Meta-analysis: preoperative transcatheter arterial chemoembolization does not improve prognosis of patients with resectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and ranks the third leading cause of cancer-related death [1]. Hepatectomy is considered the main curative treatment for HC with a 5-year survival of 23.8–54.8% as reported in the most recent series [2–5]. Tumor recurrence even after radical surgery affects 75-100% HC patients, accounting for the major cause of death of HC patients [6]. The development of appropriate strategies to prevent tumor recurrence is therefore critical for improving long-term outcomes of HC patients after surgical resection.

Transcatheter arterial chemoembolization (TACE), which induces tumor ischemic necrosis by arterial injection of chemotherapeutic drugs and embolizing agents, is recommended as the first-line palliative treatment for inoperable HCC in the 2005 practice guidelines issued by the American Association for the Study of Liver Diseases [7]. Some researchers believed that it may reduce the viability of HCC cells before surgery and reduce postoperative tumor recurrence [8]. Although several studies have demonstrated the survival benefits of preoperative TACE for patients with HCC [9, 10], others have failed to show any significant survival benefit [11–16]. Therefore, the role of preoperative TACE for HCC remains a contradictory issue. A recent review of three randomized controlled trials (RCTs) showed that preoperative TACE did not significantly improve survival [17]. However, their study only involved 257 participants, and therefore may not be convincing enough to confirm the effect conclusively [18]. To produce more reliable evidence for clinical decision-making, meta-analytic techniques could be applied to nonrandomized comparative studies (NRCTs) to ensure both the number and sample size of RCTs [19], knowing that meta-analysis of well-designed NRCTs is feasible and the results are remarkably similar to those of contemporaneous RCTs [20]. The present meta-analysis should be able to provide an updated evaluation on preoperative TACE for resectable HCC by taking into account all the currently evidence from RCTs and well-designed NRCTs.

The design of TACE is based on the principle that primary HCC is supplied almost exclusively (90%) by the hepatic arteries. The obstruction of the feeding arteries can induce tumor ischemic necrosis. A combination of chemotherapy can drastically increase the local concentration of the chemotherapeutic agent and may improve the benefit of therapy. In 2003, a review of 7 RCTs showed that TACE significantly improved 2-year overall survival compared with nonactive treatment in patients with unresectable HCC [41]. In 2005, this therapy was recommended as standard intervention for unresectable patients with large/multifocal HCC who do not have vascular invasion or extrahepatic spread [7]. In contrast, the results of present pooled analysis of 21 trials do not support the use of preoperative TACE in the management of patients with resectable HCC.

Although TACE is effective for main tumors, intrahepatic metastases, tumor thrombi in the portal veins, and capsular invasion, which are considered risk factors contributing to HCC recurrence, are more unresponsive to TACE because of collateral and portal vein blood supply [8, 13, 16]. In addition, TACE mainly affects well-differentiated HCC without completely killing poorly differentiated cells [42], which harbour a high grade of malignancy and ready spread within the portal venous system [43]. Furthermore, hematogeneous and lymphatic spread dissemination of cancer cells can precede TACE treatment. It is therefore reasonable to conclude that TACE is unable to reduce the risk of postoperative recurrence, or confer a survival advantage.

Adachi et al.[13] and Harada et al. [28] reported that the TACE subgroup with complete tumor necrosis had a better survival rate than the group without TACE. This is partly due to residual confounding, because tumors with complete necrosis are strongly associated with favorable tumor-related factors, such as smaller tumor size and tumor encapsulation or less portal involvement. On the other hand, several other reports failed to make the same conclusion [15, 28, 30, 31]. It was found in the present study that approximately 20.1% of HCC tumors responded completely to TACE, suggesting that most of the HCC tumor cells were viable even when treated with TACE. The labeling index of proliferating cell nuclear antigen (a most widely used proliferation-associated marker) was significantly higher in the TACE group, indicating that residual HCC cells following preoperative TACE exhibit more aggressive behavior [44]. In support of this observation, Liou et al. [45] indicated that incomplete HCC necrosis after TACE (especially combined with necrotic area >50% main tumor size) was associated with the development of lung metastasis that has a strong adverse impact on patient survival. Adachi et al. [13] and Kim et al.[37] found that subjects with partial tumor necrosis had the lowest disease-free survival rate among the TACE subgroups and tended to have a lower survival rate than the group without TACE. Zhou et al. [16] noted that five patients lost the chance of potentially curative liver resection because of progression of disease with metastases (n = 4) and liver failure (n = 1) during intervals between last TACE hepatic resection. The mechanism underlying accelerated tumor progression by TACE is unclear. Intratumoral necrosis was found to weaken the adhesive potential of the tumor and subsequently facilitate the release of cancer cells from the primary tumor and dislodgment into the bloodstream [46]. Xiao et al.[47] reported that mutated p53 could enhance the proliferation of HCC cells and suppress the apoptosis of HCC cells after TACE. In addition, vascular endothelial growth factor (VEGF), the most specific known angiogenic factor that plays a critical role in tumor growth, invasion, and metastasis, was up-regulated by tumor tissue ischemia and hypoxia after TACE [48].

In the present meta-analysis, in-hospital mortality did not differ significantly between TACE group patients and non-TACE group patients. However, Gerunda et al. [25] reported that three patients died of liver failure during 2–5 months after surgery in the TACE group. Sasaki et al. [34] and Uchida et al. [29] reported that late death due to liver failure was significantly higher in the TACE group than that in the non-TACE group. Uchida et al. [29] considered that hepatic function impairment induced by TACE could be repaired easily in the noncirrhotic liver, but hepatic function may gradually and progressively deteriorate due to TACE in some cirrhotic patients.

This study has several limitations. First, much of the evidence comes from NRCTs that could either exaggerate or underestimate the measured magnitude of effect size [20]. To minimize this effect, we limited the analysis to well-designed studies. As a matter of fact, the estimates from overall meta-analysis were consistent with those derived from RCTs, suggesting that the magnitude of the effect was not affected by the inclusion of NRCTs. Second, significant heterogeneity was present in some outcomes. Variability in the surgeon experience and the chemoembolization schedule may have introduced potential bias. In addition, clinicopathological factors associated with recurrence, such as hepatitis status, cirrhotic liver, and tumor staging, might be another source of potential heterogeneity. The use of random-effects models partially mitigates this concern. Third, although 21 studies involving more than 3,000 patients were enrolled for analysis, funnel plot analysis revealed the sign of publication bias. This may relate to the use of published English data only. Fourth, it is important to note that 18 of the 21 studies were from Asia. This may raise a question regarding the validity of the results and applicability to other areas. Finally, although some authors have reported the efficacy of preoperative TACE for patients with advanced HCC [33] and large HCC [31, 40], the results are not further estimable for subgroup analysis given the absence of data in this respect in the other studies.

The updated meta-analysis represents the largest body of information currently available for assessing the role of preoperative TACE for HCC. This study demonstrates that preoperative TACE does not seem to improve the prognosis and therefore it should be prudent to recommend it as a preoperative routine procedure for resectable HCC.