Abstract
Purpose
We evaluated practice patterns and survival outcomes associated with the sequencing of stereotactic body radiation therapy (SBRT) and chemotherapy in patients with clinical stage I small cell lung cancer (SCLC) in the United States.
Methods and Materials
Using a large national database, we identified patients with clinical stage I (cT1-2N0M0) SCLC treated with SBRT and chemotherapy between 2004 and 2020. To assess practice patterns in relation to survival outcomes, patients were categorized into 2 cohorts: “SBRT before chemotherapy” and “SBRT concurrent with or after chemotherapy.” χ2 tests and logistic regression models were used to determine patient characteristics associated with treatment sequencing. Univariable and multivariable Cox proportional hazard models were used to assess the association between patient characteristics and survival outcomes. Overall survival was analyzed using the Kaplan-Meier method and compared via the log-rank test. Sensitivity analyses were performed using multivariable logistic regressions and Cox proportional hazards models for treatments with a 30-day overlap and clinical T stage stratification.
Results
Among 631 patients with clinical stage I SCLC who were treated with SBRT and chemotherapy, 416 (65.9%) were categorized in “SBRT before chemotherapy” and 215 (34.1%) in “SBRT concurrent with or after chemotherapy.” Patients diagnosed after 2018 were less likely to receive SBRT concurrent with or after chemotherapy (odds ratio, 0.46; 95% CI, 0.32-0.66; P < .001). Patients diagnosed with clinical stage T2 were more likely to receive SBRT concurrent with or after chemotherapy (odds ratio, 1.76; 95% CI, 1.05-2.95; P = .03). No statistically significant difference in survival was observed between the 2 treatment sequencing cohorts (“SBRT before chemotherapy”: median, 40.5 months vs “SBRT concurrent with or after chemotherapy”: median, 35.6 months; log-rank P = .30). On multivariable analysis, SBRT sequencing was not associated with overall survival (hazard ratio = 1.11; P = .35; 95% CI, 0.89-1.37).
Conclusions
Our findings suggest that there is no statistically significant difference in survival outcomes for patients who receive SBRT before chemotherapy compared with those who receive SBRT concurrent with or after chemotherapy. Therefore, flexibility in treatment sequencing may be appropriate in this population.
Introduction
With an estimated 234,000 new cases in 2024, lung cancer remains the third most commonly diagnosed cancer and the leading cause of cancer-related deaths.1 Small cell lung cancer (SCLC) accounts for approximately 15% of all diagnoses annually, with tobacco use contributing to 98% of all cases.2,3 Given the aggressive nature of SCLC, 60% of patients present with metastatic disease at the time of diagnosis, whereas only 5% of patients present with clinical stage I disease.2,4
The current standard of care for most cases of limited-stage SCLC (LS-SCLC) consists of definitive thoracic radiation therapy (45-54 Gy twice daily fractions or 66-70 Gy once daily) with concurrent chemotherapy, followed by immunotherapy, as studied in the Study of Durvalumab + Tremelimumab, Durvalumab, and Placebo in Limited Stage Small-Cell Lung Cancer in Patients Who Have Not Progressed Following Concurrent Chemoradiation Therapy (ADRIATIC) trial.5,6 For stage I SCLC specifically, it is recommended that patients who are eligible for surgery receive a lobectomy and mediastinal lymph node dissection followed by adjuvant chemotherapy with or without radiation therapy.7 For patients with medically inoperable tumors or those who decline surgery, conventionally fractionated radiation therapy has historically been administered.
