https://orcid.org/0000-0003-3328-0160
Figures
Abstract
Background
Limited-stage small cell lung cancer (LS-SCLC) has a poor prognosis despite being potentially curable with standard concurrent chemoradiotherapy. The success of immune checkpoint inhibitors (ICIs) in extensive-stage SCLC has prompted investigation into combining immunotherapy with radiotherapy for LS-SCLC. This systematic review and single-arm meta-analysis aims to synthesize the evidence on this combined modality, providing pooled estimates of efficacy and safety to inform clinical practice and future trials.
Methods
Following PRISMA guidelines, we systematically searched PubMed, Embase, Cochrane Library, and Web of Science through July 2025 for studies evaluating radiotherapy combined with immunotherapy in patients with LS-SCLC. The primary outcomes analyzed included pooled objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS).
Results
Six studies, encompassing 487 patients, met the inclusion criteria. The pooled analysis demonstrated an ORR of 57.7% (95% CI: 24.9–90.5%), a weighted mPFS of 13.6 months (95% CI: 11.3–15.9 months), and a pooled mOS of 33.7 months (95% CI: 26.7–40.7 months). Grade 3−4 treatment-related adverse events occurred in 42.2% of patients. Subgroup analyses revealed that a concurrent treatment sequence yielded a significantly higher ORR compared to sequential approaches (77.6% vs. 65.2% for immunotherapy followed by radiation vs. 25.8% for radiation followed by immunotherapy). Radiation dose was also identified as a critical determinant of efficacy. Anti-PD-L1 agents showed a numerically higher ORR than anti-PD-1 agents (96.0% vs. 65.0%).
Conclusion
The combination of radiotherapy and immunotherapy is a promising therapeutic strategy for LS-SCLC, demonstrating encouraging efficacy outcomes that appear favorable compared to historical benchmarks for chemoradiotherapy alone. Optimizing treatment sequencing, particularly favoring a concurrent approach, is crucial for maximizing clinical benefit. These findings support further investigation in randomized controlled trials to confirm the value of this combined modality and to identify predictive biomarkers for patient selection.
Citation: Yu L, Yu X, Ma C, Zhang X, Cui R (2025) Safety and efficacy of radiotherapy combined with immunotherapy in limited-stage small cell lung cancer a single-arm meta-analysis and systematic review. PLoS One 20(11): e0337459. https://doi.org/10.1371/journal.pone.0337459
Editor: Jincheng Wang, Hokkaido University: Hokkaido Daigaku, JAPAN
Received: July 21, 2025; Accepted: November 6, 2025; Published: November 20, 2025
Copyright: © 2025 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Some relevant data are within the paper and its Supporting information files. The data and code that support the findings of this study are openly available in Figshare at https://doi.org/10.6084/m9.figshare.30335173. This repository includes the raw data extracted from the included studies (data-extraction.csv) and the Stata code used for conducting the meta-analysis (meta-analysis).”
Funding: This study was supported by 2024 research project from the Sichuan Science and Technology Department Project (Project Number: 2024ZYD0103).
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: LS-SCLC, Limited-Stage Small Cell Lung Cancer; SCLC, Small Cell Lung Cancer; ICIs, Immune Checkpoint Inhibitors; ORR, Objective Response Rate; mPFS, Median Progression-Free Survival; mOS, Median Overall Survival; PD-1, Programmed Cell Death Protein 1; PD-L1, Programmed Death-Ligand 1; CTLA-4, Cytotoxic T-Lymphocyte-Associated Protein 4; AEs, Adverse Events; ECOG, Eastern Cooperative Oncology Group (Performance Status); Gy, Gray (Radiation Dose Unit); RECIST, Response Evaluation Criteria in Solid Tumors; NOS, Newcastle–Ottawa Scale; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PROSPERO, International Prospective Register of Systematic Reviews.
Introduction
Small cell lung cancer (SCLC) makes up around 15% of all lung cancer cases. It is marked by fast proliferation, early metastatic spread, and therapeutic resistance, which collectively lead to an unfavorable prognosis [1,2]. Limited-stage SCLC (LS-SCLC), which constitutes 30% of SCLC cases, is potentially curable; however, the median survival remains only 16–24 months, with a 5-year survival rate below 30% [3]. The current standard of concurrent chemoradiotherapy achieves high initial response rates but most patients experience early relapse [4].
