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.

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.

Safety and Efficacy of Palliative Radiotherapy (25 Gy × 5 Fractions) for Symptomatic Pelvic Tumors.

BACKGROUND/AIM: Palliative radiotherapy is one of the effective treatments for pelvic tumors with bleeding or pain. In this study, we evaluated the safety and efficacy of palliative radiotherapy (RT) for symptomatic pelvic tumors when delivered as 25 Gy in 5 fractions. PATIENTS AND METHODS: We retrospectively analyzed 34 patients (gynecological cancer: n=14, rectal cancer: n=5, metastatic pelvic bone tumor: n=7, metastatic pelvic lymph node tumor: n=5, synovial sarcoma of the pelvis: n=1, prostate cancer: n=1, and urothelial cancer: n=1), who were treated between July 2016 and July 2021. The symptoms were bleeding in 16 patients, pain in 17 patients, and both bleeding and pain in 1 patient. The hemostatic effect of RT was evaluated with pre- and post-treatment hemoglobin (Hb) values. If the Hb levels reached a nadir and increased thereafter, we considered that there is a hemostatic response. The pain was evaluated with a numerical rating scale (NRS) and treatment response was defined as a decrease in NRS. RESULTS: Their median follow-up period was 4 months. A hemostatic response was observed in 82% of patients (14 of 17 patients). A pain relief response was observed in 78% of patients (14 of 18 patients). Acute adverse effects (AEs) included grade 1 diarrhea (n=3), grade 1 dermatitis (n=1) and grade 1 urinary frequency (n=1); late AEs have not been observed so far. CONCLUSION: 25 Gy of palliative RT in 5 fractions seems to be safe and effective for symptomatic pelvic tumors, similar to conventional palliative RT schedules.

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.

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.

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.

Feasibility of intensity modulated radiotherapy with involved field radiotherapy for Japanese patients with locally advanced non-small cell lung cancer.

The feasibility of intensity modulated radiotherapy (IMRT) with involved field radiotherapy (IFRT) for Japanese patients with locally advanced non-small cell lung cancer (LA-NSCLC) remains unclear. Here we reviewed our initial experience of IMRT with IFRT for Japanese patients with LA-NSCLC to evaluate the feasibility of the treatment. Twenty LA-NSCLC patients who were treated with IMRT with IFRT during November 2019 to October 2020 were retrospectively analyzed. All patients received 60 Gy in 30 fractions of IMRT and were administered concurrent platinum-based chemotherapy. The median patient age was 71 years old and the group included 15 men and 5 women. The patient group included 2 patients with stage IIB, 11 patients with stage IIIA, 5 patients with stage IIIB, and 2 patients with stage IIIC disease. Histological diagnosis was squamous cell carcinoma in 14 patients, adenocarcinoma in 5 patients, and non-small cell lung cancer in 1 patient. The median follow-up period was 8 months. The incidence of grade 3 or greater pneumonitis was 5%, and grade 3 or greater esophagitis was not observed. None of the patients developed regional lymph node, with only recurrence reported so far. These findings indicate that IMRT with IFRT for Japanese patients with LA-NSCLC is feasible in terms of acute toxicity. Further study with a larger number of patients and longer follow-up to clarify the effect of treatment on patient prognosis is required.

Incidence and risk factors for pneumonitis among patients with lung cancer who received immune checkpoint inhibitors after palliative thoracic radiotherapy.

