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  • Few studies have compared the efficacy among various

    2019-09-03

    Few studies have compared the efficacy among various dose fractionations. One study comparing 10 Gy x 5 and 20 Gy x 3 in Stage I NSCLC found no significant differences in 1-year local control, distant metastasis, or overall survival [8]. Mild late chest wall toxicity was more common in the group treated with 20 Gy x 3, although the authors stated that without further dosimetric study, it BAY-598 was difficult to determine whether the difference was solely attributable to dose. RTOG 0915 compared tumor control and rate of grade 3 or higher adverse events between single fraction 34 Gy and 48 Gy in 4 fractions in peripherally located T 1-2 N0 NSCLC less than 5 cm [32,33]. Primary tumor control rates at 5 years were similar between the two arms. However, the single fraction arm experienced fewer grade 3 or higher adverse events and was determined to be less toxic compared to the 4-fraction arm. As toxicity data is not available through NCDB, no conclusions can be drawn from this study on the relationship between different dose fractionations and adverse events. In this study, we identified a dose-response relationship between calculated BED10 and survival that was consistent with previously published reports. Koshy et al. found that in patients with Stage I NSCLC treated with SBRT, doses above the median BED10 of 150 Gy were associated with improved 3-year overall survival of 55%, compared to 46% if the BED10 was < 150 Gy [13]. Specifically, the dose response relationship was significant for T2 tumors (median size 3.7 cm), with a 14% increase in 3-year OS in the group that received “high dose” SBRT. A separate review of the Radiosurgery Society RSSearch® Patient Registry found that BED10 ≥ 105 Gy was associated with improved local control in Stage I NSCLC treated with SBRT, especially for T2 tumors, for which local control translated into an overall survival benefit [34]. Other studies have reported that BED10 ≥ 100 Gy [11] or nominal dose ≥ 54 Gy [35] were associated with improved local control and overall survival. In our study, BED10 was associated with significantly improved survival for node-negative patients with Stage II NSCLC treated with SBRT. BED10 was also found to predict local relapse on multivariate analysis in over 500 patients with Stage I NSCLC treated with SBRT [36]. It is therefore reasonable to hypothesize that the survival benefit with increased BED is derived from improved local control. However, NCDB does not collect such variables to allow for more extensive analysis. A significant correlation between BED and survival was not identified in node-positive patients. We hypothesize that these patients with lymph node metastases may have had indications to receive and benefit from systemic therapy. Because this analysis included only patients who received SBRT for their newly diagnosed Stage II NSCLC and who did not receive systemic therapy, they might have died from systemic progression prior to experiencing benefit from local control of their primary disease. Interestingly, a few recent reports suggest that given the rapidly repopulating nature of lung cancer cells, utilization of α/β ratio greater than 10 Gy may more accurately describe the biologically effective dose response relationship in the setting of lung SBRT delivered in ≤ 5 fractions. Liu et al. examined tumor control probability of lung SBRT with six radiobiological models in 46 studies, and fitting of clinical data from all models yielded α/β of about 20 Gy [37]. Chi et al. examined the correlation between BED and various randomly selected α/β ratios from 5 Gy to 50 Gy and found increasing BED was associated with increasing local control, and more significantly for α/β of 20, 30, and 50 Gy [38]. Higher BED was also associated with increased 2-year overall survival, and the correlation was strongest with α/β of 20 Gy. We performed an exploratory analysis using BED20 and found that the correlation between BED and survival was preserved with a higher α/β ratio of 20 Gy for lung SBRT (data not shown). As in our analysis using BED10, increasing BED20 was associated with improved survival in node-negative patients but not node-positive patients on multivariate analysis. Another advantage of using α/β of 20 Gy is that it has been recently suggested that the use of a greater α/β ratio for calculating tumor BED in SBRT regimens for treating NSCLC may reduce the overestimation of the actual biological effect of the linear quadratic (LQ) model in high-dose regions [39]. Examination of tumor control probability using different radiobiological models has found no deviation from the LQ model in multi-institutional lung SBRT clinical data [37,40]. BED currently remains a standardized method to compare different SBRT dose fractionation schemes despite the theoretical concern of inaccuracies in applying the LQ model for SBRT regimens. As different threshold BED10 values have been reported in the literature, our findings in conjunction with previous retrospective analyses are hypothesis-generating, and suggest that dose escalation of SBRT regimens should be considered in Stage II NSCLC to improve survival outcomes, similar to Stage I NSCLC.