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Purpose: Radiation pneumonitis (RP) is dose-limiting toxicity for non-small-cell cancer (NSCLC). This study developed an RP prediction model by integrating dose-function features from computed four-dimensional computed tomography (4DCT) ventilation using the least absolute shrinkage and selection operator (LASSO)., Methods: Between 2013 and 2020, 126 NSCLC patients were included in this study who underwent a 4DCT scan to calculate ventilation images. We computed two sets of candidate dose-function features from (1) the percentage volume receiving > 20 Gy or the mean dose on the functioning zones determined with the lower cutoff percentile ventilation value, (2) the functioning zones determined with lower and upper cutoff percentile ventilation value using 4DCT ventilation images. An RP prediction model was developed by LASSO while simultaneously determining the regression coefficient and feature selection through fivefold cross-validation., Results: We found 39.3 % of our patients had a ≥ grade 2 RP. The mean area under the curve (AUC) values for the developed models using clinical, dose-volume, and dose-function features with a lower cutoff were 0.791, and the mean AUC values with lower and upper cutoffs were 0.814. The relative regression coefficient (RRC) on dose-function features with upper and lower cutoffs revealed a relative impact of dose to each functioning zone to RP. RRCs were 0.52 for the mean dose on the functioning zone, with top 20 % of all functioning zone was two times greater than that of 0.19 for these with 60 %-80 % and 0.17 with 40 %-60 % (P < 0.01)., Conclusions: The introduction of dose-function features computed from functioning zones with lower and upper cutoffs in a machine learning framework can improve RP prediction. The RRC given by LASSO using dose-function features allows for the quantification of the RP impact of dose on each functioning zones and having the potential to support treatment planning on functional image-guided radiotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: The purpose of this prospective study was to investigate changes in longitudinal parameters after stereotactic radiotherapy for lung cancer and to identify possible pretreatment factors related to radiation-induced lung toxicity and the decline in pulmonary function after radiotherapy., Materials and Methods: Protocol-specified examinations, including 4-D CT, laboratory tests, pulmonary function tests (PFTs) and body composition measurements, were performed before SRT and at 1 month, 4 months and 12 months after stereotactic radiotherapy. Longitudinal differences were tested by using repeated-measures analysis of variance. Correlations were examined by using the Pearson product-moment correlation coefficient (r)., Results: Sixteen patients were analyzed in this study. During a median follow-up period of 26.6 months, grade 1 and 2 lung toxicity occurred in 11 patients and 1 patient, respectively. The mean Hounsfield units (HU) and standard deviation (SD) of the whole lung, as well as sialylated carbohydrate antigen KL-6 (KL-6) and surfactant protein-D (SP-D), peaked at 4 months after radiotherapy (p = 0.11, p<0.01, p = 0.04 and p<0.01, respectively). At 4 months, lung V20 Gy (%) and V40 Gy (%) were correlated with changes in SP-D, whereas changes in the mean HU of the lung were related to body mass index and lean body mass index (r = 0.54, p = 0.02; r = 0.57, p = 0.01; r = 0.69, p<0.01; and r = 0.69, p<0.01, respectively). The parameters of PFTs gradually declined over time. When regarding the change in PFTs from pretreatment to 12 months, lung V5 Gy (cc) showed significant correlations with diffusion capacity for carbon monoxide (DLCO), DLCO/alveolar volume and the relative change in DLCO (r = -0.72, p<0.01; r = -0.73, p<0.01; and r = -0.63, p = 0.01, respectively)., Conclusions: The results indicated that some parameters peaked at 4 months, but PFTs were the lowest at 12 months. Significant correlations between lung V5 Gy (cc) and changes in DLCO and DLCO/alveolar volume were observed., Competing Interests: TY, YT and RS have received lecturer fees from AstraZeneca KK. EM has received grants from Chugai Pharmaceutical Co Ltd. and Eli Lily Japan KK., honouraria from AstraZeneca KK., Taiho Pharmaceutical Co Ltd., Daiichi Sankyo KK., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co Ltd., Novartis Pharma KK., MSD KK., Kyowa Kirin Co Ltd., Merck Biopharma Co Ltd., Pfizer Inc., Ono Pharmaceutical Co Ltd., Otsuka Pharmaceutical Co Ltd. and Towa Pharmaceutical Co. Ltd., and EM has been an advisory board of Chugai Pharmaceutical Co Ltd, Boehringer Ingelheim Japan Inc and Eli Lilly Japan KK. KJ has received consulting fees from Varian Medical Systems and Elekta, and honouraria from Shimazu. Co. YK, KS, RU, NT, YS, KT, KK, SO and NK have no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2022 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study evaluated accuracy of deformable image registration (DIR) with twelve parameter settings for thoracic images. We used peak-inhale and peak-exhale images for ten patients provided by DIR-lab. We used a prototype version of iCView software (ITEM Corporation) with DIR to perform intensity, structure, and hybrid-based DIR with the twelve parameter settings. DIR accuracy was evaluated by a target registration error (TRE) using 300 bronchial bifurcations and the Dice similarity coefficient (DSC) of the lungs. For twelve parameter settings, TRE ranged from 2.83 mm to 5.27 mm, whereas DSC ranged from 0.96 to 0.98. These results demonstrated that DIR accuracy differed among parameter settings and show that appropriate parameter settings are required for clinical practice.

Purpose: We aimed to assess radiomics approaches for estimating three pulmonary function test (PFT) results (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], and the ratio of FEV1 to FVC [FEV 1 /FVC]) using data extracted from chest computed tomography (CT) images., Methods: This retrospective study included 85 lung cancer patients (mean age, 75 years ±8; 69 men) who underwent stereotactic body radiotherapy between 2012 and 2020. Their pretreatment chest breath-hold CT and PFT data before radiotherapy were obtained. A total of 107 radiomics features (Shape: 14, Intensity: 18, Texture: 75) were extracted using two methods: extraction of the lung tissue (<-250 HU) (APPROACH 1), and extraction of small blood vessels and lung tissue (APPROACH 2). The PFT results were estimated using the least absolute shrinkage and selection operator regression. Pearson's correlation coefficients (r) were determined for all PFT results, and the area under the curve (AUC) was calculated for FEV 1 /FVC (<70 %). Finally, we compared our approaches with the conventional formula (Conventional)., Results: For the estimated FEV 1 /FVC, the Pearson's r were 0.21 (P =.06), 0.69 (P <.01), and 0.73 (P <.01) for Conventional, APPROACH 1, and APPROACH 2, respectively; the AUCs for FEV 1 /FVC (<70 %) were 0.67 (95 % confidence interval [CI]: 0.55, 0.79), 0.82 (CI: 0.72, 0.91; P =.047) and 0.86 (CI: 0.78, 0.94; P =.01), respectively., Conclusions: The radiomics approach performed better than the conventional equation and may be useful for assessing lung function based on CT images., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: In clinical practice, the effect of durvalumab and radiation pneumonitis (RP) on survival after intensity-modulated radiotherapy (IMRT) is not fully understood. The purpose of this retrospective study was to investigate factors related to distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS) after IMRT for locally advanced non-small cell lung cancer (LA-NSCLC)., Methods: All patients who were treated with conventional fractionated IMRT for LA-NSCLC between April 2016 and March 2021 were eligible. Time-to-event data were assessed by using the Kaplan-Meier estimator, and the Cox proportional hazards model was used for prognostic factor analyses. Factors that emerged after the start of IMRT, such as durvalumab administration or the development of RP, were analysed as time-dependent covariates., Results: A total of 68 consecutive patients treated with conventional fractionated IMRT for LA-NSCLC were analysed. Sixty-six patients completed radiotherapy, 50 patients received concurrent chemotherapy, and 36 patients received adjuvant durvalumab. During the median follow-up period of 14.3 months, 23 patients died, and tumour progression occurred in 37 patients, including 28 patients with distant metastases. The 1-year DMFS rate, PFS rate and OS rate were 59.9%, 48.7% and 84.2%, respectively. Grade 2 RP occurred in 16 patients, grade 3 in 6 patients and grade 5 in 1 patient. The 1-year cumulative incidences of grade 2 or higher RP and grade 3 or higher RP were 33.8% and 10.3%, respectively. The results of multivariate analyses showed that durvalumab had a significantly lower hazard ratio (HR) for DMFS, PFS and OS (HR 0.31, p < 0.01; HR 0.33, p < 0.01 and HR 0.32, p = 0.02), respectively. Grade 2 or higher RP showed significance for DMFS and a nonsignificant trend for OS (HR 2.28, p = 0.04 and HR 2.12, p = 0.13), respectively, whereas a higher percentage of lung volume receiving 20 Gy or higher was significant for PFS (HR 2.25, p = 0.01)., Conclusions: In clinical practice, durvalumab administration following IMRT with concomitant chemotherapy showed a significant survival benefit. Reducing the risk of grade 2 or higher RP would also be beneficial., (© 2022. The Author(s).)

