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Outcomes Following SBRT vs. IMRT and 3DCRT for Older Patients with Stage IIA Node-Negative Non-Small Cell Lung Cancer > 5 cm

Published:November 01, 2022DOI:https://doi.org/10.1016/j.cllc.2022.10.006

      Abstract

      Background

      To describe outcomes and compare the effectiveness of stereotactic body radiotherapy (SBRT) versus 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) in patients with stage IIA lymph node-negative (N0) non-small cell lung cancer (NSCLC) tumors > 5 cm.

      Methods

      We used the SEER-Medicare database (2005-2015) to identify patients > 65 years with stage IIA (AJCC TNM7) N0 NSCLC > 5 cm tumors who were treated with SBRT, IMRT, and 3DCRT. We used propensity score methods with inverse probability weighting to compare lung cancer-specific survival (LCSS), overall survival (OS), and toxicity.

      Results

      Of 584 patients, 88 (15%), 140 (24%), and 356 (61%) underwent SBRT, IMRT, and 3DCRT, respectively. The SBRT group was older (P = .004), had more comorbidities (P = .02), smaller tumors (P = .03), and more adenocarcinomas (P < .0001). We found a trend towards higher median unadjusted OS with SBRT compared to IMRT and 3DCRT (19 vs. 13 and 14 months, respectively, P = .37). In our propensity score-adjusted analyses, SBRT was significantly associated with better OS and LCSS compared to IMRT (HROS: 0.78, 95% CI: 0.68-0.89, HRLCSS: 0.70, 95% CI: 0.60-0.81) and 3DCRT (HROS: 0.81, 95% CI: 0.72-0.93, HRLCSS: 0.80, 95% CI: 0.68-0.93). SBRT-treated patients also had lower overall adjusted complication rates compared to IMRT (OR: 0.74, 95% CI: 0.55-0.99) and 3DCRT (OR: 0.53, 95% CI: 0.40-0.71).

      Conclusion

      For patients with NSCLC tumors > 5 cm, SBRT trends towards fewer toxicities and improved survival compared to other forms of radiotherapy. Our findings support SBRT as an appropriate treatment strategy for older patients with larger inoperable NSCLC tumors.

      Keywords

      Abbreviations:

      3DCRT (3-dimensional conformal radiotherapy), ARD (absolute risk difference), CI (confidence interval), CPT-4 (Current Procedural Terminology, 4th edition), EBRT (external beam radiation treatment), HR (hazard ratio), ICD-9 (International Classification of Diseases, 9th revision), ICD-O (International Classification of Diseases for Oncology), IMRT (intensity-modulated radiotherapy), IPW (inverse probability weighting), LCSS (lung cancer-specific survival), N0 (node-negative), NCI (National Cancer Institute), NSCLC (non-small cell lung cancer), OR (odds ratio), OS (overall survival), PET (positron emission tomography), RCT (randomized controlled trial), SBRT (stereotactic body radiotherapy), RT (radiotherapy), RTOG (Radiation Therapy Oncology Group), SEER (Surveillance, Epidemiology and End Results), SPACE (Scandinavian Stereotactic Precision and Conventional Radiotherapy Evaluation), US (United States)

      Introduction

      The incidence of early-stage non-small cell lung cancer (NSCLC) in older individuals is expected to increase as screening guidelines are adopted in the United States (US) and around the world.
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      Stereotactic body radiation therapy for non-small cell lung cancer tumors greater than 5 cm: safety and efficacy.
      Therefore, SBRT may be a promising yet underutilized strategy for treating larger NSCLC tumors if more high quality data is generated. In this study, we used population-based data from the Surveillance, Epidemiology and End Results (SEER)-Medicare database to compare survival and tolerability of SBRT vs. conventional IMRT and 3DCRT in patients > 65 years of age with stage IIA node-negative (N0) NSCLCs > 5 cm in size.

