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Published online before print November 24, 2004, 10.1148/radiol.2341031008
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(Radiology 2005;234:299-309.)
© RSNA, 2004

Vascular and Interventional Radiology

Large Infiltrative Hepatocellular Carcinomas: Treatment with Percutaneous Intraarterial Ethanol Injection Alone or in Combination with Conventional Percutaneous Ethanol Injection1

Olivier Seror, MD, Giselle N'Kontchou, MD, Djamel Haddar, MD, Marius Dordea, MD, Yves Ajavon, MD, Nathalie Ganne, MD, Jean Claude Trinchet, MD, Michel Beaugrand, MD and Nicolas Sellier, MD

1 From the Departments of Radiology (O.S., D.H., M.D., Y.A., N.S.) and Hepatogastroenterology (G.N.K., N.G., J.C.T., M.B.), Hôpital Jean Verdier, Assistance Publique Hôpitaux de Paris, avenue du 14 Juillet, 93143 Bondy Cedex, France; and UPRES EA 3409, UFR SMBH, Université Paris XIII, Bobigny, France (O.S., N.G., J.C.T.). Received June 26, 2003; revision requested September 8; final revision received February 20, 2004; accepted April 6. Address correspondence to O.S. (e-mail: olivier.seror@jvr.ap-hop-paris.fr).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To retrospectively evaluate patients’ tolerance and the effectiveness of percutaneous intraarterial ethanol injection (PIAEI), alone or combined with conventional percutaneous ethanol injection (PEI), for treatment of advanced hepatocellular carcinoma (HCC).

MATERIALS AND METHODS: Neither institutional review board approval nor informed consent was required for this retrospective study; however, all patients had given their consent to be treated with PIAEI. Fourteen men and four women with cirrhosis and HCC who were ineligible for conventional curative treatment (largest tumor diameter, 35–90 mm; mean, 52 mm ± 16 [standard deviation]) and whose supplying arteries were visible on computed tomographic (CT) and color Doppler ultrasonographic (US) images were treated with US-guided PIAEI—either alone or combined with PEI. Twelve patients had infiltrative tumors, and six had nodular tumors. Four patients had portal venous tumor involvement. Tumor necrosis and recurrence were evaluated with CT, and 1- and 2-year survival rates were evaluated with Kaplan-Meier analysis.

RESULTS: In four patients, the main tumor was treated with PIAEI only, and in 14 patients, the main tumor was treated with combined PIAEI and PEI. One patient died of myocardial infarction before CT evaluation. Tumor necrosis was complete in 15 (88%) and incomplete in two (12%) of 17 patients. Results of subsequent surgery performed in three patients confirmed the radiologic findings: complete tumor necrosis in two patients and incomplete necrosis in one patient. Two severe PIAEI-related complications occurred: liver abscess, which resolved, and fatal acute pancreatitis. During the follow-up period (mean, 15 months ± 6.7), six patients died owing to recurrent HCC, and 10 patients were alive with no detectable tumor after a mean follow-up period of 18 months ± 11. One- and 2-year survival rates were 76.6% and 44.5%, respectively.

CONCLUSION: For patients with advanced HCC who are ineligible for other curative options, PIAEI could be an effective treatment, despite the associated risk of severe complications.

© RSNA, 2004


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Percutaneous ethanol injection (PEI) is a safe and effective ablative procedure for patients with cirrhosis who have hepatocellular carcinoma (HCC) tumors smaller than 3 cm in diameter (1). Percutaneous thermal therapies to treat liver tumors have recently been developed (2). Among these, radiofrequency thermal ablation is now widely considered an alternative to PEI because it yields more homogeneous and reproducible tumor necrosis and requires fewer treatment sessions (3,4). The use of radiofrequency thermal ablation has not, however, led to a substantial increase in the maximum tumor diameter that is regularly amenable to such treatment with a curative goal (5).

Patients with cirrhosis and large and/or infiltrative HCC usually are not eligible for percutaneous ablative procedures or other curative treatments (6). In such cases, transarterial chemoembolization (TACE) can be used in selected patients who do not have portal venous invasion or liver dysfunction. The results of TACE in terms of tumor necrosis are often incomplete (7–12). With rigorous selection of patients, however, TACE may help to improve the overall 2-year survival of patients as compared with the overall 2-year survival of control patients (7–10). In patients with cirrhosis, however, TACE can also induce liver failure due to ischemic damage to the nontumorous liver tissue (8–11). Moreover, no medical therapy for advanced HCC has proved to be effective in randomized trials (7,13).

Owing to advances in computed tomography (CT) (14), ultrasonography (US), and Doppler US (15), small arteries supplying HCC are now frequently and readily visualized. Consequently, it has become conceivable that the artery(ies) supplying the HCC could be percutaneously punctured during a US-guided procedure (16,17). With injection of ethanol directly into the artery supplying the HCC, a more complete and selective spread of the agent throughout the entire tumor can be expected. It might, therefore, be possible to destroy tumors larger than 3 cm in diameter—provided they are hypervascularized—even if they are infiltrative or associated with a neoplastic venous thrombus, which is usually vascularized by the same artery or arteries.

A transcatheter intraarterial approach used with fluoroscopic guidance would seem to be a safer and easier method of injecting ethanol into tumor vessels than US-guided percutaneous injection. However, the fact that, given the high toxicity of ethanol in the liver, only superselective catheterization of tumor-supplying arteries should be envisaged represents a major limitation of the transcatheter approach because superselective catheterization of small liver arteries is prone to frequent technical failures (18). In addition, several reports involving animal models (19–21) and humans (22) suggest that, because of ethanol reflux, the safety of this approach might be questionable.

