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Hepatocellular Carcinoma: Long-term Results of Combined Treatment with Laser Thermal Ablation and Transcatheter Arterial Chemoembolization¹

¹ From the Department of Radiology and Diagnostic Imaging (C.M.P., G.B., A.B., V.A., S.P.) and the Department of Endocrine, Metabolic, and Digestive Diseases (Z.R.), Regina Apostolorum Hospital, Via St Francesco 50, 00041 Albano Laziale, Rome, Italy; the Diagnostic Radiology Service, St Anna Hospital, Como, Italy (P.C., B.C.); and the Gastroenterology Unit, St Donato Hospital, Arezzo, Italy (F.M.). From the 1999 RSNA scientific assembly. Received February 9, 2000; revision requested March 24; final revision received August 30; accepted October 2. Address correspondence to C.M.P. (e-mail: cmpacel@kat.it).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the potential long-term effectiveness of laser thermal ablation (LTA) followed by transcatheter arterial chemoembolization (TACE) in the percutaneous ablation of large hepatocellular carcinoma (HCC).

MATERIALS AND METHODS: Thirty large HCCs 3.5–9.6 cm in diameter (mean diameter, 5.2 cm) and 15 small HCCs 0.8–3.0 cm (mean diameter, 1.9 cm) were treated with ultrasonographically guided LTA with TACE and with LTA alone, respectively, in 30 patients: 19 with a solitary large HCC, and 11 with one to three additional synchronous small HCCs. A 1.064-µm neodymium yttrium-aluminium-garnet (Nd-YAG) laser at a power of 5.0 W was coupled with one to four quartz optic fibers that were advanced through 21-gauge needles. Segmental TACE was performed 30–90 days after LTA. All lesions were evaluated for change in size at computed tomography (CT), -fetoprotein (AFP) levels, recurrence rates, and cumulative survival rates.

RESULTS: No major complications occurred in 127 LTA sessions. CT showed complete tumor necrosis in 27 (90%) of 30 large HCCs. Twenty-eight patients were followed up for 6–41 months (mean, 17.1 months). In 25 patients, all lesions appeared stable or smaller at CT. AFP levels decreased to the normal range in all patients with high pretreatment values. The 1-, 2-, and 3-year local recurrence rate was 7% in large HCCs. Complete tumor necrosis was achieved in all 15 (100%) small HCCs; none of them recurred locally. The 1-, 2-, and 3-year cumulative survival rates were 92%, 68%, and 40%, respectively.

CONCLUSION: LTA followed by TACE is an effective palliative therapy in treating large HCCs.

Index terms: Lasers, interstitial therapy, 761.1299 • Liver, interventional procedures, 761.1299 • Liver neoplasms, 761.323 • Liver neoplasms, chemotherapeutic embolization, 761.1266, 761.323 • Liver neoplasms, therapy, 761.1266, 761.1299, 761.323

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Only a small proportion of patients with early hepatocellular carcinoma (HCC) may currently benefit from radical options such as surgical resection and orthotopic liver transplantation. Thus, most patients with HCC are considered for some of the available palliative approaches, although no clear-cut evidence indicates that any of the approaches result in an improved outcome (1). Among these options, percutaneous ethanol injection has been highly effective when restricted to lesions smaller than 3 cm in diameter (2–4) and has been proved insufficient in patients with large lesions (>3 cm in diameter) (2,5). Transcatheter arterial chemoembolization (TACE) is widely performed in large lesions, whether single or multiple (6). Although extensive tumor necrosis can be observed (7,8), complete responses are unusual after chemoembolization (6–10), and there is no improvement in survival (11–14).

To overcome the limits of the aforementioned options and achieve more extensive necrosis in large HCCs, pretreatment with TACE and subsequent percutaneous ethanol injection were proposed for patients with a single large encapsulated lesion (15,16). In two prospective randomized trials (15,16), the therapeutic response was substantially better in patients who underwent combined treatment than in those who underwent repeated segmental or subsegmental TACE alone.

Laser thermal ablation (LTA) is a minimally invasive method of destroying tumors within solid organs by directing low-power laser light energy into a tissue through one or more implanted optic fibers (17–20). To our knowledge, few investigators (21,22) have used LTA for the percutaneous destruction of primary liver tumors, although it has been frequently used for the palliation of hepatic metastases (19,20,23).

