Abstract
Background:
The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC).
Methods:
A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS).
Results:
After IPTW analysis, 49 patients received durvalumab plus platinum–etoposide (EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs. 12.3 months (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.17–0.85, P = 0.020), and the median PFS was 8.9 months vs. 5.9 months (HR: 0.56, 95% CI: 0.32–0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs. 14.7 months) and PFS (9.1 months vs. 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs. 13.7 months and median PFS of 9.8 months vs. 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs. 15.8 months, HR: 0.48, 95% CI: 0.14–1.63, P = 0.238) and Durva + EP groups (12.3 months vs. 4.3 months, HR: 0.29, 95% CI: 0.10–0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade.
Conclusion:
Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.
Keywords: Small cell lung cancer, Immune checkpoint inhibitor, Radiotherapy, Durvalumab, Treatment beyond progression
Introduction
Small cell lung cancer (SCLC) is an aggressive cancer with a high propensity for early metastasis. Most patients (approximately two-thirds) present with extensive-stage disease (ES-SCLC) at primary diagnosis. Although SCLC is sensitive to chemotherapy (CT) and radiotherapy (RT), most patients relapse within a short time after initiation of therapy. The reported 5-year overall survival (OS) is less than 10%.[1,2]
The traditional first-line therapy for ES-SCLC is cisplatin or carboplatin plus etoposide for 4–6 cycles.[3] RT also plays an important role in the management of ES-SCLC. Several studies have shown that therapeutic efficacy can be improved by introducing thoracic radiation therapy (TRT) in ES-SCLC patients who respond to initial CT but have residual thoracic disease.[4–10] In the CREST trial, the addition of TRT and prophylactic cranial irradiation (PCI) improved the 2-year OS rate and reduced intrathoracic progression.[4] Similarly, in the RTOG 0937 trial, consolidative radiation to all-known limited metastatic sites, including TRT and PCI, delayed progression at the sites of initial disease.[8] Therefore, the American Society for Radiation Oncology (ASTRO) has developed an evidence-based practice guideline addressing the use of PCI and thoracic consolidation for ES-SCLC.[11,12]
With the advent of immunotherapy, a new standard was established by the IMpower133[13] and CASPIAN[14] studies, in which the addition of a programmed death-ligand 1 (PD-L1) inhibitor (such as atezolizumab or durvalumab) to first-line CT was found to achieve better survival. However, in the era of immunotherapy, the safety and efficacy of consolidative RT for ES-SCLC following CT combined with immunotherapy remains unclear.[15,16] Due to the observed synergy between RT and immune checkpoint inhibitor (ICI) in preclinical studies, several clinical trials are now evaluating the safety and efficacy of radiation combined with immunotherapy for lung cancer, most of which are testing the post-progressive disease state.[15–21] Early studies suggest that TRT and ICI are safe and effective in limited-stage SCLC, but this has not yet been confirmed in extensive-stage disease.[15–18,22–24] In a retrospective study, RT plus atezolizumab was not associated with increased toxicity in ES-SCLC patients, but there was no improvement in survival.[25] Another real-world study by Elegbede et al[26] found that additional TRT treatment in 4 ES-SCLC patients was associated with improved OS in a multivariate analysis with acceptable adverse event (AE) risks.
The efficacy and safety of RT (especially TRT) administered in combination with immunotherapy has not yet been clearly demonstrated. Thus, we performed a retrospective study to analyze the safety and preliminary efficacy of durvalumab combined with CT, with or without RT (including PCI, TRT, and consolidative radiation to all known limited metastatic sites) in patients with ES-SCLC.
Methods
Patients
We retrospectively reviewed the treatment data of patients with ES-SCLC diagnosed between July 2019 and December 2021 at three hospitals. Patients who started with first-line CT combined with durvalumab were enrolled in this study. Patients were divided into two groups according to whether they received additional radiation therapy. Demographic and clinical data were retrieved, including age, sex, smoking history, Eastern Cooperative Oncology Group (ECOG) score, disease stage, brain/liver/bone metastases or other sites of metastasis, and thoracic RT. This study was approved by the hospital institutional review board at each study site (LunShen [2022] No. S0230). Because of the retrospective nature of this study, which involved the analysis of existing medical records and did not require direct patient contact or intervention, the hospital institutional review board waived the need for patient consent. However, all efforts were made to ensure the confidentiality and anonymity of patient data in accordance with local laws and regulations governing the use of personal health information.
Treatment
All patients in the study received first-line durvalumab combined with CT. Platinum–etoposide (EP) consisted of etoposide at 80–100 mg/m2 administered on days 1–3 of each cycle and carboplatin with a target area under the curve (AUC) of 5–6 mg·mL−1·min−1 or cisplatin at 75–80 mg/m2 administered intravenously on day 1 of each cycle. Durvalumab (1500 mg) was administered intravenously on day 1 of each cycle. Patients received up to four to six cycles of platinum–etoposide plus 1500 mg durvalumab every 3 weeks, followed by maintenance durvalumab (1500 mg) every 4 weeks. Durvalumab was continued beyond disease progression if there was a clinical benefit as assessed by physicians. All patients underwent a comprehensive evaluation, which encompassed a chest and abdominal computed tomography scan as well as a brain magnetic resonance imaging (MRI) or computed tomography scan every 6–8 weeks, depending on physician’s preference.
