Chest wall pain after single-fraction thoracic stereotactic ablative Radiotherapy: Dosimetric analysis from the iSABR trial.

BACKGROUND AND PURPOSE: Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk. MATERIALS AND METHODS: This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting. RESULTS: There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V11Gy) and the minimum dose to the hottest 2 cc (D2cc) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D2cc > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V11Gy > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall. CONCLUSION: For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients.

A Single-Institution Prospective Study To Evaluate the Safety and Efficacy of Real- Time Image-Gated Spot-Scanning Proton Therapy (RGPT) for Prostate Cancer.

Purpose: In real-time image-gated spot-scanning proton therapy (RGPT), the dose distribution is distorted by gold fiducial markers placed in the prostate. Distortion can be suppressed by using small markers and more than 2 fields, but additional fields may increase the dose to organs at risk. Therefore, we conducted a prospective study to evaluate the safety and short-term clinical outcome of RGPT for prostate cancer. Methods and Materials: Based on the previously reported frequency of early adverse events (AE) and the noninferiority margin of 10%, the required number of cases was calculated to be 43 using the one-sample binomial test by the Southwest Oncology Group statistical tools with the one-sided significance level of 2.5% and the power 80%. Patients with localized prostate cancer were enrolled and 3 to 4 pure gold fiducial markers of 1.5-mm diameter were inserted in the prostate. The prescribed dose was 70 Gy(relative biologic effectiveness) in 30 fractions, and treatment was performed with 3 fields from the left, right, and the back, or 4 fields from either side of slightly anterior and posterior oblique fields. The primary endpoint was the frequency of early AE (≥grade 2) and the secondary endpoint was the biochemical relapse-free survival rate and the frequency of late AE. Results: Forty-five cases were enrolled between 2015 and 2017, and all patients completed the treatment protocol. The median follow-up period was 63.0 months. The frequency of early AE (≥grade 2) was observed in 4 cases (8.9%), therefore the noninferiority was verified. The overall 5-year biochemical relapse-free survival rate was 88.9%. As late AE, grade 2 rectal bleeding was observed in 8 cases (17.8%). Conclusions: The RGPT for prostate cancer with 1.5-mm markers and 3- or 4- fields was as safe as conventional proton therapy in early AE, and its efficacy was comparable with previous studies.

Probability of normal tissue complications for hematologic and gastrointestinal toxicity in postoperative whole pelvic radiotherapy for gynecologic malignancies using intensity-modulated proton therapy with robust optimization.

This retrospective treatment-planning study was conducted to determine whether intensity-modulated proton therapy with robust optimization (ro-IMPT) reduces the risk of acute hematologic toxicity (H-T) and acute and late gastrointestinal toxicity (GI-T) in postoperative whole pelvic radiotherapy for gynecologic malignancies when compared with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated X-ray (IMXT) and single-field optimization proton beam (SFO-PBT) therapies. All plans were created for 13 gynecologic-malignancy patients. The prescribed dose was 45 GyE in 25 fractions for 95% planning target volume in 3D-CRT, IMXT and SFO-PBT plans and for 99% clinical target volume (CTV) in ro-IMPT plans. The normal tissue complication probability (NTCP) of each toxicity was used as an in silico surrogate marker. Median estimated NTCP values for acute H-T and acute and late GI-T were 0.20, 0.94 and 0.58 × 10-1 in 3D-CRT; 0.19, 0.65 and 0.24 × 10-1 in IMXT; 0.04, 0.74 and 0.19 × 10-1 in SFO-PBT; and 0.06, 0.66 and 0.15 × 10-1 in ro-IMPT, respectively. Compared with 3D-CRT and IMXT plans, the ro-IMPT plan demonstrated significant reduction in acute H-T and late GI-T. The risk of acute GI-T in ro-IMPT plan is equivalent with IMXT plan. The ro-IMPT plan demonstrated potential clinical benefits for reducing the risk of acute H-T and late GI-T in the treatment of gynecologic malignances by reducing the dose to the bone marrow and bowel bag while maintaining adequate dose coverage to the CTV. Our results indicated that ro-IMPT may reduce acute H-T and late GI-T risk with potentially improving outcomes for postoperative gynecologic-malignancy patients with concurrent chemotherapy.