The revolutionary influence of immune checkpoint inhibitors (ICIs), particularly atezolizumab and durvalumab, has been evident in the management of extensive-stage SCLC, which have been shown to improve survival when combined with chemotherapy, has generated considerable interest in exploring immunotherapy for LS-SCLC [5]. Radiotherapy and immunotherapy demonstrate compelling synergy: radiation induces immunogenic cell death, enhances neoantigen presentation, and reprograms the tumor microenvironment from immunosuppressive to immunopermissive [6].
However, the optimal integration of radiotherapy with immunotherapy in LS-SCLC remains largely unexplored. Critical knowledge gaps persist regarding the synergistic potential of radiation-immunotherapy combinations, including optimal radiation doses and fractionation schemes when combined with ICIs, sequencing of concurrent versus sequential approaches, and whether radiation field design influences systemic immune responses [7,8]. Published studies exploring radiotherapy-immunotherapy combinations exhibit substantial heterogeneity in radiation protocols and immunotherapy timing. Notably, while previous systematic reviews have examined immunotherapy across all SCLC stages or radiotherapy modifications in isolation, none have specifically synthesized evidence on the combined modality approach in LS-SCLC. Here, we present this systematic review and single-arm meta-analysis specifically examining radiotherapy combined with immunotherapy in LS-SCLC, aiming to provide preliminary pooled estimates of clinical outcomes, identify critical research priorities that may inform ongoing clinical trials in this challenging disease.
Methods
Study design and registration
This systematic review and single-arm meta-analysis was conducted according to PRISMA guidelines and registered prospectively in PROSPERO (CRD420251107572). The protocol was finalized prior to the initiation of the literature search.
Search strategy
We systematically searched PubMed, Embase, Cochrane Library, and Web of Science from inception through July 2025. The search strategy combined MeSH terms and keywords: (“small cell lung cancer” OR “SCLC”) AND (“limited stage” OR “LS-SCLC”) AND (“immunotherapy” OR “immune checkpoint inhibitor” OR “PD-1” OR “PD-L1” OR “CTLA-4”) AND (“radiotherapy” OR “radiation”).
Study selection
Two investigators independently screened 4,601 identified records. Inclusion criteria were: (1) prospective or retrospective studies evaluating radiotherapy combined with immunotherapy in LS-SCLC; (2) reported efficacy outcomes (ORR, PFS, or OS); (3) minimum 10 patients. Exclusion criteria included: (1) studies with <10 patients were excluded to avoid small-cohort random error compromising pooled analysis reliability; (2) duplicate publications; (3) insufficient outcome data; (4) combination with other experimental agents. Searches were restricted to English language publications. Discrepancies were resolved through consensus with a third reviewer.
Data extraction and quality assessment
Standardized forms captured study characteristics, patient demographics, treatment regimens, and outcomes. The primary endpoints were ORR (RECIST v1.1), median PFS (mPFS), and median OS. Secondary endpoints included toxicity profiles. Study quality was assessed using the Newcastle-Ottawa Scale for retrospective studies and the Institute of Health Economics checklist for single-arm studies, with scores ≥70% considered high quality.
Statistical analysis
Pooled proportions for ORR were calculated using random-effects models with Freeman-Tukey double arcsine transformation. Median survival times were pooled using weighted averages based on sample size. Heterogeneity was assessed using I2 statistics (>50% indicating substantial heterogeneity).
Prespecified subgroup analyses examined: (1) treatment sequence (concurrent vs. sequential immunotherapy); (2) radiation dose (≥45 Gy vs. < 45 Gy); (3) ICI type (anti-PD-1 vs. anti-PD-L1); (4) performance status (ECOG 0–1 vs. 2). Sensitivity analyses excluded high-bias studies; publication bias was assessed with funnel plots and Egger’s test.
All analyses were conducted with Stata 14.0 (StataCorp, College Station, TX). Statistical significance was defined as a two-sided P < 0.05.