As an alternative to conventionally fractionated radiation therapy, stereotactic body radiation therapy (SBRT) has emerged as a treatment regimen for patients with medically inoperable small cell lung tumors given the comparable outcomes to surgery,7 based on the experience of SBRT from non-small cell lung cancer (NSCLC).8 The use of SBRT has significantly increased between 2004 and 2013 for stage I SCLC, with more recent trends indicating a 657-fold increase as of 2020.7,9 Advantages of SBRT over conventional fractionation include delivery in fewer sessions and the ability to achieve a higher biologically effective dose (BED).10 Use of SBRT has demonstrated high local control rates for SCLC, specifically 97% 1-year and 96% 3-year control rates.11 Treatment regimens for inoperable T1-T2N0 NSCLC using SBRT are frequently extrapolated for similarly staged SCLC.12 However, unlike NSCLC, it has been demonstrated that chemotherapy improves disease-free survival (DFS) and overall survival (OS) and is an important treatment component for T1-2N0 SCLC.12
Optimal SBRT and chemotherapy sequencing for patients with stage I SCLC with inoperable tumors can lead to improved OS outcomes. Despite increasing interest in the use of SBRT for SCLC tumors, no randomized controlled trials have evaluated its use, and data on the sequencing and timing of chemotherapy and SBRT remain limited.13 The majority of research has evaluated the use of SBRT for patients with NSCLC, and it is unclear how well findings on survival outcomes and practice patterns associated with SBRT can be extrapolated to patients with SCLC.8,14, 15, 16
In this descriptive and exploratory analysis, we aimed to identify national practice patterns and compare outcomes of chemotherapy timing before or after SBRT for stage I SCLC.
Methods and Materials
Data source and study cohort
We performed a retrospective study of practice patterns of SBRT and chemotherapy administration and its association with survival outcomes in patients diagnosed with clinical stage I (cT1-2N0M0) SCLC in the National Cancer Database (NCDB) from 2004 to 2020. Patients diagnosed in 2021 were excluded because of missing data involving the time elapsed between the date of diagnosis and the date of last contact or death. There were 4455 patients with clinical stage I SCLC who did not receive surgery, were treated with radiation and chemotherapy, and whose tumors were less than 5 cm in diameter. To identify those who received SBRT, we further restricted the cohort to those who received a total BED with an α/β of 10 (BED10) of 100 to 180 Gy delivered in 1 to 5 radiation fractions.
If the start date of SBRT occurred before the initiation of chemotherapy, the patient was categorized into the “SBRT before chemotherapy” cohort. If the start date of SBRT occurred on the same day or after the initiation date of chemotherapy, the patient was categorized into the “SBRT concurrent with or after chemotherapy” cohort.
Statistical analysis
χ2 tests and multivariable logistic regressions were performed to identify patient characteristics associated with sequencing of SBRT and chemotherapy. Treatment sequencing was separated into 2 categories: (1) SBRT before chemotherapy and (2) SBRT concurrent with or after chemotherapy. Patient variables included age, sex (defined as patient's sex as indicated in medical records), race, race/ethnicity (derived from race and Spanish/Hispanic Origin), insurance status, treatment facility type, treatment facility location, median income per county of residence, Charlson-Deyo comorbidity index, year of diagnosis (based on median value), year of diagnosis (based on individual year), clinical T stage, and BED10.
Univariable logistic regression was used to determine the odds ratio (OR), 95% CI, and P values for patient characteristic variables for the 2 treatment sequencing groups. Variables with a P < .05 were included in a multivariable logistic regression model to determine independent predictors of treatment sequencing.
We used the Kaplan-Meier method to estimate the survival outcomes of the 2 sequencing cohorts. OS was calculated using the months elapsed between the date of diagnosis and the date of last contact or death. OS was used in lieu of other clinically relevant endpoints, such as DFS, time to distant metastasis, and local control, given the availability of variables in the data set. The log-rank test and Cox proportional hazards model were used to determine the survival hazard ratio, 95% CI, and P values for each covariate. An α value of <.05 was used to define statistical significance. Sensitivity analyses were performed using multivariable logistic regressions and Cox proportional hazards models by (1) excluding patients who received SBRT and systemic therapy within 30 days of each other to minimize the risk of overlapping treatments, and (2) stratifying patients by clinical T1 versus T2 stage given imbalance in T-stage between arms. All statistical analyses were coded in RStudio (Version: 2024.12.1-563).
