Abstract
We retrospectively reviewed patients with early-stage and metastatic non–small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy using 2 fractionation regimens, 50 Gy in 5 fractions and 10 fractions. Local control was worse with the 10-fraction regimen but was not detrimental to progression-free or overall survival in patients with early NSCLC. Although suboptimal for local control, 50 Gy in 10 fractions could potentially be useful for reasonably durable control when dose-fractionation schemes with BED10 ≥ 100 Gy are considered unsafe.
Introduction:
At our institution, stereotactic body radiotherapy (SBRT) has commonly been prescribed with 50 Gy in 5 fractions and in select cases, 50 Gy in 10 fractions. We sought to evaluate the impact of these 2 fractionation schedules on local control and survival outcomes.
Methods:
We reviewed patients treated with SBRT with 50 Gy/5 fraction or 50 Gy/10 fraction for early-stage non–small cell lung cancer (NSCLC) and metastatic NSCLC. Cumulative incidence of local failure (LF) was estimated using competing risk methodology. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method only for patients with stage I disease.
Results:
Of the 353 lesions, 300 (85%) were treated with 50 Gy in 5 fractions and 53 (15%) with 10 fractions. LFs at 3 years were 6.5% and 23.9% and Kaplan-Meier estimate of median time to LF was 17.5 months and 26.2 months, respectively. Multivariable analysis revealed increasing planning target volume (hazard ratio 1.01, P = .04) as an independent predictor of increased LF, but tumor size, ultracentral location, and 10 fractions were not. Among patients with stage I NSCLC (n = 298), overall median PFS was 35.6 months and median OS was 42.4 months. There was no difference in PFS or OS between the 2 treatment regimens for patients with stage I NSCLC. Low rates of grade 3+ toxicity were observed, with 1 patient experiencing grade 3 pneumonitis after a 5-fraction regimen of SBRT.
Conclusion:
Dose-fractionation schemes with BED10 ≥ 100 Gy provide superior local control and should be offered when meeting commonly accepted constraints. If those regimens appear unsafe, 50 Gy in 10 fractions may provide acceptable compromise between tumor control and safety with relatively durable control, and minimal negative impact on long-term survival.
Keywords: Biological equivalent dose, BED, Lung cancer, Non-small cell lung cancer, SBRT
Introduction
Stereotactic body radiation therapy (SBRT) is an established treatment for inoperable early-stage non–small cell lung cancer (NSCLC).1 However, for those early-stage patients who are medically operable, surgical resection remains the standard of care. Large randomized evidence illustrating the equivalence of SBRT with surgery in this population is lacking.
Before the development of SBRT, conventional radiation therapy for lung tumors demonstrated poor local control (LC) and survival.2–5 The development of SBRT techniques enabled sharp dose fall off, which provided the potential for improved protection of normal structures while simultaneously dose escalating the tumor.
Multiple studies have examined differing regimens in search of an optimal standard approach.1,6–10 Several regimens have demonstrated excellent LC, but there is not a single agreed-on dose-fractionation that fits all clinical scenarios. Early analyses found that a biologically effective dose (BED) >100 Gy10 portended for improved LC and survival; however, these studies included conventional radiotherapy regimens in their comparisons.11,12 Later series including only SBRT re-demonstrated the same principle, that an increased BED led to improved LC. However, in some situations in which the tumor directly abuts critical structures, this unavoidably increases normal tissue dose and therefore increases the risks of serious toxicity.13,14 The dose-fractionation regimen chosen in a given clinical scenario depends on multiple patient-specific factors including tumor size and proximity to organs at risk. This decision is typically at the discretion of the treating physician and should balance the risks of disease failure against potential toxicities.
At our institution, SBRT has commonly been prescribed with 50 Gy in 5 fractions. In very select cases, we used 50 Gy in 10 fractions. Often, the 10-fraction scheme was used for large or central tumors that were directly abutting sensitive structures, or in cases of metastatic disease, in which a treatment with more than palliative intent was felt appropriate. This study investigated the impact of these 2 fractionation regimens on LC in patients with stage I and metastatic NSCLC. For only the stage I population, progression-free survival (PFS), and overall survival (OS) were also compared. Furthermore, we evaluated dosimetric parameters and toxicity outcomes.
Materials and Methods
Patient Population and Interventions
In this institutional review board–approved retrospective analysis, we analyzed the records of patients with NSCLC who were treated with SBRT in the lung from 2013 to 2018 inclusively. Study data were collected and managed using REDCap electronic data capture tools hosted by the Wake Forest Clinical and Translational Science Institute.15 All patients underwent multidisciplinary thoracic oncology evaluation and staging workup with computed tomography (CT) and/or [18F] fluorodeoxyglucose positron emission tomography (PET). Brain magnetic resonance imaging (MRI) was also obtained if clinically indicated based on tumor size and location. Referral for biopsy was considered in all patients with newly diagnosed primaries and in patients with newly diagnosed metastatic disease. In cases in which biopsy was unfeasible or carried unacceptable risk, lesions were treated based on a clinical diagnosis including PET avidity and lesion growth on serial imaging.
Patient simulation included patient immobilization in a vacuum cushion system with abdominal compression to restrict respiratory motion. An internal gross target volume (iGTV) was contoured by co-registering the maximum intensity projection and 4-dimensional CT (4D-CT) images without intravenous contrast. The planning target volume (PTV) was generated by an isotropic expansion of 5 mm from the iGTV. The dose regimen prescribed was determined at the discretion of the treating physician when considering the target and normal tissues at risk. The 10-fraction regimen was most often used for central tumors (defined in this study as tumors within 2 cm of proximal bronchial tree), ultracentral tumors (defined herein as PTV contacting or overlapping the proximal bronchial tree, esophagus, pulmonary vein, or pulmonary artery), or very peripheral tumors (defined as GTV within 2 cm of chest wall).1,16
Several treatment planning systems were used for SBRT during the timeframe included in the current study, including Pinnacle, Monaco, and RayStation. Similarly, a variety of techniques were used, including 8 to 11 3-dimensional beams, intensity modulated radiation therapy, and volumetric modulated radiation therapy. Treatments were delivered using 6-MV photons from gantry-based linear accelerators. Daily image guidance and imaging approval at the machine was used before each treatment for both fractionation schemes with daily cone-beam CT imaging. Treatment plans were reviewed to define the location of the target lesion as well as dosimetric factors, including the treatment volumes and PTV minimum, mean, and maximum dose.
