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Systemic Therapy for Lung Cancer for the Radiation Oncologist

  • Chandra P. Belani
Chapter
Part of the Medical Radiology book series (MEDRAD)

Abstract

Worldwide, approximately 1.6 million new cases of lung cancer are diagnosed each year. It continues to be the leading cause of cancer death. With the use of systemic therapy in addition to radiation and surgical resection, the outcome of all lung cancer patients continues to improve. There is an absolute improvement not only in overall survival (OS) but also in the quality of life of these patients, though modest at best. Non-small cell lung cancer (NSCLC) accounts for approximately 87% of all lung cancers, and is subdivided into two major types, nonsquamous carcinoma and squamous cell carcinoma, the former including adenocarcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and poorly differentiated histological subtypes. Most patients present after NSCLC have spread to regional or distant sites. Patients presenting with advanced, unresectable disease (stage IIIB or IV) and patients who develop recurrent or metastatic disease following surgical resection are candidates for systemic therapy. Even patients with early stage resected disease have improved OS with the use of adjuvant therapy. There is an urgent need to develop novel and effective regimens as the current therapies do not offer a curative potential and is palliative with benefits restricted to patients with a good performance status (Eastern Cooperative Oncology Group 0 or 1). The cisplatin-pemetrexed regimen has demonstrated preferential activity in patients with non-squamous histology. Pemetrexed and erlotinib have recently emerged as an option for maintenance therapy in patients with advanced disease following four cycles of combination chemotherapy leading to a change in treatment paradigm. Epigenetic alterations have been linked to the pathogenesis and progression of cancer as they lead to the inhibition of transcription of key cell cycle regulatory genes. Vorinostat (SAHA), with functional effects on histone acetylation attempts to restore the normal transcription of cell regulatory genes. Provocative activity has been noted with the combination of chemotherapy and vorinostat in advanced NSCLC. Thus, HDAC inhibitors are a new class of agents that will require extensive evaluation in lung cancer. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), was the first agent to demonstrate improved survival in combination with chemotherapy (ECOG 4599) in patients with advanced non-squamous NSCLC. The increase in toxicity noted with the addition of bevacizumab with chemotherapy calls for caution in selecting patients for therapy. The VEGF tyrosine kinase inhibitors (TKIs) appear promising, though they have unique toxicities such as hand–foot syndrome and fatigue in addition to hypertension. It remains to be seen whether the combination of VEGF TKI and chemotherapy will surpass the efficacy seen with bevacizumab-chemotherapy regimens. Identification or predictive biomarkers for patient selection remains elusive for anti-angiogenic agents. Molecular markers for treatment selection of patients with NSCLC are increasingly being utilized to personalize therapy. The presence of an activating mutation in the epidermal growth factor receptor (EGFR) is associated with high response rates and improved PFS with EGFR TKIs. This has already led to the use of an EGFR TKI as first-line therapy in patients with a sensitive EGFR mutation. For patients with wild-type EGFR (or if the EGFR status is unknown) chemotherapy remains as the ‘standard of care’ for first-line therapy of advanced NSCLC. The second generation EGFR inhibitors are currently under evaluation. The studies to evaluate the definitive role of an ALK inhibitor in patients with a translocation in the EML 4- ALK gene are in progress. Other markers of interest in NSCLC include: Excision repair cross-complementing gene 1 (ERCC1), RRM1, thymidylate synthase (TS), K-ras mutation, c-met expression/mutation, TRAIL R2, IGF-1R, JAK-2 and the list goes on. Thus the major focus of current research has been the proper selection of patients for optimizing the effect of molecularly targeted agents with the identification and validation of biomarkers.

Keywords

Overall Survival Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Mutation Advanced NSCLC Epidermal Growth Factor Receptor Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Springer-Verlag Berlin Heidelberg  2011

Authors and Affiliations

  1. 1.Miriam Beckner Distinguished Professor of MedicinePenn State Hershey Cancer InstituteHersheyUSA

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