Abstract
Stereotactic ablative radiotherapy (SABR) is the main treatment for inoperable early-stage non-small cell lung cancer (NSCLC). Despite the widespread use of SABR, the biological determinants of response to SABR remain poorly investigated. We developed an orthotopic NSCLC animal model to study the response to clinically-relevant doses of SABR. Image-guided intra-thoracic injection of NSCLC cells was performed in the right lung of nude rats. A highly conformal dose of 34 Gy was delivered in a single fraction using clinical photon energies. Animals were sacrificed 10–60 days post treatment. Lung tumors were assessed for tumor differentiation, proliferation and invasiveness. An analysis of 770 cancer-related genes was performed on tumor-derived cell lines from treated animals at early and late time points after SABR. The majority of animals receiving SABR demonstrated complete response (67%), while 33% demonstrated local failure. 50% of animals with complete response failed distantly. Analysis of cancer-related genes revealed significant differences between tumors treated with SABR and untreated tumors. SABR significantly modulated expression of genes involved in adhesion, migration and angiogenesis. In particular, interleukin-8 (IL8) which plays a critical role in promoting tumor invasion was found to be secreted at high levels after SABR. In vitro invasion assays confirmed SABR-induced invasion and demonstrated induction of IL-8 secretion in multiple NSCLC cell lines. Our findings underscore the importance of developing targeted therapies that can circumvent the pro-invasive effects of SABR in NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) represents a highly heterogenous group of tumors with genetic and cellular heterogeneity and diverse pathological features
The remaining 11 animals were randomized to untreated control (n = 5) or receiving Stereotactic ablative radiotherapy (SABR) comprised of 34 Gy in 1 fraction (n = 6)
The shift from conventionally fractionated www.impactjournals.com/oncotarget radiotherapy to SABR has resulted in significant gains in tumor locoregional control, patient quality of life and overall survival for early-stage inoperable non-small cell lung cancer (NSCLC) patients [21, 22]
Summary
Non-small cell lung cancer (NSCLC) represents a highly heterogenous group of tumors with genetic and cellular heterogeneity and diverse pathological features. NSCLC accounts for over 80% of all lung cancer cases and has a 5 year survival rate below 20% [1]. Significant progress has been made in the treatment of early-stage non-surgical NSCLC patients over the last decade. Patients receiving stereotactic ablative radiotherapy (SABR) have local control rates comparable to surgery [2,3,4,5,6]. The possibility of offering SABR to operable NSCLC patients remains a contentious issue [7]. Three independent, randomized controlled trials (RCT) in patients with operable stage I non-small cell lung cancer (NSCLC) (STARS, ROSEL, ACOSOG Z4099)
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