      Materials and Methods

      Patient Characteristics

      We conducted a comparative effectiveness study using nationally representative data from the SEER-Medicare database, a population-based tumor registry linked to Medicare claims that provides clinical information and longitudinal outcomes of cancer patients > 65 years old within representative areas of the US (approximately 34% of the population).
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      Study subjects were diagnosed between 2005 and 2015 with histologically confirmed, stage IIA (defined using AJCC TNM staging criteria, seventh edition),
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      N0 NSCLCs between > 5 cm and ≤ 7.0 cm in size and treated with SBRT, IMRT, or 3DCRT. International Classification of Diseases, ninth revision (ICD-9) and Current Procedural Terminology, fourth edition (CPT-4) codes from SEER-Medicare data were used to identify treatment modalities: 1) SBRT (ICD-9: 92.3, 92.30-92.39; CPT-4: 61793, 77373, 77435, G0173, G0251, G0339, G0340, 0082T); 2) IMRT (CPT-4: 77301, 77418, 77338, 0073T, G0174), and 3) 3DCRT (CPT-4: 77295). As SBRT can be planned with IMRT and 3DCRT techniques, patients who had a SBRT billing code, in addition to procedural codes for 3DCRT or IMRT, were considered treated with SBRT. Patients were excluded if they: (1) participated in health maintenance organizations or without Part B Medicare coverage due to lack of complete claims data; (2) resided in nursing homes or receiving hospice care due to concerns for poor performance status; (3) were treated with neoadjuvant chemotherapy for the lung cancer, as these cancers could represent tumor downstaging; and (4) were diagnosed with tumors located at the main bronchus, carina and hilus of the lung, which are typically not amenable to SBRT due to their central location.
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      From SEER, we retrieved patient demographic information, including age, sex, race, and marital status. Socioeconomic status was estimated by grouping patients into quartiles based on the median incomes of the census tract or zip code in which they lived. Rural residence at time of diagnosis was defined using rural-urban continuum codes (4-9).
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      Data from the Hospice and Home Health Agency files were used to identify use of home health services (ie, medical social services, home health aide, durable medical equipment, skilled nursing, physical therapy, intravenous therapy, and home oxygen) as indicators for poor functional status.
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      Study Outcomes

      For the primary outcome, we assessed both lung cancer-specific survival (LCSS) and overall survival (OS). LCSS and OS were determined as the interval from date of treatment to date of death from lung cancer or from any cause, respectively. Study participants who were alive at the last follow-up date (December 31, 2015) were treated as censored observations. Cause of death was obtained from SEER that includes data reported in death certificates. For the secondary outcome, we examined post-treatment complications within 12 months of treatment using Medicare claims data; these included: (1) radiation pneumonitis; (2) radiation fibrosis; (3) esophagitis; (4) pneumothorax; (5) bleeding (pulmonary hemorrhage or hemoptysis); and (6) rib fracture.