Results
Study selection and characteristics
From 243 records identified through systematic searching, 6 studies [9–14] met inclusion criteria after full-text review, encompassing 487 patients with LS-SCLC treated with combined radiotherapy and immunotherapy. Study characteristics varied in design, sample size and treatment regimens. All studies reported adequate follow-up for survival analyses (median follow-up: 23.1–37.2 months). The study selection process is illustrated in Fig 1, while comprehensive study characteristics are presented in Table 1.
Quality assessment
We assessed the methodological quality of the included studies using standardized tools: the Newcastle-Ottawa Scale (NOS) for the 4 non-randomized studies (evaluating selection, comparability, and outcome assessment across eight criteria) and the Jadad scale for the 2 RCTs (focusing on randomization, blinding, and follow-up). Complete quality assessment results are presented in Table 2.
NOS for non-randomized studies
The heading signs Q1-Q8 represented: Ⅰ) representative of the exposed cohort; Ⅱ) selection of the non-exposed cohort; Ⅲ) ascertainment of exposure; Ⅳ) outcome present at baseline; Ⅴ) cohort design/analysis; Ⅵ) cohort assessment; Ⅶ) sufficient outcome period; and Ⅷ) follow-up adequacy.
JADAD scale for reporting randomized controlled trials
Numbers Q1-Q4 in heading signified: Q1: Was the study described as randomized? Q2: Was the method of randomization appropriate? Q3: Was the study described as double-blind? Q4: Was there a description of withdrawals and dropouts?
Efficacy outcomes
The pooled ORR across all studies was 57.7% (95% CI: 24.9–90.5%), with moderate heterogeneity (I2 = 98.5%, P < 0.001). Individual study response rates ranged from 20.1% to 96.0%, demonstrating consistent activity of the combination approach. (Fig 2).
ORR, objective response rate.
For survival endpoints, the weighted mPFS across all studies was 13.6 months (95% CI: 11.3–15.9 months), with individual study estimates ranging from 13.1 to 19.7 months (Fig 3A). The pooled mOS was 33.7 months (95% CI: 26.7–40.7 months) (Fig 3B).
PFS, progression-free survival; OS, overall survival.
Safety profile
Treatment-related AEs were reported in all studies, with all-grade toxicities occurring in 97.6% of patients (Fig 4A) and grade 3–4 toxicities occurring in 42.2% of patients (Fig 4B). No treatment-related deaths were reported in the included studies. (Table 3).
AEs, adverse events.
Subgroup analyses
Treatment sequence significantly influenced outcomes. The ORR of concurrent treatment is better than that of sequential treatment, and among sequential treatments, the ORR of immunotherapy followed by radiation therapy is better than that of immunotherapy after radiotherapy(77.6% vs. 65.2% vs. 25.8) (Fig 5). Prolonged mPFS (13.4 vs. 16.6 months) (Fig 6A) and mOS (39.5 vs. 33.4 months) (Fig 6B) compared to sequential administration.
ORR, objective response rate.
PFS, progression-free survival; OS, overall survival.
Radiation dose emerged as a critical determinant of efficacy. Patients who received 45 Gy irradiation achieved a better ORR (55.3% vs. 63.1%) than those who received higher doses (Fig 7).
ORR, objective response rate.
ICI selection showed differential effects. Anti-PD- L1 agents demonstrated numerically higher ORR compared to anti-PD-1 agents (96.0% vs. 65.0%,), though this difference was not statistically significant. The combination of two ICIs did not achieve better results, possibly due to immune related adverse events affect treatment efficacy and patient response, resulting in suboptimal ORR in some cases compared to monotherapy ICIs (Fig 8).
ORR, objective response rate; ICIs, immune checkpoint inhibitors.
Compared with more than half of the patients having an ECOG score > 0, more than half of the patients with an ECOG score = 0 did not show better results in all efficacy parameters: ORR (64.8% vs. 51.9%) (Fig 9A), but achieved a longer mPFS (12.8 vs. 7.9 months, P < 0.001) (Fig 9B).
ORR, objective response rate; PFS, progression free survival; ECOG, eastern cooperative oncology group.
Sensitivity analysis
A sensitivity analysis was conducted by sequentially excluding one study at a time to assess its impact on aggregated results. Findings showed that pooled results and their 95% confidence intervals remained relatively stable regardless of which study was omitted, confirming the overall reliability of the meta-analysis (S1 Fig).
