Abstract
There is a paucity of data to guide management of patients with inoperable stage IIB (American Joint Committee on Cancer eighth edition) non–small-cell lung cancer. Practice patterns and comparative effectiveness analyses were performed for 10,081 adults in the National Cancer Database diagnosed between 2004 and 2015 and treated with stereotactic body radiotherapy, hypofractionated radiotherapy, or conventionally fractionated radiotherapy. Stereotactic body radiotherapy utilization for T3N0M0 non–small-cell lung cancer is increasing rapidly and was associated with improved survival.
Background:
The purpose of this study was to analyze practice patterns and perform comparative effectiveness of definitive radiotherapy techniques for inoperable stage IIB (American Joint Committee on Cancer eighth edition) non–small-cell lung cancer (NSCLC).
Materials and Methods:
Adults in the National Cancer Database diagnosed with T3N0M0 or T1–2N1M0 NCSLC between 2004 and 2015 who received definitive radiotherapy were identified. Cases were divided as stereotactic body radiotherapy (SBRT), hypofractionated radiotherapy (HFRT), or conventionally fractionated radiotherapy (CFRT) and stratified by systemic therapy (ST). Cox proportional hazards models evaluated the effect of covariates on overall survival (OS). Subgroup analysis by tumor size, chest wall invasion, multifocality, and ST use was performed with Kaplan-Meier estimates of OS.
Results:
A total of 10,081 subjects met inclusion criteria: 4401 T3N0M0 (66.5% CFRT, 11.0% HFRT, and 22.5% SBRT) and 5680 T1–2N1M0 (92.5% CFRT and 7.5% HFRT). For T3N0M0 NSCLC, SBRT utilization increased from 3.7% in 2006% to 35.4% in 2015. Subjects treated with SBRT were more likely to have smaller tumors, multifocal tumors, or adenocarcinoma histology. SBRT resulted in similar or superior OS compared with CFRT for tumors > 5 cm, tumors invading the chest wall, or multifocal tumors. SBRT was significantly associated with improved OS on multivariate analysis (hazard ratio, 0.715; P < .001). For T1–2N1M0 NSCLC, patients treated with HFRT were significantly older and less likely to receive ST; nevertheless, there was no difference in OS between HFRT and CFRT on multivariate analysis.
Conclusion:
CFRT + ST is utilized most frequently to treat stage IIB NSCLC in the United States when surgery is not performed, though it is decreasing. SBRT utilization for T3N0M0 NSCLC is increasing and was associated with improved OS.
Keywords: Definitive radiation, Hypofractionation, Non-small cell lung cancer, Stereotactic body radiation therapy Systemic therapy
Introduction
For medically inoperable stage III non–small-cell lung cancer (NSCLC), conventionally fractionated radiotherapy (CFRT) administered once daily over 6 to 7 weeks with concurrent platinum doublet-based chemotherapy followed by adjuvant immunotherapy is the preferred treatment.1–3 In contrast, stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, is the preferred treatment for medically inoperable early-stage NSCLC (T1–2N0M0).1,4 Various SBRT dose-fractionation regimens ranging from 1 to 5 fractions with a cumulative biologically effective dose (BED) ≥ 100 Gy10 for peripheral lung nodules have been well-established.1,5–7 For centrally located tumors, a more fractionated approach, such as 5 to 15 fractions of hypofractionated radiotherapy (HFRT), has been used to minimize high-grade toxicity noted in early SBRT experience.8–14 Additionally, HFRT can be used for patients with poor performance status who would otherwise poorly tolerate a combination of CFRT and systemic therapy (ST).10
There is no evidence-based optimal treatment approach for medically inoperable American Joint Committee on Cancer (AJCC) eighth edition stage IIB NSCLC, which includes larger or more locally advanced primary lung tumors (T3N0M0) or smaller tumors with metastases confined to the hilar lymph nodes (T1–2N1M0). Tumors that were T2b in the prior AJCC seventh edition based on greatest tumor dimension (> 5 cm but ≤ 7 cm) are now T3 in the current AJCC eighth edition, and tumors > 7 cm are now T4 instead of T3. All patients with stage group IIA based on the prior AJCC seventh edition are now stage IIB in the current AJCC eighth edition. Based on these changes, smaller tumors may be considered eligible for a combined regimen. Definitions for T3 disease that have not changed between the AJCC seventh and eighth editions include invasion of the chest wall, phrenic nerve, or pericardium and separate tumor nodules in the same lobe. To treat medically inoperable stage IIB NSCLC, the National Comprehensive Cancer Network guidelines recommend definitive radiotherapy, including SBRT, followed by consideration of adjuvant ST for N0 disease and definitive chemoradiotherapy for N1 disease.1
The purpose of this study is to perform both a patterns of care analysis and a comparative effectiveness analysis for node-negative and node-positive stage IIB (AJCC eighth edition) NSCLC treated with definitive radiotherapy in the United States, while controlling for the effect of ST. The 3 definitive radiotherapy fractionations to be compared include CFRT, HFRT, and SBRT, with the latter omitted from comparison in those with nodal metastasis.