Patients who achieved complete response (CR), partial response (PR), or had stable disease (SD) after induction therapy were provided the option for radiation, including PCI, whole brain radiotherapy (WBRT), TRT, or RT to other metastatic sites. PCI involved 25 Gy administered at 2.5 Gy/fraction. WBRT dosage was usually 30 Gy at 3 Gy/fraction with or without booster doses. TRT involved 45 Gy at 3 Gy/fraction or 60 Gy at 2 Gy/fraction. The administered dosage was adjusted at the discretion of the treating physicians.
Treatment assessments and endpoints
The primary endpoint of this study was progression-free survival (PFS), defined as the time from initiation of first-line treatment to disease progression or death due to any cause, whichever occurred first. The key secondary endpoint was OS, defined as the time from initiation of first-line treatment to death due to any cause. The tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1.
Statistical analysis
For classified baseline variables, the chi-squared test or Fisher exact test was used. For continuous baseline variables, we used the Student’s t-test or the Wilcoxon rank sum test. The analyses of OS and PFS were conducted using survival analysis methods. We performed an inverse probability of treatment weighting (IPTW) using the propensity score[27] to account for any imbalance with respect to baseline characteristics. The propensity score, calculated using the logistic regression model, is the predicted probability of treatment according to all variables, which possibly influenced treatment assignment or outcome; these factors included study site, age, sex, smoking status, ECOG performance status, TNM stage, oligometastasis, bone metastasis, liver metastasis, and other metastases. We used stabilized IPTW scores as weightings[28] to preserve the sample sizes of pseudo-cohorts to close to those of the original cohorts, although these were not strictly equivalent to avoid sample size inflation. Survival analysis for the two cohorts was conducted by IPTW-adjusted Kaplan–Meier plots. The IPTW-adjusted Kaplan–Meier method[29] was used to create survival curves for the two cohorts and estimate the median survival and survival rates at 12 months. The IPTW-adjusted log-rank test was used to assess between-group differences in OS and PFS. The Brookmeyer–Crowley method was used to calculate the 95% confidence intervals (CIs) for median values, and Greenwood’s formula was used to calculate the 95% CIs for the survival rates at 12 months. We further fitted an IPTW-adjusted Cox proportional hazards regression model to compute the corresponding hazard ratios (HRs) with a robust sandwich estimate of the variance to account for the weighted nature of the samples.[30] Two additional sensitivity analyses were conducted to assess the robustness of results based on the IPTW-adjusted cohorts. First, we conducted multivariable Cox regression, including all the above-mentioned covariates in the unadjusted cohorts. Second, we performed and compared results from 1:1 nearest neighbor propensity score-matched cohorts. All statistical analyses were performed using R software version 4.1.0 (The R Foundation, Vienna, Austria). All statistical tests were two-tailed and P values <0.05 were considered indicative of statistical significance.
Results
Patient characteristics
One hundred and twenty-two patients from three study sites were enrolled. The characteristics of the study population are summarized in Table 1. Seventy patients received durvalumab plus platinum-etoposide therapy (Durva + EP) and 52 patients received durvalumab plus platinum-etoposide therapy followed by RT (Durva + EP + RT). The detailed proportion of CR, PR, and SD after first-line durvalumab plus CT in the Durva + EP group was respectively 0, 72.9%, and 22.9%, which was 1.9%, 84.6%, and 13.5% in the Durva + EP + RT group, and there is no statistical difference in the detailed proportion of CR, PR, and SD between the two groups [Supplementary Table 1, http://links.lww.com/CM9/C131].
Table 1.
Baseline characteristics of all patients before and after IPTW analysis.
| Characteristics | Before IPTW | After IPTW | ||||||
|---|---|---|---|---|---|---|---|---|
| Durva + EP (N = 70) | Durva + EP + RT (N = 52) | P-value | SMD | Durva + EP (N = 72) | Durva + EP + RT (N = 49) | P-value | SMD | |
| Hospital | <0.001 | 1.002 | 0.989 | 0.023 | ||||
| Wuhan Union | 22 (31.4) | 37 (71.2) | 35 (48.6) | 24 (49.0) | ||||
| Wuhan Zhongnan | 9 (12.9) | 8 (15.4) | 11 (15.3) | 7 (14.3) | ||||
| Hunan Cancer | 39 (55.7) | 7 (13.5) | 26 (36.1) | 18 (36.7) | ||||
