Carbon Ion Radiotherapy In Patients Research Articles

Hypoxia predicts favorable response to carbon ion radiotherapy in non-small cell lung cancer (NSCLC) defined by 18F-FMISO positron emission tomography/computed tomography (PET/CT) imaging.

Hypoxia is the bottleneck that affects the response of conventional photon radiotherapy, but it does not seem to have much effect on carbon ion radiotherapy (CIRT). This study aimed to evaluate the changes of hypoxia before and after CIRT in patients with non-small cell lung cancer (NSCLC) and whether 18F-fluoromisonidazole (18F-FMISO) positron emission tomography/computed tomography (PET/CT) imaging could predict the response to CIRT in NSCLC patients. A total of 29 patients with NSCLC who received CIRT were retrospectively included. 18F-FMISO PET/CT imaging was performed before and after treatment, and chest CT was performed after radiotherapy. Radiation response within 1 week after radiotherapy and at the initial follow-up were defined as the immediate response (IR) and early response (ER), respectively. The tumor-to-muscle ratio (TMR), hypoxia volume (HV), and the ΔTMR and ΔHV values of 18F-FMISO uptake were collected. Fisher's exact test, Mann-Whitney U test, Wilcoxon signed-rank test, and binary logistic regression were used to analyze data. (I) Baseline TMR could predict the IR to CIRT with a baseline TMR cut-off value of 2.35, an area under the curve (AUC) of 0.85 [95% confidence interval (CI): 0.62-1.00], a sensitivity of 80.0%, a specificity of 87.5%, and an accuracy of 85.7%. Taking the baseline TMR =2.35 as the cut-off value of high-hypoxia and low-hypoxia group, the IR rate of the high-hypoxia group [66.7% (4/6)] and the low-hypoxia group [6.7% (1/15)] was statistically different (P=0.01). (II) ΔTMR could predict early treatment response after CIRT at initial follow-up, with a cut-off value of ΔTMR =36.6%, AUC of 0.80 (95% CI: 0.61-1.00), sensitivity of 72.7%, specificity of 90.0% and accuracy of 71.4%. A higher degree of tumor hypoxia may be associated with a better IR to CIRT. ΔTMR could predict early treatment response after CIRT.

Pencil Beam Scanning Carbon Ion Radiotherapy for Hepatocellular Carcinoma.

Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC). However, evidence of using the pencil beam scanning (PBS) technique to treat moving liver tumors remains lacking. The present study investigated the efficacy and toxicity of PBS CIRT in patients with HCC. Between January 2016 and October 2021, 90 consecutive HCC patients treated with definitive CIRT in our center were retrospectively analyzed. Fifty-eight patients received relative biological effectiveness-weighted doses of 50-70 Gy in 10 fractions, and 32 received 60-67.5 Gy in 15 fractions, which were determined by the tumor location and normal tissue constraints. Active motion-management techniques and necessary strategies were adopted to mitigate interplay effects efficiently. Oncologic outcomes and toxicities were evaluated. The median follow-up time was 28.6 months (range 5.7-74.6 months). The objective response rate was 75.0% for all 90 patients with 100 treated lesions. The overall survival rates at 1-, 2- and 3-years were 97.8%, 83.3% and 75.4%, respectively. The local control rates at 1-, 2- and 3-years were 96.4%, 96.4% and 93.1%, respectively. Radiation-induced liver disease was not documented, and 4 patients (4.4%) had their Child-Pugh score elevated by 1 point after CIRT. No grade 3 or higher acute non-hematological toxicities were observed. Six patients (6.7%) experienced grade 3 or higher late toxicities. The active scanning technique was clinically feasible to treat HCC by applying necessary mitigation measures for interplay effects. The desirable oncologic outcomes as well as favorable toxicity profiles presented in this study will be a valuable reference for other carbon-ion centers using the PBS technique and local effect model-based system, and add to a growing body of evidence about the role of CIRT in the management of HCC.

Safety of Carbon-ion Radiotherapy for Prostate Cancer After Rectal Cancer Surgery.