The purpose of our study was to retrospectively evaluate patients’ tolerance and the effectiveness of percutaneous intraarterial ethanol injection (PIAEI)—either alone or combined with conventional PEI—to treat advanced HCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients and Tumors
Between January 1999 and June 2002, 18 patients with large and/or infiltrative HCC tumors underwent US-guided PIAEI. During that period, 246 other patients with HCC also were referred to our center (Hôpital Jean Verdier). Of the 246 patients, 13 (5%) underwent liver transplantation; eight (3%), liver resection; 137 (56%), percutaneous ablation with either PEI (n = 58 [24%]) or radiofrequency (n = 79 [32%]); 34 (14%), TACE; and 54 (22%), conservative medical treatment. The treatment was determined individually for each patient by means of consensus among the medical and surgical staff members in accordance with current therapeutic recommendations (23).

One or more of the following criteria were used to select the patients (n = 18) who would undergo PIAEI: (a) main HCC tumors with a largest diameter of 35 mm or greater (18 patients); fewer than four tumors (18 patients); (c) infiltrative tumors, defined as nonencapsulated, poorly delimited tumors smaller than 10 cm in diameter without obvious diffuse spreading (12 patients); incomplete portal venous or segmental tumor invasion adjacent to the main tumor (four patients); (e) contraindications to tumor resection as the first-line treatment (18 patients: severe portal venous hypertension [n = 11], central or bilateral localization of tumors [n = 4], or poor general condition [n = 3]); and/or (f) one or more arteries supplying the tumor that were clearly visible at arterial phase spiral CT and then at color Doppler US (18 patients).

Patients were not eligible for PIAEI if they had any of the following conditions: (a) extrahepatic metastases; (b) severe liver dysfunction, as characterized by Child-Pugh class B or C cirrhosis; (c) severely abnormal coagulation test results (prothrombin activity < 40%, platelet count < 40 x 103/mm3 [40 x 109/L]); and/or (d) diffuse tumor infiltration of the liver.

In accordance with Declaration of Helsinki guidelines (24), all patients gave their consent to be treated with PIAEI after having been informed of the nature of their disease and the possible complications of the procedure. Neither institutional review board approval nor informed consent was required for our retrospective study. The patients were 14 men and four women, and they ranged in age from 50 to 82 years (mean age, 66 years ± 10 [standard deviation]). The men were aged 50–78 years (mean age, 64 years ± 8); and the women, 51–82 years (mean age, 70 years ± 13).

All patients had histologically proved HCC; when the disease was multinodular, confirmation of the malignancy was based on the results of biopsy of the main tumor. On the basis of Edmondson-Steiner criteria, the tumors were histologically differentiated as follows: One patient had grade I; 10 patients, grade II; six patients, grade III; and one patient, grade IV HCC. All 18 patients also had histologically proved cirrhosis that was attributed to hepatitis C virus (six patients), chronic alcoholism and hepatitis C virus (eight patients), hepatitis B virus (three patients), or an unknown entity (one patient).

The largest HCC tumor diameters ranged from 35 to 90 mm (mean largest diameter, 52 mm ± 16). Six patients had nodular HCC, and the remaining 12 patients had infiltrative HCC. Multinodular HCC was diagnosed in three patients: two patients with two tumors each and one patient with three tumors. In four patients, CT scans depicted tumor invasion of the portal venous branches during the arterial phase: main portal venous branch invasion in three patients (right portal branch in two patients, left portal venous branch in one patient) and segmental invasion in one patient. Serum {alpha}-fetoprotein (AFP) concentrations ranged from 2 to 3073 ng/mL but exceeded 100 ng/mL in only two patients. Clinical and imaging data are reported in Table 1.


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  		TABLE 1. Characteristics of 18 Patients with Child-Pugh Class A Cirrhosis and HCC

 
CT Scanning Technique
A similar CT scanning technique was performed in all patients, both before and after PIAEI treatment. We used a single–detector row spiral CT unit (PQ 6000; Marconi-Philips, Cleveland, Ohio) to first perform nonenhanced scanning over the entire liver with 8-mm collimation, a pitch of 1.5, and reconstructions every 8 mm. This first scanning pass was followed by two contrast material–enhanced passes with 5-mm collimation, a pitch of 1.5, and reconstructions every 5 mm for 20 seconds during the arterial phase and for 60 seconds during the portal venous phase of the intravenous injection of iodinated contrast medium. A 170-mL volume of the contrast medium (iohexol, Omnipaque [300 mg of iodine per milliliter]; Amersham, Cork, Ireland) was systematically injected, at a rate of 5 mL/min, through an 18-gauge catheter inserted into a forearm vein.

PIAEI Procedure
All PIAEI procedures were performed by one operator (O.S.), who had 4 years experience with percutaneous US-guided interventional procedures at the beginning of this study. PIAEI was performed in strict aseptic conditions, with general anesthesia induced in the patients, and by using color Doppler and B-mode US guidance with convex 3.5-MHz probes (ATL 3000; ATL-Philips Ultrasound, Bothell, Wash). Optimum conditions for color Doppler and spectral Doppler US were set dynamically during the procedure to prevent aliasing and to obtain color US images and depict flow waves with minimum background interference.