Materials and Methods
Data Source
The National Cancer Database (NCDB) is an oncology outcomes database for over 1500 commission-accredited cancer programs in the United States and Puerto Rico, developed jointly by the Commission on Cancer of the American College of Surgeons and the American Cancer Society.15 Approximately 70% of newly diagnosed cancer cases are captured at the institutional level by Certified Cancer Registrars using nationally standardized data item and coding definitions. All NCDB data are de-identified and compliant with Health Insurance Portability and Accountability Act privacy standards. This study was granted exemption by the Duke University Institutional Review Board.
Cohort Selection
The NCDB was queried for adult subjects age 18 or older diagnosed with NSCLC between January 1, 2004 and December 31, 2015. During these diagnostic years, the NCDB reported TNM staging based on the AJCC sixth and seventh editions. Using coded data regarding tumor size (ie, > 5 cm but ≤ 7 cm), local extension (eg, chest wall invasion), and site-specific factors (eg, multifocal tumors in the same lobe), subjects with stage IIB (T3N0M0 or T1–2N1M0) based on the AJCC eighth edition criteria and treated with definitive radiotherapy regardless of receipt of ST were included. Only the following histologies were included in further analysis: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma, and non–small-cell carcinoma not otherwise specified. Exclusion criteria included surgery to the primary tumor, unknown surgery status, no or unknown receipt of radiotherapy, intraoperative radiotherapy or brachytherapy, radiotherapy to a non-thoracic site, and excessively long radiotherapy duration (≥ 100 days).
Subjects were allocated into 1 of 2 cohorts: node-negative (T3N0M0) or node-positive (T1–2N1M0). Subjects were further categorized as having received SBRT, HFRT, or CFRT. SBRT was defined as 3000 to 6000 cGy in 1 to 5 fractions at ≥ 1000 cGy/fraction. HFRT was defined as 5000 to 7400 cGyin > 5 fractionsat > 200 cGy/fraction. CFRT was defined as 5000 to 7400 cGy in 180 to 200 cGy/fraction. Stringent radiotherapy thresholds were utilized owing to recently published data demonstrating that anomalous radiotherapy data in the NCDB can affect survival results.16 Subjects not meeting 1 of these 3 radiotherapy fractionation group definitions were excluded. Additionally, because it is not standard practice to treat both the primary tumor and hilar nodal metastases with SBRT, SBRT was not analyzed in the node-positive cohort.
Covariates
Demographic characteristics collected were age at diagnosis, year of diagnosis, gender, Charlson-Deyo comorbidity score, race (non-Hispanic white, non-Hispanic black, Hispanic, or other), educational attainment in the area of patients’ residence, median household income in the area of patients’ residence, insurance status, and miles between the patients’ residence and hospital. Tumor characteristics recorded included primary tumor site (ie, upper, middle, or lower lobe), histology, pathologic confirmation, clinical T-stage, clinical N-stage, tumor size, multifocal tumors in the same lobe, chest wall invasion, tumor grade, and lymphovascular invasion. Treatment data collected were facility type, radiotherapy dose, number of fractions, dose per fraction, BED using an α/β of 10, and duration of radiotherapy.