The safety of carbon-ion radiotherapy (CIRT) for patients with prostate cancer after rectal cancer surgery remains unknown. This is a retrospective analysis of the safety of CIRT in patients with prostate cancer after rectal cancer surgery. The subjects were 13 consecutive patients with prostate cancer who underwent CIRT after rectal cancer surgery at the Kanagawa Cancer Center from December 2015 to April 2022. A total dose of 51.6 Gy (relative biological effectiveness) was administered in 12 fractions over 3 weeks. The criteria stated in the Common Terminology Criteria for Adverse Events, version 5.0, were used to assess toxicity. Fisher's exact test was performed to assess the associations between patient clinical factors and rectal toxicity. The median patient age was 71 years (range=66-83 years). The median observation period was 27.4 months (range=10.6-82.4 months). The median duration from rectal surgery to CIRT was 6.9 years (1.0-16.8 years). Five (38.5%) and six (46.2%) patients had a planning target volume (PTV)-adjacent rectal anastomosis and diabetes mellitus, respectively, and two (15.4%) patients had both. Grades 1 and 2 late gastrointestinal toxicities were observed in one case each. Development of gastrointestinal toxicity was significantly associated with both a PTV adjacent rectal anastomosis and diabetes mellitus (p=0.013). Late gastrointestinal toxicity was tolerable in patients with prostate cancer treated with CIRT after rectal cancer surgery. Patients with both a PTV adjacent rectal anastomosis and diabetes mellitus were more likely to experience late gastrointestinal toxicity.

Immunomodulatory effects of carbon ion radiotherapy in patients with localized prostate cancer

PurposeRadiotherapy is one of the main local treatment modalities for prostate cancer, while immunosuppressive effect induced by radiotherapy is an important factor of radiation resistance and treatment failure. Carbon ion radiotherapy (CIRT) is a novel radiotherapy technique and the immunomodulatory effect of CIRT provides the possibility of overcoming radioresistance and improving efficacy. The aim of this study was to assess the immune response evoked by CIRT in localized prostate cancer patients.MethodsThirty-two patients were treated by CIRT combined with or without hormone therapy and peripheral blood samples were collected before and after CIRT. Investigation of peripheral immune cell frequency, proliferation, and cytokine expression was conducted by flow cytometry, real-time quantitative PCR and ELISA.ResultsThere were no significant differences in the frequencies of CD3 + , CD4 + , CD8 + T cells and NK cells after CIRT. CD4/CD8 ratio increased whereas B cells decreased. All lymphocyte subsets except regulatory T cells (Tregs) displayed increased proliferation and T cells exhibited increased functionality after CIRT, characterized by modestly increased cytokine secretion of TNF. Moreover, higher frequencies of Tregs were shown. Neither monocytic myeloid-derived suppressor cells (MDSCs) nor early MDSCs changed after CIRT. TGF-β1 gene expression decreased while IL-6 showed a non-significant trend towards a decrease. Both IL-10 gene expression and plasma TGF‐β1 level were unchanged.ConclusionCIRT demonstrates the potential to elicit immune activation in localized prostate cancer patients, based on sparing lymphocytes, increased lymphocyte proliferation, enhanced T-cell functionality, together with limited induction of immunosuppressive cells and reduced expression of immunosuppressive cytokines.

Carbon Ion Radiotherapy Evokes a Metabolic Reprogramming and Individualized Response in Prostate Cancer.

Introduction: Carbon ion radiotherapy (CIRT) is a novel treatment for prostate cancer (PCa). However, the underlying mechanism for the individualized response to CIRT is still not clear. Metabolic reprogramming is essential for tumor growth and proliferation. Although changes in metabolite profiles have been detected in patients with cancer treated with photon radiotherapy, there is limited data regarding CIRT-induced metabolic changes in PCa. Therefore, the study aimed to investigate the impact of metabolic reprogramming on individualized response to CIRT in patients with PCa.Materials and Methods: Urine samples were collected from pathologically confirmed patients with PCa before and after CIRT. A UPLC-MS/MS system was used for metabolite detection. XCMS online, MetDNA, and MS-DIAL were used for peak detection and identification of metabolites. Statistical analysis and metabolic pathway analysis were performed on MetaboAnalyst.Results: A total of 1,701 metabolites were monitored in this research. Principal component analysis (PCA) revealed a change in the patient's urine metabolite profiles following CIRT. Thirty-five metabolites were significantly altered, with the majority of them being amino acids. The arginine biosynthesis and histidine metabolism pathways were the most significantly altered pathways. Hierarchical cluster analysis (HCA) showed that after CIRT, the patients could be clustered into two groups according to their metabolite profiles. The arginine biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis pathways are the most significantly discriminated pathways.Conclusion: Our preliminary findings indicate that metabolic reprogramming and inhibition are important mechanisms involved in response to CIRT in patients with PCa. Therefore, changes in urine metabolites could be used to timely assess the individualized response to CIRT.