The operator (O.S.) first located the penetration spot, which is the point at which the supplying artery enters the tumor, as determined at color and spectral Doppler US and then at real-time B-mode US. Then, the supplying artery close to the tumor was punctured with B-mode US guidance and without patient breath holding. B-mode US was required because the color Doppler US mode frequencies were too slow for guiding the puncture accurately in real time. In addition, because of the patient’s increased breathing rate, color Doppler US images were markedly degraded by artifacts when the needle was inserted. It was possible to target the supplying artery penetration spot without color Doppler US because this spot usually appeared as a slightly hypoechoic tract at B-mode US. Landmarks around the target spot could also be used to guide the puncture. A freehand technique was used with a 9-cm, 20-gauge spinal needle (Terumo, Tokyo, Japan).

After puncturing the artery, the operator slowly repositioned the needle until a backflow of blood through the lumen, confirming intraarterial puncture, was seen. The operator then slowly injected sterile 95% ethanol with B-mode US guidance. Because the prediction of the amount of ethanol required for intraarterial injection depended not only on the tumor volume but also on the degree of tumor angiogenesis and the tumor flow rate, we determined this amount according to the hyperechoic spread of ethanol throughout the tumor monitored at real-time US. Thus, the injection was continued intermittently until the tumor and the surrounding area became blurred as a result of high echogenicity. Then, the injection was continuous until the backflow of blood into the needle stopped. To detect possible ethanol injection through an arteriovenous shunt, the main portal and hepatic veins were regularly monitored with B-mode US during the injection.

The PIAEI procedure was repeated for each detectable supplying artery during the same session. At the end of the procedure, in the cases of a persistent tumor area that was not enhanced by ethanol, the treatment was completed by performing conventional direct intratumoral PEI. For multiple HCCs, the main tumor was treated with PIAEI and smaller tumors were treated with conventional PEI during the same session. Additional sessions of PIAEI or conventional PEI were performed until apparently complete tumor destruction was achieved. No preventative antibiotic therapy was administered. After each PIAEI or additional conventional PEI procedure, patients remained hospitalized for at least 24 hours.

PIAEI Procedure, Patient Tolerance, Early Tumor Response, and Follow-up
Procedure.—The number of supplying arteries punctured per tumor, the time needed to perform the PIAEI, and the number of liver capsule passes necessary were recorded. The numbers of PIAEI sessions and additional PEI sessions for each patient also were noted. In addition, the percentages of patients treated with PIAEI only or with PIAEI combined with PEI during the same or additional sessions, and, for PIAEI combined with PEI, the ratios of the intraarterial-to-intratumoral ethanol volume injected were calculated.

Patient tolerance.—For the first seven patients, we recorded ethanol blood levels immediately after the PIAEI procedures. This measurement was abandoned because ethanol concentrations were only moderately elevated, even when large volumes had been injected. Standard blood tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, and hemoglobin levels; hemogram; platelet count; and prothrombin time) were performed in all patients 24 hours after the procedure. The total duration of hospitalization for treatment, including that for PIAEI sessions and any additional conventional PEI sessions, was recorded. With the exception of moderate pain and mild fever (body temperature < 38°C) that occurred immediately after the procedure and decreased spontaneously within 48 hours, every unexpected clinical deterioration led to a search for a potential complication; such assessment included CT examination. For each complication, the detailed circumstances of its occurrence and outcome were noted.

Early tumor response.—Nonenhanced and contrast-enhanced triphasic spiral CT examinations were performed 1 month after each PIAEI and/or each additional conventional PEI session. The tumor was considered to be completely necrosed when no enhancement was visible during the arterial phase. The imaging criteria used to assess viable tumor volume were those proposed at the 2000 Study of the Liver Conference in Barcelona (25). Early tumor response was also assessed on the basis of the serum AFP level 1 month after each ethanol injection session. CT scans were evaluated independently by radiologists (D.H., M.D., Y.A., and N.S.) experienced in liver imaging. In addition, for three patients who underwent subsequent surgery, tumor response was assessed at histopathologic examination of the liver samples. Tumor response was reported according to tumor size and type (nodular or infiltrative) and according to the presence or absence of portal venous invasion.

Follow-up.—The follow-up period started at completion of the last PIAEI or conventional PEI session. In addition to the usual clinical and biologic follow-up examinations, spiral CT and serum AFP level measurements were performed in the patients every 3 months. Local recurrence was defined as the reappearance at CT of viable tumor in the same liver segment in which the primary tumor existed; distant recurrence, as the appearance at CT of a new tumor in a different liver segment; and multiple recurrence, as the appearance of numerous (>3) nodules in the liver. We recorded the time to and the type of the HCC recurrences. We also recorded the time to and the cause of death according to the features of the treated tumor and the early response to therapy.

Statistical Analyses
Estimated patient survival curves were constructed by using the Kaplan-Meier method. Confidence intervals were calculated by using the Rothman formula. Statistical analyses were performed by using SPSS version 11.5 software (SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Ethanol Injection Procedures
Individual procedural data are reported in Table 2. We punctured 32 arteries that supplied the 18 patients’ main tumor (mean number of supplying arteries per tumor, 1.8 ± 0.8l [standard deviation]; range, 1–3) during 31 PIAEI sessions (Fig 1) (Table 2). The time required to puncture the arteries ranged from 5 to 15 minutes. The procedure required only one needle pass through the liver capsule for each arterial puncture; subsequent needle displacements were made exclusively within the liver parenchyma. In four (22%) of the 18 patients, whose largest tumor diameters ranged from 42 to 50 mm (mean largest diameter, 44 mm ± 4.3), the main tumor was treated with PIAEI only. The main tumor in the 14 (78%) other patients, whose largest tumor diameters ranged from 35 to 90 mm (mean largest diameter, 55 mm ± 17), required additional conventional PEI that was performed during the same (six patients) or subsequent (eight patients) sessions.


