LONG-TERM SURVIVAL OF TAIWANESE PATIENTS WITH HEPATOCELLULAR CARCINOMA AFTER COMBINATION THERAPY

Transcription

1 Chemoembolization/Percutaneous Ethanol Combination in HCC ORIGINAL ARTICLES LONG-TERM SURVIVAL OF TAIWANESE PATIENTS WITH HEPATOCELLULAR CARCINOMA AFTER COMBINATION THERAPY WITH TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION AND PERCUTANEOUS ETHANOL INJECTION Yu-Hsien Li, 1 Chaur-Shine Wang, 1 Li-Ying Liao, 1 Chung-Kwe Wang, 1 Li-Shun Shih, 2 Ran-Chou Chen, 3 and Pao Huei Chen 4 Background and Purpose: Several studies have shown a superior effect of combination therapy with transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) compared with either monotherapy for the treatment of advanced hepatocellular carcinoma (HCC), but there have been no reports on combination treatment from Taiwan. This study investigated the long-term survival and prognostic factors of HCC patients treated with TACE/PEI combination therapy. Methods: A total of 153 consecutive HCC patients, with tumor sizes between 2 and 3 cm in 47 patients, between 3 and 5 cm in 66 patients, and between 5 and 13 cm in 40 patients, who received TACE/PEI combination therapy were included in this retrospective study. The mean follow-up duration was 23 ± 17 months (range, 1 to 78 months). Results: The 1-, 2-, 3-, 4-, 5-, and 6-year cumulative survival rates for the patients were 78%, 54%, 40%, 22%, 12%, and 5%, respectively. Multivariate analysis using Cox s proportional hazards model showed that the stage of cirrhosis (Child s class B or C vs class A) was the only factor that significantly affected the survival rate (p = 0.02) [relative risk, 2.10; 95% confidence interval, 1.12 to 3.96]. Univariate analysis showed that survival was poorer in patients with tumors greater than 5 cm than in patients with tumors 2 to 5 cm in largest dimension; this difference was not significant in the multivariate analysis. No serious complications were observed during or after treatment. Conclusions: TACE combined with PEI is an alternative treatment for patients with larger HCC who are not suitable for surgical resection. A superior outcome can be expected in patients with Child s class A cirrhosis. Key words: Carcinoma, hepatocellular; Chemoembolization, therapeutic; Injections, intralesional; Ethanol, administration and dosage J Formos Med Assoc 2003;102:141-6 There are many therapeutic options for hepatocellular carcinoma (HCC) 1 but none are particularly effective. Surgical resection in highly selected patients was thought to be the only curative treatment for HCC. However, most HCCs are inoperable at the time of diagnosis due to poor liver function, multifocal tumors, poor physical condition, comorbidity or advanced tumor stage, 2 4 and long-term survival is still not satisfactory owing to frequent recurrence. Nonsurgical methods to treat HCC have gradually gained considerable importance. The 2 most widely employed modalities are transcatheter arterial chemoembolization (TACE) 5,6 and percutaneous ethanol injection (PEI) therapy Other less frequently used methods include percutaneous injection of acetic acid (PAI), 13,14 hot saline, 15 microwave coagulation (PMCT), 16 radiofrequency, 17 and cryotherapy. 18 TACE is widely used in treatment for inoperable HCC. However, TACE alone does not clearly improve the long-term prognosis of HCC patients because it rarely achieves complete tumor necrosis. 19 Repeated procedures are necessary to achieve complete necrosis 1 Division of Gastroenterology, Department of Internal Medicine and Departments of 2 Pathology and 3 Gastroenterologic Radiology, Taipei Municipal Jen-Ai Hospital, Taipei; 4 Kaohsiung Yuan s General Hospital, Taiwan. Received: 26 June 2002 Revised: 6 August 2002 Accepted: 7 January 2003 Reprint requests and correspondence to: Dr. Chaur-Shine Wang, Department of Gastroenterology, Taipei Municipal Jen-Ai Hospital, 10, Jen-Ai Road Sec 4, Taipei, Taiwan. J Formos Med Assoc 2003 Vol 102 No 3 141

