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Background Molecular characterization of non–small-cell lung cancer (NSCLC), defined predictive and druggable mutations that greatly modified patient prognoses. The most frequent driver mutations detected in NSCLC are epidermal growth factor receptor (EGFR) mutations, accounting for approximately 90% of exon 19 deletions and exon 21 point mutations. The other EGFR mutations are classified as uncommon or nonclassical and include exon 18 point mutations, exon 20 insertions, and combined mutations, which present different sensitivity to tyrosine kinase inhibitor (TKI) targeting. Patients and Methods We collected data from EGFR TKI-naive patients with metastatic NSCLC, harboring EGFR exon 18 mutations and EGFR combined mutations treated with first- or second-generation EGFR TKIs. Efficacy end points were evaluated considering the activity of EGFR TKIs in exon 18 versus double-mutation EGFR groups. Results Eighty-eight patients harboring uncommon EGFR mutations were evaluated in our analysis, and subdivided into 2 group: complex mutations (cohort A = 46 patients) and double mutations in exon 18 (cohort B = 42 patients). The results showed a median progression-free survival of 8.3 versus 12.3 months (hazard ratio [HR], 0.65; P = .06) and a median overall survival of 17.0 versus 31.0 months (HR, 0.62, P = .04) favoring the EGFR combination group. Within the combination group, no detrimental effect was associated with exon 20 mutations. Conclusion Our study confirmed that EGFR exon 18 and combination mutations might be considered potentially sensitive uncommon mutations, with a similar survival compared with the well known common EGFR mutations. Comparative analysis showed that patients with complex mutations achieved longer survival compared with the exon 18 group, without correlation with the presence of exon 20 mutations.

Highlights • Bronchial localization of Mucoepidermoid carcinoma (MEC) is rare (0.1%–0.2% of all lung tumors). • Knowledge of the molecular features is essential for appropriate clinical management and improved outcomes. • Only a few studies have been performed in the field of the genetic molecular alterations of MECs. • EGFR mutations seems to be of primary importance in patients in whom a targeted therapy is under consideration. • The lack of EGFR sensitizing mutations does not preclude the use of TKIs, which may be extremely useful in patients non responsive to other therapies., Introduction Bronchial localization of Mucoepidermoid carcinoma (MEC) is rare. The precise nature of these neoplasms is not yet clear and little is known on the histogenesis and pathogenesis of the disease. Here we present a case of a bronchial MEC with a detailed pathological, immunohistochemical, and molecular analysis. Presentation of a case A 46 years old Caucasian male patient was referred to our Unit for fever, non productive cough and dyspnea lasting for two months. The chest CT scan evidenced an 8-mm intraluminal lesion in the left main bronchus, in correspondence of the origin of the lingular segmental bronchus. Multiple biopsies were performed through bronchoscopy, and the diagnosis of a mucoepidermoid carcinoma of the lung was obtained. A left upper lobectomy was performed. The histopathological examination confirmed the preoperative diagnosis and stage (pT1N0M0). No further therapies were employed, given the stage of the disease. The patient is presently free of disease, approximately three years after surgery. Discussion The treatment of MECs is usually surgical by traditional or sleeve lobectomy, performed with an open or video-assisted technique, with the aim of an R0 resection. In this stage the prognosis is excellent. Conversely, high grade tumors seems to be particularly aggressive, even more than other NSCLC. Conclusions Low grade type of Bronchial MEC, as our case, is often characterized by an optimal clinical management and prognosis. The lack of EGFR sensitizing mutations does not preclude the use of TKIs, which may be extremely useful in patients non responsive to other therapies.

