A biologically effective dose threshold for stereotactic body radiation therapy—can we put the issue to BED?

Abstract

Comment on: Moreno AC, Fellman B, Hobbs BP, et al. Biologically Effective Dose in Stereotactic Body Radiotherapy and Survival for Patients With Early-Stage NSCLC. The phenomenon of stereotactic body radiotherapy (SBRT) radically altering worldwide practice patterns for patients with early stage non-small cell lung cancer (NSCLC) is unprecedented. A particularly notable observation from the National Cancer Database (NCDB) review by Moreno et al. is that SBRT utilization increased from 0.2% in 2004 to 22% in 2014 (1). The ubiquitous uptake reflects just how many patients are actually candidates for a curative-intent treatment option when that option is both effective and convenient. While the possible role of SBRT is debated for operable (or borderline operable) patients, its role for those deemed unfit for surgery is seemingly cemented. However, questions remain about the dose response relationship, and the optimal choice of regimen. Findings from the NCDB analysis suggest that SBRT biologically effective dose (BED) intensity may be directly related to patient outcomes and that the intensity prescribed has actually decreased over time. The initial North American prospective experience from Indiana University (IU) (2), and subsequently, the Radiation Therapy Oncology Group (RTOG) 0236 study utilized "intensive" three-fraction regimens. RTOG 0236 taught us that SBRT could be safely scaled to the multi-institutional level with excellent rates of local control (LC) (3). On this trial, patients were treated with 60 Gy in three fractions, but those with lesions located in the 'central' zone near the proximal bronchial tree were excluded given that treatment of such tumors on the IU study led to an increased risk of severe and lethal toxicity. With 96% in-field control, RTOG 0236 defined an excellent standard regimen for peripheral, early stage NSCLC. A post-hoc analysis suggested that the prescribed dose should be converted to 54 Gy in 3 fractions when heterogeneity corrections are applied, as is the case for most modern treatment planning algorithms (4). It is noteworthy that the actual dose delivered can vary by 10% based on the use these corrections-a factor not accounted for in the NCDB. Despite the impressive RTOG 0236 results, the three-fraction regimen was not universally adopted as standard of care for peripheral lesions. The acceptance of alternatives in clinical practice, including those with lower predicted BED, was likely tied to increasing recognition of rib and chest wall toxicity coupled with the availability of data that suggested less intensive regimens also produced excellent local tumor control. In fact, adverse events involving the soft tissue and rib-now accepted and appreciated as a common consequence of SBRT for peripheral tumors-were not initially envisioned when RTOG 0236 was designed. At about the same time, results from The Japan Clinical Oncology Group (JCOG) 0403 trial, which utilized 48 Gy in 4 fractions, first became available, and 3-year LC (~88% at 3 years) was comparable to the IU trial's intensive regimen (5). Similarly, a regimen of 45 Gy in 3 fractions was reported to provide excellent tumor control in a prospective European trial (6). These rates of LC appeared to be no worse, despite less intensive dose schemes. The fact that tumor location (central vs. peripheral) is not identified in the NCDB also bears mentioning. Many-but not all-SBRT treatment regimens were stratified by tumor location following publication of the IU data. Starting in 2009, the RTOG enrolled patients on a phase Editorial Commentary