2 Y.H. Li, C.S. Wang, L.Y. Liao, et al of the tumor, 20 which may result in the worsening of liver function or, possibly, liver failure. 21 Bruix et al reported a randomized controlled trial which compared TAE (without associated chemotherapy) versus symptomatic treatment in patients with advanced HCC. 22 None of the patients had a complete initial response and 22 patients (55%) had a partial initial response to treatment. There was no difference in survival rates between the TAE group (49% and 13% at 2 and 4 years, respectively) and those with symptomatic treatment (50% and 27% at 2 and 4 years, respectively). However, Lo et al recently reported on a randomized controlled trial of transarterial lipiodol chemoembolization in Asian patients with unresectable HCC in which transarterial lipiodol chemoembolization significantly improved survival. 23 A clinical trial by Li et al of TACE/PEI combination therapy in patients with HCC found that it was much more effective than TACE alone. 24 Although the complementary effect of TACE and PEI has been demonstrated, there have been no reports on TACE/PEI combination therapy in patients with HCC from Taiwan. This retrospective study investigated the long-term survival and prognostic factors of TACE/PEI combination therapy in the treatment of Taiwanese patients with HCC of sizes between 2 and 13 cm. We also compared these results in HCC patients receiving either TACE or PEI alone during the same time period. Methods Patients and clinical data A total of 427 consecutive HCC patients with regular follow-up in Taipei Municipal Jen-Ai Hospital from January 1990 through August 1999 were included in this study. Seventy two (17%) had undergone surgical resection, 113 (26%) had received only PEI, 58 (14%) had been treated using only TACE, and 12 (3%) received a combination of TACE and radiotherapy due to portal vein thrombosis. The remaining 172 patients (40%) received combination therapy with TACE and PEI. Patients whose largest lesion size was smaller than 2 cm (19 patients, 4%) and who received TACE/PEI due to hypervascularity (13 patients with multiple lesions) were excluded. Ultimately, 153 patients (36%) were included in the retrospective analysis. Diagnosis of HCC was based on percutaneous liver tissue core biopsy in 124 patients (81%). For the remaining patients (n = 29, 19%), a comprehensive diagnosis was made by imaging modalities including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), angiography, and carbon dioxide-enhanced US (CO 2 -US) 28 as well as tumor marker data (serum alpha-fetoprotein, AFP). The histology type was classified as well-differentiated HCC in 33 patients and moderately or poorly differentiated in 91 patients. Tumor-node-metastasis (TNM) stages were 1, 2, 3, and 4 in 10, 67, 42, and 34 patients, respectively. During the study period, 47 patients, including 35 males (74%), of mean age 62 years (range, 32 to 84 years) with HCC larger than 2 cm underwent a total of 142 courses of TACE-only (mean, 3; range, 1 to 11) at our institution. The majority of these patients had latestage disease (TNM stages of 3 to 4 in 31 of 47, 66%). Hepatitis B was the cause of HCC in the majority of subjects (30 of 47, 64%). TACE and PEI treatment TACE was performed by selectively introducing a catheter into the right or left hepatic artery or into a segmental branch of the hepatic artery. A mixture of iodized oil (lipiodol; range, 3 to 6 ml) and anticancer drugs (30-60 mg adriamycin and 4-10 mg mitomycin C) was injected through the catheter. Subsequent embolization was obtained using a gelfoam sponge. After the procedure, patients received intravenous hydration to maintain their urine output at not less than 50 ml/hour. Typical transient postembolization syndrome consisting of abdominal pain, intermittent fever, nausea or vomiting was seen in all patients to some degree. Narcotics and antiemetics were given to relieve these symptoms as needed. Three weeks after TACE, unenhanced CT was used to assess the initial therapeutic effects. Then, PEI was started using a real-time convex scanner or linear-array scanner with 3.5 MHz probes and a lateral attachable apparatus for needle guidance. Correct positioning within the lesion of a 15- or 20-cm long, 21-gauge percutaneous transhepatic biliary drainage puncture needle was ascertained under US guidance, and