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The inhibition of the Epidermal Growth Factor (EGFR) represents one of the most promising strategies in non-small cell lung cancer (NSCLC) therapy. The recently identified C797S mutation causes resistance of EGFR L858R/T790M against osimertinib, the latest approved third generation EGFR inhibitor. The identification of small molecules capable of selectively inhibiting the T790M mutations also in the late-onset C797S mutation is a desirable strategy and novel chemical structures might provide new insight in the overcoming resistance mechanisms. Here we report the identification of a novel mutant-selective privileged molecular core; guided by a structure-based drug design, a flavone skeleton has been rationally modified, and a virtual library generated. Reversible EGFR inhibitors targeting both L858R/T790M and L858R/T790M/C797S mutations with a higher affinity with respect to the wild type one are discovered via a three-track virtual screening. Selected hits were synthesized and tested in an activity-based enzyme assay against wild-type EGFR, L858R/T790M, as well as L858R/T790M/C797S. The results showed that a nitroflavone-based compound inhibits the phosphorylation of EGFR mutants at low-micromolar concentration showing selectivity over the wild type ones. Structurally similar flavone analogues have been synthesized and the following inhibition assays underlied the importance of both the presence and position of the nitrophenoxy moiety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Immune checkpoint inhibition after radiochemotherapy (RTCT) has become a new standard of care for locally advanced non-small cell lung cancer with programmed death-ligand 1 (PD-L1) expression. However, little is known about the prognostic role of immune response markers in this setting. We analysed PD-L1 expression and tumour infiltrating lymphocytes (TiLs) in tumour biopsies from the multicenter German Intergroup Lung Trial (GILT), which previously randomised patients with stage III NSCLC to RTCT with or without consolidation chemotherapy., Materials and Methods: We retrospectively analyzed tumour biopsies from patients treated in the GILT trial. PD-L1 expression was analysed using the Ventana SP263 assay and TiL score (low, intermediate, high) and pattern (excluded, inflamed, desert) were assessed. The primary endpoint of the biomarker analysis was PFS in patients with PD-L1 ≥ 1% vs. PD-L1 < 1% NSCLC. Secondary endpoints explored the prognostic relevance of additional PD-L1 expression levels and TiL score and pattern., Results: Biopsies were available from 92 patients treated with RTCT. Patients with available tumor tissue did not differ significantly from the whole study population. PD-L1 scores from 78 samples were available for analysis. There was no difference in PFS in the PD-L1 < 1% vs. PD-L1 ≥ 1% subgroups. TiL score was available in 66 patients. Patients with high TiL score showed favourable overall survival compared to the low TiL subgroup. This trend was most pronounced in those patients treated with consolidative chemotherapy., Conclusion: In this analysis, PD-L1 expression did not correlate with PFS following RTCT. However, patients with TiLs > 10% were found to have longer overall survival, especially for those patients treated with consolidation chemotherapy after the end of RTCT. Further analyses to explore the prognostic and predictive relevance of TiLs in the context of consolidative checkpoint inhibition with durvalumab are required., (Copyright © 2021. Published by Elsevier B.V.)

