-stage Liver Disease; NASH, nonalcoholic steatohepatitis.
Thirteen of 25 patients (52%) had multifocal tumor, whereas 12 had solitary lesion. The mean lesion size for solitary lesion was 9.9 ± 4.5 cm, and the maximum size of the treated HCC was 18 cm (Figure 1). Tumor distribution was unilobar in 15 and bilobar in 10 patients (Table 1).
The procedure was technically successful in all patients. A total of 67 DEB-TACE procedures were performed in 25 patients. Lesions with higher vascularity and relatively large caliber vessel took large volumes of DEB to reach stasis, whereas lesions with less vascularity/thin caliber vessels reached stasis with relatively smaller volumes of DEB. The average number of sessions per patient was 2.7 ± 1.4. Twelve patients (40.7%) received one session of DEB-TACE, whereas the remaining patients received multiple sessions of DEB-TACE, with maximum number of sessions being 6.
Treatment response and follow-up (Table 2)
Table 2.
Tumor Response at 6 and 12 Months.
| Response at 6 months | Number of patients, n (%) | Response at 12 months | Number of patients, n (%) |
|---|---|---|---|
| Complete response | 4 (16%) | Complete response | 5 (20%) |
| Partial response | 10 (40%) | Partial response | 7 (28%) |
| Stable disease | 5 (20%) | Stable disease | 4 (16%) |
| Progressive disease | 6 (24%) | Progressive disease | 9 (36%) |
The mean duration of follow-up was 24.4 months, with a maximum follow-up of 78 months. All patient had at least 12-month follow-up. At 6-month follow-up, OR was seen in 14 patients (56%), five had SD, whereas six had PD. OR at 12 months was seen in 12 patients (48%), whereas 9 (36%) had PD.
OR in various subgroups are detailed in Table 3. OR at 6 and 12 months were higher in well-defined HCC in comparison to lesions with ill-defined margins (P value 0.049 and 0.004, respectively). Similarly, OR was higher in unilobar disease compared with bilobar disease; however, the difference was not statistically significant. No significant difference was noted in OR between other subgroups.
Table 3.
Subgroup Analysis for Objective Response.
| Subgroup | Objective response |
|
|---|---|---|
| 6 months | 12 months | |
| Solitary | 7 (50.0%) | 6 (50.0%) |
| Multifocal | 7 (50.0%) | 6 (50.0%) |
| P value | 0.689 | 0.561 |
| Unilobar | 10 (71.43%) | 9 (75.0%) |
| Bilobar | 4 (28.57%) | 3 (25.0%) |
| P value | 0.241 | 0.226 |
| Well defined | 11 (78.57%) | 11 (91.67%) |
| Ill defined | 3 (21.43%) | 1 (8.33%) |
| P value | 0.049 | 0.004 |
| Tumor enhancement <50% | 8 (57.14%) | 7 (58.33%) |
| Tumor enhancement >50% | 6 (42.86%) | 5 (41.67%) |
| P value | 0.561 | 0.543 |
Adverse effects
No mortality or hepatic decompensation was seen in the study group within 30 days of the procedure. The range of hospital stay duration was 2–12 days (median 4 days and mean 4.32 days). No immediate procedure-related complications such as puncture site hematoma, pseudoaneurysm, or arterial dissection were reported. Postembolization syndrome was seen in 16 patients (64%). The most common symptom was pain, seen in 13 patients (52%) followed by fever, nausea, and vomiting. These symptoms were managed conservatively by analgesics, antipyretics, and antiemetics. In most of the patients, transient elevation of liver enzymes was seen maximum up to Grade 3 as per CTCAE version 4.0, however, returned to near baseline values in subsequent days with conservative management. Two patients (8%) had mild renal derangement that improved with conservative management without any need for dialysis.
