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Published online before print February 24, 2005, 10.1148/radiol.2351031944
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(Radiology 2005;235:299-307.)
© RSNA, 2005

Vascular and Interventional Radiology

Prognostic Factors for Survival in Patients with Hepatocellular Carcinoma after Percutaneous Microwave Ablation1

Ping Liang, MD, Baowei Dong, MD, Xiaoling Yu, MD, Dejiang Yu, MD, Yang Wang, MD, Lei Feng, MD and Qiujin Xiao, MD

1 From the Department of Ultrasound, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China. From the 2003 RSNA Annual Meeting. Received November 29, 2003; revision requested February 10, 2004; final revision received May 9; accepted June 15. Supported by a grant from the National Scientific Foundation Committee of China (30271252). Address correspondence to P.L. (e-mail: liangping301@hotmail.com).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine the long-term survival and prognostic factors in patients with hepatocellular carcinoma treated with percutaneous microwave ablation.

MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. A database of cases of hepatocellular carcinoma in 288 patients (259 men, 29 women; mean age, 54.8 years ± 11.4 [standard deviation]; age range, 25–82 years) with 477 histologically proved lesions who underwent percutaneous microwave coagulation therapy between May 1994 and October 2002 was retrospectively analyzed. Prognostic factors for survival were evaluated by means of univariate and multivariate analyses.

RESULTS: The mean follow-up period after microwave ablation was 31.41 months ± 20.43 (range, 5–106 months). The 1-, 2-, 3-, 4-, and 5-year cumulative survival rates among all 288 patients were 93%, 82%, 72%, 63%, and 51%, respectively. Ninety-three patients (32%) died. Local recurrence or new tumors occurred in 100 patients (35%). Age (P = .836), sex (P = .073), preablation serum {alpha}-fetoprotein level (P = .136), and preablation treatment (P = .256) were not related to prognosis, while tumor number (P = .004), tumor size (P < .001), Child-Pugh classification (P = .003), tumor differentiation (P = .026), and local recurrence or presence of new tumors (P = .004) significantly affected survival at univariate analysis. At multivariate analysis, only tumor size (P < .001), number of nodules (P = .005), and Child-Pugh classification (P = .01) each had a significant effect on survival.

CONCLUSION: With use of microwave ablation, there is a high probability of long-term survival of patients with a single lesion of 4.0 cm or less in maximum diameter and Child-Pugh class A cirrhosis.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors around the world (1). Progress in modern imaging techniques such as ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging has facilitated the early detection and diagnosis of HCC (2). Hepatic resection is still the first choice for treatment of HCC. However, surgical resection is not applicable in most patients with HCC because of conditions such as associated severe liver cirrhosis, multiple lesions located in different hepatic segments, or lesions located near a large hepatic vein or the junction of a large portal vein. Therefore, minimally invasive yet effective therapeutic options are essential to improving the prognosis in HCC patients (3).

Imaging-guided local thermal ablation with use of different energy sources (such as radiofrequency, microwave, or laser ablation) has gained favor within the past decade as a minimally invasive management technique for the treatment of HCC (4–20). Microwave ablation has been used in China as an effective conservative approach to HCC in cirrhosisbecause of the minimal damage to liver function, relative lack of complications, and low mortality, as well as the promising clinical results (5,15,19). Previous studies of microwave ablation were mainly focused on assessments of feasibility, safety, and therapeutic effectiveness (4,5,14,15,19). Furthermore, most of those published series results were from studies involving patients with small HCC (≤3.0 cm in diameter) or studies with a limited number of cases.

To our knowledge, no reports on prognostic factors influencing long-term survival rates with microwave ablation of HCC in a large series of patients have been published to date. Moreover, many variables related to the characteristic of the tumor and the coexisting cirrhosis may greatly influence survival in patients with HCC after microwave ablation. Thus, the purpose of our study was to determine the long-term survival and prognostic factors in patients with HCC treated with percutaneous microwave ablation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients
From May 1994 to October 2002, a total of 2245 patients with HCC were admitted and underwent treatment by means of different methods at our institution. Four hundred eighty-six patients (21.6%) underwent surgical resection, 51 patients (2.3%) underwent liver transplantation, 1320 patients (58.8%) underwent transcatheter arterial chemoembolization (TACE), 88 patients (3.9%) underwent radiofrequency or laser ablation, and 300 patients (13.4%) underwent microwave ablation.