Outcome Measures
Outcome measures were estimated from the date of completion of radiotherapy. Patients were followed with routine CT imaging of the chest and physician visits according to institutional guidelines. The primary endpoint was local failure (LF), defined as enlargement of the target lesion on successive CT imaging, FDG avidity on PET/ CT, or biopsy-proven disease. Secondary endpoints included regional failure (RF), distant failure (DF), PFS, OS, and toxicity outcomes. RF was defined as any evidence of hilar or mediastinal disease recurrence. DF was defined as any evidence of metastatic disease (ie, extrapulmonary metastases, non-regional adenopathy, progressive pulmonary metastases). Freedom from regional failure (FFRF) and freedom from distant failure (FFDF) were estimated in patients with localized Stage I (N0M0) initial disease (n = 298). PFS was defined as the time from diagnosis to death, recurrence, or last clinical follow-up, whichever came first. OS was defined as time from diagnosis to death from any cause or last clinical follow-up, whichever comes first. Toxicity, including rate and severity of chest wall pain, esophagitis, and pneumonitis were graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 based on review of the medical record.
Statistical Analysis
Data are described using count (frequency) and median (interquartile range) and compared between groups using the Fisher’s exact test or χ2 test for categorical variables and Kruskal-Wallis test for continuous variables. Cumulative incidence of LF was estimated using competing risk methodology and compared across strata using Gray’s test.17,18 Death without LF as a competing event that mitigates the risk of LF is included in all cumulative incidence analyses. Univariable competing risk regression models were performed to evaluate clinical, tumor, and dosimetric factors on the subdistribution hazard of LF. A multivariable model was generated using factors found to be associated with LF on univariable models (P ≤ .20). Time-to-event outcomes were exclusively assessed in patients with stage I NSCLC to evaluate for differences in survival outcomes between the 2 treatment regimens. These included PFS, OS, FFRF, and FFDF which were estimated from the start date of SBRT using the Kaplan-Meier method and compared across strata using the log-rank test. Follow-up was estimated using the reverse Kaplan-Meier method.19 All statistical analyses were performed using R version 3.6 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient and Tumor Characteristics
In total, 325 patients with 353 lesions were eligible for analysis. Baseline patient characteristics were well-balanced between groups as described in Table 1. The median age was 71 years, most patients were men, Eastern Cooperative Oncology Group (ECOG) 0–1, and current or former smokers. The most common indication for treatment was a new diagnosis of a single lung lesion. Supplemental oxygen was required at baseline in 16.3% of patients (17.8% 5-fraction, 8.0% 10-fraction). Most patients (93.8%) were staged with PET/CT, 47.7% underwent pre-SBRT pulmonary function testing, and 28.6% underwent staging brain MRI. Although most patients had no prior history of lung surgery, 9.5% had a history of prior lobectomy, 2.2% of prior wedge resection, and 0.6% of prior pneumonectomy.
Table 1.
Patient Characteristics
| Overall (n = 325) | 5-Fraction (n = 275) | 10-Fraction (n = 50) | P Value | |
|---|---|---|---|---|
| Gender (%) | ||||
| Female | 130 (40.0) | 111 (40.4) | 19 (38.0) | .88 |
| Male | 195 (60.0) | 164 (59.6) | 31 (62.0) | |
| Race (%) | ||||
| White | 272 (83.7) | 232 (84.4) | 40 (80.0) | .54 |
| African American | 47 (14.5) | 37 (13.5) | 10 (20.0) | |
| Asian | 3 (0.9) | 3 (1.1) | 0 (0.0) | |
| Other | 3 (0.9) | 3 (1.1) | 0 (0.0) | |
| Age, median [IQR] | 71.41 [65.38, 78.86] | 71.03 [65.15, 78.75] | 72.55 [67.90, 79.09] | .26 |
| BMI, median [IQR] | 25.30 [22.40, 30.50] | 25.19 [22.33, 30.67] | 26.10 [22.55, 30.05] | .93 |
| ECOG (%) | ||||
| 0–1 | 195 (60.0) | 166 (60.4) | 29 (58.0) | .88 |
| 2–3 | 130 (40.0) | 109 (39.6) | 21 (42.0) | |
| Smoking status (%) | ||||
| Never | 13 (4.0) | 9 (3.3) | 4 (8.0) | .23 |
| Current | 101 (31.1) | 84 (30.5) | 17 (34.0) | |
| Former | 211 (64.9) | 182 (66.2) | 29 (58.0) | |
| Pulmonary function test (%) | ||||
| No | 170 (52.3) | 146 (53.1) | 24 (48.0) | .61 |
| Yes | 155 (47.7) | 129 (46.9) | 26 (52.0) | |
| Supplemental oxygen (%) | ||||
| No | 272 (83.7) | 226 (82.2) | 46 (92.0) | .10 |
| Yes | 53 (16.3) | 49 (17.8) | 4 (8.0) | |
| PET/CT (%) | ||||
| No | 20 (6.2) | 16 (5.8) | 4 (8.0) | .53 |
| Yes | 305 (93.8) | 259 (94.2) | 46 (92.0) | |
| MRI brain (%) | ||||
| No | 232 (71.4) | 197 (71.6) | 35 (70.0) | .95 |
| Yes | 93 (28.6) | 78 (28.4) | 15 (30.0) | |
| Prior surgery (%) | ||||
| None | 285 (87.7) | 238 (86.5) | 47 (94.0) | .61 |
| Lobectomy | 31 (9.5) | 28 (10.2) | 3 (6.0) | |
| Wedge resection | 7 (2.2) | 7 (2.5) | 0 (0.0) | |
| Pneumonectomy | 2 (0.6) | 2 (0.7) | 0 (0.0) | |
| Disease status (%) | ||||
| New diagnosis of single lesion | 280 (86.2) | 238 (86.5) | 42 (84.0) | .80 |
| New diagnosis of multiple lesions | 45 (13.8) | 37 (13.5) | 8 (16.0) |
Abbreviations: BMI = body mass Index; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; IQR = interquartile range; MRI = magnetic resonance imaging; PET = positron emission tomography.
