Defining the Role of Consolidative Thoracic Radiotherapy Post Immunotherapy in ES-SCLC

Hanna_zasimova (globe) - stock.adobe.com; Strange TA, Erasmus LT, Ahuja J, et al. Spectrum of imaging patterns of lung cancer following radiation therapy. Diagnostics (Basel). 2023;13(20):3283. Published 2023 Oct 23. doi:10.3390/diagnostics13203283 (scan)

Although the addition of platinum-etoposide in the IMpower133 (NCT02763579) and CASPIAN (NCT03043872) trials modestly improved the survival outcomes of patients with extensive-stage small cell lung cancer (ES-SCLC) with an absolute median overall survival (OS) gain of approximately 2 to 3 months,^1,2 both trials prohibited consolidative thoracic radiotherapy (TRT). Consequently, prospective data on how best to integrate TRT with modern chemoimmunotherapy remains limited.

Small cell lung cancer (SCLC) accounts for approximately 13% of lung malignancies and is characterized by rapid proliferation, early dissemination, and marked radiosensitivity. Roughly two-thirds of patients present with extensive-stage disease (ES-SCLC).³ Morphologically, 75% of patients have residual thoracic disease after first-line treatment, with most experiencing intrathoracic relapse or progression within the first year, despite systemic progression being the dominant pattern.⁴ There is therefore a significant gap in the literature.

Why Consolidative TRT Remains a Relevant Question

The phase 3 CREST trial (NCT00656224) demonstrated that consolidative TRT (30 Gy in 10 fractions) delivered after chemotherapy reduced thoracic relapse and improved 2-year OS from 3% to 13% with minimal added toxicity, and greatest benefit in patients with residual thoracic disease.^5,6 Although CREST predated immunotherapy, it established a biological and clinical rationale for local consolidation in ES-SCLC. Although TRT was excluded from IMpower133 and CASPIAN, oncologists today must extrapolate from historical data and emerging real-world evidence.

Emerging Real‑World Data in the Immunotherapy Era

Several retrospective series have reported outcomes with TRT after first-line treatment with chemoimmunotherapy.^7-9 In a cohort of 276 patients, a significant OS benefit with TRT (23.9 vs 18.1 months; HR, 0.68) was demonstrated.⁸ Subgroup analysis revealed no benefit among patients with baseline liver metastases, echoing previous trial findings.⁶

Our group originally reported on a cohort of 183 patients with ES-SCLC.¹⁰ Consolidative TRT (30 Gy) was delivered to 39% of patients. Intrathoracic progression decreased from 65.2% to 42.3% (P < .001). Median progression-free survival (PFS; 6.9 vs 5.9 months) and OS (13.0 vs 12.9 months) trended higher but were not statistically significant. Only 28% of progressions occurred within the radiation field, suggesting durable local control. In an expanded analysis including nearly 350 patients, we reinforce the trends toward improved survival outcomes and reduced intrathoracic recurrence and have identified patient subgroups who may derive particular benefit.

Collectively, these data suggest that well‑selected patients who are without liver metastases, may experience meaningful clinical benefit from TRT after undergoing treatment with chemoimmunotherapy.

Guideline Perspective

The American Society for Radiation Oncology and European Society for Medical Oncology now issue conditional recommendations for TRT in ES‑SCLC responders with residual thoracic disease, endorsing 30 Gy/10 fractions or 45 Gy/15 fractions for fit patients.^11,12 The National Comprehensive Cancer Network guideline lists TRT as an option during or immediately before maintenance immunotherapy while emphasizing the lack of level 1 evidence.¹³

Practical Approach in the Clinic Ideal candidates are patients with ECOG performance status levels of 0 or 1, with partial response or stable disease, and without uncontrolled extrathoracic burden, especially those lacking baseline liver metastases.

The historical 30 Gy/10-fraction schedule remains standard; higher doses (45‑60 Gy) may improve outcomes but carry lymphopenia risk and should be reserved for trials or highly selected individuals. Use conformal or intensity-modulated techniques with daily image guidance to limit lung V₂₀ and spinal cord dose. Most centers initiate TRT from 3 to 6 weeks after induction chemoimmunotherapy.

Grade 2 or greater esophagitis (≈ 10%‑ 18%) and grade 3 or greater pneumonitis (< 5%) are the principal risks; baseline pulmonary function, smoking status, and prior thoracic irradiation should inform counseling.

Prospective Data

RAPTOR (NRG‑LU007; NCT04402788) randomly assigns patients without progression after induction atezolizumab (Tecentriq) to consolidative stereotactic radiotherapy to 5 or fewer lesions (including the thorax) vs maintenance immunotherapy alone. The primary end point is PFS with completion expected in 2027.¹⁴

Limitations and Future Directions

Current evidence is retrospective and susceptible to selection bias. Optimal dose, target volume, and sequencing relative to immunotherapy remain undefined. Future studies should explore stereotactic regimens, biomarker-guided selection (eg, circulating tumor DNA, SCLC transcriptional subtype), and patient-reported outcomes.

Conclusion Consolidative TRT after chemoimmunotherapy is biologically plausible, technically feasible, and increasingly supported by real‑world evidence. Although we await randomized confirmation, multidisciplinary discussion should consider TRT for fit ES‑SCLC patients with residual thoracic disease, particularly those without liver metastases. In experienced hands, incremental toxicity is low, and the potential for durable thoracic control, and possibly survival prolongation, justifies individualized use.

REFERENCES

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14. Testing the addition of radiation therapy to the usual immune therapy treatment (atezolizumab) for extensive stage small cell lung cancer, the RAPTOR trial. Clinicaltrials. gov. Updated May 7, 2025. https://www.clinicaltrials.gov/ study/NCT04402788