Background: Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription., Methods and Materials: We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BED min ); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BED max ); and (3) the average between near-minimum and near-maximum doses (yielding BED ave ). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion., Results: There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BED ave was the best predictor of risk of local recurrence, and a model based on BED min had substantially less evidential support. In univariable logistic regression, the model based on BED ave also performed best. Multivariable classification using fast and frugal trees revealed BED max to be the most important predictor, followed by BED ave ., Conclusions: BED ave was generally better correlated with tumor control probability than either BED max or BED min . Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: If routine diagnostics are inconclusive, neurologic deterioration and death of patients with brain cancer are attributed to tumor or therapy. Therefore, diagnosing symptoms of encephalopathy caused by human cytomegalovirus (HCMV) reactivation remains uncommon. We investigated the role of HCMV reactivation in neurologic decline and clinical outcome after the start of radiochemotherapy., Experimental Design: HCMV analyses and extended MRI studies including additional independent retrospective neuroradiologic evaluation were performed at predetermined intervals and in case of sudden neurologic decline for 118 adult patients: 63 histologically proven high-grade gliomas, 55 with brain metastases. Immunophenotyping from simultaneously taken whole-blood samples was carried out to detect immune cells serving as prognostic marker for HCMV-associated complications. Symptomatic viremia and overall survival (OS) were the endpoints., Results: Twenty-four percent (28/118) of all patients (12/44 glioblastoma, 3/13 anaplastic astrocytoma; 8/31 non-small cell lung cancer (NSCLC), 13/24 other brain metastases) developed HCMV-viremia during or within 4 weeks after radiotherapy; 21 of 28 patients experienced concurrent major neurologic decline, reversible by antiviral treatment. Identified by immunophenotyping, pretherapeutically low basophil counts predicted a high-risk for HCMV-associated encephalopathy (glioblastoma: P = 0.002, NSCLC: P = 0.02). Median OS was substantially reduced after HCMV-associated encephalopathy without MRI signs of tumor progression [glioblastoma: 99 vs. 570 days (calculated 1-year OS: 22% vs. 69%; P = 0.01) and NSCLC: 47 vs. 219 days (calculated 1-year OS: 0% vs. 32%; P = 0.02)]., Conclusions: For patients with brain cancer, HCMV reactivation after the start of radiochemotherapy is a frequent risk for cognitively detrimental but treatable encephalopathy and premature death. Routinely performed HCMV diagnostics, assessing basophil counts and study-based anti-viral regimens, are necessary to combat this hidden threat. See related commentary by Lawler et al., p. 3077 ., (©2020 American Association for Cancer Research.)

Background: High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data., Materials and Methods: We combined two large retrospective datasets, yielding 1294 SBRTs (≤10 fractions) of early stage NSCLC. Cox proportional hazards regression, a logistic tumor control probability model and a biologically motivated Bayesian cure rate model were used to estimate the α/β ratio based on the observed number of local recurrences and accounting for tumor size., Results: A total of 109 local progressions were observed after a median of 17.7 months (range 0.6-76.3 months). Cox regression, logistic regression of 3 year tumor control probability and the cure rate model yielded best-fit estimates of α/β = 12.8 Gy, 14.9 Gy and 12-16 Gy (depending on the prior for α/β), respectively, although with large uncertainties that did not rule out the conventional α/β = 10 Gy., Conclusions: Clinicians can continue to use the simple LQ formalism to compare different SBRT treatment schedules for NSCLC. While α/β = 10 Gy is not ruled out by our data, larger values in the range 12-16 Gy are more probable, consistent with recent meta-regression analyses., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors., Materials and Methods: A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison., Results: After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort., Conclusions: Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The purpose of this work is to analyze patterns of care and outcome after stereotactic body radiotherapy (SBRT) for centrally located, early-stage, non-small cell lung cancer (NSCLC) and to address the question of potential risk for increased toxicity in this entity., Methods and Materials: A total of 90 patients with centrally located NSCLC were identified among 613 cases in a database of 13 German and Austrian academic radiotherapy centers. The outcome of centrally located NSCLC was compared to that of cases with peripheral tumor location from the same database., Results: Patients with central tumors most commonly presented with UICC stage IB (50 %), while the majority of peripheral lesions were stage IA (56 %). Average tumor diameters were 3.3 cm (central) and 2.8 cm (peripheral). Staging PET/CT was available for 73 and 74 % of peripheral and central tumors, respectively. Biopsy was performed in 84 % (peripheral) and 88 % (central) of cases. Doses varied significantly between central and peripheral lesions with a median BED10 of 72 Gy and 84 Gy, respectively (p < 0.001). Fractionation differed as well with medians of 5 (central) and 3 (peripheral) fractions (p < 0.001). In the Kaplan-Meier analysis, 3-year actuarial overall survival was 29 % (central) and 51 % (peripheral; p = 0.004) and freedom from local progression was 52 % (central) and 84 % (peripheral; p < 0.001). Toxicity after treatment of central tumors was low with no grade III/IV and one grade V event. Mortality rates were 0 and 1 % after 30 and 60 days, respectively., Conclusion: Local tumor control in patients treated with SBRT for centrally located, early-stage NSCLC was favorable, provided ablative radiation doses were prescribed. This was, however, not the case in the majority of patients, possibly due to concerns about treatment-related toxicity. Reported toxicity was low, but prospective trials are needed to resolve the existing uncertainties and to establish safe high-dose regimens for this cohort of patients.