      Statistical Analyses

      Baseline characteristics of patients in each treatment group (SBRT, IMRT, 3DCRT) were compared using the χ2 test or analysis of variance for categorical and continuous variables, respectively. As several patient and tumor characteristics may have affected decisions regarding which form of RT was utilized, we used propensity score methods to control for potential selection bias. Propensity scores were estimated for each patient using nominal logistic regression indicating the probability of undergoing the treatment they received, conditional on patient characteristics (ie, socio-demographics and comorbidity score), tumor characteristics (ie, size, location, histology) and use of pretreatment evaluation (ie, PET/CT, mediastinoscopy) (see Table 1 for all covariates). We did not include adjuvant chemotherapy as a variable in our propensity score model, as this would not influence treatment allocation. To account for concurrent chemotherapy, we performed subgroup analyses stratifying the sample by SBRT vs. IMRT- or 3DCRT-based chemoradiation. We defined concurrent chemotherapy as initiation of treatment within 14 days of starting RT. For study outcomes, we adjusted for allocation bias using inverse probability weighting (IPW); weights for each patient were calculated as the inverse of the estimated probability for undergoing the type of treatment they received. We then examined the balance of covariates across groups (and subgroups) after adjustment and removal of extreme weights.
      Table 1Characteristics of Older Patients with Stage IIA Node-Negative NSCLC > 5 cm in Size Treated with SBRT vs. IMRT vs. 3DCRT
      Cohort N = 584SBRT
      Stereotactic body radiotherapy
      N = 88
      IMRT
      Intensity-modulated radiotherapy
      N = 140
      3DCRT
      3-dimensional conformal radiotherapy
      N = 356
      P-valueAdjusted P-value
      Adjusted using propensity score methods
      Age, year, mean ± std
      Standard deviation
      77 ± 680 ± 678 ± 777 ± 6.004.33
      Female, No. (%)248 (42.5)41 (46.6)62 (44.3)145 (40.7).54.86
      Married, No. (%)276 (47.3)39 (44.3)60 (42.9)177 (49.7).32.45
      Non-White, No. (%)87 (14.9)11 (12.5)22 (15.7)54 (15.2).78.95
      Median Income, No. (%).10.84
       First Quartile181 (31.0)28 (31.8)40 (28.6)113 (31.7)
       Second Quartile168 (28.8)21 (23.9)44 (31.4)103 (28.9)
       Third Quartile117 (20.0)13 (14.8)24 (17.1)80 (22.5)
       Fourth Quartile118 (20.2)26 (29.5)32 (22.9)60 (16.9)
      Rural residence< 11 (< 12.5)
      National Cancer Institute
      17 (12.1)47 (13.2).40.99
      NCI
      SEER prevents the reporting of the actual number for any variables associated with < 11 patients
      comorbidity index, No., (%)
      .02.56
       0 to < 1.0400 (68.5)51 (58.0)90 (64.3)259 (72.8)
       1.0 to < 2.0< 11 (< 12.5)< 11 (< 7.9)23 (6.5)
       ≥2.0≥ 11 (≥ 12.5)≥ 11 (≥ 7.9)74 (20.8)
      Tumor Size.03.08
       5.1 cm - 6.0 cm371 (63.5)65 (73.9)79 (56.4)227 (63.8)
       >6.0 – 7.0 cm213 (36.5)23 (26.1)61 (43.6)129 (36.2)
      Tumor Site.28.94
       Upper lobe338 (57.9)43 (48.9)81 (57.9)214 (60.1)
       Lower lobe≥ 11 (≥ 12.5)≥ 11 (≥ 7.9)123 (34.6)
       Other
      Middle site, not otherwise specified, or overlapping lesion of lung
      < 11 (< 12.5)< 11 (< 7.9)19 (5.3)
      Histology, No. (%)<.001.36
       Adenocarcinoma160 (27.4)44 (50.0)32 (22.9)84 (23.6)
       Squamous cell≥ 11(≥ 12.5)91 (65.0)205 (57.6)
       Other
      Large cell, not otherwise specified, or other
      < 11 (< 12.5)17 (12.1)67 (18.8)
      PET
      Positron emission tomography
      -scan, No. (%)
      427 (73.1)67 (76.1)118 (84.3)242 (68.0).001.001
      Mediastinoscopy, No. (%)32 (5.5)< 11 (< 12.5)< 11 (< 7.9)16 (4.5).38.79
      Home health aide or durable medical equipment123 (21.1)20 (22.7)31 (22.1)72 (20.2).82.93
      Skilled nursing services< 11 (< 12.5)13 (9.3)22 (6.2).46.53
      iLarge cell, not otherwise specified, or other
      a Stereotactic body radiotherapy
      b Intensity-modulated radiotherapy
      c 3-dimensional conformal radiotherapy
      d Adjusted using propensity score methods
      e Standard deviation
      f SEER prevents the reporting of the actual number for any variables associated with < 11 patients
      g National Cancer Institute
      h Middle site, not otherwise specified, or overlapping lesion of lung
      i Positron emission tomography
      j Large cell, not otherwise specified, or other
      For our survival analysis, we used unadjusted Kaplan-Meier estimates and the log-rank method to compare 1-year, 3-year, and 5-year LCSS and OS for each treatment group. Cox proportional hazards model was then used to compare unadjusted and adjusted survival. For our secondary outcome, we describe the proportion of patients in each group that experienced complications. Unadjusted and adjusted overall complication rates were compared. To maintain patient confidentiality, SEER prevents the reporting of the actual number for any variables associated with < 11 patients. Therefore, we report crude absolute risk differences (ARDs) between treatment groups for each complication. This study was determined exempt by the institutional review board of the Icahn School of Medicine at Mount Sinai.

