Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third major cause of cancer-related death worldwide [1]. Most HCC patients have a background of chronic liver disease resulting from alcohol abuse, infection of hepatitis C virus or hepatitis B virus [2, 3]. According to a 2005 report, the peak age range of HCC worldwide was 30 to 50 years [4]. On the other hand, in Japan, until 1990 the majority of HCC deaths were below the age of 69, but 66% of patients with HCC were over 70 in 2006 [3]. In light of the increased age of HCC patients, there is an urgent need for less-invasive local treatments.

Surgical resection, local ablation therapies including percutaneous radiofrequency ablation (RFA), and percutaneous ethanol infusion (PEI) are potentially curative treatments [2, 5]. However, many patients are not amenable to surgery or local ablation therapy for medical or anatomic reasons. Recently, proton therapy and stereotactic body radiotherapy (SBRT) with X-rays have been applied for HCC as less-invasive procedures [6‐9]. Also, carbon ion radiotherapy (C-ion RT) has been used for HCC because of its excellent dose localization property and higher relative biological effectiveness based on the characteristics of higher linear energy transfer beam [10, 11]. Although the theoretical benefit of C-ion RT would exist in elderly HCC patients with hepatic dysfunction. There was a lack of data on the clinical outcomes of C-ion RT for elderly patients with HCC. In the current study, we analyzed safety and efficacy of C-ion RT in elderly HCC patients (80 years or older).

With the increasing elderly population of HCC patients in Japan [3], a less-invasive and highly curable local treatment strategy has to be explored.

HCC has a number of local treatment options. Surgical resection is a well-established treatment, although its application has to be carefully selected in elderly patients. A meta-analysis by Huang et al. presented clinical outcomes of hepatectomy for HCC in 67 elderly patients (≥ 70 years old) and 268 control patients (< 70 years old) [27]. In their report, the 3-year OS and disease-free survival between the elderly and control groups were 55% and 40% (p = 0.017), and 58% and 41% (p = 0.157), respectively. The 2-year OS and disease-free survival rates, according to the Kaplan-Meier method, between elderly and control groups were approximately 65% and 50%, and approximately 60% and 52%, respectively. On the other hand, 9.0% of patients developed postoperative complications such as upper gastrointestinal hemorrhage and liver failure in the elderly group. Nozawa et al., in a report of surgical resection for HCC patients, divided patients into super-elderly (≥ 80 years old, n = 20), elderly (70–80 years old, n = 172) and younger (< 70 years old, n = 239) groups [28]. The 5-year OS in the super-elderly, elderly and younger groups were 67%, 60% and 65%, respectively. The 3-year tumor-free survival rates in the super-elderly, elderly and younger groups were 34%, 41% and 46%, respectively. The 2-year OS and 2-year tumor-free survival rates in the super-elderly group by Kaplan-Meier curves were approximately 100% and 10%, respectively. In these 2 studies, there was likely to exist a selection bias of the patients in the elderly groups, because inclusion criteria for resection was not fully described and because the elderly group generally presented favorable results compared with the control group. Nozawa et al. also reported a median postoperative hospital stay of 11 days in the super-elderly group [28]. Regarding complications, 30% of the super-elderly patients developed delirium ascribed to their long-term hospitalization, although psychiatric support and/or premedication were provided for the patients [28]. In addition, 10% of the patients developed cardiovascular disease and 5% of the patients developed abdominal infection and bile leakage. In the current study, the 2-year estimated OS and PFS were comparable with the result of surgery, although medically inoperable cases were included in our population. The median hospital stays with C-ion RT was 8 days, and 4 patients were treated safely as outpatients. No patients developed delirium or other severe complications, probably due to their short-term treatment period.