In this article, we highlight the fundamental importance of the simultaneous use of dose-volume histogram (DVH) and dose-function histogram (DFH) features based on functional images calculated from 4-dimensional computed tomography (4D-CT) and deformable image registration (DIR) in developing a multivariate radiation pneumonitis (RP) prediction model. The patient characteristics, DVH features and DFH features were calculated from functional images by Hounsfield unit (HU) and Jacobian metrics, for an RP grade ≥ 2 multivariate prediction models were computed from 85 non-small cell lung cancer patients. The prediction model is developed using machine learning via a kernel-based support vector machine (SVM) machine. In the patient cohort, 21 of the 85 patients (24.7%) presented with RP grade ≥ 2. The median area under curve (AUC) was 0.58 for the generated 50 prediction models with patient clinical features and DVH features. When HU metric and Jacobian metric DFH features were added, the AUC improved to 0.73 and 0.68, respectively. We conclude that predictive RP models that incorporate DFH features were successfully developed via kernel-based SVM. These results demonstrate that effectiveness of the simultaneous use of DVH features and DFH features calculated from 4D-CT and DIR on functional image-guided radiotherapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background and Purpose: Intensity-modulated radiation therapy (IMRT) is increasingly applied in concurrent chemoradiotherapy (CCRT) for locally-advanced non-small cell lung cancer (NSCLC), with improvement of target coverage and better sparing of normal tissue. IMRT tends to have a larger low-dose irradiation volume than 3D conformal radiotherapy, but the incidence of and risk factors for pneumonitis remain unclear, especially following the approval of durvalumab., Materials and Methods: We retrospectively reviewed the records of NSCLC patients treated by CCRT using IMRT at seven Japanese institutions. Primary outcomes were incidence of symptomatic pneumonitis and progression-free survival (PFS). Multivariate logistic regression analysis was used to identify risk factors for ≥grade 2 pneumonitis., Results: Median follow-up from the start of CCRT was 14.3 months (n = 107 patients; median age 70 years, 29% female). Median lung V5 and V20 was 49.2% and 19.5%, respectively. Durvalumab was administered to 87 patients (81%). Pneumonitis developed in 95 (89%) patients of which 53% had grade 1, 28% grade 2, 6.5% grade 3, and 0.9% grade 4. Durvalumab had been discontinued in 16 patients (18.4%) due to pneumonitis. By multivariate analysis, age ≥70 years, male sex, and V5 ≥58.9% were identified as significantly associated with ≥grade 2 pneumonitis (p = 0.0065, 0.036 and 0.0013 respectively). The median PFS from the start of CCRT was not reached (95% CI, 14.2 months to not reached) in patients receiving durvalumab., Conclusion: CCRT using IMRT followed by durvalumab was generally effective and tolerable; V5 <60% would be recommended to avoid symptomatic pneumonitis., Competing Interests: Conflict of Interest statement Yoko Tsukita reports personal fees from AstraZeneca and Chugai Pharmaceutical outside the submitted work. Takaya Yamamoto reports personal fees from AstraZeneca outside the submitted work. Hiroshi Mayahara reports personal fees from Accuray Japan Inc., Hitachi, Ltd, Eisai Co., Ltd., grants from MSD, grants and personal fees from AstraZeneca plc outside the submitted work. Akito Hata reports grants and personal fees from Eli Lilly, Boehringer Ingelheim and Astrazeneca, personal fees from Chugai, grants from MSD outside the submitted work. Yuichiro Takeda reports grants from Chugai and Boehringer Ingelheim, personal fees from Otsuka Pharmaceutical Co., Ltd outside the submitted work. Junji Uchida reports personal fees from Astra Zeneca K.K., Chugai pharmaceutical.co.ltd, Bristol Myers Squibb, Taiho Pharma and Boehringer Ingelheim outside the submitted work. Kazuhiro Usui reports personal fees from Astra Zeneca, Chugai, MSD, Pfizer and Boehringer Ingelheim outside the submitted work. Motohiro Tamiya reports grants and personal fees from Boehringer Ingelheim, Ono Pharmaceutical and Bristol-Myers Squibb, personal fees from Chugai Pharmaceutical, MSD, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Asahi Kasei Pharmaceutical and Pfizer outside the submitted work. Yuko Oya reports personal fees from Chugai pharma, Boehringer Ingelheim, Daiichi Sankyo, Astrazeneca, Ono pharmaceutical and Eli lilly outside the submitted work. Takeshi Kodaira reports personal fees from Merck Serono Co., Hitachi Co., Bristle Myers Squibb., Accuray Co., Elekta Co., Ono Pharmaceutical Co., AstraZeneca Co., Taiho Pharmaceutical Co. and Canon Co. outside the submitted work. Eisaku Miyauchi reports grants and personal fees from Chugai pharmaceutical co ltd, Ono pharmaceutical co., ltd., Boehringer Ingelheim and Lilly, personal fees from Astrazeneca, Taiho pharma, Kyowa kirin, Daiichi sankyo, MSD, Bristol-Meyers Squibb, Novartis and Merck Bio outside the submitted work. Keiichi Jingu reports personal fees from Varina Medical Systems, Inc., Elekta K.K., Shimadzu Medical Systems Corporation, AstraZeneca K.K., Guerbet Japan and grants and personal fees from Eisai Co., Ltd., grants from Takeda Pharmaceutical Company Limited, TAIHO Phamaceutical Co., Ltd., outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the differences in patterns of recurrence and treatment results by histology after definitive radiotherapy for stage III non-small cell lung cancer (NSCLC) in Japan., Materials and Methods: Patients with stage III NSCLC who underwent definitive radiotherapy between 2000 and 2016 in our institution were included. A total of 217 patients were enrolled. Propensity score matching was used to exclude the following confounding factors: (1) age (≥70 years or <70 years), (2) gender, (3) T factor, (4) N factor, (5) Eastern Cooperative Oncology Group performance status score and (6) smoking status (Brinkman index ≥400 or <400)., Results: The median observation period for survivors was 55.1 months. After propensity score matching, the Sqcc and adenocarcinoma groups each included 62 paired patients. There was no significant difference in OS or PFS between the adenocarcinoma and Sqcc groups. However, rates of recurrence in the GTV-primary site (p = 0.009) and GTV-lymph node site (p = 0.037) were significantly higher in patients with Sqcc than in patients with adenocarcinoma. New metastatic recurrence was more frequent in patients with adenocarcinoma than in patients with Sqcc (p = 0.025)., Conclusion: There were significant differences in patterns of recurrence after definitive (chemo)radiotherapy between patients with Sqcc and patients with adenocarcinoma.