Among the 300 patients who underwent microwave ablation, 12 were lost to follow-up and were excluded from this study. Thus, 288 patients with 477 nodules of HCC were included in our study and were closely followed up until March 2003. There were 259 men (mean age, 54.4 years ± 11.4 [± standard deviation]; age range, 25–82 years) and 29 women (mean age, 58.6 years ± 11.5; age range, 27–74 years). The mean age among all 288 patients was 54.8 years ± 11.4. No significant statistical difference in age was found between the men and women (unpaired t test: t = –1.88, P > .05). One hundred eighty patients had a single nodule, and 108 patients had multiple nodules. The maximum diameter of the nodules in each patient ranged from 1.2 to 8.0 cm (mean maximum diameter, 3.75 cm ± 1.58). The distribution of tumor sizes and numbers are shown in Table 1. The 234 patients who were the subjects in our previous study (15) were also included in this study. Institutional review board approval and patient informed consent were obtained.


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  		TABLE 1. Distribution of Tumors Categorized according to Size

 
Histologic and Laboratory Data
Histologic diagnosis of HCC and cirrhosis was obtained by means of US-guided biopsy in all patients. In patients with a single nodule, only one biopsy was performed. In patients with multiple nodules, at least one biopsy was performed. If new tumors emerged after ablation, biopsies of the new nodules were performed. Specimens obtained at biopsy were assessed blindly and independently by two pathologists. In case of interobserver disagreement, the final decisions were reached in consensus. The histologic grades of the tumors were defined as follows: well-differentiated tumor corresponding to Edmondson grade I or I–II, moderately differentiated tumor corresponding to Edmondson grade II or II–III, and poorly differentiated tumor corresponding to Edmondson grade III or III–IV. Histologic grades were assigned in all patients. Tumors were graded as well differentiated in 30% of patients (87 of 288), as moderately differentiated in 47% of patients (135 of 288), and as poorly differentiated in 23% of patients (66 of 288).

Among the entire group of 288 patients, 259 (90%) had cirrhosis, which was proved at biopsy performed with US guidance, whereas 29 (10%) had no cirrhosis. Almost all cases of cirrhosis were caused by chronic infection with the hepatitis virus (hepatitis B, 253 cases; hepatitis C, five cases). Only one case of cirrhosis had an unknown cause. The preablation Child-Pugh classification was assessed by the two pathologists in consensus: 54 of 288 patients (19%) had class A disease, 214 (74%) had class B disease, and 20 (7%) had class C disease.

Serum {alpha}-fetoprotein (AFP) assay was performed in all patients. The AFP level was normal (≤20 µg/L) in 124 patients and abnormal (>20 µg/L) in the remaining 164 patients (range, 25–4300 µg/L).

Preablation Imaging Work-up
Before treatment, all patients were examined by means of an imaging protocol of US alone or a combination of US and biphasic contrast material–enhanced CT or contrast-enhanced MR imaging to locate the target lesion and plan the interventional procedure. All patients were examined with a US system (128 XP/10 ART or Sequoia, Acuson, Mountain View, Calif; or HDI 5000, ATL, Bothell, Wash) with 3.5–5.0-MHz curved-array multifrequency transducers before treatment.

Contrast-enhanced CT was performed in 212 cases. Patients were examined with either spiral or multi–detector row CT. Spiral CT (Tomoscan SR 7000; Philips Medical Systems, Best, the Netherlands) was performed with a section thickness of 5 mm, a 1:1 pitch, 120 kV, and 250 mA. Multi–detector row CT (Lightspeed 16; GE Medical Systems, Milwaukee, Wis) was performed with a section thickness of 5 mm, a 1.35:1.0 pitch, 120 kV, and 250 mA. Biphasic contrast-enhanced scans were obtained as follows: 100 mL of a nonionic contrast agent (iopromide, Ultravist 300; Schering, Berlin, Germany) was administered by means of a power injector at a rate of 3–4 mL/sec.