Results
Patient characteristics of 2 cohorts
After applying exclusion criteria, we identified 631 patients diagnosed with clinical stage I SCLC who received SBRT and chemotherapy (Fig. 1). Of these, 416 patients received SBRT before chemotherapy and 215 patients received SBRT concurrent with or after chemotherapy (Table 1). The majority of patients in both treatment groups were greater than or equal to 65 years of age (78.4% and 78.6%), female (57.5% and 55.8%), White non-Hispanic (86.5% and 86.1%), insured through Medicare (77.4% and 75.4%), treated at a nonacademic facility (69.2% and 69.8%), and had clinical stage T1 SCLC (91.4% and 85.1%). Year of diagnosis (both as a categorical variable and median) and clinical T stage were significantly associated with treatment sequencing (P < .05).
Figure 1.
Determination of the study cohort of patients with clinical stage I SCLC treated with SBRT and chemotherapy, without surgery.
Abbreviations: BED = biologically effective dose; SBRT = stereotactic body radiation therapy; SCLC = small cell lung cancer.
Table 1.
Comparison of patient characteristics for SBRT before chemotherapy vs SBRT concurrent with or after chemotherapy cohorts
| Patient Characteristics | RT before chemotherapy (n = 416) (%) | RT concurrent with or after chemotherapy (n = 215) (%) | Unadjusted P value |
|---|---|---|---|
| Age (y) | - | - | 1.0 |
| <65 | 90 (21.6) | 46 (21.4) | - |
| ≥65 | 326 (78.4) | 169 (78.6) | - |
| Sex | - | - | .76 |
| Male | 177 (42.6) | 95 (44.2) | - |
| Female | 239 (57.5) | 120 (55.8) | - |
| Race | - | - | 1.00 |
| White | 374 (89.9) | 194 (90.2) | - |
| Non-White | 42 (10.1) | 21 (9.8) | - |
| Race/ethnicity | - | - | .53 |
| White non-Hispanic | 360 (86.5) | 185 (86.1) | - |
| Black non-Hispanic | 33 (7.9) | 13 (6.1) | - |
| White or Black Hispanic | 4 (0.9) | 2 (0.9) | - |
| Other/unknown | 19 (4.8) | 15 (6.9) | - |
| Insurance status | - | - | .69 |
| Medicaid | 24 (5.8) | 15 (6.9) | - |
| Medicare | 322 (77.4) | 162 (75.4) | - |
| Other | 16 (3.9) | 12 (5.6) | - |
| Private | 54 (12.9) | 26 (12.1) | - |
| Treatment facility | - | - | .96 |
| Academic | 128 (30.8) | 65 (30.2) | - |
| Nonacademic | 288 (69.2) | 150 (69.8) | - |
| Treatment facility location | - | - | .42 |
| New England | 24 (5.8) | 9 (4.2) | - |
| Middle Atlantic | 34 (8.2) | 24 (11.2) | - |
| South Atlantic | 76 (18.3) | 32 (14.9) | - |
| East North Central | 103 (24.8) | 50 (23.3) | - |
| East South Central | 44 (10.6) | 31 (14.4) | - |
| West North Central | 50 (12.0) | 30 (13.9) | - |
| West South Central | 28 (6.7) | 14 (6.5) | - |
| Mountain | 17 (4.1) | 12 (5.6) | - |
| Pacific | 40 (9.6) | 13 (6.1) | - |
| Treatment facility location combined | - | - | .88 |
| Northeast (New England, middle Atlantic) | 58 (13.94) | 33 (15.35) | - |
| Midwest (West North Central, East North Central) | 153 (36.78) | 80 (37.21) | - |