Aiming to achieve extensive necrosis of large HCCs with minimal damage to the surrounding hepatic parenchyma, we treated these lesions with LTA before TACE. The purpose of our study was to determine the potential long-term effectiveness of LTA followed by TACE in the percutaneous ablation of large HCCs by analyzing the long-term results in 30 patients.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study was performed with the approval of the Ethics Committee of the Ospedale Regina Apostolorum. Informed consent was obtained from all patients at the time of enrollment. Between September 1994 and December 1998, we enrolled 30 patients with histologically proved HCC. The study included previously untreated patients who had HCC that was unsuitable for surgical resection (24,25) or who had undergone liver transplantation (26) or percutaneous ethanol injection, which is appropriate only in patients with one to three HCCs, each 3 cm or less (2,4,24). Exclusion criteria were having an age greater than 80 years, uncontrolled liver disease decompensation, an invasive pattern such as portal vein thrombosis and/or extrahepatic spread, or any contraindication for an arterial procedure, such as impaired function seen with clotting test results (prothrombin activity less than 40% or platelet count less than 40 x 10⁹/L), renal failure, severe atheromatosis, severe associated diseases, or severe contrast medium allergy. We included patients with an HCC of more than 3 cm that was detectable at ultrasonography (US) and occurred singly or with additional coincidental tumors at an early stage—synchronous multiple (up to three) HCCs, each 3 cm or less—who did not have a history of HCC treatment before entry and had Child-Pugh class A or B liver cirrhosis. The resultant patient population was composed of 30 patients with 45 lesions (30 lesions > 3 cm, and 15 lesions 3 cm). The patients’ baseline characteristics are summarized in Table 1.

The main tumor was histologically graded by means of US-guided percutaneous biopsy with an 18-gauge cutting needle. Histopathologic evidence of the nature of the small lesions was obtained in the five 2.6–3.0-cm lesions in four patients. In the remaining 10 small lesions, US and CT enabled accurate characterization based on size progression and/or the number of lesions or the enhancement pattern.

Technique
All patients were treated with conscious sedation, with intravenous injection of 3–7 mg of midazolam maleate (Ipnovel 15; Roche, Milan, Italy) and 4–5 mL of fentanil citrate (Fentanest; Pharmacia & Upjohn, Milan, Italy) in the outpatient clinic. LTA was performed with a continuous-wave neodymium yttrium-aluminium-garnet, or Nd:YAG, laser (DEKA-M.E.L.A.; EL.EN, Florence, Italy) that operated at a wavelength of 1.064 µm. We used a 21-gauge modified Chiba needle (H.S., Rome, Italy) and a plane-cut-tip optic fiber with a 300-µm quartz core (Medical Energy, Pensacola, Fla). With US guidance, the needles were positioned within the lesion in the area to be treated, and the tip positions were confirmed with two-plane US images. The optic fiber was inserted through each needle to the end of the sheath, which was then retracted to leave at least 1.0 cm of bare tip in direct contact with the lesion. Both the number of needles (one to four) and the arrangement were chosen in accordance with the size, shape, and location of the lesions. Thus, up to four needles were simultaneously positioned: one to four in small lesions, and, invariably, four needles in a square configuration of 1.0–1.5 cm per side in large lesions.

In the case of large HCCs, the treatment started with the needles placed in the deepest part of the tumor. After the laser had been activated and the scheduled energy delivered, the needles were withdrawn approximately 2 cm within the lesion, and another laser illumination was performed. Each laser illumination was considered a single treatment. Up to four treatments were performed during any one session. To encompass the entire tumor, we performed multiple four-needle insertions and moved from one area to the next contiguous area. For each illumination, the laser was turned on at a power of 5.0 W, with an exposure time of 360 seconds that was adjusted to reach 1,800 J per fiber. Starting in September 1995, we used a laser splitter (DEKA-M.E.L.A.) with four separate output fibers activated concurrently (28). Thus, the total energy delivered simultaneously in each treatment was 7,200 J (1,800 x 4). At the end of the treatment, the optic fiber was slowly pulled out with the laser still on. All laser illuminations were monitored continuously with real-time US. LTA treatments were performed by one of four radiologists (C.M.P., G.B., P.C., or F.M.).

The patients’ vital signs were closely monitored during treatment. After the procedure, patients were observed for 6 hours in the outpatient recovery room. Liver function tests were performed and complete blood counts were obtained to detect clinically silent complications. In the first 12 patients, liver function, complete blood count, and prothrombin time were measured completely at 1 and 7 days and at 1 month after treatment. In the remaining patients, the degree of liver function impairment was estimated by means of routine biochemical parameters within 1 month after treatment. In addition to conventional clinical and biochemical parameters, recorded data included Child-Pugh classification, growth of the main tumor, and occurrence of extrahepatic disease.