Overall survival
The mean duration of follow-up was 24.4 months, with maximum of 78 months. At the end of the study, five patients were alive (Figure 3). The median OS was 28 months (95% confidence interval [CI], 12.3–43.6). OS rates at 1 year and 2 years from the first session of DEB-TACE was 92% and 57%, respectively.
Figure 3.
Kaplan–Meier survival curve showing overall survival rate.
Figure 4 shows Kaplan–Meier survival analysis curves in our study subgroups. Well-defined lesions and unilobar disease were associated with superior OS (Table 4). Solitary lesions had a better OS compared with multifocal disease, but the difference was not significant. No significant difference was noted in the median survival between tumor enhancement subgroup.
Figure 4.
Kaplan–Meier survival curve for survival in various subgroups (a) well-defined lesions versus ill-defined lesions, (b) solitary HCC versus multifocal HCC, (c) unilobar disease versus bilobar disease, and (d) HCC having homogeneous enhancement versus HCC with heterogeneous enhancement.
Table 4.
Overall Survival in Various Subgroups.
| Tumor characteristics | Overall survival (%) | P value | |
|---|---|---|---|
| 12 months | 24 months | ||
| Solitary | 92.86 | 62.50 | 0.522 |
| Multifocal | 92.91 | 54.55 | |
| Unilobar | 93.33 | 70.03 | 0.037 |
| Bilobar | 90.00 | 40.00 | |
| Well marginated | 93.33 | 80.00 | 0.002 |
| Ill defined | 90.00 | 24.00 | |
| Tumor enhancement <50% | 100.00 | 58.33 | 0.952 |
| Tumor enhancement >50% | 59.34 | 56.25 | |
Bold represents significant P value.
Discussion
TACE is recommended treatment for BCLC intermediate HCC with unresectable large lesions not amenable for surgical or ablative therapies.4,10 DEB-TACE overcomes many limitations of cTACE (performed using drug mixed with lipiodol), such as lack of standardization of the procedure and poor tolerance.5,6,11 Limited studies are available regarding outcome and survival benefit of DEB-TACE in large lesions particularly in Indian population. Further size being an independent prognostic factor, it is important to document the response rate in larger lesions.8,9,12 This study analyzed the outcome and survival of patients having large HCC who underwent DEB-TACE (n = 25) at our center.
Despite all lesions in the cohort being large in size, there was no uniformity of uptake of DEB. The amount and dose of DEB, which was taken up by the lesion, depended on the vascularity and caliber of the vessels supplying the tumor. HCC with large caliber arterial supply took large volume of DEB for adequate embolization, whereas HCC with small caliber vessels reached stasis with small volume of DEB. The most important step was a very slow injection of DEB within the tumor followed by a slow saline flush after each aliquot (1 ml) of DEB, leading to a uniform distribution of the DEB within the tumor bed.
Although we analyzed the treatment outcome for large HCC, our findings were consistent with the previously published results. In our study, OR at 6 and 12 months were 56% and 48%, respectively. Similarly, PD in our study was 24% and 36% at 6 and 12 months, respectively. In a recent study in Asian population,8 the OR and PD at 6 months was 55.4% and 43.8%, respectively. In PRECISION V study,13 the reported OR and PD at 6 months in DEB-TACE arm were 51.6% and 32.3%, respectively. Various studies on DEB-TACE have found 6-month OR and PD rates in the range of 51.6%–73.2% and 9.7%–34.3%, respectively.8
In our study, the median OS was 28 months (95% CI, 12.3–43.6), and the OS rates at 1 year and 2 years were 92% and 57%, respectively. Table 5 shows comparison of few other studies on survival following DEB-TACE with our study.
Table 5.
