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Background and Purpose: Current nomograms predicting survival prognosis after stereotactic body radiation therapy (SBRT) in non-small cell lung cancer (NSCLC) are based on peripherally located tumors. However, patients with a central lung tumor tend to be older, the tumor is often larger and fraction-schedules are risk-adapted. Therefore, we developed and externally validated a nomogram to predict overall survival (OS) in patients having centrally located early-stage NSCLC treated with SBRT., Materials and Methods: Patients who underwent SBRT for centrally located NSCLC were identified and baseline characteristics were obtained. A nomogram was built to predict 6-month, 1-, 2- and 3-year OS using Cox proportional hazards model. The model building procedure was validated using bootstrap sampling. To determine generalizability, external validation was performed on a cohort of patients with central NSCLC treated with SBRT from another center. Discriminatory ability was measured with the concordance index (C-index) and calibration plots were used to compare Kaplan-Meier-estimated and nomogram-predicted OS., Results: The nomogram was built on data of 220 patients and consisted of the following variables: PTV, age, WHO performance status, tumor lobe location and ultracentral location. The C-index of the nomogram (corrected for optimism) was moderate at 0.64 (95% confidence interval (CI) 0.59-0.69). Calibration plots showed favorable predictive accuracy. The external validation showed acceptable validity with a C-index of 0.62 (95% CI 0.61-0.64)., Discussion: We developed and externally validated the first nomogram to estimate the OS-probability in patients with centrally located NSCLC treated with SBRT. This nomogram is based on 5 patient and tumor characteristics and gives an individualized survival prediction., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background : Stereotactic body radiation therapy (SBRT) results in high local control (LC) rates in patients with non-small cell lung cancer (NSCLC). For central lung tumors, risk-adapted fractionation schedules are used and underdosage to the Planned Target Volume (PTV) is often accepted to respect the dose constraints of the organs at risk in order to avoid high rates of toxicity. The purpose of this study was to analyze the effect of PTV underdosage and other possible prognostic factors on local- and disease control after SBRT in patients with central lung tumors. Material and Methods : Patients with centrally located NSCLC treated with SBRT were included. The doses were converted into biologically equivalent dose using α/β-value of 10 Gy (BED 10 ). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED 10 ; (%)PTV < 100 BED 10 . Potential prognostic factors for LC and Disease Free Survival (DFS) were evaluated using Cox regression analysis. Results : Two hundred and twenty patients received ≤12 fractions of SBRT. LC-rates were 88% at 2 years and 81% at 3 years. Twenty-seven patients developed a local recurrence. Both the PTV < 100 BED 10 and %PTV < 100 BED 10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV 1 ) were independently prognostic for LC. Disease progression was reported in 75 patients with DFS-rates of 66% at 2 years and 56% at 3 years. Disease recurrence was independent significantly associated with larger tumor diameter, lower lobe tumor location and decreased FEV 1 . Grade 4-5 toxicity was reported in 10 patients (8 with ultra-central tumors) and was fatal in at least 3 patients. Conclusion : Decrease in tumor coverage was not correlated with the local recurrence probability. The LC and DFS were promising after SBRT of centrally located NSCLC with tumor size, FEV 1 and tumor location (for DFS only) as prognostic factors.