| South (South Atlantic, East South Central, West South Central) | 148 (35.58) | 77 (35.81) | - |
| West (Pacific, mountain) | 57 (13.70) | 25 (11.63) | - |
| Median income per county of residence | - | - | .93 |
| <$46,277 | 62 (14.90) | 33 (15.35) | - |
| $46,277-$57,856 | 100 (24.04) | 48 (22.33) | - |
| $57,857-$74,062 | 87 (20.91) | 47 (21.86) | - |
| $74,063+ | 106 (25.48) | 51 (23.72) | - |
| Unknown | 61 (14.66) | 36 (16.74) | - |
| Charlson-Deyo Comorbidity Index | - | - | .98 |
| 0 | 203 (48.79) | 104 (48.37) | - |
| 1 | 115 (27.64) | 60 (27.91) | - |
| 2 | 61 (14.66) | 30 (13.95) | - |
| 3 | 37 (8.89) | 21 (9.77) | - |
| Charlson-Deyo Comorbidity Index combined | - | - | .99 |
| 0 | 203 (48.79) | 104 (48.37) | - |
| 1 | 115 (27.64) | 60 (27.91) | - |
| 2+ | 98 (23.56) | 51 (23.72) | - |
| Year of diagnosis (median) | - | - | < .001⁎ |
| ≤2018 | 237 (56.97) | 160 (74.42) | - |
| 2019-2020 | 179 (43.03) | 55 (25.58) | - |
| Year of diagnosis | - | - | .001⁎ |
| 2004-2009 | 11 (2.64) | 12 (5.58) | - |
| 2010 | 4 (1.85) | 11 (5.12) | - |
| 2011 | 8 (1.92) | 6 (2.79) | - |
| 2012 | 14 (3.37) | 7 (3.26) | - |
| 2013 | 15 (3.61) | 13 (6.05) | - |
| 2014 | 22 (5.29) | 14 (6.51) | - |
| 2015 | 23 (5.53) | 15 (6.98) | - |
| 2016 | 35 (8.41) | 20 (9.30) | - |
| 2017 | 45 (10.82) | 28 (13.02) | - |
| 2018 | 60 (14.42) | 34 (15.81) | - |
| 2019 | 90 (21.63) | 27 (12.56) | - |
| 2020 | 89 (21.39) | 28 (13.02) | - |
| Clinical T stage | - | - | .02⁎ |
| T1 | 380 (91.4) | 183 (85.1) | - |
| T2 | 36 (8.7) | 32 (14.9) | - |
| Biologically effective radiation dose (a/b 10) | - | - | .28 |
| 100-110 | 225 (54.1) | 127 (59.1) | - |
| >110 | 191 (45.9) | 88 (40.9) | - |
Abbreviations: RT = radiation therapy; SBRT = stereotactic body radiation therapy.
Denotes statistical significance of P < .05.
Year of diagnosis and SBRT timing trends
When comparing the number of cases each year for the 2 cohorts, the number of cases with SBRT administered before chemotherapy exceeded the number of cases with SBRT administered concurrent with or after chemotherapy from 2011 onward (Fig. 2). The proportion of patients who received SBRT before chemotherapy increased over time, with 2019 and 2020 showing the greatest difference in the number of cases between the 2 cohorts.
Figure 2.
Comparison of the number of cases diagnosed each year for the SBRT initiated before chemotherapy versus SBRT concurrent with or after chemotherapy cohorts.
Abbreviation: SBRT = stereotactic body radiation therapy.
The median year of diagnosis was 2018. Patients diagnosed between 2019 and 2020 were less likely to receive SBRT concurrent with or after chemotherapy (OR, 0.46; 95% CI, 0.32-0.66; P < .001). Patients diagnosed with clinical stage T2 were more likely to receive SBRT concurrent with or after chemotherapy (OR, 1.76; 95% CI, 1.05-2.95; P = .03) (Table 2).
Table 2.
