Non-small cell lung cancer (NSCLC) remains the number one cause of cancer related deaths.1 While early stage NSCLC portends the best survival following complete surgical resection, as many as 37% of patients with stage I disease have recurrence within 5 years of diagnosis.2 Several studies have investigated the role of adjuvant chemotherapy for early stage disease.3^–6 However, the benefit of adjuvant therapy was mainly in patients with stage II and IIIA disease. Significant progress in improving the survival of patients with stage I NSCLC is lacking.

In this issue, Hung and colleagues7 address two very important issues with regard to the management of early stage NSCLC (see page 192): (1) the prognostic predictors of survival in patients with recurrence and (2) the optimal treatment for recurrent disease. In this retrospective study of 970 patients with resected stage I NSCLC, the clinicopathological characteristics of 123 patients with recurrence were analysed for prognostic indicators of post-recurrence survival. Seventy-four patients had local recurrence only, and 1 and 2 year survival following recurrence was 48.7% and 17.6%, respectively. Of several clinical factors analysed, tumour size (p = 0.0033) and initial treatment of recurrence (p<0.001) were significant predictors of post-recurrence survival in univariate analysis. In multivariate analysis, initial treatment of recurrence remained a significant prognostic indicator of survival (p = 0.001). Patients receiving surgery as initial treatment had a better survival than those treated with chemotherapy and/or radiotherapy. Moreover, patients receiving chemotherapy and/or radiotherapy did better than those who received no treatment.

While this study suffers from the usual pitfalls of small, retrospective studies, Hung and colleagues7 should be commended for investigating not only the natural history and survival of patients with stage I NSCLC but also the prognostic predictors of survival following recurrence. The authors bring to light a very important population of patients with potentially curable disease to remind us that our success rate with stage I NSCLC can be improved.

To a similar end, several groups have performed clinical and histological studies on various patients with stage I NSCLC to identify those who are at higher risk of recurrence and who, possibly, would benefit from aggressive adjuvant therapy following resection. In a case matched retrospective study, Brock and colleagues8 distinctly identified a correlation between DNA methylation of the promoters of the cyclin dependent kinase inhibitor 2A gene 16, H-cadherin gene CDH13, Ras association gene RASSF1A and adenomatous polyposis coli gene with early tumour recurrence. Immunohistochemistry staining of vascular endothelial growth factor (VEGF) has been found to be a prognostic factor for time to relapse and survival in patients with early stage disease.9 10 Increased carcinoembryonic antigen levels and Ki67 labelling index is associated with decreased survival and early recurrence.11 12 Additionally, the presence of tumour regulatory T cells and infiltrating–infiltrating T cells in the primary lesion has been significantly correlated with a higher risk of recurrence.13

An equally fervent group of researchers focusing on genomics have identified gene expression profiles and metagene signatures that predict recurrence in patients with early stage NSCLC.14^–18 Jiang and colleagues14 identified gene clusters via comparative genomic hybridisation and cDNA microarray analysis that may be involved in the initiation and progression of NSCLC. Potti and colleagues15 developed a lung metagene model that successfully identified subgroups of patients who were at increased risk of recurrence with an accuracy as high as 79%. Larsen and colleagues16 identified a 54 gene expression signature capable of predicting poor outcome groups of patients despite favourable clinical factors.

Collectively, these studies highlight the challenge of treating patients with stage I NSCLC. While these patients are seemingly low risk, the population is in fact quite heterogeneous with a subset of patients at higher risk of recurrence and decreased survival. The crux of treating these patients is accurate identification of the high risk patients and aggressive treatment with individualised adjuvant therapy.17 18 As Hung and colleagues7 illustrate in their concise study, risk stratification and aggressive management (with possible surgical management when appropriate) of patients with recurrent disease offers the best chance of improved outcomes. In managing patients in this manner, we anticipate significant progress in the survival of patients with stage I NSCLC.