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(Radiology. 2000;214:349-357.)
© RSNA, 2000

Vascular and Interventional Radiology

Transarterial Chemoembolization for Hepatocellular Carcinoma: Volumetric and Morphologic CT Criteria for Assessment of Prognosis and Therapeutic Success-Results from a Liver Transplantation Center1

Thomas J. Vogl, MD, Michael Trapp, MD, Henrik Schroeder, MD, Martin Mack, MD, Adrian Schuster, MD, Jan Schmitt, MD, Peter Neuhaus, MD and Roland Felix, MD

1 From the Department of Diagnostic and Interventional Radiology, J. W. Goethe University of Frankfurt, Theodor-Stern-Kai 7, 63590 Frankfurt, Germany (T.J.V., M.T., H.S., M.M., J.S.); and the Departments of Radiology (A.S., R.F.) and Surgery (P.N.), Humbolt-University of Berlin, Germany. Received January 20, 1999; revision requested March 22; revision received May 6; accepted July 30. Address reprint requests to T.J.V. (e-mail: T.Vogl@em.uni .Frankfurt.de).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate the prognostic value of volumetric computed tomography (CT) for therapy control in patients treated with repeated transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).

MATERIALS AND METHODS: Eighty-five patients with histologically proved HCC underwent 182 TACE procedures with 50 mg/m2 doxorubicin hydrochloride, 50 mg/m2 cisplatin, 10 mL/m2 iodized oil, and amilomer microspheres. The volumes of liver and tumor were measured with a region-of-interest CT technique. Iodized oil retention was estimated with CT performed 24–48 hours after treatment.

RESULTS: Tumor volume expressed as a percentage of liver volume was less than 5% in 26, less than 15% in 33, and 15% or greater in 26 patients. The overall 1-year survival rate was 57.6% (mean, 534 days; median, 428 days). There was a statistically significant prolongation of survival when the tumor volume was less than 200 mL (P < .02) and less than 5% of the liver volume (P < .01). Complete (>=75%) and good (50%–74%) iodized oil retention raised the median survival significantly (P < .001 and P < .07, respectively). Significantly reduced survival correlated with diffuse tumor growth pattern (P < .05) and presence of more than nine lesions (P < .03).

CONCLUSION: TACE resulted in significant prolongation of survival in patients with tumor volumes of less than 200 mL, tumor-to-liver volume ratios of less than 5%, and iodized oil retention greater than or equal to 75%.

Index terms: Arteries, therapeutic embolization, 952.1264, 952.1266 • Computed tomography (CT), volume rendering, 761.12111, 761.12112, 761.12115 • Liver neoplasms, 761.323 • Liver neoplasms, chemotherapeutic embolization, 761.1266, 952.1266 • Liver neoplasms, CT, 761.12111, 761.12112, 761.12115


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The prognosis of hepatocellular carcinoma (HCC) is generally poor, particularly when the tumor is unresectable or when orthotopic liver transplantation is contraindicated. By using transarterial chemoembolization (TACE) with a combination of cytostatic drugs (ie, doxorubicin hydrochloride, cisplatin, and/or microspheres), a reduction of vital tumor tissue can be achieved, although the prolongation of survival remains questionable (1–5).

When establishing an indication for palliative TACE, strict guidelines based on the patient's condition and tumor stage must be followed. Therefore, we evaluated the volumetric computed tomographic (CT) data in 85 patients with hepatocellular carcinoma (HCC) who had contraindications for surgery or transplantation and had been treated at a liver transplantation center during a 6-year period. The prognostic influence of CT measurements of intrahepatic tumor growth and iodized oil retention and of repeated treatments with palliative TACE were investigated.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Histologically proved HCC in 85 patients (65 men, 20 women; average age ± SD, 63 years ± 10; age range, 33–83 years) was treated with TACE between February 1991 and October 1997. The diagnosis was based on the results of percutaneous liver needle biopsy in 60 patients and on the results of biopsy performed with laparoscopy in 25 patients.

Cirrhosis was classified by using the Child-Pugh system. Child-Pugh grade A cirrhosis was found in 52 patients, and Child-Pugh grade B cirrhosis was found in 23. Liver cirrhosis was alcohol related in 30 patients, hepatitis related in 40 patients, and from different causes in 15 patients. In 10 patients, no clinical or radiologic signs of cirrhosis were found. TACE was performed in the absence of contraindications to the procedure. Poor liver function was overrepresented among the patients who underwent TACE, because good liver function was a prerequisite for liver resection or transplantation at our center. All patients gave signed informed consent for evaluation of the acquired data.