Background We have extensively assessed a biweekly regimen of irinotecan plus folinic acid and fluorouracil bolus (IRIFAFU) in metastatic colorectal cancer (MCRC). Here, we report on the safety and activity of BIFF (bevacizumab plus IRIFAFU) regimen in 94 mCRC patients. Patients and Methods Bevacizumab 5 mg/kg (1 hour), and irinotecan 180 mg/m 2 (1hour) were given intravenously on day 1, 6S-folinic acid 250 mg/m 2 (2 hours), and fluorouracil 850 mg/m 2 (bolus) were given intravenously on day 2 every 2 weeks for a median of 9 cycles per patient (range, 1-12), and maintenance bevacizumab alone was delivered in 16 cases. Results Grade ≥ 3 hematologic toxicities were neutropenia (50%) and febrile neutropenia (5%). Most common grade 3 nonhematologic side effects were diarrhea (20%), vomiting (7%), nausea (4%), and stomatitis (4%). Severe hypertension (1%) and epistaxis (1%) rarely occurred. Six complete responses and 44 partial responses were registered, giving a response rate of 53% (95% CI, 43%-64%). Median progression-free survival was 11.5 months (95% CI, 9.0-14.0 months). Forty-three (46%) patients eventually died, and the median overall survival was 24.0 months (95% CI, 20.2-27.8 months). Conclusion Bevacizumab appeared to increase the activity of the IRIFAFU regimen without worsening its tolerability. Efficacy of BIFF was comparable with that reported with other bevacizumab plus irinotecan-based combinations.

Purpose To estimate the safety, activity, and impact on quality of life of a combination of gemcitabine and pemetrexed in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in the context of a randomized two-stage phase II study. Patients and methods Patients in stage IIIB or IV NSCLC were randomly allocated to receive either gemcitabine 1250mg/m 2 on day 1, and pemetrexed (Alimta) 500mg/m 2 followed by gemcitabine 1250mg/m 2 on day 8 of a 3-weekly cycle (GA arm), or paclitaxel 120mg/m 2 followed by gemcitabine 1000mg/m 2 , both given on days 1 and 8 of a 3-weekly cycle (PG arm). Results 105 (GA arm, 51; PG arm, 54) eligible patients (stage IV, 32 and 30, respectively) were enrolled into this study; thereafter, accrual was stopped due to first-stage analysis. The response rate was 20% (95% confidence interval [CI], 10–33%) in the GA arm, and 32% (95% CI, 20–46%) in the PG arm. Median progression-free survival was 5.1 (95% CI, 3.7–6.5) months in the GA arm, and 8.3 (95% CI, 5.9–10.7) months in the PG arm, while median overall survival was 10.5 (95% CI 7.1–13.9), and 13.3 (95% CI 11.7–14.9) months, respectively. Severe neutropenia (36% vs 22%), and febrile neutropenia (14% vs 7%) were more common with the GA regimen, while hair loss (52% vs 16%) and any grade peripheral neuropathy (31% vs 2%) occurred more frequently with PG regimen. Other severe side effects of GA regimen were diarrhoea (10%), liver enzyme derangement (10%), and fatigue (8%). Conclusion The GA regimen was tolerated and moderately active in advanced or metastatic NSCLC. However, this combination did not yield any advantage in comparison with the PG regimen, and does not deserve further evaluation.

We retrospectively assessed tolerability and efficacy of paclitaxel plus gemcitabine combination in 259 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) enrolled in three randomized SICOG trials according to their age ( 70 years) at study entry. Apart from age, demographic and clinical characteristics were similar in the two groups. Response rate of paclitaxel plus gemcitabine was similar in younger and in elderly (36% versus 30%). Chemotherapy was well tolerated, but severe neutropenia (12% versus 7%), anaemia (6.6% versus 1.8%), and vomiting (5% versus 0) were more frequent in elderly patients. Both median progression-free survival (PFS, 5.5 months versus 4.2 months), and overall survival (OS, 11.1 months versus 9.1 months) resulted slightly prolonged for younger patients. However, only stage and performance status resulted independently affecting PFS and OS. In conclusion, paclitaxel plus gemcitabine were similarly tolerated and active in younger and elderly patients. This regimen should be considered an option for the management of fit elderly patients.