Definitive carbon ion radiotherapy for tracheobronchial adenoid cystic carcinoma: a preliminary report

BackgroundTracheobronchial adenoid cystic carcinoma (TACC) is a rare tumour. About one-third of patients miss their chance of surgery or complete resection as it is mostly detected in the advanced stage; hence, photon radiotherapy (RT) is used. However, the outcomes of photon RT remain unsatisfactory. Carbon ion radiotherapy (CIRT) is thought to improve the therapeutic gain ratio; however, the outcomes of CIRT in TACC are unclear. Therefore, we aimed to assess the effects and toxicities of CIRT in patients with TACC.MethodsThe inclusion criteria were as follows: 1) age 18–80 years; 2) Eastern Cooperative Oncology Group Performance Status 0–2; 3) histologically confirmed TACC; 4) stage III–IV disease; 5) visible primary tumour; and 6) no previous RT history. The planned prescription doses of CIRT were 66–72.6 GyE/22–23 fractions. The rates of overall survival (OS), local control (LC), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Treatment-induced toxicities and tumour response were scored according to the Common Terminology Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors, respectively.ResultsEighteen patients with a median age of 48 (range 30–73) years were enrolled. The median follow-up time was 20.7 (range 5.8–44.1) months. The overall response rate was 88.2%. Five patients developed lung metastasis after 12.2–41.0 months and one of them experienced local recurrence at 31.9 months after CIRT. The rates of 2-year OS, LC, and PFS were 100, 100, and 61.4%, respectively. Except for one patient who experienced grade 4 tracheal stenosis, which was relieved after stent implantation, no other ≥3 grade toxicities were observed.ConclusionsCIRT might be safe and effective in the management of TACC based on a short observation period. Further studies with more cases and longer observation are warranted.

Adaptive planning based on single beam optimization in passive scattering carbon ion radiotherapy for patients with pancreatic cancer

BackgroundDaily anatomical deviations may distort the dose distribution in carbon ion radiotherapy (CIRT), which may cause treatment failure. Therefore, this study aimed to perform re-planning to maintain the dose coverage in patients with pancreatic cancer with passive scattering CIRT.MethodsEight patients with pancreatic cancer and 95 daily computed tomography (CT) sets were examined. Two types of adaptive plans based on new range compensators (RCs) (AP-1) and initial RCs (AP-2) were generated. In AP-2, each beam was optimized by manually adjusting the range shifter thickness and spread-out Bragg peak size to make dose reduction by < 3% of the original plan. Doses of the original plan with bone matching (BM) and tumor matching (TM) were examined for comparison. We calculated the accumulated dose using the contour and intensity-based deformable image registration algorithm. The dosimetric differences in respect to the original plan were compared between methods.ResultsUsing TM and BM, mean ± standard deviations of daily CTV V95 (%) difference from the original plan was − 5.1 ± 6.2 and − 8.8 ± 8.8, respectively, but 1.2 ± 3.4 in AP-1 and − 0.5 ± 2.1 in AP-2 (P < 0.001). AP-1 and AP-2 enabled to maintain a satisfactory accumulated dose in all patients. The dose difference was 1.2 ± 2.8, − 2,1 ± 1.7, − 7.1 ± 5.2, and − 16.5 ± 15.0 for AP-1, AP-2, TM, and BM, respectively. However, AP-2 caused a dose increase in the duodenum, especially in the left–right beam.ConclusionsThe possible dose deterioration should be considered when performing the BM, even TM. Re-planning based on single beam optimization in passive scattering CIRT seems an effective and safe method of ensuring the treatment robustness in pancreatic cancer. Further study is necessary to spare healthy tissues, especially the duodenum.