RFA and PEI are performed to treat unresectable small HCC. Tiong et al. reported a systemic review and meta-analysis of elderly patients with small HCC, 20–30 mm, treated with RFA and PEI [29]. The 3-year disease-free survival rates were 37–43% and 17–21%, respectively. Nishikawa et al. reported clinical outcomes of RFA for elderly (≥ 75 years) and control (< 75 years) patients with HCC of 20–30 mm [30]. They reported that the 3-year OS and recurrence-free survival rates between elderly and control groups were 64% and 84% (p = 0.001), and 21% and 40% (p = 0.001), respectively. The Kaplan-Meier method showed that the 2-year OS and recurrence-free survival rates between the elderly and control groups were approximately 75% and 90%, and approximately 35% and 55%, respectively. On the other hand, there was no significant difference in major adverse events related to RFA between the two groups (p = 0.670). In the current study, clinical outcomes were similar to those of HCC treated with RFA, despite the inclusion of larger tumors (median size, 45 mm). The indication for RFA is generally unresectable tumor of 30 mm or smaller, and is limited by anatomical situation. In contrast, C-ion RT can be applied for tumors larger than 30 mm or those anatomically untreatable with RFA [10].

Hata et al. reported proton therapy for 21 elderly patients (≥ 80 years old) with HCC [31]. Their 3-year OS and 3-year local progression-free rates were 62% and 100%, respectively, and no patient developed Grade 3 or higher toxicity except for thrombocytopenia in 2 patients. Their median fraction number was 22 (range: 10–35 fractions). In the current study, the number of fractions was 4 or 12, which was generally less than that of proton therapy. Together with the safety of C-ion RT, in the present study, C-ion RT also seems to be beneficial for elderly patients in terms of avoiding long-term hospitalization that can cause cognitive impairment.

There has been no analysis that focused on the outcome of elderly patients with SBRT with X-rays. Andolino et al. reported SBRT for HCC patients with a median age of 59 years and median tumor size of 31 mm [32]. Their 2-year OS and 2-year LC were 67% and 90%, respectively. There were no Grade 3 or higher acute non-hematologic toxicities. However, 20% of the patients experienced progression in Child-Pugh class within 3 months of treatment, 7 of 36 patients with Child-Pugh class A progressing to class B and 5 of 24 patients with class B progressing to class C. On the other hand, only one patient experienced progression in Child-Pugh classification from A to B within 3 months in our study. Abe et al. previously reported the results of dosimetric comparison between SBRT with X-rays and C-ion RT for HCC [22]. In their study, a low dose volume such as 5 Gy (RBE) to 20 Gy (RBE) for normal liver tissue was significantly lower with C-ion RT than SBRT. Therefore, compared with SBRT with X-rays, C-ion RT may have an advantage of conserving liver function.

Imada et al. reported comparison of efficacy and toxicity of C-ion RT for HCC located in the porta hepatis. They defined HCC located within 2 cm of the main portal vein as a porta hepatis group. They reported that the 3-year OS and LC in 18 patients were 44.4% and 87.8%. Acute adverse events of Grade 3 or higher were developed in 9 cases. As to Child-Pugh score in late phase, cases with changes in score increasing at least 2 points was five. In the current study, 14 of 31 patients has HCC located within 2 cm of the main portal vein as a porta hepatis group. The 2-year OS and LC in porta hepatis group were 50.9% and 82.5%. No patients had Grade 2 or higher acute toxicities. One patient experienced increasing 2 points of Child-Pugh score in acute and late phase. In the current study, clinical outcomes were comparable to results of Imada et al. reported, although the current study analyzed only elderly patients. Thus, this results suggested C-ion RT for elderly patients with HCC located in porta hepatis was effective and safe treatment.

There were some limitations to our study. First, this study was a single institutional retrospective analysis with a small number of patients and short follow-up duration. However, the follow-up period of this study was considered to be sufficient to confirm the safety because long-term radiation-related adverse events are uncommon except for radiation-induced malignancies. Second, the safety of C-ion RT for elderly HCC patients with Child-Pugh class B remained unclear due to small number of patients. Further investigation is necessary to confirm the safety of C-ion RT for elderly HCC patients with Child-Pugh class B. Third, clinical outcomes were not directly compared with other treatment modalities including surgical resection and local ablation therapies. However, the current study included not amenable to surgery or local ablation therapies cases due to the anatomical and medical reasons including poor PS and co-morbidity. This patient selection would not have contributed to the favorable results of this study.

C-ion RT for patients 80 years or older with HCC was effective with minimal toxicities. This result suggested that C-ion RT may become an alternative treatment option for elderly HCC patients for whom surgery or local ablation therapies are not a viable choice. Further accumulation of clinical data with larger cohorts is warranted.