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Objectives Our objective was to report initial results of a dose escalation trial of single-fraction carbon ion radiotherapy for peripheral stage I NSCLC. Methods Between April 2003 and February 2012, a total of 218 patients were treated. The total dose was raised from 28 to 50 Gy (relative biological effectiveness [RBE]). There were 157 male and 61 female patients, with a median age of 75 years. Of the tumors, 123 were stage T1 and 95 were stage T2. A total of 134 patients (61.5%) were medically inoperable. By histological type, there were 146 adenocarcinomas, 68 squamous cell carcinomas, three large cell carcinomas, and one mucoepidermoid carcinoma. Results The median follow-up was 57.8 months (range 1.6–160.7). The overall survival rate at 5 years was 49.4%. The local control (LC) rate was 72.7%. A statistically significant difference in LC rate ( p = 0.0001, log-rank test) was seen between patients receiving 36 Gy (RBE) or more and those receiving less than 36 Gy (RBE). In 20 patients irradiated with 48 to 50 Gy (RBE), the LC rate at 5 years was 95.0%, the overall survival rate was 69.2%, and the progression-free survival rate was 60.0% (median follow-up was 58.6 months). With dose escalation, LC tended to improve. As for adverse lung and skin reactions, there were no patients with grade 3 or higher reactions, and less than 2% had a grade 2 reaction. Regarding chest wall pain, only one patient had grade 3 late toxicity. Conclusions We have reported the outcome of a dose escalation study of single-fraction carbon ion radiotherapy for stage I NSCLC, showing the feasibility of obtaining excellent results comparable to those with previous fractionated regimens.

The purpose of this study was to evaluate the efficacy and toxicities of carbon-ion radiotherapy (C-ion RT) for locally advanced cervical cancer with bladder invasion by a subset analysis of pooled data from eight prospective clinical trials at the National Institute of Radiological Sciences. Between June 1995 and January 2014, 29 patients with locally advanced cervical cancer with bladder invasion were identified. The median age was 56 years old (range 31–79 years old). The median tumor size at diagnosis on magnetic resonance imaging was 6.7 cm (range 3.5–11.0 cm). Histologically, 20 patients had squamous cell carcinoma and 9 had adenocarcinoma. C-ion RT was performed as a dose-escalation study in the initial trials. All patients received prophylactic whole-pelvic or extended-field irradiation and local boost. The total dose to the cervical tumor was 52.8–74.4 Gy (relative biological effectiveness) in 20 or 24 fractions. Weekly cisplatin (40 mg/m2/week, five cycles) was concurrently given to four patients. The median follow-up of all patients was 28.6 months (range 8.8–238.6 months). Grade 2 or higher late complications in the bladder were observed in eight patients, with seven developing vesicovaginal fistula. Six patients had Grade 2 or higher complications in the rectosigmoid colon. The 3-year overall survival rate was 47%, the 3-year local control rate was 66%, and the 3-year disease-free survival rate was 28%. In this study, C-ion RT showed favorable local control with reasonable toxicities, but the results were still unsatisfactory. We have the expectation of improvement of therapeutic effects by using C-ion RT with concurrent chemotherapy.

Purpose This multi-institutional observational study conducted among 11 countries in East and Southeast Asia aimed to assess the clinical outcomes of prophylactic extended-field concurrent chemoradiation therapy using weekly cisplatin for patients with locally advanced cervical cancer. Methods and Materials Between October 2007 and May 2016, 106 patients with untreated squamous cell carcinoma of the cervix were enrolled in the present study. Radiation therapy consisted of pelvic irradiation (total dose, 50 Gy in 25 fractions including central shielding), prophylactic paraortic regional irradiation (36-40 Gy in 20 fractions), and either high- or low-dose-rate intracavitary brachytherapy (ICBT) according to institutional practice. The planned point A dose was 21 to 28 Gy in 3 to 4 fractions for high-dose-rate ICBT and 40 to 41 Gy in 1 to 2 fractions for low-dose-rate ICBT. Five cycles of weekly cisplatin (40 mg/m2) were administered during the radiation therapy course. Results A total of 106 patients were enrolled. Of these, 9 had major protocol violations and 2 did not receive treatment because of worsened general condition. Thus, 95 patients were evaluable. The median follow-up was 56 months. Of the 95 patients, 76 (80%) received 4 or 5 cycles of chemotherapy. Acute grade 3 leukopenia was observed in 20 of the patients (21%), and late grade 3 gastrointestinal toxicity was observed in 3%. The 2-year local control, progression-free survival, and overall survival rate for all patients were 96%, 78%, and 90%, respectively. Conclusions The results indicated that prophylactic extended-field concurrent chemoradiation therapy using weekly cisplatin is feasible and effective for patients with locally advanced cervical cancer in East and Southeast Asia.

A dose audit of 16 facilities in 11 countries has been performed within the framework of the Forum for Nuclear Cooperation in Asia (FNCA) quality assurance program. The quality of radiation dosimetry varies because of the large variation in radiation therapy among the participating countries. One of the most important aspects of international multicentre clinical trials is uniformity of absolute dose between centres. The National Institute of Radiological Sciences (NIRS) in Japan has conducted a dose audit of participating countries since 2006 by using radiophotoluminescent glass dosimeters (RGDs). RGDs have been successfully applied to a domestic postal dose audit in Japan. The authors used the same audit system to perform a dose audit of the FNCA countries. The average and standard deviation of the relative deviation between the measured and intended dose among 46 beams was 0.4% and 1.5% (k = 1), respectively. This is an excellent level of uniformity for the multicountry data. However, of the 46 beams measured, a single beam exceeded the permitted tolerance level of ±5%. We investigated the cause for this and solved the problem. This event highlights the importance of external audits in radiation therapy.

Background and purpose A multi-institutional observational study (J-CROS1501PR) has been carried out to analyze outcomes of carbon-ion radiotherapy (CIRT) for patients with prostate cancer. Patients and methods Data of the patients enrolled in prospective studies of following 3 CIRT institutions were analyzed: National Institute of Radiological Sciences (NIRS; Chiba, Japan), Gunma University Heavy Ion Medical Center (GHMC; Gunma, Japan), and Ion Beam Therapy Center, SAGA HIMAT Foundation (HIMAT; Saga, Japan). Endpoints of the clinical trial are biochemical recurrence-free survival (bRFS), overall survival (OS), cause-specific survival (CSS), local control rate (LCR), and acute/late adverse effects. Results A total of 2157 patients' data were collected from NIRS ( n =1432), GHMC ( n =515), and HIMAT ( n =210). The number of patients in low-risk, intermediate-risk, and high-risk groups was 263 (12%), 679 (31%), and 1215 (56%), respectively. The five-year bRFS in low-risk, intermediate-risk, and high-risk patients was 92%, 89%, and 92%, respectively. The five-year CSS in low-risk, intermediate-risk, and high-risk patients was 100%, 100%, and 99%, respectively. The incidence of grade 2 late GU/GI toxicities was 4.6% and 0.4%, respectively, and the incidence of ⩾G3 toxicities were 0%. Conclusions Favorable overall outcomes of CIRT for prostate cancer were suggested by the analysis of the first multi-institutional data.

Background and purpose In carbon ion radiotherapy (CIRT), the use of different relative biological effectiveness (RBE) models in the RBE-weighted dose (D RBE ) calculation can lead to deviations in the physical dose (D phy ) delivered to the patient. Our aim is to reduce target D phy deviations by converting prescription dose values. Material and methods Planning data of patients treated at the National Institute of Radiological Sciences (NIRS) were collected, with prescribed doses per fraction ranging from 3.6Gy (RBE) to 4.6Gy (RBE), according to the Japanese semi-empirical model. The D phy was Monte Carlo (MC) re-calculated simulating the NIRS beamline. The local effect model (LEM)_I was then applied to estimate D RBE . Target median D RBE ratios between MC+LEM_I and NIRS plans determined correction factors for the conversion of prescription doses. Plans were re-optimized in a LEM_I-based commercial system, prescribing the NIRS uncorrected and corrected D RBE . Results The MC+LEM_I target median D RBE was respectively 15% and 5% higher than the NIRS reference, for the lowest and highest dose levels. Uncorrected D RBE prescription resulted in significantly lower target D phy in re-optimized plans, with respect to NIRS plans. Conclusions Prescription dose conversion factors could minimize target physical dose variations due to the use of different radiobiological models in the calculation of CIRT RBE-weighted dose.

