Clinical impact of Hypofractionated carbon ion radiotherapy on locally advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) involving a major branch of the portal or hepatic vein occurs in a locally advanced stage. Although molecular targeted therapy is the standard treatment for locally advanced HCC (LAHCC), according to the European Association for the Study of the Liver and European Organization for Research and Treatment of Cancer practical guidelines [1], LAHCC treated with molecular targeted therapy alone has shown dismal prognosis [2‐4]. Therefore, radiotherapy, transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy, and/or percutaneous radiofrequency ablation (RFA) were performed in LAHCC patients as an additional treatment. Recently, the report by Yoon et al. showed that TACE combined with X-ray RT improved the prognosis compared with molecular targeted therapy alone in a randomized controlled trial [5].

Carbon ion radiotherapy (C-ion RT) provides both, physical and biological advantages over X-ray RT, and several researchers have shown favorable clinical outcomes in HCC patients when they were treated with C-ion RT [6‐9]. In the physical aspect, previous studies have demonstrated a dose distribution advantage, showing that a reduced dose was delivered to the liver using C-ion RT compared with those of stereotactic body RT (SBRT) and intensity-modulated RT (IMRT) [10, 11]. This was achieved owing to the physical nature of the C-ion RT procedure with distal tail-off due to the Bragg Peak and a sharp lateral penumbra [12]. Additionally, in the biological aspect, the C-ion beams have higher linear energy transfer than X-rays, and thus have superior cell-killing effect in radioresistant tumor cells such as hypoxic and cancer stem cells [13, 14]. Although there is lack of data on the clinical outcomes in patients with LAHCC treated with C-ion RT, these advantages of C-ion RT may contribute to the improved prognosis of multidisciplinary treatment of LAHCC. Hence, in the current study, we analyzed the treatment outcomes of C-ion RT in patients with LAHCC.

The current study demonstrated that C-ion RT showed favorable clinical outcomes in patients with LAHCC. In our study, the 3-year estimated OS, LC, and PFS rates were 64, 78, and 18%, respectively, with minimal toxicities. A previous study on C-ion RT outcomes in patients with HCC in a multi-institutional analysis, which did not include locally advanced cases, showed that 3-year LC rate was 81% [9]. The result of LC shown in that study was similar to that in our study, although all patients analyzed had locally advanced disease cases. For various LAHCC treatments, the median OS in molecular targeted therapy ranged between 5.3 and 11.5 months [3‐5, 21], while that in hepatic arterial infusion chemotherapy with radiotherapy was 9.9 months [25], and that in TACE-based multidisciplinary treatment ranged from 7.0 to 12.7 months [5, 26]; the 3-year OS rates in surgery based multidisciplinary treatment ranged from 13 to 68% [15, 27, 28]. Additionally, Komatsu et al. reported on the comparison of clinical outcomes between LAHCC treated with particle therapy and liver resection in a matched-pair analysis [29]. Clinical outcomes of these other anti-cancer treatments are summarized in Table 4. They concluded that particle therapy was potentially preferable over liver resection in LAHCC. Although another anticancer therapy for LAHCC showed a wide range of outcomes in OS, the 3-year OS of 64% for C-ion RT-based multidisciplinary treatment shown in our study, appears to be comparable or favorable. Therefore, we propose that C-ion RT could be one of the therapy options for the multidisciplinary treatment of LAHCC.

The results of our study showed that patients with higher D₉₈ for CTV tended to have locally controlled tumors, including local recurrence of more than 5 years after C-ion RT (Fig. 3). Indeed, two patients with locally controlled tumors and low CTV D₉₈ who were prescribed a dose of 52.8 Gy (RBE), and all patients with CTV D₉₈ who received more than 53 Gy (RBE), had no local recurrence with long-term local control after C-ion RT. This result suggested that high-dose C-ion beam administration can achieve local control, which may result in long-term local recurrence-free survival. Previous studies compared DVH for tumorous and normal liver between C-ion RT and X-ray RT (SBRT and IMRT) [10, 11]. Particularly for LAHCC, which is a large tumor or/and a tumor with irregular shapes, the dose required for the normal liver may be higher than that used for HCC, which has no macroscopic vascular invasion. Higher doses delivered to the normal liver resulted in a higher risk of radiation-induced liver disease [30]; the prescribed dose must therefore be decreased to avoid development of radiation-induced liver disease. It is therefore difficult to administer sufficient tumor control doses for LAHCC with X-ray RT. In contrast, C-ion RT can decrease the dose delivered to the healthy liver while administering a sufficient dose to the tumor, due to its higher achievable dose concentration owing to the sharp lateral penumbra and distal tail-off.

Yoon et al. showed that TACE combined with X-ray RT resulted in improved prognosis compared with molecular targeted therapy alone [5]. In terms of dose distribution, C-ion RT showed higher dose concentrations than X-ray RT [10, 11]; therefore, C-ion RT can result in reduced dose distribution to the healthy liver region without reducing the dose delivered to the tumor, thereby preserving liver function. If liver function can be preserved, the number of treatment options for preventing HCC recurrence may be increased. Liver function preservation is crucial for HCC patients who may need repeat treatment because of frequent recurrences, such as in cases of LAHCC. In our study, nine patients needed multiple treatments for recurrent tumors (Table 2), and it may be possible that liver function preservation after C-ion RT enabled multiple treatment rounds after recurrence. Therefore, C-ion RT offers the advantage of liver function preservation during HCC treatment compared with X-ray RT, and TACE combined with C-ion RT may confer better prognosis than TACE combined with X-ray RT.

Proton beam therapy may be one of the treatment options for LAHCC in multidisciplinary treatment because of its higher dose concentration compared to X-ray RT [29, 31]. In terms of the dose fractionation schedule, proton beam therapy needs 8–38 fractions depending on the tumor location. In contrast, C-ion RT needs only 4 or 12 fractions. When combined with other anti-cancer therapies in multidisciplinary treatment, a shorter dose fractionation schedule offers an advantage in terms of the overall treatment time for planned sequential treatment. and may therefore improve the prognosis.

Our study had several limitations. First, this study was a single-institution retrospective analysis with a small number of patients. Second, there were a small number of patients with the most advanced stage of HCC involving a major branch of the portal or hepatic vein, such as the Vp4 and Vv3. Therefore, clinical outcomes observed here may have appeared favorable. Third, only the patients who were likely to benefit from local treatment were analyzed in the current study. The other reports of anti-cancer treatment for LAHCC included patients in whom systemic therapy was indicated, with little scope for local treatment; this patient bias may have affected survival rates.

Although LAHCC remains difficult to cure, C-ion RT-based multidisciplinary treatment showed favorable clinical outcomes with a high rate of local control and minimal toxicity. This finding suggests that C-ion RT may be a useful treatment option in the multidisciplinary therapy of LAHCC in patients who are likely to benefit from local treatment.