Real-time tumor-tracking radiotherapy with SyncTraX for primary liver tumors requiring isocenter shift†.

The SyncTraX series enables real-time tumor-tracking radiotherapy through the real-time recognition of a fiducial marker using fluoroscopic images. In this system, the isocenter should be located within approximately 5-7.5 cm from the marker, depending on the version, owing to the limited field of view. If the marker is placed away from the tumor, the isocenter should be shifted toward the marker. This study aimed to investigate stereotactic body radiotherapy (SBRT) outcomes of primary liver tumors treated with SyncTraX in cases where the isocenter was shifted marginally or outside the planning target volume (PTV). Twelve patients with 13 liver tumors were included in the analysis. Their isocenter was shifted toward the marker and was placed marginally or outside the PTV. The prescribed doses were generally 40 Gy in four fractions or 48 Gy in eight fractions. The overall survival (OS) and local control (LC) rates were calculated using the Kaplan-Meier method. All patients completed the scheduled SBRT. The median distance between the fiducial marker and PTV centroid was 56.0 (interquartile range [IQR]: 52.7-66.7) mm. By shifting the isocenter toward the marker, the median distance between the marker and isocenter decreased to 34.0 (IQR: 33.4-39.7) mm. With a median follow-up period of 25.3 (range: 6.9-70.0) months, the 2-year OS and LC rates were 100.0% (95% confidence interval: 100-100). An isocenter shift makes SBRT with SyncTraX feasible in cases where the fiducial marker is distant from the tumor.

Predicting the daily gastrointestinal doses of stereotactic body radiation therapy for pancreatic cancer based on the shortest distance between the tumor and the gastrointestinal tract using daily computed tomography images.

Objectives: We aimed to investigate whether daily computed tomography (CT) images could predict the daily gastroduodenal, small intestine, and large intestine doses of stereotactic body radiation therapy (SBRT) for pancreatic cancer based on the shortest distance between the gross tumor volume (GTV) and gastrointestinal (GI) tract. Methods: Twelve patients with pancreatic cancer received SBRT of 40 Gy in five fractions. We recalculated the reference clinical SBRT plan (PLANref) using daily CT images and calculated the shortest distance from the GTV to each GI tract. The maximum dose delivered to 0.5 cc (D0.5cc) was evaluated for each planning at-risk volume of the GI tract. Spearman's correlation test was used to determine the association between the daily change in the shortest distance (Δshortest distance) and the ratio of ΔD0.5cc dose to D0.5cc dose in PLANref (ΔD0.5cc/PLANref) for quantitative analysis. Results: The median shortest distance in PLANref was 0 mm in the gastroduodenum (interquartile range, 0-2.7), 16.7 mm in the small intestine (10.0-23.7), and 16.7 mm in the large intestine (8.3-28.1 mm). The D0.5cc of PLANref in the gastroduodenum was >30 Gy in all patients, with 10 (83.3%) having the highest dose. A significant association was found between the Δshortest distance and ΔD0.5cc/ PLANref in the small or large intestine (p < 0.001) but not in the gastroduodenum (p = 0.404). Conclusions: The gastroduodenum had a higher D0.5cc and predicting the daily dose was difficult. Daily dose calculations of the GI tract are recommended for safe SBRT. Advances in knowledge: This study aimed to predict the daily doses in SBRT for pancreatic cancer from the shortest distance between the GTV and the gastrointestinal tract.Daily changes in the shortest distance can predict the daily dose to the small or large intestines, but not to the gastroduodenum.

Real-World Results of Stereotactic Body Radiotherapy for 399 Medically Operable Patients with Stage I Histology-Proven Non-Small Cell Lung Cancer.