BACKGROUND Whether biochemical recurrence (BR) is a significant predictive factor of mortality after definitive radiation therapy for prostate cancer remains unknown. The aim of the current study was to investigate the relation between BR and overall mortality (OAM) in high‐risk prostate cancer patients who were treated with carbon‐ion radiotherapy (CIRT) and had long‐term follow‐up in 2 prospective trials. METHODS In the 2 phase 2 clinical trials, which involved 466 prostate cancer patients who received 63.0 to 66.0 Gy of CIRT (relative biological effect) in 20 fractions between 2000 and 2007, 324 patients who were deemed to be at high risk on the basis of the modified D'Amico classification criteria and received CIRT along with androgen‐deprivation therapy (ADT) were examined. The OAM rate was adjusted for the ADT duration, and multivariate analyses using a Cox proportional hazards model were performed for OAM with BR as a time‐dependent covariate. RESULTS The median follow‐up period was 107.4 months, and the 5‐ and 10‐year OAM rates after adjustments for the ADT duration were 7.0% (95% confidence interval [CI], 4.0%‐9.4%) and 23.9% (95% CI, 16.4%‐26.2%), respectively. A multivariate analysis revealed that the presence of BR (hazard ratio, 2.82; 95% Cl, 1.57‐5.08; P = .001) was one of the predictive factors for OAM. On the other hand, the duration of ADT had no impact on OAM. CONCLUSIONS BR after CIRT combined with ADT is an independent predictive factor for OAM in high‐risk prostate cancer patients. The results of this study could be applied to other high‐dose radiation therapies. Cancer 2016;122:3225–31. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made., Two prospective phase 2 studies involving 324 high‐risk prostate cancer patients treated with carbon‐ion radiotherapy have revealed that the presence of biochemical recurrence is an independent predictive factor for overall mortality (hazard ratio, 2.82; 95% confidence interval, 1.57‐5.08; P = .001) in patients with high‐risk prostate cancer after carbon‐ion radiotherapy according to a multivariate analysis.

Purpose To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m2 under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions under the fixed recommended gemcitabine dose determined. Results Seventy-six patients were enrolled. Among the 72 treated patients, dose-limiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion RT was found to be 1000 mg/m2. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m2) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (≥45.6 GyE) were 35% and 48%, respectively. Conclusions Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.

Purpose To evaluate the results of carbon ion radiation therapy administered to 188 patients with unresectable primary sacral chordomas. Patients and methods One hundred eighty-eight patients were treated with carbon ion radiation therapy at a single institute between 1996 and 2013 and retrospectively analyzed. The median age was 66 years. The highest proximal invasion reached past S2 level in 137 patients. The median clinical target volume was 345 cm(3). One hundred six patients received 67.2 gray equivalents (GyE)/16 fractions (fr), 74 patients received 70.4 GyE/16 fr, 7 patients received 73.6 GyE/16 fr, and 1 patient received 64.0 GyE/16 fr. Results The median follow-up period was 62 months (range, 6.8-147.5 months). Seventy percent of patients were followed for 5 years or until death. The 5-year local control, overall survival, and disease-free survival rates were 77.2%, 81.1%, and 50.3%, respectively. Forty-one patients had a local recurrence. Sex, tumor volume, level of proximal invasion, and irradiated dose were unrelated to local control. There was grade 3 toxicity of the peripheral nerves in 6 patients and grade 4 toxicity of the skin in 2 patients. Ambulation remained in 97% of patients. Conclusions Carbon ion radiation therapy was safe and effective for unresectable chordoma and provided good local control and survival while preserving ambulation.

The aim of this study was to evaluate the toxicity and efficacy of radiotherapy concurrent with weekly cisplatin for T3-4 and N0-1 nasopharyngeal cancer. Between 2005 and 2010, 70 patients with nasopharyngeal cancer (T3-4 N0-1 M0, World Health Organization Type 2-3) from Vietnam, Indonesia, Malaysia and Thailand were registered. Patients were treated with 2D radiotherapy concurrent with weekly cisplatin (30 mg/m(2)). Neither adjuvant nor induction chemotherapy was given. Ninety-three percent of the patients completed at least four cycles of weekly cisplatin during radiotherapy. The median total doses for the primary tumor and positive lymph nodes were 70 and 66 Gy, respectively. The median overall treatment time of concurrent chemoradiotherapy was 52 days. No treatment-related deaths occurred. Grade 3-4 acute toxicities of mucositis, nausea/vomiting and leukopenia were observed in 34%, 4% and 4% of patients, respectively. With a median follow-up time of 52 months for the 40 surviving patients, the 3-year local control, locoregional tumor control, distant metastasis-free survival and overall survival rates were 80%, 75%, 74% and 80%, respectively. In conclusion, the current results illustrate that our concurrent chemoradiotherapy regimen was feasible, but disease control remained insufficient. Further research is encouraged in order to improve clinical outcomes.

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.

Purpose To evaluate the applicability of carbon ion beams for the treatment of carcinoma of the lacrimal gland with regard to normal tissue morbidity and local tumor control. Methods and materials Between April 2002 and January 2011, 21 patients with locally advanced primary epithelial carcinoma of the lacrimal gland were enrolled in a Phase I/II clinical trial of carbon-ion radiotherapy (CIRT) at the National Institute of Radiological Sciences. Acute radiation toxicity was the primary endpoint of this dose-escalation study and the late toxicity, local control, and overall survival were additionally evaluated as secondary endpoints. Of the 21 subjects enrolled, all patients were followed for more than 6 months and analyzed. Results The radiation dose was increased from the initial dose of 48.0 Gy equivalents (GyE)/12 fractions at 10% increments up to 52.8 GyE. Of the 21 patients, five received a total dose of 48.0 GyE, and 16 received a total dose of 52.8 GyE. No patient developed grade 3 or higher skin toxicity. As late ocular/visual toxicity, three patients had grade 3 retinopathy and seven patients lost their vision. Among the 10 patients treated until May 2005, five patients had local recurrence, three of whom had marginal recurrence. Therefore, the margin for the CTV (clinical target volume) was set to a range according to the orbital exenteration since June 2005. After the application of the extended margin, no local recurrence has been observed. The three-year overall survival and local control rates were 82.2% and 79.0%, respectively. Conclusion CIRT can be applied for primary epithelial carcinoma of the lacrimal gland, with a borderline acceptable morbidity and sufficient antitumor effect when an extended margin is adopted.

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

BACKGROUND AND PURPOSE: \nTo evaluate the safety and efficacy of carbon ion radiotherapy (CIRT) for locally advanced sinonasal adenocarcinoma. \nMATERIAL AND METHODS: \nTwenty-two patients with sinonasal adenocarcinoma were treated with CIRT. CIRT was the primary treatment for 16 patients. Four patients received CIRT for local recurrence after surgery and two for residual tumour after surgery or chemotherapy. At the start of CIRT, 1 patient had T-classification (T) 2 disease, 2 had T3 disease, 5 had T4a disease, and 14 had T4b disease. Fourteen patients were treated with 57.6Gy equivalent (GyE)/16 fractions, and 8, with 64.0GyE/16 fractions. \nRESULTS: \nThe median follow-up period was 43months for all patients. The 3-year local control and loco-regional control rates for all patients were 76.9% (95% confidence interval [CI]=56.7-97.1%) and 61.3% (95% CI=38.5-84.1%), respectively. The 3-year overall survival and disease-specific survival rates were 59.1% (95% CI=38.6-79.6%) and 65.6% (95% CI=44.9-86.3%), respectively. Acute reactions of grade 3 of the skin and mucosa were observed in 2 and 4 patients, respectively. Late reactions included lateral visual loss (5 patients), mucosal ulceration (1 patient), and brain necrosis with clinical symptoms (1 patient). In the 5 patients who developed visual loss, the optic nerve was close to the tumour. \nCONCLUSIONS: \nCIRT was effective and generally safe for locally advanced sinonasal adenocarcinoma.