Criteria for TACE Inclusion or Exclusion
In all patients, the aim of TACE was to achieve control of local tumor growth and prolonged survival. In an interdisciplinary conference, all patients had previously been rejected as candidates for liver resection or transplantation because of local tumor stage or poor general condition. The criteria for inclusion in the TACE group included a nodular or diffuse pattern of HCC growth at spiral CT, with absent clinical and radiologic evidence of extrahepatic involvement such as lymph node metastases, lung or bone metastases, or peritoneal carcinomatosis. Partial or complete thrombosis of the main portal vein was an exclusion criterion for the procedure. Follow-up studies were performed with standard (nonenhanced) and contrast material–enhanced spiral CT.

TACE Protocol
After the introduction of a 5-F pigtail catheter through the femoral artery, an angiographic survey of the abdominal vessels was performed. First, mesenteric arteriography was performed to check for the presence of a right hepatic artery. Indirect portography was performed next to outline the portal circulation in the venous phase. A 4-F Cobra catheter (Terumo, Frankfurt/Main, Germany) was placed in the celiac trunk and advanced beyond the gastroduodenal artery. Depending on the size, location, and arterial supply of the tumor and its satellites, the tip of the catheter was advanced further into segmental arteries for selective embolization by using a Tracker catheter (Terumo). Embolization was carried out with a 4-F Cobra catheter in 37 patients and with a 3-F, 16-inch Tracker catheter in 48 patients. The embolization suspension consisted of 50 mg/m2 of doxorubicin hydrochloride, 50 mg/m2 of cisplatin, and 10 mL of iodized oil (Lipiodol; Guerbet, Aulnay-sous-Bois, France), followed by an injection of 2–10-mg microspheres of amilomer (Sperex; Pharmacia, Erlangen, Germany). After embolization, devascularization was confirmed with an additional angiographic study of the hepatic artery. Repeated chemoembolization has been a part of our regular protocol since February 1994; we administer three courses of chemoembolization at individual 6-week intervals.

All CT studies were performed prior to therapy by using a spiral technique with fourthgeneration scanners (Somatom Plus and Somatom Plus S; Siemens, Erlangen, Germany). Nonenhanced and contrast-enhanced images were obtained in all patients.

Before therapy, biphasic CT studies (Somatom Plus) were performed during the arterial (volume, 100 mL; flow, 4 mL/sec; scan delay, 15 seconds) and venous (volume, 70 mL; flow, 1 mL/sec; scan delay, 80 seconds) phases. Twenty-four to 48 hours after embolization, retention of iodized oil in the tumor and liver parenchyma was verified with conventional CT. Nonenhanced and contrast-enhanced CT examinations were performed in 3-month intervals during the 1st year and twice yearly thereafter.

Quantitative Data
Volumetric CT evaluation included analysis of tumor volume, liver tissue, and iodized oil retention by means of a region-of-interest technique (Siemens). The volumes of tumor and liver were measured with preinterventional CT studies. The following three groups, each of which consisted of a similar number of patients, were formed on the basis of tumor volume: less than 50 mL, 50–200 mL, and greater than 200 mL. The quantitative retention of iodized oil in tumor tissue and liver parenchyma was documented in percentiles of the volume as follows: less than 10%, less than 25%, less than 50%, less than 75%, and 75% or greater. The postinterventional residual tumor tissue volume was documented as a percentage ratio of tumor tissue that was not completely hypoattenuating at nonenhanced CT performed after embolization.