Purpose: Considering the various comorbidities associated with aging, the feasibility and usefulness of concurrent chemoradiotherapy (CRT) in older patients with inoperable non-small cell lung cancer (NSCLC) is a controversial issue. Here, we compared the feasibility of CRT and the effects of various comorbidities on the prognosis of a minimally selected population of inoperable NSCLC patients aged 60-77 years., Patients and Methods: The study comprised 161 patients with inoperable NSCLC who received CRT with a target radiation dose greater than  60 Gy and platinum-based chemotherapy from 1998 to 2007. The total population included 69 patients aged 60-69 years and 53 aged 70-77 years. These two age cohorts were included in the study with a follow-up of a median 14.5 months., Results: The two groups showed no differences in long-term survival, as reflected by the 5-year survival rates of 13.0 ± 4.1 % (60- to 69-year-olds) and 14.4 ± 4.9 % (70- to 77-year-olds). During the treatment phase, the groups were comparable in terms of toxicity and the feasibility of chemotherapy. Compared to patients in their 60s, the septuagenarians had more pulmonary comorbidities (p = 0.02), diabetes mellitus (p = 0.04), cardiac comorbidities (p = 0.08), and previous cancer disease (p = 0.08) that exerted a negative effect on survival. In patients without comorbidities, there were no differences between the age groups., Conclusion: Age is not a contraindication for concurrent CRT per se, because elderly patients do not have a worse long-term prognosis than younger seniors. However, "elderly patients" (≥ 70-77 years) have more concomitant diseases associated with shorter survival than "moderately aged patients" (≥ 60-69 years).

Objective: The therapeutic strategies for oligometastatic non-small cell lung cancer have changed over the last decade from palliative to curative intent. The role of surgery in this multimodal treatment in selected patients remains a subject for open discussion., Methods: Data of 34 patients with one or two metastases treated from January 1998 to January 2013 were retrospectively analysed., Results: The mean age was 59.7 (± 10.1) years. The male vs. female ratio was 20 vs. 14. Adenocarcinoma was the most common histological type (58.8 %). The synchronous metastases were present in 15 patients, the metachronous in 19 patients. Single metastases were present in 27 patients, two metastases in 7 patients. The most frequently involved organs were brain (58.8 %) and the lungs (23.6 %). The primary tumour resection was achievable in 20 patients as R0 and in 2 patients as R1. The median overall survival, the local and the systemic disease-free survivals in the entire group were 40, 38 and 25 months, respectively. The 5 year overall survival, the 5 year local and systemic disease-free survivals were 29.2, 26.9 and 16.5 %, respectively. The treatment strategies including surgery for primary tumour as well as for pulmonary metastases site, combined with the lymph node dissection and the resection of the extracerebral and cerebral metastases, were identified as independent prognostic factors for long-term survival., Conclusion: Surgery in oligometastatic non-small cell lung carcinoma is feasible for primary tumour and for metastases. It is an effective option in the multimodal treatment in highly selected patients. The lymph node dissection should remain an important integral part of the surgical treatment., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control., Methods and Materials: We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection., Results: Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED(ISO)) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED(ISO) and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED(ISO), age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively., Conclusions: These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP modeling are expected through a nonlinear combination of multiple features, eventually helping in the task of personalized treatment planning., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC)., Materials and Methods: This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs)., Results: There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20)., Conclusion: Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Introduction: To evaluate safety and efficacy of stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) in a patterns-of-care and patterns-of-outcome analysis., Methods: The working group "Extracranial Stereotactic Radiotherapy" of the German Society for Radiation Oncology performed a retrospective multicenter analysis of practice and outcome after SBRT for stage I NSCLC. Sixteen German and Austrian centers with experience in pulmonary SBRT were asked to participate., Results: Data of 582 patients treated at 13 institutions between 1998 and 2011 were collected; all institutions, except one, were academic hospitals. A time trend to more advanced radiotherapy technologies and escalated irradiation doses was observed, but patient characteristics (age, performance status, pulmonary function) remained stable over time. Interinstitutional variability was substantial in all treatment characteristics but not in patient characteristics. After an average follow-up of 21 months, 3-year freedom from local progression (FFLP) and overall survival (OS) were 79.6% and 47.1%, respectively. The biological effective dose was the most significant factor influencing FFLP and OS: after more than 106 Gy biological effective dose as planning target volume encompassing dose (N = 164), 3-year FFLP and OS were 92.5% and 62.2%, respectively. No evidence of a learning curve or improvement of results with larger SBRT experience and implementation of new radiotherapy technologies was observed., Conclusion: SBRT for stage I NSCLC was safe and effective in this multi-institutional, academic environment, despite considerable interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influencing local tumor control and OS.