Pretreatment 18F-FDG uptake heterogeneity can predict treatment outcome of carbon ion radiotherapy in patients with locally recurrent nasopharyngeal carcinoma

Our study was to investigate the value of pretreatment 18F-FDG uptake heterogeneity to predict the prognosis of patients with locally recurrent nasopharyngeal carcinoma (LRNPC) treated by carbon ion radiotherapy (CIRT). Twenty-nine LRNPC patients who underwent whole-body 18F-FDG PET/CT scanning before CIRT were enrolled. Heterogeneity index (HI)-based 18F-FDG uptake, and the PET/CT traditional parameters, including SUVmax, MTV, and TLG were assessed. Receiver operator characteristics (ROC) determined the best cutoff value, and local recurrence-free survival (LRFS) and progression-free survival (PFS) were evaluated by the Kaplan-Meier method and log-rank test. And the predictive ability was evaluated by the ROC curve. Cox analyses were performed on LRFS and PFS. In this study, univariate analysis showed that HI was a significant predictor of LRNPC treated by CIRT. HI could be used to predict LRFS and PFS. Patients with HI (≥ 0.81) had a significantly worse prognosis of LRFS (12.25 vs. NR, p = 0.008), and of PFS (10.58 vs. NR, p = 0.014). The AUC and its sensitivity and sensitivity and specificity were 0.75, 84.21% and 70.00% for LRFS and 0.82, 80.95% and 75.00% for PFS, respectively. Multivariate analysis showed that HI was an independent predictor for the LFRS of LRNPC with CIRT. 18F-FDG uptake heterogeneity may be useful for predicting the prognosis of patients with LRNPC treated by CIRT.

Carbon ion radiotherapy for patients with hepatocellular carcinoma in the caudate lobe carbon ion radiotherapy for hepatocellular carcinoma in caudate lobe.

The treatment of hepatocellular carcinoma in the caudate lobe (HCCCL) is technically challenging. We aimed to investigate the efficacy and toxicity of carbon ion radiotherapy (C-ion RT) for HCCCL. Patients with HCCCL treated with C-ion RT at our hospital between January 2011 and December 2018 were evaluated. The total dose was 52.8 or 60Gy (relative biological effectiveness) in four or 12 fractions depending on the distance between the tumor and the gastrointestinal tract. The survival outcome, the presence or absence of recurrence (local recurrence, intrahepatic recurrence outside the irradiation field, or extrahepatic recurrence), and acute/late adverse events were evaluated. Nine patients were included. The median tumor size was 3.4cm, and the median follow-up duration was 18.3months for all patients. No patient developed local recurrence during follow-up. Five patients subsequently developed intrahepatic recurrence outside the irradiation field and two had extrahepatic metastasis. Five patients died of hepatocellular carcinoma. No acute adverse events of grade ≥2 were observed. Two patients experienced grade 2 or 3 late adverse events, including obstructive jaundice, hepatic encephalopathy, ascites, and edema. Carbon ion radiotherapy for HCCCL achieved excellent local control with acceptable adverse events and can thus be a curative treatment option for HCCCL.

A clinical study of curative partial breast irradiation for stage I breast cancer using carbon ion radiotherapy

Background and purposeOur institute initiated carbon ion radiotherapy research for patients with stage I breast cancer in April 2013. The purpose of this article is to evaluate the treatment outcome of cases treated outside clinical trial up to May 2020.Materials and methodsEligibility criteria of the patients were having untreated stage I breast cancer and being unsuitable for operation for physical or mental reasons. The irradiated volume was defined as the gross tumor including intraductal components. The dose escalation study was initially conducted four times a week for a total of 52.8 Gy [relative biological efficacy (RBE)]. After confirming that adverse effects were within acceptable range, the total dose was increased to 60.0 Gy (RBE).ResultsBetween April 2013 and November 2015, 14 cases were treated. The median follow up period was 61 months. No adverse toxicities were observed except for grade 1 acute skin reaction in 10 cases. The time required from carbonion radiotherapy to tumor disappearance was 3 months in 1 case, 6 months in 3 cases, 12 months in 4 cases, and 24 months in 5 cases. The third case developed local recurrence 6 months after radiotherapy. Twelve patients with luminal subtype received 5-year endocrine therapy. Thirteen of 14 tumors have been maintaining complete response with excellent cosmetic results.ConclusionsThe time from carbon ion radiotherapy to tumor disappearance was longer than expected, but complete tumor disappearance was observed except for one high-grade case. With careful patient selection, carbonion radiotherapy in patients with stage I breast cancer is deemed effective and safe, and further research is recommended.