Background: Radiomics is a new technology to noninvasively predict survival prognosis with quantitative features extracted from medical images. Most radiomics-based prognostic studies of non-small-cell lung cancer (NSCLC) patients have used mixed datasets of different subgroups. Therefore, we investigated the radiomics-based survival prediction of NSCLC patients by focusing on subgroups with identical characteristics., Methods: A total of 304 NSCLC (Stages I-IV) patients treated with radiotherapy in our hospital were used. We extracted 107 radiomic features (i.e., 14 shape features, 18 first-order statistical features, and 75 texture features) from the gross tumor volume drawn on the free breathing planning computed tomography image. Three feature selection methods [i.e., test-retest and multiple segmentation (FS1), Pearson's correlation analysis (FS2), and a method that combined FS1 and FS2 (FS3)] were used to clarify how they affect survival prediction performance. Subgroup analysis for each histological subtype and each T stage applied the best selection method for the analysis of All data. We used a least absolute shrinkage and selection operator Cox regression model for all analyses and evaluated prognostic performance using the concordance-index (C-index) and the Kaplan-Meier method. For subgroup analysis, fivefold cross-validation was applied to ensure model reliability., Results: In the analysis of All data, the C-index for the test dataset is 0.62 (FS1), 0.63 (FS2), and 0.62 (FS3). The subgroup analysis indicated that the prediction model based on specific histological subtypes and T stages had a higher C-index for the test dataset than that based on All data (All data, 0.64 vs. SCC all , 060; ADC all , 0.69; T1, 0.68; T2, 0.65; T3, 0.66; T4, 0.70). In addition, the prediction models unified for each T stage in histological subtype showed a different trend in the C-index for the test dataset between ADC-related and SCC-related models (ADC T1 -ADC T4 , 0.72-0.83; SCC T1 -SCC T4 , 0.58-0.71)., Conclusions: Our results showed that feature selection methods moderately affected the survival prediction performance. In addition, prediction models based on specific subgroups may improve the prediction performance. These results may prove useful for determining the optimal radiomics-based predication model.

Cancer-specific death (CSD) and non-cancer-specific death (non-CSD) after stereotactic body radiotherapy (SBRT) for pulmonary oligometastases have not been studied in detail. The aim of this study was to determine the cumulative incidences of CSD and non-CSD and to reveal prognostic factors. Data from a large survey of SBRT for pulmonary oligometastases were used for analyses, and patients with unknown cause of death were excluded from current analyses. CSD was primary cancer death and non-CSD was non-primary cancer death including a series of cancer treatment-related deaths. Cumulative incidences were calculated using the Kaplan-Meier method and a stratified Cox regression model was used for multivariate analyses (MVA). Fifty-two patients with an unknown death were excluded and a total of 1326 patients was selected. CSD and non-CSD occurred in 375 and 109 patients, respectively. The median OS period was 53.2 months and the cumulative incidences of 1-, 3-, and 5-year CSD vs. non-CSD rates were 6.5% vs. 2.3%, 29.5% vs. 8.6%, and 41.2% vs. 11.0%, respectively. In MVA, the incidence of CSD was related to performance status (1 vs. 0; p < 0.001, 2-3 vs. 0; p = 0.011), oligometastatic state (sync-oligometastases vs. oligo-recurrence, p = 0.026) and maximum tumor diameter (p = 0.009), and the incidence of non-CSD was related to age (p = 0.001), sex (p = 0.030), performance status (2-3 vs. 0; p = 0.002), and irradiated tumor-located lung lobe (left lower lobe vs. other lobes, p = 0.036). CSD was main cause of death, but non-CSD was not rare after SBRT. Prognostic factors for CSD and non-CSD were different, and an understanding of the factors would help in treatment., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

This study is a subset analysis of a retrospective multicenter study performed in Japan and its purpose was to investigate the effectiveness of stereotactic body radiotherapy (SBRT) for pulmonary oligometastases from colorectal cancer. Local control (LC), freedom from further metastases, relapse-free survival and overall survival (OS) after SBRT were retrospectively analyzed. The Kaplan-Meier method was used to estimate lifetime data and the log-rank test was performed as univariate analyses. The Cox proportional hazards model was applied in multivariate analyses. Data for 330 patients with 371 tumors were used for analyses. The median follow-up period was 25.0 months. The 3-year LC, freedom from further metastases, relapse-free survival and OS rates were 64.9, 34.9, 24.9 and 63.4%, respectively. The results of multivariate analyses showed that a higher LC rate was associated with no history of local therapy for oligometastases (P = 0.01), SBRT without concurrent chemotherapy (P < 0.01), type B calculation algorithm (P < 0.01) and higher biological effective radiation doses (≥115 Gy, P = 0.04). A longer OS was associated with no history of local therapy for oligometastases (P = 0.04), a more recent period of SBRT (2010-15, P = 0.02), tumor located in the upper or middle lobe (P < 0.01) and higher biological effective radiation doses (≥115 Gy, P = 0.01). In conclusion, OS after SBRT was good, but LC rate was relatively low. The use of high biological effective radiation doses can improve both LC and OS outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Successful local therapy for oligometastases may lead to longer survival. The purpose of this multicentre retrospective study was to investigate factors affecting the local control (LC) of pulmonary oligometastases treated by stereotactic body radiotherapy (SBRT) and to investigate the impact of LC on survival., Methods: The inclusion criteria included 1 to 5 metastases, the primary lesion and other extrathoracic metastases were controlled before SBRT, and the biological effective dose (BED 10 ) of the SBRT was 75 Gy or more. The Cox proportional hazards model was used for analyses., Results: Data of 1378 patients with 1547 tumours from 68 institutions were analysed. The median follow-up period was 24.2 months. The one-year, 3-year and 5-year LC rates were 92.1, 81.3 and 78.6%, respectively, and the 1-year, 3-year and 5-year overall survival rates were 90.1, 60.3 and 45.5%, respectively. Multivariate analysis for LC showed that increased maximum tumour diameter (p = 0.011), type A dose calculation algorithm (p = 0.005), shorter overall treatment time of SBRT (p = 0.035) and colorectal primary origin (p < 0.001 excluding oesophagus origin) were significantly associated with a lower LC rate. In the survival analysis, local failure (p < 0.001), worse performance status (1 vs. 0, p = 0.013; 2-3 vs. 0, p < 0.001), oesophageal primary origin (vs. colorectal origin, p = 0.038), squamous cell carcinoma (vs. adenocarcinoma, p = 0.006) and increased maximum tumour diameter (p < 0.001) showed significant relationships with shorter survival., Conclusions: Several factors of oligometastases and SBRT affected LC. LC of pulmonary oligometastases by SBRT showed a significant survival benefit compared to patients with local failure.