Statistical Methods
Descriptive summary statistics were performed on demographic, tumor, and treatment variables. Characteristics were compared among the subjects that received CFRT, HFRT, and SBRT using χ2 and Kruskal-Wallis tests for categorical and continuous variables, respectively. Relative annual utilization of CFRT, HFRT, and SBRT by year were graphically displayed on a line plot.
The primary outcome was OS, which was calculated from the date of diagnosis until the date of last contact or death. The Kaplan-Meier method was used to estimate OS, and comparison between subgroups based on radiotherapy fractionation was performed via the log-rank test. Subgroup analysis in the node negative cohort was performed to evaluate each reason for stage T3: tumors > 5 cm, tumors with chest wall invasion, and multifocal tumors in the same lobe. Subgroup analysis in the node-positive cohort was performed for subjects that received ST and subjects that did not receive ST.
Cox proportional hazards models evaluated the effect of covariates on OS. The following covariates were analyzed: age at diagnosis, gender, Charlson-Deyo comorbidity score, histology, tumor size, chest wall invasion, multifocal tumors in the same lobe, ST use, BED, and radiotherapy fractionation group. Total radiotherapy dose, dose per fraction, number of fractions, and duration of radiotherapy were not included in multivariate survival analysis because of collinearity with radiotherapy fractionation group. For the node-negative cohort, BED was also excluded from the multivariate model because of collinearity with radiotherapy fractionation group. Otherwise, multivariate Cox regression analysis was performed separately for the node-negative and node-positive cohorts incorporating all variables that were significantly associated with OS on univariate analysis. Statistical analyses were conducted using SAS 9.4, and Kaplan-Meier figures were created using R 3.4.1. Two-sided P-values ≤ .05 were considered statistically significant.
Results
A total of 1,393,073 adults diagnosed with NSCLC between 2004 and 2015 were identified, of whom 10,081 met inclusion criteria. Among these, 4401 were in the node-negative cohort (T3N0M0), and 5680 were in the node-positive cohort (T1–2N1M0). The number of patients with documented pathologic assessment of lymph nodes was 1420 (14.1%). Use of positron emission tomography for staging is not documented in the NCDB.
Within the node-negative cohort, 2928 (66.5%) received CFRT, 484 (11.0%) received HFRT, and 989 (22.5%) received SBRT. Within the node-positive cohort, 5254 (92.5%) received CFRT and 426 (7.5%) received HFRT. The most frequently used CFRT, HFRT, and SBRT dose-fractionations were 6600 cGy in 33 fractions, 6000 cGy in 20 fractions, and 5000 cGy in 5 fractions, respectively.
Among subjects who received ST, chemotherapy accounted for the overwhelming majority of ST, and all instances included multi-agent chemotherapy when specified. Only 19 subjects received immunotherapy (17 who received CFRT and 2 who received SBRT). When administered, ST was initiated within 14 days of radiotherapy for the entire population.
Node-negative Cohort
Characteristic Differences.
Important baseline demographic, tumor, and treatment characteristics are listed in Table 1 by radiotherapy fractionation group. Within the node-negative cohort, subjects who received SBRT were significantly more likely to have adenocarcinoma histology (43.0% SBRT vs. 31% HFRT vs. 28.8% CFRT; P < .001), smaller tumor size (68.6% SBRT vs. 30.4% HFRT vs. 18.3% CFRT for tumors ≤ 3 cm; P < .001), multiple tumors in the same lobe (67.9% SBRT vs. 29.8% HFRT vs. 15.1% CFRT; P < .001), and lower lobe tumors (29.4% SBRT vs. 27.2% HFRT vs. 20.5% CFRT; P < .001). Subjects who received SBRT were significantly less likely to have chest wall invasion (14.3% SBRT vs. 32.4% HFRT vs. 41.5% CFRT; P < .001) or receive ST (9.2% SBRT vs. 25.5% HFRT vs. 76.5% CFRT; P < .001).
Table 1.