| Sex | 0.447 | 0.203 | 0.649 | 0.086 | ||||
| Female | 8 (11.4) | 3 (5.8) | 6 (8.3) | 3 (6.1) | ||||
| Male | 62 (88.6) | 49 (94.2) | 66 (91.7) | 46 (93.9) | ||||
| ECOG-PS | 0.630 | 0.133 | 0.724 | 0.066 | ||||
| 0–1 | 60 (85.7) | 42 (80.8) | 60 (83.3) | 42 (85.7) | ||||
| ≥2 | 10 (14.3) | 10 (19.2) | 12 (16.7) | 7 (14.3) | ||||
| Smoking | 0.633 | 0.123 | 0.815 | 0.067 | ||||
| No | 27 (38.6) | 17 (32.7) | 22 (30.6) | 14 (28.6) | ||||
| Yes | 43 (61.4) | 35 (67.3) | 50 (69.4) | 35 (71.4) | ||||
| Age (years) | 62 (56–67) | 63 (55–66) | 0.934 | 0.106 | 62 (57–67) | 60 (54–69) | 0.709 | 0.009 |
| T stage (AJCC eighth) | 0.006 | 0.498 | 0.946 | 0.107 | ||||
| 1 | 1 (1.4) | 6 (11.5) | 6 (8.3) | 3 (6.1) | ||||
| 2 | 14 (20.0) | 6 (11.5) | 13 (18.1) | 8 (16.3) | ||||
| 3 | 7 (10.0) | 8 (15.4) | 8 (11.1) | 5 (10.2) | ||||
| 4 | 48 (68.6) | 32 (61.5) | 45 (62.5) | 33 (67.3) | ||||
| N stage (AJCC eighth) | 0.449 | 0.314 | 0.768 | 0.184 | ||||
| 0 | 2 (2.9) | 0 | 1 (1.4) | 0 | ||||
| 1 | 4 (5.7) | 3 (5.8) | 3 (4.2) | 1 (2.0) | ||||
| 2 | 23 (32.9) | 13 (25.0) | 19 (26.4) | 14 (28.6) | ||||
| 3 | 41 (58.6) | 36 (69.2) | 49 (68.1) | 34 (69.4) | ||||
| M stage (AJCC eighth) | 0.425 | 0.218 | 0.982 | 0.004 | ||||
| 0 | 2 (2.9) | 4 (7.7) | 3 (4.2) | 2 (4.1) | ||||
| 1 | 68 (97.1) | 48 (92.3) | 69 (95.8) | 47 (95.9) | ||||
| Oligometastasis | 0.206 | 0.269 | 0.475 | 0.138 | ||||
| No | 38 (54.3) | 35 (67.3) | 46 (63.9) | 28 (57.1) | ||||
| Yes | 32 (45.7) | 17 (32.7) | 26 (36.1) | 21 (42.9) | ||||
| Brain metastasis | 0.593 | 0.141 | 0.880 | 0.028 | ||||
| No | 59 (84.3) | 41 (78.8) | 61 (84.7) | 42 (85.7) | ||||
| Yes | 11 (15.7) | 11 (21.2) | 11 (15.3) | 7 (14.3) | ||||
| Bone metastasis | 0.101 | 0.337 | 0.649 | 0.084 | ||||
| No | 49 (70.0) | 28 (53.8) | 47 (65.3) | 30 (61.2) | ||||
| Yes | 21 (30.0) | 24 (46.2) | 25 (34.9) | 19 (38.8) | ||||
| Other metastasis | 0.126 | 0.320 | 0.635 | 0.087 | ||||
| No | 11 (15.7) | 15 (28.8) | 15 (20.8) | 12 (25.5) | ||||
| Yes | 59 (84.3) | 37 (71.2) | 57 (79.2) | 37 (75.5) | ||||
Data are presented as median (Q1, Q3) or number with percentage. AJCC: American Joint Committee on Cancer; Durva: Durvalumab; ECOG-PS: Eastern Cooperative Oncology Group-Performance Status; EP: Platinum–etoposide; IPTW: Inverse probability of treatment weighting; RT: Radiotherapy; SMD: Standardized Mean Difference; TNM stage: Tumor, Node, Metastasis stage.
After IPTW analysis, there were 72 and 49 patients in the Durva + EP and Durva + EP + RT groups, respectively [Table 1]. The median age was 62 (range 57–67) years in the Durva + EP group, and most patients were male (91.7%), smokers (69.4%), and had a good ECOG performance status of 0–1 (83.3%). In the Durva + EP+ RT group, the median age was 60 (range 54–69) years, male (93.9%), smokers (71.4%), and ECOG performance status of 0–1 (85.7%). In the Durva + EP and Durva + EP + RT groups, 36.1% (26/72), and 42.9% (21/49) of patients had oligometastatic disease, respectively, while the percentage of patients with brain metastasis was 15.3% (11/72) and 14.3% (7/49), respectively. The clinical features were well-balanced between the two groups.
OS analysis
At the time of data cutoff, the median follow-up was 9.9 months (95% CI: 8.1–11.6 months). A total of 24 patients (33.3%) in the Durva + EP group and 11 patients (22.4%) in the Durva + EP + RT group died. The median OS in the Durva + EP group was 12.3 months, which was comparable to 13.0 months in the CASPIAN study, and the median OS in the Durva + EP + RT group was 17.2 months. The OS in the Durva + EP + RT group was significantly longer than that in the Durva + EP group (stratified HR for death: 0.38, 95% CI: 0.17–0.85, P = 0.020) [Figure 1A]. The 1-year OS rate was 52.7% in the Durva + EP group vs. 82.1% in the Durva + EP + RT group.
Figure 1.
Kaplan–Meier curves for OS (A) and PFS (B) of patients in the Durva + EP + RT and Durva + EP groups. CI: Confidence interval; Durva: Durvalumab; EP: Platinum–etoposide; HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival; RT: Radiotherapy.
PFS analysis
At data cutoff, a total of 41 patients (56.9%) in the Durva + EP group and 27 patients (55.1%) in the Durva + EP + RT group had disease progression or died. The median PFS in the Durva + EP group was 5.9 months, which is comparable to 5.1 months in the CASPIAN study, and the median PFS in the Durva + EP + RT group was 8.9 months. Compared with Durva + EP group, PFS was significantly longer in the Durva + EP + RT group (HR: 0.56, 95% CI: 0.32–0.97, P = 0.030) [Figure 1B].