Statistical Analysis
The survival time, beginning with the commencement of treatment, was calculated by using the Kaplan-Meier method. The prognostic influence of the following parameters was analyzed by using log-rank and Breslow tests: tumor volume, liver volume, tumor-to-liver volume ratio, liver cirrhosis grade (ie, Child-Pugh classification), pattern of tumor growth, number of lesions, number of involved liver segments, degree of iodized oil retention within the tumor, and single or repeated TACE courses.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Morphologic Features
CT depicted a mononodular pattern of growth in 18 patients. Twelve of these tumors were primarily hypoattenuating at nonenhanced CT; in the other six patients the tumor could not be identified at nonenhanced CT. During the arterial phase, all lesions showed varying degrees of hypervascularization with peripheral, central, or mixed patterns of enhancement. During the venous phase, enhancement was inhomogeneous, with hypoattenuating and hyperattenuating areas. In 30 patients, satellites surrounding the primary tumor were present. A multinodular growth pattern was seen in 24 patients, and an infiltrative (ie, diffuse) pattern was seen in 13 patients. Twenty patients presented with a solitary lesion; 21 patients, with two lesions; 21 patients, with three to nine lesions; and 23 patients, with 10 or more lesions. Tumor growth predominated in one segment in 24 patients, in two segments in 24 patients, and in three segments in 15 patients. There was infiltration of four or more segments in 22 patients.

Quantitative Data
Quantitative CT evaluation revealed a mean liver volume (± SD) of 1,975 mL ± 784.8 (range, 624–4,271 mL). Tumor volumes varied between 2 and 1,291 mL, with a mean volume of 251 mL ± 286.7. For statistical analysis, we compared the results of three tumor volume subgroups—patients with tumor volumes of less than 50 mL, those with volumes of 50–200 mL, and those with volumes of greater than 200 mL. The quantitative evaluation of the results of embolization at nonenhanced CT performed before the procedure revealed minimal (<10%) iodized oil retention in six patients and almost complete retention (>=75%) in 34 patients.

Survival
The mean and median survival and the 1-year survival rates of the subgroups are summarized in the Table. The overall survival rate was 57.6% after 1 year and 23.3% after 2 years. (Fig 1).


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  		Mean and Median Survival Following TAE for HCC
 


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  		Figure 1. Graph illustrates the overall survival in 85 patients (x) with HCC treated by using TACE.

 
A diffuse growth pattern resulted in significantly poorer survival compared with that in the other three growth pattern subgroups (P < .05). A tendency toward improved survival was calculated for the first two categories (mononodular and satellite patterns) compared with that in the group with multinodular growth (P < .1), whereas there was no significant difference in survival among the patients with mononodular tumors, with or without satellites (Fig 2). With regard to the number of segments involved in tumor growth, a significant worsening of survival was calculated for those patients with more than three affected segments (P < .002). In addition, with involvement of three segments there was a tendency toward poorer survival compared with the survival associated with monosegmental or bisegmental growth (P < .2) (Fig 3). Similarly, only the group with multiple (more than nine) lesions differed significantly from the other subgroups (P < .03) (Fig 4) in terms of survival.



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  		Figure 2. Graph of survival depending on pattern of tumor growth demonstrates a significantly poorer survival with diffuse growth pattern compared with the survival in the other growth pattern subgroups. x indicates patients with diffuse pattern (n = 13); {square}, patients with multinodular pattern (n = 24); {bigtriangledown}, patients with satellites (n = 30); and {bigcirc}, patients with mononodular pattern (n = 18).

 


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  		Figure 3. Graph of survival depending on number of involved liver segments demonstrates significantly reduced survival for patients with more than three involved liver segments. {bigcirc} indicates more than three involved liver segments (n = 22); +, three involved segments (n = 15); {square}, two involved segments (n = 24); and {bigtriangledown}, one involved segment (n = 24).

 


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  		Figure 4. Graph of survival depending on number of lesions demonstrates significantly improved survival for patients with multiple tumorous lesions. {square} indicates multiple lesions (n = 23); +, three to nine lesions (n = 21); {bigtriangledown}, two lesions (n = 21); and {bigcirc}, one lesion (n = 20).

 
The percentage of iodized oil retained in the tumor correlated with longer survival when there was complete (>=75%) retention (P < .001) and good (50%–74%) retention (P < .07) compared with the survival in the next lower category. Poor results were obtained with iodized oil retention of less than 50%, less than 25%, and less than 10%, with mean and median survival times of 269 and 241 days, 184 and 156 days, and 224 and 172 days, respectively (Table, Fig 5).



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  		Figure 5. Graph of survival depending on percentage of intratumoral retention of iodized oil demonstrates longer survival with complete (>=75%) and good (50%-74%) retention versus the survival with retention of less than 50%. {square} indicates 75% or greater retention (n = 34); {bigcirc}, less than 75% retention (n = 17); +, less than 50% retention (n = 17); {diamond}, less than 25% retention (n = 11); and x, less than 10% retention (n = 6).