Background:The purpose of this study was to evaluate the feasibility of a new shortened 3-week treatment schedule of carbon ion radiotherapy (CIRT) for prostate cancer.Methods:Beginning in May 2010, patients with T1b-T3bN0M0, histologically proven prostate adenocarcinoma were enrolled in the phase II trial of CIRT. Patients received 51.6 GyE in 12 fractions over 3 weeks (protocol 1002). The primary end point was defined as the incidence of late adverse events that were evaluated based on the Common Terminology Criteria for Adverse Events version 4.0. Biochemical failure was determined using the Phoenix definition (nadir +2.0 ng ml(-1)).Results:Forty-six patients were enrolled, and all patients were included in the analysis. The number of low-, intermediate-, and high-risk patients was 12 (26%), 9 (20%), and 25 (54%), respectively. The median follow-up period of surviving patients was 32.3 months. Two patients had intercurrent death without recurrence, and the remaining 44 patients were alive at the time of this analysis. In the analysis of late toxicities, grade 1 (G1) rectal haemorrhage was observed in 3 (7%) patients. The incidence of G1 haematuria was observed in 6 (13%) patients, and G1 urinary frequency was observed in 17 (37%) patients. No G2 late toxicities were observed. In the analysis of acute toxicities, 2 (4%) patients showed G2 urinary frequency, and no other G2 acute toxicities were observed.Conclusions:The new shortened CIRT schedule over 3 weeks was considered as feasible. The analysis of long-term outcome is warranted.British Journal of Cancer advance online publication, 10 April 2014; doi:10.1038/bjc.2014.191 www.bjcancer.com.

Background: A novel risk assessment method, Japan Cancer of the Prostate Risk Assessment, has been developed based on database of patients receiving primary androgen deprivation therapy. To investigate the usefulness of Japan Cancer of the Prostate Risk Assessment for non-metastatic, high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy. Methods: Patients with non-metastatic, high-risk prostate cancer (T3, initial prostate specific antigen level � 20 ng/ml, and/or Gleason score � 8) were included. The patients were treated with carbon ion radiotherapy (the total dose from 57.6 Gy (relative biological effectiveness)/16 fractions to 66.0 Gy(relative biological effectiveness)/20 fractions), and neoadjuvant as well as adjuvant androgen deprivation therapy for at least 24 months. Results: Four hundred and twenty-six patients were included with the median follow-up of 68.1 months. Of 426, 210 (49.3%), 270 (63.4%) and 251 (58.9%) had Gleason 8‐10, prostate specific antigen � 20 ng/ml and T3, respectively. The 10-year progression-free and cause-specific survival rates in Japan Cancer of the Prostate Risk Assessment 1‐2 group (76.5 and 98.9%) were significantly better than those in Japan Cancer of the Prostate Risk Assessment 3‐6 group (52.6 and 93.1%), (P , 0.001 and P ¼ 0.044, respectively). The median progressionfree survivals in the Japan Cancer of the Prostate Risk Assessment 1‐2 and 3‐6 groups were 158.9 months and 125.9 months (95% confidence interval: 108.6‐143.2 months), respectively. Conclusions: For non-metastatic, high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy, Japan Cancer of the Prostate Risk Assessment score was useful for predicting the progression-free and cause-specific survivals.

Objective The authors performed phase I/II clinical trial to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced squamous cell carcinoma of the uterine cervix. Methods Between April 2000 and January 2006, 22 patients for Protocol 9902 were treated with C-ion RT. The number of patients with stage IIB, IIIB, and IVA diseases was 1, 18, and 3, respectively. All patients had bulky tumors measuring 4.0–12.0cm (median 6.2cm). The whole pelvic dose was fixed at 39.0GyE for 13 fractions, and additional 15.0GyE for 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, a dose–escalation study was planned for 2 fractions to GTV. Total dose to the cervical tumor was 64.0–72.0GyE for 20 fractions. Results All patients completed the scheduled therapy and no patient developed Grade 2 or higher acute toxicity. There was no Grade 3 or higher late complications at each dose. The 5-year overall survival rate and local control rate were 50.0% and 68.2%, respectively. Seven out of the 16 patients who received 64.0–68.0GyE developed local recurrences, but all patients who received 72.0GyE maintained local control. Conclusions There were no severe acute or late complications in this trial. C-ion RT has the potential to improve the treatment for locally advanced bulky cervical cancer by applying a total dose of 72.0GyE, with the results lending incentive to further investigations to confirm the therapeutic efficacy.

Background and purpose This study aimed to determine the risk factors for radiation-induced brain injury (RIBI) after carbon ion radiotherapy (CIRT) for treating skull base tumors. Materials and methods Between April 1997 and January 2009, CIRT at a total dose of 48.0–60.8Gy equivalent (GyE) was administered in 16 fractions to 47 patients with skull base tumors. Of these patients, 39 who were followed up with magnetic resonance imaging (MRI) for more than 24months were analyzed. RIBI was assessed according to the MRI findings based on the Late Effects of Normal Tissue-Subjective, Objective, Management, Analytic criteria; clinical symptoms were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer tables. The correlations of clinical and dosimetric parameters with incidence of ⩾grade 2 RIBI were retrospectively analyzed. Results The median follow-up period was 67months. The 5-year actuarial likelihoods of ⩾grade 2 RIBI and ⩾grade 2 clinical symptoms were 24.5% and 7.0%, respectively. Multivariate analysis demonstrated that the brain volume receiving more than 50GyE (V50) was a significant risk factor for the development of ⩾grade 2 RIBI ( p =0.004). Conclusion V50 was a significant risk factor for ⩾grade 2 RIBI after CIRT using a 16-fraction regimen.

The prognosis of high-risk prostate cancer is poor with a high mortality rate. The Radiation Therapy Oncology Group (RTOG) has performed dose-escalation studies of external beam radiation therapy (EBRT) and has developed high-precision radiation therapy (RT) methods such as intensity-modulated RT, carbon ion therapy, and proton beam therapy. High-dose rate brachytherapy (HDR-BT) is also studied as an option for high-risk prostate cancer treatment. Past clinical trials have suggested that the local control rate of high-risk prostate cancer improves with total EBRT dose, even for doses >70 Gy. Several randomized controlled trials, including RTOG 94-06, have shown significantly better prognoses with higher doses (>75 Gy) than with lower doses (2 years) HT combined with definitive RT. Further studies are warranted to elucidate optimal irradiation doses, HT treatment durations, and combination therapy schedules.

Purpose To compare retrospectively outcome after photon radiotherapy alone, radiochemotherapy with temozolomide (TMZ), and carbon ion radiotherapy in patients with high-grade gliomas and to generate a hypothetical outcome curve for C12 and TMZ. Patients and methods Patients treated within a Phase I/II Trial with a carbon ion boost were compared retrospectively with randomly chosen patients treated with photons or photons in combination with TMZ in a retrospective analysis. Per treatment group, 16 patients with anaplastic astocytoma (AA), and 32 patients with glioblastoma (GBM) were included. Treatment outcome with focus on progression-free survival (PFS) and overall survival (OS) was analyzed. Results Median OS for patients with GBM was 9months with RT, 14months with RCHT group, and 18months in the C12 group. There was no significant difference between the C12 and the RCHT group. For patients with AA, median OS was 13months for RT, 39months for RCHT, and 35months after C12. The difference from RCHT to C12 was not significant. Median PFS for patients with GBM was 5months in the RT group, 6months in the RCHT group, and 8months in the C12 group. There was a significant difference between the RCHT group and the C12 group. For AA, median PFS was 15months with RT, 6months with RCHT, and 34 with C12. Comparing subgroups, C12 was significantly different from RCHT. Based on the significant OS increase from RT to RCHT, and from RT to C12, we projected the potential increase in outcome when combined C12 and TMZ would have been applied. A generated hypothetical curve based on the abovementioned outcome as well as preclinical examinations suggests there might be a benefit from the addition of C12 in patients with high-grade gliomas. Conclusions This exploratory retrospective study suggests a potential benefit of carbon ions in patients with high-grade gliomas. This hypothesis is now being evaluated prospectively in GBM within the randomized CLEOPATRA clinical trial.

