Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy.

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/ß-value of 10 Gy (BED10). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED10; (%)PTV < 100 BED10. 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 BED10 and %PTV < 100 BED10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV1) 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 FEV1. 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, FEV1 and tumor location (for DFS only) as prognostic factors.

Excessive esophageal toxicity in patients with locally advanced non-small cell lung cancer treated with concurrent hypofractionated chemoradiotherapy and 3-weekly platinum doublet chemotherapy.

Introduction: Concurrent chemoradiation followed by immunotherapy is the standard of care for patients with stage III non-small cell lung cancer (NSCLC). Prior to the introduction of adjuvant immunotherapy, we treated patients with stage III NSCLC with concurrent platinum doublet chemotherapy and 66 Gy in 24 fractions. We determined the toxicity of this treatment. Methods: A retrospective observational study was performed in a cohort of patients with stage III NSCLC, <70 years old, and WHO performance score 0-1. Patients were treated with concurrent platinum doublet chemotherapy and 66 Gy in 24 fractions. All patients were staged with a PET-scan and brain MRI-scan. Toxicity was scored using the common criteria for adverse events (CTCAE v4.03). Results: Between 2012 and 2017, 41 patients were treated with mildly hypofractionated radiotherapy and platinum doublet chemotherapy. The median follow-up was 4.7 years. The median age was 57 and 58% of patients were male. The majority of patients had stage IIIB disease (68%). The median total Gross Tumor Volume (GTV) was 104 cc (range: 15-367 cc). The median lymph node GTV was 59 cc (10-341 cc). Five patients died: four due to an esophagus perforation or fistula, and one due to pulmonary bleeding. Grade ≥ 3 esophageal toxicity occurred in 16 patients. Five patients had late grade ≥ 3 esophageal toxicity (12%). The median overall survival was 19 months. Conclusion: Toxicity was unexpectedly high in patients with stage III NSCLC (WHO 0-1) after concurrent platinum doublet chemotherapy and 66 Gy in 24 fractions.

Predicting High-Grade Esophagus Toxicity After Treating Central Lung Tumors With Stereotactic Radiation Therapy Using a Normal Tissue Complication Probability Model.

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/ß-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 (Dmax, D1cc, D2cc, D5cc) 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: D1cc ≤40 Gy for 8 fractions and D1cc ≤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.

Interobserver variability in the delineation of the primary lung cancer and lymph nodes on different four-dimensional computed tomography reconstructions.

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.

Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973).

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.

Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab.

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.

Can errors in reconstructing pre-chemotherapy target volumes contribute to the inferiority of sequential chemoradiation in stage III non-small cell lung cancer (NSCLC)?

Concurrent chemo-radiotherapy (CT-RT) has been shown to be superior to sequential CT-RT for stage III non-small cell lung cancer (NSCLC). Pre-chemotherapy gross tumor volumes (GTV) are commonly contoured for sequential CT-RT and, as significant inter-clinician variability exists in defining GTV's for lung cancer, we postulated that the poorer local control observed with sequential CT-RT may partly be due to the larger errors in defining GTV after chemotherapy-induced tumor regression. Pre-and post-chemotherapy CT scans for RT planning (RTP) were performed in ten patients who received induction chemotherapy for NSCLC. Image registration of pre- and post-chemotherapy RTP scans was performed for all patients. GTV's were first contoured in the conventional manner by two clinicians, i.e. by visual reconstruction from hard copies of the pre-chemotherapy diagnostic CT scans ('GTV-visual'). A 'GTV-match' was then contoured after image-registration, and the 'gold standard' volume was considered to be the overlap of the 'GTV-match' generated by both clinicians. The 'GTV-match' was on average 31-40% larger than 'GTV-visual'. The mean percentage of the 'gold standard', which was not covered by the 'GTV-visual' was similar for both clinicians, i.e. 26.3+/-12.5 and 28.0+/-15.0%. The inter-clinician agreement in contouring improved after image registration. These data suggest that conventional visual contouring of pre-chemotherapy GTV's may fail to treat the actual pre-chemotherapy tumor volume, and thus confound studies evaluating optimal sequencing of chemo-radiotherapy in NSCLC.