A 54 Gy in three fractions of stereotactic body radiotherapy using CyberKnife for T1b-2aN0M0 pathologically confirmed non-small cell lung cancer.

OBJECTIVE: Optimal dose-fractionation regimen of stereotactic body radiotherapy for peripheral early-stage non-small cell lung cancer remains unclear. We retrospectively investigated outcomes of stereotactic body radiotherapy using CyberKnife at 54 Gy in three fractions in 26 patients (median age: 76 years) with pathologically confirmed T1b-T2aN0M0 non-small cell lung cancer. METHODS: A 54 Gy in three fractions was prescribed to cover the 99% of gross tumor volume. We estimated cumulative local control, progression-free survival and overall survival rates (Kaplan-Meier method), and toxicity (Common Toxicity Criteria for Adverse Events, version 5.0). RESULTS: All the tumors were located at peripheral area of lung. Mean distance from chest wall to tumor was 6.5 mm (range: 0-32 mm). The patients' pathological diagnoses were: adenocarcinoma: n = 18, squamous cell carcinoma: n = 7 and non-small cell carcinoma: n = 1. Their stages were T1b: n = 9, T1c: n = 14 and T2a: n = 3. Median follow-up was 24 months (range: 6-54). Cumulative 2-year effect rates were local control: 100%, progression-free survival 70% and overall survival: 92%. Twenty patients developed grade one radiation pneumonitis, but grade 2 or greater radiation pneumonitis was not observed. CONCLUSIONS: We found CyberKnife-stereotactic body radiotherapy for pathologically confirmed T1b-T2aN0M0 non-small cell lung cancer to be effective and safe. However, these results should be validated with a larger patient cohort and prospective follow-up monitoring.

Development of an HDR-BT QA tool for source position verification.

PURPOSE: This study aimed to develop a high-dose-rate brachytherapy (HDR-BT) quality assurance (QA) tool for verification of source positions, and to report on its effectiveness. METHODS: We fabricated a cuboid phantom measuring 30 × 30×3 cm3 with spaces to embed Fletcher-Williamson tandem and ovoid applicators. Lead-based, cylindrically shaped radiopaque markers, which scatter radiation and blacken the Gafchromic® RTQA2 films placed on the applicators, were inserted into the phantom to determine the applicator tip and reference source positions. A three-dimensional image-guided brachytherapy (3D-IGBT) plan was generated, and the source positions on the film and radiation treatment planning system (RTPS) were verified with the tool. Source position errors were evaluated as the distance in the applicator axis direction between the source position and the center position of two radiopaque marker pairs. RESULTS: Source position errors on the film and RTPS were in good agreement with one another and were all within 0.5 mm for all applicators. Offset values of each applicator were in good agreement with the value determined in treatment planning (6 mm). The expanded measurement uncertainty of our QA tool was estimated to be 0.87 mm, with a coverage factor k of 2. CONCLUSIONS: Our new HDR-BT QA tool developed for comprehensive source position verification will be useful for cross checking actual source positions and planned source positions on the RTPS.

Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models.

We previously reported that eribulin mesylate (eribulin), a tubulin-binding drug (TBD), could remodel tumor vasculature (i.e. increase tumor vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling in antitumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on antitumor activities in multiple human cancer xenograft models. Microvessel densities (MVD) were evaluated by immunohistochemistry (CD31 staining), and antitumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVD compared to the controls in six out of 10 models with a correlation between enhanced MVD levels and antitumor effects (R2  = 0.54). Because of increased MVD, we next used radiolabeled liposomes to examine whether eribulin treatment would result in increased tumoral accumulation levels of these macromolecules and, indeed, we found that eribulin, unlike vinorelbine (another TBD) enhanced them. As eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance the antitumor effect of Doxil (a liposomal anticancer agent) and facilitate recruitment of immune cells into the tumor. As expected, eribulin enhanced antitumor activity of Doxil in a post-erlotinib treatment H1650 (PE-H1650) xenograft model. Furthermore, infiltrating CD11b-positive immune cells were significantly increased in multiple eribulin-treated xenografted tumors, and natural killer (NK) cell depletion reduced the antitumor effects of eribulin. These findings suggest a contribution of the immune cells for antitumor activities of eribulin. Taken together, our results suggest that vascular remodeling induced by eribulin acts as a microenvironment modulator and, consequently, this alteration enhanced the antitumor effects of eribulin.

Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma.

BACKGROUND: To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) for 80 years or older patients with hepatocellular carcinoma (HCC). METHODS: Eligibility criteria of this retrospective study were: 1) HCC confirmed by histology or typical hallmarks of HCC by imaging techniques of four-phase multidetector-row computed tomography or dynamic contrast-enhanced magnetic resonance imaging; 2) no intrahepatic metastasis or distant metastasis; 3) no findings suggesting direct infiltration of the gastrointestinal tract; 4) performance status ≤2 by Eastern Cooperative Oncology Group classification; and 5) Child-Pugh classification A or B. Patients received C-ion RT with 52.8 Gy (RBE) or 60.0 Gy (RBE) in four fractions for usual cases and 60.0 Gy (RBE) in 12 fractions for close-to-gastrointestinal tract cases. Toxicities were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (Version 4.0). RESULTS: Between March 2011 and November 2015, 31 patients were treated. The median follow-up period of all patients was 23.2 months (range: 8.4-55.3 months). Median age at the time of registration of C-ion RT was 83 years (range: 80-95 years). Child-Pugh grade A and B were 27 patients and 4 patients, respectively. The 2-year estimated overall survival, local control, and progression-free survival rates were 82.3%, 89.2%, and 51.3%, respectively. No patients had Grade 2 or higher acute toxicities (within 3 months after C-ion RT). One patient experienced progression in Child-Pugh classification from A to B within 3 months after C-ion RT. In late toxicities, Grade 3 encephalopathy was observed in 3 patients, and 2 improved with medication. CONCLUSIONS: C-ion RT was effective with minimal toxicities for 80 years or older patients with hepatocellular carcinoma. TRIAL REGISTRATION: UMIN000020571 : date of registration, 14 January 2016, retrospectively registered.

Incidence, risk factors, and dose-volume relationship of radiation-induced rib fracture after carbon ion radiotherapy for lung cancer.

BACKGROUND: The purpose of this study was to assess the incidence, risk factors, and dose-volume relationship of radiation-induced rib fracture (RIRF) after carbon ion radiotherapy for lung cancer. MATERIAL AND METHODS: Fifty-seven ribs of 18 patients with peripheral stage I non-small cell lung cancer treated with carbon ion radiotherapy were analyzed on rib fracture. The patients were treated at a total dose of 52.8 Gy [relative biologic effectiveness (RBE)] or 60.0 Gy (RBE) in 4 fractions and were followed at least six months. Patient characteristics and dosimetric parameters were analyzed for associations with RIRF. RESULTS: Eighteen patients and 57 ribs were included in this study. The median length of follow-up was 36.5 months. RIRF was observed in seven (39%) of the 18 patients, and in 11 (19%) of 57 ribs. Only one patient developed symptomatic fracture. The distance from the ribs to the tumor site was significantly shorter in fractured ribs than in non-fractured ribs (1.4 ± 0.3 cm vs. 2.5 ± 0.3 cm). Receiver operating characteristic curve analysis showed that [Formula: see text] as a cut-off value for discriminating RIRF had the largest area under the curve (AUC =0.78). Comparison of the two-year cumulative incidence of RIRF among two groups as determined by cut-off values, yielded the following result: 53% vs. 4% [[Formula: see text], ≥ 38.2 Gy (RBE) or less]. Results from the two groups were significantly different (p < 0.05). CONCLUSION: The crude incidence of RIRF after carbon ion radiotherapy was 39% but incidence of symptomatic fracture was low. The [Formula: see text] as cut-off values may be helpful for discriminating the risk of RIRF.

N-terminal hydrophobic amino acids of activating transcription factor 5 (ATF5) protein confer interleukin 1ß (IL-1ß)-induced stabilization.

Activating transcription factor 5 (ATF5) is a stress-response transcription factor that responds to amino acid limitation and exposure to cadmium chloride (CdCl2) and sodium arsenite (NaAsO2). The N-terminal amino acids contribute to the destabilization of the ATF5 protein in steady-state conditions and serve as a stabilization domain in the stress response after CdCl2 or NaAsO2 exposure. In this study, we show that interleukin 1ß (IL-1ß), a proinflammatory cytokine, increases the expression of ATF5 protein in HepG2 hepatoma cells in part by stabilizing the ATF5 protein. The N-terminal domain rich in hydrophobic amino acids that is predicted to form a hydrophobic network was responsible for destabilization in steady-state conditions and served as an IL-1ß response domain. Furthermore, IL-1ß increased the translational efficiency of ATF5 mRNA via the 5' UTRα and phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). ATF5 knockdown in HepG2 cells up-regulated the IL-1ß-induced expression of the serum amyloid A 1 (SAA1) and SAA2 genes. Our results show that the N-terminal hydrophobic amino acids play an important role in the regulation of ATF5 protein expression in IL-1ß-mediated immune response and that ATF5 is a negative regulator for IL-1ß-induced expression of SAA1 and SAA2 in HepG2 cells.