      Results

      Overall, 584 patients met inclusion criteria, of which 88 (15%) received SBRT, 140 (24%) were treated with IMRT, and 356 (61%) underwent 3DCRT (Supplementary Figure 1). For patients treated with IMRT and 3DCRT, 47 (34%) and 121 (34%) received concurrent chemotherapy, respectively. Comparisons of baseline characteristics between the groups are summarized in Table 1. Patients who received SBRT were older (P = .004) and were associated with more comorbidities (P = .02). The mean NCI comorbidity index and standard deviation (std) for patients treated with SBRT were 1.5 ± 2.1 compared to 1.4 ± 2.2 for IMRT and 0.88 ± 1.7 for 3DCRT. The SBRT group also had smaller tumors (P < .03) that were more frequently of adenocarcinoma origin (P < .0001) compared to patients who received IMRT and 3DCRT. Median tumor size was 5.6 cm (interquartile range [IQR]: 5.3-6.1 cm) for SBRT, 6.0 cm (5.5-6.6 cm) for IMRT and 6.0 cm (5.5-6.4 cm) for 3DCRT. Patients who received SBRT were also more likely to have been evaluated by PET scans compared to IMRT and 3DCRT (P < .0001). We found no significant differences in the distribution of other baseline characteristics (P > .05 for all comparisons).
      In the total cohort, unadjusted LCSS and OS and median follow-up time are found in Figure 1 and 2, respectively. Subgroup unadjusted survival analyses can be found in the e-supplementary material (Supplementary Table 1). Overall, for the unadjusted survival analyses, 1-year, 3-year and 5-year LCSS were 76.1%, 51.1% and 45.5% respectively, for SBRT-treated patients, compared to 58.6%, 38.6% and 35.7% for IMRT-treated patients, and 62.4%, 37.9% and 34.8% for patients who received 3DCRT (Figure 1). The unadjusted median LCSS was longer in the SBRT group when compared to both IMRT and 3DCRT (26 vs. 14 vs. 17 months, respectively; P = .07). One-year, 3-year and 5-year OS rates were 69.3%, 29.5% and 14.8%, respectively for SBRT-treated patients vs. 54.3%, 27.1% and 20.0%, for IMRT-treated patients vs. 54.2%, 21.6% and 14.9% for 3DCRT-treated patients (Figure 2). Median unadjusted OS was higher in the SBRT group when compared to IMRT and 3DCRT (19 vs. 13 vs. 14 months, respectively; P = .37). Adjusted analyses using the Cox regression model and IPW demonstrated SBRT was associated with significant improvement in LCSS and OS when compared to IMRT (LCSS hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.60-0.81; OS HR: 0.78, 95% CI: 0.68-0.89) and 3DCRT (LCSS HR: 0.80, 95% CI:0.68-0.93, OS HR: 0.81, 95% CI: 0.72-0.93; Table 2). In the subgroup analyses (Table 2), LCSS and OS remained higher for SBRT compared to IMRT or 3CDRT with no concurrent chemotherapy. However, there were no differences in survival among patients who received SBRT vs. IMRT with concurrent chemotherapy (LCSS HR: 1.11, 95% CI: 0.87-1.41, OS HR: 1.15, 95% CI: 0.93-1.41) or 3DCRT with concurrent chemotherapy (LCSS HR: 1.21, 95% CI: 0.96-1.53, OS HR: 1.20, 95% CI: 0.99-1.47).
      Figure 1
      Figure 1Unadjusted Kaplan-Meier estimates of lung cancer-specific survival in older patients with NSCLC > 5 cm tumors treated with SBRT vs. IMRT vs. 3DCRT. Green, red, and blue reflect unadjusted Kaplan-Meier estimates for SBRT, IMRT and 3DCRT respectively. The number at risk through 3 years and survival estimates are below the graph
      Figure 2
      Figure 2Unadjusted Kaplan-Meier estimates of overall survival in older patients with NSCLC > 5 cm tumors treated with SBRT vs. IMRT vs. 3DCRT. Green, red, and blue reflect unadjusted Kaplan-Meier estimates for SBRT, IMRT and 3DCRT respectively. The number at risk through 3 years and survival estimates are below the graph
      Table 2Adjusted Survival of Older Patients with Stage IIA Node-Negative NSCLC > 5 cm in Size Treated with SBRT vs. IMRT vs. 3DCRT
      Hazard Ratio, 95% CI
      Confidence interval
      SBRT
      Stereotactic body radiotherapy
      vs. IMRT
      Intensity-modulated radiotherapy
      SBRT vs. 3DCRT
      3-dimensional conformal radiotherapy
      UnadjustedAdjusted
      Adjusted using inverse probability weighting
      UnadjustedAdjusted
      Total CohortN=88 vs. 140N=88 vs. 356
      Lung Cancer-Specific Survival0.70 (0.50-1.00)0.70 (0.60-0.81)0.70 (0.51-0.96)0.80 (0.68-0.93)
      Overall Survival0.88 (0.66-1.18)0.78 (0.68-0.89)0.84 (0.65-1.08)0.81 (0.72-0.93)
      SBRT vs. concurrent chemoradiationN = 88 vs. 47N = 88 vs. 121