The aim of this study is to analyze the incidence and risk factors for pneumonitis when immune checkpoint inhibitors (ICIs) are combined with palliative thoracic radiotherapy (RT) for lung cancer. We retrospectively evaluated 29 patients with lung cancer who received ICIs after palliative thoracic RT (30 Gy in 10 fractions). Their ICIs were pembrolizumab (n = 17), nivolumab (n = 8) and atezolizumab (n = 4). Median follow-up period was 10 months. The median interval between starting RT and starting ICI was 25 days. Pneumonitis events were grade 1 (n = 10; 34%), grade 2 (n = 4; 14%) and grade 3 (n = 3; 10%). Obstructive pneumonia was significantly associated with grade ≥ 2 pneumonitis (P = 0.036). Age, sex, ICI agent, interval between RT and ICI and history of ICI before RT were not associated with grade ≥ 2 pneumonitis. Tumor volume; Brinkman index; dosimetric factors, such as lung V5, V10, V20, V30 and mean lung dose (MLD); lactate dehydrogenase; and C-reactive protein did not significantly differ between the grade ≤ 1 and grade ≥ 2 pneumonitis groups. Levels of sialylated carbohydrate antigen KL-6 were evaluated in 27 patients before RT; they significantly differed between patients with grade ≤ 2 pneumonitis (mean: 431 U/ml) and those with grade ≥ 3 pneumonitis (mean: 958 U/ml; P < 0.001). Patients who receive ICI after palliative thoracic RT should be carefully followed-up, especially those who have had obstructive pneumonia or high KL-6 levels.

Results of definitive radiotherapy with concurrent chemotherapy for maxillary sinus carcinomas with neck lymph node metastasis.

The purpose of this study was to describe the results of definitive radiotherapy (RT) with concurrent chemotherapy for maxillary sinus carcinomas (MSCs) with neck lymph node metastasis to clarify its limitation. Local control (LC), progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and were compared between subgroups using the log rank test. Toxicity was classified using common terminology criteria of adverse events version 5.0. Eighteen patients with inoperable MSC with neck lymph node metastasis including 12 men and 6 women with a median age of 67 years were analyzed. The histologic diagnoses were as follows: 16 patients had squamous cell carcinomas and 2 had other histology. Four patients had stage T3 MSC, 6 had T4a and 8 had T4b. Among 18 patients, 7 received concurrent systemic chemotherapy and 11 received selective arterial chemo-infusion. The median follow-up period was 17 months. The 2-year LC, PFS and OS rates for the entire cohort were 34, 31 and 46%, respectively. No significant differences were observed for LC, PFS and OS rates between systemic chemotherapy and selective arterial chemo-infusion cohorts. Grade 3 or higher acute toxicity, including both non-hematological and hematological, was observed in nine patients (50%), while no grade 3 or higher late toxicity was observed. In conclusion, we described the results of definitive RT for MSCs with neck lymph node metastasis. Local recurrence of primary tumor was a frequent pattern of failure and it should be addressed in future study.

Effect of durvalumab on local control after concurrent chemoradiotherapy for locally advanced non-small cell lung cancer in comparison with chemoradiotherapy alone.

BACKGROUND: Durvalumab after concurrent chemoradiotherapy (CCRT) for locally advanced non-small cell lung cancer (LA-NSCLC) has been found to significantly improve overall survival (OS). However, the effect of durvalumab on local control remains unclear. Here, we evaluated the effect of the durvalumab on local control in comparison with the clinical result of patients treated with CCRT alone. METHODS: A total of 120 LA-NSCLC patients including 76 patients with CCRT alone and 44 patients with CCRT followed by durvalumab were analyzed. Baseline patient characteristics of CCRT alone cohort and durvalumab cohort were compared with student's t test or Mann-Whitney U test for continuous variables and with chi-squared test for categorical variables. Local control (LC), progression free survival (PFS) and OS rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: There were 19 patients with stage II disease and 101 patients with stage III disease. Age, sex, histopathological type, T classification, N classification, clinical stage, tumor volume and dose fractionation schedule were not significantly different between the CCRT alone and durvalumab cohorts. The one-year LC rate was significantly higher in the durvalumab cohort (86%) compared with the CCRT alone cohort (62%) (P = 0.005), whereas no significant difference was observed in either PFS (P = 0.864) or OS (P = 0.443) between the CCRT and durvalumab cohorts. CONCLUSIONS: The one-year LC rate was significantly higher in the durvalumab cohort compared with the CCRT alone cohort. Although the follow-up period was too short to draw definitive conclusions, the study revealed that durvalumab might have a significant effect on LC. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Effect of durvalumab on local control after chemoradiotherapy for locally advanced non-small cell lung cancer is unclear WHAT THIS STUDY ADDS: The one-year local control rate of chemoradiotherapy followed by durvalumab was significantly higher compared with chemoradiotherapy alone.