Tumor characteristics are depicted in Table 2. Pathologic confirmation was obtained in 64.6% of tumors with adenocarcinoma (47.6%) and squamous cell carcinoma (38.8%) being the most predominant histology. The most common reasons for treatment with 10 fractions were central location (48.9%), tumor with large volume abutment of the chest wall (38.3%), and larger-sized tumors (10.6%). Those treated with 10 fractions had a higher T stage, more advanced clinical stage, were more likely to be central and/or ultracentral and less likely to be peripheral. Compared with tumors treated with 5 fractions, tumors treated with 10 fractions had a larger maximum diameter; larger PTV, iGTV, and GTV volumes; as well as lower PTV minimum dose and percent cold spot (defined as actual PTV minimum dose divided by prescribed dose). Median follow-up was 40.2 months (95% confidence interval [CI], 35.9–46.0).
Table 2.
Tumor Characteristics
| Overall (n = 353) | 5-Fraction (n = 300) | 10-Fraction (n = 53) | P Value | |
|---|---|---|---|---|
| Biopsy at diagnosis (%) | ||||
| No | 125 (35.4) | 104 (34.7) | 21 (39.6) | .59 |
| Yes | 228 (64.6) | 196 (65.3) | 32 (60.4) | |
| Histology (%) | ||||
| Adenocarcinoma | 108 (47.6) | 93 (47.7) | 15 (46.9) | .36 |
| Squamous cell carcinoma | 88 (38.8) | 79 (40.5) | 9 (28.1) | |
| Adenosquamous | 1 (0.4) | 1 (0.5) | 0 (0.0) | |
| Large cell | 3 (1.3) | 2 (1.0) | 1 (3.1) | |
| NSCLC NOS | 24 (10.6) | 18 (9.2) | 6 (18.8) | |
| Other | 3 (1.3) | 2 (1.0) | 1 (3.1) | |
| T stage* (%) | ||||
| T1a | 174 (50.3) | 154 (52.6) | 20 (37.7) | <.01 |
| T1b | 116 (33.5) | 99 (33.8) | 17 (32.1) | |
| T2a | 47 (13.6) | 34 (11.6) | 13 (24.5) | |
| T2b | 1 (0.3) | 0 (0.0) | 1 (1.9) | |
| T3 | 3 (0.9) | 1 (0.3) | 2 (3.8) | |
| T4 | 5 (1.4) | 5 (1.7) | 0 (0.0) | |
| N stage* (%) | 346 (100.0) | 293 (100.0) | 53 (100.0) | NA |
| M stage* (%) | ||||
| M0 | 326 (92.4) | 278 (92.7) | 48 (90.6) | .58 |
| M1 | 27 (7.6) | 22 (7.3) | 5 (9.4) | |
| Group Stage* (%) | ||||
| IA | 276 (78.2) | 241 (80.3) | 35 (66.0) | .09 |
| IB | 43 (12.2) | 32 (10.7) | 11 (20.8) | |
| IIA | 2 (0.6) | 1 (0.3) | 1 (1.9) | |
| IIB | 2 (0.6) | 1 (0.3) | 1 (1.9) | |
| IIIA | 3 (0.8) | 3 (1.0) | 0 (0.0) | |
| IV | 27 (7.6) | 22 (7.3) | 5 (9.4) | |
| Tumor location (%) | ||||
| Right upper lobe | 127 (36.0) | 111 (37.0) | 16 (30.2) | .73 |
| Right middle lobe | 18 (5.1) | 16 (5.3) | 2 (3.8) | |
| Right lower lobe | 50 (14.2) | 40 (13.3) | 10 (18.9) | |
| Left upper lobe | 110 (31.2) | 92 (30.7) | 18 (34.0) | |
| Left lower lobe | 45 (12.7) | 39 (13.0) | 6 (11.3) | |
| Left Lingula | 3 (0.8) | 2 (0.7) | 1 (1.9) | |
| Central (%) | ||||
| No | 290 (82.2) | 262 (87.3) | 28 (52.8) | <.01 |
| Yes | 63 (17.8) | 38 (12.7) | 25 (47.2) | |
| Ultracentral (%) | ||||
| No | 327 (92.6) | 291 (97.0) | 36 (67.9) | <.01 |
| Yes | 26 (7.4) | 9 (3.0) | 17 (32.1) | |
| Very peripheral (%) | ||||
| No | 96 (27.2) | 73 (24.3) | 23 (43.4) | .01 |
| Yes | 257 (72.8) | 227 (75.7) | 30 (56.6) | |
| Size (%) | ||||
| Mid | 186 (52.7) | 165 (55.0) | 21 (39.6) | <.01 |
| Low | 81 (22.9) | 75 (25.0) | 6 (11.3) | |
| High | 86 (24.4) | 60 (20.0) | 26 (49.1) | |
| PTV Size (%) | ||||
| Mid | 177 (50.1) | 159 (53.0) | 18 (34.0) | <.01 |
| Low | 88 (24.9) | 79 (26.3) | 9 (17.0) | |
| High | 88 (24.9) | 62 (20.7) | 26 (49.1) | |
| Tumor maximum dimension, median [IQR] | 1.90 [1.40, 2.50] | 1.80 [1.37, 2.42] | 2.50 [1.80, 3.20] | <.01 |
| PTV relative maximum, median [IQR] | 133.60 [128.80, 138.32] | 133.52 [128.80, 138.02] | 135.30 [128.52, 138.80] | .64 |
| PTV volume, median [IQR] | 26.31 [15.98, 44.27] | 25.31 [15.69, 40.52] | 43.69 [24.04, 68.75] | <.01 |
| iGTV volume, median [IQR] | 7.88 [3.83, 15.48] | 7.37 [3.63, 14.50] | 15.13 [6.30, 29.54] | <.01 |
| GTV volume, median [IQR] | 3.98 [1.86, 8.71] | 3.39 [1.68, 6.75] | 12.84 [7.15, 25.30] | <.01 |
| PTV max, median [IQR] | 66.80 [64.40, 69.16] | 66.76 [64.40, 69.01] | 67.65 [64.26, 69.40] | .64 |
| PTV mean, median [IQR] | 57.64 [56.57, 58.80] | 57.64 [56.59, 58.91] | 57.69 [56.40, 58.47] | .26 |
| PTV min, median [IQR] | 44.07 [41.60, 45.95] | 44.24 [41.89, 46.06] | 42.80 [38.20, 44.80] | <.01 |
| PTV relative minimum, median [IQR] | 88.14 [83.20, 91.91] | 88.48 [83.77, 92.12] | 85.60 [76.40, 89.60] | <.01 |
Abbreviations: ECOG = Eastern Cooperative Oncology Group performance status; GTV = gross tumor volume; IQR = interquartile range; iGTV = internal gross tumor volume; NOS = not otherwise specified; NSCLC = non–small cell lung cancer; PTV = planning target volume.
