External validation of NTCP-models for radiation pneumonitis in lung cancer patients treated with chemoradiotherapy

PURPOSE: Normal tissue complication probability (NTCP) models can be used to estimate the risk of radiation pneumonitis (RP). The aim of this study was to externally validate the most frequently used prediction models for RP, i.e., the QUANTEC and APPELT models, in a large cohort of lung cancer patients treated with IMRT or VMAT. [1-2] METHODS AND MATERIALS: This prospective cohort study, included lung cancer patients treated between 2013 and 2018. A closed testing procedure was performed to test the need for model updating. To improve model performance, modification or removal of variables was considered. Performance measures included tests for goodness of fit, discrimination, and calibration.RESULTS: In this cohort of 612 patients, the incidence of RP ≥ grade 2 was 14.5%. For the QUANTEC-model, recalibration was recommended which resulted in a revised intercept and adjusted regression coefficient (from 0.126 to 0.224) of the mean lung dose (MLD),. The APPELT-model needed revision including model updating with modification and elimination of variables. After revision, the New RP-model included the following predictors (and regression coefficients): MLD (B = 0.250), age (B = 0.049, and smoking status (B = 0.902). The discrimination of the updated APPELT-model was higher compared to the recalibrated QUANTEC-model (AUC: 0.79 vs. 0.73).CONCLUSIONS: This study demonstrated that both the QUANTEC- and APPELT-model needed revision. Next to changes of the intercept and regression coefficients, the APPELT model improved further by model updating and performed better than the recalibrated QUANTEC model. This New RP-model is widely applicable containing non-tumour site specific variables, which can easily be collected.</p

Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer:the NVALT-8 study

Background: Retrospective studies suggest that low molecular weight heparin may delay the development of metastasis in patients with resected NSCLC. Methods: Multicentre phase 3 study with patients with completely resected NSCLC who were randomised after surgery to receive chemotherapy with or without nadroparin. The main exclusion criteria were R1/2 and wedge/segmental resection. FDG-PET was required. The primary endpoint was recurrence-free survival (RFS). Results: Among 235 registered patients, 202 were randomised (nadroparin: n = 100; control n = 102). Slow accrual enabled a decrease in the number of patients needed from 600 to 202, providing 80% power to compare RFS with 94 events (α = 0.05; 2-sided). There were no differences in bleeding events between the two groups. The median RFS was 65.2 months (95% CI, 36—NA) in the nadroparin arm and 37.7 months (95% CI, 22.7—NA) in the control arm (HR 0.77 (95% CI, 0.53–1.13, P = 0.19). FDG-PET SUVmax ≥10 predicted a greater likelihood of recurrence in the first year (HR 0.48, 95% CI 0.22–0.9, P = 0.05). Conclusions: Adjuvant nadroparin did not improve RFS in patients with resected NSCLC. In this study, a high SUVmax predicted a greater likelihood of recurrence in the first year. Clinical trial registration: Netherlands Trial registry: NTR1250/1217

Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer

Background: Stage III unresectable non-small cell lung cancer (NSCLC) is preferably treated with concurrent schedules of chemoradiotherapy, but none is clearly superior Gemcitabine is a radiosensitizing cytotoxic drug that has been studied in phase 1 and 2 studies in this setting. The aim of this study was to describe outcome and toxicity of low-dose weekly gemcitabine combined with concurrent 3-dimensional conformal radiotherapy (3D-CRT). Patients & methods: Treatment consisted of two cycles of a cisplatin and gemcitabine followed by weekly gemcitabine 300 mg/m(2) during 5 weeks of 3D-CRT, 60 Gy in 5 weeks (hypofractionated-accelerated). Overall survival (OS), progression-free survival (PFS), and treatment related toxicity according to Common Toxicity Criteria of Adverse Events (CTCAE) version 3.0 were assessed. Results: Between February 2002 and August 2008, 318 patients were treated. Median age was 64 years (range 36-86); 72% were male, WHO PS 0/1/2 was 44/53/3%. Median PFS was 15.5 months (95% confidence interval [CI], 12.9-18.1) and median OS was 24.6 months (95% CI., 21.0-28.1). Main toxicity (CTCAE grade >= 3) was dysphagia (12.6%), esophagitis (9.6%), followed by radiation pneumonitis (3.0%). There were five treatment related deaths (1.6%), two due to esophagitis and three due to radiation pneumonitis. Conclusion: Concurrent low-dose gemcitabine and 3D-CRT provides a comparable survival and toxicity profile to other available treatment schemes for unresectable stage III

Rare EGFR and KRAS mutations and tumor response to EGFR TKI.

<p>PR is partial response, PD is progressive disease, –  =  no EGFR TKI treatment; (E) = erlotinib, (G) = gefitinib, ND = Not described.</p

Flow chart for biopsy specimens sent in and result of mutation analysis.

<p>* 2 KRAS mutations are outside of the hotspot, these are probably non functional.</p

A: Overall survival in patients with non-small cell lung cancer treated with EGFR-TKI in the first and second line with or without an EGFR mutation. The median overall survival for patients with EGFR mutations (n = 14) was not reached, in patients with EGFR/KRAS WT it was 9 months (95% CI., 0–28 months, n = 31). 2B: Overall survival in patients with non-small cell lung cancer treated with EGFR-TKI in the first and second line with or without KRAS mutation. The median overall survival for patients with KRAS mutations was 20 months (95% CI., 0–46, n = 14), in patients with EGFR/KRAS WT it was 9 months (95% CI., 0–28 months, n = 31).

<p>A: Overall survival in patients with non-small cell lung cancer treated with EGFR-TKI in the first and second line with or without an EGFR mutation. The median overall survival for patients with EGFR mutations (n = 14) was not reached, in patients with EGFR/KRAS WT it was 9 months (95% CI., 0–28 months, n = 31). 2B: Overall survival in patients with non-small cell lung cancer treated with EGFR-TKI in the first and second line with or without KRAS mutation. The median overall survival for patients with KRAS mutations was 20 months (95% CI., 0–46, n = 14), in patients with EGFR/KRAS WT it was 9 months (95% CI., 0–28 months, n = 31).</p