 
There were significant differences in survival between patients with tumor volumes of more than 200 mL and those with volumes of less than 200 mL (P < .02). Tumor volumes of less than 50 mL, with which there were mean and median survival of 697 and 645 days, respectively, tended to be associated with better survival compared with tumor volumes of 50–200 mL (P < .2) (Fig 6). When tumor size was related to liver volume, a significant improvement in survival was calculated for tumor-to-liver volume ratios of less than 5% (P < .01) (Fig 7), with mean and median survival of 727 and 645 days, respectively, compared with the survivals associated with ratios of 5% or greater. Comparison of tumor-to-liver volume ratios of less than 15% and of 15% or greater revealed a tendency (P < .2) toward improved survival for the less than 15% group (Fig 7).



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  		Figure 6. Graph of survival depending on tumor volume demonstrates a significant difference in survival between patients with tumor volumes of more than 200 mL and those with volumes of less than 200 mL. + indicates tumor volume greater than 200 mL (n = 34); {bigtriangledown}, tumor volume 50-200 mL (n = 30); and {square}, tumor volume less than 50 mL (n = 21).

 


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  		Figure 7. Graph of survival depending on the tumor-to-liver volume ratio demonstrates improved survival with small tumor-to-liver volume ratios. + indicates ratio 15% or greater (n = 26); {bigtriangledown}, ratio less than 15% (n = 33); and {square}, ratio less than 5% (n = 26).

 
A statistically significant difference in survival time was found between patients who underwent repeated TACE and those who underwent only one TACE procedure. Follow-up CT studies after chemoembolization enabled evaluation of the responses to TACE. Thirty-four patients had a good response, with iodized oil retention values of 75% or greater at the first follow-up CT examination after embolization (Fig 8).



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  		Figure 8. Graph of survival depending on number of TACE procedures performed indicates that differences in survival may be related to the introduction of the repeated TACE protocol. {square} indicates repeated TACE performed (n = 52); and {bigtriangledown}, single TACE performed (n = 33).

 
A prognostically favorable criterion was high peritumoral retention of embolization material, which usually could no longer be found at follow-up 3–6 months after embolization. A reduction in tumor size and a persistently high retention of the suspension also were favorable indications (Figs 9–11).



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  		Figure 9a. (a-c) Transverse CT scans obtained in a 61-year-old man with Child-Pugh grade A cirrhosis and mononodular tumor growth, with one satellite in segment 6 and an observed survival of 484 days. This patient had a tumor volume of 680 mL and tumor-to-liver volume ratio of 42%. (a) CT scan obtained after the first TACE procedure shows good iodized oil retention in the residual tumor (arrow) and the satellite (arrowhead). Region-of-interest lines have been drawn around both the liver and the tumor. 2 indicates region of interest 2. (b) CT scan obtained after the third TACE procedure shows partial necrosis and a reduction in tumor size. (c) Follow-up CT scan obtained 6 months after the third TACE procedure demonstrates reduction of the tumor; the satellite is no longer visible. In b and c, 1 indicates region of interest 1.

 


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  		Figure 9b. (a-c) Transverse CT scans obtained in a 61-year-old man with Child-Pugh grade A cirrhosis and mononodular tumor growth, with one satellite in segment 6 and an observed survival of 484 days. This patient had a tumor volume of 680 mL and tumor-to-liver volume ratio of 42%. (a) CT scan obtained after the first TACE procedure shows good iodized oil retention in the residual tumor (arrow) and the satellite (arrowhead). Region-of-interest lines have been drawn around both the liver and the tumor. 2 indicates region of interest 2. (b) CT scan obtained after the third TACE procedure shows partial necrosis and a reduction in tumor size. (c) Follow-up CT scan obtained 6 months after the third TACE procedure demonstrates reduction of the tumor; the satellite is no longer visible. In b and c, 1 indicates region of interest 1.

 


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  		Figure 9c. (a-c) Transverse CT scans obtained in a 61-year-old man with Child-Pugh grade A cirrhosis and mononodular tumor growth, with one satellite in segment 6 and an observed survival of 484 days. This patient had a tumor volume of 680 mL and tumor-to-liver volume ratio of 42%. (a) CT scan obtained after the first TACE procedure shows good iodized oil retention in the residual tumor (arrow) and the satellite (arrowhead). Region-of-interest lines have been drawn around both the liver and the tumor. 2 indicates region of interest 2. (b) CT scan obtained after the third TACE procedure shows partial necrosis and a reduction in tumor size. (c) Follow-up CT scan obtained 6 months after the third TACE procedure demonstrates reduction of the tumor; the satellite is no longer visible. In b and c, 1 indicates region of interest 1.