Demographic, Tumor, and Treatment Characteristics for Stage IIB Non–small-cell Lung Cancer (n = 10,081)
| Variable | T3N0M0 (Node-negative Cohort), n (%) | T1-2N1M0 (Node-positive Cohort), n (%) | |||||
|---|---|---|---|---|---|---|---|
| CFRT (n = 2928) | HFRT (n = 484) | SBRT (n = 989) | P Value | CFRT (n = 5254) | HFRT (n = 426) | P Value | |
| Age at diagnosis, y | 71 (64–78) | 77 (69–82) | 74 (68–80) | <.001 | 72 (65–78) | 77 (69–83) | <.001 |
| Female | 1226 (41.9) | 209 (43.2) | 523 (52.9) | <.001 | 2361 (44.9) | 187 (43.9) | .678 |
| Charlson-Deyo comorbidity score | <.001 | .938 | |||||
| 0–1 | 2530 (86.4) | 401 (82.9) | 809 (81.8) | 4423 (84.2) | 358 (84.0) | ||
| ≥2 | 398 (13.6) | 83 (17.1) | 180 (18.2) | 831 (15.8) | 68 (16.0) | ||
| Histology | <.001 | .996 | |||||
| Adenocarcinoma | 843 (28.8) | 150 (31.0) | 425 (43.0) | 1583 (30.1) | 128 (30.0) | ||
| Squamous cell carcinoma | 1559 (53.2) | 256 (52.9) | 408 (41.3) | 2558 (48.7) | 207 (48.6) | ||
| Other | 526 (18.0) | 78 (16.1) | 156 (15.8) | 1113 (21.2) | 91 (21.4) | ||
| Tumor size, cm | <.001 | .514 | |||||
| 0.1–3 | 459 (18.3) | 131 (30.4) | 652 (68.6) | 2037 (42.7) | 164 (41.7) | ||
| 3.1–5.0 | 1049 (41.9) | 172 (39.9) | 235 (24.7) | 1901 (39.8) | 151 (38.4) | ||
| 5.1–7.0 | 996 (39.8) | 128 (29.7) | 63 (6.6) | 838 (17.5) | 78 (19.8) | ||
| Chest wall invasion | 1215 (41.5) | 157 (32.4) | 141 (14.3) | <.001 | NA | NA | NA |
| Invasion of parietal pericardium or phrenic nerve | 38 (1.3) | 8 (1.7) | 6 (0.6) | .131 | NA | NA | NA |
| Multifocal in the same lobe | 442 (15.1) | 144 (29.8) | 672 (67.9) | <.001 | NA | NA | NA |
| Systemic therapy use | 2220 (76.5) | 121 (25.5) | 88 (9.2) | < .001 | 3885 (74.2) | 142 (33.6) | <.001 |
| Biologically effective dose, Gy10 | 77 (72–81) | 75 (69–84) | 106 (100–132) | <.001 | 79 (72–79) | 75 (69–85) | .341 |
Values are shown as median (interquartile range) or number (percent).
Abbreviations: CFRT = conventionally fractionated radiotherapy; HFRT = hypofractionated radiotherapy; SBRT = stereotactic body radiotherapy.
Subjects who received SBRT were also more likely to be female (52.9% SBRT vs. 43.2% HFRT vs. 41.9% CFRT; P < .001), have a Charlson-Deyo comorbidity score ≥ 2 (18.2% SBRT vs. 17.1% HFRT vs. 13.6% CFRT; P < .001), have Medicare insurance (78.8% SBRT vs. 76.6% HFRT vs. 68.5% CFRT; P < .001), reside in a ZIP code with above median education (57.3% SBRT vs. 52.6% HFRT vs. 50.3% CFRT; P < .001), reside in a ZIP code with above median income (57.1% SBRT vs. 50.6% HFRT vs. 48.5% CFRT; P < .001), reside in a metropolitan area with population ≥ 1 million (51.1% SBRT vs. 43.5% HFRT vs. 41.1% CFRT; P < .001), receive treatment at an academic facility (41.3% SBRT vs. 34.5% HFRT vs. 22.7% CFRT; P < .001), travel a further distance to the treatment facility (11.1 miles SBRT vs. 9.0 miles HFRT vs. 8.6 miles CFRT; P < .001), complete definitive radiotherapy in a shorter duration (median 9 days SBRT vs. 30 days HFRT vs. 50 days CFRT; P < .001), and receive a higher BED (median 106 Gy10 SBRT vs. 75 Gy10 HFRT vs. 77 Gy10 CFRT; P < .001).
