Comparison of hepatic resection and transarterial chemoembolization for UICC stage T3 hepatocellular carcinoma: a propensity score matching study

Hepatocellular carcinoma (HCC) has been the second leading cause of cancer death worldwide so far, estimated to be responsible for around 9.1% of the total cancer death [1]. It is the only cancer that mortality is still increasing regardless of the evolution and progress of anti-cancer therapy in North America [2]. As in China, more than 50% new developed cases occurred in this country alone, which usually arises as a result of a chronic liver disease, especially hepatitis B virus (HBV) related. Due to its greatly invasive malignant features, HCC has a characteristic propensity to invade into portal vein, or to develop intra-hepatic metastasis, which was regarded as one of the most adverse prognostic factors [3]. Although several staging systems have been proposed for determining the stage and prognosis of HCC, no consensus exists on the best classification system [2, 4]. Until now the Union for International Cancer Control and American Joint Committee on Cancer (UICC/AJCC) tumor-node-metastasis (TNM) staging system has still served as one of the most important staging systems all over the world [4].

UICC stage (7th) T3 HCC was defined as multiple lesions with any lesion larger than 5 cm (stage IIIa), or involving a major portal vein or hepatic veins (stage IIIb). According to Barcelona clinic liver cancer (BCLC) staging system, most UICC stage T3 HCC cases are classified as being Stages B or C, therefore transarterial chemoembolization (TACE) or Sorafenib, rather than hepatic resection (HR) are recommended as the optimal therapy for patients in these stages in Europe or North America [5]. However, therapy strategy may be a little different in Asian-Pacific areas [2, 3, 6, 7]. Until now, it seems difficult to reach a common consensus on the indication of HR for HCC patients worldwide. Actually, HR was reported to be performed beyond the BCLC recommendations in about 50% of HCC patients with BCLC stage B or C in Asia-Pacific areas [6, 8, 9]. It’s not yet clear what is the optimal therapeutic strategy for UICC stage T3 HCC patients. The aim of this study was to compare the clinical outcomes following HR versus TACE for UICC stage T3 HCC.

As we known, the underlying liver cirrhosis and tumor characteristics make a significant contribution to the prognosis of HCC patients. Without balancing the biases of liver cirrhosis and tumor characteristics can cause confusion. Therefore, non-randomized studies that compare the outcomes of HR and TACE in HCC patients without balancing the biases should be interpreted cautiously. Methods of balancing co-variables are needed in this specific setting. In nonrandomized studies, propensity score matching (PSM) is an optimal method of reducing the biases of treatment selection [10]. Compared with the traditional adjustment methods (stratification and covariance adjustment), PSM maximizes the covariate balance between groups and is free of the limitations of adjusting a limited number of covariates at one time [11]. Therefore, in the present study, we conducted PSM to minimize the biases to assess long-term outcomes of HR versus TACE for UICC stage T3 HCC.

HCC is one of the most serious and life-threating health problem worldwide [1]. To our knowledge, HBV or hepatitis C virus (HCV) infections is the most leading cause of HCC [18]. As hepatitis B virus was prevalent in China, the cases in our study were almost hepatitis B related HCC. Although there are studies reveal that HBV accelerate HCC via multiple mechanisms, most of the important is that HCC usually developed in the presence of chronic liver diseases, cirrhosis, and associated with impaired liver function [19, 20]. As we known, the long-term survival of HCC patients greatly depends on the well-preserved liver function as well as early-stage HCC. Although at least there are 18 HCC staging systems now available, UICC/AJCC TNM staging system and BCLC staging system are both among the most common HCC classification and scoring systems [4]. UICC/AJCC stage T3 (stage IIIa/IIIb) HCC patients, which were considered as intermediate or advanced stage in BCLC system, remains even extremely poor in prognosis. Especially as for stage IIIb cases, portal vein thrombosis develops extremely high portal hypertension which at last results in life-threatening bleeding esophageal and/or gastric varices, liver dysfunction, intrahepatic dissemination of HCC and/or distant metastasis.