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  		TABLE 2. Ethanol Injection Treatment Protocols

 


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  		Figure 1a. PIAEI in patient 4, a 68-year-old man with nodular HCC. (a) Transverse pulsed Doppler US image targeting spot of supplying artery penetration (arrowhead) into nodular HCC (arrows) of left hepatic lobe. (b) Corresponding transverse contrast-enhanced arterial phase CT image shows same supplying artery (arrowhead) and hypervascularity of the HCC (arrows). (c) Left: Transverse B-mode US image obtained at US-guided puncture of spot of penetration of same supplying artery (arrowhead) shows small hyperechoic areas corresponding to onset of ethanol injection. Right: Transverse B-mode US image obtained a few seconds later shows entire tumor with hyperechoic pattern, an indication of optimal spread of ethanol via arterial blood supply of HCC seen on left. (d) Corresponding transverse contrast-enhanced follow-up arterial phase CT image obtained 1 month after PIAEI shows no residual tumor enhancement (arrows), which is consistent with complete necrosis.

 


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  		Figure 1b. PIAEI in patient 4, a 68-year-old man with nodular HCC. (a) Transverse pulsed Doppler US image targeting spot of supplying artery penetration (arrowhead) into nodular HCC (arrows) of left hepatic lobe. (b) Corresponding transverse contrast-enhanced arterial phase CT image shows same supplying artery (arrowhead) and hypervascularity of the HCC (arrows). (c) Left: Transverse B-mode US image obtained at US-guided puncture of spot of penetration of same supplying artery (arrowhead) shows small hyperechoic areas corresponding to onset of ethanol injection. Right: Transverse B-mode US image obtained a few seconds later shows entire tumor with hyperechoic pattern, an indication of optimal spread of ethanol via arterial blood supply of HCC seen on left. (d) Corresponding transverse contrast-enhanced follow-up arterial phase CT image obtained 1 month after PIAEI shows no residual tumor enhancement (arrows), which is consistent with complete necrosis.

 


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  		Figure 1c. PIAEI in patient 4, a 68-year-old man with nodular HCC. (a) Transverse pulsed Doppler US image targeting spot of supplying artery penetration (arrowhead) into nodular HCC (arrows) of left hepatic lobe. (b) Corresponding transverse contrast-enhanced arterial phase CT image shows same supplying artery (arrowhead) and hypervascularity of the HCC (arrows). (c) Left: Transverse B-mode US image obtained at US-guided puncture of spot of penetration of same supplying artery (arrowhead) shows small hyperechoic areas corresponding to onset of ethanol injection. Right: Transverse B-mode US image obtained a few seconds later shows entire tumor with hyperechoic pattern, an indication of optimal spread of ethanol via arterial blood supply of HCC seen on left. (d) Corresponding transverse contrast-enhanced follow-up arterial phase CT image obtained 1 month after PIAEI shows no residual tumor enhancement (arrows), which is consistent with complete necrosis.

 


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  		Figure 1d. PIAEI in patient 4, a 68-year-old man with nodular HCC. (a) Transverse pulsed Doppler US image targeting spot of supplying artery penetration (arrowhead) into nodular HCC (arrows) of left hepatic lobe. (b) Corresponding transverse contrast-enhanced arterial phase CT image shows same supplying artery (arrowhead) and hypervascularity of the HCC (arrows). (c) Left: Transverse B-mode US image obtained at US-guided puncture of spot of penetration of same supplying artery (arrowhead) shows small hyperechoic areas corresponding to onset of ethanol injection. Right: Transverse B-mode US image obtained a few seconds later shows entire tumor with hyperechoic pattern, an indication of optimal spread of ethanol via arterial blood supply of HCC seen on left. (d) Corresponding transverse contrast-enhanced follow-up arterial phase CT image obtained 1 month after PIAEI shows no residual tumor enhancement (arrows), which is consistent with complete necrosis.

 
In the nine patients who underwent a single PIAEI session, the volume of ethanol injected intraarterially ranged from 12 to 50 mL (mean, 25 mL ± 13 [63% of total volume injected into tumor]), and an ethanol volume of 0 mL (four patients) to 50 mL (mean: 15 mL ± 19 [37% of total volume injected]) was injected directly into the tumor during the same (five patients) or subsequent (four patients) sessions. The remaining nine patients were treated during two to four PIAEI sessions (mean, 2.5 sessions ± 0.9). In these patients, the overall volume of ethanol injected intraarterially ranged from 15 to 100 mL (mean, 40 mL ± 25 [60% of total volume injected]), and 10 to 80 mL (mean, 26 mL ± 25 [40% of total volume injected]) was injected directly into the tumor. The overall number of PIAEI sessions ranged from one to four (mean, 1.7 sessions ± 1), and the number of additional PEI sessions ranged from zero to five (mean, 0.8 session ± 1.2).