The aim of this study was to prospectively assess 5-year health-related quality of life (HRQOL) of patients treated with carbon ion radiotherapy (C-ion RT) for clinically localized prostate cancer. A total of 417 patients received carbon ion radiotherapy at a total dose of 63–66 Gray-equivalents (GyE) in 20 fractions over 5 weeks, and neoadjuvant and adjuvant androgen deprivation therapy (ADT) were administered for intermediate and high-risk patients. A HRQOL assessment was performed at five time points (immediately before the initiation of C-ion RT, immediately after, and at 12, 36 and 60 months after completion of C-ion RT) using Functional Assessment of Cancer Therapy (FACT) questionnaires. FACT-G and FACT-P scores were significantly decreased; however, the absolute change after 60 months was minimal. The transient decreases in the Trial Outcome Index (TOI) score returned to their baseline levels. Use of ADT, presence of adverse events, and biochemical failure were related to lower scores. Scores of subdomains of FACT instruments indicated characteristic changes. The pattern of HRQOL change after C-ion RT was similar to that of other modalities. Further controlled studies focusing on a HRQOL in patients with prostate cancer are warranted.

The purpose of this study was to present our evaluation of the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for locally advanced parotid gland carcinomas.Clinicopathological features and outcomes were evaluated in 46 patients receiving C-ion RT for parotid gland carcinomas.Sixteen patients had adenoid cystic carcinoma; 8 had adenocarcinoma, 8 had mucoepidermoid carcinoma, and 14 had other carcinomas. T2, T3, T4a, and T4b diseases were diagnosed in 3, 18, 8, and 17 patients, respectively. C-ion RT was provided to 25 patients as the primary treatment, to 20 patients for local recurrences after surgery, and to 1 patient for residual tumor after surgery. During follow-up (median duration, 62 months), 5-year local control and overall survival (OS) rates were 74.5% and 70.1%, respectively. Of the 30 patients without facial nerve palsy before C-ion RT, 25 showed no radiation-induced facial nerve palsy.C-ion RT is effective and has acceptable toxicity levels for locally advanced parotid gland carcinomas. © 2016 Wiley Periodicals, Inc. Head Neck 39: 724-729, 2017.

The purpose of this study was to evaluate the efficacy and toxicity of radiotherapy concurrently with weekly cisplatin, followed by adjuvant chemotherapy, for the treatment of N2–3 nasopharyngeal cancer (NPC) in Asian countries, especially regions of South and Southeast Asian countries where NPC is endemic. Between 2005 and 2009, 121 patients with NPC (T1–4 N2–3 M0) were registered from Vietnam, Malaysia, Indonesia, Thailand, The Philippines, China and Bangladesh. Patients were treated with 2D radiotherapy concurrently with weekly cisplatin (30 mg/m 2), followed by adjuvant chemotherapy, consisting of cisplatin (80 mg/m2 on Day 1) and fluorouracil (800 mg/m2 on Days 1–5) for 3 cycles. Of the 121 patients, 56 patients (46%) required interruption of RT. The reasons for interruption of RT were acute non-hematological toxicities such as mucositis, pain and dermatitis in 35 patients, hematological toxicities in 11 patients, machine break-down in 3 patients, poor general condition in 2 patients, and others in 8 patients. Of the patients, 93% completed at least 4 cycles of weekly cisplatin during radiotherapy, and 82% completed at least 2 cycles of adjuvant chemotherapy. With a median follow-up time of 46 months for the surviving 77 patients, the 3-year locoregional control, distant metastasis-free survival and overall survival rates were 89%, 74% and 66%, respectively. No treatment-related deaths occurred. Grade 3–4 toxicities of mucositis, nausea/vomiting and leukopenia were observed in 34%, 4% and 4% of the patients, respectively. In conclusion, further improvement in survival and locoregional control is necessary, although our regimen showed acceptable toxicities.

Purpose To determine the effectiveness of carbon ion radiotherapy (CIRT) for localized primary sarcomas of the extremities in a prospective study. Patients and materials From April 2000 to May 2010, 17 (male/female: 12/5) patients with localized primary sarcoma of the extremities received CIRT. The median age was 53years (range: 14–87years). Nine patients had primary diseases and eight had recurrent diseases. Of the 17 patients, eight refused amputation, and the remaining nine refused surgical resection. Tumors were located in the upper limbs in four patients and lower limbs in 13. Histological diagnosis was osteosarcoma in three patients, liposarcoma in two, synovial sarcoma in two, rhabdomyosarcoma in two, pleomorphic sarcoma in two, and miscellaneous in six. The CIRT dose to the limb was 52.8GyE for one patient, 64GyE for three, 70.4GyE for 13 in 16 fixed fractions over 4weeks. Records were reviewed and outcomes including radiologic response, local control (progression-free), and survival were analyzed. Results The median follow-up was 37months (range: 11–97months). Radiological response rate was 65% (PR in 11, SD in 5, and PD in 1). The local control rate at 5years was 76%. The overall survival rate at 5years was 56%. Of the 17 patients, 10 survived without disease progression. Four patients had local recurrences, one was salvaged by repeated CIRT and the other three died due to systemic diseases. Distant failure was observed in six patients. One patient suffered from femoral fracture (grade 3) and received surgical fixation 27months after CIRT. No other severe reactions (grade 3) were observed. Conclusions CIRT is suggested to be an effective and safe treatment for patients who refuse surgery for localized primary sarcomas of the extremities.

PURPOSE: To assess the effects of differences in dose fractionation on late radiation toxicity and biochemical control in patients with prostate cancer treated with carbon ion radiotherapy (C-ion RT). \nMETHODS AND MATERIALS: A total of 740 prostate cancer patients who received C-ion RT between April 2000 and February 2009 were analyzed. Of those, 664 patients followed for at least 1 year were analyzed with regard to late radiation toxicity. Biochemical relapse-free (BRF) and overall survival (OS) rates in patient subgroups with each dose-fractionation were analyzed. \nRESULTS: Only 1 case of grade 3 genitourinary (GU) morbidity was observed in 20 fractions, and none of the patients developed higher grade morbidities. The incidence of late GU toxicity in patients treated with 16 fractions was lower than that of patients treated with 20 fractions. The OS rate and BRF rate of the entire group at 5 years were 95.2% and 89.7%, respectively. The 5-year BRF rate of the patients treated with 16 fractions of C-ion RT (88.5%) was comparable to that of the patients treated with 20 fractions (90.2%). \nCONCLUSION: C-ion RT of 57.6 GyE (the physical C-ion dose [Gy] x RBE) in 16 fractions could offer an even lower incidence of genitourinary toxicity and comparable BRF rate than that in 20 fractions. Advancement in hypofractionation could be safely achieved with C-ion RT for prostate cancer.