We evaluated four-dimensional cone beam computed tomography (4D-CBCT) ventilation images (VI CBCT ) acquired with two different linear accelerator systems at various gantry speeds using a deformable lung phantom. The 4D-CT and 4D-CBCT scans were performed using a computed tomography (CT) scanner, an X-ray volume imaging system (Elekta XVI) mounted in Versa HD, and an On-Board Imager (OBI) system mounted in TrueBeam. Intensity-based deformable image registration (DIR) was performed between peak-exhale and peak-inhale images. VI CBCT - and 4D-CT-based ventilation images (VI CT ) were derived by DIR using two metrics: one based on the Jacobian determinant and one on changes in the Hounsfield unit (HU). Three different DIR regularization values (λ) were used for VI CBCT . Correlations between the VI CBCT and VI CT values were evaluated using voxel-wise Spearman's rank correlation coefficient (r). In case of both metrics, the Jacobian-based VI CBCT with a gantry speed of 0.6 deg/sec in Versa HD showed the highest correlation for all the gantry speeds (e.g., λ = 0.05 and r = 0.68). Thus, the r value of the Jacobian-based VI CBCT was greater or equal to that of the HU-based VI CBCT . In addition, the ventilation accuracy of VI CBCT increased at low gantry speeds. Thus, the image quality of VI CBCT was affected by the change in gantry speed in both the imaging systems. Additionally, DIR regularization considerably influenced VI CBCT in both the imaging systems. Our results have the potential to assist in designing CBCT protocols, incorporating VI CBCT imaging into the functional avoidance planning process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Functional lung avoidance during radiotherapy can help reduce pulmonary toxicity. This study assessed the potential impact of four-dimensional computed tomography (4DCT)-ventilation imaging-guided proton radiotherapy (PT) on stereotactic body radiotherapy (SBRT) by comparing it with three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT), which employ photon beams. Thirteen lung cancer patients who received SBRT with 3D-CRT were included in the study. 4DCT ventilation was calculated using the patients' 4DCT data, deformable image registration, and a density-change-based algorithm. Three functional treatment plans sparing the functional lung regions were developed for each patient using 3D-CRT, VMAT, and PT. The prescribed doses and dose constraints were based on the Radiation Therapy Oncology Group 0618 protocol. We evaluated the region of interest (ROI) and functional map-based dose-function metrics for 4DCT ventilation and the irradiated dose. Using 3D-CRT, VMAT, and PT, the percentages of the functional lung regions that received ≥ 5 Gy (fV5) were 26.0%, 21.9%, and 10.7%, respectively; the fV10 were 14.4%, 11.4%, and 9.0%, respectively; and fV20 were 6.5%, 6.4%, and 6.6%, respectively, and the functional mean lung doses (fMLD) were 5.6 Gy, 5.2 Gy, and 3.8 Gy, respectively. These results indicated that PT resulted in a significant reduction in fMLD, fV5, and fV10, but not fV20. The use of PT reduced the radiation to highly functional lung regions compared with those for 3D-CRT and VMAT while meeting all dose constraints.

Background and Purpose: The rate of oncologic pulmonary death after stereotactic body radiotherapy for pulmonary oligometastases has never been reported. The purpose of current study was to investigate the rate of freedom from oncologic pulmonary death (FOPD) and to analyze factors affecting for FOPD., Materials and Methods: The inclusion criteria for this retrospective study were that SBRT was performed between 2004 and 2015, the number of metastases was 5 or less, the primary lesion and extrathoracic metastases needed to be controlled before SBRT and a biological effective dose (BED 10 ) of 75 Gy or more was needed. The Kaplan-Meier estimator and the log-rank test were used to calculate and compare the stratified rates of FOPD. The Cox proportional hazards model was used for multivariate analyses (MVA). Primary disease death from a non-oncologic pulmonary cause was censored in model 1 and was excluded in model 2., Results: A total of 1172 patients with 1315 tumors were enrolled. During a median follow-up period of 24.5 months, oncologic pulmonary deaths accounted for 101 of 221 primary disease deaths. The 1-year, 3-year and 5-year FOPD rates in model 1 were 98.2%, 89.4% and 84.0%, respectively. MVA for FOPD revealed that local failure of the irradiated tumor, squamous cell carcinoma pathology, and chemotherapy after SBRT had significant relationships with lower FOPD rates in both model 1 and model 2., Conclusions: Successful local control of pulmonary oligometastases by SBRT contributed to a higher FOPD rate., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Radiomics is a new technique that enables noninvasive prognostic prediction by extracting features from medical images. Homology is a concept used in many branches of algebra and topology that can quantify the contact degree. In the present study, we developed homology-based radiomic features to predict the prognosis of non-small-cell lung cancer (NSCLC) patients and then evaluated the accuracy of this prediction method., Methods: Four datasets were used: two to provide training and test data and two for the selection of robust radiomic features. All the datasets were downloaded from The Cancer Imaging Archive (TCIA). In two-dimensional cases, the Betti numbers consist of two values: b 0 (zero-dimensional Betti number), which is the number of isolated components, and b 1 (one-dimensional Betti number), which is the number of one-dimensional or "circular" holes. For homology-based evaluation, computed tomography (CT) images must be converted to binarized images in which each pixel has two possible values: 0 or 1. All CT slices of the gross tumor volume were used for calculating the homology histogram. First, by changing the threshold of the CT value (range: -150 to 300 HU) for all its slices, we developed homology-based histograms for b 0 , b 1 , and b 1 /b 0 using binarized images. All histograms were then summed, and the summed histogram was normalized by the number of slices. 144 homology-based radiomic features were defined from the histogram. To compare the standard radiomic features, 107 radiomic features were calculated using the standard radiomics technique. To clarify the prognostic power, the relationship between the values of the homology-based radiomic features and overall survival was evaluated using LASSO Cox regression model and the Kaplan-Meier method. The retained features with nonzero coefficients calculated by the LASSO Cox regression model were used for fitting the regression model. Moreover, these features were then integrated into a radiomics signature. An individualized rad score was calculated from a linear combination of the selected features, which were weighted by their respective coefficients., Results: When the patients in the training and test datasets were stratified into high-risk and low-risk groups according to the rad scores, the overall survival of the groups was significantly different. The C-index values for the homology-based features (rad score), standard features (rad score), and tumor size were 0.625, 0.603, and 0.607, respectively, for the training datasets and 0.689, 0.668, and 0.667 for the test datasets. This result showed that homology-based radiomic features had slightly higher prediction power than the standard radiomic features., Conclusions: Prediction performance using homology-based radiomic features had a comparable or slightly higher prediction power than standard radiomic features. These findings suggest that homology-based radiomic features may have great potential for improving the prognostic prediction accuracy of CT-based radiomics. In this result, it is noteworthy that there are some limitations., (© 2020 American Association of Physicists in Medicine.)