Patient Tolerance
After PIAEI, the highest blood ethanol concentration recorded was 55 mg/100 mL in patient 3, who had received 40 mL of ethanol intraarterially during one session. After the procedure, 15 patients had moderate pain and a fever (body temperature < 38°C), both of which resolved within fewer than 7 days without opioid use. These patients were discharged 24 hours after the procedure. In this group, we observed transient increases in aspartate aminotransferase and alanine aminotransferase levels—the highest concentrations recorded were 424 U/L (normal level, <40 U/L) and 193 U/L (normal level, <40 U/L), respectively—that returned to baseline levels 1 month after the procedure.

Severe complications directly related to PIAEI occurred in two patients (Table 3): Patient 12, a 76-year-old diabetic woman, developed severe sepsis associated with a liver abscess after destruction of a large (90 mm in diameter) infiltrative HCC in the left hepatic lobe. The abscess resolved after antibiotic therapy and percutaneous drainage, and the patient was discharged after 40 days of hospitalization. Patient 7, a 58-year-old man in poor general health who had infiltrative HCC involving the entire left liver lobe, developed acute pancreatitis that was probably due to ethanol reflux into the gastroduodenal artery (Fig 2). He died 90 days after the procedure at another institution. In addition, patient 14, a 54-year-old obese man with severe coronary artery disease, died of myocardial infarction 4 days after undergoing an additional conventional PEI session that was performed 15 days after uncomplicated single-injection PIAEI. These two deaths occurred in high-risk patients early in our experience.


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  		TABLE 3. Patient Tolerance and Response to PIAEI

 


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  		Figure 2a. PIAEI in patient 7, a 58-year-old man with infiltrative HCC complicated by treatment-related acute pancreatitis. (a) Transverse contrast-enhanced arterial phase CT image obtained before treatment shows infiltrative HCC of entire left hepatic lobe. Note the presence of arteries (arrows) supplying the tumor. (b) Corresponding contrast-enhanced follow-up arterial phase CT image obtained 1 month after PIAEI shows disappearance of tumor blood supply, which is consistent with complete necrosis (arrows). (c) Transverse contrast-enhanced CT image of area a few centimeters below region depicted in b shows infiltrative peripancreatic and perirenal fat (arrowheads) and necrosis of the pancreas head (arrow) corresponding to acute pancreatitis, which probably resulted from ethanol reflux into gastroduodenal artery during PIAEI.

 


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  		Figure 2b. PIAEI in patient 7, a 58-year-old man with infiltrative HCC complicated by treatment-related acute pancreatitis. (a) Transverse contrast-enhanced arterial phase CT image obtained before treatment shows infiltrative HCC of entire left hepatic lobe. Note the presence of arteries (arrows) supplying the tumor. (b) Corresponding contrast-enhanced follow-up arterial phase CT image obtained 1 month after PIAEI shows disappearance of tumor blood supply, which is consistent with complete necrosis (arrows). (c) Transverse contrast-enhanced CT image of area a few centimeters below region depicted in b shows infiltrative peripancreatic and perirenal fat (arrowheads) and necrosis of the pancreas head (arrow) corresponding to acute pancreatitis, which probably resulted from ethanol reflux into gastroduodenal artery during PIAEI.

 


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  		Figure 2c. PIAEI in patient 7, a 58-year-old man with infiltrative HCC complicated by treatment-related acute pancreatitis. (a) Transverse contrast-enhanced arterial phase CT image obtained before treatment shows infiltrative HCC of entire left hepatic lobe. Note the presence of arteries (arrows) supplying the tumor. (b) Corresponding contrast-enhanced follow-up arterial phase CT image obtained 1 month after PIAEI shows disappearance of tumor blood supply, which is consistent with complete necrosis (arrows). (c) Transverse contrast-enhanced CT image of area a few centimeters below region depicted in b shows infiltrative peripancreatic and perirenal fat (arrowheads) and necrosis of the pancreas head (arrow) corresponding to acute pancreatitis, which probably resulted from ethanol reflux into gastroduodenal artery during PIAEI.

 
Early Tumor Response
Because patient 14 died 4 days after an additional PEI session, CT assessment of tumor response was possible 1 month postoperatively for 17 of the 18 patients (Table 3). Complete necrosis was observed in 15 (88%) of these 17 patients, whose largest tumor diameters ranged from 35 to 90 mm (mean, 52 mm ± 16). PIAEI alone (two patients) or combined with PEI (one patient) enabled tumor restaging for three patients who underwent secondary surgical procedures (resection in patients 1 and 9 and liver transplantation in patient 3) 59, 45, and 97 days, respectively, after the end of the injection procedure. Histopathologic examinations of resected tissue confirmed the radiologic findings: complete tumor necrosis in patients 1 and 3 and incomplete necrosis in patient 9.

Among the 15 patients with complete tumor responses, three (patients 6, 7, and 17) had portal venous invasion before the procedure (Fig 3). However, serum AFP levels increased sharply in patient 1, in whom no active tumor was detectable at CT but HCC recurrence was subsequently documented. For the 14 other patients with initially normal or minimally elevated (<100 ng/mL) serum AFP levels, no major serum AFP level change was noted after the procedure. The initially elevated serum AFP level in patient 5 returned to normal after tumor ablation, decreasing from 987 to 2 ng/mL.