Subjects that received HFRT were significantly older (median 74 years SBRT vs. 77 years HFRT vs. 71 years CFRT; P < .001). Otherwise, the distribution of characteristics among subjects that received HFRT were intermediate between the CFRT and SBRT groups. There were no differences in racial distribution between the 3 radiotherapy groups (P = .239).
Utilization Trends.
Relative utilization of SBRT to treat T3N0M0 NSCLC increased from 3.7% in 2006% to 35.4% in 2015, a nearly 10-fold increase over the course of a decade (Figure 1). Consequently, relative utilization of CFRT in the node-negative cohort decreased from a peak of 86.8% in 2005% to 51.7% in 2015.
Figure 1. Utilization Trends for T3N0M0 Non–small-cell Lung Cancer by Definitive Radiotherapy Modality.
Abbreviations: CFRT= conventionally fractionated radiotherapy; HFRT = hypofractionated radiotherapy; SBRT = stereotactic body radiotherapy.
Survival Analyses.
The median follow-up time in the node-negative cohort was 18.8 months for all subjects and 32.1 months for living subjects. For all subjects, there was a significant difference in OS between SBRT and CFRT (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.71–0.87; P < .001), between SBRT and HFRT (HR, 0.57; 95% CI, 0.50–0.66; P < .001), and between CFRT and HFRT (HR, 0.73; 95% CI, 0.65–0.82; P < .001). The estimated 2-year OS was 54.2%, 43.4%, and 34.0%, and the estimated 5-year OS was 22.0%, 18.7%, and 9.4% for subjects treated with SBRT, CFRT, and HFRT, respectively (Figure 2A).
Figure 2. Kaplan-Meier Curves Depicting Overall Survival for T3N0M0 Non–small-cell Lung Cancer for the Entire Cohort (A), Subjects With > 5 cm Tumors (B), Subjects With Tumors Invading the Chest Wall (C), and Subjects With Multifocal Tumors in the Same Lobe (D), Each Stratified by Receipt of Conventionally Fractionated Radiotherapy, Hypofractionated Radiotherapy, or Stereotactic Body Radiotherapy.
Abbreviations: CFRT = conventionally fractionated radiotherapy; HFRT = hypofractionated radiotherapy; SBRT = stereotactic body radiotherapy.
The reasons for stage T3N0M0 NSCLC were evaluated on predefined subgroup analyses. For primary lung tumors > 5 cm, SBRT was associated with improved OS compared with HFRT (HR, 0.59; 95% CI, 0.36–0.97; P = .036) and similar OS compared with CFRT (HR, 1.07; 95% CI, 0.70–1.61; P = .766) (Figure 2B). For tumors invading the chest wall, SBRT was associated with improved OS compared with HFRT (HR, 0.68; 95% CI, 0.52–0.90; P = .006) and similar OS compared with CFRT (HR, 1.02; 95% CI, 0.82–1.27; P = .879) (Figure 2C). For multifocal tumors in the same lobe, SBRT was associated with improved OS compared with both CFRT (HR, 0.81; 95% CI, 0.68–0.97; P = .020) and HFRT (HR, 0.67; 95% CI, 0.51–0.87; P = .003) (Figure 2D).
Table 2 summarizes the multivariate analysis with respect to OS for the node-negative cohort. Factors associated with worse OS included older age at diagnosis, male gender, higher Charlson-Deyo comorbidity score, adenocarcinoma histology, larger tumor size, multifocality, and no receipt of ST. Use of SBRT remained significantly associated with improved OS on multivariate analysis (HR, 0.715; P < .001). There was no significant difference in OS between CFRT and HFRT (P = .542).
Table 2.
