TACE was the most frequently used treatment modality for real-life management of patients with early- to advanced-stage HCC [6]. The current BCLC strategy recommends curative treatment options for patients with early-stage HCC with an expected median survival of 5 years or more [24, 25]. However, for patients who are not suitable for first-line curative therapy, TACE could be considered as a treatment option even though it is usually recommended for patients in more advanced stages in an approach known as the “stage migration strategy” [25]. In the BRIDGE study, which showed the management patterns for HCC in 14 countries, TACE was the second most commonly used treatment for HCCs with BCLC stage A. However, up to 57–77% of lesions still have viable tumor portions after TACE and thus require additional TACE or other treatment modalities [10–12]. In order to establish effective treatment changes in such cases, the Japanese guidelines revised the definition of TACE failure/refractoriness as (1) two or more consecutive ineffective responses within the treated tumors, (2) two or more consecutive progressions in the liver, (3) continuous elevation of tumor markers, (4) appearance of vascular invasion, and/or (5) appearance of extrahepatic spread [17]. In Japan, molecular-targeted therapy is recommended after TACE failure, especially for intermediate-stage HCCs [26, 27]. However, the consensus on TACE failure had not been well-established. Moreover, to date, only few studies had evaluated effective local treatment options for each situation of TACE failure, especially in early-stage HCCs. Therefore, current treatment guidelines for the management of HCC lack a recommendation on this issue.
Among the patterns of TACE failure and refractoriness, effective local salvage treatment should be considered in cases of ineffective response at the site of TACE without a new lesion, which was defined as incomplete TACE in the current study. We evaluated the clinical outcomes of patients who received salvage SBRT for single viable HCC at the site of incomplete TACE, and found that SBRT had a high CR rate (95.4%), high LC rate (91.2% at 3 years), promising OS rate (72.7% at 3 years), and minimal SBRT-related toxicity.
The favorable OS in the present study can be expected in a select group of patients. A prospective single-arm study by Takeda et al. reported the efficacy of SBRT for single HCC after TACE [28] by including patients with a single HCC less than 4 cm and TACE was omitted if embolization was difficult or if the patient refused. Of 90 patients, 32 patients were treatment-naïve, 58 received TACE, and 10 had a complete accumulation of iodized oil; in these patients, SBRT showed promising outcomes with a 3-year OS rate of 66.7% and a 3-year LC rate of 96.3%, which is in line with the results of the present study. SBRT was effective on liver-related cause-specific survival and OS regardless of whether TACE was performed. Su et al. also reported favorable prognosis after SBRT for small HCCs [29]; in this study, 132 patients with small HCC (≤ 5 cm) were treated with SBRT of 42–46 Gy in 3–5 fractions or 28–30 Gy in 1 fraction. Of the 132 patients, 95 with a single nodule had a promising 3- and 5-year OS rates of 76.3% and 66.2%, respectively. Therefore, if TACE for early-stage HCC is incomplete and other curative treatments are still not suitable, subsequent SBRT should be considered as a local salvage treatment.
In the present study, SBRT for small viable HCC at the site of incomplete TACE showed an excellent LC rate of 91.2% at 3 years. These results are in line with those of previous prospective and retrospective studies on SBRT for small HCC that reported high LC rates of 90–100% [13, 18, 19, 28, 30–32]. As tumor responses after SBRT could be used as a surrogate measure for LC, rapid treatment changes can be considered if the tumor response is not sufficient. However, the interval from SBRT to the time point of reliable response had not been evaluated until one recent phase II study [33]. Accordingly, physicians usually decided on upfront treatment changes without waiting long enough even if there is no obvious local progression at the SBRT site. The recent phase II study reported excellent oncologic results (5-year LC and OS rates of 97.1% and 77.6%, respectively) after SBRT for HCC, and also showed treatment response according to the mRECIST criteria at regular intervals (2-, 4-, 6-months after SBRT). Whereas the CR rate at 2 months was 30.2%, it was increased to 84.9% at 6 months after the completion of SBRT. The results of the present study are consistent with the phase II study; the median interval from completion of SBRT to the achievement of CR was 3.4 months (IQR, 1.9–4.7), and 39.9% and 83.3% of lesions reached CR at 3 months and 6 months after SBRT, respectively; 10% of the CR was observed 7.2 months after SBRT. The achievement of anyCR was significantly associated with LC, whereas CR at 3 months was not significantly associated with LC. There was no significant difference in the OS between those who had early response (achievement of CR before 3 months) and those who had late response (after 3 months) (data not shown). Based on these findings, it may be recommended that treatment changes be withheld for at least 6 months after SBRT if there is no definite local progression at the site of SBRT.
The study has the following limitations. First, the study has inherent biases due to its retrospective single-center study design. To compensate for this weakness, we included a large number of homogeneous patients who experienced ineffective responses at the site of TACE without a new lesion. Moreover, all patients were treated with a modern SBRT technique using respiratory-gated volumetric-modulated arc therapy. Second, the consensus on TACE failure had not been well-established and the small single HCC was the status at the time of SBRT, not the initial presentation. Finally, in order to focus on the efficacy of SBRT as a local salvage treatment, we only included incomplete TACE cases and not all TACE failure situations. Lastly, the follow-up period was not long enough to determine the 5-year survival. Therefore, long-term follow-up results are needed in further studies. Notwithstanding, we were able to fully capture the overall response during the entire follow-up period. Prospective randomized studies are warranted to confirm the benefit of salvage SBRT and to better define the group of patients that will benefit from the therapy.
In conclusion, SBRT showed excellent clinical outcomes in terms of OS, LC, tumor response, and adverse events when used as an ablative treatment modality for single viable HCC at the site of incomplete TACE. SBRT should be considered for residual HCC after incomplete TACE. Treatment changes may be withheld for at least 6 months after SBRT to incomplete TACE site if there is no definite local progression at the site of SBRT.