In carbon ion radiotherapy there is an urgent clinical need to develop objective tools for the conversion of relative biological effectiveness (RBE)-weighted doses based on different models. In this work we introduce a clinically oriented method to compare NIRS-based and LEM-based GyE systems, minimizing differences in physical dose distributions between treatment plans. Carbon ion plans were optimized on target volumes of cubic and spherical shapes, for RBE-weighted dose prescription levels ranging from 3.6 to 4.4 GyE. Plans were calculated for target sizes from 4 to 12 cm defining three beam geometries: single beam, opposed beam and orthogonal beam configurations. The two treatment planning systems currently employed in clinical practice were used, providing the NIRS-based and LEM-based GyE calculations. Physical dose distributions of NIRS-based and LEM-based treatment plans were compared. LEM-based prescription doses that minimize differences in physical dose distributions between the two systems were found. These doses were compared with the mean RBE-weighted dose obtained with a Monte Carlo code (FLUKA) interfaced with LEM I. In the investigated dose range, LEM-based RBE-weighted prescription doses, that minimize differences with NIRS plans, should be higher than NIRS reported prescription doses. The optimal dose depends on target size, shape and position, number of beams and dose level. The opposed beam configuration resulted in the smallest average prescription dose difference (0.45 ± 0.09 GyE). The second approach of recalculating NIRS RBE-weighted dose with a Monte Carlo code interfaced with LEM resulted in no significant difference with the results obtained from the planning study. The delivery of a voxel by voxel iso-effective plan, if different RBE models are employed, is not feasible; it is however possible to minimize differences in a treatment plan with the simple approach presented here. Dose prescription ultimately represents a clinical task under the responsibility of the radiation oncologist, the presented analysis intends to be a quantitative and objective way to assist the clinical decision.

Purpose To evaluate the efficacy of carbon ion radiotherapy for head-and-neck cancer in a phase II clinical trial. Materials and methods Between April 1997 and February 2006, 236 patients with locally advanced, histologically proven, and new or recurrent cancer of the head and neck were treated with carbon ions. The treatment dose was 64.0GyE/16 fractions/4weeks (or 57.6GyE/16 fractions/4weeks when the wide-range skin was included in the target volume). Results There were grade 3 acute skin reactions in 6% and grade 3 acute mucosal reactions in 10% with no acute reactions worse than grade 3, and grade 2 late skin reactions in 3% and grade 2 late mucosal reactions in 2% with no late reactions worse than grade 2. The 5-year local control rate, by histological type, was 75% for the 85 patients with malignant melanoma, 73% for the 69 with adenoid cystic carcinoma, 73% for the 27 with adenocarcinoma, 61% for the 13 with papillary adenocarcinoma, 61% for the 12 with squamous cell carcinoma and 24% for the 14 with sarcomas. The 5-year over-all survival rate was 68% for adenoid cystic carcinoma, 56% for adenocarcinoma and 35% for malignant melanoma. Conclusions Carbon ion radiotherapy for head and neck cancer showed the therapeutic effectiveness for malignant melanoma and adenoid cystic carcinoma without severe morbidity of the normal tissues.

Most cases of adenoid cystic carcinoma (ACC) of the tongue base are radioresistant, and are diagnosed in the advanced stage. Therefore, we evaluated the safety and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced ACC of the tongue base.Eighteen patients with ACC of the tongue base were treated with C-ion RT between May 2002 and April 2014. Seventeen patients had T4a disease and 1 patient had T2 disease before C-ion RT.The median follow-up period was 57 months (range, 10-132 months). The 5-year local control rate was 92%. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 72% and 44%, respectively. Regarding late reactions, 2 patients developed grade 3 mandible osteoradionecrosis, and 1 had grade 3 hemorrhage of the tongue base.C-ion RT was effective with acceptable toxicities for locally advanced ACC of the tongue base. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2122-E2126, 2016.

Purpose: To measure chromosomal aberrations in peripheral blood lymphocytes from cancer patients treated with X-rays or carbon ions (C-ions). Methods and Materials: Blood samples from patients diagnosed for esophageal or uterine cervical cancer were obtained before, during, and at the end of the radiation treatment. The novel technique of interphase chromosome painting was used to detect aberrations in prematurely condensed chromosomes 2 and 4. The fraction of aberrant lymphocytes was measured as a function of the dose to the tumor volume. For comparison, blood samples were also exposed in vitro to X-rays or to carbon ions accelerated at the HIMAC. Results: C-ions were more efficient than X-rays in the induction of chromosomal aberrations in vitro . In patients with similar pathologies, tumor positions, and radiation field sizes, however, C-ions induced a lower fraction of aberrant lymphocytes than X-rays during the treatment. The initial slope of the dose–response curve for the induction of chromosomal aberrations during the treatment was correlated to the relative decrease in the number of white blood cells and lymphocytes during the treatment. Conclusion: C-ions induce a lower level of cytogenetic damage in lymphocytes than X-rays, reducing the risk of bone marrow morbidity.

Background and purpose To evaluate the potential of apparent diffusion coefficient (ADC) value before carbon ion radiotherapy (C-ion RT) for malignant mucosal melanoma (MMM) to predict prognosis. Materials and methods We recruited 37 patients with MMM in the head and neck treated by C-ion RT with concomitant chemotherapy. Univariate and multivariate analyses of minimum ADC, mean ADC, tumor volume, age, PS, and gender were performed to identify prognostic factors. Results The 3-year local control rate, distant metastasis-free survival rate and overall survival rate of all patients were 81.1%, 37.6% and 65.3%, respectively, with a median follow-up period of 19.0months. In univariate analyses, lower minimum ADC (⩽0.6380×10 −3 mm 2 /s) and lower mean ADC (⩽1.1523×10 −3 mm 2 /s) were unfavorable prognostic factors for distant metastasis ( p =0.029 and p =0.014, respectively), and lower minimum ADC was an unfavorable prognostic factor for overall survival ( p =0.019). However, there was no significant prognostic factor of local control including ADC value. In multivariate analyses, only minimum ADC was selected as a prognostic factor of distant metastasis-free survival and overall survival ( p =0.015 and p =0.006, respectively). Conclusion Minimum ADC can be a prognostic factor of MMM in the head and neck after C-ion RT.

Background and purpose To compare the efficacy and toxicity of short-course carbon ion radiotherapy (C-ion RT) for patients with hepatocellular carcinoma (HCC) in terms of tumor location: adjacent to the porta hepatis or not. Materials and methods The study consisted of 64 patients undergoing C-ion RT of 52.8GyE in four fractions between April 2000 and March 2003. Of these patients, 18 had HCC located within 2cm of the main portal vein (porta hepatis group) and 46 patients had HCC far from the porta hepatis (non-porta hepatis group). We compared local control, survival, and adverse events between the two groups. Results The 5-year overall survival and local control rates were 22.2% and 87.8% in the porta hepatis group and 34.8% and 95.7% in the non-porta hepatis group, respectively. There were no significant differences ( P= 0.252, P =0.306, respectively). Further, there were no significant differences in toxicities. Biliary stricture associated with C-ion RT did not occur. Conclusions Excellent local control was obtained independent of tumor location. The short-course C-ion RT of 52.8GyE in four fractions appears to be an effective and safe treatment modality in the porta hepatis group just as in the non-porta hepatis group.

Background and purpose To examine whether liver volume changes affect prognosis and hepatic function in patients treated with carbon ion radiotherapy (CIRT) for hepatocellular carcinoma (HCC). Material and methods Between April 1995 and March 2003, among the cases treated with CIRT, 43 patients with HCC limited to the right hepatic lobe were considered eligible for the study. The left lateral segment was defined as the non-irradiated region. Liver volume was measured using contrast CT at 0, 3, 6, and 12months after CIRT. We examined serum albumin, prothrombin activity, and total bilirubin level as hepatic functional reserve. Results After CIRT, the non-irradiated region showed significant enlargement, and enlarged volume of this region 3months after CIRT ⩾50cm 3 was a prognostic factor. The 5-year overall survival rates were 48.9% in the larger enlargement group (enlarged volume of non-irradiated region 3months after CIRT ⩾50cm 3 ) and 29.4% in the smaller enlargement group (as above, 3 ). The larger enlargement group showed better hepatic functional reserve than the smaller enlargement group 12months after CIRT. Conclusions This study suggests that compensatory enlargement in the non-irradiated liver after CIRT contributes to the improvement of prognosis.

