BACKGROUND: The objective of this study was to evaluate the safety and efficacy of carbon‐ion radiotherapy (CIRT) in patients with hepatocellular carcinoma (HCC) with stepwise dose escalation and hypofractionation in 2 combined prospective trials.METHODS: Sequential phase 1/2 (protocol 9603) and phase 2 (protocol 0004) trials were conducted for patients with histologically proven HCC. The phase 1 component of protocol 9603 was a dose‐escalation study; CIRT was delivered in 12, 8, or 4 fractions. After determination of the recommended dose, 2 phase 2 trials were performed in an expanded cohort, and the data were pooled to analyze toxicity, local control, and overall survival.RESULTS: In the phase 1 component of protocol 9603, 69.6, 58.0, and 52.8 Gy (relative biological effectiveness [RBE]) in 12, 8, and 4 fractions, respectively, constituted the maximum tolerated doses, and 52.8 Gy (RBE) in 4 fractions was established as the recommended dose regimen for the 2 phase 2 studies. In 124 patients with a total of 133 lesions, few severe adverse effects occurred, and local‐control and overall survival rates at 1, 3, and 5 years were 94.7% and 90.3%, 91.4% and 50.0%, and 90.0% and 25.0%, respectively; this included 1‐, 3‐, and 5‐year local‐control rates of 97.8%, 95.5%, and 91.6%, respectively, in the phase 2 study. In a multivariate analysis, Child‐Pugh class B and the presence of a tumor thrombus were significant factors for mortality.CONCLUSIONS: The safety and efficacy of CIRT in 12, 8, and 4 fractions were confirmed, with 52.8 Gy (RBE) in 4 fractions established as the recommended treatment course for eligible HCC patients. Cancer 2017;123:3955‐65. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

High linear energy transfer (LET) radiation carbon-ion radiotherapy (C-ion RT) is one of the most promising modalities for treating unresectable primary pancreatic cancers. However, how LET contributes to a therapeutic effect is not clear. To assess whether there is an enhanced effect of high LET radiation on tumour control, we aimed to determine the impact of dose-averaged LET on local control (LC) of primary pancreatic tumours. A retrospective analysis of 18 patients with primary pancreatic carcinomas treated with definitive C-ion RT with concurrent chemotherapy in 2013 was conducted. The dose of irradiation was 55.2 Gy (RBE). The relationship between dose-averaged LET and LC of primary tumours was evaluated. All patients had histologically confirmed adenocarcinoma. The median follow-up duration was 22 months. The actuarial LC and overall survival (OS) at 18 months were 62.5% and 70.1%, respectively. There were no cases of grade ≥3 late toxicities observed. Local recurrences developed in four patients (22%), all of which were infield central recurrences. Although there were no significant differences in gross tumour volume (GTV) dose coverage, patients with higher minimum dose-averaged LET (LETmin) values within the GTV had better LC (dose-averaged LETmin ≥44 keV/microm; 18-months LC 100.0% vs 34.3%; p = 0.0366). Dose-averaged LETmin within the GTV was significantly associated with LC of primary pancreatic cancers. Our data suggest that outcomes for patients with unresectable primary pancreatic cancers receiving C-ion RT can be improved by modulating the dose-averaged LET within the GTV.

The efficacy and safety of carbon‐ion radiotherapy (CIRT) for locally advanced non‐small‐cell lung cancer (LA‐NSCLC) remain unclear. We reported the clinical outcomes of CIRT for LA‐NSCLC. Data for 141 eligible patients who received CIRT between 1995 and 2015 were retrospectively analyzed. Local control (LC), locoregional control (LRC), progression‐free survival (PFS) and overall survival (OS) were calculated using the Kaplan‐Meier method. The median age was 75.0 years. Overall, 21 (14.9%), 57 (40.4%), 43 (30.5%) and 20 (14.2%) patients had T1, T2, T3 and T4 disease, respectively. Moreover, 51 (36.2%), 45 (31.9%), 40 (28.4%) and 5 (3.5%) patients had N0, N1, N2 and N3 disease, respectively. Furthermore, 34 (24.1%), 42 (29.8%), 45 (31.9%) and 20 (14.2%) patients had stages IIA, IIB, IIIA and ΙΙΙB disease, respectively. Overall, 62 (44.0%), 60 (42.6%), 8 (5.7%) and 11 (7.8%) patients had adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and others, respectively. The median dose was 72.0 Gy (relative biological effectiveness). No patient received concurrent chemotherapy. Median follow‐up periods were 29.3 (1.6‐207.7) and 40.0 (10.7‐207.7) months for all patients and survivors, respectively. Two‐year LC, PFS and OS rates were 80.3%, 40.2% and 58.7%, respectively. Overall, 1 (0.7%), 5 (3.5%) and 1 (0.7%) patient developed Grades 4 (mediastinal hemorrhage), 3 (radiation pneumonitis) and 3 (bronchial fistula) toxicities, respectively. Multivariate analysis showed adenocarcinoma and N2/3 classification as significant poor prognosticators of PFS. CIRT is an effective treatment with acceptable toxicity for LA‐NSCLC, especially for elderly patients or patients with severe comorbidities who cannot be treated with surgery or chemoradiotherapy.