Publication bias
To evaluate publication bias and verify the robustness of the meta – analysis results, Egger’s and Begg’s tests were carried out. The results were in line with the main study findings. For ORR (Egger’s P = 0.88, Begg’s P = 0.71), mPFS (Egger’s P = 0.08, Begg’s P = 0.30), mOS (Begg’s P = 1.00) and AEs (Egger’s P = 0.29, Begg’s P = 1.00), no significant publication bias was noted, as stated earlier.
Discussion
Our systematic review and single-arm meta-analysis provides the first comprehensive evidence synthesis evaluating radiotherapy combined with immunotherapy in LS-SCLC. The pooled analysis of 487 patients from six studies demonstrates efficacy outcomes, with an ORR of 57.7%, median PFS of 13.6 months, and median OS of 33.7 months. These results suggest that incorporating immunotherapy into the treatment paradigm for LS-SCLC may offer meaningful clinical benefits beyond historical benchmarks achieved with chemoradiotherapy alone.
The observed efficacy outcomes are comparable to those reported in historical landmark trials. The CONVERT trial reported median OS of 25–30 months with standard concurrent chemoradiotherapy [15], while our analysis revealed a median OS of 33.7 months with the addition of immunotherapy. Although cross-trial comparisons must be interpreted cautiously, the consistency of improved outcomes across multiple studies suggests a potential benefit. Notably, the ORR of 57.7% aligns with historical response rates of 80–90% for chemoradiotherapy [16], indicating that immunotherapy does not compromise initial tumor response while potentially improving durability of disease control.
Our subgroup analyses reveal critical insights for optimizing treatment delivery. Concurrent treatment yields a higher ORR than sequential treatment. Within the sequential treatment category, immunotherapy followed by radiation therapy achieves a superior ORR compared to radiation therapy followed by immunotherapy, with respective rates of 77.6%, 65.2%, and 25.8%. This finding aligns with preclinical evidence suggesting that radiation-induced immunogenic cell death and neoantigen release are temporally linked processes that may be optimally exploited through concurrent therapy [17]. The dose-response relationship observed with radiation ≥45 Gy supports maintaining adequate radiation doses despite concerns about combined toxicity.
The differential effects observed in ICIs’ selection, with anti-PD-L1 agents showing numerically higher ORR than anti-PD-1 agents (96.0% vs. 65.0%) despite the lack of statistical significance, highlight the need for deeper exploration into their distinct biological behaviors. This numerical advantage might stem from differences in ligand targeting specificity, as PD-L1 inhibitors could potentially block interactions with both PD-1 and CD80, thereby exerting a broader regulatory effect on immune checkpoint pathways [18,19]. The failure of dual ICI combinations to outperform monotherapies, possibly attributed to immune-related adverse events undermining treatment efficacy and patient response, underscores the complexity of balancing therapeutic synergy and safety in combination strategies [20]. Such findings emphasize that optimizing ICI selection—whether choosing between single-agent PD-1 or PD-L1 inhibitors or reconsidering the rationale behind dual-agent combinations—requires careful evaluation of both efficacy signals and tolerability profiles in future clinical investigations.
The contrasting efficacy patterns between patient groups with more than half having ECOG = 0 versus those with more than half having ECOG > 0, where superior ORR did not translate to better outcomes across all parameters but longer mPFS was observed, merit careful interpretation. While the numerical advantage in ORR for the ECOG = 0 group (64.8% vs. 51.9%) suggests some baseline fitness benefit, the statistically significant longer mPFS (12.8 vs. 7.9 months, P < 0.001) highlights that better performance status may particularly influence disease progression dynamics. This discrepancy could reflect that ECOG 0 status, indicating better functional capacity, enables patients to sustain treatment effects over a longer period despite not showing universal superiority in immediate response metrics, emphasizing the multifaceted role of performance status in therapeutic outcomes [21].