To evaluate the toxicity and efficacy of concurrent chemoradiotherapy using weekly cisplatin for patients with locally advanced cervical cancer in East and Southeast Asia, a multi-institutional Phase II clinical study was conducted among eight Asian countries.Between April 2003 and March 2006, 120 patients (60 with bulky Stage IIB and 60 with Stage IIIB) with previously untreated squamous cell carcinoma of the cervix were enrolled in the present study. Radiotherapy consisted of pelvic external beam radiotherapy (total dose, 50 Gy) and either high-dose-rate or low-dose-rate intracavitary brachytherapy according to institutional practice. The planned Point A dose was 24-28 Gy in four fractions for high-dose-rate-intracavitary brachytherapy and 40-45 Gy in one to two fractions for low-dose-rate-intracavitary brachytherapy. Five cycles of weekly cisplatin (40 mg/m(2)) were administered during the radiotherapy course.All patients were eligible for the study. The median follow-up was 27.3 months. Of the 120 patients, 100 (83%) received four or five cycles of chemotherapy. Acute Grade 3 leukopenia was observed in 21% of the patients, and Grade 3 gastrointestinal toxicity was observed in 6%. No patient failed to complete the radiotherapy course because of toxicity. The 2-year local control and overall survival rate for all patients was 87.1% and 79.6%, respectively. The 2-year major late rectal and bladder complication rate was 2.5% and 0%, respectively.The results have suggested that concurrent chemoradiotherapy using weekly cisplatin is feasible and effective for patients with locally advanced cervical cancer in East and Southeast Asia.

The present study evaluated whether differences in the type of radiotherapy, disease stage, and self-esteem influence psychological distress and quality of life (QOL) among cervical cancer survivors. Sixty survivors, after radiotherapy, chemoradiotherapy, or postoperative radiotherapy for cervical cancer, participated in the study. The participants were asked to complete questionnaires during follow-up visits. The questionnaires included the Japanese version of the Hospital Anxiety and Depression Scale, the Functional Assessment of Cancer Therapy-General, and the Rosenberg Self-esteem Scale. The results indicated that psychological distress and QOL in cervical cancer survivors were not significantly different among treatment modalities and disease stage. Psychological distress and QOL differed significantly in accordance with the survivor's self-esteem. Survivors in the high self-esteem group had lower levels of anxiety and depression and higher QOL scores (emotional and social/family aspects of QOL and total QOL) than those in the low self-esteem group. Psychosocial support with consideration of a patient's self-esteem is necessary throughout and beyond radiotherapy for cervical cancer.

OBJECTIVE:: We evaluated changes in tumor volume in cases of sacral chordoma after carbon ion radiotherapy. METHODS:: Thirty-four patients with sacral chordoma underwent carbon ion radiotherapy between June 1996 and June 2003. We assessed 23 patients without previous surgery using T2-weighted magnetic resonance imaging. The tumor volume was calculated semiautomatically. RESULTS:: Two cases showed local recurrence. The median interval of this examination was 46 months. At the end of the treatment, the tumor showed an enlargement larger than 10% of its volume in 13 of the 23 cases, no change in 4 cases, and regression in 6 cases. At the last examination, 20 cases showed a reduction in tumor volume, and the median ratio, determined as the tumor volume at the last examination divided by that before the treatment, was 0.36. CONCLUSIONS:: An increase in tumor volume at the end of the treatment does not indicate the ineffectiveness of carbon ion radiotherapy.

Surgical resection is the standard treatment for stage I non-small cell lung cancer (NSCLC). However, elderly patients with NSCLC often suffer from other conditions, such as chronic obstructive pulmonary disease (COPD) or cardiovascular disease, and are not suitable candidates for surgery. Different modalities to treat stage I NSCLC have been developed, such as stereotactic radiotherapy (SRT), proton beam radiotherapy and carbon ion radiotherapy (CIRT). Between April 1999 and November 2003, we treated 129 patients with stage I NSCLC using CIRT. In this study, we focused on 28 patients aged 80 years and older who underwent CIRT, and analyzed the effectiveness of CIRT in treating their lung cancer and the impact on their activity of daily life (ADL). The 5-year local control rate for these patients was 95.8%, and the 5-year overall survival rate was 30.7%, but there were no patients who started home oxygen therapy or had decreased ADL. Our data demonstrate that CIRT was effective in treating elderly patients with stage I NSCLC.

BACKGROUND: The authors previously reported that the mitotic index of a proliferating cell population (pMI) was a potent prognostic factor in cervical cancer patients treated with photon beam therapy. In this study, they investigated whether the pMI accurately predicted prognosis in cervical cancer patients treated with carbon ion beam. METHODS: Tissue sections were obtained from 27 consecutively treated patients with stage IIIB bulky (19 patients) and stage IVA (8 patients) squamous cell carcinomas of the cervix treated with carbon ion beam at the National Institute of Radiological Sciences, Japan, as a phase I/II study with dose escalation methodology (52.8-72 grays equivalent radiation dose/24 fractions). The mitotic index (MI) and Ki-67 labeling index (Ki-67-LI) were determined by hematoxylin and eosin staining and immunohistochemical staining, respectively. The pMI was calculated using the following formula: pMI ¼ MI/Ki-67-LI. RESULTS: The pMI ranged from 0.6 to 8.9 (mean, 3.9 � 2.6; median, 3.2). Twelve of the 27 specimens had a pMI >3.5. The local control rate in tumors with a pMI >3.5 was 17%, significantly lower than the 73% in the tumors with a pMI

Background and purpose Heavy ion beams are high linear energy transfer (LET) radiation characterized by a higher relative biologic effectiveness than low LET radiation. The aim of the current study was to determine the difference of gene expression between heavy ion beams and X-rays in oral squamous cell carcinoma (OSCC)-derived cells. Materials and methods The OSCC cells were irradiated with accelerated carbon or neon ion irradiation or X-rays using three different doses. We sought to identify genes the expression of which is affected by carbon and neon ion irradiation using Affymetrix GeneChip analysis. The identified genes were analyzed using the Ingenuity Pathway Analysis Tool to investigate the functional network and gene ontology. Changes in mRNA expression in the genes were assessed by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Results The microarray analysis identified 84 genes that were modulated by carbon and neon ion irradiation at all doses in OSCC cells. Among the genes, three genes ( TGFBR2 , SMURF2 , and BMP7 ) and two genes ( CCND1 and E2F3 ), respectively, were found to be involved in the transforming growth factor β-signaling pathway and cell cycle:G1/S checkpoint regulation pathway. The qRT-PCR data from the five genes after heavy ion irradiation were consistent with the microarray data ( P Conclusion Our findings should serve as a basis for global characterization of radiation-regulated genes and pathways in heavy ion-irradiated OSCC.

Purpose To determine the risk factors for persistent late genitourinary (GU) morbidity after carbon ion radiotherapy (C-ion RT) for prostate cancer. Methods and Materials Between April 2000 and November 2003, a Phase II study of 175 prostate cancer patients was performed to assess C-ion RT with a dose fractionation (66 Gray equivalent in 20 fractions) established from previous Phase I-II studies. The effects of the clinical and dosimetric parameters on the occurrence of persistent GU toxicity in 172 patients who survived for >18 months after C-ion RT were examined retrospectively. C-ion RT alone was performed for 33 low-risk patients, and 139 high-risk patients received C-ion RT combined with androgen deprivation therapy (ADT). Results Grade 1 and 2 persistent GU toxicities developed in 36 (21%) and 3 (2%) patients, respectively. The use of long-course ADT (≥24 months) and acute GU toxicity were associated with the occurrence of persistent toxicity by multivariate analysis ( p = 0.016 and p = 0.048, respectively), but short-course ADT ( p = 0.35). The 5-year actuarial complication rate of 80 patients undergoing long-course ADT was 31.1%; the corresponding rate for the 92 patients who received no ADT or short-course ADT was 22.2%. Conclusion Adverse effects with long-course ADT on persistent GU morbidity were observed in this study. Additional investigation is needed to identify suitable ADT administration according to risk groups, but long-course ADT should not be adopted for non–high-risk prostate cancer patients to reduce the GU toxicity rate with C-ion RT.