Background/aim: The aim of this multi-center retrospective study was to investigate the results of stereotactic body radiotherapy (SBRT) for pulmonary oligometastases from esophageal cancer., Patients and Methods: Oligometastases from the esophagus were identified from a dataset of a Japanese survey. The Kaplan-Meier method and Cox regression were applied to perform analyses., Results: A total of 114 patients with 132 pulmonary oligometastases were collected. The 3-year local control rate, freedom from further metastasis (FFFM) rate and overall survival (OS) rate were 70.2%, 25.3% and 37.5%, respectively. Performance status (PS) (PS 1 vs. PS 0, p<0.01), disease-free interval (p=0.03) and history of local therapy for metastasis (p=0.01) had significant relationships with FFFM and only PS was an independent prognostic factor for OS (PS 1 vs. PS 0, p=0.02; PS 2-3 vs. PS 0, p=0.04)., Conclusion: SBRT for pulmonary oligometastases from esophageal cancer provided good local control and survival., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: This study was performed to confirm the superior overall survival (OS) after pulmonary oligo-recurrence compared to pulmonary sync-oligometastases in a large nationwide study., Patients and Methods: Patients that met the following criteria were included: 1 to 5 lung-only metastases at the beginning of stereotactic body radiation therapy (SBRT) was performed between January 2004 and June 2015, and the biological effective dose (BED) of SBRT was 75 Gy or more. The parameters included in the analyses were age, gender, ECOG PS, primary lesion, pathology, oligoetastatic state, SBRT date, chemotherapy before SBRT, chemotherapy concurrent SBRT, chemotherapy after SBRT, maximum tumor diameter, number of metastases, field coplanarity, dose prescription, BED 10 , OTT of SBRT., Results: In total, 1,378 patients with 1,547 tumors were enrolled. Oligo-recurrence occurred in 1,016 patients, sync-oligometastases in 118, and unclassified oligometastases in 121. The three-year OS was 64.0% for oligo-recurrence and 47.5% for sync-oligometastasis (p<0.001). In the multivariate analysis, the hazard ratio (HR) for sync-oligometastases versus oligo-recurrence was 1.601 (p=0.014). Adverse events of Grade 5 were occurred in 3 patients., Conclusion: This is the first nationwide to indicate that the OS of patients with pulmonary oligo-recurrence is better than that of patients with sync-oligometastases., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Radiographic severity of radiation-induced lung injury (RILI) has not been well-studied. The goal of this study was to assess the CT appearance pattern and severity of RILI without consideration of the clinical presentation., Material and Methods: A total of 49 patients, 41 with primary lung cancer and 8 with metastatic lung cancer, were treated by 4-fraction stereotactic body radiotherapy (SBRT). RILI after SBRT was separately assessed by two observers. The early and late CT appearance patterns and CT-based severity grading were explored., Results: The median follow-up period was 39.0 months. In the early CT findings of observers 1 and 2, there was diffuse consolidation in 15 and 8, diffuse ground glass opacity (GGO) in 0 and 0, patchy consolidation and GGO in 17 and 20, patchy GGO in 3 and 3, and no changes in 10 and 14, respectively (kappa = 0.61). In late CT findings of observer 1 and 2, there were modified conventional pattern in 28 and 24, mass-like pattern in 8 and 11, scar-like pattern in 12 and 12, and no changes in 1 and 2, respectively (kappa = 0.63). In the results of the CT-based grading by observers 1 and 2, there were grade 0 in 1 and 2, grade 1 in 10 and 14, grade 2 in 31 and 29, grade 3 in 7 and 4, and none of grade 4 or more, respectively (kappa = 0.66). According to multivariate analyses (MVA), the significant predicting factors of grade 2 or more CT-based RILI were age (p = 0.01), oxygen dependence (p = 0.03) and interstitial shadow (p = 0.03)., Conclusions: The agreement of the CT appearance and CT-based grading between two observers was good. These indicators may be able to provide us with more objective information and a better understanding of RILI., Competing Interests: The authors have declared that no competing interests exist.

The purpose of this study is to evaluate the dosimetric impact of the margin on the multileaf collimator-based dynamic tumor tracking plan. Furthermore, an equivalent setup margin (EM) of the tracking plan was determined according to the gated plan. A 4-dimensional extended cardiac-torso was used to create 9 digital phantom datasets of different tumor diameters (TDs) of 1, 3, and 5 cm and motion ranges (MRs) of 1, 2, and 3 cm. For each dataset, respiratory gating (30% to 70% phase) and tumor tracking treatment plans were prepared using 8-field 3-dimensional conformal radiation therapy by 4-dimensional dose calculation. The total lung V20 was calculated to evaluate the dosimetric impact for each case and to estimate the EM with the same impact on lung V20 obtained with the gating plan with a setup margin of 5 mm. The EMs for {TD = 1 cm, MR = 1 cm}, {TD = 1 cm, MR = 2 cm}, and {TD = 1 cm, MR = 3 cm} were estimated as 5.00, 4.16, and 4.24 mm, respectively. The EMs for {TD = 5 cm, MR = 1 cm}, {TD = 5 cm, MR = 2 cm}, and {TD = 5 cm, MR = 3 cm} were estimated as 4.24 mm, 6.35 mm, and 7.49 mm, respectively. This result showed that with a larger MR, the EM was found to be increased. In addition, with a larger TD, the EM became smaller. Our result showing the EMs provided the desired accuracy for multileaf collimator-based dynamic tumor tracking radiotherapy., (Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to determine the prognostic factors of radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT)., Patients and Methods: A total of 50 patients (36 male and 14 female) were treated with SBRT for 42 primary lung cancers and 8 metastatic lung cancers. SBRT was performed with 48 Gy in 4 fractions to the isocenter or with 40 Gy in 4 fractions covering 95% of the planning target volume. Percentage of low attenuation area (%LAA) was defined as percentage of the lung area with attenuation of -860 Hounsfield units (HU) or lower (%LAA-860) or of -960 HU or lower (%LAA-960). The dosimetric parameter of V 20 Gy , which means percentage volume of the lung receiving 20 Gy or more, was recalculated. RP was assessed using Common Terminology Criteria for Adverse Events version 4.0., Results: The median follow-up period was 39.0 months (range, 7.2-94.5 months). RP of Grade 0, Grade 1, and Grade 2 to 3 was diagnosed in 11, 29, and 10 patients, respectively. Multivariate analyses (MVA) for Grade 1 showed that higher %LAA-860 and higher %LAA-960 were significantly associated with a lower rate of Grade 1 RP. MVA for Grade 2 to 3 showed that lower Brinkman index and lower lung V 20 Gy were significantly associated with a lower rate of Grade 2 to 3 RP, and, in contrast, %LAA-860 and %LAA-960 had no association with Grade 2 to 3 RP., Conclusion: This result suggests that high %LAA is associated with radiological changes (Grade 1) but that %LAA has no correlation with Grade 2 to 3 RP because symptomatic RP might also be affected by other factors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine whether pulmonary oligometastases from colorectal cancer have greater radioresistance than that of pulmonary oligometastases from other cancers and whether good local control can be achieved by dose escalation in stereotactic body radiotherapy., Materials and Methods: This systematic review and meta-analysis were conducted according to the preferred reporting items for systematic reviews and meta-analyses statement and methods. Studies were obtained from a database search of PubMed, Web of Science, and Google Scholar for publications using search terms designed to identify studies on "oligometastases," "lung," "stereotactic radiotherapy," and "colorectal cancer." For meta-analysis 1, studies that showed the number of local failures after stereotactic body radiotherapy for pulmonary metastases from colorectal carcinoma and other cancers were included. For meta-analysis2, studies in which a comparison was made of local control rates of pulmonary metastases from colorectal carcinoma by stereotactic body radiotherapy with a higher dose and that with a lower dose were included. A meta-analysis was performed using Mantel-Haenszel statics with the fixed or random-effect model by Review Manager 5.3., Results: Eighteen retrospective studies with 1920 patients with pulmonary oligometastases were used in meta-analysis 1. The local control rate in patients with pulmonary oligometastases from colorectal cancer was significantly lower than that in patients with pulmonary oligometastases from other cancers (odds ratio = 3.10, P < .00001). Next, 8 retrospective studies with 478 patients were included in meta-analysis 2 for dose escalation. Better local control was achieved by a higher prescription dose than by a lower prescription dose (odds ratio = 0.16, P < .00001)., Conclusion: Our meta-analysis indicated that local control of pulmonary oligometastases from colorectal cancer by stereotactic body radiotherapy was significantly worse than that of pulmonary metastases from other cancers; however, our results also indicated that good local control of pulmonary oligometastases from colorectal cancer can be achieved by dose escalation.