Surgery is the standard treatment for stage I non-small cell lung cancer (NSCLC); however, no clear randomized trial demonstrates its superiority to stereotactic body radiotherapy (SBRT) regarding survival. We aimed to retrospectively evaluate the treatment outcomes of SBRT in operable patients with stage I NSCLC using a large Japanese multi-institutional database to show real-world outcome. Exactly 399 patients (median age 75 years; 262 males and 137 females) with stage I (IA 292, IB 107) histologically proven NSCLC (adenocarcinoma 267, squamous cell carcinoma 96, others 36) treated at 20 institutions were reviewed. SBRT was prescribed at a total dose of 48-70 Gy in 4-10 fractions. The median follow-up period was 38 months. Local progression-free survival rates were 84.2% in all patients and 86.1% in the T1, 78.6% in T2, 89.2% in adenocarcinoma, and 70.5% in squamous cell subgroups. Overall 3-year survival rates were 77.0% in all patients: 90.7% in females, 69.6% in males, and 41.2% in patients with pulmonary interstitial changes. Fatal radiation pneumonitis was observed in two patients, all of whom had pulmonary interstitial changes. This real-world evidence will be useful in shared decision-making for optimal treatment, including SBRT for operable stage I NSCLC, particularly in older patients.

Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial.

Importance: Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy. Objective: To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control. Design, Setting, and Participants: This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3). Intervention: Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3. Main outcome: Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up. Results: In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01463423.

Clinical results of proton beam radiotherapy for inoperable stage III non-small cell lung cancer: a Japanese national registry study.

This study presents the first data of a Japanese nationwide multi-institutional cohort and compares them with the findings of systematic literature reviews on radiation therapies and inoperable stage III non-small cell lung cancer (NSCLC) conducted by the Lung Cancer Working Group in the Particle Beam Therapy (PBT) Committee and Subcommittee at Japanese Society for Radiation Oncology. The Lung Cancer Working Group extracted eight reports and compared their data with those of the PBT registry from May 2016 to June 2018. All the analyzed 75 patients aged ≤80 years underwent proton therapy (PT) with concurrent chemotherapy for inoperable stage III NSCLC. The median follow-up period of the surviving patients was 39.5 (range, 1.6-55.6) months. The 2- and 3-year overall survival (OS) and progression-free survival rates were 73.6%/64.7% and 28.9%/25.1%, respectively. During the follow-up period, six patients (8.0%) had adverse events of Grade ≥ 3, excluding abnormal laboratory values. These included esophagitis in four patients, dermatitis in one and pneumonitis in one. Adverse events of Grade ≥ 4 were not observed. The results of these PBT registry data in patients with inoperable stage III NSCLC suggest that the OS rate was at least equivalent to that of radiation therapy using X-rays and that the incidence of severe radiation pneumonitis was low. PT may be an effective treatment to reduce toxicities of healthy tissues, including the lungs and heart, in patients with inoperable stage III NSCLC.

Analysis of particle therapy registries based on a unified treatment policy for esophageal cancer.

This study aimed to evaluate the efficacy and safety of particle therapy (proton beam therapy and carbon-ion radiotherapy) for esophageal cancer by analyzing prospective nationwide registry data from particle therapy facilities throughout Japan. Patients diagnosed with esophageal cancer who received particle therapy between May 2016 and June 2018 were recruited from the registries of 12 particle therapy centers in Japan. Eventually, we enrolled 174 patients who met the inclusion criteria. Of the 174 patients, 137 (78.7%) were male, with a median age of 69 years (range: 41-88 years). Clinical stages included I (n = 55; 31.6%), II (n = 31; 17.8%), III (n = 82; 47.1%), IV (n = 3; 1.7%) and unknown (n = 3; 1.7%) (Union for International Cancer Control, seventh edition), and the median follow-up period was 908 days (range: 76-1669 days) for all patients. The 3-year overall survival (OS) rate, the 3-year progression-free survival (PFS) rate and the 3-year local control (LC) rates were 60.5, 53.2 and 72.7%, respectively. For each clinical stage, the 3-year OS rates were I, 84.8%; II, 60.3% and III, 42.9%; the 3-year PFS rates were I, 71.9%; II, 58.3% and III, 37.0% and the 3-year LC were I, 78.4%; II, 79.8% and III, 65.2%, respectively. Notably, four patients (2.3%) with ≥Grade 3 cardiopulmonary toxicities were observed (Common Terminology Criteria for Adverse Events, version 5.0). Our study showed that particle therapy for esophageal cancer has lower rates of adverse cardiopulmonary events than X-ray radiotherapy.