 


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  		Figure 10a. Transverse CT scans obtained in a 77-year-old man with Child-Pugh grade A cirrhosis and mononodular tumor growth in segment 6. This patient had a tumor volume of 17 mL, tumor-to-liver volume ratio of 1%, and observed survival of 738 days. (a) Pretreatment arterial phase CT scan shows a small hypervascularized area (arrow) in segment 6. (b) CT scan obtained after repeated TACE shows several tumorous lesions with retention of iodized oil. (c) CT scan obtained 2 months after TACE demonstrates reduction of the size of the original tumor and reduced retention of iodized oil in the parenchyma surrounding the satellite. (d) Follow-up CT scan obtained 6 months after repeated TACE shows residual iodized oil retention in the two lesions (arrows).

 


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  		Figure 10b. Transverse CT scans obtained in a 77-year-old man with Child-Pugh grade A cirrhosis and mononodular tumor growth in segment 6. This patient had a tumor volume of 17 mL, tumor-to-liver volume ratio of 1%, and observed survival of 738 days. (a) Pretreatment arterial phase CT scan shows a small hypervascularized area (arrow) in segment 6. (b) CT scan obtained after repeated TACE shows several tumorous lesions with retention of iodized oil. (c) CT scan obtained 2 months after TACE demonstrates reduction of the size of the original tumor and reduced retention of iodized oil in the parenchyma surrounding the satellite. (d) Follow-up CT scan obtained 6 months after repeated TACE shows residual iodized oil retention in the two lesions (arrows).

 


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  		Figure 10c. Transverse CT scans obtained in a 77-year-old man with Child-Pugh grade A cirrhosis and mononodular tumor growth in segment 6. This patient had a tumor volume of 17 mL, tumor-to-liver volume ratio of 1%, and observed survival of 738 days. (a) Pretreatment arterial phase CT scan shows a small hypervascularized area (arrow) in segment 6. (b) CT scan obtained after repeated TACE shows several tumorous lesions with retention of iodized oil. (c) CT scan obtained 2 months after TACE demonstrates reduction of the size of the original tumor and reduced retention of iodized oil in the parenchyma surrounding the satellite. (d) Follow-up CT scan obtained 6 months after repeated TACE shows residual iodized oil retention in the two lesions (arrows).

 


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  		Figure 10d. Transverse CT scans obtained in a 77-year-old man with Child-Pugh grade A cirrhosis and mononodular tumor growth in segment 6. This patient had a tumor volume of 17 mL, tumor-to-liver volume ratio of 1%, and observed survival of 738 days. (a) Pretreatment arterial phase CT scan shows a small hypervascularized area (arrow) in segment 6. (b) CT scan obtained after repeated TACE shows several tumorous lesions with retention of iodized oil. (c) CT scan obtained 2 months after TACE demonstrates reduction of the size of the original tumor and reduced retention of iodized oil in the parenchyma surrounding the satellite. (d) Follow-up CT scan obtained 6 months after repeated TACE shows residual iodized oil retention in the two lesions (arrows).

 


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  		Figure 11a. Transverse CT scans obtained in a 58-year-old woman with Child-Pugh grade A cirrhosis and multinodular tumor growth in the right lobe. This patient had a tumor volume of 160 mL, tumor-to-liver volume ratio of 10%, and observed survival of 241 days. (a) CT scan obtained after the first TACE procedure shows retention of iodized oil in the tumor nodules in segments 4, 5, and 6. (b) Arterial phase CT scan obtained after the first TACE procedure shows hypervascularization in the rim of the larger tumor nodule (arrows) in segment 4. (c) Venous phase CT scan obtained after the first TACE procedure shows extensive necrosis in the larger tumor nodule (arrows) in segment 4. (d) Nonenhanced CT scan shows increased iodized oil retention in the rim of the larger tumor nodule in segment 4 and in the smaller nodules as a result of repeated TACE. (e) Arterial venous phase spiral CT scan obtained 2 months after repeated TACE shows an absence of arterialization of the larger nodule in segment 6. (f) Arterial phase spiral CT obtained 6 months after the last course of TACE treatment shows massively enlarged tumor vessels (arrow) (ie, hypervascularization) in the larger tumor nodule in segment 4.