Purpose: The treatment of central lung tumors with stereotactic body radiation therapy (SBRT) is challenged by the risk of excessive esophageal toxicity. To improve clinical decision making, we aimed to derive normal tissue complication probability (NTCP) models in a patient cohort with central lung tumors treated with SBRT and to evaluate the currently used esophagus dose constraints., Methods and Materials: Patients with a central lung tumor who received SBRT (8 fractions of 7.5 Gy or 12 fractions of 5 Gy) were included. Doses were recalculated to an equivalent dose of 2 Gy with an α/β-ratio of 10 Gy for acute and 3 Gy for late toxicity (the cut-off was 3 months). The esophagus was manually delineated. NTCP modeling based on logistic regression was used to relate dose-volume histogram parameters (D max , D 1cc , D 2cc , D 5cc ) to acute and late toxicity. Parameters with a P < .05 were included in the model. Based on the NTCP models, we determined the probability of toxicity for the currently used dose constraints: D 1cc ≤40 Gy for 8 fractions and D 1cc ≤48 Gy for 12 fractions., Results: For this study, 188 patients with 203 tumors were eligible. Esophagus toxicity occurred in 33 patients (18%). Late high-grade toxicity consisted of 2 possible treatment-related deaths (grade 5) and 2 patients with grade 3 toxicity. Acute toxicity consisted of only grade 1 (n = 19) and grade 2 toxicity (n = 10). All investigated dose-volume histogram parameters were significantly correlated to acute and late toxicity. The probability of late high-grade toxicity is 1.1% for 8 fractions and 1.4% for 12 fractions when applying the current dose constraints., Conclusions: High-grade esophageal toxicity occurred in 2.1% of the patients, including 2 possible treatment-related deaths. The currently used dose constraints correspond to a low risk of high-grade toxicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The study compared interobserver variation in the delineation of the primary tumour (GTVp) and lymph nodes (GTVln) between three different 4DCT reconstruction types; Maximum Intensity Projection (MIP), Mid-Ventilation (Mid-V) and Mid-Position (Mid-P)., Material and Methods: Seven radiation oncologists delineated the GTVp and GTVln on the MIP, Mid-V and Mid-P 4DCT image reconstructions of 10 lung cancer patients. The volumes, the mean standard deviation (SD) and distribution of SD (SD/area) over the median surface contour were compared for different tumour regions., Results: The overall mean delineated volume on the MIP was significantly larger (p < 0.001) than the Mid-V and Mid-P. For the GTVp the Mid-P had the lowest interobserver variation (SD = 0.261 cm), followed by Mid-V (SD = 0.314 cm) and MIP (SD = 0.330 cm) For GTVln the Mid-V had the lowest interobserver variation (SD = 0.425 cm) followed by the MIP (SD = 0.477 cm) and Mid-P (SD = 0.543 cm). The SD/area distribution showed a statistically significant difference between the MIP versus Mid-P and Mid-P versus Mid-V for both GTVp and GTVln (p < 0.001), with outliers indicating interpretation differences for GTVp located close to the mediastinum and GTVln., Conclusion: The Mid-P reduced the interobserver variation for the GTVp. Delineation protocols must be improved to benefit from the improved image quality of Mid-P for the GTVln., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Radiation dose escalation using hypofractionation might improve overall survival (OS). We investigated OS in a phase II multicenter study in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypofractionated concurrent chemoradiotherapy., Materials and Methods: A 2-armed phase II, multi-center study (NTR2230) was performed with the aim to assess the effect of cetuximab to concurrent chemoradiotherapy in LA-NSCLC patients (stage II/IIIA/B). Arm A received high dose radiotherapy (24 × 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m(2)). Arm B received an identical treatment regimen with additional weekly cetuximab. Kaplan-Meier survival curves and 1-, 2- and 5-year OS proportions were calculated., Results: Between February 2009 and May 2011, 102 patients were randomly allocated in two arms. Median OS was 31.5 months (range 12.8-52.3), not significantly different between arms A and B; 33.0 (range 17.0-57.0) and 30.0 (11.0-52.0) months. 1-, 2- and 5-year OS rates were 74.5%, 59.4% and 37.3%, respectively. In multivariate analyses, worse performance score, V35 of the esophagus and the existence of comorbidities were significantly (P-value<0.05) associated with a shorter OS., Discussion: In this phase II trial, the median OS for the entire group was remarkably high; 31.5 months. Furthermore, 5-year OS was still 37.3%. Hypofractionation might contribute to improved OS in LA-NSCLC patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: A randomised phase III study was performed comparing sequential (S) and concurrent (C) chemo-radiotherapy (CRT) in non-small cell lung cancer (NSCLC) patients., Methods: One hundred and fifty-eight patients were randomised to receive two courses of Gemcitabine (1250mg/m(2) days 1, 8) and Cisplatin (75mg/m(2) day 2) prior to, or daily low-dose Cisplatin (6mg/m(2)) concurrent with radiotherapy, consisting of 24 fractions of 2.75Gy in 32 days, with a total dose of 66Gy., Results: Acute haematological toxicity grade 3/4 was more pronounced in the sequential (S) (30% versus 6%), oesophagitis grade 3/4 more frequent in the concurrent (C) arm (5% versus 14%). Late oesophagitis grade 3 was 4% (S and C), pneumonitis grade 3/4 14% (S) and 18% (C). Because of the poor power of the study no significant differences in median survival (MS), overall survival (OS) and progression-free survival (PFS) could be detected. MS was 16.2 (S) and 16.5 (C) months, 2-year OS was 34% (S) and 39% (C), 3-year OS was 22% (S) and 34% (C)., Conclusion: Radiotherapy 66Gy given concurrently with daily low-dose Cisplatin or after two courses of Gemcitabine/Cisplatin was well tolerated. Due to early closure no conclusions can be reached on the relative merits; both arms showed good OS.