Contrast-enhanced MR imaging was performed in 54 patients by using a 1.5-T unit (Signa Echo-Speed, GE Medical Systems). The following sequences were used: a spin-echo T1-weighted sequence with 500/15 (repetition time msec/echo time msec), a matrix of 256 x 192, and two signals acquired; a fat-suppressed T2-weighted respiratory-triggered fast spin-echo sequence with 3000–4000/102, a matrix of 256 x 256, and three signals acquired; and a fat-suppressed spin-echo T1-weighted sequence with 500/15, a matrix of 256 x 192, and two signals acquired. If the lesion showed high signal intensity on a conventional T1-weighted image, a subsequent bolus injection of gadopentetate dimeglumine (Magnevist; Schering) was administered at a standard dose (0.1 mmol per kilogram of body weight), and fast multiplanar spoiled gradient-recalled-echo sequences with fat saturation (125/4.2; flip angle, 90°; matrix, 256 x 192; breath hold, 16–25 seconds) were performed dynamically.

Criteria for Treatment
Taking all patient characteristics into account, surgeons with at least 15 years of experience in hepatic resection decided what kind of treatment the patients should undergo (surgical resection, microwave ablation, or TACE). For a patient to be assigned to undergo microwave ablation, the following criteria needed to be met: single nodular HCC lesions of 8 cm or smaller; five or fewer multiple nodular HCC lesions with a maximum dimensionof 6 cm or less in each nodule; absence of portal vein thrombosis or extrahepatic metastases; prothrombin time of less than 25 seconds, prothrombin activity higher than 40%, and platelet count higher than 40 cells x 109/L; HCC nodule at least 5 mm away from the main biliary duct of the hepatic hilum and the bowel; and presence of an appropriate route for percutaneous puncture under US guidance. The number of tumor nodules and the absence of portal vein thrombosis were evaluated on the basis of US findings, as well as CT or MR imaging findings when available. Maximum diameter of nodules was measured at US. The absence of extrahepatic metastases was determined by means of a thorough clinical assessment, chest radiography, abdominal US, and abdominal CT.

Of the 288 patients, 235 (82%) had been excluded from undergoing surgery for the following reasons: liver dysfunction (impaired blood coagulation, low serum albumin level, ascites) in 108 patients; advanced age with chronic kidney or heart disease in 25 patients; multiple lesions located in different hepatic segments in 59 patients; new HCC after curative resection of the initial lesions in 33 patients; unsuccessful TACE because of enlargement or lack of shrinkage of the target lesions, poor lipiodol retention, and/or residual viable tumor tissue suggested at contrast-enhanced CT or MR imaging in 33 patients; and/or new tumors with unsatisfactory TACE after curative resection in 12 patients. Some patients had more than one reason for exclusion from surgery. Resectability was judged by surgeons experienced in hepatic tumor resection. A common consensus was reached when making the decision.

Microwave Ablation Procedure
All treatments were performed at our institution. Tumors were treated by means of microwave ablation with a microwave applicator (PLA General Hospital and Institute 207 of the Aerospace Industry Company, Beijing, China) with a frequency of 2450 MHz delivering a maximum power of 80 W through 16-gauge needle antennas. With US guidance, a single antenna or multiple antennas were used, depending on the tumor size (15). Percutaneous placement of the antenna was applied by any one of the three experienced radiologists (B.D., P.L., X.Y.) for all tumors. A detailed protocol was worked out for each patient on an individual basis before treatment and included the placement of the antennas, power output setting, emission time, and appropriate approach (15). In general, for tumors less than 1.7 cm in diameter, a single antenna was used; for tumors 1.7 cm or larger, multiple antennas were required. An output setting of 60 W for 300 seconds was routinely used during ablations. A thermal monitoring system was used during treatment. With US guidance, one to three thermal couples were placed at different sites 0.5 cm outside the tumor to monitor temperature throughout the procedure. If the measured temperature at 0.5 cm outside the tumor did not reach 60°C by the end of 300 seconds and did not remain at 54°C for at least 3 minutes, a prolonged emission time was required depending on the temperature, monitored dynamically. General anesthesia was achieved by using a combination of two anesthetics, propofol (Diprivan; Zeneca Pharmaceuticals, Wilmington, Del) and ketamine (Shuanghe Pharmaceuticals, Beijing, China), which were administered by two anesthetists to all patients by means of the peripheral veins.