Complication rate, functional outcomes, and risk factors associated with carbon ion radiotherapy for patients with unresectable pelvic bone sarcoma.

To the authors' knowledge, carbon ion radiotherapy (CIRT) is one of the few curative treatments for unresectable pelvic bone sarcoma. The current study investigated the complications, functional outcomes, and risk factors of CIRT. Of 112 patients who were treated with CIRT for unresectable pelvic bone sarcoma, the authors enrolled 29 patients who were without local disease recurrence or distant metastasis. The mean follow-up was 93 months. Complications, functional outcomes, and quality of life scores were assessed. Risk factors were analyzed, including the dose-volume histogram of the femoral head. Femoral head necrosis occurred in approximately 37% of patients, pelvic fractures were reported in 48% of patients, and neurological deficits were noted in 52% of patients. Femoral head necrosis was found to be significantly more prevalent among patients with periacetabular tumors (P=.018). The dose-volume histogram of the femoral head indicated tolerable volume percentages of the femoral head to be <33% for 40 grays (relative biological effectiveness) and 16% for 60 grays ( relative biological effectiveness). The mean Musculoskeletal Tumor Society score and Toronto Extremity Salvage Score were 53% and 64%, respectively, and the mean EuroQol 5 dimensions questionnaire index was 0.587. Patients aged >50 years and those with periacetabular tumors were found to have significantly lower Toronto Extremity Salvage Scores. Femoral head necrosis, pelvic fracture, and nerve damage are common complications with the use of CIRT for pelvic bone sarcoma. To prevent femoral head necrosis, the radiation dose to the femoral head should be kept below the estimated tolerance curve presented in the current study. The functional outcome is nearly equivalent to that of surgery. CIRT may be a promising alternative to surgery for patients with unresectable pelvic bone sarcoma.

Volumetric parameters derived from FLT-PET performed at completion of treatment predict efficacy of Carbon-ion Radiotherapy in patients with locally recurrent Nasopharyngeal Carcinoma.

The purpose of this study was to investigate the role of 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET for predicting the outcome of patients with locally recurrent nasopharyngeal carcinoma (LR-NPC) treated by carbon-ion radiotherapy (CIRT). Patients received FLT-PET/CT scan one-week prior to or after completion of CIRT were enrolled in the study. All patients were from prospective trials or treated using a standardized protocol. Time-dependent receiver operator characteristics (ROC) were used to determine the optimal cutoff values for FLT-PET parameters. Univariable and multivariable analyses of local progression-free survival (LPFS) were performed using Cox regression, to examine the prognostic value of FLT-PET parameters, including SUVmax, metabolic tumor volume (MTV) and total lesion thymidine (TLT). A total of 41 patients were enrolled. Elevated MTV and TLT were significantly associated with worse LPFS, in both univariable and multivariable analyses. ROC analysis revealed that both an MTV value higher than 8.6 and a TLT value higher than 14.9 were predictive of increased risk of developing local recurrence, the adjusted HRs were 5.59 (p=0.009) and 7.76 (p=0.002), respectively. In conclusion, FLT-PET was found to be a promising prognostic tool for LR-NPC patients and might play a role in the treatment guidance.

A Transcriptional Fingerprint of Carbon Ion Radiotherapy in Patients with Recurrent Glioma Utilizing Peripheral Blood as a Sentinel Organ

A Transcriptional Fingerprint of Carbon Ion Radiotherapy in Patients with Recurrent Glioma Utilizing Peripheral Blood as a Sentinel Organ

Carbon Ion Radiotherapy for Patients with Extracranial Chordoma or Chondrosarcoma - Initial Experience from Shanghai Proton and Heavy Ion Center

