Dose escalation in the era of ablative lung irradiation: is more dose better when it comes to delivery of lung stereotactic body radiation therapy?

摘要

Dose escalation has been an enduring and elusive target when it comes to improving clinical outcomes for both early stage and locally advanced non-small cell lung cancer (NSCLC). In locally advanced disease a dose threshold of 60 Gy delivered in conventional fractionation together with chemotherapy has been solidified after roughly 50 years of prospective investigation namely due to limitations on normal tissues when treating large thoracic volumes (1). In high risk surgical and medically inoperable stage I NSCLC, the application of four-dimensional image guided planning and delivery of highly conformal stereotactic radiation to small volume parenchymal lung tumors with sharp dose gradients has allowed for safe dose escalation above biologically effective dose (BED) of 100 Gy or achievement of “ablative” radiobiological tumor effects (2). The seminal 2004 publication of a large multi-institutional analysis of Japanese patients treated with various stereotactic body radiation therapy (SBRT) dose fractionation schedules showed that, when applying the Linear Quadratic formulation to correct for BED with an alpha/beta ratio of 10, delivering a high BED10 ≥100 Gy significantly improved overall survival (3-year overall survival 88% vs. 69%) (3). Experience delivering doses in this range has translated to high rates of local control (98% at 2 years) and improved overall survival when compared to conventionally fractionated radiotherapy (4,5). Clinical practice patterns and most institutions have embraced the clear cut-point of BED10 of 100 Gy to define SBRT lung delivery, but the optimal dose fractionation beyond this point remains unclear and currently employed prescriptions are heterogenous ranging between 100–180 Gy BED10.