Increasing Radiation Therapy Dose Is Associated With Improved Survival in Patients Undergoing Stereotactic Body Radiation Therapy for Stage I Non–Small-Cell Lung Cancer

doi:10.1016/j.ijrobp.2014.10.002

International Journal of Radiation OncologyBiologyPhysics

Volume 91, Issue 2, 1 February 2015, Pages 344-350

https://doi.org/10.1016/j.ijrobp.2014.10.002 Get rights and content

Purpose

To determine the comparative effectiveness of different stereotactic body radiation therapy (SBRT) dosing regimens for early-stage non–small-cell lung cancer, using a large national database, focusing on the relative impact of dose as a function of tumor stage.

Methods and Materials

The study included patients in the National Cancer Database from 2003 to 2006 with T1-T2N0M0 inoperable lung cancer (n=498). The biologically effective dose (BED) was calculated according to the linear quadratic formula using an α/β ratio of 10. High versus lower-dose (HD vs LD) SBRT was defined as a calculated BED above or below 150 Gy. Overall survival was estimated using Kaplan-Meier methods and Cox proportional hazard regression.

Results

The 5 most common dose fractionation schemes (percentage of cohort) used were 20 Gy × 3 (34%), 12 Gy × 4 (16%), 18 Gy × 3 (10%), 15 Gy × 3 (10%), and 16 Gy × 3 (4%). The median calculated BED was 150 Gy (interquartile range 106-166 Gy). The 3-year overall survival (OS) for patients who received HD versus LD was 55% versus 46% (log–rank P=.03). On subset analysis of the T1 cohort there was no association between calculated BED and 3-year OS (61% vs 60% with HD vs LD, P=.9). Among the T2 cohort, patients receiving HD experienced superior 3-year OS (37% vs 24%, P=.01). On multivariable analysis, factors independently prognostic for mortality were female gender (hazard ratio [HR] 0.76, P=.01), T2 tumor (HR 1.99, P=.0001), and HD (HR 0.68, P=.001).

Conclusions

This comparative effectiveness analysis of SBRT dose for patients with stage I non–small-cell lung cancer suggests that higher doses (>150 Gy BED) are associated with a significant survival benefit in patients with T2 tumors.

Introduction

Prospective and retrospective studies have shown improved outcomes with the use of stereotactic body radiation therapy (SBRT) in the treatment of patients with medically inoperable early-stage lung cancer 1, 2, 3. However, the optimal dose and fractionation scheme for this treatment is unknown, and patterns-of-care studies have documented extensive variation in dose throughout the community (4).

Previously published studies have used 1 to 10 fractions delivering from 6 Gy to 34 Gy per fraction, and these dose schedules are associated with a large range of calculated biologically equivalent effective doses (BED) 5, 6, 7, 8, 9, 10, 11, 12, 13. Although previous data have indicated that a calculated BED (10) >100 Gy is associated with improved outcomes, there are conflicting studies on whether biologically effective doses higher than 120 Gy or 150 Gy are beneficial or necessary 11, 14. One inherent challenge in interpreting these retrospective outcomes is the confounding relationship between tumor size and dose: smaller tumors are intrinsically easier to control but also more likely to be treated by higher doses owing to more favorable lung metrics.

In this study we used the National Cancer Data Base (NCDB) to examine the different dose fractionation schemes used and determine their impact on overall survival. The use of a large national database allows for an analysis of a much larger cohort of patients treated at different institutions with a variety of radiation doses.

Section snippets

Database

This study used information from the NCDB, which is a hospital cancer registry that collects data from the American College of Surgeons–Commission on Cancer accredited facilities (15). The database is sponsored by the American College of Surgeons and the American Cancer Society and includes approximately 70% of all malignant cancers diagnosed in the United States. The database contains information on patient demographics, primary tumor site, histology, site at diagnosis, insurance status, first

Results

A total of 498 patients met eligibility criteria for this study. Patient characteristics are shown in Table 1. The median tumor size for T1 tumors was 2 cm (interquartile range, 1.6-2.5 cm) and for T2 tumors was 3.7 cm (interquartile range, 3.2-4.5 cm). The cohort included 115 different treatment centers. The 5 most common dose fractionation schemes (percentage of cohort) used were 20 Gy × 3 (34%), 12 Gy × 4 (16%), 18 Gy × 3 (10%), 15 Gy × 3 (10%), and 16 Gy × 3 (4%), which represent calculated

Discussion

This study analyzed different radiation doses used in SBRT for the treatment of early-stage lung cancer. The results revealed a significant survival benefit with using a calculated BED ≥150 Gy that was limited to patients with a larger volume of disease (T2 tumors).