Multivariate Cox Regression Model of Overall Survival for T3N0M0 Non–small-cell Lung Cancer (n = 3257)
| Variable | Hazard Ratio | 95% Confidence Interval | P Value |
|---|---|---|---|
| Age at diagnosis (unit: 10 y) | 1.202 | 1.149–1.258 | <.001 |
| Female (ref: male) | 0.916 | 0.844–0.995 | .038 |
| Charlson-Deyo comorbidity score ≥ 2 (ref: 0–1) | 1.200 | 1.072–1.342 | .002 |
| Adenocarcinoma (ref: squamous cell) | 0.816 | 0.740–0.900 | <.001 |
| Tumor size (ref: 0.1–3.0 cm) | |||
| 3.1–5.0 cm | 1.178 | 1.054–1.317 | .004 |
| 5.1–7.0 cm | 1.265 | 1.119–1.429 | <.001 |
| Multifocal in the same lobe | 0.790 | 0.705–0.886 | <.001 |
| Systemic therapy use | 0.641 | 0.576–0.712 | <.001 |
| Radiotherapy fractionation (ref: CFRT) | |||
| HFRT | 1.044 | 0.909–1.200 | .542 |
| SBRT | 0.715 | 0.626–0.817 | <.001 |
Abbreviations: CFRT = conventionally fractionated radiotherapy; HFRT = hypofractionated radiotherapy; SBRT = stereotactic body radiotherapy
Node-positive Cohort
Characteristic Differences.
Within the node-positive cohort, subjects who received HFRT were significantly older (median 77 years vs. 72 years; P < .001) and less likely to receive ST (33.6% vs. 74.2%; P < .001) compared with subjects who received CFRT (Table 1). Gender, comorbidity score, race, histology, tumor size, and BED were well-balanced. Subjects who received HFRT were also significantly more likely to reside in a ZIP code with the highest education quartile (24.9% vs. 17.7%; P = .003), reside in a ZIP code above median income (53.3% vs. 48.4%; P = .034), receive treatment at an academic facility (34.7% vs. 22.7%; P < .001), and complete definitive radiotherapy in a shorter duration (median 32 days vs. 50 days; P < .001) relative to CFRT. Conversely, subjects who received CFRT were significantly more likely to reside in a non-metropolitan area (21.7% vs. 16.9%; P = .045) and have private insurance (17.4% vs. 13.4%; P = .010) relative to HFRT.
Utilization Trends.
The relative annual utilization of CFRT and HFRT in the node-positive cohort was stable and largely unchanged during the 12 years analyzed. The relative utilization of CFRT to treat T1–2N1M0 NSCLC was 93.8% in 2004% and 91.2% in 2015, with a peak of 95.3% in 2010.
Survival Analyses.
The median follow-up time in the node-positive cohort was 19.6 months for all subjects and 33.5 months for living subjects. CFRT and HFRT were compared based on receipt of ST. Among subjects that received ST, there was no significant difference in OS between HFRT and CFRT (HR, 1.14; 95% CI, 0.93–1.39; P = .201) (Figure 3A). Similarly, among subjects that did not receive ST, there was no significant difference in OS between HFRT and CFRT (HR, 1.00; 95% CI, 0.86–1.17; P = .957) (Figure 3B). The estimated 2-year OS was 50.1% with CFRT and 46.2% with HFRT for subjects that received ST, whereas the estimated 2-year OS was 34.3% with CFRT and 33.2% with HFRT for subjects that did not receive ST (P < .001).
Figure 3. Kaplan-Meier Curves Depicting Overall Survival for T1–2N1M0 Non–small-cell Lung Cancer for Subjects that Received Systemic Therapy (A) and Subjects that did not Receive Systemic Therapy (B), Stratified by Receipt of Conventionally Fractionated Radiotherapy or Hypofractionated Radiotherapy.
Abbreviations: CFRT = conventionally fractionated radiotherapy; chemo = chemotherapy; HFRT = hypofractionated radiotherapy.
