Curative Radiotherapy for Stage I Non-small Cell Lung Cancer: Is There Evidence for Further Dose Escalation?

Abstract

To determine the relationship between tumor control probability (TCP) and average biological effective dose (aBED) for dose-escalated 3D Conformal (3D-CRT) and stereotactic body radiation therapy (SBRT) in medically inoperable stage I Non-Small Cell Lung Cancer (NSCLC). Forty-two original prospective or retrospective studies on 3D-CRT and SBRT for Stage I NSCLC were reviewed (published from July 1988 - March 2010) in the context of tumor control (TC) - defined as crude local control ≥ 2 years, as a function of aBED. Only studies with at least 2-year TC data were included. For a given dose-fractionation schedule, aBED was calculated at isocenter using the linear quadratic formula: BED = d [1+(d/n)/(α/β)], assuming an α/β ratio of 10 (n = number of fractions, d = total dose). A scatter plot of TC versus aBED for each included study was generated and fitted to the standard TCP equation by the least-squares method: TCP = exp ([d - TCD50]/k) / [1+exp([d - TCD50]/k)]. Daily fraction size ≥ 6 Gy was considered SBRT. Two thousand six hundred ninety-six patients were included in this study (SBRT:1640; 3D-CRT:1056). Median patient age was 73 (22-95). By histology, 704 tumors were adenocarcinoma, 847 squamous cell carcinoma, and 1145 were not otherwise specified. Daily fraction size was 1.2 - 4 Gy (total dose: 48-102.9) for patients treated with 3D-CRT and 6 - 26 Gy (total dose: 20-66) for patients treated with SBRT. Median aBED was 105.6 Gy (range 59.6-286.6). aBED to achieve 50% TC (TCD50) was 60.6 Gy (95% CI, 50.2-71.1) and the slope50, defined as 25/k, was 0.73%/Gy (95% CI, 0.47-1.0), r = 0.87. TCP as a function of aBED was sigmoidal, with the following values (TCP range, aBED range): (42-60%, 50-75 Gy); (61-76%, 76-100 Gy); (76-87%, 101-125 Gy); (87-93%, 126-150 Gy); (93-96%, 151-175 Gy); (97-98%, 176-200 Gy); and (≥ 98%, > 200 Gy). This is the largest meta-analysis to model TCP as a function of aBED for curative radiotherapy in stage I NSCLC. Near the plateau of the sigmoidal curve, the predicted TCP is ≥ 90% for aBED ≥ 135 Gy. Dose-escalation beyond this aBED likely translates into clinically insignificant gain in the TCP but may result in the addition of clinically significant toxicity. When delivered with SBRT, aBED of 135 Gy corresponds to a total dose of 50 Gy in 3 fractions at the isocenter. Analysis of additional predictive variables for TC for curative radiotherapy in stage I NSCLC is underway.