TACE was performed 30–90 days after LTA by using a digital angiography unit (Integris DVI 3000; Philips, Eindhoven, the Netherlands) and injection of an emulsion of 10 mL of iodized oil (Lipiodol UltraFluid; Laboratoires Guerbet, Aulnay-sous-Bois, France) and 20 mg of doxorubicin hydrochloride (Adriablastina; Farmitalia Carlo Erba, Milan, Italy) followed by 1.0 mL dry volume per vial of polyvinyl alcohol particles (ITC Contour Emboli [250–350 µm]; Interventional Therapeutics, Fremont, Calif) suspended in 20 mL of radiologic contrast material (iopromide in water solution) into the segmental or subsegmental arteries feeding the residual tumor at the lesion periphery. The anticancer-in-oil emulsion was injected until the iodized oil had accumulated thickly in the residual vital tumor at the periphery of the lesion and in the tumor-bearing areas or until nearly complete stasis of blood flow was achieved. The embolic particles were injected until the feeding arteries appeared completely embolized. We injected a freshly prepared suspension of 10 mL of iodized oil, 20 mg of doxorubicin hydrochloride dissolved in 5 mL of distilled water (4 mg/mL), and radiologic contrast material (iopromide in water solution) in a final volume of 30 mL. As a rule, patients received an analgesic (30 mg of ketorolac tromethamine, Toradol; Recordati, Milan, Italy) and a sedative (10–20 mg of diazepam, Valium; Roche, Milan, Italy) intravenously to alleviate pain during embolization. After the procedure, vigorous hydration (normal saline solution, 3 L/24 h) was begun, and antibiotic (1 g of cephazolin, Cefamezin; Pharmacia & Upjohn) and antiemetic (50 mg of alizaride hydrochloride, Limican; Synthelabo, Limito, Milan, Italy) therapy was administered intravenously. The procedure was performed by one of two radiologists (C.M.P. or G.B.).

Study Design and Assessment of Treatment Effectiveness
To reduce the number of hepatic segments to be treated with TACE, we planned to treat the small HCCs with LTA alone. Hence, in patients with plurinodular lesions, we scheduled one or more LTA sessions to destroy all synchronous lesions at a time different from that scheduled for the combined treatment of large HCCs. Thus, we used different treatment options for lesions of different sizes to investigate the effect on short- and long-term results of both treatments. Large lesions all received combined treatment because our intention was to debulk the tumor substantially and reduce the volume of viable tissue to be treated with TACE rather than to achieve 100% necrosis with LTA alone. In such lesions, CT was planned for 24–48 hours after the last scheduled LTA treatment to assess the extent of necrosis.

In accordance with tumor size, all large nodules were further subdivided into four subsets of 3.1–4.0, 4.1–5.0, 5.1–6.0, and greater than 6.0 cm in diameter. The size of the area of supposed necrosis was calculated as a percentage of the total tumor size by dividing the estimated volume of tumor necrosis on scans obtained after LTA by the estimated total tumor volume on scans obtained before LTA, with the volumes defined as the three largest perpendicular diameters of the lesion at CT multiplied by 0.525. Results were classified into two groups at initial imaging after LTA: more than 50% of tumor avascularized (>50% necrosis of tumor volume), and 50% or less of tumor avascularized (<50% necrosis of tumor volume).

Contrast material–enhanced CT was performed to determine the actual extent of ablation and plan further intervention. At CT, areas of hypoattenuation that did not enhance after contrast material administration were considered to represent necrotic tissue. In small HCCs treated only with LTA, complete tumor necrosis was diagnosed when the lesion was replaced with homogeneous, hypoattenuating, nonenhancing areas, which indicated avascularity (19). Still-enhancing areas were assumed to indicate residual viable tumor. If a CT scan obtained at 1 month showed persistent residual tumor, a further course of LTA was performed. If there was no evidence of viable HCC (necrosis equal to or larger than the neoplasm) at helical CT 24–48 hours after the last additional LTA treatment, the treatment was considered successful and was discontinued. In large HCCs, the therapeutic response of the tumor was assessed at CT 15–20 days after TACE. Complete necrosis was diagnosed when the tumors had only areas of high-grade iodized oil retention and of hypoattenuation without contrast material enhancement. When images showed persistent residual tumor after combined treatment, TACE was performed in additional sessions. Tumor necrosis was considered complete when no areas of enhancement were seen in the tumor or at its periphery on CT scans obtained 1 month after the last additional TACE session. The response to treatment thus determined was defined in accordance with World Health Organization criteria (29) as complete response, no evidence of neoplastic disease; partial response, total tumor load reduction greater than 50%; no change, reduction less than 50% or increase less than 25%; and progressive disease, increase of greater than 25%.

Change in tumor size was also studied with follow-up CT at 6–41 months, at 3- to 6-month intervals. During follow-up, therapeutic effectiveness was also assessed with AFP assay 3 months after the end of treatment and every 6 months thereafter. Local recurrence was defined as any sign of tumor progression in the treated area, such as development of tumor staining at the margin of the treated tumor or visibly enhancing foci within or near the treated area. When CT findings were marginal, diagnosis of local recurrence was deferred until the next follow-up CT examination. CT scans were interpreted by means of consensus of two radiologists (C.M.P., G.B.) experienced in abdominal imaging.