There are no clinical reports of long‐term follow‐up after carbon‐ion radiotherapy (CIRT) using a dose of 51.6 Gy (relative biological effectiveness [RBE]) in 12 fractions for localized prostate cancer, or of a comparison of clinical outcomes between passive and scanning beam irradiation. A total of 256 patients with localized prostate cancer who received CIRT at a dose of 51.6 Gy (RBE) in 12 fractions using two different beam delivery techniques (passive [n = 45] and scanning [n = 211]), and who were followed for more than 1 year, were analyzed. The biochemical relapse‐free (bRF) rate was defined by the Phoenix definition, and the actuarial toxicity rates were evaluated using the Kaplan‐Meier method. Of the 256 patients, 41 (16.0%), 111 (43.4%), and 104 (40.6%) were classified as low, intermediate, and high risk, respectively, after a median follow‐up of 7.0 (range 1.1‐10.4) years. Androgen deprivation therapy was performed in 212 patients (82.8%). The 5‐year bRF rates of the low‐, intermediate‐, and high‐risk patients were 95.1%, 90.9%, and 91.1%, respectively. The 5‐year rates of grade 2 late gastrointestinal and genitourinary toxicities in all patients were 0.4% and 6.3%, respectively. No grade ≥3 toxicities were observed. There were no significant differences in the rates of bRF or grade 2 toxicities in patients who received passive irradiation versus scanning irradiation. Our long‐term follow‐up results showed that a CIRT regimen of 51.6 Gy (RBE) in 12 fractions for localized prostate cancer yielded a good therapeutic outcome and low toxicity rates irrespective of the beam delivery technique.

Several studies have focused on increasing the linear energy transfer (LET) within tumours to achieve higher biological effects in carbon-ion radiotherapy (C-ion RT). However, it remains unclear whether LET affects late complications. We assessed whether physical dose and LET distribution can be specific factors for late rectal complications in C-ion RT. Overall, 134 patients with uterine carcinomas were registered and retrospectively analysed. Of 134 patients, 132 who were followed up for >6 months were enrolled. The correlations between the relative biological effectiveness (RBE)-weighted dose based on the Kanai model (the ostensible "clinical dose"), dose-averaged LET (LETd), or physical dose and rectal complications were evaluated. Rectal complications were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Nine patients developed grade 3 or 4 late rectal complications. Linear regression analysis found that D_2cc in clinical dose was the sole risk factor for ≥grade 3 late rectal complications (p = 0.012). The receiver operating characteristic analysis found that D_2cc of 60.2 Gy (RBE) was a suitable cut-off value for predicting ≥grade 3 late rectal complications. Among 35 patients whose rectal D_2cc was ≥60.2 Gy (RBE), no correlations were found between severe rectal toxicities and LETd alone or physical dose per se. We demonstrated that severe rectal toxicities were related to the rectal D_2cc of the clinical dose in C-ion RT. However, no correlations were found between severe rectal toxicities and LETd alone or physical dose per se.

Lung cancer is frequently complicated by interstitial lung disease (ILD). Treatment protocols for lung cancer patients with ILD have not been established; surgery, chemotherapy, and radiotherapy can all cause acute exacerbation of ILD. This study evaluated the toxicity and efficacy of carbon ion radiotherapy (CIRT) in patients with non-small cell lung cancer (NSCLC) and ILD. Between June 2004 and November 2014, 29 patients diagnosed with NSCLC and ILD were treated with CIRT. No patient was eligible for curative surgery or conventional radiotherapy secondary to ILD. Owing to prior symptomology, radiation pneumonitis (RP) and symptom progression pre- and post-treatment were evaluated. The relationships between RP and clinical factors were investigated. Twenty-eight men and one woman, aged 62 to 90 years old, were followed for 2.7–77.1 months (median: 22.8 months). Single-grade symptomatic progression (grade 2–3) was observed in 4 patients, while 1 patient experiencedtwo-grade progression. Two patients experienced radiation-induced acute exacerbation. Local control at 3 years was 63.3% (72.2% for stage I disease); survival at 3 years was 46.3% (57.2% for stage I disease). Eighteen patients had died by the time of this writing, 10 of lung cancer progression. Radiation pneumonitis post-treatment progression correlated with dosimetric factors of the lungs (V5, V10) and a low pre-treatment serum surfactant protein-D. We found that CIRT may be useful as a low-risk, curative option for NSCLC patients with ILD, a population that is typically ineligible for conventional therapy. The DVH analysis showed that minimizing the low-dose region is important for reducing the risk of severe RP. NIRS-9404 . Registered 1 March 1994.