[Alveolar hemorrhage as a possible adverse drug reaction by gefitinib (ZD1839, Iressa)].

We experienced a case in which severe alveolar hemorrhage occurred in the course of gefitinib therapy. A 56-year-old man with non-small cell lung cancer had been treated with CDDP + CPT-11, CDDP + GEM + VNR, CDDP + TXT. After the chemotherapy with these regimens was found to be ineffective, daily oral gefitinib was started. Four weeks later, the patient complained of cough, bloody sputum and dyspnea. Chest X-ray and CT showed bilateral infiltrations with air bronchogram. Fiberoptic bronchoscopy revealed alveolar hemorrhage with an increase of lymphocytes in the BALF. After the cessation of gefitinib therapy and the administration of steroid, he gradually recovered.

Pharmacological profiles of high-concentration (20 microg/g) tacalcitol ointment: effects on cutaneous inflammation, epidermal proliferation, and differentiation in mice.

This study focused on the effects of tacalcitol (1,24 (R) (OH)2D3, TV-02) ointment (20 micro g/g) on cutaneous inflammation, epidermal proliferation, and differentiation and compared them with tacalcitol ointment (2 micro g/g) and other anti-psoriatic ointments using hairless mice. Tacalcitol ointment (0, 2 and 20 micro g/g) significantly inhibited 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cutaneous inflammation, histopathologically. The effect of tacalcitol ointment (20 micro g/g) on cutaneous inflammation was much stronger than that of tacalcitol ointment (0, 2 micro g/g), and as effective as calcipotriol ointment (50 micro g/g) or betamethasone valerate ointment (1.2 mg/g). Tacalcitol ointment (20 micro g/g) also significantly inhibited TPA-induced myeloperoxidase (MPO) activity, as effectively as calcipotriol ointment (50 micro g/g) or betamethasone valerate ointment (1.2 mg/g). The effect of tacalcitol ointment on epidermal proliferation [ornithine decarboxylase (ODC) activity] and differentiation [transglutaminase (TGase) activity] was dose-dependent from 0 micro g/g to 20 micro g/g. The effect of tacalcitol ointments on epidermal proliferation was significant at the doses of 2 micro g/g and 20 micro g/g, and that on epidermal differentiation was significant at the doses of 0.2 micro g/g or more. The effect of tacalcitol ointment (20 micro g/g) on epidermal differentiation was significantly stronger than tacalcitol ointment (2 micro g/g). In this study, tacalcitol ointment (20 micro g/g) was found to have a marked effect on cutaneous inflammation and improved effect on epidermal differentiation, although tacalcitol ointment (2 micro g/g) also had significant effects on epidermal proliferation and differentiation. These findings support the clinical effectiveness of tacalcitol ointment (20 micro g/g) against psoriasis.

1 alpha,25-dihydroxyvitamin D3 suppresses interleukin-1beta-induced interleukin-8 production in human whole blood: an involvement of erythrocytes in the inhibition.

Interleukin (IL)-8, which is involved in inflammatory responses, is produced by a variety of cell types, monocytes/macrophages and neutrophils, in response to inflammatory stimuli including lipopolysaccharide, IL-1, and tumor necrosis factor alpha. Here we report the inhibitory effects of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on IL-8 production in human whole blood culture. 1,25(OH)2D3 inhibited only the late phase of the biphasic IL-8 production in lipopolysaccharide-stimulated human whole blood. It also effectively inhibited IL-8 production induced by IL-lbeta compared with that induced by tumor necrosis factor alpha. IL-8 mRNA expression in IL-lbeta-stimulated whole blood was found to require de novo protein synthesis. Although monocytes were found to be mainly responsible for IL-1beta-induced IL-8 production in whole blood, 1,25(OH)2D3 inhibited IL-8 production by isolated mononuclear cells only marginally. The inhibitory effect of 1,25(OH)2D3 on mononuclear cells was restored by adding erythrocytes. These results suggest that erythrocytes play a role in mediating the inhibitory effects of 1,25(OH)2D3 on IL-8 production in IL-1beta-stimulated whole blood.