ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.

OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Illustration of a fatal radiation-induced lung aneurysm: Is central lung stereotactic radiotherapy to be banned?

Stereotactic body radiation therapy is still controversial for inoperable patients with central lung lesion. We report the case of a 59-year-old woman with previous history of head and neck squamous cell carcinoma who was treated by lung stereotactic body irradiation for an inoperable lymph node in station 10R. One year after, a fibroscopy showed a necrosis of the right main bronchus mucosae and the CT showed a radio-induced aneurysm protruding into the right inferior lobular bronchus. The patient eventually died a few hours later with a massive haemoptysis. This case highlights the potential toxicity of central lung stereotactic body radiation therapy and raises the question of its legitimacy.

Effectiveness of crizotinib in a patient with ALK IHC-positive/FISH-negative metastatic lung adenocarcinoma.

We report a case of crizotinib effectiveness in a heavily pretreated patient with a metastatic NSCLC initially considered IHC-positive and FISH-negative for ALK rearrangement. After repeated analyses of tumor samples, borderline ALK FISH-positivity (18.5% positive cells) was demonstrated.

Combined endoscopic ultrasonography and endobronchial ultrasound-fine-needle aspiration for evaluation of mediastinal lymph nodes.

OBJECTIVES: Endoscopic ultrasonography (EUS) and endobronchial ultrasound-fine-needle aspiration (EBUS-FNA), is an accurate technique for evaluation of mediastinal lymph nodes (MLN) and stadification of lung cancer. The aims of the study are to evaluate the feasibility and the efficacy of the combined technique compared with mediastinoscopy for the diagnosis of MLN. DESIGN AND METHODS: All patients with suspected malignant MLN and/or lung lesion identified by positron emission tomography-computed tomography underwent combined EUS-EBUS-FNA. The combined procedure was performed in outpatients under general anesthesia for EUS and sedation by intravenous midazolam for EBUS when performed separately, using linear-array echoendoscopes. The MLN were punctured during the EUS and EBUS-FNA procedures with a 22 gauge needle. RESULTS: Thirty-four patients underwent consecutively EUS and EBUS-FNA between September 2011 and November 2013 (8 women, 26 men, mean age of 65.9 year, range: 51-83). Combined EUS-EBUS-FNA was performed in a single time procedure in 26 patients (mean time 50 min) and in two different times in eight patients (mean delay 3 days). Twenty-five malignant and 9 inflammatory lesions were diagnosed. Mediastinoscopy was performed in nine patients and confirmed in eight patients the initial combined EUS-EBUS-FNA diagnosis. The diagnosis was obtained in 91.2% with EUS-FNA, 70.6% with EBUS-FNA and 97% when combined procedure was performed. The overall sensitivity, specificity, positive and negative predictive values of EUS-EBUS-FNA for diagnosing malignancy were 96.5%, 100%, 100% and 90% respectively. No complications related to the procedure were observed. CONCLUSION: Combined EUS-EBUS-FNA represents an accurate technique in the diagnosis of MLN, can be done in a single time procedure and has the advantage of being less invasive than mediastinoscopy.

Gefitinib monotherapy in advanced nonsmall cell lung cancer: a large Western community implementation study.

Epidermal growth factor receptor tyrosine kinase inhibitors represent a new treatment option for patients with advanced nonsmall cell lung cancer (NSCLC). This retrospective study examined to what extent previous clinical trial experience matches large-scale Western community implementation of this treatment. In the Belgian expanded access programme, the data from 513 patients with advanced or metastatic NSCLC, not suitable for further chemotherapy and receiving oral gefitinib 250 mg.day(-1) until disease progression, death or unacceptable toxicity, were analysed. The median (range) duration of gefitinib treatment was 2.3 months (0.0-32.7). Its use was predominantly in second- or third-line treatment. The overall response and disease control rates were 8.9 and 41.2%, respectively. In univariate analysis, response was more common in females and never-smokers. In multivariate analysis, female sex was the only significant predictive factor (odds ratio (OR) (95% confidence interval (CI)) 0.329 (0.129-0.839)). Symptom improvement was reported in 108 patients of whom 32 (29.6%) had an objective response, 66 (61.1%) experienced disease stabilisation and 10 (9.3%) progressed. Gefitinib was well tolerated; only 7.8% of the patients reported grade 3 or 4 toxicity. The overall median survival was 4.7 months, with a 1-yr survival rate of 21%. Survival was strongly influenced by a better performance status (PS) (good PS: hazard ratio (HR) (95%CI) 0.110 (0.077-0.157)) and adenocarcinoma with bronchioloalveolar carcinoma features histology (HR (95%CI) 0.483 (0.279-0.834)). In conclusion, the activity of gefitinib was confirmed in the present large Western community implementation study. Response, present in a small subgroup, led to a rewarding survival and could be predicted by sex only. Baseline performance status and adenocarcinoma with bronchioloalveolar carcinoma features histology were significant factors for survival.