Particle beam therapy for pelvic recurrence of colorectal cancer: a registry data analysis in Japan and a systematic review.

The aim of this study was to investigate the efficacy and safety of particle beam therapy (PBT) with proton or carbon ion beam for pelvic recurrence of colorectal cancer (PRCC) by comparing the clinical outcomes of a dataset of prospectively enrolled patients for PBT with those from the literature, which were collected by a systematic review of external X-ray radiotherapy (XRT) and PBT. Patients with PRCC treated at 14 domestic facilities between May 2016 and June 2019 and entered the database for prospective observational follow-up were analyzed. The registry data analyzed included 159 PRCC patients treated with PBT of whom 126 (79%) were treated with carbon ion radiation therapy (CIRT). The 3-year overall survival and local control rate were 81.8 and 76.4%, respectively. Among these PRCC patients, 5.7% had Grade 3 or higher toxicity. Systematic search of PubMed and Cochrane databases published from January 2000 to September 2020 resulted in 409 abstracts for the primary selection. Twelve studies fulfilled the inclusion criteria. With one additional publication, 13 studies were selected for qualitative analysis, including 9 on XRT and 4 on PBT. There were nine XRT studies, which included six on 3D conformal radiotherapy and three on stereotactic body radiation therapy, and four PBT studies included three on CIRT and one on proton therapy. A pilot meta-analysis using literatures with median survival time extractable over a 20-month observation period suggested that PBT, especially CIRT, may be a promising treatment option for PRCC not amenable to curative resection.

Brain metastases in Japanese NSCLC patients: prognostic assessment and the use of osimertinib and immune checkpoint inhibitors-retrospective study.

BACKGROUND: The Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed. METHODS: We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results. RESULTS: The median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months). CONCLUSIONS: We confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.

Study of hepatic toxicity in small liver tumors after photon or proton therapy based on factors predicting the benefits of proton.

OBJECTIVES: In a previous study of hepatic toxicity, the following three factors were identified to predict the benefits of proton beam therapy (PBT) for hepatocellular carcinomas (HCCs) with a maximum diameter of ≤5 cm and Child-pugh grade A (CP-A): number of tumors (1 vs ≥2), the location of tumors (hepatic hilum or others), and the sum of the diameters of lesions. The aim of this study is to analyze the association between these three factors and hepatic toxicity. METHODS: We retrospectively reviewed patients of CP-A treated with PBT or photon stereotactic body radiotherapy (X-ray radiotherapy, XRT) for HCC ≤5 cm. For normal liver dose, the V5, V10, V20 (volumes receiving 5, 10, and 20 Gy at least), and the mean dose was evaluated. The albumin-bilirubin (ALBI) and CP score changes from the baseline were evaluated at 3 and 6 months after treatment. RESULTS: In 89 patients (XRT: 48, PBT: 41), those with two or three (2-3) predictive factors were higher normal liver doses than with zero or one (0-1) factor. In the PBT group, the ALBI score worsened more in patients with 2-3 factors than those with 0-1 factor, at 3 months (median: 0.26 vs 0.02, p = 0.032) and at 6 months (median: 0.35 vs 0.10, p = 0.009). The ALBI score change in the XRT group and CP score change in either modality were not significantly different in the number of predictive factors. CONCLUSION: The predictive factor numbers predicted the ALBI score change in PBT but not in XRT. ADVANCES IN KNOWLEDGE: This study suggest that the number of predictive factors previously identified (0-1 vs 2-3) were significantly associated with dosimetric parameters of the normal liver in both modalities. In the proton group, the number of predictive factors was associated with a worsening ALBI score at 3 and 6 months, but these associations were not found in the photon SBRT group.

Evaluation of short-term gastrointestinal motion and its impact on dosimetric parameters in stereotactic body radiation therapy for pancreatic cancer.