 


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  		Figure 11b. Transverse CT scans obtained in a 58-year-old woman with Child-Pugh grade A cirrhosis and multinodular tumor growth in the right lobe. This patient had a tumor volume of 160 mL, tumor-to-liver volume ratio of 10%, and observed survival of 241 days. (a) CT scan obtained after the first TACE procedure shows retention of iodized oil in the tumor nodules in segments 4, 5, and 6. (b) Arterial phase CT scan obtained after the first TACE procedure shows hypervascularization in the rim of the larger tumor nodule (arrows) in segment 4. (c) Venous phase CT scan obtained after the first TACE procedure shows extensive necrosis in the larger tumor nodule (arrows) in segment 4. (d) Nonenhanced CT scan shows increased iodized oil retention in the rim of the larger tumor nodule in segment 4 and in the smaller nodules as a result of repeated TACE. (e) Arterial venous phase spiral CT scan obtained 2 months after repeated TACE shows an absence of arterialization of the larger nodule in segment 6. (f) Arterial phase spiral CT obtained 6 months after the last course of TACE treatment shows massively enlarged tumor vessels (arrow) (ie, hypervascularization) in the larger tumor nodule in segment 4.

 


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  		Figure 11c. Transverse CT scans obtained in a 58-year-old woman with Child-Pugh grade A cirrhosis and multinodular tumor growth in the right lobe. This patient had a tumor volume of 160 mL, tumor-to-liver volume ratio of 10%, and observed survival of 241 days. (a) CT scan obtained after the first TACE procedure shows retention of iodized oil in the tumor nodules in segments 4, 5, and 6. (b) Arterial phase CT scan obtained after the first TACE procedure shows hypervascularization in the rim of the larger tumor nodule (arrows) in segment 4. (c) Venous phase CT scan obtained after the first TACE procedure shows extensive necrosis in the larger tumor nodule (arrows) in segment 4. (d) Nonenhanced CT scan shows increased iodized oil retention in the rim of the larger tumor nodule in segment 4 and in the smaller nodules as a result of repeated TACE. (e) Arterial venous phase spiral CT scan obtained 2 months after repeated TACE shows an absence of arterialization of the larger nodule in segment 6. (f) Arterial phase spiral CT obtained 6 months after the last course of TACE treatment shows massively enlarged tumor vessels (arrow) (ie, hypervascularization) in the larger tumor nodule in segment 4.

 


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  		Figure 11d. Transverse CT scans obtained in a 58-year-old woman with Child-Pugh grade A cirrhosis and multinodular tumor growth in the right lobe. This patient had a tumor volume of 160 mL, tumor-to-liver volume ratio of 10%, and observed survival of 241 days. (a) CT scan obtained after the first TACE procedure shows retention of iodized oil in the tumor nodules in segments 4, 5, and 6. (b) Arterial phase CT scan obtained after the first TACE procedure shows hypervascularization in the rim of the larger tumor nodule (arrows) in segment 4. (c) Venous phase CT scan obtained after the first TACE procedure shows extensive necrosis in the larger tumor nodule (arrows) in segment 4. (d) Nonenhanced CT scan shows increased iodized oil retention in the rim of the larger tumor nodule in segment 4 and in the smaller nodules as a result of repeated TACE. (e) Arterial venous phase spiral CT scan obtained 2 months after repeated TACE shows an absence of arterialization of the larger nodule in segment 6. (f) Arterial phase spiral CT obtained 6 months after the last course of TACE treatment shows massively enlarged tumor vessels (arrow) (ie, hypervascularization) in the larger tumor nodule in segment 4.

 


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  		Figure 11e. Transverse CT scans obtained in a 58-year-old woman with Child-Pugh grade A cirrhosis and multinodular tumor growth in the right lobe. This patient had a tumor volume of 160 mL, tumor-to-liver volume ratio of 10%, and observed survival of 241 days. (a) CT scan obtained after the first TACE procedure shows retention of iodized oil in the tumor nodules in segments 4, 5, and 6. (b) Arterial phase CT scan obtained after the first TACE procedure shows hypervascularization in the rim of the larger tumor nodule (arrows) in segment 4. (c) Venous phase CT scan obtained after the first TACE procedure shows extensive necrosis in the larger tumor nodule (arrows) in segment 4. (d) Nonenhanced CT scan shows increased iodized oil retention in the rim of the larger tumor nodule in segment 4 and in the smaller nodules as a result of repeated TACE. (e) Arterial venous phase spiral CT scan obtained 2 months after repeated TACE shows an absence of arterialization of the larger nodule in segment 6. (f) Arterial phase spiral CT obtained 6 months after the last course of TACE treatment shows massively enlarged tumor vessels (arrow) (ie, hypervascularization) in the larger tumor nodule in segment 4.