Statistical Analysis
The baseline characteristics and follow-up results of the patients are presented as means plus or minus SDs, ranges, and ratios. Rates of cumulative survival, local recurrence, and cancer-free survival were calculated from the time of initial treatment of the original HCC by using the Kaplan-Meier method (30). Comparison was made by performing the log-rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
A total of 45 tumors were treated. The large HCCs treated with combined therapy received LTA in 269 treatments (range, 2–32 treatments; median, 7; mean, 9) during 127 sessions (range, 1–14 sessions per patient; median, 4; mean, 4.2). The total energy used at each session was 3,600–28,400 J (median, 10,000 J). The mean volume of necrosis obtained was 42 mL (range, 4–226 mL). In all cases, it was technically possible to insert the laser fiber into the chosen site of the tumor with US guidance. TACE was technically possible in all 30 patients. Thirty-nine TACE sessions occurred, since nine of these 30 patients (six tumors were 6.1–9.6 cm in diameter; three, 4.0–4.5 cm) underwent a second TACE session owing to the persistence of residual tumor, which indicated a need for further treatment. The mean amount of emulsion used was 20.8 mL (range, 10.0–30.0 mL) per session and 28.5 mL (range, 10.0–60.0 mL) per tumor.

In the synchronous small HCCs, treated exclusively with LTA, 40 tumor treatments (range, 1–6 treatments; median, 2; mean, 2.6) were performed during 23 sessions (range, 1–4 sessions per patient; median, 1; mean, 1.5). The total energy used at each session was 1,800–21,600 J (median, 9,000 J). The mean volume of necrosis obtained was 10 mL (range, 2–29 mL).

Imaging
During laser application, changes similar to those seen during experiments in animal models were seen at US in all tumors treated (31). At the end of treatment, the whole tumor or the whole treated area was occupied by an irregular and poorly defined echogenic zone. These changes precluded accurate assessment of the actual extent of the thermal lesion after LTA. Because of this inhomogeneous echogenicity, US findings during the follow-up period did not assist in distinguishing between coagulative necrosis and viable tissue (Figs 1, 2).

View larger version (137K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. US images obtained before and at the beginning and end of laser thermal ablation of a large HCC. (a) Transverse US image obtained before laser irradiation shows a large hypoechoic lesion (arrows) in segment 7 of the liver. (b) Transverse US image obtained at the beginning of laser irradiation shows the fiber and the needle tips (arrowheads) within the lesion. (c) Transverse US image obtained at the end of laser irradiation shows the entire tumor (arrows) as occupied by an irregular and poorly defined echogenic area. (d) Transverse US image obtained after 12 months of laser irradiation shows a marked size reduction of the lesion (arrows) with a heterogeneous pattern.

View larger version (136K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. US images obtained before and at the beginning and end of laser thermal ablation of a large HCC. (a) Transverse US image obtained before laser irradiation shows a large hypoechoic lesion (arrows) in segment 7 of the liver. (b) Transverse US image obtained at the beginning of laser irradiation shows the fiber and the needle tips (arrowheads) within the lesion. (c) Transverse US image obtained at the end of laser irradiation shows the entire tumor (arrows) as occupied by an irregular and poorly defined echogenic area. (d) Transverse US image obtained after 12 months of laser irradiation shows a marked size reduction of the lesion (arrows) with a heterogeneous pattern.

View larger version (145K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. US images obtained before and at the beginning and end of laser thermal ablation of a large HCC. (a) Transverse US image obtained before laser irradiation shows a large hypoechoic lesion (arrows) in segment 7 of the liver. (b) Transverse US image obtained at the beginning of laser irradiation shows the fiber and the needle tips (arrowheads) within the lesion. (c) Transverse US image obtained at the end of laser irradiation shows the entire tumor (arrows) as occupied by an irregular and poorly defined echogenic area. (d) Transverse US image obtained after 12 months of laser irradiation shows a marked size reduction of the lesion (arrows) with a heterogeneous pattern.

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 1d. US images obtained before and at the beginning and end of laser thermal ablation of a large HCC. (a) Transverse US image obtained before laser irradiation shows a large hypoechoic lesion (arrows) in segment 7 of the liver. (b) Transverse US image obtained at the beginning of laser irradiation shows the fiber and the needle tips (arrowheads) within the lesion. (c) Transverse US image obtained at the end of laser irradiation shows the entire tumor (arrows) as occupied by an irregular and poorly defined echogenic area. (d) Transverse US image obtained after 12 months of laser irradiation shows a marked size reduction of the lesion (arrows) with a heterogeneous pattern.

View larger version (163K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. US images obtained before and after laser thermal ablation in a large lesion. (a) Transverse US image obtained before treatment shows a large hyperechoic lesion (arrows) with a hypoechoic rim in segment 8 of the liver. (b) Transverse US image obtained during follow-up shows the heterogeneous pattern of the lesion (arrows). US cannot be used to distinguish between coagulative necrosis and viable tumor tissue.