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  		Figure 3a. Transverse contrast-enhanced arterial phase CT images of infiltrative HCC with portal venous involvement in patient 6, a 75-year-old man, who underwent PIAEI. (a) Image obtained before treatment shows infiltrative HCC (arrow) and its supplying artery. (b) Image of area a few centimeters below region depicted in a shows hypervascularized tumor thrombus (arrow) in the lumen at origin of right portal vein branch. (c) Corresponding to a, follow-up image obtained 1 month after PIAEI shows complete necrosis of the infiltrative HCC (arrow). (d) Corresponding to b, follow-up image obtained 1 month after PIAEI shows complete necrosis of the tumor thrombus (arrow).

 


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  		Figure 3b. Transverse contrast-enhanced arterial phase CT images of infiltrative HCC with portal venous involvement in patient 6, a 75-year-old man, who underwent PIAEI. (a) Image obtained before treatment shows infiltrative HCC (arrow) and its supplying artery. (b) Image of area a few centimeters below region depicted in a shows hypervascularized tumor thrombus (arrow) in the lumen at origin of right portal vein branch. (c) Corresponding to a, follow-up image obtained 1 month after PIAEI shows complete necrosis of the infiltrative HCC (arrow). (d) Corresponding to b, follow-up image obtained 1 month after PIAEI shows complete necrosis of the tumor thrombus (arrow).

 


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  		Figure 3c. Transverse contrast-enhanced arterial phase CT images of infiltrative HCC with portal venous involvement in patient 6, a 75-year-old man, who underwent PIAEI. (a) Image obtained before treatment shows infiltrative HCC (arrow) and its supplying artery. (b) Image of area a few centimeters below region depicted in a shows hypervascularized tumor thrombus (arrow) in the lumen at origin of right portal vein branch. (c) Corresponding to a, follow-up image obtained 1 month after PIAEI shows complete necrosis of the infiltrative HCC (arrow). (d) Corresponding to b, follow-up image obtained 1 month after PIAEI shows complete necrosis of the tumor thrombus (arrow).

 


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  		Figure 3d. Transverse contrast-enhanced arterial phase CT images of infiltrative HCC with portal venous involvement in patient 6, a 75-year-old man, who underwent PIAEI. (a) Image obtained before treatment shows infiltrative HCC (arrow) and its supplying artery. (b) Image of area a few centimeters below region depicted in a shows hypervascularized tumor thrombus (arrow) in the lumen at origin of right portal vein branch. (c) Corresponding to a, follow-up image obtained 1 month after PIAEI shows complete necrosis of the infiltrative HCC (arrow). (d) Corresponding to b, follow-up image obtained 1 month after PIAEI shows complete necrosis of the tumor thrombus (arrow).

 
For two (12%) of the 17 patients, CT performed 1 month after the end of treatment revealed incomplete tumor necrosis. Patient 18 had a nodular tumor with a largest diameter of 40 mm, and his AFP level increased from 24 to 237 ng/mL after ethanol injection. Patient 9 had a 70-mm-diameter infiltrative tumor with portal venous involvement (Fig 4); the subsequent restaging based on treatment response enabled surgical resection 45 days after PIAEI. At histopathologic examination of the resected liver, the tumor response was estimated to be 90%, with incomplete intraportal thrombus necrosis.



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  		Figure 4a. Transverse contrast-enhanced CT images of infiltrative HCC with portal venous involvement in patient 9, a 67-year-old man who underwent PIAEI. (a) Arterial phase image obtained before treatment shows infiltrative HCC (thick arrows), its supplying artery (thin arrow), and involvement of the posterior branch of the right portal vein (arrowheads). (b) Corresponding follow-up portal venous phase image obtained 1 month after PIAEI shows islet of residual viable tumor (thin arrow) inside large area of necrotic parenchyma (thick arrows). Incomplete thrombus necrosis (arrowheads) is also visible as a fine posteromedial band of residual enhancement. At histopathologic examination of the entire resected tumor, tumor necrosis was estimated to be 90%.

 


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  		Figure 4b. Transverse contrast-enhanced CT images of infiltrative HCC with portal venous involvement in patient 9, a 67-year-old man who underwent PIAEI. (a) Arterial phase image obtained before treatment shows infiltrative HCC (thick arrows), its supplying artery (thin arrow), and involvement of the posterior branch of the right portal vein (arrowheads). (b) Corresponding follow-up portal venous phase image obtained 1 month after PIAEI shows islet of residual viable tumor (thin arrow) inside large area of necrotic parenchyma (thick arrows). Incomplete thrombus necrosis (arrowheads) is also visible as a fine posteromedial band of residual enhancement. At histopathologic examination of the entire resected tumor, tumor necrosis was estimated to be 90%.

 
Follow-up
The Kaplan-Meier survival curve is shown in Figure 5. Of the 16 patients who were alive 90 days after PIAEI, six (patients 1, 5, 6, 8, 11, and 18) died of HCC recurrence after a posttreatment period that ranged from 9 to 24 months (mean, 15 months ± 6.7) (Table 3). All of these patients had a single HCC tumor with a largest diameter that ranged from 40 to 65 mm (mean, 49 mm ± 10); all but two of these tumors were infiltrative. Patient 6 had portal venous invasion. The tumor in patient 18 was refractory to PIAEI: Although four PIAEI procedures were performed, only incomplete necrosis was achieved. Patients 1, 6, 8, and 11 had local and diffuse recurrences 2–6 months (mean, 3.5 months ± 1.7) after treatment, and patient 5 had a rapidly growing distant hepatic tumor 12 months after PIAEI.



