Patient Characteristics
In total 53 articles were collected [1-53], including 5 (9.4%) retrospective studies [3, 11, 23, 50, 53], 4 (7.5%) case series [1, 21, 43, 49], and 44 (83.0%) case reports [2, 4–10, 12–20, 22, 24–42, 44–48, 51, 52], with 187 patients involved. Even though cohort studies, case-control studies and case series are considered to form a hierarchy of increasing risk of bias. These studies reflected closely a routine practice or the usual setting where the intervention would be implemented. The heterogeneity between the studies was not significant.
On current admission, patients were at the age of 58.7±12.4 (range, 23-84; median, 60) years (n=93). Gender was known for 105 patients: 88 (83.8%) were male and 17 (16.2%) were female (χ2=96.0, p<0.001). In total 166 (88.8%) patients had a medical history of liver disease (Table II).
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.
In 8 patients with recurrent HCC, treatment had been done with hepatectomy in 2 (25%) patients [1, 30], TACE in 3 (37.5%) patients [1, 19], and TACE plus direct-acting antiviral therapy (sofosbuvir) [5], radiofrequency ablation plus doxorubicin and sorafenib chemotherapy [15], and TACE plus radiofrequency ablation plus sorafenib [40] in 1 (12.5%) patient each.
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.
The timing of diagnosis of RA thrombi was described for 53 patients. The diagnosis was made at the time of HCC recurrence in 5 (9.4%) patients [1, 5, 13, 15, 30], in the progression of HCC in 13 (24.5%) patients [1, 17, 19, 34, 36–38, 40, 42, 48, 51], and simultaneously with primary HCC in 35 (66.0%) patients [2, 4, 6–10, 12, 14, 16, 18, 20–22, 24–29, 31–33, 35, 39, 41, 44–47, 49, 52].
The time interval between diagnoses of HCC and of RA tumor thrombus was 33.5±22.1 (range, 9–56; median, 35) months (n=4) for patients with recurrent HCC and 33.4±46.2 (range, 2–144; median, 12) months (n=9) for patients at HCC progression (t=0.002, p=0.998).
Tumor Characteristics
The size of the liver tumor was described for 57 patients. The calculated tumor size was 8.4±4.1 (range, 1.3–21; median, 7.6) cm, with only 3 (5.3%) tumors of 3 patients <3 cm [1, 6, 51].
The locations of liver tumors were described for 56 patients: 16 (28.6%) were located in the left lobe [2, 8, 12, 16–18, 21, 27, 31, 35, 46, 47, 52, 53], one of which extended to the right lobe at a later stage [17], while 35 (62.5%) tumors were located in the right lobe [1, 6, 7, 9, 10, 13, 14, 20–22, 24, 28, 29, 34, 39, 41, 42, 48, 49, 53], and 5 (8.9%) involved both lobes [25, 26, 32, 33, 53] (χ2=37.0, p<0.001). There was no significant difference in tumor size between tumors located in the left and in the right lobes (8.6±4.2 cm vs. 8.9±4.4 cm, t=-0.207, p=0.837).
The segmental locations of liver tumors were described for 31 patients, and a total of 68 segments were invaded with 1–4 invaded segments in each patient [2, 10, 13, 18, 21, 22, 25, 27–29, 34, 41, 42, 53]. Segments 7 and 8 were the most commonly invaded by liver tumors (Figure 1).
Apart from RA thrombus, tumor thrombus in alternative vasculatures developed in 106 (56.7%) patients, and IVC thrombus was the most frequent (Table IV). Maximal size of RA tumor thrombus was 4.6±2.3 (range, 2–15; median, 4.4) cm (n=42). RA tumor thrombus-induced tricuspid orifice occlusion of different degrees was noted in 3 patients [10, 15, 31].
Simultaneous lung metastasis was noted in 6 patients [2, 8, 10, 17, 37, 47]. Diaphragm metastasis occurred in 1 patient [7].
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).
The 30 patients with a one-stage operation for both HCC and RA thrombus survived 14.4±12.8 (range, 1.3–56; median, 11.2) months (n=25) [2–4, 12, 13, 18, 20, 21, 25, 28–30, 35, 42, 43, 45, 49–52]. One patient receiving a two-stage operation survived 6 months [38]. The surgical operation was performed under cardiopulmonary bypass (CPB) in 18 patients [2, 3, 18, 21, 28–30, 35, 38, 43, 45, 51, 52], under veno-venous bypass in 1 patient [25] and with total hepatic vascular exclusion (THVE) with no CPB in 15 patients [3, 4, 12, 13, 20, 42, 49, 50].
The operation time was 9.1±2.5 (range, 5.6–12.3; median 9.0) hours (n=12) [4, 7, 12, 25, 29–31, 35, 42, 45, 51, 52], the CPB time was 40.6±23.9 (range, 16–100; median, 38) min (n=9) [2, 7, 12, 29, 30, 45, 50, 51, 52], and the hepatic occlusion time was 29.4±26.3 (range, 10-87; median, 19) min (n=11) [4, 12, 13, 20, 25, 29–31, 42, 45, 52]. The total blood loss amount was 3.562,0±2,692.2 (range, 650-8,200; median, 2,692) mL (n=10) [7, 13, 25, 29–31, 35, 42, 51, 52].
TACE, solely or combined with chemotherapy/radiotherapy/surgery, was done 1–7 time per patient, and thalidomide 100 mg bid was the usual regimen. Complete/partial regression of liver and RA tumor, α-fetoprotein decrease and symptom-free were observed at 1–4 months [1]. Selective embolization with pirarubicin 30 mg, oxaliplatin 200 mg, hydroxycamptothecine 20 mg and iodized-oil was also reported obtaining similar effects to thalidomide [46].
Systemic chemotherapy with sorafenib were applied in 4 patients [9, 14, 27, 47].
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].
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.
Follow-up and Survival data
Patients were under a follow-up of 15.7±16.6 (range, 0.5–97; median 10) months (n=75). 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).
The overall survival rate of this cohort was 40.8% (20/49). The survival rate of patients receiving TACE was 33.3% (4/12) and that of surgical patients was 41.9% (13/31) (χ2=0.3, p=0.735). The prognoses of the patients with different treatments were shown in Table V. The survival time of TACE patients was longer than that of surgical patients, but lack of a statistical significance (20.0±3.4 months vs. 13.3±12.1 months, t=-1.455, p=0.151). The mortality rates of patients with different treatments in a decremental sequence were supportive care > radiotherapy > surgery > TACE > intervention (Table VI). No difference was noted in mortality between patients reported from case reports and those from non-case reports (Table VIII).
The pathology of HCC was available for 18 patients: 10 (55.6%) were moderately differentiated [2, 11, 13, 25, 35, 42, 52], 3 (16.7%) were moderately to poorly differentiated [7, 18, 33], and 5 (27.8%) were poorly differentiated [4, 11, 12, 29, 30].