View larger version (192K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. US images obtained before and after laser thermal ablation in a large lesion. (a) Transverse US image obtained before treatment shows a large hyperechoic lesion (arrows) with a hypoechoic rim in segment 8 of the liver. (b) Transverse US image obtained during follow-up shows the heterogeneous pattern of the lesion (arrows). US cannot be used to distinguish between coagulative necrosis and viable tumor tissue.

View larger version (201K): [in this window] [in a new window] [Download PPT slide]   Figure 3a. CT scans obtained after laser thermal ablation in the same lesion as in (a) Transverse precontrast CT scan shows that the entire treated tumor is replaced by an irregular and poorly defined area of hyperattenuation (arrowheads), which is surrounded by an irregular band of hypoattenuation (arrows). (b) Transverse CT scan obtained during the early arterial-dominant phase shows a central well-defined nonenhancing area that is consistent with necrosis and encircled by a thin enhancing peripheral halo (arrows), which may represent an inflammatory response. Residual viable tissue (arrowhead) is seen at the periphery of the treated area in the posteromedial aspect of the lesion.

View larger version (193K): [in this window] [in a new window] [Download PPT slide]   Figure 3b. CT scans obtained after laser thermal ablation in the same lesion as in (a) Transverse precontrast CT scan shows that the entire treated tumor is replaced by an irregular and poorly defined area of hyperattenuation (arrowheads), which is surrounded by an irregular band of hypoattenuation (arrows). (b) Transverse CT scan obtained during the early arterial-dominant phase shows a central well-defined nonenhancing area that is consistent with necrosis and encircled by a thin enhancing peripheral halo (arrows), which may represent an inflammatory response. Residual viable tissue (arrowhead) is seen at the periphery of the treated area in the posteromedial aspect of the lesion.

View larger version (184K): [in this window] [in a new window] [Download PPT slide]   Figure 4a. CT scans show complete response in a large encapsulated HCC. (a) Transverse contrast-enhanced CT scan obtained before treatment during the arterial-dominant phase shows a solitary large HCC (arrows) in segment 7 of the liver. (b) Transverse CT scan obtained during the arterial-dominant phase after LTA treatment shows a band of peripheral enhancing tissue (arrows), which indicates residual viable tumor and is clearly differentiable from a central homogeneous hypoattenuating area—an indication of avascularity and necrosis. (c) Transverse CT scan obtained during the arterial-dominant phase after TACE shows compact retention of iodized oil in the residual tumoral tissue (arrows). (d) Transverse CT scan obtained during the arterial-dominant phase 36 months after treatment demonstrates a lack of enhancement, with reduction of the necrotic area and clear shrinkage of the lesion (arrows).

View larger version (185K): [in this window] [in a new window] [Download PPT slide]   Figure 4b. CT scans show complete response in a large encapsulated HCC. (a) Transverse contrast-enhanced CT scan obtained before treatment during the arterial-dominant phase shows a solitary large HCC (arrows) in segment 7 of the liver. (b) Transverse CT scan obtained during the arterial-dominant phase after LTA treatment shows a band of peripheral enhancing tissue (arrows), which indicates residual viable tumor and is clearly differentiable from a central homogeneous hypoattenuating area—an indication of avascularity and necrosis. (c) Transverse CT scan obtained during the arterial-dominant phase after TACE shows compact retention of iodized oil in the residual tumoral tissue (arrows). (d) Transverse CT scan obtained during the arterial-dominant phase 36 months after treatment demonstrates a lack of enhancement, with reduction of the necrotic area and clear shrinkage of the lesion (arrows).

View larger version (183K): [in this window] [in a new window] [Download PPT slide]   Figure 4c. CT scans show complete response in a large encapsulated HCC. (a) Transverse contrast-enhanced CT scan obtained before treatment during the arterial-dominant phase shows a solitary large HCC (arrows) in segment 7 of the liver. (b) Transverse CT scan obtained during the arterial-dominant phase after LTA treatment shows a band of peripheral enhancing tissue (arrows), which indicates residual viable tumor and is clearly differentiable from a central homogeneous hypoattenuating area—an indication of avascularity and necrosis. (c) Transverse CT scan obtained during the arterial-dominant phase after TACE shows compact retention of iodized oil in the residual tumoral tissue (arrows). (d) Transverse CT scan obtained during the arterial-dominant phase 36 months after treatment demonstrates a lack of enhancement, with reduction of the necrotic area and clear shrinkage of the lesion (arrows).