Follow-up
The follow-up protocol was performed according to previously published recommendations (5,15). The follow-up period was calculated starting from the beginning of microwave ablation for all patients. Therapeutic effectiveness was assessed on the basis of changes detected through a combination of evaluations that included imaging, US-guided biopsies, and evaluation of serum AFP levels. Color-flow Doppler US was repeated at 1-month intervals (Fig 1a–1d). Routine contrast-enhanced CT or MR imaging was repeated at 1 month and at 3 months and then at 6-month intervals after microwave ablation treatment. The therapeutic response was considered complete when CT or MR imaging findings showed no areas of contrast material enhancement in the lesion (Fig 1e–1h). When contrast-enhanced CT or MR imaging failed to allow definitive judgment of whether necrosis was complete, posttreatment biopsy was performed in 165 patients with 203 lesions within 1–3 months after microwave ablation. When incomplete necrosis or local recurrence was confirmed with use of imaging modalities or posttreatment biopsy, treatment was repeated as long as the patient still met the requirements for microwave ablation.



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  		Figure 1a. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 


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  		Figure 1b. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 


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  		Figure 1c. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 


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  		Figure 1d. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 


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  		Figure 1e. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 


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  		Figure 1f. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 


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  		Figure 1g. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 


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  		Figure 1h. Transverse images in a 56-year-old man with a single focus of HCC and accompanying cirrhosis. (a) Sonogram obtained before microwave ablation shows a 4.6 x 3.9-cm hypoechoic nodule (arrows) in segment V of the liver. (b) Sonogram obtained 1 month after ablation shows that the nodule (arrows) has become heterogeneously hyperechoic; the border is not well delineated. (c) Power Doppler image obtained before microwave ablation depicts liver vessels surrounding the lesion (arrows) and intratumoral blood flow. (d) On a power Doppler image obtained after ablation, no blood signal is detected in the treatment region (arrows), suggesting the absence of viable neoplastic tissue. (e) Unenhanced CT scan obtained before ablation shows a well-demarcated tumor (arrows) with a central hypoattenuating zone and a hypoattenuating rim in segment V of the liver. (f) Unenhanced CT scan obtained 1 month after ablation shows an enlarged hypoattenuating coagulation zone (arrows) at the site of the treated tumor. (g) Transverse arterial phase CT scan obtained before treatment shows an enhanced area within the tumor (arrows). (h) On an arterial phase CT scan obtained 1 month after treatment, no enhancement is seen in the enlarged coagulation zone (arrows), suggesting the absence of residual tumor.

 
Since an increase in AFP levels may indicate recurrence or new lesions, serum AFP assay was performed 1 month after microwave ablation and was followed up at an interval of 3 months.

Prognostic Factors Analyzed
The prognostic factors analyzed included patient- and tumor-related variables. Patient-related variables were sex (male or female), age (40 years or younger, 41–60 years, or older than 60 years), degree of liver dysfunction (Child-Pugh class A, B, or C disease), associated liver cirrhosis (present or absent), and preablation treatments received (no treatment, curative resection of initial lesions, TACE, or a combination of curative resection and TACE). Tumor-related variables were maximum tumor size (<2.5 cm, 2.5–4.0 cm, or >4.0 cm), number of tumor nodules (single or multiple), degree of tumor cell differentiation (well, moderately, or poorly differentiated), preablation serum AFP level (20 µg/L or less; more than 20 µg/L), and local recurrence or new nodules after microwave treatment (present or absent).