Purpose: Little is known about the effects of cardiopulmonary function on the prognosis of concurrent chemoradiotherapy in patients with inoperable non-small-cell lung cancer (NSCLC)., Methods and Materials: A retrospective analysis of the effects of tumor- and patient-related factors and parameters of cardiopulmonary function and heart morphology on the feasibility, toxicity, and prognosis was performed., Results: Cardiopulmonary function had no effect on the toxicity or feasibility of treatment; effects on survival were observed in the univariate analysis. Median survival varied as follows: cardiac function: 13.0 ± 1.6 months for left ventricular ejection fraction (LVEF) > 50% vs. 10.0 ± 1.9 months for LVEF ≤ 50% (p = 0.003); pulmonary function: 16.0 ± 0.6 months for no lung function deficits (vital capacity [VC] ≥ 60%, forced expiratory volume in 1 s ≥ 80%, and diffusing capacity of the lung for carbon monoxide (DLCO) ≥60%) vs. 14.0 ± 1.5 months for one or two function deficits vs. 8.0 ± 1.5 months for three lung function deficits (p = 0.001); T stage: 19.0 ± 3.1 months for rcT0/cT1/cT2 vs. 12.0 ± 0.8 months for cT3/cT4 (p = 0.039); and age: 11.0 ± 1.5 months for <60 years vs. 18.0 ± 2.5 months for 60-69 years vs. 12.0 ± 1.2 months for ≥70 years (p = 0.008). Prognostic factors identified in the multivariate analysis were LVEF ≤50% (p = 0.043; hazard ratio [HR], 1.74), reduced pulmonary function (p = 0.001; HR, 1.71 or 5.05) and T stage (p = 0.026; HR: 1.71)., Conclusions: In addition to T-stage, cardiac and pulmonary function variables affected the survival of non-small-cell lung cancer patients after chemoradiotherapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Concurrent chemoradiotherapy is presently the standard treatment for stage III inoperable non-small cell lung cancer. Within this treatment framework, conventionally fractionated radiotherapy to a total dose of 60-66 Gy has proven effective. The chemotherapy should be performed using a cisplatin-based regimen or, if contraindicated, carboplatin. The base drug can be combined with another cytostatic, such as etoposide, vinorelbine, paclitaxel or gemcitabine. There is no evidence from randomized clinical trials suggesting that addition of induction chemotherapy or adjuvant chemotherapy to the concurrent chemotherapy regimen improves the prognosis of these patients. Therefore, induction or adjuvant chemotherapy should not be used outside the framework of clinical trials. Age over 70 years and concomitant diseases are not contraindications for concurrent radiochemotherapy per se, but an increased rate of side effects can be expected in such elderly patients or patients with comorbidities. Consequently, these patients require intensive supportive care. Presumably, advanced age is not an adverse prognostic factor per se, but reduced heart and lung function are. Conclusive evidence confirming this assumption is lacking., (Copyright 2010 S. Karger AG, Basel.)