View larger version (189K): [in this window] [in a new window] [Download PPT slide]   Figure 4d. CT scans show complete response in a large encapsulated HCC. (a) Transverse contrast-enhanced CT scan obtained before treatment during the arterial-dominant phase shows a solitary large HCC (arrows) in segment 7 of the liver. (b) Transverse CT scan obtained during the arterial-dominant phase after LTA treatment shows a band of peripheral enhancing tissue (arrows), which indicates residual viable tumor and is clearly differentiable from a central homogeneous hypoattenuating area—an indication of avascularity and necrosis. (c) Transverse CT scan obtained during the arterial-dominant phase after TACE shows compact retention of iodized oil in the residual tumoral tissue (arrows). (d) Transverse CT scan obtained during the arterial-dominant phase 36 months after treatment demonstrates a lack of enhancement, with reduction of the necrotic area and clear shrinkage of the lesion (arrows).

View larger version (173K): [in this window] [in a new window] [Download PPT slide]   Figure 5a. CT scans show total necrosis of large and small HCCs. (a) Transverse CT scan obtained during the arterial-dominant phase shows a large HCC (arrows) and an additional coincidental small HCC (arrowhead) in segments 7 and 4 of the liver, respectively. (b) Transverse CT scan obtained during the arterial-dominant phase after LTA shows a central hypoattenuating area of LTA-induced necrosis surrounded by an enhancing peripheral rim of viable tumor (arrows) and an additional coincidental small HCC (arrowhead) before LTA treatment. (c) Transverse contrast-enhanced CT scan obtained 3 months after a second TACE session shows a marked volume reduction in the large lesion (arrows), which indicates complete necrosis. A homogeneous, hypoattenuating, nonenhancing area (arrowhead) indicates complete response of the small HCC after previous LTA.

View larger version (180K): [in this window] [in a new window] [Download PPT slide]   Figure 5b. CT scans show total necrosis of large and small HCCs. (a) Transverse CT scan obtained during the arterial-dominant phase shows a large HCC (arrows) and an additional coincidental small HCC (arrowhead) in segments 7 and 4 of the liver, respectively. (b) Transverse CT scan obtained during the arterial-dominant phase after LTA shows a central hypoattenuating area of LTA-induced necrosis surrounded by an enhancing peripheral rim of viable tumor (arrows) and an additional coincidental small HCC (arrowhead) before LTA treatment. (c) Transverse contrast-enhanced CT scan obtained 3 months after a second TACE session shows a marked volume reduction in the large lesion (arrows), which indicates complete necrosis. A homogeneous, hypoattenuating, nonenhancing area (arrowhead) indicates complete response of the small HCC after previous LTA.

View larger version (182K): [in this window] [in a new window] [Download PPT slide]   Figure 5c. CT scans show total necrosis of large and small HCCs. (a) Transverse CT scan obtained during the arterial-dominant phase shows a large HCC (arrows) and an additional coincidental small HCC (arrowhead) in segments 7 and 4 of the liver, respectively. (b) Transverse CT scan obtained during the arterial-dominant phase after LTA shows a central hypoattenuating area of LTA-induced necrosis surrounded by an enhancing peripheral rim of viable tumor (arrows) and an additional coincidental small HCC (arrowhead) before LTA treatment. (c) Transverse contrast-enhanced CT scan obtained 3 months after a second TACE session shows a marked volume reduction in the large lesion (arrows), which indicates complete necrosis. A homogeneous, hypoattenuating, nonenhancing area (arrowhead) indicates complete response of the small HCC after previous LTA.

Survival Rates
The 1-, 2-, and 3-year local recurrence rate for main tumors was 7% (two of 27) (Fig 6). The two tumors that recurred locally were 4.0 cm and 6.4 cm. The 12-, 24-, and 36-month recurrence rates in segments of the liver other than that of the primary lesion were 19%, 66%, and 83%, respectively. These recurrences were treated with additional courses of LTA (three lesions) or, in cases of multiple new lesions, additional courses of TACE (five lesions); the remaining patients (n = 3) did not undergo further treatment because they had developed severe liver decompensation (Child-Pugh class C cirrhosis; n = 2) or tumor progression in other segments of the liver (n = 1). The 12- and 24-month cancer-free survival rates were 74% and 34% (Fig 7), respectively. During the follow-up period, six (21%) patients died; the causes of death were hepatic failure (50%), variceal bleeding (17%), and HCC (33%).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 6. Graph shows actuarial local recurrence rate, calculated with the Kaplan-Meier method, for patients treated with combined LTA and TACE. All recurrences were observed within the 1st year after LTA.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 7. Graph shows the actuarial cancer-free survival rate, calculated with the Kaplan-Meier method, in patients treated with combined LTA and TACE. The new lesions are part of the natural history of HCC in patients with cirrhosis. New HCCs far from the original tumor were frequent and due to multiple metachronous or unnoticed small synchronous lesions that were undetected at imaging.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 8. Graph shows actuarial cumulative survival curves, calculated with the Kaplan-Meier method, for patients treated with combined LTA and TACE. The 3-year survival rate was 40%.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 9. Graph shows actuarial survival curves, calculated with the Kaplan-Meier method, in accordance with the degree of liver dysfunction on the basis of Child-Pugh classification. Patients with Child-Pugh class A (n = 20, ) exhibit substantially higher survival rates (P < .001, log-rank test) than do patients with Child-Pugh class B (n = 10, ). The hepatic functional reserve influences survival rate.