Statistical Analysis
The unit of analysis was numbers of patients (not numbers of tumors). Cumulative survival rates were expressed according to the Kaplan-Meier method. The differences in survival among the groups were compared by using the log-rank test. The results of univariate analysis helped to substantially reduce the number of prognostic factors. Ten prognostic factors were included in the univariate study. Only variables found to show significance at univariate analysis were used for the subsequent multivariate analysis, which was performed by using the Cox proportional hazards model. All statistical analysis was performed by using Stata software (version 7.0; Stata Corporation, College Station, Tex). A P value of less than .05 was considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Survival Rates and Causes of Death
Survival was measured from the first day of treatment until death from HCC and its related diseases or to the last day of follow-up. Surviving patients and those who died from diseases other than HCC and its related diseases were defined as "censored cases."

The mean follow-up period for the 288 patients after percutaneous microwave ablation was 31.41 months ± 20.43 (range, 5–106 months). The period of observation for these patients was less than 1 year for 59 patients (20%), 1–2 years for 64 patients (22%), 2–3 years for 57 patients (20%), 3–4 years for 45 patients (16%), 4–5 years for 33 patients (12%), and more than 5 years for 30 patients (10%). The 1-, 2-, 3-, 4-, and 5-year cumulative survival rates were 93%, 82%, 72%, 63%, and 51%, respectively. One hundred eighty-eight (65%) disease-free surviving patients were followed up: 143 patients for 1 year or more, 98 patients for 2 years or more, 58 patients for 3 years or more, 32 patients for 4 years or more, and eight patients for 5 years or more. One hundred ninety-five patients (68%) remained alive and consulted our hospital periodically as outpatients. Eighty-six patients died of HCC and its complications, and seven patients died of nonhepatic diseases. Causes of deaths among these 93 patients were as follows: variceal bleeding or liver failure in 45 patients, progression of HCC in 40 patients, respiratory failure in three patients, myocardial infarction in one patient, renal failure in one patient, and cerebral hemorrhage in one patient. One other patient died during hepatic resection 5 months after microwave ablation, and another patient died the 2nd day after orthotropic liver transplantation.

Local Recurrence and New Tumors
Local recurrence or new tumors were observed in 100 patients during the follow-up period. Among the entire group of 288 patients, 24 (8%) had local regrowth of a lesion treated with microwave ablation. New tumors occurred in the same Couinaud segment but apart from the original sites in 25 patients (9%). New tumors were found in different Couinaud segments of the liver in 34 patients (12%), while new tumors occurred extrahepatically in 17 patients (6%). Microwave ablation was used as the preferred treatment method for local recurrence and new tumors if the patient still met the requirements for microwave ablation. A total of 62 patients underwent new courses of microwave ablation. Thirty patients were not candidates for microwave ablation because of portal vein thrombosis and/or extrahepatic metastases (19 patients), presence of more than five nodules (five patients), or recurrent or new lesions adjacent to the liver hilum or bowel (six patients).

Univariate Analysis
The influence of patient- and tumor-related factors on survival is shown in Table 2. The results revealed that there were statistically significant differences in survival rates depending on the numbers of tumors ({chi}2 = 8.13, P = .004; Fig 2), tumor size ({chi}2 = 46.56, P < .001; Fig 3), Child-Pugh classification ({chi}2 = 11.48, P = .003; Fig 4), presence of local recurrence or new tumors ({chi}2 = 8.44, P = .004; Fig 5), and degree of tumor differentiation ({chi}2 = 7.27, P = .026). Statistical results also showed there were no significant differences in survival rates attributable to sex ({chi}2 = 3.21, P = .073), age ({chi}2 = 0.36, P = .836), presence of cirrhosis ({chi}2 = 0.88, P = .348), preablation serum AFP level ({chi}2 = 2.22, P = .136), or type of preablation treatment ({chi}2 = 4.05, P = .256).


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  		TABLE 2. Univariate Analysis of Prognostic Factors for Overall Survival

 


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  		Figure 2. Graph shows 5-year cumulative survival rate after percutaneous microwave ablation, compared between patients with a single nodule (A) and those with multiple nodules (B). The survival rate of patients with a single nodule was significantly higher than that of patients with multiple nodules.