Background: The aim of this study is to quantify the short-term motion of the gastrointestinal tract (GI-tract) and its impact on dosimetric parameters in stereotactic body radiation therapy (SBRT) for pancreatic cancer. Methods: The analyzed patients were eleven pancreatic cancer patients treated with SBRT or proton beam therapy. To ensure a fair analysis, the simulation SBRT plan was generated on the planning CT in all patients with the dose prescription of 40 Gy in 5 fractions. The GI-tract motion (stomach, duodenum, small and large intestine) was evaluated using three CT images scanned at spontaneous expiration. After fiducial-based rigid image registration, the contours in each CT image were generated and transferred to the planning CT, then the organ motion was evaluated. Planning at risk volumes (PRV) of each GI-tract were generated by adding 5 mm margins, and the volume receiving at least 33 Gy (V33) < 0.5 cm3 was evaluated as the dose constraint. Results: The median interval between the first and last CT scans was 736 s (interquartile range, IQR:624-986). To compensate for the GI-tract motion based on the planning CT, the necessary median margin was 8.0 mm (IQR: 8.0-10.0) for the duodenum and 14.0 mm (12.0-16.0) for the small intestine. Compared to the planned V33 with the worst case, the median V33 in the PRV of the duodenum significantly increased from 0.20 cm3 (IQR: 0.02-0.26) to 0.33 cm3 (0.10-0.59) at Wilcoxon signed-rank test (p = 0.031). Conclusion: The short-term motions of the GI-tract lead to high dose differences.

Technical note: Performance evaluation of volumetric imaging based on motion modeling by principal component analysis.

PURPOSE: To quantitatively evaluate the achievable performance of volumetric imaging based on lung motion modeling by principal component analysis (PCA). METHODS: In volumetric imaging based on PCA, internal deformation was represented as a linear combination of the eigenvectors derived by PCA of the deformation vector fields evaluated from patient-specific four-dimensional-computed tomography (4DCT) datasets. The volumetric image was synthesized by warping the reference CT image with a deformation vector field which was evaluated using optimal principal component coefficients (PCs). Larger PCs were hypothesized to reproduce deformations larger than those included in the original 4DCT dataset. To evaluate the reproducibility of PCA-reconstructed volumetric images synthesized to be close to the ground truth as possible, mean absolute error (MAE), structure similarity index measure (SSIM) and discrepancy of diaphragm position were evaluated using 22 4DCT datasets of nine patients. RESULTS: Mean MAE and SSIM values for the PCA-reconstructed volumetric images were approximately 80 HU and 0.88, respectively, regardless of the respiratory phase. In most test cases including the data of which motion range was exceeding that of the modeling data, the positional error of diaphragm was less than 5 mm. The results suggested that large deformations not included in the modeling 4DCT dataset could be reproduced. Furthermore, since the first PC correlated with the displacement of the diaphragm position, the first eigenvector became the dominant factor representing the respiration-associated deformations. However, other PCs did not necessarily change with the same trend as the first PC, and no correlation was observed between the coefficients. Hence, randomly allocating or sampling these PCs in expanded ranges may be applicable to reasonably generate an augmented dataset with various deformations. CONCLUSIONS: Reasonable accuracy of image synthesis comparable to those in the previous research were shown by using clinical data. These results indicate the potential of PCA-based volumetric imaging for clinical applications.

A study on predicting cases that would benefit from proton beam therapy in primary liver tumors of less than or equal to 5 cm based on the estimated incidence of hepatic toxicity.