Purpose. A comparative treatment planning study has been performed between carbon ion radiotherapy (CIRT) and photon radiotherapy [three-dimensional conformal radiotherapy (3D-CRT) and intensitymodulated radiotherapy (IMRT)] to assess the potential improvements and limitations that could result for locally advanced, nonresectable head and neck tumors. Materials and methods. Seven patients, originally treated with CIRT, were randomly selected for the comparative study. The evaluations analyzed using dose–volume histogram parameters, conformity index, inhomogeneity coeffi cient, and dose to the organs at risk (OARs). Results. The mean conformity index was 1.46, 1.43, and 1.22 for 3D-CRT, IMRT, and CIRT, respectively. The mean inhomogeneity coeffi cient was 0.05, 0.07, and 0.02 for 3D-CRT, IMRT, and CIRT respectively. Photon plans resulted in greater volumes of normal tissues at 10% to 95% isodose levels compared with the corresponding carbon ion plans where the volumes increased by a factor of 1.2 to 2.7 for 3D-CRT and 1.2 to 2.0 for IMRT. Conclusion. CIRT has the potential to improve the target dose conformity, inhomogeneity coeffi cient, and OAR sparing when compared with 3D-CRT and IMRT. Compared with 3D-CRT, normal tissue exposure was reduced mainly in the mid- to low-isodose levels using IMRT. Additional improvement was obtained using CIRT.

Purpose To prospectively assess patient quality of life (QOL) after carbon ion radiotherapy (C-ion RT) for prostate cancer, using established questionnaires. Methods and Material The subjects were 150 patients who underwent C-ion RT. Of these, 25 patients with low-risk prostate cancer received C-ion RT alone, whereas the remaining 125 patients with a high-risk tumor also received androgen deprivation therapy. Quality of life was assessed using the self-administered Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire in all patients three times. In addition, the University of California-Los Angeles Prostate Cancer Index (UCLA-PCI) was conducted in the low-risk patients. Results The FACT–General (FACT-G) and FACT-P scores at 12 months after treatment averaged over all 150 patients showed no significant change compared with those before C-ion RT. In FACT-P subscales, emotional well-being increased significantly just after and 12 months after treatment. In contrast, physical well-being (PWB) and social/family well-being (S/FWB) decreased significantly at 12 months, whereas the prostate cancer subscale (PCS) decreased significantly just after treatment. Average scores for FACT-G, FACT-P, PWB, S/FWB, and PCS for the 125 patients receiving hormone therapy showed substantial detrimental changes at 12 months. In contrast, those of the 25 low-risk patients who had no hormone therapy showed no significant change. Similarly no significant change in the average of the UCLA-PCI scores in the low-risk patients was seen at 12 months. Conclusions Average QOL parameters reported by patients with localized prostate cancer treated with C-ion RT, in the absence of hormone therapy, showed no significant decrease 12 months after C-ion RT.

Purpose \nTo evaluate the toxicity and efficacy of accelerated hyperfractionated radiotherapy (RT) for locally advanced cervical cancer. Methods and Materials \nA multi-institutional prospective single-arm study was conducted among eight Asian countries. Between 1999 and 2002, 120 patients (64 with Stage IIB and 56 with Stage IIIB) with squamous cell carcinoma of the cervix were treated with accelerated hyperfractionated RT. External beam RT consisted of 30 Gy to the whole pelvis, 1.5 Gy/fraction twice daily, followed by 20 Gy of pelvic RT with central shielding at a dose of 2-Gy fractions daily. A small bowel displacement device was used with the patient in the prone position. In addition to central shielding RT, intracavitary brachytherapy was started. Acute and late morbidities were graded according to the Radiation Therapy Oncology Group and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Results \nThe median overall treatment time was 35 days. The median follow-up time for surviving patients was 4.7 years. The 5-year pelvic control and overall survival rate for all patients was 84% and 70%, respectively. The 5-year pelvic control and overall survival rate was 78% and 69% for tumors ≥6 cm in diameter, respectively. No treatment-related death occurred. Grade 3-4 late toxicities of the small intestine, large intestine, and bladder were observed in 1, 1, and 2 patients, respectively. The 5-year actuarial rate of Grade 3-4 late toxicity at any site was 5%. Conclusion \nThe results of our study have shown that accelerated hyperfractionated RT achieved sufficient pelvic control and survival without increasing severe toxicity. This treatment could be feasible in those Asian countries where chemoradiotherapy is not available.

Purpose p73 belongs to the p53 tumor suppressor family of genes and can inhibit cell growth in a p53-like manner by inducing apoptosis or cell cycle arrest. Here, we investigated whether p73 could compensate for impaired p53 function in apoptosis induced by radiation therapy (RT) for cervical cancer. Methods and Materials Sixty-eight patients with squamous cell carcinoma of the cervix who received definitive RT combined with (n = 37) or without (n = 31) cisplatin were investigated. Biopsy specimens were excised from the cervical tumor before RT and after 9 Gy. \nResults Mean apoptosis index (AI) was 0.93% before RT and 1.97% after 9 Gy with a significant increase (p < 0.001). For all patients, there was a significant correlation between p73 expression positivity after 9 Gy and AI ratio (AI after 9 Gy/AI before RT) (p = 0.021). Forty-one patients were regarded as the p53-responding group according to the expression of p53 after 9 Gy, whereas the remaining 27 patients were regarded as the p53–nonresponding group. A significant correlation between p73 expression after 9 Gy and AI ratio was observed in the p53-non-responding group (p < 0.001) but not in the p53-responding group (p = 0.940). \nConclusion Our results suggest that p73 plays an important role in compensating for the lack of p53 function in radiation-induced apoptosis of cervical cancer.

Purpose: To elucidate the molecular changes in response to carbon beams (C-ions) in melanoma. Materials and methods: We examined expression profiles of 6 melanoma cell lines exposed to C-ions or X-rays with 2 Gy using single-color microarrays. Results: Twenty-two genes, including nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA), responded to C-ions in all six cell lines, based on analysis of variance (ANOVA) filtering (p < 0.001). We found 173 genes that responded in common to C-ions in four cell lines. We identified many down-regulated genes including the cell cycle - related genes that were more responsive to C-ions than X-rays. In contrast, most of the up-regulated genes including the tumor protein p53 (p53) target genes responded to both C-ions and X-rays. C-ions induced G2/M arrest significantly more than X-rays at 30 h (p < 0.05). Conclusion: Our findings suggest that down-regulation of gene expression plays a key role in the response to C-ions. Regulation of cell cycle - related genes and induction of prolonged G2/M arrest may be responsible for the extra sensitivity to C-ions, whereas p53-related genes may have similar roles in the sensitivities to both C-ions and X-rays.

Purpose: To identify haplotypes of single nucleotide polymorphism markers associated with the risk of early adverse skin reactions (EASRs) after radiotherapy in breast cancer patients. Methods and Materials: DNAwas sampled from 399 Japanese breast cancer patients who qualified for breast-conservingradiotherapy.UsingtheNationalCancerInstitute-CommonToxicityCriteriascoringsystem,version2,the patients were grouped according to EASRs, defined as those occurring within 3 months of starting radiotherapy (Grade 1 or less, n = 290; Grade 2 or greater, n = 109). A total of 999 single nucleotide polymorphisms from 137 candidategenesforradiationsusceptibilityweregenotyped,andthehaplotypeassociationsbetweengroupswereassessed. Results: The global haplotype association analysis (p < 0.05 and false discovery rate < 0.05) indicated that estimated haplotypes in six loci were associated with EASR risk. A comparison of the risk haplotype with the most frequent haplotype in each locus showed haplotype GGTT in CD44 (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.07‐4.43) resulted in a significantly greater EASR risk. Five haplotypes, CG in MAD2L2 (OR = 0.55; 95% CI, 0.35‐0.87), GTTG in PTTG1 (OR = 0.48; 95% CI, 0.24‐0.96), TCC (OR = 0.48; 95% CI, 0.26‐ 0.89) and CCG (OR = 0.50; 95% CI, 0.27‐0.92) in RAD9A, and GCT in LIG3 (OR = 0.46; 95% CI, 0.22‐0.93) were associated with a reduced EASR risk. No significant risk haplotype was observed in REV3L. Conclusion: Individual radiosensitivity can be partly determined by these haplotypes in multiple loci. Ourfindings may lead to a better understanding of the mechanisms underlying the genetic variation in radiation sensitivity and resistance among breast cancer patients. 2007 Elsevier Inc. Radiosensitivity, Single nucleotide polymorphism, SNP, Haplotype, Early adverse skin reaction.