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  		Figure 5. Kaplan-Meier survival curve with confidence intervals (Rothman formula) for the 18 patients treated with PIAEI for advanced HCC. Numbers in parentheses are the numbers of patients (initially-study end) used to calculate the survival rates for each time plateau.

 
Ten (56%) of the 18 patients were alive after a follow-up period that ranged from 3 to 41 months (mean, 18 months ± 11). Nine (50%) of the 18 patients, including patient 3, who subsequently underwent liver transplantation, had no apparent tumor relapse after complete necrosis was induced by using PIAEI alone in three (33%) and by using combined PIAEI and PEI in six (67%) patients. In this group—with four nodular and five infiltrative tumors, including three multinodular HCCs and one case of portal venous invasion—the largest HCC diameters ranged from 35 to 90 mm (mean, 47 mm ± 17). Patient 9 underwent secondary surgical resection, as described earlier, but had distant tumor recurrence in the liver 9 months after surgery. After undergoing radiofrequency ablation of the new tumor, the patient was alive with no detectable tumor 17 months after the PIAEI procedure. During the follow-up period, none of these 10 patients had a serum AFP level higher than 100 ng/mL.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Despite the existence of US screening programs, large nonresectable HCCs are still frequently encountered and remain a major therapeutic challenge (26). Several palliative approaches—for example, TACE alone or combined with other therapies—have been proposed (7–12,27,28). These treatments are associated with a low rate of complete response. Livraghi et al (29) achieved a 35% complete response rate for large HCCs after injecting large volumes of ethanol during a single PEI session. However, severe complications can result from this "single-shot" PEI technique (29–33). With regard to HCC with portal venous invasion, there are only scarce reports describing prolonged survival after portal thrombus PEI (34), TACE (35), or surgical thrombectomy (36).

In the setting of large HCC with or without portal venous invasion, the search for new treatments is mandatory. The rationale for using PIAEI is as follows: Ethanol is a highly fluid agent that causes blood sludging, protein coagulation, and damage to the vascular intima, resulting in definitive distal vascular occlusion (19). These properties of intravascular ethanol injection have already been exploited to treat renal tumors (37). Yamakado et al (38) used TACE combined with transportal ethanol injection to treat nonresectable HCC. In their study, two patients developed irreversible liver failure as a result of extensive liver infarction. Because of the selective injection of ethanol into the arteries supplying the tumor, the PIAEI approach to treating large HCC tumors theoretically causes less damage to nonneoplastic liver tissue.

In two previous studies, the short-term results of PIAEI in patients with large HCC indicated complete tumor necrosis rates of 96% (16) and 93% (17). Our study results confirm the high effectiveness of PIAEI: Complete necrosis occurred in 88% (15 of 17) of patients when it was used either alone (in four of four patients) or in combination with PEI (in 11 of 13 patients) to treat large HCC. Another encouraging result was the favorable early outcome (complete tumor necrosis at CT) for three of the four patients with portal venous involvement, given that in preliminary studies of PIAEI (16,17), such patients were considered ineligible for the procedure.

However, the most important end point of HCC treatment remains survival. It was too early to assess the long-term outcome in the two preliminary reports on PIAEI (16,17). In our study, after a mean follow-up period of 18 months after the end of treatment, complete remission was achieved in 10 (56%) of the 18 patients, including one patient in whom PIAEI enabled tumor restaging and subsequent transplantation and one patient who underwent resection. The 1- and 2-year survival rates were 76.6% and 44.5%, respectively.

Although comparisons of different series might be misleading, our study results suggest that PIAEI performed either alone or in combination with PEI in patients with advanced HCC yields better survival rates than does single-shot PEI (31) or TACE (10,11). In addition, unlike the outcomes seen after TACE (7–12), no worsening liver function and a much higher complete response rate were observed in our study.

However, we noted two major complications that were directly attributable to PIAEI and that have not been previously reported in association with the procedure (16,17). One liver abscess occurred in a diabetic patient after complete necrosis of a large infiltrating HCC. Since the risk of sepsis is positively correlated with the volume of necrosis (33), we presume that prescribing an antibiotic prophylaxis would be justified in this setting. Another patient, who had complete necrosis of an infiltrating HCC involving the entire left hepatic lobe, developed fatal acute pancreatitis of the head of the pancreas.

Although the PIAEI technique was described several years ago (16,17), it is still not widely applied, presumably because the use of Doppler and B-mode US to target supplying arteries is an operator-dependent technique. Unlike angiography, Doppler US cannot depict the entire arterial blood supply to the tumor. However, in our experience, the accuracy of color Doppler US in depicting the tumor blood supply is clearly improved when the examination is performed after localization of the small arteries feeding the tumor at arterial phase spiral CT. For experienced operators, US is the modality of choice for guiding the puncturing of small moving target structures because it yields good spontaneous contrast resolution and has real-time imaging capability. The use of new US contrast agents in the near future should facilitate US-guided puncture of supplying arteries (39–41).

The choice of the percutaneous route of ethanol injection could also be questioned, given that one of our study patients developed fatal acute pancreatitis presumably owing to ethanol reflux into the gastroduodenal artery. A transcatheter intraarterial approach might be easier and safer, but as demonstrated in several studies involving animal models (19–21) and humans (22), use of transcatheter ethanol injection does not completely prevent reflux. This potential drawback of the transcatheter approach could be avoided by using a balloon occlusion catheter; however, in this setting, the use of balloon occlusion would lead to a dramatic reduction in the blood flow supplying the tumor and potentially cause the high clotting power of ethanol to induce immediate proximal thrombosis and thereby prevent the optimal spread of ethanol throughout the entire tumor. In addition, considering the high toxicity of ethanol (19,20), only superselective catheterization of tumor-supplying arteries should be performed, but this procedure is associated with a high risk of failure because small arteries supplying liver tumors are frequently tortuous and arise from different arteries (18).