Malignant melanoma of the nasal cavity treated with stereotactic radiotherapy using CyberKnife: report of 2 cases.

Radiotherapy with high doses per fraction may have the potential to control radioresistant tumors, such as malignant melanoma. Here we report 2 cases with malignant melanoma of the nasal cavity treated with hypofractionated stereotactic radiotherapy using CyberKnife®.

Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway-induced resistance to vascular endothelial growth factor receptor inhibitor.

Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.

Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities.

E7130 is a novel anticancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAF) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging modalities, including multiplexed mass cytometry [cytometry by time-of-flight (CyTOF)] analysis, multiplex IHC analysis, and MRI. Experimental solid tumors characterized by large numbers of CAFs in TME were treated with E7130. E7130 suppressed LAP-TGFß1 production, a precursor of TGFß1, in CAFs but not in cancer cells; an effect that was accompanied by a reduction of circulating TGFß1 in plasma. To our best knowledge, this is the first report to show a reduction of TGFß1 production in TME. Furthermore, multiplex IHC analysis revealed reduced cellularity and increased TUNEL-positive apoptotic cells in E7130-treated xenografts. Increased microvessel density (MVD) and collagen IV (Col IV), an extracellular matrix (ECM) component associated with endothelial cells, were also observed in the TME, and plasma Col IV levels were also increased by E7130 treatment. MRI revealed increased accumulation of a contrast agent in xenografts. Moreover, diffusion-weighted MRI after E7130 treatment indicated reduction of tumor cellularity and interstitial fluid pressure. Overall, our findings strongly support the mechanism of action that E7130 alters the TME in therapeutically beneficial ways. Importantly, from a translational perspective, our data demonstrated MRI as a noninvasive biomarker to detect TME amelioration by E7130, supported by consistent changes in plasma biomarkers.

Results of Definitive (Chemo)radiotherapy Using Computed Tomography-based Brachytherapy for Cervical Cancer.

BACKGROUND/AIM: Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer. Especially, CCRT with magnetic resonance imaging (MRI) or computed tomography-based image-guided brachytherapy (CT-based 3D-IGBT) for cervical cancer has resulted in good LC rates. However, progression-free survival (PFS) and overall survival (OS) rates for locally advanced cervical cancer are still low and could be improved. The aim of the study was to evaluate treatment efficacy and late toxicity of external beam radiotherapy (EBRT) and CT-based IGBT with or without concurrent chemotherapy in patients with squamous cell carcinoma of the uterine cervix and investigate patterns of failure. PATIENTS AND METHODS: We retrospectively analyzed clinical data of cervical squamous cell carcinoma patients treated with definitive radiotherapy with or without concurrent chemotherapy at Saitama Medical University International Medical Center. Local control (LC), PFS, patterns of failure, and late toxicity were the evaluated outcomes. RESULTS: Overall, 290 patients were enrolled in the study. Median follow-up was 51.5 months. During follow-up, 74 patients developed recurrence: 10 patients with intra-pelvic failure only, 45 with extra-pelvic failure only, and 19 with both. The 3-year LC was 100% for T1b-T2a, 96.8% for T2b, 89.5% for T3b, and 88.5% for T4 disease. The 3-year PFS was 100% for stage IB-IIA, 89.0% for stage IIB, 70.7% for stage IIIB, 72.6% for stage IIIC1r, and 40.1% for stage IVA. The incidence of grade 3-4 gastrointestinal and genitourinary toxicities was 3.0% and 1.7%, respectively. CONCLUSION: Combination of EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC with acceptable rates of late toxicities. However, extra-pelvic failures frequently occurred and PFS was less satisfactory in patients with stage III-IVA disease, which indicated the need for additional treatment in these patients.