      Lung Cancer-Specific Survival1.02 (0.63-1.65)1.11 (0.87-1.41)0.89 (0.62-1.28)1.21 (0.96-1.53)
      Overall Survival1.27 (0.85-1.91)1.15 (0.93-1.41)1.01 (0.81-1.47)1.20 (0.99-1.47)
      SBRT vs. no concurrent chemoradiationN = 88 vs. 93N = 88 vs. 235
      Lung Cancer-Specific Survival0.57 (0.40-0.83)0.60 (0.51-0.71)0.61 (0.44-0.84)0.75 (0.63-0.89)
      Overall Survival0.72 (0.53-0.98)0.68 (0.58-0.79)0.71 (0.55-0.93)0.74 (0.64-0.86)
      a Confidence interval
      b Stereotactic body radiotherapy
      c Intensity-modulated radiotherapy
      d 3-dimensional conformal radiotherapy
      e Adjusted using inverse probability weighting
      Patients treated with SBRT had lower numerical overall complications within 12 months of treatment compared to those treated with IMRT and 3DCRT (20.5% vs. 23.6% vs 29.2%, P = .17) (Table 3). Compared to patients treated with IMRT, SBRT-treated patients had significantly higher unadjusted ARDs for pneumothorax than IMRT (ARD: -6.5%, 95% CI: -12.5 to -0.5%). Compared to 3DCRT-treated patients, the SBRT group had significantly lower unadjusted ARDs for radiation fibrosis (ARD: 2.3%, 95% CI: 0.7%-3.8%) and esophagitis (ARD: 8.1%, 95% CI: 0.7%-3.8%). After adjusting for potential confounders with IPW, SBRT was associated with lower overall treatment-related toxicity when compared to IMRT (odds ratio [OR]: 0.74, 95% CI: 0.55-0.99) and 3DCRT (OR: 0.53, 95% CI: 0.40-0.71). This significant result was also observed in the SBRT vs. concurrent chemoradiation subgroup analysis (SBRT vs. IMRT OR: 0.52, 95% CI: 0.34-0.80; SBRT vs. 3DCRT OR: 0.64, 95% CI: 0.42-0.96). When stratifying the cohort to SBRT vs. IMRT and 3DCRT with no concurrent chemotherapy, SBRT-treated patients had lower adjusted complication rates compared to 3DCRT (OR: 0.68, 95% CI: 0.49-0.94) but not IMRT (OR: 1.07, 95% CI: 0.76-1.50).
      Table 3Treatment-Related Toxicities within 12 Months in Older Patients with NSCLC > 5 cm Treated with SBRT vs. IMRT vs. 3DCRT
      Outcome3DCRT
      3-dimensional conformal radiotherapy
      N = 356
      P-value
      UnadjustedAdjusted
      Adjusted using inverse probability weighting
      Any complication, No. (%)18 (20.5)33 (23.6)104 (29.2).17<.0001
      SBRT
      Stereotactic body radiotherapy
      N=88
      IMRT
      Intensity-modulated radiotherapy
      N=140
      3DCRT
      3-dimensional conformal radiotherapy
      N=356
      P-valuee
      Total CohortSBRT
      Stereotactic body radiotherapy
      N=88
      IMRT
      Intensity-modulated radiotherapy
      N=140
      3DCRT
      3-dimensional conformal radiotherapy
      N=356
      P-valueAdjustedP-value
      Adjusted using inverse probability weighting
      Any complication, No. (%)18 (20.5)33 (23.6)104 (29.2).17<0.001
      SBRT vs. 3DCRT
      Adjusted Odds Ratio
      Adjusted using inverse probability weighting
      (95% CI)
      Confidence interval
      Any complication0.74 (0.55-0.99)0.53 (0.40-0.71)
      Unadjusted % Absolute Risk Difference, (95% CI)Bleeding1.3% (-3.1%-5.7%)0.8% (-2.8%-4.4%)
      Radiation Pneumonitis0.8% (-5.6%-7.1%)0.5% (-5.0%-5.9%)
      Radiation Fibrosis1.4% (-0.5%-3.4%)2.3% (0.7%-3.8%)
      Esophagitis6.5% (-0.8%-13.7%)8.1% (2.1%-14.1%)
      Pneumothorax-6.5% (-12.5% to -0.5%)-2.9% (-9.0%-3.2%)
      Rib Fracture-3.2% (-7.2%-0.9%)2.5% (-0.4%-5.5%)
      SBRT vs. concurrent chemoradiation
      SBRT vs. concurrent chemoradiationSBRT N= 88IMRT N = 473DCRT N = 121P-value
      SBRT vs. concurrent chemoradiationSBRT N=88IMRT N=473DCRT N=121P-valueAdjusted P-value
      Any complication, No. (%)18 (20.5)15 (31.9)40 (33.1).14.009
      SBRT vs. IMRTSBRT vs. 3DCRT
      Adjusted Odds Ratio (95% CI)Any complication 0.52 (0.34-0.80)0.64 (0.42-0.96)
      SBRT vs. no concurrent chemoradiation
      SBRT vs. no concurrent chemoradiationSBRT N = 88IMRT N = 933DCRT N = 235P-value
      SBRT vs. no concurrent chemoradiationSBRT N=88IMRT N=933DCRT N=235P-valueAdjusted P-value
      Any complication, No. (%)18 (20.5)18 (19.4)64 (27.2).22.009
      SBRT vs. IMRTSBRT vs. 3DCRT
      Adjusted Odds Ratio (95% CI)Any complication1.07 (0.76-1.50)0.68 (0.49-0.94)
      a Stereotactic body radiotherapy
      b Intensity-modulated radiotherapy
      c 3-dimensional conformal radiotherapy
      d Adjusted using inverse probability weighting
      e Confidence interval

