Transarterial chemoembolization (TACE) is recommended for patients with intermediate hepatocellular carcinoma (HCC) according to treatment guidelines. However, a large number of patients with advanced HCC also receive TACE in clinical practice, especially for those with liver-confined HCC and Eastern Cooperative Oncology Group score (ECOG) 1. In view of previous studies, such patients have different prognoses from advanced HCC patients with macrovascular invasion or extrahepatic spread; therefore, patients with ECOG 1 alone might be classified into the intermediate stage and benefit from TACE treatment, but a study particularly focusing on such patients and exploring the effectiveness of TACE therapy is lacking.

To investigate treatment outcomes of TACE in HCC patients with ECOG 1 alone and propose a specific prognostic model.

Patients from 24 Chinese tertiary hospitals were selected in this nationwide multicenter observational study from January 2010 to May 2016. Overall survival (OS) was estimated using Kaplan–Meier curves and compared by the log-rank test. Multivariate Cox regression was used to develop the potential prognostic models. The discriminatory ability of the models was compared and validated in various patient subgroups. The individual survival prediction for six-and-twelve (6&12) criteria, defined as the algebraic sum of tumor size (cm) and tumor number, was illustrated by contour plot of 3-year survival probability and nomogram.

A total of 792 eligible patients were included. During follow-up, median OS reached 18.9 mo [95% confidence interval (CI): 16.9-21.0]. Three independent multivariate analyses demonstrated that tumor size, tumor number, α-fetoprotein level, albumin–bilirubin grade and total bilirubin were prognostic factors of OS (P < 0.05). The previously proposed 6&12 criteria was comparable or even better than currently proposed with the highest predictive ability. In addition, the 6&12 criteria was correlated with OS in various subgroups of patients. The patients were stratified into three strata with score ≤ 6, > 6 but ≤ 12, and > 12 with different median OS of 39.8 mo (95%CI: 23.9-55.7), 21.1 mo (95%CI: 18.4-23.8) and 9.8 mo (95%CI: 8.3-11.3), respectively (P < 0.001).

TACE is effective for advanced HCC patients with ECOG 1 alone, and the 6&12 criteria may help with clinical decision-making.

According to the Barcelona Clinic Liver Cancer (BCLC) staging system and treatment guidelines, transarterial chemoembolization (TACE) is currently the only recommended therapy for patients with hepatocellular carcinoma (HCC) of intermediate stage[1-3]. However, the application of TACE is beyond such recommendations in clinical practice especially for advanced diseases[4-6]. In the BCLC system, advanced HCC is characteristic of macrovascular invasion (MVI), extrahepatic spread (EHS) and tumor-related symptoms based on Eastern Cooperative Oncology Group (ECOG) scoring. With at least one of these features, except preserved liver function, the patients should be stratified into advanced stage[1,7]. However, the population is of high heterogeneity because of such definitions.

Previously, it has been demonstrated that advanced HCC patients with ECOG 1 alone are different from those with MVI and/or EHS[8]. The presence of mild tumor-related symptoms (ECOG 1) should not be considered as an independent feature of advanced HCC[9]. Therefore, it is unclear whether patients with liver-confined HCC and mild symptoms ought to be included in intermediate or advanced stage. This group of patients is considered to be substage B4 according to the substratification of BCLC, which is different from its original definitions[10]. The Hong Kong Liver Cancer system regards patients with asymptomatic and mild symptomatic HCC to be the same and recommends that patients with ECOG 1 receive TACE[11]. Similarly, advanced HCC patients with ECOG 1 have been recruited for evaluation of TACE in several observational studies and randomized controlled trials[12-15].

Consequently, whether advanced HCC patients with ECOG 1 alone should be classified into the intermediate stage and recommended for TACE remains inconclusive. This study focused on such patients and investigated the treatment outcomes of TACE and the independent predictive factors of survival and proposed a special prognostic score for patient stratification and individual prediction.

In this nationwide multicenter study, we retrospectively explored the treatment outcomes of TACE in advanced HCC patients with ECOG 1 alone and investigated the prognostic factors for OS. Overall, the median OS for all patients reached 18.9 mo. Remarkably, it was demonstrated that tumor size and number were robust prognostic factors of OS, based on which the 6&12 criteria showed consistent discriminatory ability. In addition, the 6&12 criteria could stratify these patients into three subgroups with significantly different OS after TACE.

According to the current treatment guidelines, TACE is recommended for patients with intermediate HCC[2,3]. However, many advanced HCC patients receive TACE in clinical practice especially those with tumors confined to the liver[4,17]. The median OS of 18.9 mo in our study was consistent with previous reports in real-world conditions with a median OS of 19.2 mo in which the patients with unresectable early or intermediate HCC were included[18]. Therefore, the treatment outcomes of the current study indicated that those advanced HCC patients with ECOG 1 would be suitable for TACE and could be included in the intermediate stage. In the Hong Kong Liver Cancer staging system, ECOG 1 was regarded the same as ECOG 0, and those patients should be treated with TACE or curative therapies[11]. In the BCLC system, inclusion of patients with ECOG 1 but without MVI/EHS in BCLC B stage improved the discrimination of the staging system[9]. However, according to the substratification of BCLC B stage, advanced HCC patients with ECOG 1 were recognized as B4 stage, who had a worse prognosis compared with others in B stage[19,20]. In addition, best supportive care was initially recommended to them rather than TACE and even systemic therapies[10]. Consequently, the risk stratification and treatment arrangement of these patients remain controversial.