We evaluated the reproducibility and predictive value of texture parameters and existing parameters of 18F-FDG PET/CT images in Stage I non-small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). Twenty-six patients with Stage I NSCLC (T1-2N0M0) were retrospectively analyzed. All of the patients underwent an 18F-FDG PET/CT scan before treatment and were treated with SBRT. Each tumor was delineated using PET Edge (MIM Software Inc., Cleveland, OH), and texture parameters were calculated using open-source code CGITA. From 18F-FDG PET/CT images, three conventional parameters, including maximum standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG), and four texture parameters, including entropy and dissimilarity (derived from a co-occurrence matrix) and high-intensity large-area emphasis (HILAE) and zone percentage (derived from a size-zone matrix) were analyzed. Reproducibility was evaluated using two independent delineations conducted by two observers. The ability to predict local control (LC), progression-free survival (PFS) and overall survival (OS) was tested for each parameter. All of the seven parameters except zone percentage showed good reproducibility, with intraclass correlation coefficient values >0.8. In univariate analysis, only HILAE was a significant predictor for LC. Histology, dose fractionation, and maximum SUV were associated with PFS, and histology and dose fractionation were associated with OS. We showed that texture parameters derived from 18F-FDG PET/CT were reproducible and potentially beneficial for predicting LC in Stage I lung cancer patients treated with SBRT., (© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Aim: To evaluate the efficacy of stereotactic body radiotherapy (SBRT) for pulmonary metastasis from colorectal cancer., Patients and Methods: Data for 104 lesions from 93 patients who underwent SBRT for pulmonary oligometastases from colorectal cancer at ten Institutions were retrospectively analyzed. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0., Results: The median calculated biological effective dose using the linear-quadratic model with α/β of 10 Gy (BED10) was 105.6 Gy. Adjuvant chemotherapy after SBRT was performed in 47 patients. The median observation period was 28 months. The 3- and 5-year local control rates were 65.2% and 56.2%, respectively. The 3- and 5-year overall survival rates were 55.9% and 42.7%, respectively. Only two patients had grade 3 radiation pneumonitis. In multivariate analysis for local control, primary site, age, adjuvant chemotherapy after SBRT and BED10 were selected as prognostic factors., Conclusion: Dose escalation and adjuvant chemotherapy might improve local control in SBRT for pulmonary oligometastases from colorectal cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We evaluated the accuracy of an in-house program in lung stereotactic body radiation therapy (SBRT) cancer patients, and explored the prognostic factors associated with the accuracy of deformable image registrations (DIRs). The accuracy of the 3 programs which implement the free-form deformation and the B-spline algorithm was compared regarding the structures on 4-dimensional computed tomography (4DCT) image datasets between the peak-inhale and peak-exhale phases. The dice similarity coefficient (DSC) and normalized DSC (NDSC) were measured for the gross tumor volumes from 19 lung SBRT patients. We evaluated the accuracy of DIR using gross tumor volume, magnitude of displacement from 0% phase to 50% phase, whole lung volume in the 50% phase image, and status of tumor pleural attachment. The median NDSC values using the NiftyReg, MIM Maestro and Velocity AI programs were 1.027, 1.005, and 0.946, respectively, indicating that NiftyReg and MIM Maestro programs had similar accuracy with an uncertainty of < 1 mm. Larger uncertainty of 1 to 2 mm was observed using the Velocity AI program. The NiftyReg and the MIM programs provided higher NDSC values than the median values when the gross tumor volume was attached to the pleura (p <0.05). However, it showed a different trend in using the Velocity AI program. All software programs provided unexpected results, and there is a possibility that such results would reduce the accuracy of 4D treatment planning and adaptive radiotherapy. The unexpected results may be because the tumors are surrounded by other tissues, and there are differences regarding the region of interest for rigid and nonrigid registration. Furthermore, our results indicated that the pleural attachment status might be an important predictor of DIR accuracy for thoracic images, indicating that there is a potentially large dose distribution discrepancy concerning 4D treatment planning and adaptive radiotherapy., (Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to determine whether metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are associated with outcomes in Stage I lung cancer patients treated with stereotactic body radiation therapy (SBRT). Thirty-eight patients underwent [ 18 F] fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) within 60 days before SBRT at our institution between January 2001 and December 2011. The maximum standardized uptake value (SUV max ), MTV 2 , MTV 4 , MTV 6 , TLG 40% , TLG 50% and TLG 60% were calculated. Prognostic factors for overall survival (OS) and local control (LC) were analyzed using Cox's proportional hazards model, and survival curves were calculated using the Kaplan-Meier method. Receiver operating characteristics (ROC) curves of PET parameters for OS and LC were calculated. The median follow-up period for survivors was 37.7 months. Three-year OS and LC rates were 56.4% and 70.5%, respectively, and 5-year OS and LC rates were 36.8% and 70.5%, respectively. In univariate analyses, tumor diameter (P = 0.019), single dose ≥10 Gy (P = 0.017), MTV 2 (P = 0.030) and MTV 4 (P = 0.048) were significant predictors for OS. Tumor diameter (P < 0.001), single dose ≥10 Gy (P = 0.007), SUV max (P = 0.035), MTV 2 (P < 0.001), MTV 4 (P = 0.003), MTV 6 (P = 0.017), TLG 40% (P < 0.001), TLG 50% (P = 0.001) and TLG 60% (P = 0.003) were significant predictors for LC. SUVmax was not a significant predictor for OS. We made the ROC curves at PET parameters, and the largest area under the curve value for OS was MTV 2 and for LC was TLG 40% Tumor diameter, single dose ≥10 Gy, MTV2 and MTV 4 are prognostic factors for OS and LC rates and MTV 2 is a better prognostic factor for OS than other PET parameters., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: To 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)., Methods: Patients 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) ≥70., Results: The median overall survival (OS) of all 61 patients was 26 months (95 % CI: 17.5-34.5 months). The 2-year and 5-year overall survival rates were 60.7 and 15.7 %, respectively. Stratified by oligostatus, the sync-oligometastases group achieved a median OS of 18 months (95 % CI: 14.8-21.1 months) and a 5-year OS of 0 %, while the oligo-recurrence group achieved a median OS of 41 months (95 % CI: 27.8-54.2 months) and a 5-year OS of 18.6 %. 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) (p = 0.025)., Conclusions: The presence of oligo-recurrence can predict a favorable prognosis of brain-only oligometastases in patients with NSCLC treated with SRS or SRT.

Background: Oligometastases can be divided into sync-oligometastases and oligo-recurrence. The difference is whether the primary site is uncontrolled or controlled. The goal of this multicenter study was to evaluate treatment outcomes and factors affecting survival after stereotactic body radiotherapy for pulmonary oligometastases., Methods: The information after stereotactic body radiotherapy from January 2004 to April 2014 was retrospectively collected. Ninety-six patients (65 males, 31 females) were enrolled. Ten cases (10%) were sync-oligometastases, 79 cases (82%) were oligo-recurrences and 7 (7%) were unclassified oligometastases with <6 months of disease-free interval. The median disease-free interval between initial therapy and stereotactic body radiotherapy was 24 months. The median calculated biological effective dose was 105.6 Gy., Results: The median follow-up period was 32 months for survivors. The 3-year overall survival and relapse-free survival rates were 53% and 32%, respectively. No Grade 5 toxicity occurred. The median overall survival was 23.9 months for sync-oligometastases and 66.6 months for oligo-recurrence (P = 0.0029). On multivariate analysis, sync-oligometastases and multiple oligometastatic tumors were significant unfavorable factors for both overall survival and relapse-free survival., Conclusions: In stereotactic body radiotherapy for oligometastatic lung tumors, the state of oligo-recurrence has the potential of a significant prognostic factor for survival., (© The Author 2016. Published by Oxford University Press.)