      Discussion

      A significant percentage of patients diagnosed with larger localized NSCLC tumors are not able to tolerate surgical resection due to age- and/or smoking-related comorbidities. While these patients can undergo standard 3DCRT or IMRT with or without concurrent chemotherapy, SBRT has emerged as a potential alternative. Though SBRT has been increasingly used for larger tumors in clinical practice,
      • Schneider CS
      • Oster RA
      • Hegde A
      • Dobelbower MC
      • Stahl JM
      • Kole AJ.
      Nonoperative treatment of large (5-7 cm), node-negative non–small cell lung cancer commonly deviates from NCCN guidelines.
      ,
      • Post CM
      • Verma V
      • Zhen W
      • Simone CB.
      Stereotactic body radiation therapy for≥ 5 cm node-negative non-small cell lung cancer: Survey of US academic thoracic radiation oncologists.
      there is limited comparative data. Using nationally representative data from SEER-Medicare, this study shows that older patients who received SBRT for NSCLCs > 5 cm and ≤ 7.0 cm in size were associated with better LCSS and OS compared to those who received 3DCRT or IMRT. SBRT was also associated with reduced adjusted rates of overall complications, compared to those receiving IMRT and 3DCRT. Patients who received concurrent chemotherapy with IMRT or 3DCRT seemed to have similar survival but higher complication rates. Our findings therefore provide support that SBRT may be considered an acceptable non-invasive treatment strategy for older patients with stage IIA N0 NSCLC > 5 cm tumors.
      SBRT is currently used in smaller (< 5 cm) NSCLC tumors and is supported by a growing body of data demonstrating excellent local control and improvement in survival. In the Radiation Therapy Oncology Group (RTOG) 0236 trial, the 3-year and 5-year primary tumor control rates with SBRT were 98% and 93%, respectively, while the 5-year primary tumor and involved lobe rate was 80%.
      • Timmerman RD
      • Paulus R
      • Pass HI
      • et al.
      Stereotactic body radiation therapy for operable early-stage lung cancer: findings from the NRG oncology RTOG 0618 Trial.
      • Timmerman R
      • Paulus R
      • Galvin J
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      • Timmerman RD
      • Hu C
      • Michalski JM
      • et al.
      Long-term results of stereotactic body radiation therapy in medically inoperable stage I non–small cell lung cancer.
      Compared to other forms of RT, the CHISEL phase III randomized controlled trial (RCT) demonstrated a 2-year OS in < 5 cm NSCLCs of 77% (95% CI: 67-88) for patients treated with SBRT compared to 59% (95% CI: 44-78) for patients treated with 3DCRT.
      • Ball D
      • Mai GT
      • Vinod S
      • et al.
      Stereotactic ablative radiotherapy vs. standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomized controlled trial.
      However, the Scandinavian Stereotactic Precision and Conventional Radiotherapy Evaluation (SPACE) trial, which used a different biological effective dose and fraction schedule and enrolled patients with poorer performance status than the CHISEL trial, found no significant OS differences between patients treated with SBRT and patients treated with 3DCRT.
      • Nyman J
      • Hallqvist A
      • Lund JA
      • et al.
      SPACE - A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC.
      While these studies have helped provide support for SBRT as the curative treatment option over 3DCRT for smaller inoperable NSCLC tumors, no prospective studies to date have directly compared SBRT to conventionally fractionated IMRT for smaller early-stage NSCLC tumors.
      Data evaluating SBRT outcomes in patients with NSCLC > 5 cm is limited mostly to single-institution case series without a comparator arm. Among 40 patients with larger NSCLCs treated with SBRT at an academic medical center, OS was 60% at 18 months.
      • Woody NM
      • Stephans KL
      • Marwaha G
      • Djemil T
      • Videtic GM.
      Stereotactic body radiation therapy for non-small cell lung cancer tumors greater than 5 cm: safety and efficacy.
      Other case series of similar numbered patients demonstrated 1-year survival rates between 65% and 81%.
      • Peterson J
      • Niles C
      • Patel A
      • et al.
      Stereotactic body radiotherapy for large (>5 cm) non-small-cell lung cancer.
      ,
      • Tekatli H
      • van 't Hof S
      • Nossent EJ
      • et al.
      Use of Stereotactic Ablative Radiotherapy (SABR) in non-small cell lung cancer measuring more than 5 cm.
      A recent study using the National Cancer Database (NCDB) comprising 201 patients who either received SBRT with chemotherapy or SBRT alone for NSCLC ≥ 5 cm reported 1-year OS of 77% in the SBRT-only group (N = 171).
      • Verma V
      • McMillan MT
      • Grover S
      • Simone 2nd, CB.