American Joint Committee on Cancer, Seventh Edition.
Local Control
The cumulative incidence of LF at 1-, 2- and 3-years was 1.8% (95% CI, 0.4–3.2), 6.3% (3.5–9.1), and 9.1% (5.6–12.6), respectively. The cumulative incidence of death without failure (competing event) was 20.7% (95% CI, 16.4–25.0), 32.3% (27.1–37.5), and 39.7% (33.9–45.4) for the corresponding time points. LF rates at 3 years were 6.5% (95% CI, 3.4–9.7) for tumors treated with 5 fractions and 23.9% (95% CI, 9.6–38.1) for those treated with 10 fractions (Gray’s P < .01) (Figure 1). Kaplan-Meier estimate of overall median time to LF (n = 31 lesions that experienced local failure) was 20.2 months (95% CI, 14.0–29.6). Median time to LF was 17.5 months (13.3–31.4) in the 5-fraction group and 26.2 months (20.2-not reached [NR]) in the 10-fraction group (logrank P = .60).
Figure 1.
Cumulative Incidence of Local Failure for Lung Tumors Treated With 50 Gy in 5 or 10 Fractions. Black line: Local Failure; Gray line: Death Without Local Failure
Factors associated with LF on univariable analysis included 10 (versus 5) fractions, larger tumor size (in cm) and larger PTV volume (in cm3) (Table 3). Further exploration of the continuous variables tumor size and PTV volume was performed by categorizing tumors into 3 groups: lower quartile: 0.5 to <1.4 (small); middle 2 quartiles, 1.4–2.5 (medium); and upper quartile, >2.5 cm3 (large). Compared with the medium-size group, large tumors were associated with a significantly increased hazard of LF (hazard ratio [HR] 2.21; 95% CI, 1.03–474; P = .04), whereas small tumors were not (HR 0.91; 95% CI, 0.32–2.54; P = .85). Similarly, large PTV volumes were associated with LF (HR 2.33; 95% CI, 1.10–4.90; P = .03) but small PTV was not (HR 0.61; 95% CI, 0.20–1.83; P = .37). For early-stage NSCLC, compared with American Joint Commission on Cancer Seventh Edition T1a lesions, T2a lesions were associated with a significant increase in the hazard of LF (HR 3.03; 95% CI, 1.16–7.93; P = .02), whereas T1b lesions were not (HR 1.27; P = .60). Multivariable competing risks regression analysis including factors identified on univariable analysis revealed increasing PTV volume (HR 1.01; P = .04) as an independent predictor of increased hazard of LF (Table 3). Tumor size (HR 1.02; P = .94), ultracentral location (HR 1.32; P = .67), and 10 fractions (HR 2.23; P = .16) were not significantly associated with LF.
Table 3.
Competing Risk Regression Analysis of Local Failure
| Univariable |
Multivariable |
|||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P Value | HR | 95% CI | P Value | |
| Age | 0.99 | 0.96–1.02 | .56 | - | - | - |
| Gender | 1.12 | 0.56–2.26 | .75 | - | - | - |
| ECOG 2–3 | 0.98 | 0.48–2.02 | .96 | - | - | - |
| Ever smoker | 0.47 | 0.12–1.84 | .28 | - | - | - |
| Biopsy (yes vs. no) | 0.97 | 0.47–2.00 | .93 | - | - | - |
| Central | 1.31 | 0.57–2.98 | .53 | - | - | - |
| Ultracentral | 2.63 | 1.06–6.52 | .04 | 1.32 | 0.38–4.61 | .67 |
| Very peripheral | 0.75 | 0.36–1.57 | .44 | - | - | - |
| 10 Fractions (vs. 5) | 3.32 | 1.62–6.81 | <.01 | 2.23 | 0.73–6.80 | .16 |
| Size | 1.20 | 1.00–1.45 | .05 | 1.02 | 0.78–1.34 | .89 |
| PTV volume | 1.02 | 1.01–1.03 | <.01 | 1.01 | 1.00–1.03 | .04 |
| PTV max | 1.06 | 0.96–1.16 | .25 | - | - | - |
| PTV mean | 0.97 | 0.86–1.06 | .51 | - | - | - |
| PTV min | 0.98 | 0.92–1.04 | .54 | - | - | - |
| PTV relative maximum (%) | 1.03 | 0.98–1.08 | .25 | - | - | - |
| PTV relative minimum % | 0.99 | 0.96–1.02 | .54 | - | - | - |
Abbreviations: CI = confidence interval; ECOG = Eastern Cooperative Oncology Group performance status; HR = hazard ratio; PTV = planning target volume.
