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There are limited studies on the risk of secondary cancers after carbon-ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period.This retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated.The analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person-years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6-2.1) in the CIRT group and 1.4 (95% CI, 1.0-2.1) in the photon RT group. The 10-year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0-21.5) in the CIRT group and 9.4% (95% CI, 6.2-14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268).The incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long-term observation is warranted.

Background Daily anatomical deviations may distort the dose distribution in carbon ion radiotherapy (CIRT), which may cause treatment failure. Therefore, this study aimed to perform re-planning to maintain the dose coverage in patients with pancreatic cancer with passive scattering CIRT. Methods Eight patients with pancreatic cancer and 95 daily computed tomography (CT) sets were examined. Two types of adaptive plans based on new range compensators (RCs) (AP-1) and initial RCs (AP-2) were generated. In AP-2, each beam was optimized by manually adjusting the range shifter thickness and spread-out Bragg peak size to make dose reduction by Results Using TM and BM, mean ± standard deviations of daily CTV V95 (%) difference from the original plan was − 5.1 ± 6.2 and − 8.8 ± 8.8, respectively, but 1.2 ± 3.4 in AP-1 and − 0.5 ± 2.1 in AP-2 (P Conclusions The possible dose deterioration should be considered when performing the BM, even TM. Re-planning based on single beam optimization in passive scattering CIRT seems an effective and safe method of ensuring the treatment robustness in pancreatic cancer. Further study is necessary to spare healthy tissues, especially the duodenum.

α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.

Background and purpose Usefulness of carbon ion radiotherapy (CIRT) for sacral chordoma has been reported from single institutions. We conducted a retrospective nationwide multicentre study to evaluate the clinical outcomes of CIRT for sacral chordoma in Japan. Materials and methods A total of 219 patients who underwent CIRT for sacral chordoma at institutions across Japan between December 2003 and July 2014 were included in this study. Results Median patient age was 67 years (range, 26–87 years). Most patients had no history of surgical resection (96%). The most frequent planning target volume (PTV) range was 100–500 mL (65%). The most frequently used dose-fractionation was 67.2 Gy (relative biological effectiveness) in 16 fractions (65%). The median follow-up was 56 months (range, 7–132 months). The 5-year overall survival (OS), progression-free survival, and local control rates were 84%, 48%, and 72%, respectively. Frequent sites of out-of-field recurrence included bone (9%) and lung (9%) metastases. The Cox proportional hazards model revealed that both younger age (P = 0.004) and smaller PTV (P = 0.001) were associated with significantly better OS. Acute toxicities of ≥Grade 3 occurred in eight patients (4%). Late toxicities of ≥Grade 3 occurred in 13 patients (6%): skin disorders in six patients (3%), pain in three (1%), myositis in three (1%), etc. Conclusion Our retrospective nationwide multicentre study showed that CIRT for sacral chordoma was effective and safe, and replicated the previously reported data from a representative CIRT institution in Japan demonstrating high local control and low toxicity rates.

Introduction Most patients with pancreatic metastasis from lung cancer are not candidates for surgical treatment because they have widespread systemic disease at the time of diagnosis. But it was reported that some patients with long-term survival were resected for pancreatic metastasis from lung cancer. We herein report a surgical case of pancreatic metastasis from lung cancer. Case Presentation A 61-year-old man was admitted to our hospital because of a lung tumor. He underwent right middle lobectomy. A histopathologic examination showed poorly differentiated adenocarcinoma. About 1 year after lung resection, brain metastasis was demonstrated and radiation therapy was subsequently performed. Seven years after lung resection, his serum carcinoembryonic antigen levels were again elevated. FDG–PET (fluorodeoxyglucose-positron emission tomography) showed a slight uptake by the pancreatic head. Computed tomography (CT) showed an irregular and poorly enhanced tumor in the pancreatic head. EUS–FNA (endoscopic ultrasonography fine-needle aspiration) of the tumor in the pancreatic head was performed. A histopathologic examination showed thyroid transcription factor (TTF)-1 positive adenocarcinoma. The preoperative diagnosis was pancreatic metastasis from lung cancer. We performed subtotal stomach-preserving pancreaticoduodenectomy for the pancreatic head tumor because the primary lung cancer and brain metastasis responded to chemoradiation. A histopathologic examination of the resected specimen revealed moderately differentiated adenocarcinoma. Immunohistochemistry revealed TTF-1 positive cells in the tumor. The patient was discharged from the hospital on the 12th day after surgery. He is currently alive 22 months after pancreatic surgery. Conclusion Resection of pancreatic metastasis from lung cancer may improve the patient outcome when the metastasis is localized in the pancreas or other organ metastases are controlled.

Background The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer. Methods In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given. Results In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies. Conclusion Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable. ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347)

Objective To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. Methods Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. Results Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1–4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. Conclusions FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.

Aims Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis and limited treatment options. Cisplatin plus pemetrexed is the only approved first‐line treatment for patients with unresectable MPM. Recently, promising outcomes were observed with first‐line bevacizumab combined with cisplatin/pemetrexed, leading to the recommendation of this regimen as a first‐line treatment option for patients with MPM. Bevacizumab plus cisplatin/pemetrexed has been shown to be safe and effective in non–small cell lung cancer, however, there are no efficacy or safety data in Japanese patients with MPM treated with this regimen. We conducted a multicenter study to evaluate tolerability and safety for Japanese patients with chemotherapy‐naïve, unresectable MPM. Methods Eligible patients (n = 7) received bevacizumab plus cisplatin/pemetrexed (up to six cycles), then single‐agent bevacizumab until disease progression or onset of unacceptable adverse events (AEs), according to the 3+3 design analogy. Results One patient (14.3%) reported an AE (gastric ulcer) meeting tolerability criteria. All patients experienced gastrointestinal disorders, including nausea (grade 1/2 only, n = 6, 85.7%) and constipation (grade 1/2 only, n = 5, 71.4%). Five patients (71.4%) had grade 3 hypertension. Two patients discontinued treatment due to gastric ulcer (n = 1) and proteinuria (n = 1). At data cut‐off, four patients had stable disease, two had partial response and one had non‐complete response/non‐progressive disease due to the absence of target lesions. Conclusions Bevacizumab plus cisplatin/pemetrexed then bevacizumab was well tolerated in Japanese patients with MPM., The addition of bevacizumab to standard cisplatin/pemetrexed showed survival benefit in mesothelioma patients, leading to its recommendation as a first‐line treatment option. Until now, there have been no tolerability or safety data for the triplet combination in Japanese mesothelioma patients. We evaluated this triplet combination for Japanese mesothelioma patients in a clinical trial according to the 3+3 design analogy and demonstrated its safety and tolerability.

Background The Japanese bladder cancer treatment guidelines recommend concurrent chemoradiotherapy, including wide pelvic irradiation. Many elderly patients, however, cannot tolerate standard treatment because of low performance status. Therefore, to reduce complications, elderly patients sometimes receive radiation therapy without elective nodal irradiation or chemotherapy. Patients and methods Outcomes were retrospectively analyzed in 19 elderly patients with N0 muscle-invasive bladder cancer treated with whole-bladder irradiation without chemotherapy. Results The 3- and 5-year overall survival rates were 30.7% and 12.2%, respectively. No patient experienced severe late complications (grade 3 or higher). Recurrence was observed in 11 patients (57.9%). The initial location of recurrence was within the bladder. Conclusion Whole-bladder irradiation alone did not increase lymph node metastases or severe complications in elderly patients. Whole-bladder radiation therapy without chemotherapy or wide pelvic irradiation may be a promising treatment method for patients who are not candidates for standardized treatment.

Phenylalanine derivatives, which target tumors especially through L-type amino acid transporter-1 (LAT1), have elicited considerable attention. In this study, we evaluated the treatment effect of phenylalanine labeled with the alpha emitter astatine (211At-PA) in tumor bearing mice. The C6 glioma, U-87MG, and GL261 cell lines were subjected to a cellular 211At-PA uptake analysis that included an evaluation of the uptake inhibition by the system L amino acid transporter inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). BCH significantly inhibited para-211At-PA uptake in C6 glioma (12.2 ± 0.8%), U-87MG (27.6 ± 1.1%), and GL261 (12.6 ± 2.0%) cells compared to baseline, suggesting an uptake contribution by system L amino acid transporters. Subsequently, xenograft and allograft models were prepared by subcutaneously injecting C6 glioma (n = 12) or GL-261 cells (n = 12), respectively. C6 glioma mice received three 211At-PA doses (0.1, 0.5, or 1 MBq, n = 3/dose), while GL261 mice received one high dose (1 MBq, n = 7). 211At-PA exhibited a tumor growth suppression effect in C6 glioma models in a dose-dependent manner as well as in GL-261 models. This phenylalanine derivative labeled with astatine may be applicable as an alpha therapy that specifically targets system L amino acid transporters.

The current study aimed to evaluate the outcomes of patients with adenocarcinoma (AC) of the uterine cervix after definitive radiotherapy (RT) and to evaluate prognostic factors, including immunity-related molecules. A total of 71 patients with AC of the uterine cervix from multiple Japanese institutions were retrospectively analysed. Histological subtypes were diagnosed according to the 2014 World Health Organization classification. All patients underwent definitive RT comprising external beam RT and intracavitary brachytherapy with or without concurrent chemotherapy. Immunohistochemical studies were performed to detect the expression of programmed cell death-ligand 1(PD-L1) and CD8. The 5-year locoregional control (LC), overall survival (OS) and progression-free survival (PFS) rates for all patients were 61.8, 49.7 and 36.1%, respectively. The LC, OS and PFS rates were not significantly different among the histological subtypes. Membranous PD-L1 expression was not significantly associated with prognosis. Patients with CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) in the tumor nests had significantly better OS than patients without CD8+TILs in the tumor nests (5-year OS: 53.8 vs 23.8%, P = 0.038). As expected, the International Federation of Gynecology and Obstetrics (FIGO) stage (2008) III–IVA and maximum tumor diameter > 40 mm were significantly associated with worse prognosis. In summary, the presence of CD8+TILs in the tumor nests has the potential to be an independent favorable prognostic factor for patients with AC of the uterine cervix after definitive RT.

Malignant mesothelioma is associated with the exposure to asbestos fibers. Recent discovery of the BAP1 cancer syndrome, a Mendelian disorder with high-penetrance autosomal dominant inheritance fostered the genotyping for nucleotide-level or larger structural alteration of germline DNA. Inherited heterozygous mutations of the BAP1 gene increase the susceptibility to carcinogenic fibers, leading to a concept of gene x environment interaction (GxE) as a pathogenetic mechanism of mesothelioma. Several studies on cohorts of unselected patients with mesothelioma or on familial/early-onset cohorts of mesothelioma cases converged on BAP1 as the more frequent germline mutated gene, followed by other genes involved in DNA repair and homologous recombination. Evidence has been emerging that patients with mesothelioma carrying germline mutations of BAP1 and of other genes, such as those involved in DNA repair and tumor suppressor genes, have better prognosis and higher chemosensitivity when compared with patients with germline wildtype Bap1. We report here a germline genomic analysis targeted 22 genes in a cohort of 101 Japanese patients irrespective of asbestos exposure, age at diagnosis, or personal or family history of cancer. By comparing the results with the Human Genetic Variation Database (HGVD) and the Genome Aggregation Database (gnomAD) we selected rare germline variants with a Combined Annotation Dependent Depletion (CADD) >20. We show here that 31 of 101 subjects were carrying 25 rare variants in 14 genes, neither reported in the HGVD nor in the gnomAD database for 14/25 variants. Besides pathogenic variants of BAP1, rare missense variants were found in genes encoding lysine-specific histone methyltransferase SETD2 and SETDB1 and genes encoding subunits of the mSWI/SNF chromatin remodeling complex. The complete scenario of the genetic background consisting of pathogenic germline variants required for the predisposition and GxE for pathogenesis of mesothelioma appears complex, and further large-scale studies are warranted.

Oral microbiota may be associated with serious local or systemic medical conditions resulting from chemotherapy. This study was conducted to evaluate the changes in the oral microbiota following the initiation of chemotherapy in patients with hematopoietic malignancies and to identify the characteristics of the oral microbiota associated with oral mucositis. Oral samples were collected from 57 patients with hematopoietic malignancies at 2 time points: before the start of chemotherapy and 8 to 20 days after the start of chemotherapy, when chemotherapy-induced oral mucositis often occurs, and 16S rRNA metagenomic analyses were performed. Comparative and linear discriminant analysis effect size (LEfSe) analyses were used to determine the characteristic bacterial groups before and after the initiation of chemotherapy and in those who developed oral mucositis. The alpha and beta diversities of oral microbiota before and after the initiation of chemotherapy differed significantly (operational taxonomic unit index, P

The growing importance of antitumour immunity by cancer immunotherapy has prompted studies on radiotherapy-induced immune response. Previous studies have indicated that programmed cell death-1 ligand (PD-L1) expression is regulated by DNA damage signalling. However, PD-L1 up-regulation after radiotherapy has not been fully investigated at the clinical level, particularly in the context of expression of DNA repair factors. The present study examined the correlation of mRNA expression between PD-L1 and non-homologous end joining (NHEJ) factors using The Cancer Genome Atlas database analysis. Among NHEJ factors, Ku80 mRNA expression was negatively correlated with PD-L1 mRNA expression levels in several types of cancer (colon adenocarcinoma, breast invasive carcinoma, skin cutaneous melanoma, lung adenocarcinoma, head and neck squamous cell carcinoma, uterine corpus endometrial carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma). To verify the negative correlation in clinical samples, the present study analysed whether Ku80 expression levels affected PD-L1 up-regulation after radiotherapy using cervical squamous cell carcinoma samples. Quantitative evaluation using software analysis of immunohistochemically stained slides revealed that patients with low Ku80 positivity in biopsy specimens demonstrated increased PD-L1 expression levels after 10 Gy irradiation (Spearman's rank correlation coefficient=−0.274; P=0.017). Furthermore, PD-L1 induction levels in tumour cells after 10 Gy of irradiation were significantly inversely correlated with Ku80 expression levels (Spearman's rank correlation coefficient=−0.379; P

Background Recently, the gut microbiota has been shown to play an important role in the response and resistance to chemotherapy. Although there is much knowledge about chemotherapy-induced changes in the gut microbiota, chemotherapy-associated changes in the oral microbiota remain unclear. Herein, we aimed to evaluate the changes in oral microbiota associated with the initiation of chemotherapy in patients with malignant hematopoietic tumors. Methods Oral samples were collected before and 8–20 days after the start of chemotherapy from 50 patients with malignant hematopoietic tumors who were starting chemotherapy for the first time. The 16S ribosomal RNA gene sequencing of bacterial DNA extracted from oral samples was performed to compare the oral microbiota before and after the initiation of chemotherapy. Results The richness or evenness of diversity in the ‘after start of chemotherapy’ group decreased significantly, compared with the ‘before start of chemotherapy’ group (alpha-diversity; observed operational taxonomic units (OTUs) index, p p p = 0.001; and weighted UniFrac distances, p = 0.003). Linear discriminant analysis effect size analysis demonstrated an increased abundance of species of certain genera, such as Staphylococcus, and decreased abundance of species of some genera, such as Streptococcus and Neisseria, in the ‘after-chemotherapy’ group, compared with those in the ‘before-chemotherapy’ group. The amounts and trends of change in the oral microbiota before and after the start of chemotherapy differed among the subjects. Of the 25 bacterial genera whose prevalence changed significantly before and after the start of chemotherapy, the proportion of oral commensals such as Streptococcus and Neisseria decreased in many subjects. In contrast, Staphylococcus and Pseudomonas were detected only in a few subjects, but their relative abundance increased significantly after the start of chemotherapy. Conclusions The oral microbiota of patients with hematopoietic tumors changed markedly after the initiation of chemotherapy. Our findings are expected to aid the elucidation of the pathogenesis of oral mucositis, which is an adverse event of chemotherapy, and the development of treatment methods for this condition.

Simple Summary Recently, it has been shown that radiation therapy (RT) together with androgen-depletion therapy (ADT) might be more beneficial compared with ADT alone for clinically node-positive (cN1) prostate cancer. However, there are a limited number of studies that have addressed specific RT techniques and analyzed their clinical results. The present study was a retrospective analysis of cN1 prostate cancer patients treated with intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT), in addition to ADT, in our hospital. The present study suggests that ADT plus SIB-IMRT for cN1 prostate cancer treatment was safe and effective, was well tolerated, and had acceptable rates of late toxicity. Further prospective multicenter studies would be required to confirm the robustness of the present results. Abstract This study aimed to evaluate clinical outcomes and the toxicity of intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT) combined with androgen-deprivation therapy for clinically node-positive (cN1) prostate cancer. We retrospectively analyzed 97 patients with cN1 prostate cancer who received SIB-IMRT between June 2008 and October 2017 at our hospital. The prescribed dosages delivered to the prostate and seminal vesicle, elective node area, and residual lymph nodes were 69, 54, and 60 Gy in 30 fractions, respectively. Kaplan–Meier analysis was used to determine 5-year biochemical relapse-free survival (bRFS), relapse-free survival (RFS), overall survival (OS), and prostate cancer-specific survival (PCSS). Toxicity was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0. Over a median follow-up duration of 60 months, the 5-year bRFS, RFS, OS, and PCSS were 85.1%, 88.1%, 92.7% and 95.0%, respectively. Acute Grade 2 genito-urinary (GU) and gastro-intestinal (GI) toxicities were observed in 10.2% and 2.1%, respectively, with no grade ≥3 toxicities being detected. The cumulative incidence rates of 5-year Grade ≥2 late GU and GI toxicities were 4.7% and 7.4%, respectively, with no Grade 4 toxicities being detected. SIB-IMRT for cN1 prostate cancer demonstrated favorable 5-year outcomes with low incidences of toxicity.

Background Although carbon‐ion radiotherapy (C‐ion RT) with concurrent chemotherapy (chemo‐C‐ion RT) is a promising treatment for adenocarcinoma (AC) of the uterine cervix, its long‐term efficacy remains unclear. We evaluated the long‐term significance of concurrent weekly cisplatin and C‐ion RT for locally advanced AC of the uterine cervix. Methods We performed a pooled analysis of patients with stage IIB–IVA AC of the uterine cervix who underwent C‐ion RT alone or chemo‐C‐ion RT between September 2007 and December 2018 at our institution. Patients received 74.4 Gy (relative biological effectiveness) with or without cisplatin (40 mg/m2 per week for up to 5 weeks), underwent no prior pelvic RT or systemic therapy, and had a performance status of 0‐2. Propensity score matching was based on the year of diagnosis, regional lymph node metastasis, and stage. Results The matched cohort contained 26 patients who underwent C‐ion RT and 26 who underwent chemo‐C‐ion RT. The median age and follow‐up period were 57 (range, 28‐79) years and 34 (range, 2‐126) months, respectively. The 5‐year overall survival rate was significantly better in the chemo‐C‐ion RT group (72%) than in the C‐ion RT group (46%; P = .041). The 5‐year distant metastatic‐free rate was also significantly better in the chemo‐C‐ion RT group (66%) than in the C‐ion RT group (41%; P = .048). The incidence of grade ≥ 3 late toxicities was comparable between the two groups. Conclusions Chemo‐C‐ion RT for locally advanced AC of the uterine cervix is associated with a long‐term survival benefit., Chemo‐C‐ion radiotherapy improves survival for uterine cervical adenocarcinoma. Chemo‐C‐ion radiotherapy has improved distant metastatic‐free rates. C‐ion radiotherapy with cisplatin is more effective than C‐ion radiotherapy alone.

Little information is available on the risk factors for nasolacrimal duct obstruction after radiotherapy for head and neck tumors. We investigated the incidence and predictive dosimetric parameters for nasolacrimal duct obstruction following carbon-ion radiotherapy for head and neck tumors.Twenty-eight patients with head and neck non-squamous cell carcinoma were analyzed in this single-institution prospective study. More than half of the tumors were located in the nasal cavity and maxillary sinus. Carbon-ion radiotherapy consisting of 57.6 or 64.0 Gy(relative biological effectiveness; RBE) in 16 fractions was administered. Nasolacrimal duct obstruction was recorded according to Common Terminology Criteria for Adverse Events version 4.0. Cutoff values were determined using receiver operating characteristic (ROC) curve analysis. VX indicates the volume irradiated with X Gy(RBE).The median follow-up period was 60.3 months. Incidences of Grade 1 and 2 nasolacrimal duct obstructions were 46% (13/28) and 7% (2/28), respectively; no Grade 3 or greater toxicities were recorded. Throughout the dose range, the volumes of the irradiated nasolacrimal ducts were significantly higher in the obstruction-positive patients than in the obstruction-negative patients (p 0.001 for V10, V20, V30, V40, V50, and V60). Cutoff values determined by the ROC curve analysis classified the obstruction-positive patients with an accuracy of96% over the entire range of V10-V60.The incidence and predictive dosimetric parameters for nasolacrimal duct obstruction after carbon-ion radiotherapy were demonstrated in a prospective cohort. These data should help optimize carbon-ion radiotherapy treatments for patients with head and neck tumors.

This phase II study's aim was to confirm the efficacy and safety of hypofractionated carbon‐ion radiotherapy in patients with stage I peripheral nonsmall cell lung cancer (NSCLC). The study encompassed 37 patients with histologically proven peripheral stage I NSCLC in the period June 2010‐March 2015. All underwent the planned full dose of carbon‐ion radiotherapy, administered with relative biological effectiveness of 52.8 Gy and 60 Gy (divided into four fractions over 1 week) for T1 and T2a tumors, respectively. The 2‐year local control rate was set as the primary endpoint, while overall survival, progression‐free survival, and the incidence rates of acute and late adverse events were secondary endpoints. The patients were followed up for 56.3 months overall and 62.2 months in the surviving patients, respectively. The actuarial local control rates were 91.2% after 2 years, and 88.1% after 5 years. No differences were found between the T1 and T2a tumors in the 5‐year local control rate (90.9% vs 86.7%, P = .75). The actuarial overall survival rates achieved 91.9% for 2‐year and 74.9% for 5‐year period. T1 tumors showed actuarial 5‐year overall survival rates of 80%, compared to 66.7% in T2a tumors. Two patients with T2a tumors and either severe emphysema or bronchiectasis experienced lung toxicity ≥ grade 2, in contrast to T1 patients who only experienced mild toxicities (lower than grade 2). The findings suggest that carbon‐ion radiotherapy is effective and safe for peripheral stage I NSCLC; however, further clinical evaluations are needed to confirm its therapeutic efficacy. Trial registration: UMIN000003797. Registered 21 June 2010, prospectively registered., The aim of this phase II study was to confirm the feasibility and safety of hypofractionated carbon‐ion radiotherapy for patients with stage I peripheral nonsmall cell lung cancer. The actuarial 2‐year and 5‐year local control rates were 91.2% and 88.1%, respectively. The actuarial 2‐year and 5‐year overall survival rates were 91.9% and 74.9%, respectively.

This study aimed to evaluate the efficacy of carbon‐ion radiotherapy in combination with chemotherapy using dacarbazine, nimustine, and vincristine (DAV therapy) in mucosal melanoma. Twenty‐one patients with clinically localized mucosal melanoma of the head and neck were enrolled. The primary endpoint was 3‐year overall survival (OS). Secondary endpoints included local control, progression‐free survival (PFS), and adverse event occurrence. Carbon‐ion radiotherapy with a dose of 57.6‐64.0 Gy (relative biological effectiveness) in 16 fractions was delivered concurrently with DAV therapy, and 2 cycles of adjuvant DAV therapy were administered every 6 weeks. The median follow‐up periods were 15.5 months for all patients, and 31.2 months for 12 surviving patients. All patients had locally advanced T4a or T4b disease in the rhino‐sinus area. In 16 patients (76.2%), 3 cycles of planned DAV therapy were completed. The 3‐year OS and PFS rates were 49.2% and 37.0% respectively. The 3‐year local control rate was 92.3%. Eleven patients (52%) developed distant metastasis, which was the most frequent pattern of the first failure. Commonly presenting acute grade 2‐3 toxicities associated with radiotherapy and chemotherapy were mucositis (11 patients [53%]) and leukopenia (9 patients [43%]), which improved with conservative therapy. None of the patients developed grade 3 or greater late toxicities. Carbon‐ion radiotherapy in combination with DAV therapy led to excellent local control for advanced mucosal melanoma within acceptable toxicities. The efficacy of additional DAV therapy in improving survival was weaker than expected as distant metastases still occurred frequently. Trial registration no. UMIN000007939., It is the first prospective trial to evaluate the clinical outcomes of carbon‐ion radiotherapy combined with chemotherapy.

Background and purpose Integrated analysis of existing radiosensitivity data obtained by the gold-standard clonogenic assay has the potential to improve our understanding of cancer cell radioresistance. However, extraction of radiosensitivity data from the literature is highly labor-intensive. To aid in this task, using deep convolutional neural networks (CNNs) and other computer technologies, we developed an analysis pipeline that extracts radiosensitivity data derived from clonogenic assays from the literature. Materials and methods Three classifiers (C1–3) were developed to identify publications containing radiosensitivity data derived from clonogenic assays. C1 uses Faster Regions CNN with Inception Resnet v2 (fRCNN-IRv2), VGG-16, and Optical Character Recognition (OCR) to identify publications that contain semi-logarithmic graphs showing radiosensitivity data derived from clonogenic assays. C2 uses fRCNN-IRv2 and OCR to identify publications that contain bar graphs showing radiosensitivity data derived from clonogenic assays. C3 is a program that identifies publications containing keywords related to radiosensitivity data derived from clonogenic assays. A program (iSF2) was developed using Mask RCNN and OCR to extract surviving fraction after 2-Gy irradiation (SF2) as assessed by clonogenic assays, presented in semi-logarithmic graphs. The efficacy of C1–3 and iSF2 was tested using seven datasets (1805 and 222 publications in total, respectively). Results C1–3 yielded sensitivity of 91.2% ± 3.4% and specificity of 90.7% ± 3.6%. iSF2 returned SF2 values that were within 2.9% ± 2.6% of the SF2 values determined by radiation oncologists. Conclusion Our analysis pipeline is potentially useful to acquire radiosensitivity data derived from clonogenic assays from the literature.

Background The aim of this study was to evaluate the efficacy and safety of carbon‐ion radiation therapy for nonsquamous cell carcinomas of the oral cavity in a multicenter study. Methods Retrospective analysis of the clinicopathological features and outcomes of 76 patients with oral nonsquamous cell carcinomas with N0‐1 M0 status and were treated with carbon‐ion radiation therapy at four institutions in Japan between November 2003 and December 2014 was performed. Results Salivary gland carcinoma, mucosal melanoma, and three other carcinomas were found in 46, 27, and 3 patients, respectively. T1‐3, T4a, and T4b disease was diagnosed in 27, 18, and 31 patients, respectively. Median follow‐up period was 31.1 months (range, 3‐118 months). Three‐year local control, progression‐free survival, and overall survival of all patients were 86.8%, 63.1%, and 78.4%, respectively. Multivariate analysis showed T classification (T4) to be a significant independent poor prognostic factor for local control. Acute grade 3 mucositis was observed in 38 patients. Grades 3 and 4 late morbidities were observed in 9 and 4 patients, respectively. No grade 5 late toxicity was observed. Conclusions Oral nonsquamous cell carcinomas could be treated effectively, with acceptable toxicity, by carbon‐ion radiation therapy., This retrospective multicenter study aimed to evaluate the safety and efficacy of carbon‐ion radiotherapy as a primary treatment for oral malignancies, and our results indicate that most patients had salivary gland carcinoma or mucosal melanoma. The 3‐year rates were 86.4% for local control, 63.1% for progression‐free survival, and 78.4% for overall survival. Oral nonsquamous cell carcinomas could be treated effectively, with acceptable toxicity, by carbon‐ion radiation therapy.

Purpose This study evaluated the safety and efficacy of carbon-ion radiation therapy (C-ion RT) with concurrent chemotherapy for locally advanced uterine cervical squamous cell carcinoma in a phase 1/2 clinical trial. Methods and Materials Twenty-two patients were treated with C-ion RT with concurrent weekly cisplatin at a dose of 40 mg/m2. The phase 1 component evaluated the safety of 72.0 Gy (relative biological effectiveness) of C-ion RT with concurrent chemotherapy. In the phase 2 component, the safety and efficacy of C-ion RT with concurrent chemotherapy were assessed using the dose determined in phase 1. Results The median follow-up period was 32 months, and the median tumor size was 71 mm (range, 51-150 mm). No patient had dose-limiting toxicities in the phase 1 component; the recommended dose was determined to be 72.0 Gy (relative biological effectiveness) with 40 mg/m2 of cisplatin. In the phase 2 component, 2 patients developed grade 3 gastrointestinal tract toxicities. In patients treated with the recommended dose, the 2-year local control (LC), LC including salvage therapy, and overall survival rates were 67%, 81%, and 82%, respectively. The 2-year LC and overall survival rates for patients with tumor sizes ≤7.1 cm were 92% and 100%, respectively; for those with tumor sizes >7.1 cm they were 33% and 60%, respectively. Conclusions C-ion RT with concurrent weekly cisplatin was tolerated by patients with locally advanced uterine cervical squamous cell carcinoma. Outcomes were good in patients with tumor sizes ≤7.1 cm but not in those with larger tumors. The results of the present study should be validated with larger multi-institutional prospective studies. Further study is needed, and perhaps incorporating carbon ion external beam radiation with brachytherapy will further reduce the risk of central recurrence.

Definitive radiotherapy for cervical cancer consists of external-beam radiotherapy (EBRT) and brachytherapy. In EBRT, a central shield (CS) reduces the dose to the rectum and bladder. The combination of whole-pelvic (WP)- and CS-EBRT and brachytherapy is the standard radiotherapy protocol in Japan. Despite clinical studies, including multi-institutional clinical trials, showing that the Japanese treatment protocol yields favorable treatment outcomes with low rates of late radiation toxicities, dose–volume parameters for the Japanese treatment protocol remain to be established. We conducted a retrospective dose–volume analysis of 103 patients with uterine cervical cancer treated with the Japanese protocol using computed tomography–based adaptive brachytherapy. The 2-year overall survival and 2-year local control rates according to FIGO stage were 100% and 100% for Stage I, 92% and 94% for Stage II, and 85% and 87% for Stage III–IV, respectively. Late adverse effects in the rectum and bladder were acceptable. Receiver operating characteristic analysis discriminated recurrence within the high-risk clinical target volume (HR-CTV) (n = 5) from no local recurrence (n = 96), with the optimal response obtained at a dose of 36.0 GyEQD2 for HR-CTV D90 and 28.0 GyEQD2 for HR-CTV D98. These values were used as cut-offs in Fisher exact tests to show that high HR-CTV D90 and HR-CTV D98 doses for brachytherapy sessions were significantly associated with tumor control within the HR-CTV. These data suggest a contribution of brachytherapy to local tumor control in WP- and CS-EBRT and brachytherapy combination treatment, warranting validation in multi-institutional prospective studies.

To evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF-RT) for cervical esophageal cancer (CEC), we performed a retrospective analysis of CEC patients treated by DCF-RT at a single institution. We conducted a single-center retrospective study. Twenty-one patients with CEC who underwent DCF-RT between 1999 and 2017 at our institute were included in this study. Chemotherapy consisted of intravenous docetaxel at 50 mg/m2 on day 1, intravenous CDDP at 60 mg/m2 on day 1, and intravenous 5-FU at 600 mg/m2 on days 1–4, repeated every 4 weeks for two cycles. Among the 21 patients, six were irradiated using three-dimensional conformal RT (3D- conformal RT) and 15 were treated using intensity-modulated RT (IMRT) consisting of 60 Gy in 30 fractions. The median follow-up period was 49.6 months (range 4.6–97.6). The overall complete response (CR) and local CR rates were 61.9% and 81.0% for all patients, and 76.9% and 84.6% for patients without hypopharyngeal and/or thoracic esophageal invasion, respectively. The 3-year overall survival (OS), progression-free survival (PFS), and local failure-free survival (LFFS) rates were 79.6, 52.4, and 74.7%, respectively. Grade 3–4 leucopenia developed in 12 patients (70.6%), neutropenia developed in 13 patients (81.2%), and mucositis developed in 2 patients (9.5%). There were no treatment-related deaths. The 3-year OS and LFFS of patients who underwent DCF-RT were higher than those in the previous studies. Although the high rate of myelosuppression requires careful management, DCF-RT is a safe and effective modality for CEC.

PURPOSE Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin). On this basis, we designed a randomized, phase II trial to investigate whether defactinib as maintenance therapy after standard first-line chemotherapy could improve progression-free survival (PFS) in patients with malignant pleural mesothelioma (MPM). METHODS This global, double-blind, randomized, placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy. Patients were stratified for merlin and then randomly assigned (in a 1:1 fashion) to receive either oral defactinib or placebo until disease progression, unacceptable toxicity, or withdrawal occurred. The coprimary end points were PFS and overall survival (OS). Quality of life (QoL) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool. RESULTS Three hundred forty-four patients were randomly assigned to receive either defactinib (n = 173) or placebo (n = 171). The median PFS was 4.1 months (95% CI, 2.9 to 5.6 months) for defactinib versus 4.0 months (95% CI, 2.9 to 4.2 months) for placebo. The median OS was 12.7 months (95% CI, 9.1 to 21 months) for defactinib versus 13.6 months (95% CI, 9.6 to 21.2 months) for placebo (hazard ratio, 1.0; 95% CI, 0.7 to 1.4). Although shorter survival for both defactinib- and placebo-treated patients was observed, in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM, there were no statistical differences in response rate, PFS, OS, or QoL between the treatment groups. The most common grade 3 or worse adverse events were nausea, diarrhea, fatigue, dyspnea, and decreased appetite. CONCLUSION Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinib cannot be recommended as maintenance therapy for advanced MPM.

Malignant pleural mesothelioma (MPM) is a global health issue, the principal cause of which is exposure to asbestos. The prevalence is anticipated to rise over the next 2 decades, particularly in developing countries, due to the 30-50-year latency period between exposure to asbestos and carcinogenic development. Unresectable MPM has a poor prognosis and limited treatment options and, as such, there is a broad range of therapeutic targets of interest, including angiogenesis, immune checkpoints, mesothelin, as well as chemotherapeutic agents. Recently, the results of several randomized trials in the first-line setting combining antiangiogenic agents with chemotherapy have been reported. This review examines the scientific rationale for targeting angiogenesis in the treatment of unresectable MPM and analyzes recent clinical results with antiangiogenic agents in development (bevacizumab, nintedanib, and cediranib) for the management of MPM.

Aim We developed a vaginal immobilization device for external radiotherapy in gynaecological malignancies and evaluated its bowel dose-reduction effect during carbon-ion radiotherapy (CIRT) and intensity-modulated radiation therapy (IMRT) in patients with cervical cancer. Patients and methods Computed tomographic images obtained with and without the device in seven patients with cervical cancer were assessed. Treatment plans for CIRT and IMRT were generated, and dose-volume parameters (V20, V25, V35, and D2cc) of the rectum, sigmoidal colon, and bladder were evaluated. Results The mean±standard deviation of the rectal volume in CIRT for V35 with and without the device were 2.1±2.1 and 13.6±4.4 ml, respectively, and those in IMRT were 2.0±2.2 and 13.7±3.8 ml, respectively; these values were significantly lower in CIRT and IMRT using this device. Conclusion Using our novel vaginal immobilization device, high rectal doses were largely reduced in CIRT and IMRT.

Purpose We investigated the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for locally recurrent rectal cancer (LRRC). Patients and methods Data from patients with LRRC treated with C-ion RT from November 2003 to December 2014 at three institutions were retrospectively analyzed. The endpoints of this clinical trial were overall survival (OS), local control (LC), and acute/late toxicity. Results A total of 224 patients' data were collected. The prescribed dose was 70.4 Gy (relative biological effectiveness [RBE]-weighted absorbed dose) or 73.6 Gy (RBE) in 16 fractions. The median follow-up period from the initiation of C-ion RT was 62 months (range 6–169 months). The OS rates were 73% (95% confidence interval [CI], 67%–79%) at 3 years and 51% (95%CI 44%–58%) at 5 years. The LC rates were 93% (95%CI 88%–96%) at 3 years, and 88% (95%CI 82%–93%) at 5 years. Grade 3 acute toxicity was observed in three patients: gastrointestinal toxicity (n = 1) and pelvic infection (n = 2). Grade 3 late toxicity was observed in 12 patients: skin reaction (n = 2), gastrointestinal toxicity (n = 2), neuropathy (n = 1), and pelvic infection (n = 7). There was no grade 4 or 5 acute or late toxicity. Conclusions This first multi-institutional analysis of C-ion RT for LRRC indicated relatively favorable outcomes with limited toxicities.

Background and purpose To evaluate the safety of carbon-ion radiotherapy (C-ion RT) using 60 Gy (relative biological effectiveness, RBE) in four fractions for patients with hepatocellular carcinoma (HCC). Materials and methods The primary outcome was acute toxicities within 90 days. The secondary outcomes were late toxicities, local control, and progression-free survival and overall survival rates. The key inclusion criteria were as follows: (1) 3 cm or larger HCC without major vascular invasion and not adjacent to the alimentary tract; (2) Child–Pugh’s grade A/B; and (3) without extrahepatic metastasis. Results A total of 21 cases were analyzed between October 2012 and April 2016. The median follow-up period among the 17 survivors was 24.2 (range: 6.3–43.7) months. Grade 3 or higher acute toxicity was not observed, while three (14.3%) of the 21 patients experienced grade 3 late toxicities. The 1- and 2-year local control, progression-free survival, and overall survival rates were 100% and 92.3%, 81.0% and 50.0%, and 90.5% and 80.0%, respectively. Conclusion C-ion RT using 60 Gy (RBE) in four fractions was safe and achieved promising local tumor control.

Simple Summary Quality of life (QOL) and functional outcomes in patients with inoperable bone and soft tissue sarcoma treated with definitive carbon-ion radiotherapy (CIRT) were prospectively investigated. CIRT showed favorable clinical efficacy and safety, maintaining the physical component of QOL and functional outcomes, and improving the mental component of QOL. The physical component of QOL was positively correlated with functional outcomes. Poor performance status at diagnosis and female gender were independent predictors of the physical component of QOL and functional outcomes after CIRT. Abstract Carbon-ion radiotherapy (CIRT) represents a definitive treatment for inoperable bone and soft tissue sarcoma (BSTS). This prospective study analyzed 61 patients with inoperable BSTS who were treated with CIRT to evaluate QOL, functional outcomes, and predictive factors in patients with inoperable BSTS treated with definitive CIRT. The Musculoskeletal Tumor Society (MSTS) scoring system and the Short Form (SF)-8 questionnaire were completed before and at 1, 3, 6, 12, and 24 months after CIRT. The median follow-up period was 38 months. The main site of primary disease was the pelvis (70.5%), and the most common pathologic diagnosis was chordoma (45.9%). The 3-year overall survival and local control rates were 87.8% and 83.8%, respectively. The MSTS score and physical component score (PCS) of SF-8 did not change significantly between the baseline and subsequent values. The mental component score of SF-8 significantly improved after CIRT. Multivariate analysis showed that the normalized MSTS and normalized PCS of SF-8 at the final follow-up were significantly affected by performance status at diagnosis and sex. CIRT showed clinical efficacy, preserving the physical component of QOL and functional outcomes and improving the mental component of QOL, suggesting its potential value for the treatment of patients with inoperable BSTS.

Radiotherapy induces an immune response in the cancer microenvironment that may influence clinical outcome. The present study aimed to analyse the alteration of CD8(+) T-cell infiltration and programmed death-ligand 1 (PD-L1) expression following radiotherapy in clinical samples from patients with uterine cervical squamous cell carcinoma. Additionally, the current study sought to analyse the association between these immune responses and clinical outcomes. A total of 75 patients who received either definitive chemoradiotherapy or radiotherapy were retrospectively analyzed. CD8(+) T-cell infiltration and PD-L1 expression were determined by immunohistochemistry using biopsy specimens before radiotherapy (pre-RT) and after 10 Gy radiotherapy (post-10 Gy). The PD-L1(+) rate was significantly increased from 5% (4/75) pre-RT to 52% (39/75) post-10 Gy (P

Simple Summary The standard treatment for bone sarcoma is surgery with or without additional chemotherapy; however, complete resection of the tumor might not be possible in patients with locally advanced lesions. Management of patients with bone sarcoma who are unsuitable for surgery is challenging. Carbon ion radiotherapy (C-ion RT) was initiated in 1994 for treating various cancers in Japan and is being considered to be an effective treatment for unresectable bone sarcoma. However, there is a limited number of reports on the clinical outcomes of C-ion RT for bone sarcoma. Here, we aimed to analyze the clinical outcomes and prognostic factors among patients with unresectable bone sarcoma who were treated with C-ion RT. We found that C-ion RT had favorable overall survival and local control with low toxicity rates compared to surgery. Therefore, our results suggest a potential role for C-ion RT in the radical treatment of inoperable bone sarcoma. Abstract Management of patients with bone sarcoma who are unsuitable for surgery is challenging. We aimed to analyze the clinical outcomes among such patients who were treated with carbon ion radiotherapy (C-ion RT). We reviewed the medical records of the patients treated with C-ion RT between April 2011 and February 2019 and analyzed the data of 53 patients. Toxicities were classified using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (Version 4.0). The median follow-up duration for all patients was 36.9 months. Histologically, 32 patients had chordoma, 9 had chondrosarcoma, 8 had osteosarcoma, 3 had undifferentiated pleomorphic sarcoma, and 1 had sclerosing epithelioid fibrosarcoma. The estimated 3-year overall survival (OS), local control (LC), and progression-free survival (PFS) rates were 79.7%, 88.6%, and 68.9%, respectively. No patients developed grade 3 or higher acute toxicities. Three patients developed both grade 3 radiation dermatitis and osteomyelitis, one developed both grade 3 radiation dermatitis and soft tissue infection, and one developed rectum-sacrum-cutaneous fistula. C-ion RT showed favorable clinical outcomes in terms of OS, LC, and PFS and low rates of toxicity in bone sarcoma patients. These results suggest a potential role for C-ion RT in the management of this population.

Purpose We aimed to assess the robustness of accumulated dose distributions for inter-fractional changes in passive carbon-ion radiotherapy for pancreatic cancer. Methods Ninety-five daily CT image sets acquired after the treatment of eight patients with pancreatic cancer were used in this prospective study. Dose distributions with treatment beam fields were recalculated for bone matching (BM) and tumor matching (TM) positions on all daily CT images, the accumulated doses being calculated using deformable image registration methods. The prescribed dose was 55.2 Gy (relative biological effectiveness [RBE]) in 12 fractions. Dose volume parameters of V95 (%) for CTV and GTV, and D2cc (Gy(RBE)) for the stomach and duodenum were evaluated. Results The medians (range) of CTV V95 (%) were 91.9 (86.1–100.0), 80.5 (56.1–90.6), and 86.4 (72.5–96.5) for the Plan, accumulated with BM and TM, respectively; GTV values (%) were 98.0 (85.7–100.0), 93.3 (65.7–99.9), and 96.2 (84.8–100.0), respectively. There were significant differences between all combinations apart from the Plan and TM for both targets. The values of stomach D2cc (Gy(RBE)) were 36.0 (16.9–43.4), 36.7 (17.9–45.0), and 35.2 (16.8–43.5), respectively; duodenum values (Gy(RBE)) were 25.2 (21.3–40.3), 30.1 (23.3–48.6), and 28.3 (20.4–50.6), respectively. There was a significant difference between the Plan and BM for duodenum only. Conclusions TM is recommended over BM because it can achieve higher target dose coverage than BM. Nevertheless, it is not enough in some cases. Further technical improvements are necessary to improve the target dose coverage.

Background and Purpose There is growing evidence on the role of carbon-ion radiotherapy (C-ion RT) for gynaecological tumours. Pelvic insufficiency fracture (PIF) decreases the quality of life after photon beam radiotherapy (RT). However, there is little information on PIF after C-ion RT. This study retrospectively assessed incidence of PIF after C-ion RT for uterine carcinomas (UCs) and the associations of clinical and dosimetric parameters with PIF incidence. Material and Methods We performed a pooled analysis of 102 patients with UCs who underwent definitive C-ion RT alone and were followed up for >6 months without any additional RT in the pelvic region. PIF occurrence was surveyed using magnetic resonance imaging and/or computed tomography. Associations of clinical and dosimetric parameters with PIF incidence were analysed. Results The 2- and 5-year actuarial incidences of ≥grade 1 PIF in all pelvic regions were 22.3% and 42.4%, respectively. The most frequent site of involvement was the sacrum. Log-rank tests showed that higher volumes receiving >10 Gy (relative biological effectiveness) (V10), V20, V30, and V40, body mass index (BMI) under 18.5, and current smoking were associated with increased incidence of ≥grade 1 PIF in the sacrum. Conclusions We clarified the actuarial incidence of PIF after C-ion RT for UCs. Higher V10, V20, V30, V40, D50%, Dmean, current smoking, BMI

BACKGROUND/AIM The cell-killing and radiosensitizing effects of carbon-ion (C-ion) beams with low linear energy transfer (LET) are underexplored. We aimed to demonstrate the cell-killing effects of 60Co gamma rays and C-ion beams at various LET values and the radiosensitizing effect of C-ion beams at various LET and cisplatin levels. MATERIALS AND METHODS Human uterine cervical cancer cells were irradiated with 60Co gamma rays and C-ion beams at different levels of LET, with and without cisplatin treatment. RESULTS Low-LET C-ion beams had a superior cell-killing effect compared to 60Co gamma rays. Survival curves under low-LET C-ion beams were more similar to that of 60Co gamma rays than that of high-LET C-ion beams. Cisplatin significantly reduced cell survival after 1, 2, and 3 Gy C-ion beam irradiations at LET values of 13/30/70 keV/μm, 13/30 keV/μm, and 13 keV/μm, respectively. CONCLUSION Low-LET C-ion beams combined with cisplatin have higher radiosensitizing effects than high-LET C-ion beams.

Purpose: We quantified the inter-fractional changes associated with passive carbon-ion radiotherapy using vertical and horizontal beam fields for prostate cancer. Methods: In total, 118 treatment-room computed tomography (TRCT) image sets were acquired from 10 patients. Vertical (anterior–posterior) and horizontal (left–right) fields were generated on the planning target volume identified by treatment planning CT. The dose distribution for each field was recalculated on each TRCT image set at the bone-matching position and evaluated using the dose–volume parameters for the prostate and rectum V95 values. To confirm adequate margins, we generated vertical and horizontal fields with 0-, 2-, 4-, and 6-mm isotropic margins from the prostate and recalculated the dose distributions on all TRCT image sets. Sigmoid functions were fitted to a plot of acceptable ratios (that is, when prostate V95 > 98%) vs. the isotropic margin size to identify the margin at which this ratio was achieved in 95% of patients with a vertical or horizontal field. Results: The prostate V95 values (mean ± standard deviation) were 99.89 ± 0.62% and 99.99 ± 0.00% with vertical and horizontal fields, respectively; this difference was not statistically significant (p = 0.067). The rectum V95 values were 1.93 ± 1.25 and 1.88 ± 0.96 ml with vertical and horizontal fields, respectively; the difference was not statistically significant (p = 0.432). The estimated adequate margins were 2.2 and 3.0 mm for vertical and horizontal fields, respectively. Conclusions: Although there is no significant difference, horizontal fields offer higher reproducibility for prostate dosing than vertical fields in our clinical setting, and 3.0 mm was found to be an adequate margin for inter-fractional changes.

BackgroundHepatocellular carcinoma (HCC) involving a major branch of the portal or hepatic vein is in a locally advanced stage and remains difficult to cure. This study aimed to evaluate the clinical effects of carbon ion radiotherapy (C-ion RT) in locally advanced HCC (LAHCC).MethodsThe data of 11 consecutive patients with LAHCC who received C-ion RT were analyzed. The C-ion RT doses of 52.8 Gy (relative biological effectiveness [RBE]) and 60.0 Gy (RBE) were delivered in 4 fractions for standard cases, and the 60.0 Gy dose was delivered in 12 fractions for close-to-gastrointestinal-tract cases. Survival and local control probabilities were calculated using the Kaplan-Meier method.ResultsThe median follow-up duration after C-ion RT was 36.4 months. The median age at the time of registration for C-ion RT was 76 years. The median tumor size was 53 mm. The numbers of treatment-naive and recurrent HCC patients were 1 and 10, respectively. Direct invasion of the major branch of the portal vein, hepatic vein, or both portal and hepatic veins was observed in three, five, and three patients, respectively. The 3-year overall survival, local control, and progression-free survival rates were 64, 78, and 18%, respectively. No patient developed radiation-induced liver diseases or grade 3 or higher toxicities in the acute and late phases.ConclusionsC-ion RT showed favorable clinical outcomes with a high rate of local control and minimal toxicities in LAHCC. Our findings suggest that C-ion RT is a promising multidisciplinary treatment option in LAHCC.

We recently reported the dose-dependent therapeutic effect of 211At-NaAt in differentiated thyroid cancer xenograft models. In the present study, we evaluated the radiation-induced toxicity of 211At-NaAt using detailed hematological, biochemical, and histological analyses. Biodistribution of 211At-NaAt was measured in normal ICR mice (n = 12), absorbed doses in the major organs were calculated. Groups of ICR mice (n = 60) were injected with 0.1 MBq or 1 MBq of 211At-NaAt, using saline as the control group (n = 30). Body weight and food intake were followed up for 60 days. Blood cell counts and serum level of biochemical parameters were measured 3, 7, 15, 29, 60 days after injection. Histological analyses of the major organs with hematoxylin and eosin staining were performed. Biodistribution study revealed a high-absorbed dose in the thyroid gland, stomach, bladder, heart, lungs, spleen, kidneys, and testis. The 0.1 MBq group showed no abnormalities. The 1 MBq group showed decreased body weight and food intake. Histological analysis showed atrophy and fibrosis in the thyroid gland, a transient hypospermatogenesis in the testis on day 29 was found in one mouse. Hematological toxicity was mild and transient. The total cholesterol, albumin, and total protein increased with no signs of recovery, which was considered to be caused by hypothyroidism. High-dose administration of 211At-NaAt showed transient toxicity in the white blood cells and testis without severe hematological or renal toxicity, suggesting its tolerable safety as targeted alpha-therapy for differentiated thyroid cancer in the 1 MBq group.

In Asia, several challenges hinder the delivery of high-quality cancer treatment, especially radiation therapy (RT). Many Asian countries face large-scale shortage of RT centres and treatment machines. Additionally, there is also a significant technological gap, with many RT centres in Asia still using outdated technology. There is an urgent need to improve radiation treatment quality in Asia. The Federation of Asian Organizations for Radiation Oncology (FARO) was set up to foster regional collaboration, which we believe can help to identify and solve some of these issues collectively. This report describes the background and rationale of starting FARO, and puts forth some of the early achievements of the group, including fact-finding and educational activities. Finally, we discuss future possibilities, including strategic proposals that may benefit the RT community and our patients in Asia.

This study aimed to first elucidate prostate-specific antigen (PSA) kinetics in prostate cancer patients treated with carbon ion radiotherapy (CIRT). From 2010 to 2015, 131 patients with prostate adenocarcinoma treated with CIRT (57.6 Gy relative biological effectiveness (RBE) in 16 fractions) alone were recruited. PSA was measured at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post-CIRT. PSA bounce was defined as PSA increase over a cutoff followed by spontaneous decrease to or below the pre-bounce nadir. PSA failure was determined using the Phoenix criteria (nadir + 2.0 ng/mL). As a result, non-failure-associated temporary increase in PSA exhibited two distinct patterns, namely a classical bounce and a surge at one month. PSA bounce of &sup3, 0.2 ng/mL was observed in 55.7% of the patients. Bounce amplitude was &lt, 2.0 ng/mL in 97.6% of cases. Bounce occurred significantly earlier than PSA failure. Younger age was a significant predictor of bounce occurrence. Bounce positivity was a significant predictor of favorable 5-year PSA failure-free survival. Meanwhile, a PSA surge of &sup3, 0.2 ng/mL was observed in 67.9% of patients. Surge amplitude was significantly larger than bounce amplitude. Larger prostate volume was a significant predictor of PSA surge occurrence. PSA surge positivity did not significantly predict PSA failure. In summary, PSA bounce was distinguishable from PSA failure with regard to timing of occurrence and amplitude (earlier and lower for bounce, respectively). These data are useful for post-CIRT surveillance of prostate cancer patients.

Background Carbon ion Radiotherapy for prostate cancer is widely used, however reports are limited from single institute or short follow up. We performed a prospective observational study (GUNMA0702) to evaluate the feasibility and efficacy of carbon ion radiotherapy for localized and locally advanced prostate cancer. Methods Between June 2010 and August 2013, 304 patients with localized prostate cancer were treated, with a median follow-up duration of 60 months. All patients received carbon ion radiotherapy with 57.6 Gy (RBE) in 16 fractions over 4 weeks. Hormonal therapy was given according to the risk group. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 by the National Cancer Institute. Results The overall 5-year biochemical relapse-free rate was 92.7%, with rates of 91.7, 93.4, and 92.0% in low-risk, intermediate-risk, and high-risk patients, respectively. The 5-year local control and overall survival rates were 98.4 and 96.6%, respectively. Acute grade 3 or greater toxicity was not observed. Late grade 2 and grade 3 genitourinary and gastrointestinal toxicity rates were 9 and 0.3%, and 0.3, and 0%, respectively. Conclusions The present protocol of carbon ion radiotherapy for prostate cancer provided low genitourinary and gastrointestinal toxicity with good biochemical control within 5 years. Trial registration University Medical Information Network Clinical Trial Registry number: UMIN000003827.

Background We conducted a retrospective multicenter study to assess the clinical outcomes of carbon‐ion radiotherapy (CIRT) for head and neck malignancies (Japan Carbon‐Ion Radiation Oncology Study Group [J‐CROS] study: 1402 HN). We aimed to evaluate the safety and efficacy of CIRT in patients with external auditory canal (EAC) and middle ear (ME) carcinomas. Methods Thirty‐one patients treated with CIRT at four Japanese institutions were analyzed. Fourteen patients (45.2%) had squamous cell carcinomas, 13 (41.9%) had adenoid cystic carcinomas, and four (12.9%) had other types. Nineteen (61.3%), six (19.4%), three (9.7%), and three (9.7%) patients had T4, T3, T2, and T1 disease, respectively. All patients had N0M0 status. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 33.3 mL. Results The median follow‐up period was 18.4 months (range, 5.1‐85.6). The 1‐ and 3‐year local control and overall survival rates were 75.0% and 55.0% and 79.3% and 58.7%, respectively. Regarding grade 3 or higher toxicities, three patients (9.7%) had grade 3 dermatitis, one (3.2%) had grade 3 mucositis, and two (6.5%) had grade 3 central nervous necrosis (ie, radiation‐induced brain necrosis). No grade 4 or worse reactions were observed. Conclusion CIRT was effective for EAC and ME carcinomas.

Background This multi‐institutional retrospective study focused on the clinical outcome of carbon‐ion radiotherapy (C‐ion RT) for non‐squamous cell malignant tumors of the nasopharynx. Methods The Japan Carbon‐ion Radiation Oncology Study Group collected and analyzed data for 43 patients with non‐squamous cell malignant tumors of the nasopharynx treated with C‐ion RT at four institutions in Japan. Results Twenty‐nine patients had adenoid cystic carcinomas, seven had malignant melanomas, three had adenocarcinomas, two had mucoepidermoid carcinomas, and two had other pathologies. Twenty‐six of the 43 patients (61%) had T4 tumors. The most common dose‐fractionation schedule was 64 Gy (relative biological effectiveness) in 16 fractions. The median follow‐up period was 30 months. The 2‐year local control (LC) and overall survival (OS) rates were 88% and 84%, respectively. For late toxicity, one patient developed grade 4 optic nerve disorder and two developed grade 5 pharyngeal hemorrhage. Actual incidence of grade 3 or higher late adverse events was 19%, and included cranial nerve dysfunction, jaw bone necrosis, central nervous system necrosis, and ear inflammation. Conclusions C‐ion RT provided good LC and OS rates with acceptable toxicity for treatment of non‐squamous cell malignant tumors of the nasopharynx.

Purpose The aim of this study was to investigate the efficacy of combination therapy with intravenously injected microglia (MI) and radiation therapy (RT) for malignant glioma in rats. Methods and Materials Transgenic rats expressing v-erbB and spontaneously developing malignant glioma were used. The rats were divided into 4 groups: control (n = 19), RT alone (n = 10), MI alone (n = 9), and combination MI and RT (MI + RT) (n = 10). Cranial x-ray irradiation (8 Gy per fraction; once per week) was performed at 50 and 51 weeks of age. Cultured rat microglial cells (5 × 106 cells/rat) were intravenously injected via the tail vein within 30 minutes after RT. Results No evidence of side effects, including thrombosis or graft-versus-host disease, was noted. Rats treated with RT alone, MI alone, MI + RT, and control survived 60.9, 56.3, 66.0, and 56.1 weeks, respectively. The survival period of MI + RT was significantly longer than that of control (P = .014), MI alone (P = .027), and RT alone (P = .049). Immunohistochemical analysis showed a significantly higher number of tumor-infiltrated MI in the RT alone (P = .041) and MI + RT groups (P = .014) compared with the control. Significantly more CD8-positive lymphocytes were observed in the MI + RT group (P = .049) compared with the control. A positive correlation was found between the number of MI and CD8-positive lymphocytes (R2 = 0.556). A positive correlation was also found between CD8-positive lymphocytes and survival periods (R2 = 0.460). Conclusions MI + RT increased infiltrated MI and CD8-positive T cells and prolonged survival in transgenic rats that spontaneously developed malignant glioma. Combined immunocellular therapy and RT may provide a novel treatment strategy for malignant glioma.