Univariable and multivariable logistic regression comparisons for the 2 treatment groups (SBRT before chemotherapy and SBRT concurrent with or after chemotherapy)
| Univariable | Multivariable | |||||
|---|---|---|---|---|---|---|
| Patient Characteristics | Odds ratio | 95% CI | P value | Odds ratio | 95% CI | P value |
| Age (ref: <65) | 1.01 | 0.68-1.52 | .94 | - | - | - |
| Sex (ref: female) | 1.07 | 0.77-1.49 | .69 | - | - | - |
| Race (ref: non-White) | 1.04 | 0.60-1.83 | .89 | - | - | - |
| Race/ethnicity (ref: Black non-Hispanic) | - | - | - | - | - | - |
| Other/unknown | 2.00 | 0.79-5.17 | .14 | - | - | - |
| White non-Hispanic | 1.30 | 0.69-2.63 | .43 | - | - | - |
| White or Black Hispanic | 1.27 | 0.16-7.37 | .79 | - | - | - |
| Insurance status (ref: Medicaid) | - | - | - | - | - | - |
| Medicare | 0.81 | 0.42-1.61 | .53 | - | - | - |
| Other | 1.20 | 0.44-3.24 | .72 | - | - | - |
| Private | 0.77 | 0.35-1.73 | .52 | - | - | - |
| Treatment facility (ref: academic) | 1.03 | 0.72-1.47 | .89 | - | - | - |
| Treatment facility location combined (ref: Midwest) | - | - | - | - | - | - |
| Northeast | 1.09 | 0.65-1.79 | .74 | - | - | - |
| South | 0.99 | 0.68-1.46 | .98 | - | - | - |
| West | 0.84 | 0.48-1.43 | .53 | - | - | - |
| Median income per county of residence (ref: <$46,277) | - | - | - | - | - | - |
| $46,227-$57,856 | 0.90 | 0.52-1.56 | .71 | - | - | - |
| $57,857-$74,062 | 1.02 | 0.59-1.77 | .96 | - | - | - |
| $73,063+ | 0.90 | 0.53-1.56 | .71 | - | - | - |
| Unknown | 1.11 | 0.62-2.01 | .73 | - | - | - |
| Charlson-Deyo Comorbidity Index combined (ref: 0) | - | - | - | - | - | - |
| 1 | 1.02 | 0.69-1.50 | .93 | - | - | - |
| 2+ | 1.02 | 0.67-1.53 | .94 | - | - | - |
| Year of diagnosis (median) (ref: ≤2018) | 0.46 | 0.31-0.65 | < .001* | 0.46 | 0.32-0.66 | < .001⁎ |
| Clinical T stage (ref: T1) | 1.85 | 1.11-3.07 | .02* | 1.76 | 1.05-2.95 | .03⁎ |
| Biologically effective radiation dose (ref: >110 Gy) | 1.23 | 0.88-1.71 | .23 | - | - | - |
Abbreviations: ref = reference; SBRT = stereotactic body radiation therapy.
Denotes statistical significance of P < .05.
Overall survival
There was no statistically significant difference in OS between the 2 treatment sequencing cohorts (“SBRT before chemotherapy”: median, 40.5 months; “SBRT concurrent with or after chemotherapy”: median, 35.6 months; log-rank P = .30) (Fig. 3). Initially, there appeared to be a numerical survival benefit for patients in the “radiation before chemo” sequencing cohort compared with those in the “radiation concurrent with or after chemo” sequencing cohort. However, as time progressed, there was no notable numerical difference in survival between the 2 cohorts.
Figure 3.
Kaplan-Meier curve comparing survival outcomes for SBRT initiated before chemotherapy versus SBRT concurrent with or after chemotherapy cohorts.
Abbreviation: SBRT = stereotactic body radiation therapy.
In adjusted analyses, the treatment sequencing group variable did not reach statistical significance (HR, 1.11; 95% CI, 0.89-1.37; P = .35) in the multivariable model (Table 3).
Table 3.