Several mechanisms may underlie the observed synergy between radiotherapy and immunotherapy in LS-SCLC. Radiotherapy induces immunogenic cell death, leading to the release of tumor-associated antigens and damage-associated molecular patterns, which in turn activate dendritic cells [22]. Additionally, radiation upregulates MHC class I expression and modulates the tumor microenvironment from immunosuppressive to immunopermissive [23]. The localized nature of LS-SCLC may be particularly amenable to these effects, as the entire tumor burden can be encompassed within the radiation field, potentially maximizing systemic immune activation [24].
The reported grade 3–4 toxicity rate of 42.2% requires careful consideration. This heightened risk necessitates vigilant monitoring and may require protocol modifications, such as stricter lung dose constraints or prophylactic corticosteroid use in selected patients. Future studies should incorporate comprehensive quality-of-life assessments to better characterize the risk-benefit profile.
The landscape of LS-SCLC treatment is rapidly evolving with multiple ongoing trials evaluating different immunotherapy strategies (Table 4). Key questions being addressed include optimal timing (concurrent vs. consolidation), agent selection (PD-1 vs. PD-L1 inhibitors), and combination approaches (dual checkpoint blockade, PARP inhibition).
Biomarker development remains critical for personalized treatment selection. While PD-L1 expression and tumor mutational burden have shown limited predictive value in SCLC, emerging markers including circulating tumor cells [25], inflammatory gene signatures, and specific molecular subtypes may enable patient stratification [26]. Integration of these biomarkers into prospective trials will be essential for optimizing treatment selection [27].
Several limitations warrant acknowledgment. First, the single-arm design prevents definitive conclusions regarding the added benefit of immunotherapy beyond chemoradiotherapy alone. Second, heterogeneity across study designs, immunotherapy agents, and treatment schedules may influence pooled estimates. This is particularly evident in the wide variation of reported overall response rates (ORR) (24.9%–90.5%), with a pooled average of 57.7%. Notably, higher-quality randomized controlled trials (RCTs) reported lower ORRs (15–25% and 23–45%). This discrepancy suggests potential overestimation of immunotherapy efficacy in non-randomized studies due to inherent methodological biases. Selection bias is a significant concern, as non-randomized studies often enroll patients with more favorable baseline characteristics (e.g., better ECOG performance status [0–1], fewer comorbidities, or earlier tumor stage). RCTs mitigate this by using randomization to balance patient characteristics. Outcome assessment bias is also a factor, with non-randomized studies relying on retrospective data or non-standardized radiological evaluation, whereas RCTs typically employ centralized, blinded independent review committees. Differences in follow-up duration may also contribute, as shorter follow-up in some non-randomized studies might inflate short-term ORR. While both study types predominantly used the “chemoradiotherapy followed by immunotherapy” (QT-RT + IT) sequence, this minimizes treatment sequencing as a primary driver of the ORR discrepancy. Third, the relatively short follow-up in some studies may not capture late toxicities or the full spectrum of survival benefits. Finally, it is worth noting a limitation regarding the scope of our findings in relation to our search strategy. While we systematically searched for studies involving CTLA-4 inhibitors, no studies meeting our inclusion criteria utilized a CTLA-4 inhibitor as a monotherapy in combination with radiotherapy. The only included study that involved a CTLA-4 agent employed it in combination with a PD-1 inhibitor, which was analyzed under the ‘combination ICI’ subgroup. Therefore, our results do not provide specific insights into the efficacy or safety of exclusive CTLA-4 and radiotherapy combinations.
Conclusions
This meta-analysis demonstrates that radiotherapy combined with immunotherapy represents a promising therapeutic strategy in LS-SCLC, with encouraging efficacy outcomes that warrant further investigation in randomized controlled trials. The identification of optimal treatment sequencing, radiation dose thresholds, and predictive biomarkers will be crucial for maximizing clinical benefit while minimizing toxicity. As multiple phase III trials near completion, the treatment landscape for LS-SCLC is poised for transformation, offering hope for improved outcomes in this challenging disease.
Supporting information
S1 Fig. Sensitivity analysis based on (A) ORR, (B) mPFS, (C) mOS, (D) AEs.
ORR, objective response rate; mPFS, median progression-free survival; mOS, median overall survival; AEs, adverse events.
https://doi.org/10.1371/journal.pone.0337459.s001
(DOCX)
Acknowledgments
The authors acknowledge the assistance of DeepL in improving the grammar, word choice, and writing of this manuscript.
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