Purpose: To evaluate four-dimensional computed tomography (4D-CT)-derived pulmonary ventilation by comparing with (81m)Kr-gas ventilation (VRI). We also proposed two methods to improve the functional accuracy of 4D-CT ventilation images and evaluated these methods., Methods and Materials: Eleven lung cancer patients with 4D-CT and VRI were analyzed. Hounsfield unit-based (VHU) and a Jacobian-based (VJac) 4D-CT ventilation images were calculated. They were evaluated by voxel-by-voxel spearman's rank correlation coefficient (r) between 4D-CT ventilation and VRI images. After applying an averaging ventilation method and a slope calculating method, correlations were also calculated., Results: 4D-CT ventilation showed the high correlation to VRI (r=0.875 with VHU). An averaging method brought significantly higher (p=0.012) correlations to nuclear medicine images with VHU. The improvement was not significant (p=0.619) with VJac. Slope calculating method improved the correlation with VHU and slightly worsened the correlation with VJac., Conclusions: The averaging method we proposed might be useful to improve 4D-CT ventilation images. We found good agreement between 4D-CT ventilation and nuclear medicine ventilation, indicating the high physiologic accuracy of 4D-CT ventilation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Proton beam therapy (PBT) is the preferred modality for early-stage lung cancer. Compared with X-ray therapy, PBT offers good dose concentration as revealed by the characteristics of the Bragg peak. Rib fractures (RFs) after PBT lead to decreased quality of life for patients. However, the incidence of and the risk factors for RFs after PBT have not yet been clarified. We therefore explored the relationship between irradiated rib volume and RFs after PBT for early-stage lung cancer. The purpose of this study was to investigate the incidence and the risk factors for RFs following PBT for early-stage lung cancer. We investigated 52 early-stage lung cancer patients and analyzed a total of 215 irradiated ribs after PBT. Grade 2 RFs occurred in 12 patients (20 ribs); these RFs were symptomatic without displacement. No patient experienced more severe RFs. The median time to grade 2 RFs development was 17 months (range: 9-29 months). The three-year incidence of grade 2 RFs was 30.2%. According to the analysis comparing radiation dose and rib volume using receiver operating characteristic curves, we demonstrated that the volume of ribs receiving more than 120 Gy3 (relative biological effectiveness (RBE)) was more than 3.7 cm(3) at an area under the curve of 0.81, which increased the incidence of RFs after PBT (P < 0.001). In this study, RFs were frequently observed following PBT for early-stage lung cancer. We demonstrated that the volume of ribs receiving more than 120 Gy3 (RBE) was the most significant parameter for predicting RFs.

Pulmonary sarcomatoid carcinoma is a rare subtype of non-small cell lung cancer with a poor prognosis. We herein report on a case of pulmonary sarcomatoid carcinoma that was treated successfully by concurrent chemoradiotherapy. A 65-year-old man was diagnosed to have pulmonary pleomorphic carcinoma (clinical T4N2M0 stage IIIB). He received concurrent chemoradiotherapy (60 Gy of radiotherapy in 30 fractionations and two courses of chemotherapy with carboplatin and paclitaxel). After chemoradiotherapy, a significant reduction of the tumor size was observed. Two courses of adjuvant chemotherapy were performed. He is currently alive at 15 months after the first treatment without any recurrence or metastasis.

Objective: It is known that the partial volume effect and respiratory motion blur affect quantitative parameters such as the maximum standardized uptake value (SUVmax) in FDG-PET, especially in small lesions. The purpose of this study was to assess the prognostic value of corrected SUVmax, which was corrected SUVmax for the partial volume effect and respiratory motion blur, in patients with stage I non-small cell lung cancer (NSCLC) after treatment with stereotactic body radiotherapy (SBRT)., Methods: Fifty-one patients who were treated with SBRT between 2005 and 2011 in our institute were enrolled. The median tumor diameter was 2.2 cm (range 0.9-3.9 cm). The prescribed dose was typically 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions to the isocenter of irradiation fields. Each raw SUVmax was corrected using the recently proposed formula, and the correlations of raw SUVmax and corrected SUVmax with local control rate (LCR) were analyzed retrospectively., Results: Median raw SUVmax before SBRT was 6.4 (range 0.6-22.8). Median corrected SUVmax was 8.0 (range 0.8-22.8), which was significantly increased (p < 0.01). The median follow-up period for survivors was 45.3 months (range 18.5-82.0 months). The 3-year LCR and overall survival rates were 81.8 and 65.2 %, respectively. In univariate analysis, raw SUVmax [per 1 increase; p = 0.02, hazard ratio (HR) 1.20, 95 % confidence interval (CI) 1.03-1.42] was significantly correlated with LCR, but corrected SUVmax did not show a significant correlation with LCR (per 1 increase; p = 0.15, HR 1.07, 95 % CI 0.96-1.19). Other factors significantly correlated with LCR were diagnosis (pathological diagnosis vs. clinical diagnosis; p = 0.04, HR 6.17, 95 % CI 1.08-116) and tumor diameter (per 1 mm increase; p < 0.01, HR 1.33, 95 % CI 1.15-1.61)., Conclusions: Tumor diameter was the most significant predictor of LCR after SBRT. Correction for the partial volume effect and respiratory motion blur may weaken the prognostic value of SUVmax.

Background: Pleural invasion status is known to be a predictor of survival after pulmonary resection for non-small cell lung cancer. Our goal was to determine whether the length of tumor attachment to the pleura on a pretreatment CT image has prognostic value as an alternative to pleural invasion status for stage I non-small cell lung cancer treated with stereotactic body radiotherapy (SBRT)., Methods: A total of 90 tumors in 87 patients (males: 68, females: 19) who received SBRT between March 2005 and September 2011 in our institution were reviewed. The median age of the patients was 78 years (range, 48-90 years). The median tumor diameter was 2.2 cm (range, 0.9-4.2 cm). The prescribed dose was typically 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions to the isocenter with 6 MV X-ray using 4 non-coplanar and 3 coplanar static beams. The lengths of attachment were measured using pretreatment CT images at the lung window. Cumulative incidence rates were calculated using Kaplan-Meier curves, and univariate and multivariate analyses for in-field tumor control, locoregional control (LRC), freedom from distant metastasis and freedom from progression (FFP) were performed using a Cox proportional hazards model., Results: Of the 90 tumors, 42 tumors were attached to the pleura (median, 14.7 mm; range, 4.3-36.0 mm), 21 tumors had pleural indentation and 27 tumors had no attachment. The median follow-up period for survivors was 46.1 months. The 3-year in-field control, LRC, FFP and overall survival rates were 91.2%, 75.3%, 63.8% and 68.6%, respectively. SBRT dose and tumor diameter were independently significant predictors of in-field control (p = 0.02 and p = 0.04, respectively). Broad attachment to the pleura, the length being more than 14.7 mm, was a negative independent predictor of LRC and FFP (p = 0.02 and p = 0.01, respectively)., Conclusions: Pleural attachment status on a pretreatment CT image might be an important predictor of LRC and FFP.