The outcomes of treatments for those patients with such advanced stage have been disappointing in a long time. Curative options such as hepatic resection (HR), liver transplantation (LT) or radiofrequency ablation (RFA) were not recommended in Europe and North America. Although TACE might offer improved overall survival benefits in some non-randomized control trials, it is not yet recommended by practice guidelines [21–23]. On the other hand, therapy choices for those patients in such stage in Asian-Pacific areas may be pretty different. Surgical resection was recognized as the last but not least option for these patients to obtain long-term survival [2, 3, 5, 6]. Several studies have reported that radical resection of the tumor and involved vessels can prolong survival and may eventually offer a chance of cure in selected cases [3, 12, 24, 25]. However, even in these areas, there is still controversy over optimum treatment strategy for HCC patients in these stage, regardless guidelines for practice. Although there were several studies comparing en bloc with peeling off technique in the resection for HCC with portal vein tumor thrombus (PVTT), we conducted one of the largest study population and longest follow-up data in our previous study that demonstrated en bloc HR yielded more preferable survival outcomes over peeling off resection for HCC with PVTT [3, 26, 27]. In this study, we demonstrated that hepatic resection contributed to better OS compared with TACE in UICC/AJCC stage IIIa/IIIb HCC cases. The medium OS in HR group were 17.8 m, which were 6 months longer than that of TACE group (11.8 m). The 1, 3, and 5-year OS in HR group was significantly higher than that of TACE group, respectively, (log rank = 19.908, P < 0.01). Several studies reported that the response rate to TACE was around 40% with supra-selective technique, and the OS of the patients after TACE treatment ranged from 16 months to 25 months and even 48 months in selective recent series [28, 29]. However, the response rate to TACE was about 25% in this study. The median OS was 11 months (12 months after matching), which was consistent to the previous findings [15, 30, 31]. One of the reasons might be that the clinical stage of the included cases in this study was UICC stage T3 HCC. The mean size of tumor was 9.5 cm, with more than one lesion in most cases, or with portal vein involved. Kadalayil, et al. [32] has reported a simple prognostic scoring system, the Hepatoma arterial-embolization prognostic (HAP) score. In this prognostic scoring system, patients with low albumin (< 36 g/dl), high bilirubin (> 17 μmol/l) or α-fetoprotein (AFP) (> 400 ng/ml), and large tumor size (> 7 cm) were associated with increased risks of death when underwent TACE. In this study, the HAP score was a little bit high (albumin, 41.1 g/dl; bilirubin 17.8 μmol/l; tumor size, 8.6 cm; and 47% of cases with AFP > 400 ng/ml). However, the clinical and pathologic data in this study was consistent well with our previous studies [3, 12, 14]. According to the guideline of diagnosis and treatment of hepatocellular carcinoma of China [33], the cases with UICC T3 HCC were suitable for TACE treatment. Although before matching, more than 50% of the patients received only one TACE session, and 50% of these patients had disease progression after the session, the medium OS in TACE group was 10.9 (95% CI, 9.7–12.1) months, which was consistent with other studies [34, 35].

The OS in HR group was lower than those reported in other researches [36, 37]. However, the results in this study were consistent with those we previously reported [3, 12, 14]. One of the reasons might be that the patients enrolled in our studies were at a more advanced stage. Some patients with advanced HCC might benefit from resection [38, 39]. In this study, 36% of the patients after matching had one tumor, the most frequent liver disease etiology was HBV infection, the median age of the patients was 49.5 y, and the platelet count was 200 × 10⁹/L (which means no portal hypertension). In view of these characteristics, a surgical management should be done.

Until now, there have been several studies and meta-analysis accessing HR and TACE in the management of intermediate or advanced stage of HCC [25, 40–44]. However, to our knowledge, the study we presented here was one of the several studies to access the survival outcome of HR versus TACE in UICC/AJCC stage IIIa/IIIb HCC patients [12, 45, 46]. Moreover, this study comprised the largest study population and presented the longest follow-up data reported to date [3, 12, 25–37]. At last but not least, our findings were obtained after PSM which balanced patient demographics, liver functions, and tumor characteristics between two groups. Therefore, it provided us the most important data that might be used to establish an optimal strategy for the management of UICC stage IIIa/IIIb HCC patients.

In terms of safety, our study revealed that either HR or TACE was generally well tolerated and just several manageable adverse events occurred in patients with UICC stage T3 HCC patients. Although patients in TACE group were less likely to develop grades 3–4 edema, ascites, and pleural effusion before matching, patients in HR group were more likely to develop pleural effusion after matching. These were similar to those results reported in the previous studies [3, 12, 25, 45–48].

In this study, we performed univariate and multivariate analysis to examine demographics and clinical characteristics associated with prognosis. Although Cox analysis showed that PT, tumor size, tumor numbers, UICC stage were independent prognostic factors, the hazard ratio was just a little scale, which seemed to be not so clear advantage for either arm. On the other hand, initial treatment of hepatic resection yielded a hazard ratio of 0.646 over TACE, which meant there was a 35.6% reduction in risk of death in HR group, that was a clear advantage in HR arm. Although Kadalayil, et al. [32] reported that α-fetoprotein (AFP) (> 400 ng/ml) was associated with increased risks of death when underwent TACE, in this study, the AFP level was not an independent prognostic variable. Other studies suggested some risk factors for OS in UICC stage T3 HCC, such as ALB < 3.5 g/dL, tumor size more than 55 mm, multiple tumors, peeling off thrombectomy in HR, and treatment option of TACE alone, et al [3, 14, 46, 47] These observations were partly compatible with our current results. Not surprisingly, patients with long-term OS were more likely to have normal PT time, smaller tumors, and less likely to be multiple tumors.

Due to retrospective study, our study ineluctably had some limitations. The most significant one was lack of a well-balanced randomization. The treatment choices were recommended by our Multiple Disciplinary Team (MDT) in consideration of various clinical features and guidelines available, which were more likely to increase the possibility of unbalanced treatment allocation through the treatment distribution and potential selection bias occurred. Although some studies revealed that propensity scores matching (PSM) methods was not necessarily superior to conventional covariate adjustment, it was still an increasingly popular method to balance bias in observational studies [49]. Therefore, the problem of imbalance was supposed to be partially addressed by using propensity score matching that yielded similar baseline characteristics between two groups. Among the risk factors of OS, an additional analysis to define a subgroup which is really saved by HR compared to TACE in even UICC T3 HCC would give more practical information for the treat. However, we did not perform the subgroup analysis. This is the second limitation of this study.

Our study revealed that TACE was an option for UICC stage T3 HCC patients. However, potentially radical hepatic resection (HR) yielded a result of overall survival advantage on TACE for UICC stage T3 HCC patients. Therefore, HR seemed to represent the optimal therapy strategy for the management of UICC stage T3 HCC and should be recommended as a preferable treatment especially for patients with a good underlying liver function.