Yoshiyuki Shioyama

Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer.

PURPOSEnTo 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.nnnMETHODS AND MATERIALSnEligibility 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/m(2) 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.nnnRESULTSnSeventy-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/m(2). The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m(2)) 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.nnnCONCLUSIONSnCarbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.

Particle radiotherapy for prostate cancer.

Recent advances in external beam radiotherapy have allowed us to deliver higher doses to the tumors while decreasing doses to the surrounding tissues. Dose escalation using high‐precision radiotherapy has improved the treatment outcomes of prostate cancer. Intensity‐modulated radiation therapy has been widely used throughout the world as the most advanced form of photon radiotherapy. In contrast, particle radiotherapy has also been under development, and has been used as an effective and non‐invasive radiation modality for prostate and other cancers. Among the particles used in such treatments, protons and carbon ions have the physical advantage that the dose can be focused on the tumor with only minimal exposure of the surrounding normal tissues. Furthermore, carbon ions also have radiobiological advantages that include higher killing effects on intrinsic radio‐resistant tumors, hypoxic tumor cells and tumor cells in the G0 or S phase. However, the degree of clinical benefit derived from these theoretical advantages in the treatment of prostate cancer has not been adequately determined. The present article reviews the available literature on the use of particle radiotherapy for prostate cancer as well as the literature on the physical and radiobiological properties of this treatment, and discusses the role and the relative merits of particle radiotherapy compared with current photon‐based radiotherapy, with a focus on proton beam therapy and carbon ion radiotherapy.

Multicenter Study of Carbon-Ion Radiation Therapy for Mucosal Melanoma of the Head and Neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN)

PURPOSEnToxa0evaluate the efficacy and safety of carbon-ion radiation therapy (RT) for mucosal melanoma of the head and neck (MMHN) in the Japan Carbon-Ion Radiation Oncology Study Group study.nnnMETHODS AND MATERIALSnPatients with MMHN with N0-1M0 status who were treated with carbon-ion RT at 4 institutions in Japan between November 2003 and December 2014 were analyzed retrospectively. Two hundred sixty patients (male, 111; female, 149; median age, 68xa0years) with histologically proven MMHN were enrolled.nnnRESULTSnPrimary sites included the nasal cavity in 178 patients, paranasal sinuses in 43, oral cavity in 27, and pharynx in 12. Eighty-six patients had T3 tumors, 147 had T4a tumors, and 27 had T4b tumors. Two hundred fifty-one patients were diagnosed with N0 disease, and 9 with N1 disease. The median total dose and number of fractions were 57.6xa0Gy RBE (relative biological effectiveness) and 16, respectively. Chemotherapy including dimethyl traizeno imidazole carboxamide was used concurrently in 129 patients. The median follow-up duration was 22xa0months (range, 1-132xa0months). The 2-year overall survival and local control rates were 69.4% and 83.9%, respectively. Multivariate analysis showed that gross tumor volume and concurrent chemotherapy were significant prognostic factors for overall survival. Grade 3 and grade 4 late morbidities were observed in 27 and 7 patients (5 developed ipsilateral blindness, 1 mucosal ulcer, and 1xa0second malignant disease in the irradiated volume), respectively. No patients developed grade 5 late morbidities.nnnCONCLUSIONnCarbon-ion RT is a promising treatment option for MMHN.

A multi-institutional analysis of prospective studies of carbon ion radiotherapy for prostate cancer: A report from the Japan Carbon ion Radiation Oncology Study Group (J-CROS).

BACKGROUND AND PURPOSEnA multi-institutional observational study (J-CROS1501PR) has been carried out to analyze outcomes of carbon-ion radiotherapy (CIRT) for patients with prostate cancer.nnnPATIENTS AND METHODSnData 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.nnnRESULTSnA 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%.nnnCONCLUSIONSnFavorable overall outcomes of CIRT for prostate cancer were suggested by the analysis of the first multi-institutional data.

Dosimetric analysis of upper gastrointestinal ulcer after carbon-ion radiotherapy for pancreatic cancer.