Purpose: The purpose of this study was to evaluate the outcomes of patients with extracranial chordoma or chondrosarcoma treated by carbon ion radiotherapy (CIRT).Patients and methods: Between May 2015 and April 2018, 21 consecutive patients with chordoma (n=16) or chondrosarcoma (n=5) treated by CIRT at Shanghai Proton and Heavy Ion Center (SPHIC) were enrolled. The local control (LC), progression free survival (PFS), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Association between each of the candidate prognostic factors and the estimated LC, PFS or OS was tested using the log rank test.Results: The median gross tumor volume (GTV) was 512.7 ml (range, 142.6-2893.0 ml). The median prescription dose was 69 gray equivalent (GyE) (range, 57-80 GyE). After a median follow-up of 21.8 months (range, 7.2-39.2 months), the 1-year LC, PFS, and OS were 93.8%, 88.4%, and 100%, respectively, whereas the 2-year LC, PFS, and OS were 85.2%, 80.4%, and 100%, respectively. A univariate analysis revealed that age, metal implant status, treatment status, sex, dose, and GTV were not significant prognostic factors for LC, PFS or OS. No grade 2 or higher early and late toxicities were observed within the follow-up.Conclusion: The results of this retrospective study are encouraging. Patients with extracranial chordoma or chondrosarcoma treated by CIRT in our center achieved a favorable shot-term outcome, without developing severe acute or late adverse events. The long-term results deserve further investigation, even in a prospective randomized trial.

A retrospective multicenter study of carbon-ion radiotherapy for external auditory canal and middle ear carcinomas.

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

Clinical Efficacy of Carbon Ion Radiotherapy for Unresectable Chondrosarcomas.

Carbon ion radiotherapy has precise dose distribution and high biological effectiveness and is likely a promising therapy for patients with sarcomas. We evaluated the outcomes of carbon ion radiotherapy in patients with unresectable chondrosarcomas. A retrospective analysis of 75 tumors in 73 patients treated with carbon ion radiotherapy was performed. There were 26 spinal, 38 pelvic, and 11 other types of tumors. Seventy conventional and five dedifferentiated chondrosarcomas were treated in 69 and four patients, respectively. The median follow-up period was 49.4 (range=6.4-146.4) months. The 5-year local control, overall survival, and disease-free survival rates were 53%, 53%, and 34%, respectively. By multivariate analysis, tumor volume and histological grade were significantly related to overall and disease-free survival. Five patients required surgical intervention because of adverse events in the bones. Carbon ion radiotherapy might be a treatment option for unresectable chondrosarcoma.

Carbon-ion radiotherapy for patients with advanced stage non-small-cell lung cancer at multicenters.

ABSTRACTCarbon-ion radiation therapy (CIRT) for advanced non–small-cell lung cancer (NSCLC) has not been well studied to date. This paper aimed to analyze a retrospective multicenter survey for detecting problems with the use of CIRT for Stage II and III NSCLC (7th UICC TNM Staging System). Inclusion was restricted to patients with Stage II and III NSCLC who received CIRT from November 2003 to December 2014. We gathered the data from three CIRT operating centers on July 2015. Patients with radiotherapy history, patients with cancers other than lung cancer, and those receiving palliative therapies were excluded. The patient characteristics, prescribed dose/fraction, survival rates, and adverse effects were analyzed. The total number of patients was 64 (male: 49, female: 15). Of these, 53 patients were medically inoperable. The median age was 76 years (range 46–91), and the median follow-up period was 18.5 months (range 3.2–121.5). The clinical staging consisted of 10 Stage IIA, 30 Stage IIB, 23 Stage IIIA and 1 Stage IIIB. The median prescribed dose was 72.0 Gy (RBE) (range 52.8–72.0) in 16 fractions (range 4–16). The 2-year overall survival, progression-free survival, and local control rates were 62.2% [confidence interval (CI): 47.5–76.9], 42.3% (CI: 28.8–55.8) and 81.8% (CI: 69.9–94.0), respectively. There were no higher than Grade 2 adverse effects observed. CIRT for inoperable Stage II and III NSCLC could be implemented without severe adverse effects, but the clinical staging (including lymph node status) was inhomogeneous. In addition, the prescribed dose and fractionation were not standardized. Further data accumulation and a multiple centers prospective trial for evaluating clinical stage–based results are required.