Background: For small primary liver tumors, favorable outcomes have been reported with both of proton beam therapy (PBT) and X-ray therapy (XRT). However, no clear criteria have been proposed in the cases for which and when of PBT or XRT has to be used. The aim of this study is to investigate cases that would benefit from PBT based on the predicted rate of hepatic toxicity. Materials and methods: Eligible patients were those who underwent PBT for primary liver tumors with a maximum diameter of ≤ 5 cm and Child-Pugh grade A (n = 40). To compare the PBT-plan, the treatment plan using volumetric modulated arc therapy was generated as the XRT-plan. The rate of predicted hepatic toxicity was estimated using five normal tissue complication probability (NTCP) models with three different endpoints. The differences in NTCP values (ΔNTCP) were calculated to determine the relative advantage of PBT. Factors predicting benefits of PBT were analyzed by logistic regression analysis. Results: From the dose-volume histogram comparisons, an advantage of PBT was found in sparing of the normal liver receiving low doses. The factors predicting the benefit of PBT differed depending on the selected NTCP model. From the five models, the total tumor diameter (sum of the target tumors), location (hepatic hilum vs other), and number of tumors (1 vs 2) were significant factors. Conclusions: From the radiation-related hepatic toxicity, factors were identified to predict benefits of PBT in primary liver tumors with Child-Pugh grade A, with the maximum tumor diameter of ≤ 5 cm.

Real-time CT image generation based on voxel-by-voxel modeling of internal deformation by utilizing the displacement of fiducial markers.

PURPOSE: To show the feasibility of real-time CT image generation technique utilizing internal fiducial markers that facilitate the evaluation of internal deformation. METHODS: In the proposed method, a linear regression model that can derive internal deformation from the displacement of fiducial markers is built for each voxel in the training process before the treatment session. Marker displacement and internal deformation are derived from the four-dimensional computed tomography (4DCT) dataset. In the treatment session, the three-dimensional deformation vector field is derived according to the marker displacement, which is monitored by the real-time imaging system. The whole CT image can be synthesized by deforming the reference CT image with a deformation vector field in real-time. To show the feasibility of the technique, image synthesis accuracy and tumor localization accuracy were evaluated using the dataset generated by extended NURBS-Based Cardiac-Torso (XCAT) phantom and clinical 4DCT datasets from six patients, containing 10 CT datasets each. In the validation with XCAT phantom, motion range of the tumor in training data and validation data were about 10 and 15 mm, respectively, so as to simulate motion variation between 4DCT acquisition and treatment session. In the validation with patient 4DCT dataset, eight CT datasets from the 4DCT dataset were used in the training process. Two excluded inhale CT datasets can be regarded as the datasets with large deformations more than training dataset. CT images were generated for each respiratory phase using the corresponding marker displacement. Root mean squared error (RMSE), normalized RMSE (NRMSE), and structural similarity index measure (SSIM) between the original CT images and the synthesized CT images were evaluated as the quantitative indices of the accuracy of image synthesis. The accuracy of tumor localization was also evaluated. RESULTS: In the validation with XCAT phantom, the mean NRMSE, SSIM, and three-dimensional tumor localization error were 7.5 ± 1.1%, 0.95 ± 0.02, and 0.4 ± 0.3 mm, respectively. In the validation with patient 4DCT dataset, the mean RMSE, NRMSE, SSIM, and three-dimensional tumor localization error in six patients were 73.7 ± 19.6 HU, 9.2 ± 2.6%, 0.88 ± 0.04, and 0.8 ± 0.6 mm, respectively. These results suggest that the accuracy of the proposed technique is adequate when the respiratory motion is within the range of the training dataset. In the evaluation with a marker displacement larger than that of the training dataset, the mean RMSE, NRMSE, and tumor localization error were about 100 HU, 13%, and <2.0 mm, respectively, except for one case having large motion variation. The performance of the proposed method was similar to those of previous studies. Processing time to generate the volumetric image was <100 ms. CONCLUSION: We have shown the feasibility of the real-time CT image generation technique for volumetric imaging.

Treatment outcomes of stereotactic body radiation therapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinomas.