Sensitivity analyses
Univariate and multivariable Cox regression analyses were performed to identify the prognostic factors [Supplementary Tables 2 and 3, http://links.lww.com/CM9/C131]. Multivariable analysis revealed that RT treatment was a significant factor affecting OS (HR: 0.38, 95% CI: 0.15–0.96, P = 0.040) and PFS (HR: 0.36, 95% CI: 0.18–0.70, P = 0.003). Propensity score matching (PSM) analysis was also performed to assess sensitivity. The results showed the median OS in the Durva + EP + RT group was 6.8 months longer compared to the Durva + EP group, and the median PFS was 6.2 months longer than the Durva + EP group; both these differences were significant [Supplementary Figure 1A, B, http://links.lww.com/CM9/C131], which was consistent with the IPTW analysis.
Survival outcomes in selected patient subgroups
Of the 49 patients who received RT, 38 (77.6%) received TRT and only 11 (22.4%) received consolidative radiation to other metastatic sites without TRT. The median interval time between immunotherapy and TRT was 26 days (95% CI: 16–38 days). The median OS in the TRT subgroup (17.2 months) was significantly longer than that in the Durva + EP group (12.3 months) (HR: 0.33, 95% CI: 0.14–0.79, P = 0.013), while the OS in the subgroup receiving radiation to other sites (14.7 months) was not significantly different from that in the Durva + EP group (HR: 0.65, 95% CI: 0.29–1.45, P = 0.408) [Figure 2A]. The PFS of these three subgroups showed the same trend: 9.1 months in the TRT subgroup, 5.9 months in the Durva + EP group, and 7.2 months in the group receiving radiation to other sites. In addition, there was a significant difference in PFS between the TRT group and the Durva + EP group (HR: 0.53, 95% CI: 0.29–0.97, P = 0.041), and no significant difference between the group receiving radiation to other sites and the Durva + EP group (HR: 0.65, 95% CI: 0.29–1.45, P = 0.293) [Figure 2B].
Figure 2.
Kaplan–Meier curves for OS (A) and PFS (B) of patients in the different subgroups who received TRT, radiation to other sites only, or no radiation. CI: Confidence interval; Durva: Durvalumab; EP: Platinum–etoposide; HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival; RT: Radiotherapy; TRT: Thoracic radiation therapy.
A total of 25 patients (34.7%) in the Durva + EP group and 21 patients (42.9%) in the Durva + EP + RT group had oligometastatic ES-SCLC at the time of diagnosis. Among these patients, survival was longer in the Durva + EP + RT group than in the Durva + EP group, with a median OS [Figure 3A] of 17.4 months vs. 13.7 months, and median PFS [Figure 3B] of 9.8 months vs. 5.9 months. However, these differences were not statistically significant.
Figure 3.
Kaplan–Meier curves for OS (A) and PFS (B) of patients with oligometastasis who received radiation or not. CI: Confidence interval; Durva: Durvalumab; EP: Platinum–etoposide; HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival; RT: Radiotherapy.
We also analyzed the benefit–risk profile of continuous durvalumab treatment beyond progression (TBP) after first-line therapy. In the Durva + EP group, 38 patients showed disease progression, 21 of whom continued durvalumab treatment; the median OS was 12.3 months vs. 4.3 months in the no-TBP subgroup (HR: 0.29, 95% CI: 0.10–0.81, P = 0.018) [Figure 4A]. In the Durva + EP + RT group, 27 patients had disease progression, 14 of whom continued durvalumab treatment; durvalumab TBP also conferred a survival benefit with a 0.48 HR (95% CI: 0.14–1.63, P = 0.238) [Figure 4B]. For all patients who received durvalumab TBP, radiation combined with Durva + EP reduced the risk of death by 64% compared to Durva + EP alone (HR: 0.36, 95% CI: 0.10–1.30, P = 0.119) [Figure 4C].
Figure 4.
Kaplan–Meier curves for OS of patients with continuous durvalumab TBP after first-line therapy. Differences within: (A) the Durva + EP group; (B) the Durva + EP + RT group; (C) all patients who received durvalumab TBP (the difference between those who received radiation and those who did not). CI: Confidence interval; Durva: Durvalumab; EP: Platinum–etoposide; HR: Hazard ratio; OS: Overall survival; RT: Radiotherapy; TBP: Treatment beyond progression.
Progression patterns
Isolated intrathoracic failure was rarer in the Durva + EP + RT group (n = 7, 25.9%) than in the Durva + EP group (n = 20, 51.3%). The proportion of patients demonstrating distant metastasis was 29.6% and 10.3%, respectively, while 44.4% and 38.5% of patients had both local and distant failure upon progression. However, this difference was not statistically significant (P = 0.051). The proportion of patients who experienced brain metastasis was 28.2% and 51.9%, respectively (P = 0.052) [Table 2].
Table 2.
Progression pattern of patients in different groups.
| Items | Durva + EP (N = 39) | Durva + EP + RT (N = 27) | P-value |
|---|---|---|---|
| Progression pattern | 0.051 | ||
| Local | 20 (51.3) | 7 (25.9) | |
| Distant | 4 (10.3) | 8 (29.6) | |
| Both | 15 (38.5) | 12 (44.4) | |
| New brain metastasis | 11 (28.2) | 14 (51.9) | 0.052 |
Durva: Durvalumab; EP: Platinum–etoposide; RT: Radiotherapy.
Safety
AEs of any cause and grade occurred in 44 (89.8%) of 49 patients in the Durva + EP + RT group and 61 (84.7%) of 72 patients in the Durva + EP group [Table 3]. Grade 3 or 4 AEs occurred in 26.5% (13/49) patients and 18.1% (13/72) patients in Durva + EP + RT and Durva + EP groups, respectively. The most common grade 3 or 4 AEs were elevated transaminase (8.2%, 4/49) in the Durva + EP + RT group and leukopenia (9.7%, 7/72) in the Durva + EP group.