Liver function tests showed a marked increase in serum (transaminase) levels in all patients. At 12–24 hours after LTA, the increase was two to eight times the pretreatment levels but always returned to normal by 3–20 days thereafter. In 10 (91%) of 11 patients in whom the lesion was in segment 8, pleural effusion was seen on CT scans; however, no respiratory symptoms were present, hospital admission was not necessary, and the effusions resolved in a few days. A transient and mild body temperature increase due to the necrotic liver tissue was reported in 28 (93%) of the 30 patients 12–24 hours after LTA. In one patient with Child-Pugh class B, we observed transient decompensation of liver function, which was indicated by ascites and a total serum bilirubin level twice the baseline value. This complication occurred during the first 12 hours after the procedure; did not require treatment or hospital admission; and was resolved, with a decrease to normal baseline value, within 10 days.

TACE was well tolerated. Eighteen (60%) of the 30 patients developed a self-limited postembolization syndrome of fever, abdominal pain, and nausea. All patients who underwent TACE were discharged within 24 hours after the procedure.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Some investigators (2,32) have performed percutaneous ethanol injection for larger nodules up to 10 cm, although ethanol may not diffuse evenly through the tumors and may leave some areas unaffected. The one-shot technique performed in a single session with the patient having received general anesthesia (32) is an aggressive procedure and, in our opinion, should be approached with caution for ablating tumor tissue in patients with cirrhosis and poor hepatic reserve.

TACE seems most effective against encapsulated small HCCs without extracapsular invasion (9,10), whereas in large HCCs, viable residual tumor cells remain (6,8), and the tumor frequently recurs (6,33). Moreover, in patients with large lesions, multiple TACE sessions are necessary to control tumor growth but increase the risk of worsening hepatic function through damage to noncancerous liver parenchyma (16,34).

Survival after chemoembolization is difficult to assess because of the multiplicity of techniques used in available studies (35), the heterogeneity of the disease, and the fact that most of the published studies are retrospective (6,35). Investigators in recent controlled trials in which chemoembolization with adriamycin or cisplatin was compared with no treatment (11,36) and transarterial embolization was compared with treatment of symptoms (14) failed to disclose a substantial benefit in survival rates. TACE with iodized oil reduced tumor growth but often caused acute liver failure and did not substantially improve the short-term survival of patients with nonsurgical HCC (11,36). Reduction of tumor mass was not paralleled by an improvement in survival or at least by a reduction or delay in the appearance of cancer-related complications. It could be argued that the antitumoral effect of arterial obstruction and the potential advantages of tumor mass reduction by using ischemia may be counteracted by deleterious side effects from the obstruction itself (14).

In the present study, we enrolled 30 consecutive patients with large unresectable lesions who were referred to our hospital during a 4-year period. These patients had advanced tumoral growth not associated with invasive tumoral patterns but did not have advanced liver disease. This pattern gave us the time and scope to see results and evaluate the effect of our treatment on tumor progression and survival that end-stage phases would not have allowed (35). The rationale for combining two techniques is based on the fact that LTA reduces the volume of viable tissue and brings the lesion back within the range of TACE effectiveness (8–10,37). Moreover, in the case of multiple lesions in the same patient, it was possible to treat the small lesions with LTA alone and thus reduce the number of hepatic segments requiring TACE. In 21 (70%) of the 30 patients, we achieved complete response with a single segmental TACE session. The possibility that this kind of treatment reduces the detrimental consequences and deleterious side effects of embolization deserves further study (14).

Furthermore, since US cannot be used to clearly distinguish residual viable tissue from necrotic tumor after TACE, we chose to perform LTA before TACE. In addition, in a normal pig liver, portal inflow occlusion suffices to overcome the cooling effect of the blood flow, and additional clamping of the hepatic artery does not enhance the volume of coagulation (38). With extrapolation of these findings to humans with HCCs in cirrhotic liver, portal inflow occlusion may not be needed, since the portal flow is often negligible or even retrograde (39). In this situation, the magnitude of the arterial flow should be considered a potential cooling source, although one might argue that the additional occlusion of segmental hepatic feeding arteries could impair noncancerous liver tissue (34) without increasing the volume of necrosis (38). Ultimately, the poorly organized vascular bed in the tumor would probably cause only minimal tissue cooling and thus minimal lesion reduction (40).