In our study experience, ethanol reflux into the pancreaticoduodenal artery appeared to be the main specific complication of the PIAEI procedure. It probably occurred when ethanol was injected into an arterial branch that arose from a short left hepatic artery close to the origin of the pancreaticoduodenal trunk. This risk might be enhanced when a large volume of ethanol is required or when the pancreaticoduodenal artery arises from an abnormally located left hepatic artery. In either situation, performing pretherapeutic three-dimensional CT or magnetic resonance angiographic mapping might be helpful.

The main limitation of this study was that in only four (22%) of the 18 patients, the main tumor was treated strictly with PIAEI, whereas the main tumor in the remaining 14 (78%) patients was treated with combined intraarterial and direct intratumoral ethanol injections. This combined technique was required because the CT and Doppler US examinations did not reveal all of the arteries supplying the large tumors. Although use of the combined injection technique is a confounding factor in the evaluation of the specific effectiveness of PIAEI (16), some of our findings clearly demonstrate the predominant role of PIAEI in tumor destruction. In accordance with the study findings of Lin et al (17), three of our four study patients in whom the main tumor was treated with PIAEI only, including one with an infiltrative tumor, were alive with no detectable viable tumor after the follow-up period. Among the remaining 14 patients treated with the combined technique, complete necrosis was achieved in eight (89%) of the nine of them with infiltrative tumors and in three (75%) of the four of them with portal venous invasion.

PIAEI effectiveness is strongly indicated by the outcomes of patients with infiltrative tumors and/or portal venous invasion because single-shot PEI (31) or TACE (12) almost never results in complete necrosis of these kinds of tumors. The fact that up to half of the total ethanol volume administered was injected intraarterially in the patients treated with the combined technique is additional evidence of the predominant role of PIAEI. Moreover, the mean total volume of ethanol injected per tumor in our study was lower than that administered by Livraghi et al (31) with single-shot PEI: 44.5 versus 62.0 mL, respectively.

Another limitation of this retrospective study was the absence of a direct comparison between PIAEI and other HCC treatments. Hence, it is difficult to precisely establish a specific category of patients for whom PIAEI could be proposed. PIAEI therapy cannot be considered suitable for all patients with nonresectable hypervascularized HCC. It is now widely accepted that PEI or radiofrequency ablation is safe and effective for treatment of HCC tumors smaller than 3 cm in diameter. Furthermore, PIAEI should not be proposed as a palliative treatment for diffuse HCC because the potential risks are not counterbalanced by expectations of a substantially prolonged survival. Thus, patients with Child-Pugh class A cirrhosis and advanced but not diffuse HCC, particularly those with infiltrative tumors, seem to be the ideal candidates for PIAEI, provided the tumor-supplying arteries are visible at CT and then at color Doppler US. At our institution, with use of these selection criteria, PIAEI was proposed for only a small percentage (7% [18 of 264]) of patients with HCC. However, this percentage reached 17% (18 of 106 patients) when only those patients who were ineligible for curative treatments (transplantation, resection, or classic percutaneous ablation) were considered, and it reached 35% (18 of 52 patients) when only potential TACE candidates were considered.

In conclusion, PIAEI alone or combined with PEI could be considered an effective treatment for patients with large but not diffuse HCCs—for example, those that are infiltrative and/or those invading the portal venous system. However, severe complications can occur and stringent patient selection criteria are required. Further studies are needed to confirm these results.


   ACKNOWLEDGMENTS
 
For their contributions to the care and follow-up of the patients, we thank Daniel Cherqui, MD, Department of Liver Transplantation and Visceral Surgery, and Jeanne Tran Van Nhieu, MD, and Marie Therese Chaumette-Planckaert, MD, Department of Pathology, Henri-Mondor Hospital, Creteil, France; and Veronique Grando, MD, Department of Hepatogastroenterology, and Emmanuelle Coderc, MD, Carole Ghenassia, MD, Hayette Amerane, MD, Marion Bernard, MD, and Sabine Hovasse, MD, Department of Radiology, Jean-Verdier Hospital. We also thank Josep Llovet, MD, of the Liver Unit of Barcelona-Liver Cancer Clinic, Barcelona, Spain, for his critiques.


   FOOTNOTES
 
Abbreviations: AFP = {alpha}-fetoprotein, HCC = hepatocellular carcinoma, PEI = percutaneous ethanol injection, PIAEI = percutaneous intraarterial ethanol injection, TACE = transarterial chemoembolization

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, O.S.; study concepts and design, O.S., Y.A., N.S.; literature research, O.S., J.C.T.; clinical studies, O.S., G.N.K., N.G., J.C.T., M.B.; data acquisition and analysis/interpretation, O.S., G.N.K., D.H., M.D., N.G.; statistical analysis, O.S.; manuscript preparation, O.S., G.N.K., D.H., M.B.; manuscript definition of intellectual content, O.S., J.C.T., M.B., N.S.; manuscript editing and final version approval, all authors; manuscript revision/review, J.C.T., M.B., N.S., N.G., Y.A.


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