Table 3.
Incidence of treatment-related AEs.
| Events | Durva + EP (n = 72) | Durva + EP + RT (n = 49) | ||
|---|---|---|---|---|
| Any grade | Grade 3 or 4 | Any grade | Grade 3 or 4 | |
| Hematotoxicity | ||||
| Leukopenia | 22 (30.1) | 7 (9.7) | 14 (28.6) | 2 (4.1) |
| Neutropenia | 8 (11.1) | 2 (2.8) | 8 (16.3) | 3 (6.1) |
| Thrombocytopenia | 9 (12.5) | 0 | 10 (20.4) | 1 (2.0) |
| Anemia | 48 (66.7) | 2 (2.8) | 27 (55.1) | 1 (2.0) |
| Elevated transaminase | 19 (26.4) | 0 | 13 (26.5) | 4 (8.2) |
| Elevated bilirubin | 16 (22.2) | 1 (1.4) | 7 (14.3) | 0 |
| Increased serum creatinine | 3 (4.2) | 0 | 0 | 0 |
| ICI-related event | ||||
| Pneumonitis | 5 (6.9) | 2 (2.8) | 11 (22.4) | 3 (6.1) |
| Hepatitis | 1 (1.4) | 0 | 0 | 0 |
| Myocarditis | 1 (1.4) | 1 (1.4) | 0 | 0 |
| Enteritis | 0 | 0 | 1 (2.0) | 0 |
| Pancreatitis | 1 (1.4) | 0 | 0 | 0 |
| Radiation-related event | ||||
| Pneumonitis | NA | NA | 12 (24.5) | 1 (2.0) |
| Esophagitis | NA | NA | 2 (4.1) | 0 |
| Enteritis | NA | NA | 1 (2.0) | 0 |
| Mucositis | NA | NA | 1 (2.0) | 0 |
| Any event | 61 (84.7) | 13 (18.1) | 44 (89.8) | 13 (26.5) |
AE: Adverse event; Durva: Durvalumab; EP: Platinum–etoposide; RT: Radiotherapy; ICI: Immune checkpoint inhibitor; NA: Not applicable; RT: Radiotherapy.
Immune-mediated adverse events (imAEs) were reported in 12 (24.5%) of 49 patients in the Durva + EP + RT group and 8 (11.1%) of 72 patients in the Durva + EP group. Both groups had 3 patients experiencing Grade 3 or 4 imAEs (Durva + EP + RT group: 6.1%; Durva + EP group: 4.2%). The most common imAE was pneumonitis occurring in 11 (22.4%) patients in the Durva + EP + RT group and 5 (6.9%) patients in the Durva + EP group, which was mostly grade 1 or 2 in severity. Radiation-mediated AEs were reported in 16 (32.6%) of 49 patients in the Durva + EP + RT group. The most common was radiation pneumonitis, occurring in 12 (24.5%) patients; these cases were mostly grade 1 or 2 in severity. In the Durva + EP + RT group, the rates of immune pneumonitis and radiation pneumonitis were similar to reported rates in the Pacific study,[31] and the incidence of clinically important grade 3 or 4 events was 6.1% for ICI-related and 2.0% for radiation-related pneumonitis, indicating that the introduction of RT, especially thoracic RT, was safe and controllable.
Discussion
Due to the paucity of data on the application of radiation treatment with ICI in ES-SCLC, this study evaluated the safety and efficacy of adding RT, especially TRT, to durvalumab plus CT for ES-SCLC treatment in a real-world Chinese population compared to a cohort that received durvalumab plus CT. The findings of this retrospective study demonstrated that the addition of RT, especially TRT, to durvalumab plus platinum–etoposide significantly improved OS and PFS, compared with durvalumab plus platinum–etoposide alone. The median OS was 5 months longer and the median PFS was 3 months longer in the Durva + EP + RT group compared to the Durva + EP group, and the 1-year OS rate was approximately 30% higher in the Durva + EP + RT group than the Durva + EP group. Moreover, the median OS in the TRT subgroup was significantly longer than that in the Durva + EP group.
The IMpower 133 and CASPIAN trials illustrate the new standard of first-line treatment for ES-SCLC.[13,14,32] Although approximately 70% of patients respond to immunochemotherapy, 70% of patients relapse in 6 months.[13,14] Thus, it is imperative to develop a new regimen to further improve survival and decrease the treatment failure rate of immunotherapy for ES-SCLC. Previously, RT has been shown to confer survival benefits in both limited-stage and ES-SCLC in the CT era.[33,34] Moreover, the guidelines also recommend the administration of PCI and TRT for ES-SCLC.[11,12] This study has provided evidence of the added value of RT in this new immunochemotherapy era.
TRT showed high efficacy when added to immunochemotherapy. The subgroup analysis revealed a statistically significant prolongation of median OS in the TRT subgroup compared to the Durva + EP group, whereas no such difference was observed in the subgroup receiving radiation to other sites. Furthermore, in the safety analysis, the rate of immune pneumonitis and radiation pneumonitis in the Durva + EP + RT group was 22.4% and 32.6%, respectively, and mostly grade 1 or 2 in severity. These results are similar to the outcomes of the Pacific study,[31] implying that TRT in combination with immunotherapy presents acceptable AE risks. These results were broadly in line with the CREST study,[4] some retrospective studies,[35,36] and other non-randomized studies[37] that added thoracic RT to a CT regimen.
