RISK FACTORS FOR EARLY RECURRENCE OF HEPATOCELLULAR CARCINOMA AFTER CURATIVE RESECTION

Introduction Hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and its incidence is increasing in Western countries. With advances in surgical techniques and perioperative care, results of hepatic resection for HCC have greatly improved. Nonetheless, the long-term survival after hepatectomy is disappointing because of the high incidence of recurrence, that reaches 70-100% after 5 years. More than 60-80% of intrahepatic recurrences of HCC are susceptible to new treatments and survival rates are more than 50% in patients undergoing new treatments with radical intent. Prevention and effective management of recurrence with aggressive multimodality treatments are the most important strategies to improve the long term survival results. The aims of this study were: to identify risk factors for the early recurrence of HCC, identify the prognostic significance of the time of recurrence and to evaluate results of aggressive multimodal treatment of recurrent disease. Patients and Methods: We collected a series of 269 patients who underwent curative liver resection for HCC from January 1990 to December 2012. All patients after surgery underwent 6 months follow-up. Post-treatment monitoring was performed with clinical physical examination, contrast-enhanced imaging using computed tomography (CT) or Magnetic resonance (MRI) and the monitoring of serum level of alphafetoprotein (αFP). Patients with intrahepatic recurrences were evaluated for new treatment: transplant, re-resection, ablative therapy, chemoembolization, chemotherapy, supportive care; according to tumor stage, liver function impairment and general condition. The principle of selection for treatment was that repeated hepatic resection was the first choice whenever the tumor was considered resectable. The functional liver reserve was evaluated by blood chemical tests, Child's classification of liver function and retention rate of Indocyanine green at 15 minutes. Data were collected and analyzed with SPSS statistical software (SPSS version 19.0 Inc. Chicago Ill.) Variables included in the univariate and multivariate analyses to identify factors related to survival and recurrence were the following: sex, age, underlying liver disease (histologic status of the liver), tumor size, tumor numbers, Child-Pugh class, bilirubin level, albumin level, AFP level, tumor factors (histologic differentiation, encapsulation, vascular infiltration and type of resection). The differences between categorical and continue variables were analyzed with a chi-square test and Fisher’s exact tests. Survival curves were calculated using the Kaplan-Meier method. Clinical and pathological variables were evaluated by univariate survival analysis using a log rank test to determine any prognostic factors. Competing-risks Cox regression analysis was used for the multivariate analysis. Results: Median survival time for patients included into the study was 57,6 months (95 % CI 49,5 – 65,6); the actuarial 1- 3- 5- 10 years survival rate were 87,5%, 67,9%, 48,1%, 17,1%. In 159 (59%) patients cancer recurred after surgical resection in the remaining liver at median time of 24,5 months (SD ± 22,7 months). In 56 patients (35%) cancer recurred within 1 year and in 103 (65%) after 1 year. Median disease free survival was 30,3 months (range 24,1-36,4), with a 1, 3 and 5-years disease free survival of 76,2 %, 41,8 % and 22,0 % respectively. Survival was significant shorter in patients with early recurrence in comparison to patients with late recurrence, with a median survival time of 18,7 (95% CI 7,0-20,4) and 63,8 months (95% CI 48,7-66,7), respectively (p<0.001). Factors related with early recurrence were: size of the tumor, satellite lesions, vascular invasion, serum levels of αFP. 123 (77% ) patients with recurrence had new treatment : 28% were submitted to chemoembolization (TACE), 42% to local ablative therapy (PEI or/and RFA) 1% to transplant and 9% to re-resection, instead 3% were submitted to chemotheraphy. 17% of patients were not submit to additional treatment due to advanced stage of HCC or severe liver impairment and were submitted to supportive care. A curative treatment of the recurrent disease was feasible in 36% of patients with early recurrence and in 61% of patient with late recurrence. Patients without any treatment of the recurrent disease showed shorter overall survival compared to those submitted to treatment with radical intent of the recurrent disease, with a median survival time of 42,5 months and 65,6 months,respectively (p<0.001). Patients who developed a single recurrence had a significantly lower survival compared with patients with 2-3 or more than 3 recurrences with a median survival time of 49,5; 105,4; 74,2 months respectively. Conclusions: Recurrence after surgical resection of HCC is very frequent and aggressive treatment for HCC recurrences after curative resection improves survival. Patients with early recurrence and those with single recurrence have worse prognosis compared to those with late recurrence and those with multiple recurrences. So patients at risk for early recurrence and for single recurrence are poor candidate to surgical resection and probably these groups of patients should be addressed to other treatments or evaluated for aggressive adjuvant therapy. Furthermore aggressive treatment of relapses increases the survival and the number of relapses does not adversely influence the survival.