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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.

A retrospective multicenter study was carried out to assess the clinical outcomes of carbon-ion radiotherapy for head and neck malignancies (Japan Carbon-Ion Radiation Oncology Study Group [J-CROS] study: 1402 HN). We evaluated the safety and efficacy of carbon-ion radiotherapy in patients with major salivary gland carcinoma. Sixty-nine patients treated with carbon-ion radiotherapy at four Japanese institutions were analyzed. Thirty-three patients (48%) had adenoid cystic carcinomas, 10 (14%) had mucoepidermoid carcinomas, and 26 (38%) had other disease types. Three patients (4%) had T1 disease, 8 (12%) had T2, 25 (36%) had T3, and 33 (48%) had T4. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 27 mL. The median follow-up period was 32.7 months. The 3-year local control rate and overall survival rate were 81% and 94%, respectively. Regarding acute toxicities, seven patients had grade 3 mucositis and seven had grade 3 dermatitis. Regarding late toxicities, one patient had grade 3 dysphagia and one had a grade 3 brain abscess. No grade 4 or worse late reactions were observed. In conclusion, definitive carbon-ion radiotherapy was effective with acceptable toxicity for major salivary gland carcinomas.

Summary To evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26 patients who underwent carbon-ion radiotherapy in four facilities were analyzed in this multi-institutional retrospective study: the Japan Carbon-ion Radiation Oncology Study Group (J-CROS). The median follow-up time was 34 months. One patient experienced local recurrence, and the 3-year local control rate was 95%. One patient developed lymph node recurrence and five developed distant metastases. The 3-year progression-free survival rate was 73%. Five patients died, two of mucoepidermoid carcinoma and three of intercurrent disease. The 3-year overall survival rate was 89%. Acute mucositis and dermatitis of grade 3 or higher were experienced by 19% and 8% of patients, respectively; these improved with conservative therapy. Late mucositis and osteonecrosis of jaw were observed in 12% and 23% of patients, respectively. The 3-year cumulative rate of any late adverse event of grade 3 or higher was 14%. None of the patients died of the acute or late adverse events. Carbon-ion radiotherapy was efficacious and safe for treating mucoepidermoid carcinoma in this multi-institutional retrospective study. We are currently conducting a prospective multicenter study. (UMIN000024473) This article is protected by copyright. All rights reserved.

Peritoneal metastasis of gastric cancer (PMGC) is incurable and thus has an extremely poor prognosis. We have found, however, that locoregionally administered trastuzumab armed with astatine-211 (211At-trastuzumab) is effective against human epidermal growth factor receptor 2 (HER2)-positive PMGC in a xenograft mouse model. We first observed that 211At-trastuzumab can specifically bind and effectively kill NCI-N87 (N87) cells, which are HER2-positive human metastatic GC cells, both in vitro and in s.c. tumors. We established a PMGC mouse model using N87 xenografts stably expressing luciferase to test a-particle radioimmunotherapy with 211At-trastuzumab against PMGC. Biodistribution analysis in this PMGC mouse model revealed that the i.p. administration of 211At-trastuzumab (1 MBq) was a more efficient means of delivery of 211At into metastatic tumors than i.v.injection; the maximum tumor uptake with i.p. administration was over 60% injected dose per gram of tissue (%ID/g) compared to approximately 18%ID/g with i.v. injection. Surprisingly, a single i.p. injection of 211At-trastuzumab (1 MBq) was sufficient to completely eradicate intraperitoneally disseminated HER2-positive GC xenografts in two of six treated mice by inducing DNA doublestrand breaks, and to drastically reduce the tumor burden in another three mice. No bodyweight loss, leukocytopenia, or significant biochemical changes in liver or kidney function were observed in the treatment group. Accordingly, locoregionally administered 211At-trastuzumab significantly prolonged the survival time of HER2-positive PMGC mice compared with control treatments. Our results provide a proof-of-concept demonstration that locoregional therapy with 211At-trastuzumab may offer a new treatment option for HER2-positive PMGC.