 


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  		Figure 11f. Transverse CT scans obtained in a 58-year-old woman with Child-Pugh grade A cirrhosis and multinodular tumor growth in the right lobe. This patient had a tumor volume of 160 mL, tumor-to-liver volume ratio of 10%, and observed survival of 241 days. (a) CT scan obtained after the first TACE procedure shows retention of iodized oil in the tumor nodules in segments 4, 5, and 6. (b) Arterial phase CT scan obtained after the first TACE procedure shows hypervascularization in the rim of the larger tumor nodule (arrows) in segment 4. (c) Venous phase CT scan obtained after the first TACE procedure shows extensive necrosis in the larger tumor nodule (arrows) in segment 4. (d) Nonenhanced CT scan shows increased iodized oil retention in the rim of the larger tumor nodule in segment 4 and in the smaller nodules as a result of repeated TACE. (e) Arterial venous phase spiral CT scan obtained 2 months after repeated TACE shows an absence of arterialization of the larger nodule in segment 6. (f) Arterial phase spiral CT obtained 6 months after the last course of TACE treatment shows massively enlarged tumor vessels (arrow) (ie, hypervascularization) in the larger tumor nodule in segment 4.

 
In 46 patients, a reduction of an initially high iodized oil retention was noted at follow-up after 6 months. In 25 patients with large tumor volumes and initially low iodized oil retention values, repeated TACE failed, and there was recurrence of tumor.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Standard treatment for HCC includes surgical procedures, such as resection and transplantation, and interventional procedures, particularly transarterial embolization or local ethanol injection (3,5–7). The tumors in more than 80% of patients with HCC are unresectable at the time of diagnosis, and due to poor local circumstances or the patient's general condition, the prognosis is poor (8). Because HCC tumors are fed exclusively by the hepatic artery (9), successful TACE leads to tumor necrosis (5). The liver parenchyma is rarely damaged because it is fed by the portal vein. Injection of an emulsion of iodized oil and cytostatic agents into the hepatic artery leads to selective deposition of the emulsion in the tumor (7,10). Compared with intravenous administration of embolization material, TACE reduces the maximum plasma concentration, lengthens the half-life, and increases the average concentration of cytostatic agents in the tumor, especially when the TACE material is combined with gelatin powder particles (11). The concentration of an emulsion of cisplatin in iodized oil 4–9 weeks after intraarterial administration is 42 times greater in the tumor than in parenchyma (10).

In a clinical trial with encapsulated tumors, it was shown that the extent of necrosis that was approximated at CT performed 1–3 weeks after TACE was 98% in the cases of complete iodized oil retention and 64% in the cases of incomplete iodized oil retention (2). Furthermore, after doxorubicin hydrochloride–gelatin powder TACE of small encapsulated tumors, complete necrosis could be histopathologically proved in four of eight patients; the other four patients had an incomplete response due to accessory arterialization of the tumor, tumor invasion of the portal vein, or multiple tumors (5). Our study results showed a strong correlation between better survival and small tumors; iodized oil retention of 75% or greater further improved survival.

Okuda et al (12) observed an average spontaneous survival of 0.7–8.3 months, depending on tumor size and liver function. In patients treated with TACE, the average survival was 9.5–10.3 months. The survival in patients with large tumors was 2 months spontaneously (n = 134) and 9.5 months following TACE (n = 64). In more recent studies (1,13), the 1-year survival rose to 62%–75%.

Our protocol resulted in a 1-year survival rate of 57.6%. The aim of TACE at our center is largely palliative due to the extensive use of surgical techniques, which include orthotopic liver transplantation. The prospective repeated TACE protocol was introduced in the middle of this study, and it was clearly associated with better survival in the later-treated group (P = .001).