Objective: To investigate the protein expression change of FGF2 in cervical cancers during chemoradiotherapy, as indicated in our previous study using microarray analysis. In addition, we sought to examine the predictive value of such changes in expression for disease failure after chemoradiotherapy. Patients and Methods: Biopsy specimens were obtained from 35 patients with cervical cancers before (pretreatment) and 1 week after initiation (midtreatment) of chemoradiotherapy (CRT) (9 Gy and 40 mg/m2 of cisplatin). Immunohistochemical studies (IHS) were performed to detect FGF2, laminin, and CD44 expression using an automated streptavidin-biotin immunoperoxidase staining system. Positive area proportion (%) of FGF2 and CD44 were analyzed using an image analysis system, and laminin staining pattern was scored by continuity of the basement membrane immunopositivity. Patients were defined as good (n =18) or poor responders (n =10) based on their two-year disease-free survival. Results: Protein expression of FGF2 in midtreatment samples (mid) was significantly higher than in pretreatment samples (pre). Discontinuity of laminin staining pattern in mid was significantly higher than in pre. Protein expression of CD44 was not significantly different between mid and pre. The ratio change (mid versus pre) of FGF2 expression in poor responders was significantly lower than that in good responders (P < 0.05). The number of cases with discontinuity of laminin staining pattern at pre was significantly increased in the poor responders (P < 0.05). Ratio changes of FGF2 or CD44 expression in mid correlated with laminin staining pattern in pre. Conclusions: Using biopsy specimens from pretreatment and midtreatment cervical cancers, we revealed significant changes in FGF2 protein expression during fractionated radiotherapy with cisplatin. We also found that FGF2 ratio change and laminin discontinuity staining pattern at pretreatment were significantly associated with prognosis. These molecular features might help us to identify patients at high risk of disease failure after CRT.

Background A phase I/II study was first conducted for the treatment of stage I non-small cell lung cancer (NSCLC) from 1994 to 1999 to determine the optimal dose. On the basis on the results, a phase II study using a regimen of four fractions during 1 week was performed. The purpose of the present study was to determine the local control and 5-year survival rates. Methods From December 2000 to November 2003, 79 patients with 80 primary lesions were treated. Using a fixed dose of 52.8 GyE for stage IA NSCLC and 60.0 GyE for stage IB NSCLC in four fractions during 1 week, the primary tumors were irradiated with carbon beams alone. The average age of the patients was 74.8 years. Sixty-two (78.5%) of these patients were medically inoperable. Local control and survival were determined using the Kaplan-Meier method. The data were statistically processed using the log-rank test. Results All patients were observed for a minimum of 3 years or until death, with a median follow-up time of 38.6 months, ranging from 2.5 to 72.2 months. The local control rate for all patients was 90% (T1: 98%, T2: 80%). The patients' 5-year lung cancer-specific survival rate was 68% (IA: 87%, IB: 42%). The overall survival was 45% (IA: 62%, IB: 25%). Half of the deaths were attributable to intercurrent diseases. No toxic reactions in the lung greater than grade 3 were detected. Conclusion Carbon ion beam radiotherapy with a regimen of four fractions during 1 week has been proven as a valid alternative to surgery for stage I NSCLC and to offer particular benefits, especially for elderly and inoperable patients.

Background We have conducted charged-particle radiotherapy for mucosal malignant melanoma (MMM) in the head and neck, using carbon ion beams. However, even with the use of carbon ion radiotherapy that is characterized by high local tumor control, a significant number of patients develop metastases after therapy. We conducted research on the assumption that, in MMM, the detection of loss of heterozygosity (LOH) from free DNA in the circulating plasma may be of practical use in the diagnosis of recurrence and metastasis. Methods We took blood samples prior to therapy from 17 patients with MMM in the head and neck, and extracted free DNA in plasma. Four types of microsatellite markers were used for LOH detection. Results LOH was detected in 1 of 5 patients (20%) for D1S243, 2 of 5 patients (40%) for D6S311, 11 of 17 patients (65%) for D9S161, and 1 of 6 patients (17%) for D19S246. Conclusion Evidence based on the irradiated tumor volume suggested a tendency for the group of patients found to have LOH in two loci to have a larger mean tumor volume than the patient groups with no detectable LOH or with LOH detectable in only one locus. Of the 17 patients in this study 4 patients had recurrence and/or metastasis, and all 4 of these patients were found to have LOH in at least one or more loci for any region. LOH analysis of free DNA in plasma may be useful for the early diagnosis of MMM.

Purpose \nRadiotherapy differed widely in east and south-east Asia because of technical, cultural, and socio-economic differences. With the purpose of standardizing radiotherapy for cervical cancer in the region, an international clinical study was conducted. \nMaterials and methods \nEleven institutions in eight Asian countries participated in the study. Between 1996 and 1998, 210 patients with stage IIIB cervical cancer were enrolled. Patients were treated with a combination of external beam radiotherapy (total dose, 50 Gy) and either high-dose-rate (HDR) or low-dose-rate (LDR) intracavitary brachytherapy (ICBT) according to the institutional practice. The planned point A dose was 20-28 Gy/4 fractions for HDR-ICBT and 30-40 Gy/1-2 fractions for LDR-ICBT. \nResults \nHundred patients were treated with HDR-ICBT and 110 were treated with LDR-ICBT. The ICBT doses actually delivered to point A ranged widely: 12-32 Gy in the HDR group and 26-52.7 Gy in the LDR group. The 5-year follow-up rate among the countries differed greatly, from 29% to 100%. The 5-year major complication rates were 6% in the HDR group and 10% in the LDR group. The 5-year overall survival rates were 51.1% in the HDR group and 57.5% in the LDR group. \nConclusions \nAlthough there were several problems with treatment compliance and patients follow-up, the study suggests that the protocols provided favorable outcomes with acceptable rates of late complications in the treatment of advanced cervical cancer in east and south-east Asia. \nKeywords: Cervical cancer; Radiotherapy; Developing country; International clinical study; East and south-east Asia

Malignant melanoma of the vagina is a very rare neoplasm and resistant to conventional radiotherapy. We report a case of vaginal malignant melanoma that was locally well controlled by carbon ion radiotherapy. A 55-year-old postmenopausal woman presented with abnormal vaginal bleeding. On pelvic and imaging examinations, an irregular mass of the posterior vaginal wall sized 7.5 × 5 × 5 cm, an enlarged right inguinal lymph node, and two lung metastases were observed. Histologic diagnosis based on positive immunostaining for HMB-45 was malignant melanoma. She received dacarbazine-based chemotherapy and carbon ion radiotherapy for vaginal and inguinal tumor sites with 57.6 Gy equivalent dose per 16 fractions using five ports. Six months later, she was also given carbon ion radiotherapy for regrowing lung metastasis with 52.8 Gy equivalent dose per four fractions using four ports. She died 19 months after initial treatment due to brain metastases. The primary irradiated tumor disappeared completely 12 months after initial treatment. The vaginal tumor, right inguinal lymph node, and lung tumor treated with carbon ion radiotherapy did not show any evidence of recurrence until her death. Carbon ion radiotherapy may be of value for vaginal malignant melanoma as a conservative approach.