 


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  		Figure 3. Graph shows 5-year cumulative survival rate of 288 patients with HCC treated with microwave ablation. Data are stratified according the maximum diameter of the tumor: A = smaller than 2.5 cm, B = 2.5 to 4.0 cm, C = larger than 4.0 cm.

 


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  		Figure 4. Graph shows 5-year cumulative survival rate of 288 patients with HCC treated with microwave ablation. Data are stratified according to Child-Pugh classification of preablation liver dysfunction: A = class A disease, B = class B disease, C = class C disease.

 


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  		Figure 5. Graph shows 5-year cumulative survival rate of 288 patients with HCC treated with microwave ablation. The survival rate of patients with recurrent and/or new tumors (B) was significantly lower than that of patients without recurrent or new tumors (A).

 
The survival rate for patients with a single nodule was significantly higher than that for patients with multiple nodules (Fig 2). The 1-, 3-, and 5-year cumulative survival rates were 96%, 78%, and 60%, respectively, for patients with a single nodule and 91%, 61% and 28%, respectively, for patients with multiple nodules.

The survival rate for patients with a tumor no larger than 4.0 cm in maximum diameter was significantly higher than that for patients with a tumor larger than 4.0 cm in maximum diameter (Fig 3). However, there were no statistical differences between the survival curve for patients with a maximum tumor diameter of 2.5–4.0 cm and that for patients with a maximum tumor diameter smaller than 2.5 cm.

Comparison of survival curves for different levels of preablation liver dysfunction is shown in Figure 4. Patients in the Child-Pugh class A group did significantly better than those in the class B group, and the patients in the class B group, in turn, did better than those in the class C group.

First, we compared the influence on survival rate between patients with local recurrence (local regrowth of a lesion treated with microwave ablation) and those with new tumors. Statistical results showed that there was no significant difference in terms of survival between the group with local recurrence and the group with new tumors (P = .375). Since the number of patients with local recurrence was too small (24 patients) for this factor to be analyzed as a variable, and since there was a similarity in the presence of viable tumor cells during the follow-up period between groups, the two groups were merged into one group. The survival rate for patients with local recurrence or new tumors was significantly lower than that for patients without local recurrence or new tumors (Fig 5). The 1-, 3-, and 5-year cumulative survival rates were 96%, 77% and 67%, respectively, for patients without recurrence or new tumors and 91%, 66%, and 37%, respectively, for patients with local recurrence or new tumors.

Although treatment with preablation surgical resection and TACE may be an influential factor on prognosis, the comparison of survival curves for groups that received different preablation treatments revealed that there were no statistically significant differences among the groups (P = .256).

Multivariate Analysis
Multivariate analysis was performed by using the variables deemed significant at univariate analysis as covariates. The multivariate analysis (Table 3) showed survival rates related to number of tumors (single or multiple; t = 2.84, P = .005), tumor size (t = 4.93, P < .001), and Child-Pugh classification (t = 2.56, P = .01). Degree of tumor differentiation and presence of local recurrence or new tumors appeared to be significant risk factors when univariate analysis was performed. However, the survival rates were not significantly related to the degree of tumor differentiation (t = –1.53, P = .125) or to the presence of local recurrence or new tumors (t = 1.83, P = .068) by using the Cox proportional hazards model. The hazard ratio of death in the group with multiple nodules was 1.9 times higher than that in the group with only a single nodule. The hazard ratio of death was significantly higher in patients with a tumor larger than 4.0 cm in diameter. The better the preablation liver function, the lower the hazard ratio of death. The prognosis was poorest in patients with Child-Pugh class C disease.