then an adequate volume of 3 to 10 ml absolute ethanol according to the tumor size and the distribution of the ethanol was rapidly injected. The treatment procedure was repeated in 2 or 3 sessions per week. Four or more treatment sessions were performed according to the lesion size, the texture of the tumor parenchyma, patient compliance, and the distribution of ethanol in 1 treatment series. Post-treatment follow-up Post-treatment follow-up included US, MRI, angiography, and CO 2 -US. The flow chart of treatment is shown in Fig. 1. An MRI study was arranged 2 weeks after PEI to detect any viable lesions, and the result was confirmed by angiography and CO 2 -US if necessary. The mean follow-up duration was 23 ± 17 months (range, 1 to 78 months). 142 J Formos Med Assoc 2003 Vol 102 No 3

3 Chemoembolization/Percutaneous Ethanol Combination in HCC Angio, CO 2 -US Large viable Viable tumor Small viable Advanced HCC TACE PEI MRI (dynamic CT) 3 weeks Nonviable Lipiodol CT Follow-up Fig. 1. Scheme of transcatheter arterial chemoembolization (TACE)/percutaneous ethanol injection (PEI) combination therapy for hepatocellular carcinoma (HCC) patients. CT = computed tomography; MRI = magnetic resonance imaging; lipiodol CT = unenhanced computed tomography performed 3 weeks after TACE; CO 2 -US = carbon dioxideenhanced ultrasound. The CO 2 -US procedure involved injection of 2 to 6 ml of CO 2 gas into the hepatic propria artery as a single bolus during TACE or angiography. US was performed immediately after the injection. The CO 2 enhancement of the tumor was categorized as parenchymal or late phase based on comparison with CO 2 enhancement in the liver parenchyma. The CO 2 gas washes out earlier in normal liver parenchyma (3 to 5 minutes, parenchymal phase) than in viable liver tumors (12 to 15 minutes, late phase). Tumors without any CO 2 enhancement in both phases were diagnosed as non-viable. Tumors with positive enhancement in any phase were diagnosed as viable. Subsequent management depended on the resulting size of the viable lesion. Patients received regular follow-up if no viable lesion was noted. If one or more of these methods, TACE for large viable lesions and/or PEI for small viable lesions, detected a viable lesion, repeated sessions were performed. Statistical analysis Survival rate was estimated by the Kaplan-Meier method. The prognostic relevance of different patient characteristics on survival was assessed by Cox s proportional hazards regression model for multivariate analysis. A p value of < 0.05 was considered statistically significant. Results The clinical profiles of the 153 patients are shown in Table 1. Overall survival of patients who received TACE/PEI combination therapy calculated by the Kaplan-Meier method is shown in Fig. 2. The 1-, 2-, 3-, 4-, 5-, and 6-year cumulative survival rates were 78%, 54%, 40%, 22%, 12%, and 5%, respectively. The variables used in analyses included gender, age, virology, stage of cirrhosis, a baseline initial AFP level, histological differentiation, the size of the largest lesion and number of lesions. The parameters assessed before treatment that were significant in the univariate analysis were tested by the multivariate Cox s proportional hazards model (Table 2). According to the results of multivariate analysis, patients with compensated liver cirrhosis (Child s class A vs class B or C) Table 1. Clinical data of 153 hepatocellular carcinoma (HCC) patients who received combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection. Variable n* Gender (M/F) 117/36 Age (years) 62 ± 10 (33 83) Child-Pugh classification A 127 B 25 C 1 Cause of HCC Alcohol 1 HBsAg-positive 76 HBsAg-positive, anti-hcv antibody-positive 7 Anti-HCV antibody-positive 63 Unknown 6 AFP level (ng/ml) < > Tumor number Solitary 72 Multiple 81 Tumor size (cm) Tumor histology Well 26 Moderately-poorly 98 TNM stage * Except age (mean ± SD, range). Classification of primary liver cancer of the Liver Cancer Study Group of Japan. TNM classification of malignant tumors (International Union Against Cancer; UICC). HBsAg = hepatitis B surface antigen; HCV = hepatitis C; AFP = serum alphafetoprotein; TNM = tumor-node-metastasis. J Formos Med Assoc 2003 Vol 102 No 3 143

