Pathways to improving combined modality therapy for stage III nonsmall-cell lung cancer

Lung cancer is the leading cause of cancer deaths, having caused an estimated 1.6 million deaths worldwide in 2012 [Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359-E386].

Although the majority of patients are not cured with currently available therapies, there have been significant improvements in stage-specific outcomes over time [Videtic G, Vokes E, Turrisi A et al. The survival of patients treated for stage III non-small cell lung cancer in North America has increased during the past 25 years. In The 39th Annual Meeting of the American Society of Clinical Oncology, ASCO 2003, Chicago, IL. Abstract 2557. p. 291]. This review focuses on past progress and ongoing research in the treatment of locally advanced, inoperable nonsmall-cell lung cancer (NSCLC).

In the past, randomized trials revealed advantages to the use of thoracic radiotherapy (TRT) and then, the addition of induction chemotherapy. This was followed by studies that determined concurrent chemoradiotherapy to be superior to sequential therapy. A recent large phase III trial found that the administration of 74 Gy of conventionally fractionated photon-based TRT provided poorer survival than did the standard 60 Gy. However, further research on other methods of applying radiotherapy (hypofractionation, adaptive TRT, proton therapy, and stereotactic TRT boosting) is proceeding and may improve outcomes. The molecular characterization of tumors has provided more effective and less toxic targeted treatments in the stage IV setting and these agents are currently under investigation for earlier stage disease. Similarly, immune-enhancing therapies have shown promise in stage IV disease and are also being tested in the locally advanced setting.

For locally advanced, inoperable NSCLC, standard therapy has evolved from TRT alone to combined modality therapy. We summarize the recent clinical trial experience and outline promising areas of investigation in an era of greater molecular and immunologic understanding of cancer care.