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  		TABLE 3. Multivariate Analysis of Prognostic Factors with Cox Proportional Hazards Model

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
In this study, the patients were selected according to the enrollment criteria. Among all the patients, 63% (180 of 288) had a single HCC lesion, 73% (210 of 288) had HCC lesions 4.0 cm or smaller, and no patients had portal vein thrombosis and extrahepatic metastases. Therefore, microwave ablation was performed with a curative aim in the majority of patients. The results demonstrated that use of microwave ablation could produce complete necrosis of the tumors in most cases. The 5-year survival rate with microwave ablation of HCC is fairly high. Although there were no controlled studies of microwave ablation versus other methods of treatment, our results were close to the results in studies of surgical resection (21) and radiofrequency ablation (12) and were better than the results in studies of ethanol ablation (22), but our results were inferior to the latest outcome in studies of liver transplantation (23,24).

Our focus was to analyze, in a large series of patients with HCC, the prognostic factors of various clinicopathologic parameters regarding long-term survival, with the aim of clarifying which patients are most likely to benefit from microwave ablation.

Ethnicity may be a significant prognostic variable for long-term survival in patients with HCC (25). The cause of cirrhosis may influence the long-term survival in patients with HCC as well. The prognosis was worse in patients with HCC that developed following viral cirrhosis than in those with HCC that occurred following alcoholic cirrhosis (26). In our study, almost all cirrhosis was caused by a chronic hepatitis virus infection and all patients were Chinese, so this study was not subject to the influence of ethnicity and causes of cirrhosis.

Statistical results showed that survival rates were not significantly influenced by age, sex, or accompanying cirrhosis; these results correspond to the results found with several other treatment modalities (22,27–29). Meanwhile, the survival rates were not attributable to the pretreatment AFP level. This result is consistent with those of previously reported ethanol ablation studies (3,22).

In the present study, five variables (Child-Pugh classification, degree of tumor differentiation, number of HCC lesions, tumor size, and presence of local recurrence or new lesions) were found to be important risk factors that affected survival rates at univariate analysis. However, since univariate analysis does not always reflect the actual significance of a factor (2), multivariate analysis, in which multiple variables are considered simultaneously, was applied. Only three variables (Child-Pugh classification, number of HCC lesions, and tumor size) were shown to have independent prognostic value at multivariable analysis. Degree of tumor differentiation and presence of local recurrence or new lesions did not show significance because of the overpowering influence of the former three factors.

Our data from multivariate analysis indicated that tumor size was one of the most important prognostic factors in determining survival rates. This result was confirmed by using results from studies of several other treatment modalities (2,21,22,27,29). Lencioni et al (11) revealed that the indication for radiofrequency treatment of liver cancer should be a tumor with a maximum diameter of 3.0–4.0 cm. In our experience, smaller tumors were more easily destroyed than were larger tumors during microwave ablation. The survival rate for patients with HCCs 4.0 cm or smaller in greatest dimension was significantly higher than it was for those patients with HCCs larger than 4.0 cm. However, there were no statistically significant differences between survival curves for patients with HCCs smaller than 2.5 cm and those for patients with HCCs 2.5–4.0 cm. The possible reason for this may be that the coagulated area of microwave ablation was large enough to envelop HCCs smaller than or equal to 4.0 cm in maximum diameter, and a tumor-free margin of at least 5.0 mm could be obtained at one stroke.

In our previous study (30), the maximum width of coagulated tumor volume at different outputs was varied from 4.5 to 6.0 cm by inserting four electrodes simultaneously by using our improved technique. This may explain why the differences were not significant between survival curves of patients with HCCs smaller than 2.5 cm and those of patients with HCCs 2.5–4.0 cm. For tumors larger than 4.0 cm in maximum diameter, it was difficult to cover the tumor volume completely in three dimensions at one session. More ablations were required.

Meanwhile, whether complete necrosis could be obtained for larger tumors depended not only on the adjuvant techniques (strict geometric analysis) but also on the position of the tumors. The ribs and air in the lung limited accurate puncture in some cases. In addition, the level of experience of the doctors performing the procedure in placing the electrodes to cover the entire tumor played an important role.

