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Purpose: The epidermal growth factor receptor (EGFR) is recognized as a key mediator of proliferation and progression in many human tumors. A series of EGFR-specific inhibitors have recently gained Food and Drug Administration approval in oncology. These strategies of EGFR inhibition have shown major tumor regressions in approximately 10% to 20% of advanced cancer patients. Many tumors, however, eventually manifest resistance to treatment. Efforts to better understand the underlying mechanisms of acquired resistance to EGFR inhibitors, and potential strategies to overcome resistance, are greatly needed. Experimental Design: To develop cell lines with acquired resistance to EGFR inhibitors we utilized the human head and neck squamous cell carcinoma tumor cell line SCC-1. Cells were treated with increasing concentrations of cetuximab, gefitinib, or erlotinib, and characterized for the molecular changes in the EGFR inhibitor^resistant lines relative to the EGFR inhibitorŝ ensitive lines.Results: EGFR inhibitor^resistant lines were able to maintain their resistant phenotype in both drug-free medium and in athymic nude mouse xenografts. In addition, EGFR inhibitor^resistant lines showed a markedly increased proliferation rate. EGFR inhibitor^resistant lines had elevated levels of phosphorylated EGFR, mitogen-activated protein kinase, AKT, and signal transducer and activator of transcription 3, which were associated with reduced apoptotic capacity. Subsequent in vivo experiments indicated enhanced angiogenic potential in EGFR inhibitor^resistant lines. Finally, EGFR inhibitor^resistant lines showed cross-resistance to ionizing radiation. Conclusions:We have developed EGFR inhibitor^resistant human head and neck squamous cell carcinoma cell lines. This model provides a valuable preclinical tool to investigate molecular mechanisms of acquired resistance to EGFR blockade.

Brain metastases are not only the most common intracranial neoplasm in adults but also very prevalent in patients with lung cancer. Patients have been grouped into different classes based on the presence of prognostic factors such as control of the primary tumor, functional performance status, age, and number of brain metastases. Patients with good prognosis may benefit from more aggressive treatment because of the potential for prolonged survival for some of them. In this review, we will comprehensively discuss the therapeutic options for treating brain metastases, which arise mostly from a lung cancer primary. In particular, we will focus on the patient selection for combined modality treatment of brain metastases, such as surgical resection or stereotactic radiosurgery (SRS) combined with whole brain irradiation; the use of radiosensitizers; and the neurocognitive deficits after whole brain irradiation with or without SRS. The benefit of prophylactic cranial irradiation (PCI) and its potentially associated neuro-toxicity for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are also discussed, along with the combined treatment of intrathoracic primary disease and solitary brain metastasis. The roles of SRS to the surgical bed, fractionated stereotactic radiotherapy, WBRT with an integrated boost to the gross brain metastases, as well as combining WBRT with epidermal growth factor receptor (EGFR) inhibitors, are explored as well.

Key PointsQuestionHow does the long-term survival after curative-intent surgery with regional lymph node examination of various extents compare with long-term survival after stereotactic body radiotherapy for early-stage non–small cell lung cancer?FindingsIn this cohort study of 104 709 patients in the US National Cancer Database with early-stage non–small cell lung cancer, those who received surgery coupled with regional lymph node examination of an appropriate extent had significantly better long-term survival than those who received stereotactic body radiotherapy.MeaningThese findings suggest that curative-intent surgery, when coupled with regional lymph node examination, is generally associated with the best long-term overall survival in patients with early-stage non–small cell lung cancer.

Purpose To assess hypo-fractionated particle beam therapy (PBT)'s efficacy relative to that of photon stereotactic body radiotherapy (SBRT) for early stage (ES) non-small cell lung cancer (NSCLC). Methods Eligible studies were identified through extensive searches of the PubMed, Medline, Google-scholar, and Cochrane library databases from 2000 to 2016. Original English publications of ES NSCLC were included. A meta-analysis was performed to compare the survival outcome, toxicity profile, and patterns of failure following each treatment. Results 72 SBRT studies and 9 hypo-fractionated PBT studies (mostly single-arm) were included. PBT was associated with improved overall survival (OS; p = 0.005) and progression-free survival (PFS; p = 0.01) in the univariate meta-analysis. The OS benefit did not reach its statistical significance after inclusion of operability into the final multivariate meta-analysis (p = 0.11); while the 3-year local control (LC) still favored PBT (p = 0.03). Conclusion Although hypo-fractionated PBT may lead to additional clinical benefit when compared with photon SBRT, no statistically significant survival benefit from PBT over SBRT was observed in the treatment of ES NSCLC in this hypothesis-generating meta-analysis after adjusting for potential confounding variables.