In addition, this study reported an almost 25% reduction in intrathoracic recurrences in the Durva + EP + RT group compared with the Durva + EP group, which is consistent with previous studies.[4–10] However, the rate of new brain metastasis was higher in the Durva + EP + RT group, which might be attributable to the relatively long survival in patients receiving radiation as well as immunochemotherapy. As the analysis of the recurrence pattern showed, RT, especially TRT, decreased the risk of intrathoracic recurrences and may have contributed to the improved PFS and OS in patients with ES-SCLC. Nevertheless, evidence on the efficacy of radiation and ICI for ES-SCLC remains inconclusive, and further studies are required to determine their benefit on survival outcomes in this patient population.
Oligometastasis was defined by Hellman and Weichselbaum[38] as a transitional state between the localized and polymetastatic states, and is most likely to benefit from local therapy to achieve long-term local control and improve survival. Oligometastatic cases, which are systemic, are rare in the context of ES-SCLC. A retrospective study reported a rate of 28.9% for oligometastasis, and TRT was found to improve survival in both oligo- and polymetastatic ES-SCLC.[39] The definitions of oligometastases in our study are as follows according to the former studies[38,39]: (1) only one organ metastasis or metastatic lymph node metastases (able to be covered by a safe RT portal); (2) multiple brain metastases (treated with whole brain RT); or (3) continuous vertebral bone metastases treated in a single RT field. This study also showed a trend for improved OS and PFS when radiation was combined with immunochemotherapy in patients with oligometastasis (HR: 0.34 and 0.36, respectively). However, these findings require validation with a larger sample size.
TBP with immunotherapy has been reported in some studies. The OAK study showed a positive benefit-risk profile of atezolizumab TBP in patients with advanced non-small cell lung cancer (NSCLC).[40] According to a systematic review, the response rate of patients with advanced solid tumors receiving TBP was 19.7%.[41] In ES-SCLC, immunotherapy has changed the standard first-line treatment, but disease progression still occurs in approximately 50% of patients at 6 months, as reported in the IMpower 133 and CASPIAN trials. Second-line TBP after immunotherapy is rare. In this study, continuous Durva TBP was found to confer a survival benefit irrespective of whether it was administered in combination with radiation; however, the difference was not statistically significant. These findings also need to be verified in a larger patient sample.
In this study, the overall safety profile was similar in both the Durva + EP and Durva + EP + RT groups, with a similar frequency of grade 3 or 4 AEs. Although the incidence of ICI-related and radiation-related pneumonitis was higher in the radiation group, this was expected after definitive immunochemotherapy. Pneumonitis in patients who received radiation was mostly low-grade, and the incidence of clinically important grade 3 or 4 events was 6.1% for ICI-related and 2.0% for radiation-related pneumonitis. This is consistent with a previous study which found a 4.1% incidence of grade 2 or higher pneumonitis in lung cancer patients receiving TRT with ICI treatment.[42] These data suggest that RT following immunochemotherapy has manageable side effects. Both immunotherapy and TRT are known to have the risk of interstitial pneumonia; hence, the ideal mode of combination and interval time for immunotherapy and TRT remain unclear. This study showed the median interval time between immunotherapy and TRT was 26 days in the patients receiving TRT in the Durva + EP + RT group, which provided a clue for the appropriate and safe interval between immunotherapy and chest RT.
Some limitations of this study should be acknowledged. This was a retrospective study with a small sample size and involved a short follow-up time. Additionally, the patient characteristics were somewhat varied. And there was certain selectivity bias, as the patients in the radiation group were those who obtained disease control rate (DCR) after induction therapy (including PR, CR, and SD patients), but the control group included progression disease patients, who could not be given RT. Third, several traditional factors pertaining to radiation therapy (e.g., dose, fractionation, and target volumes) were not analyzed with respect to their relationship with pneumonia and survival, due to the limited number of cases. Nevertheless, the outcomes of this study are of great significance as they provide evidence for the beneficial effects of RT in ES-SCLC patients who received immunochemotherapy. Further studies with a larger patient cohort are required to confirm these findings.
In conclusion, RT, especially TRT, following durvalumab plus platinum–etoposide therapy significantly improved the PFS and OS of patients with ES-SCLC. Lack of radiation therapy was an independent predictor of poor PFS and OS. Moreover, continuous durvalumab TBP conferred a survival benefit for ES-SCLC patients. Consolidation radiation therapy delayed progression and decreased the local failure rate in this population. The regimen was well-tolerated with few high-grade AEs. Therefore, RT after chemotherapy + ICI treatment might improve the survival outcome with manageable toxicity in ES-SCLC, further perspective study is warranted.
Acknowledgments
We were indebted to the staff of the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; the Department of Thoracic Medical Oncology, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University; and the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, for their support and assistance.
Funding
This work was supported by the Bethune-Cancer Radiotherapy Translational Medicine Research Fund of China (No. flzh202117).
Conflicts of interest
None.
Supplementary Material
Footnotes
Lingjuan Chen, Yi Kong, and Fan Tong contributed equally to this work.