Univariable and multivariable Cox proportional hazard models assessing survival outcomes
| Univariable | Multivariable | |||||
|---|---|---|---|---|---|---|
| Patient Characteristics | Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value |
| Age (ref: <65) | 1.10 | 0.85-1.42 | .46 | - | - | - |
| Sex (ref: Female) | 1.11 | 0.91-1.37 | .31 | - | - | - |
| Race (ref: non-White) | 1.26 | 0.87-1.84 | .22 | - | - | - |
| Race/ethnicity (ref: Black non-Hispanic) | - | - | - | - | - | - |
| Other | 1.53 | 0.83-2.83 | .18 | - | - | - |
| White non-Hispanic | 1.29 | 0.84-1.99 | .24 | - | - | - |
| White or Black Hispanic | 1.11 | 0.38-3.24 | .84 | - | - | - |
| Insurance status (ref: Medicaid) | - | - | - | - | - | - |
| Medicare | 1.12 | 0.69-1.81 | .63 | - | - | - |
| Other | 0.83 | 0.41-1.67 | .61 | - | - | - |
| Private | 1.09 | 0.63-1.87 | .74 | - | - | - |
| Treatment facility (ref: academic) | 0.88 | 0.71-1.09 | .26 | - | - | - |
| Treatment facility location combined (ref: Midwest) | - | - | - | - | - | - |
| Northeast | 1.05 | 0.77-1.43 | .76 | 1.05 | 0.77-1.43 | .75 |
| South | 0.73 | 0.57-0.93 | .02⁎ | 0.73 | 0.57-0.94 | .01⁎ |
| West | 0.79 | 0.56-1.09 | .15 | 0.79 | 0.57-1.10 | .16 |
| Median income per county of residence (ref: <$46,277) | - | - | - | - | - | - |
| $46,227-$57,856 | 0.91 | 0.65-1.28 | .61 | - | - | - |
| $57,856-$74,062 | 0.95 | 0.67-1.33 | .75 | - | - | - |
| $74,063+ | 0.91 | 0.65-1.28 | .58 | - | - | - |
| Unknown | 0.79 | 0.54-1.15 | .22 | - | - | - |
| Charlson-Deyo Comorbidity Index combined (ref: 0) | - | - | - | |||
| 1 | 0.91 | 0.71-1.17 | .47 | - | - | - |
| 2+ | 1.01 | 0.78-1.30 | .96 | - | - | - |
| Year of diagnosis (median) (ref: y ≤ 2018) | 0.79 | 0.61-1.03 | .08 | - | - | - |
| Clinical T stage (ref: T1) | 1.32 | 0.98-1.80 | .07 | - | - | - |
| Biologically effective radiation dose (ref: >110 Gy) | 1.10 | 0.91-1.36 | .36 | - | - | - |
| Treatment group (ref: RT before chemo) | 1.12 | 0.90-1.38 | .30 | 1.11 | 0.89-1.37 | .35 |
Abbreviations: ref = reference; RT = radiation therapy.
Denotes statistical significance of P < .05.
Sensitivity analyses demonstrated the robustness of the lack of association between the primary variable of interest and OS. When excluding the 409 patients who started SBRT and chemotherapy within 30 days of each other, there were 222 patients remaining in the cohort. Multivariable analysis did not show statistical significance for the treatment cohorts (HR, 0.94; 95% CI, 0.67-1.32; P = .73) (Fig. E1). In the T-stage analysis, treatment sequencing did not have an association with OS among T1 patients (HR, 1.13; 95% CI, 0.90-1.43; P = .30) or among T2 patients (HR, 0.72; 95% CI, 0.36-1.46; P = .36).
Discussion
In this national retrospective study of 631 patients with clinical stage I SCLC, we found no statistically significant difference in OS for patients who received SBRT before chemotherapy compared with those who received SBRT concurrent with or after chemotherapy. Over time, we observed increased use of SBRT with chemotherapy among patients with stage I SCLC and an increased proportion of patients receiving SBRT before chemotherapy, particularly among those diagnosed in 2019 to 2020. Despite these changes in practice patterns, we did not find evidence that the order of sequencing impacts survival outcomes.
Although lobectomy remains the standard of care for operable stage I lung cancer, use of SBRT has increased over time as an established alternative for medically inoperable tumors,17,18 particularly for early-stage NSCLC because of its ability to achieve high primary tumor control.18, 19, 20 SBRT is a particularly compelling treatment option for SCLC, which is thought to be more radiosensitive than NSCLC and has a higher competing risk of distant failure.4 However, the timing of SBRT relative to chemotherapy in stage I SCLC has remained controversial.21 If chemotherapy is started before SBRT, there is a risk that the lesion may regress during chemotherapy and as a result be difficult to target and treat with SBRT. Furthermore, administering SBRT before chemotherapy emulates the surgical paradigm of resection followed by adjuvant chemotherapy. Some retrospective studies suggest that for patients with LS-SCLC, starting RT within 30 days while receiving a platinum-based chemotherapy regimen may have an increased 2-year and 5-year OS.22 Early initiation of local therapy has been shown to be beneficial in concurrent chemoradiation using standard fractionation for LS-SCLC. Conversely, there could be a theoretical advantage to initiating chemotherapy as early as possible to expeditiously address the potential burden of micrometastatic disease.