AIM: To report the outcomes of stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinoma patients. METHODS: From January 2005 to July 2018, 63 patients with 74 lesions with a maximum diameter ≤52 mm were treated by stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system. No patient with a Child-Pugh Score ≥9 was included, and 85.6% had a score of 5 or 6. Using the biological effective dose (BED) with an α/ß ratio of 10 (BED10 ), the median dose in BED10 at the reference point was 76.8 Gy (range 60-122.5 Gy). Overall survival (OS) and local control rates were assessed using the Kaplan-Meier method. RESULTS: With a median follow-up period of 24.6 months (range 0.9-118.4 months), the 1-year and 2-year OS rates were 86.8% (95% confidence interval [95% CI] 75.8-93.3) and 71.1% (57.8-81.6), respectively. The 2-year OS was 89.6% in patients with the baseline modified albumin-bilirubin (mALBI) grade =1, and 61.7% in patients with grade ≥2a. In the multivariate analysis, the mALBI grade (=1 vs. ≥2a) was a significant factor for OS (p = 0.028, 95% CI 1.11-6.18). The 1-year and 2-year local control rates were 100% (100-100%) and 92.0% (77.5-97.5%). The local control rates were significantly higher in the BED10 ≥100 Gy group than in the BED10 <100 Gy group (2-year 100% vs. 86.5%, p = 0.049) at the reference point. CONCLUSION: This retrospective study of stereotactic body radiotherapy using real-time tumor-tracking radiotherapy for hepatocellular carcinoma showed favorable outcomes with lower incidence of toxicities, especially in patients treated with BED10 ≥100 Gy to the reference point.

A case of radio-insensitive SMARCA4-deficient thoracic undifferentiated carcinoma with severe right heart failure.

SMARCA4-deficient thoracic sarcomatoid tumors were characterized by inactivating mutations of SMARCA4 and often found in the chest of young and middle-aged males with a smoking history. Recently, SMARCA4-deficient thoracic sarcomatoid tumors were reported to represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. The main complication of this tumor is compression of the respiratory tract and/or blood vessels. A 39-year-old man presented with a 2-month history of fever and dyspnea. Computed tomography revealed a mediastinal tumor invading the right and left pulmonary arteries. Because of severe right heart failure, we considered him ineligible for bronchoscopy. We scheduled palliative irradiation with 40 Gy/20 Fr to improve hemodynamics and perform endobronchial ultrasound transbronchial needle aspiration later. However, irradiation was ineffective, and his general condition deteriorated quickly and he died after a 7-week hospitalization. An autopsy revealed that the diagnosis was SMARCA4-deficient thoracic undifferentiated carcinoma. It has been reported that this tumor is insensitive to radiotherapy and there were some cases which responded to an immune checkpoint inhibitor. Therefore, when caring for patients with mediastinal tumors that invade and compress the trachea and large vessels, it is important to consider this tumor as a differential diagnosis and try to make a pathological diagnosis as soon as possible.

Construction of a detachable artificial trachea model for three age groups for use in an endotracheal suctioning training environment simulator.

Tracheal suctioning is an important procedure to maintain airway patency by removing secretions. Today, suctioning operators include not only medical staff, but also family caregivers. The use of a simulation system has been noted to be the most effective way to learn the tracheal suctioning technique for operators. While the size of the trachea varies across different age groups, the artificial trachea model in the simulation system has only one fixed model. Thus, this study aimed to construct multiple removable trachea models according to different age groups. We enrolled 20 patients who had previously received proton beam therapy in our institution and acquired the treatment planning computed tomography (CT) image data. To construct the artificial trachea model for three age groups (children, adolescents and young adults, and adults), we analyzed the three-dimensional coordinates of the entire trachea, tracheal carina, and the end of the main bronchus. We also analyzed the diameter of the trachea and main bronchus. Finally, we evaluated the accuracy of the model by analyzing the difference between the constructed model and actual measurements. The trachea model was 8 cm long for children and 12 cm for adolescents and young adults, and for adults. The angle between the trachea and bed was about 20 degrees, regardless of age. The mean model accuracy was less than 0.4 cm. We constructed detachable artificial trachea models for three age groups for implementation in the endotracheal suctioning training environment simulator (ESTE-SIM) based on the treatment planning CT image. Our constructed artificial trachea models will be able to provide a simulation environment for various age groups in the ESTE-SIM.

Analysis of acute-phase toxicities of intensity-modulated proton therapy using a model-based approach in pharyngeal cancer patients.

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of these patients had a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% for mucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.