Deformable image registration (DIR) is fundamental technique for adaptive radiotherapy and image-guided radiotherapy. However, further improvement of DIR is still needed. We evaluated the accuracy of B-spline transformation-based DIR implemented in elastix. This registration package is largely based on the Insight Segmentation and Registration Toolkit (ITK), and several new functions were implemented to achieve high DIR accuracy. The purpose of this study was to clarify whether new functions implemented in elastix are useful for improving DIR accuracy. Thoracic 4D computed tomography images of ten patients with esophageal or lung cancer were studied. Datasets for these patients were provided by DIR-lab (dir-lab.com) and included a coordinate list of anatomical landmarks that had been manually identified. DIR between peak-inhale and peak-exhale images was performed with four types of parameter settings. The first one represents original ITK (Parameter 1). The second employs the new function of elastix (Parameter 2), and the third was created to verify whether new functions improve DIR accuracy while keeping computational time (Parameter 3). The last one partially employs a new function (Parameter 4). Registration errors for these parameter settings were calculated using the manually determined landmark pairs. 3D registration errors with standard deviation over all cases were 1.78 (1.57), 1.28 (1.10), 1.44 (1.09) and 1.36 (1.35) mm for Parameter 1, 2, 3 and 4, respectively, indicating that the new functions are useful for improving DIR accuracy, even while maintaining the computational time, and this B-spline-based DIR could be used clinically to achieve high-accuracy adaptive radiotherapy., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: The goal of this study was to determine the prognostic factors associated with an improved overall outcome after stereotactic body radiotherapy (SBRT) for primary lung cancer and metastatic lung tumors., Methods: A total of 229 lung tumors in 201 patients were included in the study. SBRT of 45 Gy in 3 fractions, 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions was typically used to treat 172 primary lungs cancer in 164 patients and 57 metastatic lung tumors in 37 patients between January 2001 and December 2011. Prognostic factors for local control (LC) and overall survival (OS) were analyzed using a Cox proportional hazards model., Results: The median biologically effective dose was 105.6 Gy based on alpha/beta = 10 (BED10). The median follow-up period was 41.9 months. The 3-year LC and OS rates were 72.5% and 60.9%, and the 5-year LC and OS rates were 67.8% and 38.1%, respectively. Radiation pneumonitis of grades 2, 3 and 5 occurred in 22 patients, 6 patients and 1 patient, respectively. Multivariate analyses revealed that tumor origin (primary lung cancer or metastatic lung tumor, p < 0.001), tumor diameter (p = 0.005), BED10 (p = 0.029) and date of treatment (p = 0.011) were significant independent predictors for LC and that gender (p = 0.012), tumor origin (p = 0.001) and tumor diameter (p < 0.001) were significant independent predictors for OS., Conclusions: SBRT resulted in good LC and tolerable treatment-related toxicities. Tumor origin and tumor diameter are significant independent predictors for both overall survival and local control.

Background: The purpose of this study is to investigate the prognostic factors of stereotactic radiotherapy for stage I NSCLC to improve outcomes., Methods: Stage I non-small cell lung cancer patients who were treated with stereotactic radiotherapy between 2005 and 2009 at our hospital were enrolled in this study. The primary endpoint was local control rate. Survival estimates were calculated from the completion date of radiotherapy using the Kaplan-Meier method. The prognostic factors including patients' characteristics and dose-volume histogram parameters were evaluated using Cox's proportional hazard regression model., Results: Eighty patients (81 lesions) treated with 3 dose levels, 48 Gy/4 fractions, 60 Gy/8 fractions and 60 Gy/15 fractions, were enrolled in this study. Median follow-up was 30.4 months (range, 0.3 - 78.5 months). A Cox regression model showed T factor (p = 0.013), biological effective dose calculated from prescribed dose (BED10) (p = 0.048), and minimum dose for PTV (p = 0.013) to be prognostic factors for local control. Three-year overall survival rate and local control rate were 89.9% (T1: 86.8%, T2: 100%) and 89.0% (T1: 97.9%; T2: 64.8%), respectively. When the 3-year local control rates were examined by prescribed doses, they were 100% for the dose per fraction of 48 Gy /4 fractions (105.6 Gy BED10), 82.1% for 60 Gy/8 fractions (105 Gy BED10), and 57.1% for 60 Gy/15 fractions (84 Gy BED10). The median value of the minimum dose for PTV (%) was 89.88 (%), and the 3-year local control rates were 100% in those with the minimum dose for PTV (%) ≥ 89.88% and 79.2% in those with the minimum dose for PTV (%) < 89.88%., Conclusions: Our results suggest that T factor, BED10, and minimum dose for PTV influence the local control rate. Local control rate can be improved by securing the minimum dose for PTV.

Background and Purpose: The outcome of stage I non-small cell lung cancer (NSCLC) patients treated with conventional radiotherapy is inferior to that of patients treated surgically. We aimed to evaluate the clinical outcome of stereotactic body radiotherapy (SBRT) in the treatment of stage I NSCLC., Materials and Methods: We performed SBRT for 31 stage I NSCLC patients. Of these, 20 were medically inoperable, and 11 refused surgery. Nineteen tumours were T1-stage masses, and 12 tumours were T2. Median tumour size was 25 mm. SBRT was administered as 45 Gy/3 fractions; however, when the tumour was close to an organ at risk, 60 Gy/8 fractions were used. These doses were prescribed at the centre of the tumours., Results: The median duration of observation for all patients was 32 months (range, 4-87 months). In 9 of the 31 cases, local recurrence was observed. The 3-year local control rates of T1 and T2 tumours were 77.9% and 40.0%, respectively. The 3-year overall and cause-specific survival rates were 71.7% and 83.5%, respectively. Although the symptoms improved with medical treatment, 5 patients developed acute pulmonary toxicity > or =grade 2., Conclusions: SBRT is safe and effective for stage I NSCLC patients. However, a more intensive treatment regimen should be considered for T2 tumours.

Unlabelled: 18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxia imaging agent for positron emission tomography. This compound was synthesized by 18F-labeling of RP170, which was developed as a new hydrophilic 2-nitroimidazole analog. In the present study, we analyzed dynamic whole-body imaging in healthy volunteers and dynamic tumor imaging in three patients with lung cancer., Methods: Four healthy male volunteers and three lung cancer patients were enrolled in this study. Volunteers underwent dynamic whole-body scans just after injection of 18F-FRP170 for about 90 min, while the lung cancer patients underwent dynamic tumor imaging for about 60 or 120 min. Data are expressed as standardized uptake values (SUV). Regions of interest were placed over images of each organ or tumor to generate time-SUV curves., Results: The series of dynamic whole-body scans showed rapid elimination of 18F-FRP170 from the kidneys following elimination from the liver. Very low physiological uptake was observed above the diaphragm. 18F-FRP170 uptake in the lung cancer lesion could be visualized clearly from early after injection. The changes of tumor SUV, tumor/blood ratio, or tumor/muscle ratio about 30 min after injection or later were small., Conclusions: Dynamic imaging using 18F-FRP170 demonstrated rapid elimination from the kidney, suggesting the high hydrophilicity of this imaging agent. The background activity above the diaphragm was very low, and patients with lung cancer showed clear tumor uptake of 18F-FRP170 early after injection.

A 62-year-old male patient was admitted for spontaneous rupture of hepatocellular carcinoma. He also had multiple lung metastases and liver dysfunction. So neither operation nor trans-arterial embolization could be performed. He had been administered UFT (400 mg/day) orally every day. After 5 months of daily administration, there was complete disappearance of multiple lung metastasis and reduction of the primary tumor. This case suggests that UFT is effective for some advanced hepatocellular carcinoma with extrahepatic metastasis.