      Stereotactic body radiation therapy and the influence of chemotherapy on overall survival for large (≥ 5 cm) non-small cell lung cancer.
      However, this study did not report LCSS rates and was unable to assess for toxicities related to SBRT. In the study reported here, we used nationally representative data from the SEER-Medicare registry directly comparing older patients receiving SBRT vs. 3DCRT or IMRT for local treatment of NSCLCs > 5 cm in size. We found data consistent with survival rates reported in previous case series examining SBRT in tumors > 5 cm in size. Importantly, this present study advances our current understanding by showing that SBRT may be associated with higher survival compared to IMRT and 3DCRT overall but not when compared to patients receiving SBRT vs. concurrent chemoradiation with IMRT or 3DCRT.
      Treatment-related toxicities are an important consideration in the management of older patients with NSCLC. In the RTOG 0236 trial for smaller NSCLC tumors, 16.4% of non-operable patients receiving SBRT experienced ≥ grade 3 adverse event, while a significantly less subset (7.7%) of potentially operable patients in RTOG 0618 experienced a protocol-specified grade 3 adverse event, suggesting that performance status and comorbidities have an important association with SBRT tolerability.
      • Timmerman RD
      • Paulus R
      • Pass HI
      • et al.
      Stereotactic body radiation therapy for operable early-stage lung cancer: findings from the NRG oncology RTOG 0618 Trial.
      ,
      • Timmerman R
      • Paulus R
      • Galvin J
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      In our study, specifically looking at older patients at the highest risk of toxicities, we found that patients who received SBRT experienced significantly lower rates of overall treatment-related toxicity within the first 12 months compared to patients receiving 3DCRT and IMRT, including those receiving concurrent chemotherapy. This finding was particularly evident after adjusting for important confounding factors between treatment groups, suggesting that SBRT is a safer and well-tolerated modality that may be used to treat larger tumors in older patient populations.
      This study has strengths and limitations. We used nationally representative, population-based data to study treatment outcomes of different RT modalities in a real-world patient population, providing our study important external validity. Moreover, our study focuses on older patients (> 65 years), an important subset most likely to derive benefit from RT given both the high incidence of lung cancer and significant challenges with surgical management in this age group. The main limitation, inherent to all observational data, is lack of treatment randomization creating baseline differences between treatment groups that may impact treatment allocation and outcomes. To account for this selection bias, we used robust propensity score models and IPW methods of all measured variables. However, despite accounting for the most important patient baseline characteristics and tumor factors, there potentially may remain unmeasured confounders. For example, while we excluded centrally located tumors that are often associated with worse outcomes and increased toxicities using ICD codes, tumor location may not be completely captured based on these data and therefore may impact our findings. Additionally, SEER-Medicare does not provide data or validated surrogate variables that would reliably estimate dose and fractionation for RT, and receipt of palliative vs. curative IMRT or 3DCRT treatment is not clear. However, (1) it is unlikely that patients who received IMRT were given palliative doses based on guideline recommendations to use external beam radiation treatment (EBRT; most commonly 2DCRT) for this indication;
      • Moeller B
      • Balagamwala EH
      • Chen A
      • et al.
      Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 update of an American Society for Radiation Oncology (ASTRO) evidence-based guideline.
      (2) we stratified patients who received concurrent chemotherapy who are unlikely to receive palliative doses; and (3) all patients had localized tumors without lymph node involvement and therefore were eligible and should receive curative intent treatment. Lastly, our ability to detect differences only in overall but not individual complication rates and ARDs (ie, rib fracture, esophagitis, etc.) across groups is likely due to low incidence rates. Though patients may have experienced late toxicities, we detected few complications occurring after 12 months, which may be due to short follow-up time. Despite these limitations, given that no RCTs have compared RT modalities for the treatment of larger > 5 cm tumors, our results provide national data describing real-world outcomes in this understudied population.