How to cite this article: Chen LJ, Kong Y, Tong F, Zhang RG, Ding P, Zhang S, Wang Y, Zhou R, Pu XX, Chen BL, Liang F, Tan QY, Xu Y, Wu L, Dong XR. Role of radiotherapy in extensive-stage small cell lung cancer after durvalumab-based immunochemotherapy: A retrospective study. Chin Med J 2025;138:2130–2138. doi: 10.1097/CM9.0000000000003283
References
- 1.Govindan R Page N Morgensztern D Read W Tierney R Vlahiotis A, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24:4539–4544. doi: 10.1200/JCO.2005.04.4859. [DOI] [PubMed] [Google Scholar]
- 2.Islami F Baeker Bispo J Lee H Wiese D Yabroff KR Bandi P, et al. American Cancer Society’s report on the status of cancer disparities in the United States, 2023. CA Cancer J Clin 2024;74:136–166. doi: 10.3322/caac.21812. [DOI] [PubMed] [Google Scholar]
- 3.van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet 2011;378:1741–1755. doi: 10.1016/S0140-6736(11)60165-7. [DOI] [PubMed] [Google Scholar]
- 4.Slotman BJ van Tinteren H Praag JO Knegjens JL El Sharouni SY Hatton M, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: A phase 3 randomised controlled trial. Lancet 2015;385:36–42. doi: 10.1016/S0140-6736(14)61085-0. [DOI] [PubMed] [Google Scholar]
- 5.O’Sullivan DE Cheung WY Syed IA Moldaver D Shanahan MK Bebb DG, et al. Real-world treatment patterns, clinical outcomes, and health care resource utilization in extensive-stage small cell lung cancer in Canada. Curr Oncol 2021;28:3091–3103. doi: 10.3390/curroncol28040270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sheikh S Dey A Datta S Podder TK Jindal C Dowlati A, et al. Role of radiation in extensive stage small cell lung cancer: A National Cancer Database registry analysis. Future Oncol 2021;17:2713–2724. doi: 10.2217/fon-2020-1095. [DOI] [PubMed] [Google Scholar]
- 7.Nosaki K, Seto T, Shimokawa M, Takahashi T, Yamamoto N. Is prophylactic cranial irradiation (PCI) needed in patients with extensive-stage small cell lung cancer showing complete response to first-line chemotherapy? Radiother Oncol 2018;127:344–348. doi: 10.1016/j.radonc.2018.04.010. [DOI] [PubMed] [Google Scholar]
- 8.Gore EM Hu C Sun AY Grimm DF Ramalingam SS Dunlap NE, et al. Randomized phase II study comparing prophylactic cranial irradiation alone to prophylactic cranial irradiation and consolidative extracranial irradiation for extensive-disease small cell lung cancer (ED SCLC): NRG oncology RTOG 0937. J Thorac Oncol 2017;12:1561–1570. doi: 10.1016/j.jtho.2017.06.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Palma DA, Warner A, Louie AV, Senan S, Slotman B, Rodrigues GB. Thoracic radiotherapy for extensive stage small-cell lung cancer: A meta-analysis. Clin Lung Cancer 2016;17:239–244. doi: 10.1016/j.cllc.2015.09.007. [DOI] [PubMed] [Google Scholar]
- 10.Slotman B Faivre-Finn C Kramer G Rankin E Snee M Hatton M, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–672. doi: 10.1056/NEJMoa071780. [DOI] [PubMed] [Google Scholar]
- 11.Simone CB 2nd Bogart JA Cabrera AR Daly ME DeNunzio NJ Detterbeck F, et al. Radiation therapy for small cell lung cancer: An ASTRO clinical practice guideline. Pract Radiat Oncol 2020;10:158–173. doi: 10.1016/j.prro.2020.02.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Daly ME Ismaila N Decker RH Higgins K Owen D Saxena A, et al. Radiation Therapy for small-cell lung cancer: ASCO guideline endorsement of an ASTRO guideline. J Clin Oncol 2021;39:931–939. doi: 10.1200/JCO.20.03364. [DOI] [PubMed] [Google Scholar]
- 13.Horn L Mansfield AS Szczęsna A Havel L Krzakowski M Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220–2229. doi: 10.1056/NEJMoa1809064. [DOI] [PubMed] [Google Scholar]
- 14.Paz-Ares L Dvorkin M Chen Y Reinmuth N Hotta K Trukhin D, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929–1939. doi: 10.1016/S0140-6736(19)32222-6. [DOI] [PubMed] [Google Scholar]
- 15.Badiyan SN Roach MC Chuong MD Rice SR Onyeuku NE Remick J, et al. Combining immunotherapy with radiation therapy in thoracic oncology. J Thorac Dis 2018;10(Suppl 21):S2492–S2507. doi: 10.21037/jtd.2018.05.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Patel SH, Rimner A, Cohen RB. Combining immunotherapy and radiation therapy for small cell lung cancer and thymic tumors. Transl Lung Cancer Res 2017;6:186–195. doi: 10.21037/tlcr.2017.03.04. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Williamson CW Sherer MV Zamarin D Sharabi AB Dyer BA Mell LK, et al. Immunotherapy and radiation therapy sequencing: State of the data on timing, efficacy, and safety. Cancer 2021;127:1553–1567. doi: 10.1002/cncr.33424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Pakkala S Higgins K Chen Z Sica G Steuer C Zhang C, et al. Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: A randomized phase II study. J Immunother Cancer 2020;8:e001302. doi: 10.1136/jitc-2020-001302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Welsh J Menon H Chen D Verma V Tang C Altan M, et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: A randomized phase I/II trial. J Immunother Cancer 2020;8:e001001. doi: 10.1136/jitc-2020-001001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Theelen WSME Peulen HMU Lalezari F van der Noort V de Vries JF Aerts JGJV, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: Results of the PEMBRO-RT phase 2 randomized clinical trial. JAMA Oncol 2019;5:1276–1282. doi: 10.1001/jamaoncol.2019.1478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Wu CT, Chen WC, Chang YH, Lin WY, Chen MF. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep 2016;6:19740. doi: 10.1038/srep19740. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ma X, Wang S, Zhang Y, Wei H, Yu J. Efficacy and safety of immune checkpoint inhibitors (ICIs) in extensive-stage small cell lung cancer (SCLC). J Cancer Res Clin Oncol 2021;147:593–606. doi: 10.1007/s00432-020-03362-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Schmid S Mauti LA Friedlaender A Blum V Rothschild SI Bouchaab H, et al. Outcomes with immune checkpoint inhibitors for relapsed small-cell lung cancer in a Swiss cohort. Cancer Immunol Immunother 2020;69:1605–1613. doi: 10.1007/s00262-020-02565-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Welsh JW Heymach JV Guo C Menon H Klein K Cushman TR, et al. Phase 1/2 trial of pembrolizumab and concurrent chemoradiation therapy for limited-stage SCLC. J Thorac Oncol 2020;15:1919–1927. doi: 10.1016/j.jtho.2020.08.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Galuba J, Stöver I, Koziorowski A, Bölükbas S, Nilius G, Christoph D. P63.10 safety of simultaneously performed radiotherapy in patients with small-cell lung cancer undergoing atezolizumab treatment. J Thorac Oncol 2021;16:S1186. doi: 10.1016/j.jtho.2021.08.666. [Google Scholar]
- 26.Elegbede AA Gibson AJ Fung AS Cheung WY Dean ML Bebb DG, et al. A real-world evaluation of atezolizumab plus platinum-etoposide chemotherapy in patients with extensive-stage SCLC in Canada. JTO Clin Res Rep 2021;2:100249. doi: 10.1016/j.jtocrr.2021.100249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Robins JM, Hernán MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:550–560. doi: 10.1097/00001648-200009000-00011. [DOI] [PubMed] [Google Scholar]
- 28.Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health 2010;13:273–277. doi: 10.1111/j.1524-4733.2009.00671.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Xie J, Liu C. Adjusted Kaplan-Meier estimator and log-rank test with inverse probability of treatment weighting for survival data. Stat Med 2005;24:3089–3110. doi: 10.1002/sim.2174. [DOI] [PubMed] [Google Scholar]
- 30.Austin PC. The performance of different propensity score methods for estimating marginal hazard ratios. Stat Med 2013;32:2837–2849. doi: 10.1002/sim.5705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Antonia SJ Villegas A Daniel D Vicente D Murakami S Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:1919–1929. doi: 10.1056/NEJMoa1709937. [DOI] [PubMed] [Google Scholar]
- 32.Dingemans AC Früh M Ardizzoni A Besse B Faivre-Finn C Hendriks LE, et al. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol 2021;32:839–853. doi: 10.1016/j.annonc.2021.03.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Froeschl S, Nicholas G, Gallant V, Laurie SA. Outcomes of second-line chemotherapy in patients with relapsed extensive small cell lung cancer. J Thorac Oncol 2008;3:163–169. doi: 10.1097/JTO.0b013e318160c0cb. [DOI] [PubMed] [Google Scholar]
- 34.O’Brien ME Ciuleanu TE Tsekov H Shparyk Y Cuceviá B Juhasz G, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 2006;24:5441–5447. doi: 10.1200/JCO.2006.06.5821. [DOI] [PubMed] [Google Scholar]
- 35.Giuliani ME Atallah S Sun A Bezjak A Le LW Brade A, et al. Clinical outcomes of extensive stage small cell lung carcinoma patients treated with consolidative thoracic radiotherapy. Clin Lung Cancer 2011;12:375–379. doi: 10.1016/j.cllc.2011.03.028. [DOI] [PubMed] [Google Scholar]
- 36.Zhu H Zhou Z Wang Y Bi N Feng Q Li J, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011;117:5423–5431. doi: 10.1002/cncr.26206. [DOI] [PubMed] [Google Scholar]
- 37.Yee D Butts C Reiman A Joy A Smylie M Fenton D, et al. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234–238. doi: 10.1016/j.radonc.2011.08.042. [DOI] [PubMed] [Google Scholar]
- 38.Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8–10. doi: 10.1200/JCO.1995.13.1.8. [DOI] [PubMed] [Google Scholar]
- 39.Xu LM Cheng C Kang M Luo J Gong LL Pang QS, et al. Thoracic radiotherapy (TRT) improved survival in both oligo- and polymetastatic extensive stage small cell lung cancer. Sci Rep 2017;7:9255. doi: 10.1038/s41598-017-09775-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Gandara DR von Pawel J Mazieres J Sullivan R Helland Å Han JY, et al. Atezolizumab treatment beyond progression in advanced NSCLC: Results from the randomized, phase III OAK study. J Thorac Oncol 2018;13:1906–1918. doi: 10.1016/j.jtho.2018.08.2027. [DOI] [PubMed] [Google Scholar]
- 41.Spagnolo F, Boutros A, Cecchi F, Croce E, Tanda ET, Queirolo P. Treatment beyond progression with anti-PD-1/PD-L1 based regimens in advanced solid tumors: A systematic review. BMC Cancer 2021;21:425. doi: 10.1186/s12885-021-08165-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Hwang WL Niemierko A Hwang KL Hubbeling H Schapira E Gainor JF, et al. Clinical outcomes in patients with metastatic lung cancer treated with PD-1/PD-L1 inhibitors and thoracic radiotherapy. JAMA Oncol 2018;4:253–255. doi: 10.1001/jamaoncol.2017.3808. [DOI] [PMC free article] [PubMed] [Google Scholar]