Inhibition of Notch4 using Novel Neutralizing Antibodies Reduces Tumor Growth in Murine Cancer Models by Targeting the Tumor Endothelium.

Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed on tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancer. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms.

Validation of nomogram-based prediction of survival probability after salvage re-irradiation of head and neck cancer.

OBJECTIVE: Treatment outcomes after salvage re-irradiation in patients with recurrent head and neck cancer vary widely due to heterogeneous patient characteristics, and it is difficult to evaluate optimal re-irradiation schedules. This study aimed to validate a nomogram, originally developed by Tanvetyanon et al., used to predict the survival probability of patients with recurrent head and neck cancer after re-irradiation. METHODS: Twenty-eight patients with recurrent head and neck cancer who underwent salvage re-irradiation between June 2007 and November 2011 were evaluated. The median total dose used for initial radiotherapy was 60 Gy (range, 22-72). Re-irradiation sites included the nasopharynx or Rouviere's node (n = 14), external ear (n = 4), neck lymph node (n = 3) and other sites (n = 7). Overall survival after re-irradiation was calculated using the Kaplan-Meier method, and the 2-year survival probability was estimated using Tanvetyanon's nomogram. RESULTS: Twenty-two patients were treated with stereotactic body radiotherapy using a median total dose of 30 Gy (range, 15-40) in 1-7 fractions and six patients were treated with conventional external beam radiotherapy using 45 Gy (range, 23.4-60) in 10-30 fractions. The 2-year overall survival was 21.7% (95% confidence interval: 9.3-41.3), and the 2-year survival probability was 16.8% (95% confidence interval: 9.9-23.6). The 2-year overall survival in 20 patients with unfavorable prognosis (median 2-year survival probability, 5.5%) and in 8 patients with favorable prognosis (median 2-year survival probability, 45%) were 11.0 and 45.7%, respectively (P = 0.05). CONCLUSIONS: Our findings show that Tanvetyanon's nomogram accurately estimates the survival probability in patients with recurrent head and neck cancer after re-irradiation.

Progression of coronary artery calcification after radiation therapy for esophageal cancer.

BACKGROUND: Advances in cancer treatment have resulted in increased attention toward potential cardiac complications, especially following treatment for esophageal cancer, which is associated with a risk of coronary artery disease. As the heart is directly irradiated during radiotherapy, coronary artery calcification (CAC) may progress in the short term. Therefore, we aimed to investigate the characteristics of patients with esophageal cancer that predispose them to coronary artery disease, CAC progression on PET-computed tomography and the associated factors, and the impact of CAC progression on clinical outcomes. METHODS: We retrospectively screened 517 consecutive patients who received radiation therapy for esophageal cancer from our institutional cancer treatment database between May 2007 and August 2019. CAC scores were analyzed clinically for 187 patients who remained by exclusion criteria. RESULTS: A significant increase in the Agatston score was observed in all patients (1 year: P  = 0.001*, 2 years: P  < 0.001*). Specifically for patients receiving middle-lower chest irradiation (1 year: P  = 0.001*, 2 years: P  < 0.001*) and those with CAC at baseline (1 year: P  = 0.001*, 2 years: P  < 0.001*), a significant increase in the Agatston score was observed. There was a trend for a difference in all-cause mortality between patients who had irradiation of the middle-lower chest ( P  = 0.053) and those who did not. CONCLUSION: CAC can progress within 2 years after the initiation of radiotherapy to the middle or lower chest for esophageal cancer, particularly in patients with detectable CAC before radiotherapy initiation.

Learning curve of lung dose optimization in intensity-modulated radiotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) has been increasingly used for patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, there are some barriers to implementing IMRT for LA-NSCLC, including the complexity of treatment plan optimization. This study aimed to evaluate the learning curve of lung dose optimization in IMRT for LA-NSCLC and identify the factors that affect the degree of achievement of lung dose optimization. METHODS: We retrospectively evaluated 40 consecutive patients with LA-NSCLC who received concurrent chemoradiotherapy at our institution. These 40 patients were divided into two groups: 20 initially treated patients (earlier group) and 20 subsequently treated patients (later group). Patient and tumor characteristics were compared between the two groups. The dose-volume parameter ratio between the actually delivered IMRT plan and the simulated three-dimensional conformal radiotherapy plan was also compared between the two groups to determine the learning curve of lung dose optimization. RESULTS: The dose-volume parameter ratio for lung volume to receive more than 5 Gy (lung V5) and mean lung dose (MLD) significantly decreased in later groups. The spread of the beam path and insufficient optimization of dose coverage of planning target volume (PTV) might cause poor control of lung V5, MLD. CONCLUSIONS: A learning curve for lung dose optimization was observed with the accumulation of experience. Appropriate techniques, such as restricting the beam path and ensuring dose coverage of PTV during the optimization process, are essential to control lung dose in IMRT for LA-NSCLC.

