Hepatocellular carcinoma with right atrial tumor thrombus: a systematic review

Background: Hepatocellular carcinoma with right atrial tumor thrombus is uncommon but with a dismal prognosis. Methods: By comprehensive literature retrieval of 2000–2019, 53 reports were obtained with 187 patients recruited into this study. The extracted data included patient characteristics, tumor characteristics, treatment, follow-up and outcomes. Statistical analyses applied were student t, Fisher exact and I2 tests. Patients were divided into 6 groups according to the treatment of choices: transarterial chemoembolization (TACE), surgery, radiotherapy, chemotherapy, intervention and supportive care. Results: The overall survival rate of this cohort was 40.8%. The survival rate of patients receiving TACE was 33.3% and that of surgical patients was 41.9%. The survival time of patients with TACE treatment was longer than surgical patients, but lack of statistical significance. Patients were under a follow-up of 15.7±16.6 (median 10) months. Patients receiving radiotherapy had under a longest follow-up among all groups. Intra- and/or extrahepatic recurrence of hepatocellular carcinoma was the major morbidity and also often causes of death. The mortality rates of patients with different treatments in a decremental sequence were supportive care >radiotherapy >surgery >TACE >intervention. No difference was noted in mortality between patients reported from case reports and those from non-case reports. Conclusions: Even though advanced hepatocellular carcinoma with right atrial thrombus is an aggressive malignancy, the present study showed that patients’ prognoses were improved and survival time elongated with active treatments such as TACE and surgery. Active treatments were thus advised to patients with hepatocellular carcinoma with right atrial tumor thrombus.

a decremental sequence were supportive care >radiotherapy >surgery >TACE >intervention. No difference was noted in mortality between patients reported from case reports and those from non-case reports. Conclusions: Even though advanced hepatocellular carcinoma with right atrial thrombus is an aggressive malignancy, the present study showed that patients' prognoses were improved and survival time elongated with active treatments such as TACE and surgery. Active treatments were thus advised to patients with hepatocellular carcinoma with right atrial tumor thrombus.
Background Hepatocellular carcinoma (HCC) is an aggressive malignancy with a potential to invade intrahepatic vasculatures [1]. HCC with a tumor thrombus extending into the right atrium (RA) via the inferior vena cava (IVC) is rare, with a documented incidence of 1-4.8% in autopsy series [1,2], but it is increasingly reported clinically with the development of medical imaging techniques [3]. The advanced HCC can be managed by non-surgical treatments, such as conservative treatment, transarterial chemoembolization (TACE) and radiotherapy [4]. Nevertheless, HCC patients with RA tumor thrombus often have a dismal prognosis and limited survival time, and respond poorly to the usual therapeutics [4].
Moreover, RA tumor thrombi often lead to sudden death as a result of right heart failure, tricuspid orifice occlusion, or pulmonary embolism [4]. Therefore, aggressive surgical treatment of HCC with RA tumor thrombus has been attempted. However, there is not any consensus on the therapeutic regimens of advanced HCC [3]. This article is intended to give an overview of advanced HCC with RA tumor thrombus and to discuss the management and outcomes.

Methods
English language literature was carefully retrieved in the PubMed database for articles published 2000-2019. The keywords entered in this search to identify articles were "hepatocellular carcinoma", "liver tumor", "tumor thrombus" and "right atrium". The screening of the bibliographic references helped in completing the literature retrieval. The inclusion criteria were clinical research, case series, or case report of HCC with RA thrombus with substantial patient information for statistical analysis. Seventy articles were found related to the topic and keywords in the literature search. The exclusion criteria were articles reporting: HCC with right ventricle metastasis (n=6), HCC with portal vein or IVC thrombus without RA extension (n=3), RA invasion by metastatic esophageal/pancreas/colon carcinoma (n=3), HCC with RA thrombus where patient information was scanty (n=2), fibrolamellar hepatocellular carcinoma with RA thrombus 4 (n=1), liver transplantation in Budd-Chiari syndrome (n=1) and cardiac complications after liver transplantation (n=1). In total, 17 articles were excluded and 53 articles were considered materials of the present review.
The data independently extracted from each study were patient characteristics, tumor characteristics, treatment, follow-up and outcomes. Data extraction was proceeded by tabulating all the necessary information of each report. This process was repeated three times to avoid omissions and ensure the integrity and credibility of the data. Publication bias that might come from the case reports and case series might affect the cumulative evidence.
The quantitative data were expressed in mean±standard deviation and were compared by independent samples t-test. Categorical variables were compared with Fisher exact test with continuity correction. p<0.05 was considered statistically significant. The extent of heterogeneity was determined by an I 2 method, and a p value of <0.1 was taken at a statistically significant level of heterogeneity.
Patients were divided into 6 groups according to the treatment of choices: TACE, surgery, radiotherapy, chemotherapy, intervention and supportive care. Besides, some patients were not treated, while treatment was not described in others.
The clinical symptoms were described for 36 patients, with pedal edema being the most common (Table I). Laboratory investigational results on admission were shown in Table III.