Survival analysis is limited by the small number of patients and the relatively short follow-up time. Longer follow-up of our patients will result in more valid data. Our results are roughly comparable with those of other combined treatments (15,16). Comparison with other options is limited by various biases, such as the different clinical characteristics of the patient population, different recruitment methods, different inclusion criteria, and different follow-up methods (11–13,36). Most studies refer to patients in whom the disease was diagnosed and who underwent staging and treatment a few years ago, when regular screening was uncommon, imaging techniques were less accurate, and the medical treatment of patients with liver function impairment was less effective (11–13,15,16,36). This must also be considered when we compare results of our treatment with those of other combined treatments. Comparison with patients with untreated HCC is difficult. In a recent study, Llovet et al (35) reported the survival of 102 patients with untreated HCC at an intermediate stage. Their survival rates were 54%, 40%, and 28% at 1, 2, and 3 years, respectively.

The results of the present study demonstrate the possibility of using LTA to treat HCCs in patients with cirrhosis. In our view, our results demonstrate that this technique is flexible and safe. LTA enabled us to decrease the volume of viable tissue to be treated with TACE. The use of thin needles makes it possible to reach all lesions easily and safely, which is not the case with other heating techniques (41,42). This approach may help us explain the absence of major complications in our series. An important advantage of combined LTA and TACE is the low number of sessions required to achieve complete necrosis in larger lesions. The mean number of sessions needed to control large HCCs was 4.2.

Other authors (15,16) performing percutaneous ethanol injection after TACE reported six to 16 cycles of sessions in a series of patients with a single large encapsulated lesion (15) and no more than two daughter nodules (16). In small lesions, we achieved complete necrosis with a mean of 1.5 sessions per tumor with LTA alone. In a large series in which percutaneous ethanol injection was performed (3,41), three to four sessions were required to achieve complete necrosis of lesions smaller than 2.0 cm, and six to eight sessions were required to eradicate HCCs 2.0–3.5 cm, with a mean of 4.8 sessions per tumor for small HCCs 3.0 cm or less. This substantial reduction in the number of sessions is an advantage not only for patients but also for hospital staff members. Moreover, tumor seeding has been reported with radio-frequency electrocoagulative ablation and microwave coagulation (42) and is not unusual after percutaneous ethanol injection (43). Finally, it should be pointed out that LTA is cheaper than the other hyperthermic methods. A set of fibers costs approximately $1,000–$1,500 but can be used to treat up to 50 patients (44).

The success rate of LTA in coagulating entire tumors depends on four factors: (a) optimal placement of the optic fibers at the target area; (b) the volume of coagulation being larger than the tumor volume or as large as possible in the case of large lesions; (c) real-time monitoring of the effects of treatment, with careful assessment of thermal damage to tumor tissue; and (d) avoidance of damage to adjacent normal structures such as hepatic veins and hilar structures.

Further research is needed to obtain a greater volume of coagulated tissue in a single session and reliably monitor laser-induced effects during LTA. Experimental data regarding simultaneous multiple fiber application with a heat-resistant cylindric light-diffusing tip (18), the optimal combination of laser power and distance between the fibers (38), and magnetic resonance imaging techniques suitable for measuring temperature during the procedure (20) seem to justify further clinical investigation to establish the role of LTA in the percutaneous treatment of large HCCs. Further experimental and clinical data are needed for a thorough understanding of the relationship between portal hypertension and the extent of necrosis (39) and between histopathologic structure, histologic subtype, and LTA. Thus, both the histologic grade of all lesions to be treated and the presence of portal hypertension, ascertained by measuring portal pressure and performing triple-phase helical CT (27) should be clear beforehand. Ultimately, further prospective and, if possible, randomized studies are required to determine whether these treatments, alone or in combination, produce a substantial improvement in survival rates in patients with HCC diagnosed at an intermediate evolutionary stage.

	FOOTNOTES

 
Abbreviations: AFP = -fetoprotein, HCC = hepatocellular carcinoma, LTA = laser thermal ablation, TACE = transcatheter arterial chemoembolization

Author contributions: Guarantor of integrity of entire study, C.M.P.; study concepts, C.M.P., G.B., Z.R.; study design, C.M.P., G.B., P.C.; literature research, S.P.; clinical studies, Z.R.; data acquisition, A.B., S.P.; data analysis/interpretation, G.B., P.C, B.C., F.M., A.B.; statistical analysis, G.B., A.B.; manuscript preparation, C.M.P., A.B., V.A., S.P., Z.R.; manuscript definition of intellectual content, C.M.P., G.B., P.C., B.C., F.M.; manuscript editing, A.B., S.P.; manuscript revision/review, C.M.P., P.C., B.C., V.A., Z.R.; manuscript final version approval, all authors.

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