Optimal Number of Needle Applicators Inserted in Combined Intracavitary and Interstitial Brachytherapy for Cervical Cancer.

BACKGROUND/AIM: Combined intracavitary and interstitial brachytherapy (IC/IS-BT) is an effective treatment for extensive and bulky cervical cancer. However, the optimum number of interstitial needle applicators ("needles") inserted in IC/IS-BT can be difficult to determine. To examine the number of needles required for adequate dose coverage of cervical tumors, we retrospectively analyzed IC/IS-BT plans. PATIENTS AND METHODS: IC/IS-BT plans for cervical cancer patients treated from January 2014 to January 2021 were analyzed. All tumors were controlled locally at the time of analysis (August 2022). The relationship between the number of needles and several volumetric parameters of high-risk clinical target volume (CTVHR) were analyzed, including maximum diameter, maximum cross-sectional area, and the volume of CTVHR Spearman's rank correlation coefficients (r) were used to evaluate correlations. RESULTS: Eighty-two plans in 32 patients were analyzed. The median maximum cross-sectional area and volume of CTVHR were 18.9 (12.3-42.5) cm2 and 53.8 (30.1-152.2) cm3, respectively. The mean D90% and D98% of CTVHR at each BT session were 7.0±0.8 Gy and 5.9±0.8 Gy, respectively. There was a positive correlation between the number of needles and the maximum cross-sectional area of CTVHR (r=0.53). The average numbers of needles were 1.3, 1.9, 2.2, 3.1, and 4.0 when the maximum cross-sectional area of CTVHR were ≤15 cm2, 15-20 cm2, 20-25 cm2, 25-30 cm2, and >30 cm2, respectively. CONCLUSION: The optimal number of needles can be determined from the maximum cross-sectional area of CTVHR.

Comparison of the Efficacy and Toxicity of Concurrent Chemoradiotherapy and Durvalumab and Concurrent Chemoradiotherapy Alone for Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Metastasis.

BACKGROUND/AIM: Efficacy and toxicity of concurrent chemoradiotherapy (CCRT) and durvalumab for locally advanced non-small cell lung cancer (LA-NSCLC) with N3 lymph node metastasis remain unclear. We aimed to evaluate the clinical outcomes of patients who received CCRT and durvalumab (durvalumab cohort) and compare their outcomes with those of patients who received CCRT alone (CCRT-alone cohort). PATIENTS AND METHODS: The data of patients who had received treatment between November 2008 and February 2022 and were followed up for at least 3 months were retrospectively analyzed. Local control, progression-free survival, and overall survival were evaluated using Kaplan-Meier analysis and compared using the log-rank test. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The data of 29 patients were analyzed (median follow-up period: 22 months). Among them, 17 received CCRT alone and 12 received CCRT and durvalumab. There were 14 patients with stage IIIB and 15 with stage IIIC LA-NSCLC. The durvalumab cohort (89%) had a significantly higher 1-year local control rate than the CCRT-alone cohort (47%; p=0.035). No significant difference was observed in either progression-free or overall survival between the two cohorts. Grade ≥2 pneumonitis was observed in 6 (50%) and 7 (41%) patients in the durvalumab and CCRT-alone cohorts, respectively. CONCLUSION: CCRT with durvalumab may be effective against LA-NSCLC with N3 lymph node metastasis. The incidence of grade 2 pneumonitis was slightly higher in the durvalumab cohort than in the CCRT-alone cohort, suggesting the need for careful patient monitoring after treatment.

Results of computer tomography-based adaptive brachytherapy in combination with whole-pelvic- and central-shielding-external beam radiotherapy for cervical cancer.