      Conclusion

      In summary, this population-based study demonstrated that SBRT is associated with better survival when compared to IMRT and 3DCRT in patients with larger NSCLCs > 5 cm in size after adjusting for important clinical confounders. Survival outcomes were similar when comparing patients who underwent SBRT vs. IMRT and 3DCRT with concurrent chemotherapy. However, with a lower overall incidence of treatment-related toxicities associated with SBRT than with IMRT or 3DCRT, SBRT may be an appropriate option for treating older patients with larger inoperable NSCLC tumors. These results should be validated by future prospective studies, which should also consider evaluating long-term outcomes, patterns of recurrence, and cost-effectiveness of these radiotherapies.

      Clinical Practice Points

      • Older patients with non-small cell lung cancer (NSCLC) are often at high risk for surgery due to multiple age- and smoking-related comorbidities.
      • Although stereotactic radiotherapy (SBRT) has emerged as a non-invasive alternative for early-stage small NSCLC tumors, there is limited data for the treatment of larger tumors.
      • Using SEER-Medicare data, we examined outcomes in patients > 65 years with Stage IIA node-negative NSCLC tumors > 5 cm who received SBRT vs. intensity-modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3DCRT).
      • In the overall cohort (N=584), SBRT was associated with higher survival compared to IMRT and 3DCRT.
      • Subgroup analysis showed no difference in survival between patients who received SBRT (N=88) vs. concurrent chemoradiation with IMRT (N=47) or 3DCRT (N=121).
      • SBRT was associated with fewer complications than IMRT or 3DCRT, including those receiving concurrent chemoradiation.

      Author Contributions

      JHT, GM, HSP, JPW, RRV contributed to the conception/design of the work, statistical analysis, interpretation of data of the work, and drafting of the work. DCM, KR, and QW contributed to the interpretation of data for the work and revising it for important intellectual content. All authors had final approval of the version to be published and agreement to be accountable for all aspects of the work.

      Data Availability

      Research data cannot be shared in accordance with NCI SEER-Medicare policies.

      Disclosure

      RRV serves on advisory boards for Bristol-Myers Squibb (BMS), AstraZeneca, Merck and Novocure, on speaker's bureau of AstraZeneca, received consulting honorarium from Onconova Therapeutics, and research grants from BMS, Lung Cancer Research Foundation and AstraZeneca. JPW received consulting honorarium from Banook, Atea, PPD, and Sanofi and research grants from Sanofi, Regeneron and Arnold Consulting. HSP serves on an advisory board for Galera Therapeutics, received honorarium from BMS, Guidepoint, Grand Rounds Health, Healthcasts, Healthline and RadOncQuestions, consulting fees from AstraZeneca, speaking fees from BMS and research grants from RefleXion Medical and U.S. FDA. DM receives a research grant from the NIH T32 program. JHT, GM, QW, and KR have no conflicts of interest to declare.

      Acknowledgments

      The authors would like to thank: the Tisch Cancer Institute Summer Scholars Program at Mount Sinai Hospital; the Applied Research Branch, Division of Cancer Prevention and Population Science, National Cancer Institute; the Office of Information Services and the Office of Strategic Planning, Health Care Finance Administration; Information Management Services, Inc.; the SEER Program tumor registries for their efforts in the creation of the SEER-Medicare Database. The collection, interpretation, and reporting of these data are the sole responsibilities of the authors. All significant contributors of this manuscript have been listed.
      Jessica H. Tran, BS received internal funding from the Tisch Cancer Institute Summer Scholars Program at Mount Sinai Hospital to support this study.

      Appendix. Supplementary materials

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