What are the options for second-line treatment of small cell lung cancer (SCLC)?

Second-Line Treatment Options for Small Cell Lung Cancer (SCLC)

Single-agent chemotherapy is the recommended standard approach for second-line treatment of small cell lung cancer, with the choice of agent primarily determined by the time interval since completion of first-line therapy. 1

Treatment Selection Based on Relapse Timing

For Relapse ≤6 Months (Refractory/Resistant Disease)

• Topotecan (oral or intravenous) is FDA-approved and recommended as a subsequent therapy option for patients with relapsed SCLC, with expected response rates of approximately 10% 1
• The standard regimen for IV topotecan is 1.5 mg/m² daily for 5 consecutive days, repeated every 21 days 2
• Many clinicians have noted excessive toxicity with the standard IV regimen, and studies suggest an attenuated dose may be equally efficacious with lower toxicity 1
• Either oral or IV topotecan may be used, as efficacy and toxicity are similar with either route 1, 3

For Relapse >6 Months (Sensitive Disease)

• Reinitiation of the original platinum regimen is recommended as the preferred approach for patients who relapse more than 6 months after completion of initial chemotherapy 1
• Expected response rates are approximately 25% in this setting 1

Alternative Second-Line Options

Other active single agents with demonstrated activity in second-line SCLC include:

• Paclitaxel 1
• Docetaxel 1
• Irinotecan 1
• Vinorelbine 1
• Gemcitabine 1
• Temozolomide (may be particularly useful for patients with brain metastases) 1
• Oral etoposide 1
• Lurbinectedin 1
• Nivolumab or pembrolizumab 1

Evidence Supporting Topotecan

• A randomized phase III trial comparing single-agent IV topotecan with the combination regimen CAV (cyclophosphamide, doxorubicin, vincristine) showed similar response rates and survival, but topotecan caused less toxicity 1
• Another phase III trial demonstrated that oral topotecan improved overall survival compared with best supportive care (26 vs. 14 weeks) 1
• Oral and IV topotecan have shown similar efficacy, though with slightly different toxicity profiles (more diarrhea with oral, more neutropenia with IV) 3

Treatment Duration

• Subsequent chemotherapy should be given until 2 cycles beyond best response, progression of disease, or development of unacceptable toxicity 1
• The duration is usually short, and cumulative toxicity is frequently limiting even in patients who experience response 1

Toxicity Considerations

• Myelosuppression is the primary toxicity concern with topotecan, with grade 3/4 neutropenia occurring in 47-64% of patients 2, 3
• Common non-hematologic adverse events include nausea, fatigue, alopecia, and diarrhea 3
• For patients with renal impairment (creatinine clearance 20-39 mL/min), reduce topotecan dose to 0.75 mg/m²/day 2

Special Considerations

• Performance status is an important factor in selecting patients for second-line therapy, as patients with poor PS may not derive meaningful benefit 1
• For refractory patients (no response to initial therapy) and those with very early relapse (<6 weeks), outcomes are poor and clinical benefit of further systemic therapy is uncertain 1
• The selection of patients for treatment with second-line therapy should depend on treatment-free interval, extent of response to first-line therapy, residual toxicity from first-line therapy, and performance status 1

Despite advances in treatment, the prognosis for patients with relapsed SCLC remains poor, with median survival typically 4-5 months when treated with second-line chemotherapy 1. Clinical trial participation should be encouraged whenever possible 1.