We aimed to investigate whether biological factors related to radiosensitivity and chemosensitivity have prognostic significance in non-small-cell-lung-cancer (NSCLC) patients treated with daily low doses of cisplatin and radiotherapy. We treated 27 NSCLC patients with concomitant daily low-dose cisplatin and radiotherapy between 1993 and 1995. Tumour specimens were analyzed for p53 and bcl-2 expression, and for cell proliferation using antibodies against ki-67. In addition, apoptosis was measured by an end-labeling technique (TUNEL). Finally, cisplatin-induced DNA modification in buccal cells was assessed immunocytochemically using a specific anti-serum. Univariate and multivariate analyses were performed to assess the association between the different variables and survival. The median follow-up was 41 months, and 21 patients (78%) have died. In a univariate analysis, age, tumour stage and cisplatin-DNA-adduct staining were the only factors significantly associated with survival (p < 0.05, log-rank test). p53, bcl-2, Ki-67 and apoptosis showed no relationship with outcome. Multivariate analysis revealed that cisplatin-DNA-adduct staining remained an independent prognostic factor (hazard ratio, 0.10, 95% CI, 0.02-0.49), with shorter survival times for patients with low adduct staining., (Copyright 2000 Wiley-Liss, Inc.)

The aim of this study was to determine whether it is feasible to reduce the overall treatment time from 7 to 4 weeks in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy with cisplatin. This follows an EORTC phase III randomised trial (08844) in which cisplatin given before each radiation dose resulted in improved local control and survival, but which had a relatively long treatment period of 7 weeks [Schaake-Koning et al., N Engl J Med 1992, 326, 524-530]. 38 patients with confirmed NSCLC (2 stage I, 1 stage II, 18 stage IIIA, 17 stage IIIB) received a total tumour dose of 55 Gy/20 fractions/26 days, from January 1992 to March 1994. Daily fractions of 2 Gy (5 times/week) were given to the macroscopic tumour and the non-involved adjacent lymph node areas. During the same session, a dose of 0.75 Gy was given to the macroscopic tumour (simultaneous boost). Cisplatin 6 mg/m2 was administered 1-2 h before each fraction, in an escalating total dose, during week 1 in 3 patients, during weeks 1 and 2 in 6 patients, during weeks 1, 2 and 3 in 5 patients and during the whole treatment in 24 patients. 38 patients were evaluable for acute side-effects (WHO). Maximal therapy-related toxicity (WHO) was grade 3 (nausea/vomiting in 2 patients, oesophagitis in 3 patients, dyspnoea in 3 patients, cough in 1 patient). Late side-effects were evaluated in 34 patients. There was grade 2 oesophagitis in 2 patients; grade 3 toxicity in 8 patients (tiredness in 3 patients, dyspnoea in 3 patients, oesophagitis in 2 patients); grade 4 toxicity in 4 patients (dyspnoea in 3 patients, cough in 1 patient). Pulmonary fibrosis grade 3 occurred in 4 and grade 4 in 6 patients. One patient developed a severe (grade 3) radiation pneumonitis. The low incidence of acute and late side-effects with this treatment, combining daily administration of 6 mg cisplatin with radical radiotherapy using a simultaneous boost technique, indicates that escalation of the radiation dose seems feasible.