As a highly complex technical procedure, TACE is operator-dependent and heterogeneity exists in the techniques and agents used, which might explain variations in outcomes in patients with HCC[21]. However, there is no consensus on the optimal chemotherapeutic agent to use in TACE. Worldwide, the most popular anticancer drug injected is doxorubicin[22]. In addition, a recent randomized controlled trial comparing TACE with transarterial embolization found no differences in terms of tumor response and OS, which questioned the effects of chemotherapy agents[12]. Considering these points, using the mixture of doxorubicin, cisplatin, epirubicin or oxaliplatin might have little effect on our current analysis. Although TACE was the most commonly used treatment for patients with unresectable HCC, sorafenib was the recommended systemic therapy for advanced disease and has been effective worldwide[4,6,23,24]. Furthermore, combining TACE and sorafenib might be a “good marriage” for unresectable HCC[25,26]. In addition, systemic chemotherapy with doxorubicin or FOLFOX did not demonstrate survival benefits[27,28]. Major emphasis has been focused on the efficacy of transarterial radioembolization. In cohort studies, transarterial radioembolization showed tumor response rates between 40% and 90%, and survival was comparable to that obtained with TACE and sorafenib[29,30]. However, randomized controlled trials failed to demonstrate a survival benefit from transarterial radioembolization compared with sorafenib[31]. Recently, lenvatinib was found to be non-inferior to sorafenib, offering another treatment option for patients with advanced HCC[32]; however, large multicenter real-world studies are highly needed.

In the current study, we performed in-depth investigation into this population and stratified the patients according to tumor burden. For patients with low tumor burden based on 6&12 criteria, the median OS was 39.8 mo, which was comparable to that of the patients with intermediate HCC[16]. It might be inferred that this group of patients would be suitable for TACE alone and should be preferably regarded as intermediate stage. As for patients with high tumor burden, they had a median OS of 9.8 mo. Compared with the advanced HCC patients receiving systemic therapy, TACE might be unacceptable[32-35]. Because of the potential adverse effect of TACE on liver function, HCC tumors > 10 cm are commonly considered to be a contraindication for TACE[21]. In addition, the patients with moderate tumor burden had a median OS of 21.1 mo. For them, combining TACE with systemic treatment might make a difference. Consequently, according to the patient stratification with 6&12 criteria, these findings might not only facilitate the outcome prediction but also provide a reference for stratified staging of these patients and help the decision-making.

The current study, for the first time, focused on advanced HCC patients with ECOG 1 alone, investigated the treatment outcomes of TACE and proposed a specific prognostic system for patient stratification and survival prediction, which could better guide treatment selection in this controversial population. There were several limitations to this retrospective cohort study. Firstly, the potential patient selection bias was unavoidable for this retrospective observational study. Nevertheless, this bias might be reduced by including a large cohort of consecutive patients. Secondly, TACE is not recommended by the guidelines for treatment of advanced HCC[2,3]. Although systemic therapies are recommended for advanced HCC, they mainly refer to patients with MVI/EHS, and it is inconclusive whether advanced HCC patients with ECOG 1 alone should be placed in intermediate or advanced stages. Finally, with the absence of external validation, the generalization and extrapolation of the current findings should be made with caution. However, the results of this study came from a multicenter cohort from 24 tertiary Chinese hospitals, and subgroup analysis demonstrated the reliable and consistent predictive factors of the proposed 6&12 criteria.

In summary, our study demonstrated that TACE was safe and effective for advanced HCC patients with ECOG 1 alone; tumor size and tumor number, rather than the liver function or AFP level, were robust prognostic factors of OS after TACE. Based on these findings, the 6&12 criteria could predict prognosis regardless of baseline characteristics. Future studies focusing on these patients with other treatment modalities are still required.

We gratefully acknowledge the following investigators for their dedication in performing TACE procedures and follow-up of patients: Professor Junhui Sun, Department of Hepatobiliary and Pancreatic Interventional Cancer, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Professor Ming Huang, Department of Minimally Invasive International Therapy, The Third Affiliated Hospital of Kunming University, Tumor Hospital of Yunnan Province, Kunming, China; Professor Wei Mu, Department of Radiology, The Southwest Hospital, Third Military Medical University, Chongqing, China; Professor Guowen Yin, Department of Interventional Radiology, Jiangsu Provincial Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; Professor Hailiang Li, Department of Interventional Radiology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China; Professor Hui Zhao, Department of Interventional Radiology, The Affiliated Hospital of Nantong University, Nantong, China; Professor Jing Li , Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Professor Chunqing Zhang, Department of Gastroenterology and Hepatology, Shandong Province Hospital Affiliated to Shandong University, Jinan, China; Professor Xiaoli Zhu, Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China; Professor Jianbing Wu, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China; Professor Jiaping Li, Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Professor Weidong Gong, Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China; Professor Zixiang Li, Interventional Medical Centre of the Affiliated Hospital of Qingdao University, Qingdao, China; Professor Zhengyu Lin, Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Professor Xingnan Pan, Clinical Liver Diseases Research Centre, Nanjing Military Command, 180th Hospital of PLA, Quanzhou, China; Professor Haibin Shi, Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Professor Guoliang Shao, Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, China; Professor Jueshi Liu, Department of Interventional Radiology and Vascular Surgery, Hunan Provincial People’s Hospital, Changsha, China; Professor Shufa Yang, Department of Interventional Radiology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China; Professor Yanbo Zheng, Department of Interventional Radiology, Yantai Yuhuangding Hospital, Yantai, China; Professor Jian Xu, Department of Medical Imaging, Nanjing General Hospital of the Nanjing Military Command, Nanjing, China; Professor Jinlong Song, Department of Interventional Therapy, Shandong Tumor Hospital, Jinan, China; Professor Wenhui Wang, Department of Interventional Medicine, The First Affiliated Hospital of Lanzhou University, Lanzhou, China.