Results of many studies have demonstrated that Child-Pugh classification is one of the most powerful predictors of long-term prognosis (22,27). Livraghi et al (22) reported that there was a statistically significant difference between the survival curves in the Child-Pugh class A group versus the class B group and in the Child-Pugh class A group versus the class C group and in the Child-Pugh class B group versus the class C group. Our data confirmed this. Child-Pugh classification is an important factor in evaluating hepatic reserve. Shiina et al (31) found that most patients with Child-Pugh class A disease died of progression of neoplastic disease while most patients with Child-Pugh class C disease died of cirrhosis. Patients with Child-Pugh class C disease have an extremely poor prognosis regardless of the presence of HCC (27). Among these patients, treatment of the tumor with ethanol ablation hardly improved survival (22,31,32). In our series, the 5-year survival rates were 87% in the Child-Pugh class A group, 51% in the class B group, and 24% in the class C group.

Although the 5-year survival rate in patients with Child-Pugh class C disease was only 24%, many patients may benefit from microwave ablation. We found that liver function in 10 patients with Child-Pugh class C disease improved 1–2 weeks after microwave ablation. The reason may be that microwave ablation got rid of the tumor burden and therefore improved the liver function and general condition in the patients. The majority of Child-Pugh class C patients with HCC were not candidates for many therapeutic modalities such as surgery, TACE, or even ethanol ablation (27). Microwave ablation as a minimally invasive technique may become one of the treatments of choice in some Child-Pugh class C patients with small HCC lesions. Further studies need to be performed to enroll more patients with class C disease, study patients over longer follow-up periods, and perform comparative studies for different therapeutic modalities.

In our series, the total recurrence and metastases rate was 35% (100 of 288 patients), including local recurrences in 24 of 288 patients (8%) and new nodular lesions remote from the treated tumor in 76 of 288 patients (27%). The incidence of local recurrence or new tumors in our series was close to that in tumors treated by means of curative surgical resection (33,34) or previously reported radiofrequency or microwave ablation treatment regimens (17,35,36) and was lower than that in those treated by means of ethanol ablation (17,22,37). Results of multivariate analysis showed there was no relationship between survival rates and local recurrence or new tumors. However, the survival rate of patients without local recurrence and new tumors was higher than that of patients with local recurrence or new tumors. The possible reason why presence of local recurrence or new tumors was no longer significant at multivariate analysis may be that the survival rate may be more influenced by tumor number, tumor size, and Child-Pugh classification. The other possible reasons for this result include a higher percentage of complete tumor necrosis, close follow-up, detection of recurrent lesions as early as possible, and appropriate treatment.

This study had some limitations. First, these data were obtained from a single center at which there was much experience with microwave ablation procedures. Therefore, there were higher survival rates and lower local recurrence rates. A multicenter study with a larger number of patients and a prolonged observation time is required. Second, as enrollment criteria and staging methods were standardized, if patients’ cases are passed through some sort of clinical "filter" before patients can become eligible for a study, it may lead to results from a sample that is systematically different from the underlying population of interest. Third, this study was not a prospective trial and lacked a control group. Further studies are needed for a randomized controlled comparison with surgical resection or other treatments.

In conclusion, results of this study confirmed the long-term effectiveness of percutaneous microwave ablation for patients with HCC. Child-Pugh classification, tumor size, and number of tumors were identified as significant independent prognostic factors in patients with HCC treated with microwave ablation. There is a significantly higher probability of long-term survival for patients with a single tumor of 4.0 cm or smaller in maximum diameter and Child-Pugh class A cirrhosis.


   ACKNOWLEDGMENTS
 
We thank Diane Russell, BA, for her help in the English writing of the manuscript.


   FOOTNOTES
 
Abbreviations: AFP = {alpha}-fetoprotein, HCC = hepatocellular carcinoma, TACE = transcatheter arterial chemoembolization

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, P.L., B.D.; study concepts, P.L.; study design, P.L., B.D.; literature research, P.L., Y.W.; clinical studies, P.L., B.D., X.Y., D.Y.; data acquisition, P.L., Y.W.; data analysis/interpretation, L.F., Y.W., Q.X.; statistical analysis, L.F., Y.W., Q.X.; manuscript preparation, editing, and revision/review, P.L., Y.W.; manuscript definition of intellectual content and final version approval, P.L., B.D.


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