Table 3 summarizes the multivariate analysis with respect to OS for the node-positive cohort. Similar to the node negative cohort, older age at diagnosis, male gender, higher Charlson-Deyo comorbidity score, larger tumor size, and no receipt of ST were associated with worse OS. However, unlike the node-negative cohort, there was no significant difference in OS by tumor histology. There was no significant difference in OS between CFRT and HFRT (P = .421); however, independent of fractionation, a higher BED was associated with improved OS (HR, 0.984; P < .001).
Table 3.
Multivariate Cox Regression Model of Overall Survival for T1–2N1M0 Non–small-cell Lung Cancer (n = 4519)
| Variable | Hazard Ratio | 95% Confidence Interval | P Value |
|---|---|---|---|
| Age at diagnosis (unit: 10 y) | 1.128 | 1.086–1.172 | <.001 |
| Female (ref: male) | 0.837 | 0.782–0.895 | <.001 |
| Charlson-Deyo comorbidity score ≥ 2 (ref: 0–1) | 1.139 | 1.040–1.249 | .005 |
| Adenocarcinoma (ref: squamous cell) | 0.957 | 0.883–1.037 | .283 |
| Tumor size (ref: 0.1–3.0 cm) | |||
| 3.1–5.0 cm | 1.151 | 1.069–1.239 | <.001 |
| 5.1–7.0 cm | 1.279 | 1.164–1.406 | <.001 |
| Systemic therapy use | 0.670 | 0.621–0.724 | <.001 |
| Biologically effective dose (unit: 1 Gy10) | 0.984 | 0.978–0.989 | <.001 |
| HFRT (ref: CFRT) | 1.054 | 0.928–1.197 | .421 |
Abbreviations: CFRT = conventionally fractionated radiotherapy; HFRT = hypofractionated radiotherapy.
Discussion
Stage IIB NSCLC represents a heterogeneous population ranging from large primary tumors without lymph node involvement to patients with small primary tumors with hilar lymph node metastases. The optimal nonoperative management of stage IIB NSCLC continues to evolve. A combination of CFRT and ST was most frequently utilized to treat stage IIB NSCLC in the United States when surgery was not performed, though SBRT utilization for T3N0M0 has rapidly increased.
The increased utility of SBRT appears to be appropriate. On multivariate analysis, use of SBRT was significantly associated with improved OS for the entire T3N0M0 NSCLC population (HR, 0.715; P < .001). Although the multivariate model accounted for known differences at baseline between the radiotherapy groups, there are important prognostic factors that could not be accounted for within the NCDB, such as use of positron emission tomography for staging, performance status, and weight loss. On unadjusted subgroup analysis, SBRT was associated with improved OS compared with CFRT and HFRT for multifocal tumors in the same lobe (Figure 2D), which may have represented synchronous stage I tumors. For subjects whose tumor invaded the chest wall, SBRT and CFRT were associated with comparable OS and improved OS compared with HFRT (Figure 2C).
Use of SBRT compared with CFRT/HFRT in patients with inoperable peripherally located T1–2N0M0 NSCLC enrolled on the CHISEL trial resulted in superior local control (89% vs. 65% at 2 years) and median OS (5 years vs. 3 years) without an increase in major toxicity.4 The observed improvement in local control and survival may be related to the significantly higher BED that can be delivered with SBRT (a median absolute increase of about 30 Gy10 in this analysis). Extrapolating the CHISEL results to T3N0M0 NSCLC, it would be expected that SBRT would similarly result in better local control. Several institutions have published their results using SBRT for T3N0M0 NSCLC and have shown that it is well-tolerated with low morbidity.17–22 Moreover, utilizing SBRT has inherent conveniences for patients compared with CFRT. The total radiotherapy duration is significantly shorter (median of 9 days vs. 50 days in this analysis), which may have contributed to the observation that subjects who received SBRT were more likely to live further away from the treatment facility.