Survival Outcomes of Patients with Stage I NSCLC
Among patients with Stage I NSCLC (n = 298), median PFS was 35.6 months (95% CI, 31.1–41.8) and median OS was 42.4 months (95% CI, 36.2–51.4). Median PFS was numerically, but not statistically significantly shorter after 10 fractions (30.9 months) compared with 5 fractions (38.5 months; P = .13) (Figure 2A). Median OS was 42.6 months in the 5-fraction group versus 36.4 months in the 10-fraction group; no difference in OS was observed between regimens (P = .27) (Figure 2B). Median values for FFRF and FFDF were not reached. The 3-year Kaplan-Meier estimate of FFRF was 85.6% (95% CI, 80.3–91.2); 86.0% (80.3–92.1) for the 5-fraction group and 82.8% (69.6–98.5) in the 10-fraction group (P = .31) (Figure 2C). Overall 3-year FFDF was 75.7% (69.1–83.1); 76.5% (69.4–84.2) in the 5-fraction group versus 70.1 (51.3–95.8) in the 10-fraction group (P = .70) (Figure 2D). The overall patterns of failure for all patients are shown in Figure 3.
Figure 2.
Kaplan-Meier Plots of Progression-Free Survival: (A) Overall Survival; (B) Freedom From Regional Failure; (C) and Freedom From Distant Failure (D) for Patients With Early-Stage NSCLC Treated With 5 or 10 Fractions
Figure 3.
Venn Diagram Demonstrating the Initial Pattern of Failure Among Only New Diagnoses of Early-Stage Non–small Cell Lung Cancer (n [ 298) Including Synchronous Primaries Following Stereotactic Body Radiotherapy. Patients With Metastatic Disease Were Excluded
Among patients with early-stage NSCLC with LF (n = 27), salvage therapies included in decreasing order: re-SBRT, immunotherapy, surgery, chemoradiation, interventional procedures, and chemotherapy. Of the 18 patients who were initially treated with 5 fractions, 11 received salvage therapy compared with 4 of the 9 patients initially treated with 10 fractions. With a median follow-up of 14.6 months from date of LF, median OS was 11.9 months (95% CI, 5.8-NR). Median OS was 13.3 months for those treated with salvage therapy versus 2.2 months for patients not treated with salvage therapy (P = .01). Due to the low number of patients with local failure as first failure, PFS analyses from the time of LF were not feasible.
Toxicity
Rates of lung and esophageal toxicity within 6 months of treatment as well as chest wall toxicity at any point in follow-up are described in Table 4. The highest-grade chest wall pain toxicity was grade 2, which occurred in 15 (4.3%) cases. Pneumonitis occurred after treatment of 162 tumors (in 149 patients) with severity as follows: 157 (44.7%) grade 1, 4 (1.1%) grade 2, and 1 (0.3%) Grade 3. There was no significant difference between toxicity and number of fractions in this cohort (P ≥ .05 for all comparisons).
Table 4.
Toxicity After SBRT
| CTCAE vs. 4 Grade | Overall (n = 353) | 5-Fraction (n = 300) | 10-Fraction (n = 53) | P Value | |
|---|---|---|---|---|---|
| Chest wall pain (%) | 0 | 306 (87.4) | 261 (87.6) | 45 (86.5) | .08 |
| 1 | 29 (8.3) | 22 (7.4) | 7 (13.5) | ||
| 2 | 15 (4.3) | 15 (5.0) | 0 (0.0) | ||
| Pneumonitis (%) | 0 | 189 (53.8) | 153 (51.2) | 36 (69.2) | .05 |
| 1 | 157 (44.7) | 142 (47.5) | 15 (28.8) | ||
| 2 | 4 (1.1) | 3 (1.0) | 1 (1.9) | ||
| 3 | 1 (0.3) | 1 (0.3) | 0 (0.0) | ||
| Esophagitis (%) | 0 | 339 (96.6) | 290 (97.0) | 49 (94.2) | .15 |
| 1 | 8 (2.3) | 7 (2.3) | 1 (1.9) | ||
| 2 | 4 (1.1) | 2 (0.7) | 2 (3.8) |
Abbreviations: Pneumonitis and esophagitis present within 6 months and maximum grade of chest wall pain in the area of treatment during follow-up after SBRT.
CTCAE = Common Terminology Criteria for Adverse Events; SBRT = stereotactic body radiotherapy.
Discussion
This single-institution retrospective review of patients treated with SBRT for early-stage primary NSCLC and intrathoracic metastatic NSCLC, examined the efficacy and safety of 2 different dose-fractionation regimens. Improved LC was found with 50 Gy in 5 fractions at 3 years with LF occurring in 6.5% of tumors versus 23.9% treated in 10 fractions. Despite having worse LC at 3 years, the median time to LF was numerically longer in the 10-fraction group compared with the 5-fraction group, although not statistically significant. Specifically, in patients with stage I NSCLC, both treatment regimens showed no significant difference in PFS and OS. Both regimens were also found to be well tolerated with low levels of grade 2 or greater toxicity.
