© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60103-4

 

 

Contributors: TLS proposed the study. CX and ZHB performed research and wrote the first draft. CX collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. TLS is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

ABSTRACT: Transarterial chemoembolization (TACE) may ravage normal liver tissues apart from the neoplastic nodules which offset the anti-tumor effect. This study aimed to evaluate the recovery of liver reserve function (LRF) after TACE by indocyanine green (ICG) clearance test and other routine liver function tests. Forty-six newly diagnosed HCC patients who had undergone TACE as the initial treatment from January 2011 to January 2012 were enrolled in this study. The effects of age, basic ICG clearance rate and interval time between two assessments on the recovery of LRF were analyzed. We found that ICG retention rate at the 15 minutes (ICGR15) was significantly increased after TACE (12.3±8.1% vs 16.8±12.1%, P<0.01) in all the 46 patients. In particular, the ICGR15 value was increased in older patients (age>55 years, 20.3±12.5% vs 13.7±7.2%, P<0.01). The interval of ICG test also affected the ICGR15 value (≤47 days, 17.8±11.4% after vs 12.1±7.1% before TACE, P<0.01). Our data suggested that TACE decreased LRF, especially in older patients. ICG test was more sensitive to evaluate the recovery of LRF after TACE than the Child-Pugh grade and routine liver function tests.

 

(Hepatobiliary Pancreat Dis Int 2013;12:656-660)

 

KEY WORDS: hepatocellular carcinoma; transarterial chemoembolization; liver reserve function; indocyanine green clearance

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer death worldwide.^[1] The first choice of curative treatment for HCC is surgical resection.^[2] Although programs have been recommended to high risk population for early detection of HCC, most cases of HCC are still diagnosed at advanced stage and the therapeutic options are limited.^[3] Transarterial chemoembolization (TACE) has been utilized in clinical practice for more than 20 years and become a preferred treatment for unresectable HCC.^{[4, 5]} The long-term prognosis of preoperative TACE in patients with resectable HCC is uncertain.^[6] However, when surgery is temporarily impossible, TACE may help to reduce the size of the tumor so as to increase the chance of resectablility or to control HCC.^[7]

 

Eighty percent of cases of HCC are associated with liver cirrhosis.^[8] The presence and degree of cirrhosis may be related to liver function, thus directly influencing the choice of surgery. As a safe procedure, TACE could damage the non-tumor tissues and worsen the liver function. The most severe side-effect of TACE is treatment-induced liver failure which may offset the therapeutic benefit.^[9] To the present, the study of TACE on liver reserve function (LRF) is rare.^{[10, 11]}

 

Indocyanine green (ICG) clearance test is commonly used to evaluate LRF in Asia and it is increasingly popularized in other parts of the world. Fan^[12] reported that there was no difference in the hospital mortality rates between Child-Pugh grade A and B patients undergoing hepatectomy. However, based on that ICG retention rate at the 15 minutes (ICGR15) cutoff values of 10%, 14%, and 17%, significantly higher hospital mortality rates were observed in patients with higher ICGR15 values, indicating that ICGR15 values are more predictive of the outcome than that of the Child-Pugh classification in HCC patients undergoing hepatectomy. In the present study, we analyzed the value of ICG clearance test from the patients receiving TACE to assess the recovery of LRF after TACE. The sensitivity of ICG clearance test to evaluate the LRF was compared with that of Child-Pugh grade and routine liver function tests.

 

 

The medical records of newly diagnosed HCC patients who had received TACE as initial treatment in our hospital from January 2011 to January 2012 were retrospectively reviewed. Forty-six patients who had received ICG clearance test before and after TACE treatment were finally enrolled in this study. Among them, 44 were in Child-Pugh grade A and 2 in early B. The ICGR15 in these patients ranged from 0.8% to 33.5% before TACE. The ICGR15 exceeded 22% in 6 of these patients, was below 14% in 28, and ranged from 14% to 22% in 12 (ICGR15=14% and ICGR15=22% are regarded as the safe limitation for major and minor hepatectomy, respectively).^[12] All of the patients did not have the following complications: obstructive jaundice, main portal vein invasion, and hepatic encephalopathy. Seven patients were in BCLC (Barcelona clinic liver cancer) stage B, and the others were in stage A. Each patient had HBV-associated HCC. Twenty-six of the 46 patients were tested HBV DNA positive and underwent antiviral therapy.