Background: The value of concurrent chemoradiotherapy (CRT) for treatment of locally advanced non-small cell lung cancer (NSCLC) in elderly and multimorbid patients is generally disputed due to the assumed lack of toxicity compensation or the limited prognosis of the accompanying morbidity., Aim: We investigated correlation between impaired organ function, age, tumor-associated symptoms, social factors and acute toxicity as well as survival following CRT., Patients and Methods: Retrospective data collection and analysis were performed on the variables age, functional parameters: FEV1, VC, DLCO, LVEF, creatinine clearance, age, several categories of comorbidities, WHO performance status, alcohol and nicotine habits, toxicity according CTC-criteria and survival of all patients (n=66) with inoperable NSCLC suffering substantial comorbidities or advanced age (>70 years) treated with an CRT consisting of two cycles cisplatin or carboplatin plus vinorelbine and a conventionally fractionated radiotherapy up to 63Gy., Results: Median survival of all patients was 13 months (10.6-15.4 months, 95% confidence interval). Univariate analyses showed significantly poorer survival (12 months vs. 15 months) in patients with LVEF<50% compared with LVEF> or = 50% (P=0.022, in log-rank test). All other variables did not exhibit any significant correlation to survival. Multivariate analyses revealed significantly inferior survival in patients suffering from cardiac or pulmonary dysfunction (P=0.039, hazard ratio [HR]: 2.18; 95% CI of HR [1.04-4.59]). Elderly patients (>70 years) had a higher prevalence of hematotoxicity of higher degree than younger patients (< or = 70 years), but without significant impact on the feasibility of both treatment modalities., Conclusion: Our results suggest that cardiac and pulmonary dysfunction may be associated with a reduced survival in elderly or poor-risk patients with inoperable NSCLC after CRT.

Background and Purpose: Although poor-risk patients represent no minority in inoperable non-small cell lung cancer (NSCLC), there is little experience with concurrent radiochemotherapy (RCT) in this group. Here, the authors report on the feasibility and efficacy of RCT with vinorelbine plus carboplatin or cisplatin in NSCLC patients with comorbidities and poor general health or advanced age., Patients and Methods: A total of 66 patients (ten women, 56 men, median age 68 years) with inoperable NSCLC and an increased risk of treatment side effects (WHO performance score of 2-3; cardiac, pulmonary or renal failure or extensive weight loss before treatment, or an age of 71-78 years) were treated with vinorelbine 12.5 mg/m(2) on days 1, 8, 15, 29, 36, and 43 in combination with either carboplatin 70 mg/m(2) (n = 59) or cisplatin 20 mg/m(2) (n = 7) on days 1-5 and 29-33 in addition to receiving conventional fractionated radiotherapy with doses of up to 63 Gy (90% isodose)., Results: 62 of 66 patients (94%) reached the 90% level of the prescribed radiation dose, and 41/66 patient (62%) received at least two cycles of the platinum compound and four cycles of vinorelbine. The following hematologic side effects (CTC classification [Common Toxicity Criteria]) were observed: grade 3 (12%) and grade 4 (15%) thrombocytopenia, grade 3 (38%) and grade 4 (4%) leukocytopenia, and anemia requiring transfusion (26%). Other side effects (CTC) included grade 3 (3%) and grade 4 (2%) esophagitis and grade 3 pneumonitis (3%). The response rates were as follows: complete remission 18%, partial remission 56%, stable disease 21%, and progressive disease 5%. The cumulative survival rates were 53%, 24%, and 8% at 12 months, 24 months, and 5 years, respectively., Conclusion: After including a larger group of patients than in 2003 and following the patients for several years, the authors determine that concurrent RCT consisting of vinorelbine plus a platinum compound and conventional fractionated radiotherapy can be carried out with manageable toxicity, even in this negatively selected population of patients. Their survival rates were comparable to those achieved in other studies with simultaneous RCT.