Our 5-fraction 3-year LF of 6.5% compared favorably with RTOG 0813, with 3-year LC rates from 75% to 100% for 5-fraction regimens, and the reported in-field failure rates are also comparable.7 However, lesions treated with 10 fractions showed a decrease in long-term LC with a 3-year LF rate of 23.9%, although LF rates up to 24 months appeared similar. Differences in the tumors treated must also be taken into account, as the lesions that were treated with 10 fractions had significantly larger diameter, as well as iGTV and PTV volumes. Furthermore, these tumors were often central/ultracentral in location, requiring lower minimum doses to the PTV and increases in cold spot percentages as a result of deliberate target undercoverage to spare critical adjacent organs at risk. This has been previously shown to increase the risk of LF.20
Patients with stage I NSCLC had reasonable survival outcomes with median PFS of 35.6 months and median OS of 42.4 months following treatment with SBRT. Most of the first failures following SBRT included distant failures, occurring in 18.7% of patients followed by RF (8.6%) and LF (6.7%). These rates are similar to those seen in prior reports of patterns of failure after SBRT for early-stage NSCLC, and there was no difference in the rates of RF or DF between the 2 fractionation schemes.21 In addition, survival outcomes between the 2 dose regimens when compared only in patients with Stage I NSCLC were similar in terms of PFS and OS. This may suggest that the decrease in long-term LC does not negatively impact survival. One explanation may be due to the predominant pattern of failure being more commonly distant or regional in early-stage NSCLC, as has been established in other series.21 Another explanation is that the salvage therapies that were given to most patients experiencing LF, were effective enough to eliminate potential differences in survival.
Overall, our finding of decreased LC with 50 Gy in 10 fractions is consistent with other retrospectives analyzing BED and tumor control trends.11–14,22 The BED of 50 Gy delivered in 10 fractions is 75 Gy10, which is below the cutoff of 100 to 105 Gy10 generally considered a minimal threshold for ensuring optimal tumor control. However, the patients treated with 50 Gy in 10 fractions still had relatively durable LC with median time to LF of 26.2 months. These patients also had very low toxicity rates, despite the larger-sized and higher risk location of the tumors treated with this regimen.
One difficulty with interpreting many of the initial studies reporting on the association between LC and BED is accounting for the heterogeneity of the tumor size and location across different series and the inclusion of conventional fractionation in some.11 Early studies demonstrated increased toxicity when using SBRT for central tumors and larger tumors.23–25 These reports likely influenced which tumors physicians were willing to treat with high-BED regimens due to fear of increased toxicity and may have biased early models regarding optimal SBRT BED.
A later systematic review of 20 studies showed that tumor location did not affect OS, and that grade 3 or 4 toxicity occurred more commonly with central tumors.26 Furthermore, a similar dose-response relationship for LC was noted with the central tumors, where a BED10 tumor dose greater than 100 Gy10 led to improved outcomes and a BED3 normal tissue dose less than 210 Gy3 reduced the risk of death. One meta-analysis accounted for the differences in size of the treated tumors by separately analyzing T1 vs T2 tumors and categorizing the tumor BED10 into low (<83.2 Gy10), medium (83.2–106 Gy10), medium to high (106–146 Gy10), and high (>146 Gy10).27 The differences in percentages of T1 tumors between each of the BED ranges significantly modified the results of the meta-analysis. Further investigations have shown that GTV size was associated with local recurrence, with a 2-year local recurrence of 3% for GTV <2.7 cm and 9% for ≥2.7 cm.28 If the BED10 was greater than 105 Gy10, then tumor size no longer appeared to have an impact on local recurrence. This was in contrast to a BED10 of less than 105 Gy, which showed 7% local recurrence in tumors <2.7 cm versus 17% in tumors ≥2.7 cm.
In the current study, the most common reason for using 50 Gy in 10 fractions was to treat central or ultracentral lung tumors. Treating tumors in these locations often requires careful and thoughtful design of volumes to spare critical OARs. RTOG 0813, a seamless phase I/II study, treated patients with central NSCLC in dose-escalating 5-fraction schedules.7 No patients treated with 10, 10.5, or 11 Gy/fraction had a grade 3 adverse event in the first year, but 4 patients in the 11.5 and 12 Gy/fraction arms did. After the first year, 4 patients had grade 5 events, 3 in the 11.5 Gy/fraction arm and 1 in the 12 Gy/fraction arm. However, there have been reports of fatal toxicity after SBRT for central and ultracentral lung lesions with less aggressive regimens, including 50 Gy in 5 fractions and 60 Gy in 8 fractions.29,30 Treatment with anti-angiogenic agents has been reported to substantially increase this risk.30 Patients in this study who were treated with either 50 Gy in 5 or 10 fractions tolerated treatment well with minimal to no grade 3 or greater toxicity. In our study, multivariable competing risks regression analysis adjusting for number of fractions, ultracentral location, tumor size, and PTV volume showed that neither ultracentral location nor 10-fraction regimen were associated with LF. This finding may be confounded by unconsidered variables or may be a result of an underpowered analysis to detect a persistent increase in the hazard of LF, even after adjustment for clear confounding variables such as location and size.
In this study there were 26 patients with ultracentral tumors, defined as the PTV contacting or overlapping the proximal bronchial tree, esophagus, pulmonary vein, or pulmonary artery. Most (65%) of these patients were treated with 50 Gy in 10 fractions. Acceptable doses and fractionations for ultracentral tumors near sensitive mediastinal structures continues to evolve as the planning and image guidance techniques improve. One recent retrospective review of patients treated with SBRT for ultracentral (PTV overlapping the proximal bronchial tree or esophagus), central (located within 2 cm of the PBT but not meeting the criteria for central), and paramediastinal (PTV touching or overlapping the mediastinal pleura but not central or ultracentral) lung tumors found that ultracentral tumors had similar LC and OS among all groups, but an increased risk of grade 2+ toxicity at 57.6% versus 14.2% for central tumors at 2 years.31 In contrast, other studies using similar dose-fractionation schemes have suggested that there is no difference in the observed toxicity between central and ultracentral tumors.32,33
Approaches to limit toxicity have included more moderately hypofractionated dose-fractionation schemes. One early study compared SBRT with moderate hypofractionation regimens (30–63 Gy in 2.5–5.0 Gy fractions) and found reasonable LC.10 Even in the patients receiving moderate hypofractionation, there were early deaths from pulmonary conditions that may have been caused by radiation therapy.10 Other hypofractionation regimens have been explored and showed good response rates.34–36 A major downside of these dose-fractionation schemes is their relatively long treatment period. This is particularly relevant for patients with metastatic disease, where a prolonged interruption in systemic therapy is more likely to lead to distant failures than for those with stage I disease.