PURPOSEnThe aim of this study was to clarify the incidence, clinical risk factors, and dose-volume relationship of upper gastrointestinal (GI) ulcer after carbon-ion radiotherapy (C-ion RT) for pancreatic cancer.nnnMATERIALS AND METHODSnFifty-eight pancreatic cancer patients were treated with C-ion RT from April 2014 to December 2015. The total dose was 55.2Gy (RBE) in 12 fractions. D2cm3 of GI tracts were restricted under 46Gy (RBE); RBE-weighted absorbed dose. The association between dosimetric parameters (V10-50, Dmax, D1cm3, D2cm3) and GI ulcer was examined using Spearmans correlation. The incidence of GI ulcer was compared between the two groups divided by the cutoff value.nnnRESULTSnTwelve patients (21%) experienced gastric ulcer including only one (2%) grade 3 ulcer. There was no grade 4/5 toxicity or duodenal ulcer. V10-30 was significantly associated with gastric ulcer. The 1-year estimated risk of gastric ulcer for the determined cutoff values were 51% vs. 10% (V10, ⩾102cm(3) or less), 42% vs. 9% (V20, ⩾24cm(3) or less), 34% vs. 4% (V30, ⩾6cm(3) or less).nnnCONCLUSIONSnThe incidence of GI ulcer after C-ion RT was very low with the dose constraint of D2cm3 <46Gy (RBE). To further minimize the risk of GI ulcer, V10-30 should also be reduced.

Computer-assisted framework for machine-learning–based delineation of GTV regions on datasets of planning CT and PET/CT images

We have proposed a computer-assisted framework for machine-learning–based delineation of gross tumor volumes (GTVs) following an optimum contour selection (OCS) method. The key idea of the proposed framework was to feed image features around GTV contours (determined based on the knowledge of radiation oncologists) into a machine-learning classifier during the training step, after which the classifier produces the ‘degree of GTV’ for each voxel in the testing step. Initial GTV regions were extracted using a support vector machine (SVM) that learned the image features inside and outside each tumor region (determined by radiation oncologists). The leave-one-out-by-patient test was employed for training and testing the steps of the proposed framework. The final GTV regions were determined using the OCS method that can be used to select a global optimum object contour based on multiple active delineations with a LSM around the GTV. The efficacy of the proposed framework was evaluated in 14 lung cancer cases [solid: 6, ground-glass opacity (GGO): 4, mixed GGO: 4] using the 3D Dice similarity coefficient (DSC), which denotes the degree of region similarity between the GTVs contoured by radiation oncologists and those determined using the proposed framework. The proposed framework achieved an average DSC of 0.777 for 14 cases, whereas the OCS-based framework produced an average DSC of 0.507. The average DSCs for GGO and mixed GGO were 0.763 and 0.701, respectively, obtained by the proposed framework. The proposed framework can be employed as a tool to assist radiation oncologists in delineating various GTV regions.

A Multicenter Study of Carbon-Ion Radiation Therapy for Head and Neck Adenocarcinoma

PURPOSEnHead and neck (HN) adenocarcinoma is rare, and to date, there have been no reports of prospective studies. We retrospectively evaluated the efficacy and safety of carbon-ion radiation therapy (C-ion RT) for HN adenocarcinoma in institutions in Japan.nnnMETHODS AND MATERIALSnHN adenocarcinoma patients with N0M0 or N1M0 disease who were treated with C-ion RT at institutions in Japan between November 2003 and December 2014 were analyzed retrospectively.xa0We enrolled 47 patients (30 male and 17 female patients; median age, 60xa0years) with HN adenocarcinoma.nnnRESULTSnPrimary sites included the nasal and paranasal sinus in 21 patients, orbit in 11, salivary grand in 7, oral cavity and pharynx in 6, and acoustic organ in 2. Thirty-two patients had T4 tumors, 6 had T3, and 6 had T2. Forty-five patients received a diagnosis of N0 disease, whereas 2 had N1 disease. The median total dose of C-ion RT and the number of fractions were 64.0xa0Gy (relative biological effectiveness) and 16 fractions, respectively. The median follow-up period was 51xa0months (range, 6-118xa0months). The 2- and 5-year overall survival rates were 87.9% and 60.4%, respectively, and the 2- and 5-year local control rates were 83.3% and 79.3%, respectively. Multivariate analysis showed that operability (patients with operable tumors) (P=.045) and fractionation (16 fractions) (P=.010) were significant independent prognostic factors for better overall survival. No grade 5 late morbidities were observed. Grade 4 late morbidities were observed in 4 patients, and all of thesexa0grade 4 morbidities were visual impairments. All 4 patients with grade 4 visual impairment had T4 tumors in the nasopharynx or paranasal sinuses, which implied inoperable tumors with orbital or brain invasion.nnnCONCLUSIONSnC-ion RT resulted in excellent local control. C-ion RT could become a curative treatment option for HN adenocarcinoma with acceptable toxicities.