Background We evaluated safety and efficacy of PTK787/ZK222584 (PTK/ZK), a novel tyrosine kinase inhibitor of KIT, platelet-derived growth factor receptors and vascular endothelial cell growth factor receptors (VEGFRs), in patients with imatinib-resistant gastrointestinal stromal tumor (GIST). This is the first study of PTK/ZK in this population. Patients and methods Patients with metastatic GIST that had progressed after ≥ 4-week treatment with imatinib mesylate were eligible. Prior VEGFR-2 inhibitor therapy was not permitted. PTK/ZK 1250 mg orally once-daily was administered to 15 patients (accrued as a two-stage procedure), most of whom (n = 11) had been unsuccessfully treated with imatinib 800 mg daily, until treatment failure. Patients were monitored at 4- to 8-week intervals. Results All 15 patients enrolled were eligible; two (13%) achieved partial response (PR), eight (53%) had stable disease (SD) ≥3 months, and five (33%) progressed. The clinical benefit rate (PR + SD) was 67% (95% CI 38% to 86%). Median time to progression was 8.5 months (range 0.9–24.8+ months). Three patients had not progressed at the time of analysis, including one PR at 24.8 months and two SDs at 16.6 and 18.6 months on treatment. PTK/ZK was generally well tolerated. Conclusion PTK/ZK 1250 mg p.o. once daily is active and well tolerated in patients with imatinib-resistant GIST.

Summary Purpose This study was undertaken to select the best schedule of administration for the paclitaxel plus gemcitabine combination in fit elderly patients affected by locally advanced or metastatic non-small cell lung cancer (NSCLC). Patients and methods Ninety-eight patients in stage III or IV NSCLC, aged 70 years or more and in ECOG performance status (PS) ≤ 1, were randomly allocated to receive: paclitaxel 80 mg/m 2 plus gemcitabine 1000 mg/m 2 i.v. on days 1 and 8, with an intra-patient alternated dose escalation up to 100 and 1200 mg/m 2 , respectively, over three cycles (arm A); or paclitaxel 80 mg/m 2 followed by gemcitabine 1000 mg/m 2 i.v. (100 min) on days 1 and 8 (arm B). Treatment was repeated in both arms every 3 weeks for a maximum of six cycles. Results With a median of 3 (range, 1–6) delivered cycles, the two schedules yielded a similar response rate (25% versus 26%), failure-free survival (median, 3.3 months versus 3.2 months), progression-free survival (median, 5.1 months versus 5.2 months), and overall survival (median, 9.7 months versus 9.6 months). Survival was independently affected by the PS of patients and by the metastatic spread. Severe side effects were comparable and negligible in both arms. Conclusion A substantial difference between these two schedules in terms of efficacy and safety can be ruled-out. Paclitaxel plus gemcitabine is an advisable combination for treating fit elderly patients with advanced NSCLC.

Background We have assessed the survival rate of patients with non–small cell lung cancer and synchronous hematogenous solitary metastasis identified with complete staging workup, including total body [ 18 F]fluorodeoxyglucose positron emission tomography scan, and treated with a multidisciplinary approach. Methods We examined the database of all patients who underwent surgery for primary non–small cell lung cancer in our institute. The criteria required for inclusion in this analysis were diagnosis of non–small cell lung cancer with synchronous hematogenous solitary metastasis by staging workup with total body computed tomography scan and brain magnetic resonance if indicated, total body positron emission tomography scan, radical surgery for the primary tumors, local treatment of the solitary metastasis, and systemic chemotherapy administration. Results We analyzed the data from 1,509 patients treated from January 2000 to December 2005: 10 patients (0.7%) satisfied the selection criteria. The median overall survival was 26 months, and the median time to progression was 20 months; 6 patients were alive at the time of analysis, with a median follow-up of 30 months. Four patients were tumor progression–free after 9, 18, 23, and 32 months from the start of their treatment. Conclusions The presentation of non–small cell lung cancer with a synchronous hematogenous solitary metastasis identified by [ 18 F]fluorodeoxyglucose positron emission tomography containing complete staging workup is extremely rare. This subset of patients can achieve long-term survival after a multidisciplinary treatment approach.