Overall, our finding of decreased LC with 50 Gy in 10 fractions is consistent with other series comparing tumor BED and LC trends.11–14,19 By reporting these data, we are certainly not advocating for the routine use of 50 Gy in 10 fractions, which provided clearly suboptimal LC. Rather, we are attempting to provide some expectations of LC that can be achieved when using this regimen. The information from this study could be particularly useful for clinicians who are faced with challenging situations in which tumors may be not be amenable to ablative radiotherapy, but are perhaps still suitable for a nonpalliative approach. It is worth noting that the competing risk of death without LF in both groups was nearly twice the risk of an LF event. In this patient population, with high rates of comorbidity and a 40% rate of performance status 2 to 3, the potential toxicities of SBRT cannot be ignored. Possible clinical scenarios where this regimen may be reasonable (with the expectation of higher chance of delayed LF) include large ultracentral tumors with a higher risk of potential treatment-related toxicity, particularly in elderly patients with poorer performance status, patients with metastatic disease, or patients with other advanced comorbidities. In these patients, minimizing toxicity is paramount and a late isolated LF may be of lesser concern.
This observational study is limited by its single-institution retrospective design. Therefore, it is prone to selection biases with regard to SBRT fractionation and patient fitness as well as loss of patient follow-up due to frequent death and comorbid illnesses in this population of patients with lung cancer. In addition, limitations exist regarding the detection of toxicity events by review of the electronic medical record, and there exists a small risk of underestimation of these toxicity rates. Several treatment planning systems and SBRT techniques were used in treatment of patients over the time frame included in this study. Many of these represent unavoidable limitations which are common among retrospective studies. Despite these limitations, we believe these results are a valuable addition to the literature
Conclusion
In this study comparing SBRT with a dose of 50 Gy delivered in 5 versus 10 fractions, we demonstrated that the 5-fraction regimen had superior LC, although the median time to failure in the 10-fraction group was more than 2 years. The improvement in late LC with the 5-fraction regimen did not translate to benefits in PFS or OS, despite the 10-fraction group including more tumors that were larger and more often central or ultracentral. If dosimetric constraints permit the use of a dose-fractionation scheme with a BED10 ≥100 Gy, it should be used. However, should such a regimen be unsafe, 50 Gy in 10 fractions may provide an acceptable compromise between tumor control and safety with relatively durable control and little to minimal negative impact on long-term survival.
Clinical Practice Points
SBRT is an established treatment for inoperable early-stage NSCLC and is increasingly used for patients who are medically operable, although surgical resection remains the standard of care. Multiple studies have examined differing regimens in search of an optimal standard approach. Early analysis found that a BED >100 Gy10 portended for improved LC and survival. In some situations in which the tumor directly abuts critical structures, however, this unavoidably increases normal tissue dose and therefore increases risks of serious toxicity.
In our study, we examined patients treated with SBRT with 50 Gy in 5 fractions or 10 fractions for early-stage NSCLC as well as metastatic NSCLC. This study is unique in its comparison of these 2 specific dose-fractionation schemes. We found that the LC was improved with the 5-fraction regimen, although surprisingly the median time to failure was numerically longer for the 10-fraction regimen. Perhaps, this is simply a reflection of the fact that patients who do fail a regimen of 50 Gy in 5 fractions inherently have a more aggressive tumor biology. In the patients with early stage NSCLC, PFS and OS were not worse despite the decreased LC.
These findings support the accepted principle that a BED >100 Gy10 provides improved LC and treatments abiding by this principle are preferred. If a lesion has tumor characteristics in which this preferred treatment regimen may be unsafe, then using 50 Gy in 10 fractions may provide durable control that is likely salvageable if a failure does occur. It is clear from the inferior LC seen here, that the 50 Gy in 10 fractions dosing is suboptimalin terms of BED. By reporting these outcomes, we are not advocating for the use of 50 Gy in 10 fractions. Rather, we are attempting to provide some expectations of LC when using this regimen. This regimen may be useful for challenging situations in which tumors are not amenable to ablative radiotherapy, but are perhaps still suitable for a non-palliative approach.
Acknowledgments
This work was supported by the Wake Forest Baptist Medical Center and National Center for Advancing Translational Sciences, National Institutes of Health–funded Wake Forest Clinical and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. government.