Treatment
Liver tumor resection was performed with RA tumor thrombi remained followed by chemotherapy with bevacizumab in 1 patient [48], and RA and IVC tumor thrombi removal followed by microwave ablation/TACE for liver tumor in 2 patients [26,16]. Their survival time was 6, 6 and 7 months, respectively (median, 6 months).
Interventional therapy was performed in 2 patients: mechanical thrombectomy of the mobile right atrial mass using the AngioVac cannula thrombectomy catheter with subcutaneous enoxaparin and oral sorafenib in one who did not respond to sorafenib and died [41] and percutaneous microwave ablation in another but intrahepatic tumor recurrence at 3 months while tumors were completely ablated by TACE and salvage microwave ablation who was alive [22]. 8 Radiotherapy included external beam radiotherapy with 2500 cGy in 5 fractions in one patient, the RA mass was reduced at 1 month but died of multiple metastasis [15] and hypofractionated radiotherapy in 18 patients with 2 alive at a follow-up of 3-40 month [23]. The outcomes of each group were shown in Table V.
Patients receiving radiotherapy had under a longest follow-up among all groups (Table VI).
Intra-and/or extrahepatic recurrence of HCC was the major morbidity and also the cause of death in most cases (Table VII).

Discussion
The etiology of HCC in the present study is comparable to that reported by Wakayama et al. [50], with hepatitis B virus infection being the most common etiology, followed by 9 hepatitis C virus infection. Advanced HCCs are aggressive and refractory, often with multiple focuses, portal and hepatic vein invasions, and extrahepatic metastases to the lungs, adrenal gland and mediastinal lymph node [50]. RA thrombus is an infrequent sequel of advanced HCCs, but prognosis is poor with limited treatment options [41]. The incidence of tumor thrombus may be higher in those patients with a serum α-fetoprotein level >1,000 μg/L and a tumor size >5 cm [10]. TACE has become a acceptable and safe treatment for unresectable HCCs [54, 55], but extrahepatic collateral artery supply to the tumor thrombus may require sequential repeated TACE, and marked arteriovenous shunts associated with tumor thrombus may limit the therapeutic effect of TACE [56]. TACE with and without combined radiotherapy, and chemotherapy with thalidomide have been reported, but with no reliable evidence of benefits from these treatments [3]. Patients with IVC/RA tumor thrombus treated with TACE had a mean survival time of 4.2 (range, 1.5-76.7) months as reported by Chern et al. [55]. Wang et al. [3] reported the median survival time of such patients was 4.6 months.
Duan et al. [11] retrospectively observed 11 cases of HCC with IVC/RA tumor thrombus treated with combined TACE and external beam radiation. They pointed out that all patients died of disease progression, and the median survival time was 21 months. The clinical effects of TACE in the treatment of HCC with IVC/RA tumor thrombus were heterogeneous and warrant further observations [3]. Nevertheless, TACE helps tumor thrombectomy by stabilizing the tumor thrombi, reducing the size, easy removal and preventing fragmentation [42].
Liver resection with thrombectomy has been advocated for HCC patients with IVC/RA tumor thrombus, but its curative effect remains debating. Patients may still show a poor prognosis even with surgical treatment [3]. The surgical indications of HCC patients for major hepatectomy were noncirrhotic or cirrhotic patients at Pugh-Child Class A with no portal hypertension and the indocyanine green clearance value is ≤12% at 15 minutes [57]. However, higher values of indocyanine green clearance are not an absolute surgical contraindication as for the possible clearance impairment by tumor-related vascular obstruction [57]. Pesi et al. [35] summarized that RA tumor thrombus removal could be performed in three ways: 1) with the use of THVE of the liver without CPB, which is indicated for tumor thrombi with an initial contiguity to the RA; 2) normothermic CPB with THVE; and 3) CPB with hypothermic circulatory arrest, but its use is limited due to potentially intraoperative bleeding, possible brain damage and postoperative liver dysfunction. Wang et al. [3] reported that they performed cavoatrial thrombectomy for HCC patients with RA thrombus by modifying procedures as minimally invasive as possible depending on the extension of the tumor thrombus. When the tumor thrombus just slightly entered the RA, median sternotomy or thoracotomy and CPB were not used, but THVE was utilized instead. As a consequence, a significant survival benefit of surgical treatment for HCC patients with IVC/RA tumor thrombus was obtained.
Based on Response Evaluation Criteria in Solid Tumor (RECIST), sorafenib showed a dismal response rate of 2%, but a remarkable improvement of overall survival [58]. A modified RECIST (mRECIST) was termed by modifying the target lesion from the entire lesion to only the contrast-enhanced hepatic lesion at the arterial phase of a dynamic imaging technique [59]. Edeline et al. [58] suggested, after retrospectively studied 53 patients with advanced HCC, that mRECIST should be used for the standard assessment of treatment efficacy due to its wider applicability to patients and the usefulness in guiding the 11 continuation of sorafenib.
HCC with macrovascular invasion is an extensively debated topic. Guidelines often struggle to fit these cases in, leaving them in a "grey area". There is increasing evidence suggesting that alternative strategies to sorafenib might improve patients' survival advanced HCC with macrovascular invasion but lack of sufficient evidence [60]. A recent meta-analysis by Chen et al. [61] revealed that the overall survival is higher in hepatectomy than in the TACE group, and that hepatectomy was superior over TACE in 1-     Figure 1 The distribution of segmental invasion of the liver by hepatocellular carcinoma.