Peritoneal metastasis of gastric cancer (PMGC) is incurable and thus has an extremely poor prognosis. We have found however that locoregionally administered trastuzumab armed with a radionuclide astatine-211 (211At)-emitting α-particle (211At-trastuzumab) is effective against HER2-positive PMGC in a xenograft mouse model. We first observed that 211At-trastuzumab can specifically bind and effectively kill NCI-N87 (N87) cells, which are HER2-positive human metastatic GC cells, both in vitro and in subcutaneous tumors. We established a PMGC mouse model using N87 xenografts stably expressing luciferase to test α-particle radioimmunotherapy with 211At-trastuzumab against PMGC. Biodistribution analysis in this PMGC mouse model revealed that the intraperitoneal administration of 211At-trastuzumab (1 MBq) was a more efficient means of delivery of 211At into metastatic tumors than intravenous injection; the maximum tumor uptake with intraperitoneal administration was over 60 percent injected dose per gram (%ID/g) compared to about 18%ID/g with intravenous injection. Surprisingly, a single intraperitoneal injection of 211At-trastuzumab (1 MBq) was sufficient to completely eradicate intraperitoneally disseminated HER2-positive GC xenografts in two of six treated mice by inducing DNA double-strand breaks, and to drastically reduce the tumor burden in three further mice. No body weight loss, leukocytopenia or significant biochemical changes in liver and kidney function were observed in the treatment group. Accordingly, locoregionally administered 211At-trastuzumab significantly prolonged the survival time of HER2-positive PMGC mice compared with control treatments. Our results provide a proof-of-concept demonstration that locoregional therapy with 211At-trastuzumab may offer a new treatment option for HER2-positive PMGC. This article is protected by copyright. All rights reserved.

Long-term oncological outcomes for primary renal cell carcinoma (RCC) treated with carbon-ion radiotherapy (CIRT) are poorly understood. Patients with primary RCC were treated with 12 or 16-fraction CIRT at The Hospital of the National Institute of Radiological Sciences outside of clinical trials. Outcome data were pooled and retrospectively analyzed for toxicity, local control, and disease-free, cancer-specific, and overall survival. From 1997 to 2014, 19 RCC patients (11 with T1aN0M0, 4 with T1bN0M0, and 4 with inoperable advanced stage [T4N0M0, T3aN1M0, and T1aN0M1]) were treated with CIRT and followed up for a median of 6.6 (range, 0.7-16.5) years; 9 of these patients were inoperable because of comorbidities or advanced-stage disease. Diagnoses were confirmed by imaging in 11 patients and by biopsy in the remaining 8. In 4 of 5 patients with definitive renal comorbidities, including diabetic nephropathy, sclerotic kidney or solitary kidney pre-CIRT progressed to grade 4 chronic kidney disease (CKD). In contrast, the remaining 14 patients without definitive renal comorbidities did not progress to grade 3 or higher CKD. Furthermore, although 1 case of grade 4 dermatitis was observed, there were no other grade 3 or higher non-renal adverse events. Local control rate, and disease-free, cancer-specific, and overall survival rates at 5 years of all 19 patients were 94.1%, 68.9%, 100%, and 89.2%, respectively. This updated retrospective analysis based on long-term follow-up data suggests that CIRT is a safe treatment for primary RCC patients without definitive renal comorbidities pre-CIRT, and yield favorable treatment outcomes, even in inoperable cases.

Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re-irradiation with carbon-ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors.

The treatment outcomes of patients with high-risk localized prostate cancer (PC) after carbon-ion radiotherapy (CIRT) combined with long-term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high-risk or very-high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated. The median follow-up time was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10 and percentage of positive biopsy cores >75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three (n = 16), two (n = 74) or one of these risk factors (n = 217) were 27.1, 11.6 and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (P