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Carbon-ion radiotherapy (CIRT) for prostate cancer is both safe and efficacious; beam range calculations use relative stopping power ratio, which is derived from computed tomography (CT) values. However, hip prostheses are made of high atomic number materials and show severe artifacts on CT images. Therefore, it is not possible to accurately calculate dose distribution for CIRT in patients with prostate cancer with hip prostheses. Here, we describe the management of a 77-year-old man with prostate cancer who had previously undergone bilateral hip replacement. CIRT, in combination with androgen deprivation therapy, was recommended as definitive treatment for prostate cancer. Planning CT, magnetic resonance (MRI), and CT images with metal artifact reduction (MAR) were acquired for CIRT planning. MRI and MAR images were superimposed on the planning CT to delineate target volume and organs at risk. The radiation treatment plan consisted of a total dose of 51.6 Gy (relative biological effect) to be delivered in 12 fractions over 3 weeks, and the patient was irradiated in the supine and prone positions with a vertical beam, on alternating days. CIRT was completed as scheduled. No adverse events were observed during treatment or at 3 months after treatment initiation. While we show that CIRT may be a treatment option for patients with prostate cancer with bilateral hip prostheses, further studies are needed to evaluate treatment efficacy and late toxicity and to determine how CIRT can be administered to patients with prostate cancer with bilateral hip prostheses.

PurposeCarbon-ion beam (C-beam) has a sharp dose distribution called the Bragg peak. Carbon-ion radiation therapy, such as stereotactic body radiotherapy in photon radiotherapy, can be completed in a short period by concentrating the radiation dose on the tumor while minimizing the dose to organs at-risk. However, the stopping position of C-beam is sensitive to density variations along the beam path and such variations can lower the tumor dose as well as cause the delivery of an unexpectedly high dose to the organs at risk. We evaluated the clinical efficacy of a robust planning technique considering gastrointestinal gas (G-gas) to deliver accurate radiation doses in carbon-ion radiotherapy for pancreatic cancer.Materials and methodsWe focused on the computed tomography (CT) value replacement method. Replacement signifies the overwriting of CT values in the CT images. The most effective replacement method for robust treatment planning was determined by verifying the effects of the three replacement patterns. We selected 10 consecutive patients. Pattern 1 replaces the CT value of the G-gas contours with the value of the region without G-gas (P1). This condition indicates a no-gas state. Pattern 2 replaces each gastrointestinal contour using the mean CT value of each contour (P2). The effect of G-gas was included in the replacement value. Pattern 3 indicates no replacement (P3). We analyzed variations in the target coverage (TC) and homogeneity index (HI) from the initial plan using in-room CT images. We then performed correlation analysis on the variations in G-gas, TC, and HI to evaluate the robustness against G-gas.ResultsAnalysis of variations in TC and HI revealed a significant difference between P1 and P3 and between P2 and P3. Although no statistically significant difference was observed between P1 and P2, variations, including the median, tended to be fewer in P2. The correlation analyses for G-gas, TC, and HI showed that P2 was less likely to be affected by G-gas.ConclusionFor a treatment plan that is robust to G-gas, P2 mean replacement method should be used. This method does not necessitate any particular software or equipment, and is convenient to implement in clinical practice.

Abstract Background Carbon-ion radiotherapy (CIRT) for prostate cancer was initiated at Kanagawa Cancer Center in 2015. The present study analyzed the preliminary clinical outcomes of CIRT for prostate cancer. Methods The clinical outcomes of 253 patients with prostate cancer who were treated with CIRT delivered using the spot scanning method between December 2015 and December 2017 were retrospectively analyzed. The irradiation dose was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. Biochemical relapse was defined using the Phoenix definition. Toxicities were assessed according to CTCAE version 4.0. Results: The median patient age was 70 (47–86) years. The median follow-up duration was 35.3 (4.1–52.9) months. According to the D’Amico classification system, 8, 88, and 157 patients were classified as having low, intermediate, and high risks, respectively. Androgen deprivation therapy was administered in 244 patients. The biochemical relapse-free rate in the low-, intermediate-, and high-risk groups at 3 years was 87.5, 88.0, and 97.5%, respectively (P = 0.036). Grade 2 acute urinary toxicity was observed in 12 (4.7%) patients. Grade 2 acute rectal toxicity was not observed. Grade 2 late urinary toxicity and grade 2 late rectal toxicity were observed in 17 (6.7%) and 3 patients (1.2%), respectively. Previous transurethral resection of the prostate was significantly associated with late grade 2 toxicity in univariate analysis. The predictive factor for late rectal toxicity was not detected. Conclusion The present study demonstrated that CIRT using the spot scanning method for prostate cancer produces favorable outcomes.

Purpose: Carbon ion beams have several physical and biological advantages compared with conventional radiation for cancer therapy. The objective of this study is to evaluate the safety and effectiveness of 2-fraction carbon ion radiation therapy (CIRT) in patients with hepatocellular carcinoma (HCC). Methods and Materials: Between December 2008 and March 2013, 57 patients with localized HCC were treated with CIRT at a total dose of 45 Gy (relative biological effectiveness) in 2 fractions and retrospectively analyzed after long-term observation. The main endpoints of this study were treatment-related toxicity and local tumor control. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Changes in the Child-Pugh score from before to after CIRT were also examined to evaluate hepatic toxicity. Local control was defined as no progression of the irradiated lesion according to the modified Response Evaluation Criteria in Solid Tumors. Results: The median age of the patients was 75 years (range, 49-89 years). Of these patients, 41 had a newly diagnosed lesion, and 16 had residual or recurrent lesions after previous treatments. The median follow-up duration was 54 months (range, 7-103 months). All surviving patients were followed for more than 51 months. Two patients experienced grade 3 acute skin reactions, but no other grade 3 or higher toxicities were observed in any organ. No patient exhibited an increase in the Child-Pugh score of 2 or more points after CIRT. The local tumor control rates at 1, 3, and 5 years were 98%, 91%, and 91% after CIRT, respectively. All lesions that failed to respond to previous treatments were successfully controlled by CIRT. The 1-, 3-, and 5-year overall survival rates were 97%, 67%, and 45%, respectively. Conclusions: Two-fraction CIRT was a well-tolerated and effective treatment for patients with HCC.

Abstract 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.

BackgroundThis study aimed to explain the dynamics of prostate-specific antigen (PSA) levels in patients with prostate cancer who were treated with carbon ion radiotherapy (CIRT) and neoadjuvant androgen-deprivation therapy (ADT).MethodsEighty-five patients with intermediate-risk prostate cancer who received CIRT and neoadjuvant ADT from December 2015 to December 2017 were analyzed in the present study. The total dose of CIRT was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. The PSA bounce was defined as a ≥0.4 ng/ml increase of PSA levels from the nadir, followed by any decrease. PSA failure was defined using the Phoenix criteria.ResultsThe median patient age was 68 (range, 48-81) years. The median follow-up duration was 33 (range, 20-48) months. The clinical T stage was T1c, T2a, and T2b in 27, 44, and 14 patients, respectively. The Gleason score was 6 in 3 patients and 7 in 82 patients. The median pretreatment PSA level was 7.37 (range, 3.33-19.0) ng/ml. All patients received neoadjuvant ADT for a median of 6 (range, 2-117) months. PSA bounces were observed in 39 patients (45.9%), occurring a median of 12 (range, 6-30) months after CIRT. PSA failure was observed in eight patients (9.4%), occurring a median of 21 (range, 15-33) months after CIRT. The 3-year PSA failure-free survival rate was 88.5%. No clinical recurrence was observed during the follow-up period. Younger age and lower T stage were significant predictors of PSA bounce. Younger age was a significant predictor of PSA failure.ConclusionsIn this study, we identified the significant predictors of the occurrence of PSA bounce and failure. Further follow-up is needed to reveal the clinical significance of PSA dynamics.

Abstract Carbon ion radiotherapy is known for its high‐precision dose distribution and high biological effectiveness. We evaluated the results of carbon ion radiotherapy in 128 patients with unresectable localized axial soft tissue sarcoma at a single institution. The patients’ median age was 54 years, and the median follow‐up period was 49.4 (range 6.4‐146.4) months. The median tumor volume was 356 cm3. The 5‐year local control, overall survival, and disease‐free survival rates were 65%, 46%, and 39%, respectively. In the univariate analysis, tumor volume, local control, and incidences of metastases were significantly related to overall survival. In the multivariate analysis, tumor volume and local control were significantly related to overall survival. We did not find any factors related to local control. Five patients required surgical intervention because of adverse events in the bones. Carbon ion radiotherapy may be a treatment option for unresectable axial soft tissue sarcoma.

Abstract Background Carbon-ion radiotherapy (C-ion RT) provides better dose distribution in cancer treatment compared to photons. Additionally, carbon-ion beams provide a higher biological effectiveness, and thus a higher tumor control probability. However, information regarding the dose constraints for organs at risk in C-ion RT is limited. This study aimed to determine the predictive factors for late morbidities in the rectum and bladder after carbon-ion C-ion RT for uterus carcinomas. Methods Between June 1995 and January 2010, 134 patients with uterus carcinomas were treated with C-ion RT with curative intent; prescription doses of 52.8–74.4 Gy (relative biological effectiveness) were delivered in 20–24 fractions. Of these patients, 132 who were followed up for > 6 months were analyzed. We separated the data in two subgroups, a 24 fractions group and a 20 fractions group. Late morbidities, proctitis, and cystitis were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. The correlations of clinical and dosimetric parameters, V10–V60, D5cc, D2cc, and Dmax, with the incidence of ≥grade 1 morbidities were retrospectively analyzed. Results In the 24 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 64 and 9%, respectively. In addition, in the 20 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 32 and 19%, respectively. Regarding the dose–volume histogram data on the rectum, the D5cc and D2cc were significantly higher in patients with ≥grade 1 proctitis than in those without morbidity. In addition, the D5cc for the bladder was significantly higher in patients with ≥grade 1 cystitis than in those without morbidity. Results of univariate analyses showed that D2cc of the rectum was correlated with the development of ≥grade 1 late proctitis. Moreover, D5cc of the bladder was correlated with the development of ≥grade 1 late cystitis. Conclusions The present study identified the dose–volume relationships in C-ion RT regarding the occurrence of late morbidities in the rectum and bladder. Assessment of the factors discussed herein would be beneficial in preventing late morbidities after C-ion RT for pelvic malignancies. Trial registration Retrospectively registered (NIRS: 16–040).

Abstract Background 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. Methods 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. Results 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. Conclusions 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. Trial registration NIRS-9404 . Registered 1 March 1994.

Abstract Background Carbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) ≥ grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer. Methods Clinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68–76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months. Results Grade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving ≥5 Gy (RBE) (V5), V10, V20 and V30 were determined to be the significant predictive factors for ≥ grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V5, V10, V20 and V30 for ≥ grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC

To evaluate the efficacy and the toxicity of prophylactic extended-field carbon-ion radiotherapy (C-ion RT, Protocol 0508) for locally advanced squamous cell carcinoma of the uterine cervix in phase I / II clinical trial. Between May 2006 and January 2012, 26 patients of Protocol 0508 were treated with C-ion RT. The numbers of patients with stage IIB, IIIB, and IVA disease were 13, 11, and 2, respectively. Twenty patients had pelvic lymph node metastases. Median tumor size was 6.1 cm (range, 4.0–10.0 cm). The treatment consisted of extended-field irradiation of 39.0 gray equivalents (GyE) in 13 fractions, and additional 15.0 GyE in 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, 18.0 GyE in 2 fractions was given to GTV only. Total dose to the cervical tumor was 72.0 GyE over 20 fractions. The median follow-up period was 37 months. Twenty-one patients had grade 1 or 2 acute gastrointestinal toxicity, but all patients completed the treatment on schedule. There were no grade 3 or higher late complications, with 8 patients having grade 1 or 2 toxicities, 1 had grade 2 gastrointestinal toxicity and 2 had grade 2 genitourinary toxicity. Four patients (15.4%) developed local recurrence, and 8 patients (30.8%) had distant metastases. The 2-year local control rate, progression-free survival rate and overall survival rate were 83.6%, 61.5% and 73.1%, respectively. There were no severe acute or late complications in this trial. Prophylactic extended-field C-ion RT for locally advanced squamous cell carcinoma of the uterine cervix was a safe treatment. Although the number of patients in this study was small, the results support further investigations to confirm the therapeutic efficacy and to avoid or reduce toxicity.UMIN-CTR UMIN000016169.

The clinical results after carbon ion radiotherapy for the metastatic lung tumors believed to be in the state of oligo-recurrence were evaluated. One hundred and sixteen lesions in 91 patients with lung cancer metastasis were treated with carbon ion radiotherapy at our institute from April 1997 to February 2011. Regarding the prescribed dose, total dose ranged between 40 gray equivalents (GyE) and 80 GyE, and fraction size ranged from 1 to 16 fractions. After a median followup period of 2.3 years (range, 0.3–13.1 years), the statistical overall survival rate and local control rate were 71.2% and 91.9% at 2 years after treatment, respectively. Treatment-related side effects were not a clinical problem. When classified by the primary organ, there were 49 cases of lung cancer, 20 cases of colorectal cancer, and 22 cases of others. The overall survival rate and local control rate for lung metastasis cases from lung cancer at 2 years after treatment were 81.5% and 92.4%, respectively, and 65.0% and 92.0% regarding lung metastasis from colorectal cancer. Carbon ion beam therapy for the metastatic lung tumors is a safe therapy, and the therapeutic effect is comparable to the outcome obtained from reported surgical resections.

Background/Aim: The curative treatment for solitary fibrous tumors (SFTs) consists of surgery. However, surgery for SFTs in the skull base is difficult due to the anatomy and curative surgery may not be possible. Carbon-ion radiotherapy (C-ion RT) might be useful in the treatment of inoperable SFTs in the skull base because of its biological and physical nature. This study presents the clinical outcomes of Cion RT for an inoperable SFT of the skull base. Case Report: A 68-year-old female patient experienced hoarseness, deafness on the right side, right facial nerve paralysis, and dysphagia. Magnetic resonance imaging revealed a tumor located in the right cerebello-pontine angle with destruction of the petrous bone, and immunohistochemical studies of the biopsy specimen showed a grade 2 SFT. Firstly, the patient underwent tumor embolization and surgery. However, 5 months after surgery, magnetic resonance imaging revealed regrowth of residual tumor. Subsequently, the patient was referred to our hospital for C-ion RT because curative surgery was unsuitable. The patient received 64 Gy (relative biological effectiveness) of Cion RT in 16 fractions. Two years after C-ion RT, the tumor showed a partial response. The patient was still alive at the last follow-up without evidence of local recurrence, distant metastasis, or late toxicities. Conclusion: These findings suggest that C-ion RT is a suitable treatment option for inoperable SFTs of the skull base. [ABSTRACT FROM AUTHOR]

Background/Aim: To evaluate treatment outcomes of carbon-ion radiotherapy for oropharyngeal non-squamous cell carcinoma at four carbon-ion facilities in Japan. Patients and Methods: We retrospectively analyzed the cases of 33 patients with oropharyngeal non-squamous cell carcinoma who were treated with carbon-ion radiotherapy between November 2003 and December 2014. Results: The histology included adenoid cystic carcinoma (n=25) and mucosal malignant melanoma (n=4). No patients had T1 tumors; 23 had T4 tumors. The most-commonly prescribed dose was 57.6 Gy (RBE) in 16 fractions. The median follow-up period was 34.8 months (range=4.2-122.8 months). The 3-year local control and overall survival rates were 94.7% and 90.7%, respectively. There were no grade ≥4 acute adverse events. Only one patient experienced a grade ≥4 late adverse event. No patients experienced late adverse events related to swallowing or salivary function. Conclusion: Carbon-ion radiotherapy appears to be a promising treatment option for oropharyngeal non-squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background/Aim: The present study aimed to compare the radiation dose distribution of carbon-ion radiotherapy (CIRT) for stage I esophageal cancer with three-dimensional conformal radiotherapy (3DCRT) and volumetric modulated arc therapy (VMAT). Patients and Methods: Fifteen patients with cT1bN0M0 esophageal cancer who received 3DCRT at Kanagawa Cancer Center between January 2014 and April 2019 were enrolled. The dose-volume histogram parameters of the target volume and normal organs planned with CIRT, 3DCRT, and VMAT were evaluated. Results: The homogeneity index for the target volume of CIRT was significantly lower than that of 3DCRT and VMAT. In addition, the radiation dose of CIRT to the heart, lungs, spinal cord, and skin was significantly lower than that of 3DCRT and VMAT. Conclusion: Favorable dose distributions with CIRT were demonstrated compared with 3DCRT and VMAT for esophageal cancer. [ABSTRACT FROM AUTHOR]

Objective: Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT). Methods: The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes. Results: The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS. Conclusion: CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA. [ABSTRACT FROM AUTHOR]

Objective: Pancreatic cancer is a difficult to treat disease with a persistently high mortality rate. We evaluated dose distribution simulation with respiratory-gated carbon-ion pencil beam scanning (C-PBS) with a simultaneous integrated boost (SIB) to increase tumour dose, sparing organs at risk (OARs). Methods: Using four-dimensional CT data of 12 patients, we delineated gross tumour volume and two clinical target volumes (CTVs). To consider beam range intrafractional uncertainty, we calculated field-specific target volumes, from which two planning target volumes (PTVs) were generated. PTV1 would receive a planned dose of 55.2 Gy [relative biological effectiveness (RBE)-weighted absorbed dose] in 12 fractions, and PTV2 would receive an SIB dose up to 67.2 Gy (RBE). Dose assessments were conducted with regard to the targets and OARs. Results: CTV2 dose covering 95% of the volume (D95%) increased from 50.3 ± 5.1 Gy (RBE) to 62.5 ± 3.5 Gy (RBE) for a planned dose from 55.2 Gy (RBE) to 67.2 Gy (RBE). For 4 of 12 patients with a distance of ≥5 mm between the tumour and the gastrointestinal tract, CTV2 D95% was ≥95% of planned dose at all dose levels. Conclusion: We quantified dose escalation with respiratory-gated C-PBS using SIB for pancreatic cancer and revealed that OAR dose was not affected to the same degree as the tumour dose. Advances in knowledge: A simulation study on respiratory-gated C-PBS with SIB for pancreatic cancer was performed. The results indicated the feasibility of dose escalation for pancreatic cancer, which should be confirmed in clinical trials. [ABSTRACT FROM AUTHOR]

Cancer treatment, today, consists of surgery, chemotherapy, radiation, and most recently immunotherapy. Combination immunotherapy-radiotherapy (CIR) has experienced a surge in public attention due to numerous clinical publications outlining the reduction or elimination of metastatic disease, following treatment with specifically ipilimumab and radiotherapy. The mechanism behind CIR, however, remains unclear, though it is hypothesized that radiation transforms the tumor into an in situ vaccine which immunotherapy modulates into a larger immune response. To date, the majority of attention has focused on rotating out immunotherapeutics with conventional radiation; however, the unique biological and physical benefits of particle irradiation may prove superior in generation of systemic effect. Here, we review recent advances in CIR, with a particular focus on the usage of charged particles to induce or enhance response to cancerous disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Carbon ion radiotherapy (CIRT) has been expected to be an alternative for surgery for early-stage non-small-cell lung cancer (NSCLC) and adopted as the second-best choice even in operable patients although local recurrence after CIRT is sometimes experienced. The purpose of this study was to investigate the demographic data, perioperative courses and therapeutic outcomes of patients who underwent salvage resection for local recurrence after CIRT. METHODS: From November 1994 to February 2012, CIRT was applied for 602 c-T1/T2/T3N0M0 NSCLC lesions of 599 patients at the National Institute of Radiological Science. A total of 95 (16%) patients were diagnosed as having local recurrence, of whom 12 underwent salvage surgeries. The medical records were retrospectively reviewed. RESULTS: There were 7 men and 5 women (mean age, 63 ± 7.4 years). The clinical stages upon initial presentation with NSCLC were as follows: 4 IA, 7 IB and 1 IIB. All the patients were operable, but refused surgery and underwent CIRT. The median progression-free survival time after CIRT was 20 months (range, 7.1-77 months), and salvage surgery was performed at a median of 24 months (range, 9-78 months) after CIRT. All surgeries were successfully performed without any significant CIRT-related adhesions during the surgery, resulting in no mortality or Clavien-Dindo grade 3-4 postoperative complications. However, the distribution of pathological stages was as follows: 4 IA, 3 IB, 2 IIB, 2 IIIA and 1 IV, which included 6 upstages from the clinical stages before CIRT. The Kaplan-Meier estimate of overall survival after the salvage surgery showed that the 3-year survival rate was 82%. CONCLUSIONS: The dose intensity of CIRT spared the hilum of the lungs and parietal pleura, none of the patients developed adhesions outside of the radiation field, such that the salvage surgeries for local recurrence after CIRT were safe and feasible. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of rectal invasion is still unclear in stage IVA cervical cancer. The objective of this study is to evaluate patient outcome and prognostic factors in stage IVA cervical cancer treated with radiation therapy.Methods: A retrospective review of the medical records of patients treated with definitive photon radiation therapy for pathologically proven stage IVA cervical cancer between 1980 and 2010 was performed. Eligible patients for the present study were diagnosed with clinical stage IVA cervical cancer by cystoscopy or/and proctoscopy, and they received definitive radiation therapy consisting of a combination of external beam radiotherapy and high-dose-rate brachytherapy. All patients underwent CT scans of the abdomen and pelvis.Results: Among the 67 stage IVA patients studied, 53 patients were stage IVA on the basis of bladder invasion, 7 according to rectal mucosal invasion, and 7 because of both bladder and rectal mucosal invasion. Median follow-up of all patients and surviving patients was 19 months (range, 2-235 months) and 114 months (range, 14-223 months), respectively. The 5-year local control (LC), disease-free survival (DFS), and overall survival (OS) rate were 55, 17, and 24%, respectively. Rectal invasion had significant impact on DFS, but bladder invasion had the opposite effect (p = 0.00006 and 0.005, respectively). There were significant differences of LC, DFS and OS rates between patients with and without rectal invasion (p = 0.006, 0.00006 and 0.05, respectively).Conclusions: Patients with stage IVA cervical cancer had poor prognosis, with 5-year survival of only 24%. Furthermore, in stage IVA, rectal invasion might be a worse prognostic factor than bladder invasion. [ABSTRACT FROM AUTHOR]

The present study investigated the effect of targeted mutations in the DNA-dependent protein kinase catalytic subunit and phosphorylation domains on the survival of cells in response to different qualities of ionizing radiation. Mutated Chinese hamster ovary V3 cells were exposed to 500 MeV/nucleon initial energy and 200 keV/µm monoenergetic Fe ions; 290 MeV/nucleon initial energy and average 50 keV/µm spread-out Bragg peak C ions; 70 MeV/nucleon initial energy and 1 keV/µm monoenergetic protons; and 0.663 MeV initial energy and 0.3 keV/µm Cs137 γ radiation. The results demonstrated that sensitivity to high linear energy transfer radiation is increased when both S2056 and T2609 clusters each contain a point mutation or multiple mutations are present in either cluster, whereas the phosphoinositide 3 kinase cluster only requires a single mutation to induce the sensitized phenotype of V3 cells. Additionally, the present study demonstrated that sensitivity to DNA cross-linking damage by cisplatin only requires a single mutation in one of the three clusters and that additional point mutations do not increase cell sensitivity. [ABSTRACT FROM AUTHOR]

Background: To moving lung tumors, we applied a respiratory-gated strategy to carbon-ion pencil beam scanning with multiple phase-controlled rescanning (PCR). In this simulation study, we quantitatively evaluated dose distributions based on 4-dimensional CT (4DCT) treatment planning. Methods: Volumetric 4DCTs were acquired for 14 patients with lung tumors. Gross tumor volume, clinical target volume (CTV) and organs at risk (OARs) were delineated. Field-specific target volumes (FTVs) were calculated, and 48Gy(RBE) in a single fraction was prescribed to the FTVs delivered from four beam angles. The dose assessment metrics were quantified by changing the number of PCR and the results for the ungated and gated scenarios were then compared. Results: For the ungated strategy, the mean dose delivered to 95% of the volume of the CTV (CTV-D95) was in average 45.3 ± 0.9 Gy(RBE) even with a single rescanning (1 × PCR). Using 4 × PCR or more achieved adequate target coverage (CTV-D95 = 46.6 ± 0.3 Gy(RBE) for ungated 4 × PCR) and excellent dose homogeneity (homogeneity index =1.0 ± 0.2% for ungated 4 × PCR). Applying respiratory gating, percentage of lung receiving at least 20 Gy(RBE) (lung-V20) and heart maximal dose, averaged over all patients, significantly decreased by 12% (p < 0.05) and 13% (p < 0.05), respectively. Conclusions: Four or more PCR during PBS-CIRT improved dose conformation to moving lung tumors without gating. The use of a respiratory-gated strategy in combination with PCR reduced excessive doses to OARs. [ABSTRACT FROM AUTHOR]

Background Osteoradionecrosis (ORN) is a critical complication after carbon ion (C-ion) or photon radiotherapy (RT) for head and neck tumors. However, the risk factors for ORN after C-ion RT remain unclear. Therefore, the present study aimed to investigate the effects of the dosevolume relationship on and risk factors for ORN development after C-ion RT. We, however, focused on the maxillary bone because most tumors treated with C-ion RT were primarily located in the sinonasal cavity. Methods The patients enrolled in this study received more than 10% of the prescribed total dose of 57.6 Gy equivalent (GyE) in 16 fractions to their maxilla. All patients were followed up for more than 2 years after C-ion RT. Those with tumor invasion to the maxilla before C-ion RT or local recurrence after the treatment were excluded from the study to accurately evaluate the effects of irradiation on the bone. Sixty-three patients were finally selected. The severity of ORN was assessed according to the Common Terminology Criteria for Adverse Events version 4.0. The correlation between clinical and dosimetric parameters and ORN incidence was retrospectively analyzed. Results The median follow-up period was 79 months. Of the 63 enrolled patients, 26 developed ORN of grade ⩾1. Multivariate analysis revealed that the maxilla volume receiving more than 50 GyE (V50) and the presence of teeth within the planning target volume were significant risk factors for ORN. Dose-volume histogram analysis revealed that V10 to V50 parameters were significantly higher in patients with ORN than in those without ORN. Conclusions V50 and the presence of teeth within the planning target volume were independent risk factors for the development of ORN after C-ion RT using a 16-fraction protocol. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to evaluate the efficacy and feasibility of carbon ion radiotherapy (CIRT) for oligo-recurrent lung tumors from colorectal cancer (CRC). Methods From May 1997 to October 2012, 34 consecutive patients with oligo-recurrent pulmonary metastases from CRC were treated with CIRT. The patients were not surgical candidates for medical reasons or patient refusal. Using a respiratory-gated technique, carbon ion therapy was delivered with curative intent using 4 coplanar beam angles. A median dose of 60 GyE (range, 44-64.8 GyE) was delivered to the planning target volume (PTV), with a median daily dose of 15 GyE (range, 3.6-44 GyE). Treatment outcome was analyzed in terms of local control rate (LCR), survival rate, and treatment-related complications. Results In total, 34 patients with 44 oligo-recurrent pulmonary lesions were treated with CIRT. Median follow-up period was 23.7 months. The 2- and 3-year actuarial LCRs of the treated patients were 85.4% ± 6.2% and 85.4% ± 6.2%, respectively. Overall survival was 65.1% ± 9.5% at 2 years, and 50.1% ± 10.5% at 3 years. Although survival rates were relatively worse in the subsets of patients aged < 63 years or with early metastasis (< 36 months after resection of primary site), these factors were not significantly correlated with overall survival (P = 0.13 and 0.19, respectively). All treatment-related complications were self-limited, without any grade 3-5 toxicity. Conclusions CIRT is one of the most effective nonsurgical treatments for colorectal lung metastases, which are relatively resistant to stereotactic body radiotherapy. CIRT is considered to be the least invasive approach even in patients who have undergone repeated prior thoracic metastasectomies. [ABSTRACT FROM AUTHOR]

Electron-transfer disproportionation of a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH...) occurred in the presence of Sc3+ acting as a strong Lewis acid in deaerated acetonitrile. In contrast, in the case of weaker Lewis acids than Sc3+, such as Mg2+ and Li+, external protons from acetic acid were required for the disproportionation of DPPH... to occur. [ABSTRACT FROM AUTHOR]

The biological effect of charged-particle beams depends on both dose and particle spectrum. As one of the physical quantities describing the particle spectrum of charged-particle beams, we considered the linear energy transfer (LET) throughout this study. We investigated a new therapeutic technique using two or more ion species in one treatment session, which we call an intensity modulated composite particle therapy (IMPACT), for optimizing the physical dose and dose-averaged LET distributions in a patient as its proof of principle. Protons and helium, carbon, and oxygen ions were considered as ion species for IMPACT. For three cubic targets of 4  ×  4  ×  4, 8  ×  8  ×  8, and 12  ×  12  ×  12 cm3, defined at the center of the water phantom of 20  ×  20  ×  20 cm3, we made IMPACT plans of two composite fields with opposing and orthogonal geometries. The prescribed dose to the target was fixed at 1 Gy, while the prescribed LET to the target was varied from 1 keV µm−1 to 120 keV µm−1 to investigate the range of LET valid for prescription. The minimum and maximum prescribed LETs, (LT_min, LT_max), by the opposing-field geometry, were (3 keV µm−1, 115 keV µm−1), (2 keV µm−1, 84 keV µm−1),and (2 keV µm−1, 66 keV µm−1), while those by the orthogonal-field geometry were (8 keV µm−1, 98 keV µm−1), (7 keV µm−1, 72 keV µm−1), and (8 keV µm−1, 57 keV µm−1) for the three targets, respectively. To show the proof of principle of IMPACT in a clinical situation, we made IMPACT plans for a prostate case. In accordance with the prescriptions, the LETs in prostate, planning target volume (PTV), and rectum could be adjusted at 80 keV µm−1, at 50 keV µm−1, and below 30 keV µm−1, respectively, while keeping the dose to the PTV at 2 Gy uniformly. IMPACT enables the optimization of the dose and the LET distributions in a patient, which will maximize the potential of charged-particle therapy by expanding the therapeutic window. Further studies and developments will enable this therapeutic technique to be used in clinical practice. [ABSTRACT FROM AUTHOR]

At the National Institute of Radiological Sciences (NIRS), more than 8,000 patients have been treated for various tumors with carbon-ion (C-ion) radiotherapy in the past 20 years based on a radiobiologically defined clinical-dose system. Through clinical experience, including extensive dose escalation studies, optimum dose-fractionation protocols have been established for respective tumors, which may be considered as the standards in C-ion radiotherapy. Although the therapeutic appropriateness of the clinical-dose system has been widely demonstrated by clinical results, the system incorporates several oversimplifications such as dose-independent relative biological effectiveness (RBE), empirical nuclear fragmentation model, and use of dose-averaged linear energy transfer to represent the spectrum of particles. We took the opportunity to update the clinical-dose system at the time we started clinical treatment with pencil beam scanning, a new beam delivery method, in 2011. The requirements for the updated system were to correct the oversimplifications made in the original system, while harmonizing with the original system to maintain the established dose-fractionation protocols. In the updated system, the radiation quality of the therapeutic C-ion beam was derived with Monte Carlo simulations, and its biological effectiveness was predicted with a theoretical model. We selected the most used C-ion beam with αr = 0.764 Gy−1 and β = 0.0615 Gy−2 as reference radiation for RBE. The C-equivalent biological dose distribution is designed to allow the prescribed survival of tumor cells of the human salivary gland (HSG) in entire spread-out Bragg peak (SOBP) region, with consideration to the dose dependence of the RBE. This C-equivalent biological dose distribution is scaled to a clinical dose distribution to harmonize with our clinical experiences with C-ion radiotherapy. Treatment plans were made with the original and the updated clinical-dose systems, and both physical and clinical dose distributions were compared with regard to the prescribed dose level, beam energy, and SOBP width. Both systems provided uniform clinical dose distributions within the targets consistent with the prescriptions. The mean physical doses delivered to targets by the updated system agreed with the doses by the original system within ±1.5% for all tested conditions. The updated system reflects the physical and biological characteristics of the therapeutic C-ion beam more accurately than the original system, while at the same time allowing the continued use of the dose-fractionation protocols established with the original system at NIRS. [ABSTRACT FROM AUTHOR]

Our hospital started the charged particle therapy since 1996. New institutions for charged particle therapy are planned in the world. Our hospital are accepting many visitors from those newly planned medical institutions and having many opportunities to provide with the training to them. Based upon our experiences, we have developed the radiation oncology teaching files system for charged particle therapy. We adopted the PowerPoint of Microsoft as a basic framework of our teaching files system. By using our export function of the viewer any physician can create teaching files easily and effectively. Now our teaching file system has 33 cases for clinical and physics contents. We expect that we can improve the safety and accuracy of charged particle therapy by using our teaching files system substantially. [ABSTRACT FROM AUTHOR]