Previous Studies on Survival Following DEB-TACE.
| Study, year (reference) | Number of patients | Median overall survivol (months) | Survival rate (%) |
|
|---|---|---|---|---|
| 1 year | 2 years | |||
| Kalva et al, 201114 | 54 | 14.8 | 59 | 32 |
| Song et al, 201215 | 60 | 32.2 | 88 | – |
| Malagari et al, 201216 | 173 | 43.8 | 93.6 | 83.8 |
| Kalva et al, 201311 | 130 | 14.7 | 51.6 | 32.3 |
| Golfieri et al, 201417 | 89 | 29 | 86.2 | 56.8 |
| Present study | 25 | 28 | 92 | 57 |
Given the variations in outcome and survival benefit, it is important to look for factors that may predict the response and survival for patients receiving DEB-TACE. Most of the previous studies regarding prognostic factors are based on cTACE with limited studies on DEB chemoembolization. Table 6 shows few of them.
Table 6.
Previous Studies on Prognostic Factors Affecting Response and Survival.
| Study, year (reference) | Prognostic factors |
|---|---|
| Dhanasekaran et al, 201018 | Child-Pugh class, Okuda staging, bilirubin >2 mg/dl, albumin <3 g/dl, MELD score, serum AFP, CLIP score, Milan criteria, ECOG performance status and BCLC staging (OS) |
| Kalva et al, 201311 | Necrosis more than 50% after chemoembolization, CLIP score of 1 or lower, RECIST response/SD after chemoembolization (PFS) and necrosis of more than 50% after chemoembolization, CLIP score of 1 or lower, absence of PV thrombosis, and ECOG PS of 1 or lower (OS). |
| Chang et al, 201919 | Vascular lake phenomenon, lack of residual tumor blush, and homogenous tumor enhancement on CBCT (response) and tumor burden <50% and homogenous tumor enhancement on CBCT (OS). |
Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona-Clinic Liver Cancer; CBCT, cone-beam computed tomography; CLIP, Cancer of the Liver Italian Programme; ECOG, Eastern Cooperative Oncology Group; INR, international normalized ratio; MELD, Model of End-stage Liver Disease; OS, overall survival; PFS, progression-free survival; PS, performance status; PV, portal vein; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease.
In this study, the response to DEB-TACE and survival were correlated with tumor morphology based on imaging to understand the association between varied morphology and the outcome achieved. A better OR was seen in well-defined lesions compared with ill-defined lesions. However, no significant difference was seen in unilobar versus bilobar disease. Well-defined lesions and unilobar disease were also associated with superior OS. While comparing response to TACE based on contrast enhancement, no significant difference was noted in patient with HCC having >50% enhancement in comparison to patients having HCC with <50% enhancement. Possible explanation for this could be favorable histopathological differentiation, resulting in less aggressiveness of well-marginated lesions and lesser tumor dissemination in unilobar disease. No significant difference was seen in response or survival in other subgroups.
There are various limitations of this study, which includes a single-center and a retrospective study, small sample size, patient group comprised of on Childs A/early Child B cirrhosis. There was no control group or comparative therapy arm. Only imaging morphology was analyzed as a predictor of outcome. Finally, some of the patients were receiving sorafenib, which could have affected the outcome. However, despite these limitations, this study highlights the fact that DEB-TACE may be offered to patients with large HCC. DEB-TACE has shown a good response and survival benefit in large/multifocal lesions with a good safety profile. Better OR was seen in well-defined lesions, whereas a superior OS was observed in patients having well-defined lesions and unilobar disease.
Credit authorship contribution statement
A.M. conceptualized the study, analyzed the data, and revised the manuscript and gave the final approval for submission. K.B. acquired, analyzed, and interpreted the data and prepared the first draft. A.C. revised it critically for important intellectual content. S.K.S. helped in the conception and design of the study.
Conflicts of interest
The authors have none to declare.
Financial disclosure (each author)
This study was not supported by any funding.
Institutional review boardstatement
The study was performed in accordance with the principles of the Declaration of Helsinki, and the Institutional Review Board approved this retrospective study.
Informed consent
The Institutional Review Board approved this retrospective study and waived the requirement of informed consent.
Consent for publication
Consent for publication was obtained for every individual person's data included in the study.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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