References
- 1.Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010; 303:1070–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Armstrong JG, Minsky BD. Radiation therapy for medically inoperable stage I and II non-small cell lung cancer. Cancer Treat Rev 1989; 16:247–55. [DOI] [PubMed] [Google Scholar]
- 3.Dosoretz DE, Katin MJ, Blitzer PH, et al. Medically inoperable lung carcinoma: the role of radiation therapy. Semin Radiat Oncol 1996; 6:98–104. [DOI] [PubMed] [Google Scholar]
- 4.Kaskowitz L, Graham MV, Emami B, Halverson KJ, Rush C. Radiation therapy alone for stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 1993; 27: 517–23. [DOI] [PubMed] [Google Scholar]
- 5.Graham PH, Gebski VJ, Langlands AO. Radical radiotherapy for early nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 1995; 31:261–6. [DOI] [PubMed] [Google Scholar]
- 6.Videtic GMM, Hu C, Singh AK, et al. A randomized phase 2 study comparing 2 stereotactic body radiation therapy schedules for medically inoperable patients with stage i peripheral non-small cell lung cancer: NRG Oncology RTOG 0915 (NCCTG N0927). Int J Radiat Oncol Biol Phys 2015; 93:757–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Bezjak A, Paulus R, Gaspar LE, et al. Safety and efficacy of a five-fraction stereotactic body radiotherapy schedule for centrally located non-small-cell lung cancer: NRG Oncology/RTOG 0813 Trial. J Clin Oncol 2019; 37:1316–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Haasbeek CJA, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol 2011; 6:2036–43. [DOI] [PubMed] [Google Scholar]
- 9.Chang JY, Li Q-Q, Xu Q-Y, et al. Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: how to fly in a “no fly zone. Int J Radiat Oncol Biol Phys 2014; 88: 1120–8. [DOI] [PubMed] [Google Scholar]
- 10.Milano MT, Chen Y, Katz AW, Philip A, Schell MC, Okunieff P. Central thoracic lesions treated with hypofractionated stereotactic body radiotherapy. Radiother Oncol 2009; 91:301–6. [DOI] [PubMed] [Google Scholar]
- 11.Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 2004; 101:1623–31. [DOI] [PubMed] [Google Scholar]
- 12.Wulf J, Baier K, Mueller G, Flentje MP. Dose-response in stereotactic irradiation of lung tumors. Radiother Oncol 2005; 77:83–7. [DOI] [PubMed] [Google Scholar]
- 13.Olsen JR, Robinson CG, El Naqa I, et al. Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011; 81:e299–303. [DOI] [PubMed] [Google Scholar]
- 14.Rowe BP, Boffa DJ, Wilson LD, Kim AW, Detterbeck FC, Decker RH. Stereotactic body radiotherapy for central lung tumors. J Thorac Oncol 2012; 7:1394–9. [DOI] [PubMed] [Google Scholar]
- 15.Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Giuliani M, Mathew AS, Bahig H, et al. SUNSET: Stereotactic Radiation for Ultracentral Non-Small-Cell Lung Cancer-a safety and efficacy trial. Clin Lung Cancer 2018; 19:e529–32. [DOI] [PubMed] [Google Scholar]
- 17.Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94:496–509. [Google Scholar]
- 18.Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16:1141–54. [Google Scholar]
- 19.Shuster JJ. Median follow-up in clinical trials. J Clin Oncol 1991; 9:191–2. [DOI] [PubMed] [Google Scholar]
- 20.Ohri N, Werner-Wasik M, Grills IS, et al. Modeling local control after hypofractionated stereotactic body radiation therapy for stage I non-small cell lung cancer: a report from the elekta collaborative lung research group. Int J Radiat Oncol Biol Phys 2012; 84:e379–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Senthi S, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, Senan S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol 2012; 13:802–9. [DOI] [PubMed] [Google Scholar]
- 22.Stephans KL, Woody NM, Reddy CA, et al. Tumor control and toxicity for common stereotactic body radiation therapy dose-fractionation regimens in Stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2018; 100:462–9. [DOI] [PubMed] [Google Scholar]
- 23.Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006; 24:4833–9. [DOI] [PubMed] [Google Scholar]
- 24.Bral S, Gevaert T, Linthout N, et al. Prospective, risk-adapted strategy of stereotactic body radiotherapy for early-stage non-small-cell lung cancer: results of a Phase II trial. Int J Radiat Oncol Biol Phys 2011; 80:1343–9. [DOI] [PubMed] [Google Scholar]
- 25.Ong CL, Palma D, Verbakel WF, Slotman BJ, Senan S. Treatment of large stage III lung tumors using stereotactic body radiotherapy (SBRT): planning considerations and early toxicity. Radiother Oncol 2010; 97:431–6. [DOI] [PubMed] [Google Scholar]
- 26.Senthi S, Haasbeek CJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiother Oncol 2013; 106:276–82. [DOI] [PubMed] [Google Scholar]
- 27.Zhang J, Yang F, Li B, et al. Which is the optimal biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell lung cancer? A meta-analysis. Int J Radiat Oncol Biol Phys 2011; 81:e305–16. [DOI] [PubMed] [Google Scholar]
- 28.Kestin L, Grills I, Guckenberger M, et al. Dose-response relationship with clinical outcome for lung stereotactic body radiotherapy (SBRT) delivered via online image guidance. Radiother Oncol 2014; 110:499–504. [DOI] [PubMed] [Google Scholar]
- 29.Corradetti MN, Haas AR, Rengan R. Central-airway necrosis after stereotactic body-radiation therapy. N Engl J Med 2012; 366:2327–9. [DOI] [PubMed] [Google Scholar]
- 30.Wang C, Rimner A, Gelblum DY, et al. Analysis of toxic effects with anti-angiogenic agents plus stereotactic body radiation in ultracentral lung tumors. JAMA Oncol 2019; 5:737–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Nguyen KNB, Hause DJ, Novak J, Monjazeb AM, Daly ME. Tumor control and toxicity after SBRT for ultracentral, central, and paramediastinal lung tumors. Pract Radiat Oncol 2019; 9:e196–202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Raman S, Yau V, Pineda S, et al. Ultracentral tumors treated with stereotactic body radiotherapy: single-institution experience. Clin Lung Cancer 2018; 19: e803–10. [DOI] [PubMed] [Google Scholar]
- 33.Chang JH, Poon I, Erler D, Zhang L, Cheung P. The safety and effectiveness of stereotactic body radiotherapy for central versus ultracentral lung tumors. Radiother Oncol 2018; 129:277–83. [DOI] [PubMed] [Google Scholar]
- 34.Bogart JA, Hodgson L, Seagren SL, et al. Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904. J Clin Oncol 2010; 28:202–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Cheung P, Faria S, Ahmed S, et al. Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1–3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25. J Natl Cancer Inst 2014; 106:dju164. [DOI] [PubMed] [Google Scholar]
- 36.Hughes RT, Helis CA, Soike MH, Levine BJ, Farris M, Blackstock AW. Moderately hypofractionated radiotherapy alone for Stage I-IIB non-small cell lung cancer. Cureus 2019; 11:e4969. [DOI] [PMC free article] [PubMed] [Google Scholar]