We retrospectively evaluated the treatment results of RT with or without chemotherapy for 43 patients with HCC that invaded PV, HV, IVC, or BD, and the one-year OS rate for all the patients was 60% and their ORR was 58%.
Although there are various treatment modalities for advanced HCC, including sorafenib, regorafenib, surgery, TACE, HAIC, and RT, no standard therapeutic options are as of yet established.
In particular, the selection of treatment for HCC with a vascular invasion that causes poor prognosis is still controversial. Sorafenib and regorafenib have demonstrated significant benefits for OS and safety in the analysis of randomized phase III trials [5, 6, 14, 15]. The trial showed that the median OS for patients with advanced HCC, a well-preserved liver function, and undergoing treatment with sorafenib was 10.7 months, and the ORR was only 2–3%. Although the disease control rate (DCR), that was defined as the percentage of patients with CR, PR, or SD based on radiologic review, was 43%. Moreover, the median OS of the patients with macroscopic vascular invasion (MVI) and treated by sorafenib was 8.1 months and the DCR was 38.9% [14]. In a nationwide survey of advanced HCC in Japan it was shown that HAIC can have a significant positive impact on OS, the median OS was 7.9 months in patients with PVTT and 4.8 months longer than the control group [8]. Analysis in a non-randomized prospective study showed that TACE can be an effective treatment for PVTT, and the one-year OS rate was 30% and the ORR was 19% [7]. Although the multicenter cohort studies of surgery for PVTT showed that the five-year OS was 10–39% and median survival time was 11–21 months [16-18], surgery is generally not feasible in patients with advanced HCC due to the spreading of multiple intrahepatic tumors or insufficient function of the remaining liver.
Previous studies have suggested the potential therapeutic role of RT in patients with vascular invasion of HCC, and the OS rates in those studies were better than any other studies with other treatment modalities. A large multicenter study has already assessed the efficacy of RT [19], and the one-year OS of patients with PVTT was found to be 43% and the ORR was 52%. Moreover, the PVTT responders had a better median survival time than the non-responders (14 months versus 6 months, p < 0.05). In our study, the OS rate was similar to that of the multicenter study, and the OS rate of responders was also significantly better than that of non-responders (75% versus 35%, p = 0.009). The objective response must be an important endpoint, because reducing the tumor thrombosis size can delay intravascular tumor growth and the deterioration of liver function, by preserving adequate vascular flow, as well as by facilitating subsequent treatment of the primary tumor.
We analyzed the prognostic factors relating to the ORR, which was evaluated using dynamic imaging studies according to the modified criteria, and a prescribed dose was a unique significant factor (Odds ratio 6.1, 95% CI [1.3, 30], p = 0.025) in the multivariate analysis. This finding was consistent with the results of previous studies that recommended a prescribed dose higher than 45–50 in EQD2 [2, 19-22]. Although some studies emphasized the impact of the local response in relation to the OS, few studies have suggested factors relating to the ORR. The Child-Pugh class, T stage, cause of hepatitis, tumor size, site of tumor thrombosis (PV, HV, IVC, or BD), combined chemotherapy including sorafenib, HAIC, or TACE, none of them were found to be related with ORR in our study.
The OS of patients with EOCG PS 0-1, Child-Pugh class A, a tumor thrombosis length of less than 3.8 cm, more than 48.75 Gy of EQD2, or combined chemotherapy was significantly better than that of other patients, in the univariate analysis. The length of tumor thrombosis was extracted as a significant prognostic factor among all the aforementioned factors, in the multivariate analysis. In our study, ROC curve analysis was used to calculate a threshold value for the length of tumor thrombosis in relation to response, and that was found to be 3.8 cm. To our knowledge, there has been no study that has demonstrated the significant correlation between the length of tumor thrombosis and OS. It was interesting to note that the length of tumor thrombosis was only a unique factor related with OS, in the multivariate analysis, although the local response was significantly related with OS and the significant prognostic factor of local response was the RT dose (EQD2). Moreover, a small difference of 6.4 Gy in EQD2 unexpectedly resulted in a significant impact on response. This might be because short tumor thrombosis tended to be irradiated in 48.75 Gy of EQD2 and long tumor thrombosis in 42.35 Gy in order to minimize the risk of the liver damage.
Yoon et al. [1] treated PVTT with a combination of TACE and RT and reported that the involvement of main or bilateral PV, a higher level of α-fetoprotein (AFP), and advanced modified UICC stage were independent predictors of decreased OS. Pao et al. [2] treated IVCTT with RT and reported that the median OS was significantly longer for patients with Child-Pugh class A, without LN metastasis, and without lung metastasis. The results of these previous studies have shown that the OS was influenced by factors that affected liver functions and systemic dissemination. The size of the tumor thrombosis must influence the liver function because of the blood supply, and the liver dysfunction causes portal hypertension resulting in the rupture of collateral vessels, ascites, and hepatic encephalopathy. Even if CR or PR is not achieved for a patient with small tumor thrombosis, the maintaining SD must lead to a long-term prognosis, and small field irradiation reduces the risk of radiation-induced liver disease (RILD).
The general guideline was that the fraction of the normal liver treated with more than 50% of prescribed dose should be less than 50% of the normal liver volume (V50% < 50%), and the volume of the normal liver that was damaged by irradiation was defined as the fraction volume of normal liver that received more than 30 Gy (V30Gy), with no more than 30% of the normal liver exposed to more than 30 Gy (V30Gy < 30%) [23]. In our study, the correlation between RILD and a dose-volume histogram was not acknowledged. This might be because we used the system of respiratory-gated irradiation to reduce the volume of the liver that was irradiated. Recently, some studies have reported the efficacy of SRT or proton beam irradiation for HCC with vascular invasion [21, 22, 24, 25]. Focal irradiation using such a high-tech RT may be able to help change the strategy for this disease with poor prognosis.
In our study, neither the N nor M factor was significantly related to OS. This might be because systemic treatment controlled those metastases and their prognosis was not different from the patients without N or M factor. In detail, 78% of the patients with N or M factor had received systemic treatment after RT. Prospective studies are needed to evaluate the efficacy of combination therapy between the local treatment of RT and systemic treatment of sorafenib for the treatment of advanced HCC with N and/or M factors.
Limitations of this study are the small number of patients and inhomogeneity of patients’ characteristics, as the number of patients with HCC involving the vascular system is relatively small in the general population and in one hospital, and we excluded the patients who didn’t undergo follow-up dynamic imaging studies after completion of RT to evaluate the ORR. Even though these limitations, we have to choose an optimal treatment option case by case because there is no high-level evidence for tumor thrombosis treatment. Furthermore, this was a retrospective study, and because the dose-volume histograms were not calculated in half of the patients and the duration of follow-up was limited, it was impossible to fully evaluate any adverse effects on the liver function.