Background: Concurrent chemoradiotherapy has improved survival in inoperable stage III non-small cell lung cancer (NSCLC). This phase I trial was performed in order to establish a dose recommendation for oral vinorelbine in combination with cisplatin and simultaneous radiotherapy., Patients and Methods: Previously untreated patients with stage IIIB NSCLC received concurrent chemoradiotherapy with 66 Gy and 2 cycles of cisplatin and oral vinorelbine which was administered at 3 different levels (40, 50 and 60 mg/m2). This was to be followed by 2 cycles of cisplatin/ vinorelbine oral consolidation chemotherapy. The study goal was to determine the maximal recommended dose of oral vinorelbine during concurrent treatment., Results: 11 stage IIIB patients were entered into the study. The median radiotherapy dose was 66 Gy. Grade 3-4 toxicity included neutropenia, esophagitis, gastritis and febrile neutropenia. The dose-limiting toxicity for concurrent chemoradiotherapy was esophagitis. 9 patients received consolidation chemotherapy, with neutropenia and anemia/thrombocytopenia grade 3 being the only toxicities. The overall response was 73%., Conclusion: Oral vinorelbine 50 mg/m2 (days 1, 8, 15 over 4 weeks) in combination with cisplatin 20 mg/m2 (days 1-4) is the recommended dose in combination with radiotherapy (66 Gy) and will be used for concurrent chemoradiotherapy in a forthcoming phase III trial testing the efficacy of consolidation chemotherapy in patients not progressing after chemoradiotherapy.

Background: In elderly patients, patients with multiple morbidities, and patients with a reduced general condition, the standard treatment of inoperable non-small-cell lung cancer (NSCLC) consists of either chemotherapy or radiation therapy alone and is associated with an extremely poor prognosis. We therefore investigated the feasibility, toxicity, and efficacy of radiotherapy with concurrent chemotherapy using vinorelbine plus cisplatin or carboplatin in NSCLC patients at risk for treatment complications., Patients and Methods: A total of 33 patients (six women, 27 men, median age 65 years) with locally advanced, functionally inoperable pulmonary carcinomas, recurrent lung cancer or postoperative macroscopic residual tumors (R2) with an increased risk of treatment complications (WHO performance status 2/3; cardiac, renal or pulmonary failure; marked pretherapeutic weight loss; age between 71-75 years) received 12.5 mg of vinorelbine per m(2) body surface area (BSA) on days 1, 8, 15, 29, 36 and 43 plus either cisplatin 20 mg/m(2) BSA (ten patients) or carboplatin 70 mg/m(2) BSA (23 patients) on days 1-5 and 29-33 together with conventionally fractionated radiotherapy. The tumor regions were irradiated with doses of up to 63 Gy (90% isodose), and potentially affected lymph nodes received doses of up to 45.0 or 50.4 Gy (90% isodose)., Results: Briefly, 31 of 33 patients successfully completed radiation therapy and 26 received four cycles of vinorelbine plus at least two cycles of cisplatin or carboplatin. Hematotoxic side effects included grade III leukocytopenia (n = 8), grade III thrombocytopenia (n = 5), and grade IV thrombocytopenia (n = 2). Other side effects consisted of peripheral neuropathy grade III (n = 1) and esophagitis grade IV (n = 1). Severe pneumonitis did not occur. Six patients had pneumonia before radiochemotherapy. 21 patients (63%) exhibited a complete (n = 7) or partial response (n = 14) to chemoradiation. The twelve nonresponders had either stable (n = 9) or progressive disease (n = 3). The survival rates plus standard deviations were as follows: 1-year survival: 60 +/- 8%, 2-year survival: 36 +/- 9%, 3-year survival: 24 +/- 9%, median survival time: 17 months (5;29 months; 95% confidence interval [CI]), median progression-free survival: 11 months (9;13 months; 95% CI). The median follow-up time was 14 months., Conclusion: Conventionally fractionated radiochemotherapy with vinorelbine plus a platinum derivative is feasible in patients with NSCLC and increased risk of treatment complications. Compared to patient populations described in the literature, the survival rates achieved by concurrent radiochemotherapy appear to be better than those achieved with radiotherapy alone.