 

These patients received TACE as an initial treatment because of the following reasons: Eighteen patients were not suitable for hepatectomy because of the abnormal ICGR15 value (ICGR15>22% in 6 patients and 14%-22% in 12 patients who need major hepatectomy). Seven patients were in BCLC stage B, and 10 patients preferred to receive liver transplantation. Eleven patients refused to accept surgery immediately for personal reasons.

 

In our practice, neoadjuvant TACE was not recommended for patients with resectable HCC. ICG clearance test is not a routine test for the patients who require TACE. These patients may be the potential candidates for hepatectomy. The value of ICGR15 was taken as a preoperative assessment, not an inclusion criterion of TACE. Other tests in this study included tests of cholinesterase (CHE), albumin (ALB), alanine aminotransferase (ALT), total bilirubin (TB), and prothrombin time (PT) in addition to image examinations such as abdominal ultrasonography, CT and/or MRI, which were performed to know the stage of disease, the presence of ascites, and the degree of liver cirrhosis. Electrocardiogram and chest radiography were also performed to determine serious heart and lung diseases. Patients received TACE within one week after all examinations were completed. All of the tests were repeated in the next hospitalization (mean interval time was 47.7±11.5 days). The characteristics of the patients with HCC are listed in Table 1.

 

TACE was performed using the Seldinger technique followed by arterial embolization. After a vascular catheter was inserted through the femoral artery, hepatic angiography and superior mesenteric arterial portoveno­graphy were performed. After the assessment of the hepatic vascular anatomy, the arteries supplying the tumors were catheterized superselectively as close as possible to the tumor. An emulsion consisting of a mixture of 10 mL of iodized oil and 40 mg of doxorubicin hydrochloride was injected, followed by the injection of a particulate embolic agent of the radiologist's choice until stasis.

 

Blood ICG concentrations were monitored via an optical probe attached to the patient's finger. Pulse dye densitometry was tested using a noninvasive densitometer (DDG-3300K, Nihon Kohden, Tokyo, Japan). The ICG dose was calculated according to patient's body weight (0.25 mg/kg).

 

ICGR15 value, Child-Pugh grade, CHE, ALB, ALT, TB and PT were compared before and after TACE. We focused mainly on the influencing factors on the recovery of LRF after TACE. These patients were classified into two groups according to their basic ICGR15, age and interval time between the two ICG clearance tests. The classification criteria were basic ICGR15=14% (regarded as the safe limitation for major hepatectomy),^[12] age= 55 years old, and the interval time of ICG clearance tests=47 days (both are mean values).

 

Statistical analyses were conducted using Student's t test, Student's paired t test and the Chi-square test when appropriate. Data were analyzed using SPSS 18.0 (SPSS, Chicago, IL, USA). A P value of <0.05 was considered statistically significant.

 

 

No patient developed or died from acute liver failure due to TACE in our study. All patients were discharged within one week after TACE. Routine liver function tests such as ALT, TB, PT indicated liver function recovered quickly. Child-Pugh grade did not change after TACE. ALB and CHE were decreased significantly but the mean values were still within the normal range (ALB=36.8±5.7 g/L, CHE=5191.2±2008.8 U/L). However, ICGR15 value was significantly increased after TACE compared with the baseline (12.3±8.1% vs 16.8±12.1%, P<0.01), which indicated that the LRF was not completely recovered after TACE (Table 1).

 

The effects of different factors on ICGR15 after TACE are shown in Tables 2-4. ICGR15 was significantly increased after TACE in patients with basic ICGR15 equal to or lower than 14% (6.7±3.4% vs 9.3±5.0%, P<0.01) and higher than 14% (28.3±10.9% vs 20.9±5.1%, P=0.04). In the patients with ICGR15≤14%, ICGR15 after TACE was still within the normal range (9.3±5.0%), indicating that these patients were tolerable to TACE. In the patients whose basic ICGR15 was higher than 14%, their LRF can not recover easily even 7 weeks after TACE, patients will face higher risk for hepatectomy or lose surgical opportunity.

 

Our results also showed that patients' age affected the recovery of LRF after TACE. ICGR15 value was increased significantly (13.7±7.2% vs 20.3±12.5%, P<0.01) in patients aged >55 years. However, ICGR15 did not change significantly (10.6±9.0% before vs 12.6±10.5% after TACE, P=0.115) in the patients aged ≤55 years. In patients with the interval ≤47 days, ICGR15 value was increased significantly (12.1±7.1% vs 17.8±11.4%, P<0.01), but in patients with the interval >47 days, no statistically significant difference was noted (12.5±9.4% before vs 15.5±13.2 after TACE, P=0.8). In addition, CHE and ALB changed significantly in all groups of patients after TACE, but the mean value was slightly out of the normal range in the patients with ICGR15>14%. TB, PT and Child-Pugh grade were not changed significantly in any situation. ALT was even lower in all patients after TACE.

