Survival benefit of chemoembolization plus Iodine125 seed implantation in unresectable hepatitis B-related hepatocellular carcinoma with PVTT: a retrospective matched cohort study

Current treatment recommendations for HCC provide very limited data on PVTT management. Despite the controversy, TACE remains the first-line treatment for BCLC stage C HCC patients in China. In the present study, all HCC participants successfully received TACE treatment without serious complications (i.e., TACE-related liver failure). Notably, the following steps were crucial for the performance of TACE for HCC-PVTT patients in this study. First, the careful selection of qualified patients was crucial for the success of TACE. Only patients with CHILD-PUGH A/B and ECOG 0-2 whose blood supply in the main portal vein was normal or incompletely disrupted or had imaging-confirmed portal-collateral circulation were indicated for TACE in our study. Second, all TACE procedures were carefully performed with a superselective catheterization technique. For patients with PVTT, some studies have also shown that using less aggressive embolization after superselective catheterization is safe, with no increase in morbidity or mortality [22, 23].

Although TACE has been proven to be an effective and safe basic therapeutic method for intrahepatic primary HCC lesions, combined treatment with TACE and novel drugs or other therapies might be a better alternative strategy for HCC with PVTT. TACE combined with sorafenib was considered to be an effective combination treatment for HCC-PVTT [24] and was first recommended by the attending physician in our institute if the main portal vein was patent or multiple collateral vessels from the obstructed portal vein were observed in the CT or MRI imaging [19]. Nevertheless, sorafenib does not represent a cost-effective drug in this indication in some developing countries [25]. Additionally, some patients are afraid of a deterioration of their quality of life owing to drug-induced side effects, and consequently refuse to take sorafenib. In this study, although we recommended that all HCC-PVTT patients take sorafenib as a standard treatment, these patients refused for the above reasons and consented to TACE alone or TACE plus Iodine125 seed implantation.

There is increasing evidence that Yttrium-90 radioactive microsphere hepatic artery embolization (TARE) can be delivered safely and effectively in HCC-PVTT patients, leading to a median OS of approximately 10 months following the procedure [26]. TARE might have an advantage over TACE in Child-Pugh A patients with very large tumours where TACE does not provide a very effective treatment [27]. Similar to Yttrium-90, Iodine131 is another β-emitter with a physical half-life of 8.05 days that can be used as a radionuclide therapy for HCC and PVTT. Because Iodine131-lipiodol is a noparticle embolization at the end of the procedure, PVTT is not considered to be a relative or absolute contraindication for Iodine131-lipiodol. Although most studies have failed to demonstrate any survival benefits, Iodine131-lipiodol seems to be much better tolerated than chemoembolization, both in terms of clinically expressed side effects and arteriographic findings [28]. Lintia-Gaultier et al [29] reported a median survival of 32 weeks in fifty patients (86 % of them complicated with PVTT) treated with Iodine131-lipiodol compared with 8 weeks in the untreated group. Raoul et al. [30] reported a similar result of a median survival of 6 months in the Iodine131-lipiodol group compared with 1.5 months in the control group for Child-Pugh A and B patients with PVTT. However, the treatment tolerance and effectiveness of radioembolization or Iodine131-lipiodol may be affected when it is used for cirrhotic patients or patients with APS or arterio-venous shunts (AVS) [31]. Three-dimensional conformal radiation therapy (3-DCRT) is another novel radiotherapy for PVTT [13]. Tang et al. [32] reported that combined TACE and 3-DCRT resulted in a median survival time of 12.3 months and survival rates of 51.6 %, 28.4 %, and 19.9 % at 1, 2, and 3 years, respectively, among 185 HCC-PVTT cases. However, no prospective study has compared Iodine-131-lipiodol, TARE, 3-DCRT and Iodine-125 seed implantation in HCC patients with PVTT.

Yang et al. [33] adopted a strategy of TACE combined with intravascular implantation of Iodine125 seed strands into the portal vein for the treatment of 43 HCC-PVTT patients and reported that the average and median survival times were 221.7 ± 16.3 days and 210.0 ± 17.5 days, respectively. However, the potential problem associated with the intravascular implantation of radioactive seed strands is that insufficient irradiation of PVTT may occur due to the uneven distribution of the Iodine125 seed strand radioactive sources inside the PVTT. Based on the pre-procedural TPS planning and CT scan surveillance during the procedure, percutaneous transhepatic puncture of the PVTT and implantation of Iodine125 seeds inside and around the PVTT could allow an even and quantifiable distribution of the radioactive source.

Our results showed that the OS of patients who had a radiologic response to PVTT was more favourable than patients who had no response to PVTT. There were no significant differences in the survival of patients with no response to PVTT between the TACE-I125 and TACE groups. Our results indicated that the separate treatment of PVTT was very important for prolonging the survival time of patients with HCC and PVTT. We speculate that the effective treatment of PVTT can partially or completely reopen the portal venous system, which can in turn maintain the oxygen supply to the liver, induce a good state of liver function, and effectively reduce the incidence of portal hypertension-related complications. Additionally, effective PVTT treatment can also prevent or delay intrahepatic metastasis and tumour recurrence.

APS was considered to be another independent predictor of poor prognosis and a typical complication of PVTT [12, 34]. Although the exact reason was unknown, some studies found that APS could be decreased or cured with radiotherapy [31]. However, future studies are required to prove that Iodine125 implantation in the PVTT can lead to a good APS response.

Some studies showed that Child-Pugh B patients had significantly poorer survival compared to Child-Pugh A patients [35]. This present study did not demonstrate a favourable survival benefit in Child-Pugh A compared with Child-Pugh B patients, which may be related to the fact that the 81 (73 %) Child-Pugh B patients in this study had a Child-Pugh numeric score of 7 (B7). A previous study demonstrated that Child-Pugh B7 patients had a larger survival rate than Child-Pugh B8 and B9 patients [36]. Piscaglia et al. [36] reported that Child-Pugh B7 HCC patients achieved an acceptable median survival of 22.0 months (range 0–60.0) after TACE. That result was comparable to the results included in Llovet’s meta-analysis [37], which was largely based on Child-Pugh A patients. In another retrospective study by Federico et al. [38], the OS in Child-Pugh A patients was not significantly different compared to Child-Pugh B7 patients. Future trials should validate this observation.

The main limitation of retrospective studies is selection bias. To reduce bias caused by using the TACE group as the control, the factors most likely to affect the survival outcome were used as matching factors to select a matching cohort of patients. However, the retrospective nature of the study dictated that selection bias was unavoidable. A randomized clinical trial is required to validate the findings from this study. Furthermore, only patients with HB-HCC were studied here. Thus, the results from this study may not be applicable to other HCC populations.

In conclusion, combined treatment with TACE and Iodine125 seed implantation achieved a promising OS in selected unresectable HB-HCC patients with PVTT. Therefore, TACE combined with Iodine125 seed implantation might be an alternative treatment for these patients. A randomized clinical trial is warranted to validate the findings of this study.