Although SBRT has not been evaluated in randomized controlled trials for SCLC, retrospective data have suggested it to be a safe and effective treatment option for patients with SCLC.4,23 Our findings provide additional insight to guide chemotherapy and SBRT timing for stage I SCLC. Because National Comprehensive Cancer Network guidelines recommend SBRT followed by systemic therapy, it has been more common to deliver SBRT before chemotherapy. The exploratory findings in our study raise questions about this recommendation and warrant further study to determine if there is true clinical equivalence with initiating chemotherapy rather than SBRT first.
One limitation of this study includes the uneven distribution between the 2 cohorts in our sample because of the lack of randomization and the retrospective nature of the study using the NCDB. A second limitation of this study is that the NCDB does not contain data on the extensive staging procedures for diagnoses. As a result, it is unclear as to whether patients received positron emission tomography scans and/or pathologic mediastinal staging, which could have influenced the staging and eligibility criteria of patients included in the study sample. It is also unclear as to how immunotherapy would affect survival outcomes for this cohort of patients. Additionally, clinically relevant endpoints, including time to distant metastasis, DFS, local control, and adverse events, are not available in the NCDB, which limits our ability to make definitive conclusions about the clinical impact of sequencing on disease control, particularly in a disease like SCLC for which distant metastasis is the primary driver of outcomes. Lastly, there is an imbalance in the distribution of patients for clinical T stage, which could potentially act as a source of bias. There are also limited data available within the data set regarding chemotherapy because it does not include variables such as the number of chemotherapy sessions patients received. The number of chemotherapy cycles can impact OS, which could serve as a potential source of bias.
In particular, future work should investigate whether initiating chemotherapy first may compromise the ability to deliver SBRT by causing significant tumor shrinkage, leading to potential loss of a clear radiographic target. Additionally, it remains to be determined whether certain subsets of patients may benefit from earlier sequencing of SBRT relative to chemotherapy based on biomarkers. Identifying predictors of rapid response to chemotherapy that may make the tumor difficult to target if SBRT is initiated later may provide insight into sequencing timeframes for these cohorts of patients.
Conclusion
In this national cohort of patients, there was no statistically significant difference in OS for patients with clinical stage I SCLC who received SBRT before chemotherapy compared with those who received SBRT concurrent with or after chemotherapy initiation. Because current guidelines recommend SBRT before chemotherapy, we do not disagree with continuing to proceed with National Comprehensive Cancer Network guideline–recommended care, but rather suggest that if chemotherapy is administered before SBRT and the tumor is still visible and suitable for SBRT, OS may not necessarily be compromised in this cohort of patients. Our findings support further investigation into the flexible sequencing of SBRT and chemotherapy that may be at least partially based on logistical and patient-specific considerations. Future research is warranted to explore the full clinical utility of SBRT for stage I SCLC, including prospective and ideally randomized evaluation of treatment sequencing.
Disclosures
James Laird: Grants or contracts from any entity: Conquer Cancer Foundation, outside the submitted work; Nipun Verma: Grants or contracts from any entity: American Society for Radiation Oncology, Cancer Prevention and Research Institute of Texas; Christin A. Knowlton: Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: American Society for Radiation Oncology; Stock or stock options: Doximity, Inc, outside the submitted work; Thomas J. Hayman: Grants or contracts from any entity: National Institutes of Health, American Cancer Society; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Associate Editor JNCI Cancer Spectrum (unpaid), outside the submitted work; Henry S. Park: Grants or contracts from any entity: RefleXion, Merck; Consulting fees: AstraZeneca, RefleXion; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, G1 Therapeutics, Daichii Sankyo, RefleXion; Participation on an Advisory Board: AstraZeneca, Galera, Regeneron, outside the submitted work. All other authors declare no competing interests.
Acknowledgments
Therese J. Ziaks was responsible for statistical analysis.
Footnotes
Sources of support: This work had no specific funding.
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.adro.2026.102175.
Appendix. Supplementary materials
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