Evolution of systemic therapy for stages I-III non-metastatic non-small-cell lung cancer

Abstract

The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.

Fig. 1 |. Treatment of metastatic and non-metastatic NSCLC.

Timeline showing drugs approved or indicated for the treatment of metastatic and non-metastatic non-small cell lung cancer (NSCLC) as of December 2020. When several approvals were made in a year, they are arranged chronologically from top to bottom.

Fig. 2 |. Graphic depiction of a definitive proton radiotherapy dose distribution in a patient with stage IIIC non-small cell lung cancer (NSCLC).

On the axial (upper left), coronal (lower left) and sagittal (lower right) views of the radiotherapy plan, the red target delineation represents the gross tumour volume extending from the primary tumour in the medial right lower lobe to the bilateral hilar areas, mediastinum and right supraclavicular fossa. The dose–volume histogram (upper right) represents the radiation dose delivered to each structure of interest; it demonstrates that the gross tumour volume (red) receives close to 100% of the intended radiation dose with a steep dose fall-off to the oesophagus (green), bilateral lungs combined (yellow) and the heart (blue). Courtesy of Dr A.F. Shepherd, Memorial Sloan Kettering Cancer Center, New York, USA.