PURPOSE: To evaluate treatment results and investigate predictors of local control. METHODS AND MATERIALS: In this retrospective study of 236 patients with cervical cancer, we administered CT-based adaptive brachytherapy (BT) in combination with whole- pelvic (WP)- and central shielding (CS)- external beam radiotherapy (EBRT) with or without chemotherapy. The study cohort comprised patients with cervical cancer treated with definitive radiotherapy (RT) or concurrent chemoradiotherapy between June 2013 and March 2019. Local control (LC), overall survival (OS), and late toxicity were evaluated. Predictive factors for LC were analyzed by univariate and multivariate analyses. RESULTS: Median doses of WP- and CS-EBRT and BT were 30.6 GyEQD2, 19.8 GyEQD2, and 40.3 GyEQD2, respectively. The 3-year LC rates for T1b2, T2a, T2b, T3b, and T4 were 100%, 100%, 97.3%, 86.9%, and 91.7%, respectively (p = 0.346). The 3-year OS for Stages IB, IIB, IIIB, IIIC, and IVA were 100%, 94.8%, 82.5%, 81.7%, and 74.6%, respectively (p = 0.037). Rates of Grade 3-4 gastrointestinal and genitourinary toxicities were 3.8% and 1.7%, respectively. Multivariate analysis showed that T3-4, nonsquamous cell histology, and high-risk clinical target volume (CTVHR) D90 of BT < 36GyEQD2 were independently associated with significantly poorer LC. CONCLUSIONS: The combination of WP- and CS-EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC outcomes with low rates of late toxicities for patients with small or medium-sized tumors. However, LC was less favorable for patients who had large T3 disease, and the use of CS requires caution in these patients.

High-dose stereotactic body radiotherapy using CyberKnife® for stage I peripheral lung cancer: a single-center retrospective study.

BACKGROUND: This retrospective study was performed to evaluate the efficacy and toxicity of high-dose stereotactic body radiotherapy (SBRT) using a CyberKnife® for patients with stage I peripheral non-small cell lung cancer (NSCLC). METHODS: Ninety-six patients with stage I peripheral NSCLC who were treated with SBRT using a CyberKnife® from August 2010 to June 2019 were identified and included in this study. Local control (LC), local progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS), and late toxicity were evaluated. Potential risk factors associated with LC, LPFS, PFS, or OS were investigated by univariate analyses. RESULTS: Data of 96 patients were examined. The prescribed dose to the tumor was 54 Gy in 3 fractions in 91 patients and 60 Gy in 3 fractions in 5 patients. The median follow-up duration was 27 months. The 2-year LC, LPFS, PFS, and OS rates were 97%, 88%, 84%, and 90%, respectively. The T factor was significantly correlated with LC, LPFS, and PFS. The 2-year LC rate for patients with T1a/T1b and T1c/T2a disease was 100% and 90%, respectively (p < 0.05), and the 2-year PFS rate for the corresponding patients was 95% and 65%, respectively (p < 0.001). One patient (1%) developed grade 3 radiation pneumonitis. CONCLUSIONS: High-dose SBRT using a CyberKnife® for stage I peripheral NSCLC produced favorable treatment outcomes with acceptable late toxicity. Further studies are needed to improve the treatment outcomes for patients with T1c/T2a disease.

Simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non-small cell lung cancer treated with intensity modulated radiotherapy.

BACKGROUND: In this study, we developed a simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiotherapy (IMRT). METHODS: Data of 28 patients with stage IIB to IIIC NSCLC were retrospectively analyzed. All patients were treated with IMRT and a simulated three-dimensional conformal radiotherapy (3D-CRT) plan created for them. Dose-volume parameters of lung were analyzed for their correlation with radiation pneumonitis (RP). RESULTS: Over a median follow-up of 14 months, grade 1 pneumonitis was diagnosed in 14 patients (50%), grade 2 pneumonitis in 11 (39%), and grade 3 pneumonitis in one (4%). Two patients did not develop pneumonitis. None of the patients developed grade 4 or 5 pneumonitis. Regarding dose-volume parameter ratios between IMRT and simulated 3D-CRT, receiver operating characteristic analysis showed that mean lung dose (MLD)IMRT /MLD3D-CRT had the largest area under curve (0.750). Cumulative 6-month incidences of grade 2 or greater RP were 78.4% versus 19.5% (MLDIMRT /MLD3D-CRT, ≥1.0 or less); this difference was significant (p < 0.05). CONCLUSIONS: We found that cutoff values for dose volume parameter ratios significantly predict grade 2 or greater RP. We believe that these parameter ratios could be useful in assisting evaluation of achievement degree of lung dose optimization in IMRT for LA-NSCLC.