When resection was compared with TACE of multifocal but resectable HCC, the 1- and 3-year survival rates were 89% and 75%, respectively, after resection in 67 patients and 90% and 50%, respectively, after TACE in 20 patients. Thus, the margin in favor of resection is decreasing (14).

The French study group (15) observed a tendency toward better survival with TACE only when it was compared with symptomatic therapy in a prospective randomized clinical trial. In a highly selected subgroup of patients with HCC, they achieved a 1-year survival rate of 62% with TACE in 50 patients and of 44% with palliative therapy in 46 patients. The calculated relative risk of death in the palliative treatment group was 1.3 times greater than that in the TACE group (P = .13). The results of TACE in the present study are comparable to those in other studies, whereas spontaneous survival in patients with HCC varies widely (8,16). We must suppose a much lower rate of spontaneous survival in our study population because of the preselected nature of our data.

As of yet, proof of a statistically significant prolongation of survival by using TACE has been obtainable only in subgroups. A general treatment schedule has not been established because survival is limited due to the tumor characteristics and accompanying cirrhosis. Statistically significant influences on survival have been reported to be associated with growth pattern (17–19), response to TACE (1,4,20), extent of tumor growth and invasion of the portal vein (18), and degree of cirrhosis (17). Tumor volume (16,17) and the Okuda grading system have yielded contradictory results. No associations between improved survival and age, sex, {alpha}-fetoproteins, or hepatitis serology have been found (18).

The survivals of our study patients differed significantly, depending on the tumor growth pattern, number of tumors, number of segments involved, and response to TACE. Retention of iodized oil in the tumor depended on the tumor volume and tumor-to-liver volume ratio. Although tumors may have a volume of up to 200 mL before retention is compromised, they may not exceed 5% of the parenchyma volume if good results are to be obtained in terms of retention and survival. In tumors with a higher volume, or with greater tumor-to-liver volume ratios, survival correlates well with repeated therapy. A tendency toward better survival was observed in the patients who underwent repeated TACE treatments and in those with low-grade cirrhosis.

The following issues regarding the use of TACE in patients with HCC must be considered individually to establish an optimal therapy schedule and achieve local control of tumor growth. Our study data support the use of the common criteria for TACE, such as Child-Pugh grade A cirrhosis and absence of extrahepatic tumor manifestation. Nonenhanced and contrast-enhanced follow-up CT should be performed because this modality is superior for the evaluation of retention or loss of the emulsion.

In patients who have HCC, liver resection and transplantation are feasible in only a small number of patients; thus, there is a need for adjunctive treatment methods such as TACE to improve the resectability rate and diminish the frequency of tumor recurrence after surgery. The results of several studies (21,22) have shown that TACE appears to be a useful technique for the management of cirrhosis-associated HCC before liver resection or transplantation is attempted.

In the present study, we observed different values for survival that were possibly based on a more fundamentally structured statistical evaluation. In 1997, we reported that survival was improved in only those patients with a tumor volume of less than 50 mL (23); our current study results indicate improved survival with tumor volumes of less than 200 mL.

It is essential that the patient maintain a satisfactory general condition. Our repeated TACE schedule was tolerated well with no major impairments. The described volumetric CT technique is a reasonable method to better quantitatively predict the prognosis of patients who undergo chemoembolization. The prognostic parameters presented herein support the clinical use of tumor volumes of less than 200 mL, tumor-to-liver volume ratios of less than 5%, all but diffuse tumor growth, and high iodized oil retention as great prognostic factors. In cases of rapid loss of embolization material, as determined at CT, reembolization should be performed immediately. For tumors with a diffuse growth pattern, or with tumor volumes of greater than 200 mL, a repeated TACE schedule should be followed. The use of TACE as a pretransplantation and presurgical technique to further improve the outcome in patients with HCC will be analyzed in further studies.


   Footnotes
 
Abbreviations: HCC = hepatocellular carcinoma TACE = transarterial chemoembolization

Author contributions: Guarantor of integrity of entire study, T.J.V.; study concepts, T.J.V.; study design, T.J.V., M.T.; definition of intellectual content, H.S.; literature research, A.S., J.S.; clinical studies, T.J.V., P.N.; experimental studies, A.S.; data acquisition, T.J.V., R.F.; data analysis, M.M.; statistical analysis, M.M., J.S.; manuscript preparation, T.J.V., P.N.; manuscript editing, M.T., A.S.; manuscript review, R.F.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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