Previous single- and multi-institutional retrospective research has examined associations between dose and survival after SBRT for early-stage lung cancer. Kestin et al (14) analyzed 505 tumors treated at 5 institutions with SBRT and

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However, the impact of improved local control on survival remains unclear owing to limited randomized data comparing between higher and standard doses. Several retrospective studies and meta-analyses that compared between standard and high doses have shown that higher doses benefit local control.36-10 However, these studies yielded conflicting results regarding whether improved local control leads to improved overall survival (OS).
The purpose of this study was to assess the impact of local recurrence (LR) on cause-specific death (CSD) in patients with non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). A dynamic prediction model that incorporated LR as a time-dependent covariate was used.
This study included 535 stage I (cT1–T2aN0M0) NSCLC patients treated with SBRT from two institutions. We developed a landmark dynamic prediction model to estimate the probability of a CSD. This model determined the probability of surviving for an additional 3 years at different prediction time points during follow-up, given the history of recurrence status. The baseline covariates included in the model were age, sex, T stage, and histology, while the time-dependent covariates were LR and regional and/or distant recurrence (RDR) status.
Overall, 137 patients (25.6%) died of lung cancer within a median follow-up of 4.1 years. Of the 195 patients who developed recurrence, 28, 125, and 42 patients had LR only, RDR only, and both, respectively. The landmark model showed that older age, advanced T stage, LR, and RDR were significantly associated with an increased risk of subsequent CSD. Among these covariates, LR (odds ratio [OR], 8.5; 95% confidence interval [CI], 6.0–12.0; P < .001) and RDR (OR, 11.6; 95% CI, 9.1–14.9; P < .001) demonstrated strong effects on CSD within 3 years after the prediction time points. The dynamic prediction provided information on the probability of future CSD according to individual recurrence status during follow-up.
Dynamic prediction using the landmark model showed that LR had a substantial impact on subsequent CSD, which was comparable to that of RDR. This result supports the notion that strategies to improve local control are reasonable.
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Gated 4DRRO was highly robust against setup and motion uncertainties. BS increased the dose to healthy tissues but were more robust than SS. The selected optimization settings guaranteed adequate target coverage during the simulated treatment course with acceptable risk of toxicity.
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The optimal treatment of stage I non–small-cell lung carcinoma is subject to debate. The aim of this study was to compare overall survival and oncologic outcomes of lobar resection (LR), sublobar resection (SR), and stereotactic body radiotherapy (SBRT).
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Owing to its short computation time and simplicity, the Ray-Tracing algorithm (RAT) has long been used to calculate dose distributions for the CyberKnife system. However, it is known that RAT fails to fully account for tissue heterogeneity and is therefore inaccurate in the lung. The aim of this study is to make a dosimetric assessment of 219 non-small cell lung cancer CyberKnife plans by recalculating their dose distributions using an independent Monte Carlo (MC) method. For plans initially calculated by RAT without heterogeneity corrections, target coverage was found to be significantly compromised when considering MC doses. Only 35.4% of plans were found to comply to their prescription doses. If the normal tissue dose limits were respected in the treatment planning dose, the MC recalculated dose did not exceed these limits in over 97% of the plans. Comparison of RAT and recalculated-MC doses confirmed the overestimation of RAT doses observed in previous studies. An inverse correlation between the RAT/MC dose ratio and the target size was also found to be statistically significant ( $p < 10^{- 4}$ ), consistent with other studies. In addition, the inaccuracy and variability in target coverage incurred from dose calculations using RAT without heterogeneity corrections was demonstrated. On average, no clinically relevant differences were observed between MC-calculated dose-to-water and dose-to-medium for all tissues investigated ( $⩽$ 1%). Patients receiving a dose $D_{95 %}$ larger than 119 Gy in EQD2₁₀ (or $\approx$ 52 Gy in 3 fractions) as recalculated by MC were observed to have significantly superior loco-regional progression-free survival rates ( $p = 0.02$ ) with a hazard ratio of 3.45 (95%CI: 1.14–10.5).

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Clinical InvestigationIncreasing Radiation Therapy Dose Is Associated With Improved Survival in Patients Undergoing Stereotactic Body Radiation Therapy for Stage I Non–Small-Cell Lung Cancer

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Database

Results

Discussion

Surg Oncol Clin N Am

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

J Clin Epidemiol

J Clin Epidemiol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Pract Radiat Oncol

Clinical Investigation
Increasing Radiation Therapy Dose Is Associated With Improved Survival in Patients Undergoing Stereotactic Body Radiation Therapy for Stage I Non–Small-Cell Lung Cancer