What is the 3-weekly regimen for etoposide (chemotherapy agent) and cisplatin (chemotherapy agent) for combined chemotherapy and radiotherapy in small cell lung cancer?

3-Weekly Etoposide-Cisplatin Regimen for Combined Chemoradiotherapy in Small Cell Lung Cancer

The standard 3-weekly regimen for etoposide-cisplatin in combined chemoradiotherapy for small cell lung cancer consists of cisplatin 60-80 mg/m² IV on day 1 and etoposide 100-120 mg/m² IV on days 1,2, and 3, repeated every 21 days for 4 cycles, with concurrent thoracic radiotherapy starting with cycle 1 or 2. 1

Standard Dosing Schedule

The recommended dosing for the 3-weekly regimen is:

• Cisplatin: 60-80 mg/m² IV administered once on day 1 1
• Etoposide: 100-120 mg/m² IV administered once daily on days 1,2, and 3 1
• Cycle length: Every 3 weeks (21-day cycles) 1
• Total cycles: 4 cycles when combined with twice-daily radiotherapy 1
• Total cycles: 4-6 cycles when combined with once-daily radiotherapy 1

Critical Timing with Radiotherapy

Thoracic radiotherapy must be initiated early—within 30 days of starting chemotherapy, ideally beginning with cycle 1 or 2—as delayed radiotherapy significantly reduces survival benefit. 1, 2, 3

• Meta-analysis demonstrates improved 5-year survival when total treatment time (first day of chemotherapy to last day of radiotherapy) is <30 days (HR 0.62,95% CI 0.49-0.80, p=0.0003) 1, 2
• Early concurrent radiotherapy is superior to sequential approaches for limited-stage disease 3

Dose Intensity Considerations

Attempts should be made to minimize dose reductions, especially during the first two cycles, to maintain optimal outcomes. 1

• The etoposide-cisplatin combination replaced alkylator/anthracycline-based regimens based on superior efficacy and toxicity profile in limited-stage disease 1
• This regimen is the most commonly used and guideline-recommended initial combination for small cell lung cancer 1

Alternative Dosing Schedules from Clinical Trials

While the standard 3-weekly regimen above is preferred, several alternative schedules have been studied:

• Split-dose cisplatin: Cisplatin 50 mg/m² on days 1 and 7 with etoposide 170 mg/m² on days 3-5 every 21 days 4
• Daily × 5 schedule: Cisplatin 20 mg/m² daily and etoposide 75 mg/m² daily for 5 consecutive days every 21 days 5
• Modified schedule: Cisplatin 25-30 mg/m² days 1-3 with etoposide 50-70 mg/m² days 1-3 6

However, the standard day 1 cisplatin with days 1-3 etoposide schedule remains the guideline-recommended approach 1

Carboplatin Substitution

Carboplatin may be substituted for cisplatin only in patients with contraindications to cisplatin (hypersensitivity, severe nephrotoxicity risk, neuropathy, or ototoxicity), but cisplatin is preferred in limited-stage disease and younger patients. 1

• Carboplatin carries greater risk of myelosuppression compared to cisplatin 1
• Meta-analysis showed equivalent efficacy in extensive-stage disease but carboplatin substitution in limited-stage disease is less well-validated 1

Common Pitfalls to Avoid

• Do not delay radiotherapy: Starting radiotherapy after cycle 2 or beyond 30 days from chemotherapy initiation reduces survival 2, 3
• Do not reduce doses prematurely: Maintain full doses especially in cycles 1-2 to optimize outcomes 1
• Do not use carboplatin routinely: Reserve for patients with specific cisplatin contraindications, particularly in limited-stage disease 1, 2
• Do not extend beyond 4 cycles with twice-daily radiotherapy: No survival benefit demonstrated for extending chemotherapy to 6 cycles in this setting 1

Expected Toxicity Profile

• Hematologic: Leukopenia and neutropenia are the most common toxicities, with grade 3-4 neutropenia occurring in 24-42% of patients 7, 6, 8
• Esophagitis: Grade 2-3 esophagitis occurs in 6-72% when combined with radiotherapy 6
• Non-hematologic: Universal nausea/vomiting, with severe neurotoxicity in approximately 7% 7