4 Y.H. Li, C.S. Wang, L.Y. Liao, et al Survival rate Time (months) Fig. 2. Cumulative survival of hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization/ percutaneous ethanol injection combination therapy. Table 2. Multivariate analysis of prognostic factors using Cox s proportional hazards model. Factor Hazard ratio (95%CI) p Gender (M/F) 0.59 ( ) 0.08 Age (> 55 years/< 55 years) 0.71 ( ) 0.24 Causes (HBsAg-positive/-negative) 1.67 ( ) 0.07 Child s class (B+C/A) 2.10 ( ) 0.02 AFP (> 1000/< 10 ng/ml) 1.69 ( ) 0.19 Histology (mod.-poorly/well) 1.30 ( ) 0.49 Tumor size (> 5 cm/2 5 cm) 1.36 ( ) 0.33 Tumor number (multiple/solitary) 1.24 ( ) 0.41 CI = confidence interval; HBsAg = hepatitis B surface antigen; AFP = serum alpha-fetoprotein. had the best long-term prognosis (p = 0.02). The tumor size was of marginal prognostic relevance. Survival was poorer in patients with tumors greater than 5 cm than patients with tumors 2 to 5 cm in the largest dimension, showing significant differences in univariate analysis, but no significant differences in multivariate analysis. There were no significant differences in gender, age, a baseline initial AFP level, histological differentiation, and tumor number between patients with different tumor sizes. During the study period, 47 patients who were mostly in the latter stage of the disease (TNM stages 3 to 4 in 31 of 47, 66%) underwent TACE only, resulting in cumulative survival rates of 66%, 42%, 17%, 17%, and 17% at 1, 2, 3, 4, and 5 years, respectively, with a median survival of 14 months. The 1-, 2-, 3-, 4-, and 5-year cumulative survival rates for the 113 HCC patients with less than 3 tumors greater than 5 cm in size and who received PEI only, were 85%, 55%, 40%, 24%, and 8%, respectively, with a median survival of 31 months. Evaluation of clinical course by CO 2 -US At the time of analysis, 130 patients (85%) had developed tumor recurrence as evidenced by follow-up US, CT, MRI, angiography, CO 2 -US, or liver biopsy. We evaluated 41 patients with a total of 66 tumors. Forty six tumors were positively enhanced by CO 2 -US and 40 of them were enhanced on angiography. These 46 tumors were shown to be viable tumors either by biopsy or in follow-up studies. The positive predictive value was 100% for CO 2 -US and 87.7% for angiography. CO 2 -US guided PEI was performed for small viable tumors, if necessary. Twenty tumors were negative using CO 2 -US and these were also negative by angiography. The 1-, 2-, 3-, 4-, and 5-year cumulative recurrence rates for these patients were 37%, 48%, 62%, 74%, and 84%, respectively. Causes of death Of the 153 patients in the analysis, 57 (35%) died during the study period. The causes of death were upper gastrointestinal bleeding in 14 patients(25%), hepatic failure in 14 (25%), cancer in 11 (19%), spontaneous bacterial peritonitis in 8 (14%), tumor rupture in 5 (8%), hepatorenal syndrome in 2 (4%), and other in 3 patients (5%). Discussion Tsang et al first reported on 120 HCC patients treated with TACE in Taiwan. 29 The 1- and 2-year survival rates were 37% and 16%. The 1-year survival rate increased to 79% in 14 patients with tumors smaller than 5 cm. Recently, Huang et al reported on 419 patients with resectable HCC in Taiwan. 30 They compared the results of surgical resection in 311 patients with those of TACE in 46 and noted no difference in survival rate. The cumulative survival rates at 1, 2, 3, 4, and 5 years were 78%, 66%, 55%, 48%, and 43% for the surgery group, and 87%, 63%, 51%, 47%, and 34% for the TACE group, respectively. Several studies have shown the superiority of TACE/PEI combination therapy to either TACE or PEI monotherapy for advanced HCC. Tanaka et al reported that the 3-, 5-, and 7-year calculated survival rates for patients with large HCC (3 to 11 cm, mean 4.3 cm) who received TACE/PEI combination therapy were 68%, 35%, and 14%, respectively. 31 Our results for 1-, 2-, 3-, 4-, 5-, and 6-year cumulative survival rates were 78%, 54%, 40%, 22%, 12%, and 5%, respectively. Both of these studies showed a positive palliative effect of TACE/PEI combination therapy in patients with large HCC, compared to results of other treatment modalities. Multivariate analysis of data from a surgical series by the Liver Cancer Study Group of Japan found that the severity of any accompanying cirrhosis, the size of the lesion, and the number of lesions were independent predictive factors in the prognosis of 144 J Formos Med Assoc 2003 Vol 102 No 3