 

 

TACE is a safe procedure, its long-term prognosis for resectable HCC patients is uncertain.^[6] TACE is considered the only palliative treatment for patients with HCC, especially for those who are initially not eligible for hepatectomy.^{[13, 14]} TACE also helps to reduce tumor size and increase the chance of resectablility. Recent studies^[2,15,16] showed that surgical resection increased the survival rate of patients with HCC compared with TACE treatment of HCC patients in the intermediate-stage. TACE combined with hepatectomy is suitable for some of patients with unresectable tumor. However, TACE may damage LRF which decreases the chance of surgical resection. To the present, two studies^[10,11] investigated the negative effects of TACE on non-tumor liver tissues. Caturelli et al^[10] reported that TACE resulted in slightly and clinically negligible long-term impairment of liver function in cirrhotic patients with Child-Pugh grade A or B and without portal venous obstruction. The side-effects of TACE were not related to the age of patients, site of embolization and repeated treatment. Lu et al^[11] found that the conventional dose of anticancer agents deteriorated liver function. It is known that Child-Pugh grade and routine liver function tests are frequently used to assess LRF, but they are not sensitive enough to reflect LRF precisely.^[17] For the patients who receive TACE preoperatively as a bridge treatment to surgery or liver transplantation, a more reliable and sensitive test is needed to assess LRF. It was reported that ICG test was more reliable in LRF assessment.^[18] A significant difference in ICGR15 has been observed between the patients with Child-Pugh grade A and B. Child-Pugh score is not an indicator of hospital mortality after partial hepatectomy. However, ICGR15 value can predict the mortality of patients.^[12]

 

In our study, 18 patients were received TACE because of abnormal ICGR15 value, and 28 patients chosed to receive TACE. They were all potential candidates for hepatectomy and were subjected to ICG test and other routine preoperative examinations. Hence we used the clinical data to analyze the effects of TACE on LRF. We found that the value of ICGR15 changed significantly after TACE in the patients. The cutoff values of ICGR15 for a safe major hepatectomy and a minor hepatectomy are 14% and 22%, respectively.^[12] Three patients (3 out of 28 patients) who were tolerable to major hepatectomy became unsuitable when ICGR15 was ≤14%, whereas 7 patients (7 out of 12 patients) who were tolerable to minor hepatectomy turned to be unsuitable. In patients with ICGR15>14%, LRF was further deteriorated in 6 patients (6 out of 6 patients). The results showed that patients with good LRF are likely to recover easily from TACE treatment, but patients with poor LRF are difficult to recover even after a long-time rest (more than 7 weeks). These patients may lose the opportunity of surgical treatment. Therefore, patients with a temporarily unresectable tumor because of increasing ICGR15 value should be cautiously given TACE as a preoperative treatment.

 

In our study, we found that patients' age and interval time were helpful for the recovery of LRF after TACE. In patients aged ≤55 years and with an interval of >47 days, no difference was observed in ICGR15 value after TACE. But 4 patients aged ≤55 years and 2 patients (2/20) with an interval of >47 days got higher surgical risk even lost opportunity for surgical treatment. The criteria for surgery could be changed by TACE, even after a two-month rest or in patients who were not very old. In patients aged >55 years and with an interval of ≤47 days, ICGR15 value was changed significantly after TACE. More patients (7 out of 25 patients aged >55 years and 8 out of 26 patients with an interval of ≤47 days) followed the changed criteria for surgery.

 

In addition, ALB and CHE were changed significantly almost in all groups, but they were out of normal range only in patients with ICGR15>14%. These changes were statistically significant in comparison with baseline and had no clinical significance. No change was seen in TB, PT and Child-Pugh grade. ALT level was even lower after TACE.

 

ICG clearance test is not a routinely performed procedure before TACE in our practice. The present study is only a small one. We could not extend the inclusion and exclusion criteria for TACE in patients with good liver function but unacceptable ICG clearance and could not investigate the relationship between ICG clearance and complications induced by TACE. However, our data suggested that ICG clearance test is more sensitive than Child-Pugh grade and routine liver function tests to detect the LRF recovery after TACE. More importantly, TACE caused serious damage to LRF, which was not easy to recover, especially in older patients and those with poor basic LRF, thus increased surgical risk and even made resection impossible. Therefore, patients should be carefully selected to undergo TACE when surgery is temporarily impossible.

 

 

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