Changes in arrhythmogenic properties and five-year prognosis after carbon-ion radiotherapy in patients with mediastinum cancer.

Carbon-ion irradiation of rabbit hearts has improved left ventricular conduction abnormalities through upregulation of gap junctions. However, to date, there has been no investigation on the effect of carbon-ion irradiation on electrophysiological properties in human. We investigated this effect in patients with mediastinum extra-cardiac cancer treated with carbon-ion radiotherapy that included irradiating the heart. In April-December 2009, eight patients were prospectively enrolled (including two male, aged 72.5±13.0years). They were treated with 44-72 Gray equivalent (GyE), with their hearts exposed to 1.3-19.1 GyE. High-resolution ambulatory electrocardiography was performed before and after radiotherapy to investigate arrhythmic events, late potentials (LPs), and heart rate variability. Five patients had pre-existing premature ventricular contraction (PVC)/atrial contraction (PAC) or paroxysmal atrial fibrillation (PAF)/AF; after irradiation, this improved in four patients with PVC/PAF/AF and did not deteriorate in one patient with PAC. Ventricular LP findings did not deteriorate and improved in one patient. In eight cases with available atrial LP findings, there was no deterioration, and two patients showed improvements. The low frequency/high frequency ratio of heart rate variability improved or did not deteriorate in the six patients who received radiation exposure to the bilateral stellate ganglions. During the five-year follow-up for the prognosis, six of the eight patients died because of cancer; there was no history of hospitalization for cardiac events. Although this preliminary study has several limitations, carbon-ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction.

Prognostic analysis of radiation pneumonitis: carbon-ion radiotherapy in patients with locally advanced lung cancer

BackgroundCarbon-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.MethodsClinical 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.ResultsGrade 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 <86.9% (odds ratio = 13.7; p = 0.0041) and V30 ≥ 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors.ConclusionsOur study demonstrated the risk factors for ≥ grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer.

Local effect and gastrointestinal toxicity for carbon-ion radiotherapy in patients with unresectable locally advanced pancreatic cancer.

410 Background: Carbon-ion radiotherapy (CIRT) is a unique external radiotherapy that has an excellent dose conformity and higher biological effectiveness compared to conventional radiotherapy. The sensitivity of the organs in upper abdomen has limited the radiation dose to levels that are ineffective against pancreatic cancer, which has extreme radioresisnatnce. We investigated effectiveness and gastrointestinal (GI) toxicity of CIRT. Methods: From April 2014 to June 2015, 41 patients with pancreatic cancer were treated with definitive CIRT. 26 patients who were confirmed as unresectable locally advanced pancreatic cancer pathologically and by imaging techniques were included in this retrospective analysis. 15 patients were excluded because of resectable disease (n = 3), borderline disease (n = 4), no cell evidence (n = 11). CIRT was performed with 55.2 Gy (RBE) at 12 fractions. The maximal absolute dose with covered 2cm3 of the organ (D2) was restricted under 46 Gy (RBE). All patients were followed up using CT, FDG-PET and upper gastrointestinal endoscopy at least every six months. Anti-tumor effect was evaluated using CT and FDG-PET according to RECIST. If FDG accumulation was negative or equal to normal pancreatic tissue after CIRT, it was defined CR even no decreasing in seize on CT. GI toxicity was evaluated using CTCAE. Results: Tumor location were head in 7, head-body in 2, body-tail in 16. Median tumor size was 35mm (range 21-50). In all patients, sequential and/or concurrent chemotherapy was performed. The median follow-up period was 7.7 months. Local effect using CT criteria was CR in 0, PR in 2, SD in 22, and PD in 2. The evaluation adding FDG-PET criteria was CR in 12, PR in 4, SD in 8, and PD in 2. Two patients who were SD by CT and CR by FDG-PET performed tumor resection and were revealed pCR. The actual incidence of gastric ulcer/bleeding was 15% (n = 4). Only one patient (4%) received blood transfusion because of grade 3 gastric ulcer. The other patients experienced grade 1/2 gastric ulcer. There was no duodenal ulcer. Conclusions: CIRT were effective and well tolerated under the restriction of D2 &lt; 46 Gy (RBE). FDG-PET was useful for the evaluation of local effect after CIRT.