What is the recommended first‑line treatment for limited‑stage versus extensive‑stage small cell lung cancer, including chemotherapy, radiotherapy, immunotherapy, and prophylactic cranial irradiation?

First-Line Treatment for Small Cell Lung Cancer

For limited-stage SCLC, the standard treatment is 4 cycles of cisplatin-etoposide with concurrent thoracic radiotherapy (45 Gy twice-daily preferred), followed by prophylactic cranial irradiation for responders; for extensive-stage SCLC, the preferred regimen is now platinum-etoposide plus immunotherapy (atezolizumab or durvalumab) for 4 cycles, with PCI considered for responders. 1

Limited-Stage SCLC Treatment Algorithm

Chemotherapy Backbone

• Cisplatin 100 mg/m² day 1 plus etoposide 120 mg/m² days 1-3 for 4 cycles is the preferred regimen for patients with good performance status (PS 0-2) 1
• Carboplatin (AUC 5-6) may substitute for cisplatin only when cisplatin is contraindicated or poorly tolerated, though this substitution has not been adequately evaluated in limited-stage disease 1
• In younger patients (<70 years) with limited-stage disease, cisplatin is preferred over carboplatin due to superior outcomes in this population 1

Concurrent Thoracic Radiotherapy

• Radiotherapy must begin early—with cycle 1 or 2 of chemotherapy—as delayed radiotherapy reduces survival benefit 1
• The preferred dose is 45 Gy delivered twice-daily (1.5 Gy BID) in 30 fractions over 3 weeks, which provides superior 5-year survival (26% vs 16%) compared to once-daily fractionation 1
• Once-daily radiotherapy (60-70 Gy) is an acceptable alternative for patients who cannot tolerate twice-daily treatment due to logistics, performance status, or comorbidities 1
• Sequential chemoradiotherapy (chemotherapy followed by radiotherapy) is inferior and should only be used when concurrent therapy is not feasible due to poor PS, comorbidities, or excessive disease volume 1

Radiation Field Planning

• Include post-chemotherapy primary tumor volume and pre-chemotherapy nodal stations that responded to treatment 1
• Omit elective nodal irradiation; only irradiate involved nodes (FDG-avid on PET-CT, enlarged on CT, or biopsy-positive) 1

Prophylactic Cranial Irradiation (PCI)

• Offer PCI (25 Gy in 10 fractions) to all patients with stage III limited-stage SCLC who achieve response after chemoradiotherapy and maintain PS 0-1 1
• PCI reduces brain metastases and improves overall survival 1
• Consider PCI for PS 2 patients, though evidence is less robust 1
• The role of PCI is less defined in stage I-II SCLC and patients >70 years; use shared decision-making in these cases 1

Extensive-Stage SCLC Treatment Algorithm

First-Line Immunotherapy-Based Regimens (Preferred)

For patients with PS 0-1 and no contraindications to immunotherapy:

• Atezolizumab or durvalumab plus platinum-etoposide for 4 cycles, followed by maintenance immunotherapy, is now the preferred standard of care 1
• Both atezolizumab and durvalumab have ESMO-MCBS scores of 3, indicating substantial clinical benefit 1
• Contraindications include active or previously documented autoimmune disease and concurrent use of immunosuppressive agents 1

Chemotherapy-Only Regimens (For Immunotherapy-Ineligible Patients)

For patients with contraindications to immunotherapy:

• Carboplatin-etoposide for 4-6 cycles is the preferred chemotherapy-only regimen 1
• Carboplatin (AUC 5-6 day 1) plus etoposide (100 mg/m² days 1-3) is equivalent to cisplatin-based regimens in extensive-stage disease (response rate 67% vs 66%, median OS 9.6 vs 9.4 months) 1
• Alternative regimens include cisplatin-irinotecan or cisplatin-oral topotecan 1

For patients with PS 2 due to SCLC:

• Carboplatin-etoposide with dose reduction and/or G-CSF prophylaxis 1

For patients with PS 2 due to comorbidities or poor prognosis:

• Gemcitabine-carboplatin is an alternative option 1

For patients with PS 3-4:

• Best supportive care is recommended 1

Consolidation Radiotherapy in Extensive-Stage

• For patients achieving response after chemotherapy with PS 0-2, consolidation thoracic RT (30 Gy in 10 fractions) to residual primary tumor and lymph nodes is a treatment option 1
• This is not standard but may be considered in selected patients 1

Prophylactic Cranial Irradiation in Extensive-Stage

• PCI (20-25 Gy in 5-10 fractions) is justified in patients <75 years with PS 0-2 who achieved response after chemotherapy 1
• PCI may be omitted in patients without brain metastases on MRI who can be followed with regular brain MRI (every 3 months for first year, then every 6 months) 1
• The role of PCI in combination with immunotherapy is not well-defined due to limited data; use shared decision-making 1

Management of Brain Metastases at Diagnosis

• In patients with extensive-stage disease and brain metastases, chemotherapy can be given before or after whole-brain radiotherapy depending on neurologic symptoms 1
• If systemic therapy is given first, brain radiotherapy follows completion of chemotherapy 1

Critical Timing and Pitfalls

Common Pitfalls to Avoid

• Do not delay staging beyond 1 week, as patients may experience significant performance status decline 1
• Do not delay thoracic radiotherapy in limited-stage disease; starting RT with cycle 3 or later reduces survival benefit 1
• Do not routinely use carboplatin in limited-stage disease unless cisplatin is contraindicated; cisplatin is preferred in this setting 1
• Do not use myeloid growth factors during concurrent chemoradiotherapy due to increased toxicity 1
• Do not continue maintenance chemotherapy beyond 4-6 cycles; it does not improve survival 1

Toxicity Management

• Concurrent chemoradiotherapy increases risk of esophagitis, pulmonary toxicity, and hematologic toxicity 1
• Carboplatin causes greater myelosuppression than cisplatin but less neuropathy, nephropathy, and emesis 1
• Healthcare providers must be aware of immune-mediated adverse events with atezolizumab/durvalumab and manage with high-dose corticosteroids when indicated 1

Expected Outcomes

• Limited-stage disease: 5-year survival 20-25% with optimal concurrent chemoradiotherapy and PCI 1
• Extensive-stage disease with immunotherapy: median survival improved compared to chemotherapy alone 1
• Extensive-stage disease with chemotherapy only: median survival 9-10 months 1, 2