Gefitinib Combined With Standard Chemoradiotherapy in EGFR-Mutant Locally Advanced Non–Small-Cell Lung Cancer: The LOGIK0902/OLCSG0905 Intergroup Study Protocol

Herein, we describe an ongoing phase II trial in patients with locally advanced non-small-cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR). Patients with chemotherapy-naive locally advanced disease with active EGFR mutations will receive the induction treatment, specified as gefitinib monotherapy (250 mg/body) for 8 weeks. Patients whose disease has not progressed during the induction therapy will receive cisplatin and docetaxel (40 mg/m(2)) on days 1, 8, 29, and 36, and concurrent 3-dimensional conformal thoracic radiotherapy with a single daily fraction of 2 Gy, for 5 consecutive days each week to provide a total dose of 60 Gy. The primary end point is overall survival at 24 months. A target sample size of 21 evaluable patients is considered sufficient to validate an expected rate of 85%, and 60% would be the lower limit of interest, with 80% power and a 1-sided α of 5%. Secondary end points include toxicity, response rate, and overall survival. This study will clarify whether tyrosine kinase inhibitors targeted to EGFR can produce a maximal effect in selected NSCLC patients with the relevant driver mutation, even in the locally advanced setting.

Oligo-recurrence predicts favorable prognosis of brain-only oligometastases in patients with non-small cell lung cancer treated with stereotactic radiosurgery or stereotactic radiotherapy: a multi-institutional study of 61 subjects

BackgroundTo investigate the prognostic value of oligo-recurrence in patients with brain-only oligometastases of non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT).MethodsPatients treated with SRS or SRT for brain-only NSCLC oligometastases in 6 high-volume institutions in Japan between 1996 and 2008 were reviewed. Eligible patients met 1), 2), and 4) or 1), 3), and 4) of the following: 1) NSCLC with 1 to 4 brain metastases on magnetic resonance imaging (MRI) treated with SRS or SRT; 2) control of the primary lesions (thorax) at the time of SRS or SRT for brain metastases (patients meeting this criterion formed the oligo-recurrence group); 3) with SRS or SRT for brain metastases, concomitant treatment for active primary lesions (thorax) with curative surgery or curative stereotactic body radiotherapy (SBRT), or curative chemoradiotherapy (sync-oligometastases group); and 4) Karnofsky performance status (KPS)u2009≥70.ResultsThe median overall survival (OS) of all 61 patients was 26xa0months (95 % CI: 17.5–34.5xa0months). The 2-year and 5-year overall survival rates were 60.7 and 15.7xa0%, respectively. Stratified by oligostatus, the sync-oligometastases group achieved a median OS of 18xa0months (95 % CI: 14.8–21.1xa0months) and a 5-year OS of 0xa0%, while the oligo-recurrence group achieved a median OS of 41xa0months (95 % CI: 27.8–54.2xa0months) and a 5-year OS of 18.6xa0%. On multivariate analysis, oligo-recurrence was the only significant independent factor related to a favorable prognosis (hazard ratio: 0.253 (95 % CI: 0.082–0.043) (pu2009=u20090.025).ConclusionsThe presence of oligo-recurrence can predict a favorable prognosis of brain-only oligometastases in patients with NSCLC treated with SRS or SRT.

Impact of pixel-based machine-learning techniques on automated frameworks for delineation of gross tumor volume regions for stereotactic body radiation therapy

The aim of this study was to investigate the impact of pixel-based machine learning (ML) techniques, i.e., fuzzy-c-means clustering method (FCM), and the artificial neural network (ANN) and support vector machine (SVM), on an automated framework for delineation of gross tumor volume (GTV) regions of lung cancer for stereotactic body radiation therapy. The morphological and metabolic features for GTV regions, which were determined based on the knowledge of radiation oncologists, were fed on a pixel-by-pixel basis into the respective FCM, ANN, and SVM ML techniques. Then, the ML techniques were incorporated into the automated delineation framework of GTVs followed by an optimum contour selection (OCS) method, which we proposed in a previous study. The three-ML-based frameworks were evaluated for 16 lung cancer cases (six solid, four ground glass opacity (GGO), six part-solid GGO) with the datasets of planning computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT images using the three-dimensional Dice similarity coefficient (DSC). DSC denotes the degree of region similarity between the GTVs contoured by radiation oncologists and those estimated using the automated framework. The FCM-based framework achieved the highest DSCs of 0.79±0.06, whereas DSCs of the ANN-based and SVM-based frameworks were 0.76±0.14 and 0.73±0.14, respectively. The FCM-based framework provided the highest segmentation accuracy and precision without a learning process (lowest calculation cost). Therefore, the FCM-based framework can be useful for delineation of tumor regions in practical treatment planning.