Long-term survival for stage IIB NSCLC following definitive radiotherapy is poor. Use of ST was associated with improved OS on multivariate analysis in this study, but a significant portion did not receive ST. Adjuvant chemotherapy for large primary lung tumors has been shown to result in improved survival and is often given for tumors > 4 cm that are surgically resected.23–26 A hypothesis-generating NCDB analysis noted that adjuvant chemotherapy following surgical resection is also associated with increased OS among patients with T3N0M0 NSCLC owing to multiple tumors in the same lobe.27 There may be a role for ST combined with SBRT for T3N0M0 in carefully selected patients, but high-quality data are lacking.18,28 Questions regarding optimal agent(s), dosage(s), and timing of ST relative to SBRT remain unanswered.
In both the node-negative and node-positive stage IIB cohorts, subjects who received HFRT were significantly older and less likely to receive ST compared with CFRT. On subgroup analysis in the node-positive cohort and multivariate analysis in both the node-negative and node-positive cohorts, when controlling for the imbalances in ST receipt, there was no significant OS difference between HFRT and CFRT. Many international institutions have similarly reported favorable outcomes and acceptable toxicity with HFRT for stage IIB NSCLC using HFRT fraction sizes of 275 cGy,29–31 300 cGy,32 ≥ 350 cGy,33 400 cGy,34 and 500 cGy using a simultaneous integrated boost technique.35 In the present analysis, HFRT was heterogeneous with a wide range of permitted fraction sizes and a mode of 300 cGy/fraction. Potential advantages of HFRT over CFRT include patient convenience with decreased treatment duration, reduced duration of acute toxicity, decreased health care costs, and possible reduction in tumor repopulation during treatment.
This study is subject to the inherent limitations of the NCDB including but not limited to coding errors, incomplete data, selection bias, pertinent unreported data (eg, cause of inoperability, performance status, staging examinations, locoregional recurrence, development of distant metastasis, toxicity data), and unknown confounders that may influence comparative effectiveness evaluations performed in administrative datasets. However, only subjects with complete and stage-appropriate radiotherapy data were included in this analysis. The study is strengthened by a large sample size of over 10,000 patients treated in a contemporary period when advanced radiotherapy techniques were available. Additionally, stringent radiotherapy thresholds were utilized to minimize underestimating the benefit of SBRT, HFRT, or CFRT.
In conclusion, a combination of CFRT and ST is utilized most frequently to treat stage IIB NSCLC in the United States when surgery is not performed. SBRT utilization for T3N0M0 NSCLC is increasing rapidly, nearly 10-fold over the course of a decade. Use of SBRT was associated with significantly improved OS on multivariate analysis, and subgroup analyses demonstrated similar or improved OS following SBRT relative to those treated with CFRT. Additionally, while attempting to control for cofounding and baseline imbalances through multivariable regression, HFRT resulted in comparable OS as CFRT in both the node-negative and node-positive cohorts. Prospective studies confirming the safety and effectiveness of SBRT in all types of T3N0M0 NSCLC (tumors > 5 cm, multiple nodules in the same lobe, and chest wall invasion) are warranted. Furthermore, prospective studies evaluating the utility of ST in combination with SBRT are needed.
Clinical Practice Points.
In contrast to stage I and III NSCLC, there is a paucity of data to guide management of patients with medically inoperable stage IIB (AJCC eighth edition) NSCLC. Practice patterns from the NCDB indicate that a combination of CFRT and ST is presently utilized most commonly to treat stage IIB NSCLC in the United States when surgery is not performed. However, SBRT utilization for T3N0M0 NSCLC is increasing rapidly, nearly 10-fold over the course of a decade.
Use of SBRT for T3N0M0 NSCLC was associated with significantly improved OS on multivariate analysis, and subgroup analyses based on tumors > 5 cm, chest wall invasion, and multifocal tumors in the same lobe demonstrated similar or improved OS following SBRT relative to those treated with CFRT. Additionally, after controlling for cofounding and baseline imbalances through multivariable regression, HFRT resulted in comparable OS to CFRT for both T3N0M0 and T1–2N1M0 NSCLC.
These findings may continue to alter practice patterns toward moderately and extremely hypofractionated definitive radiotherapy approaches for inoperable stage IIB NSCLC. Prospective studies evaluating the utility of systemic therapy in combination with SBRT are needed.
Acknowledgments
The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator.
Footnotes
Disclosure
The authors have stated that they have no conflicts of interest.
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