5 Chemoembolization/Percutaneous Ethanol Combination in HCC HCC patients. 32 Our results showed that a favorable outcome of TACE/PEI combination treatment can only be expected if patients have compensated cirrhosis (Child s A, according to the Child-Pugh classification). Patients with Child s class A cirrhosis survived significantly longer than those with Child s class B or C. In this series, cirrhosis-related complications (e.g. hepatic failure, variceal bleeding, and spontaneous bacterial peritonitis) were shown to play a key role as major causes of death. Segmental or subsegmental TACE caused fewer adverse effects on hepatic function than conventional TACE. Therefore, it was also important to select HCC patients with Child s class B or C cirrhosis to apply these methods to preserve liver function during the treatment. The biological features that are indicative of clinical aggressiveness of cancer cells are useful in the identification of patients at low or high risk of disease progression. Putative predictors of HCC in diagnosis and treatment include histologic grade and AFP level. TACE is more effective in overt HCC with hypervascularity. Most patients with overt HCC in this study had the histological features of moderately or poorly differentiated HCC as well as a high AFP level. This may explain why no relation was found between the baseline AFP level and histological differentiation in our study. Tanaka et al reported that patients with lesions 3 to 5 cm in the largest dimension survived significantly longer than those who had lesions greater than 5 cm in the largest dimension. 31 They considered that this result might be secondary to differences in tumor response after treatment; the recurrence rate of initially treated lesions was significantly higher in larger lesions than in small lesions. Our results showed no significant differences in survival between tumors 2 to 3 cm and tumors 3 to 5 cm in the largest dimension. Patients who had lesions 2 to 5 cm in largest dimension survived longer than those who had lesions larger than 5 cm on univariate analysis. However, this significance was not found on multivariate analysis. The success of CO 2 -US guided PEI in treating the viable or recurrent lesions that were difficult to detect may explain this finding. In our experience, CO 2 -US is a good imaging modality for detecting the viability of treated HCC. The positive predictive value of viable HCC by CO 2 -US is 100% compared to 87.7% by angiography. We suggest that CO 2 -US is a more reliable method for detecting the viable portion of treated HCC compared with conventional angiography. 33 Furthermore, for small viable lesions found by US in difficult to treat locations while performing PEI, CO 2 -US guided PEI is a good choice for complete ablation treatment. Therefore, the long-term survival of patients with larger lesions was not inferior to that of patients with small lesions. Tanaka et al reported that the number of lesions is a significant factor in predicting survival in univariate analysis 31 ; however, its significance was not confirmed by multivariate analysis. In our series, no significant differences were found in the number of lesions, possibly because most of the patients with multiple lesions had multicentric HCC. Also, there were no significant differences by TNM stage. Our results indicate that the well-known TNM stage criteria do not define the relative prognostic weight of variables for HCC. Well-controlled clinical trials are needed to assess new experimental modes of therapy and new prognostic systems. 34 In summary, TACE/PEI combination therapy remains the treatment of choice for patients with multinodular and/or larger HCC. 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