What are the guidelines for concurrent chemoradiotherapy (CCRT) with cisplatin (Platinol) and etoposide (Toposar) for small cell lung cancer?

Guidelines for 3-Weekly Cisplatin and Etoposide Chemotherapy for CCRT in Small Cell Lung Cancer

For limited-stage small cell lung cancer, the standard chemotherapy regimen during concurrent chemoradiotherapy is cisplatin 60-80 mg/m² on day 1 and etoposide 100-120 mg/m² on days 1,2, and 3 of every 3-week cycle for 4 cycles total, with dose reductions avoided especially during the first two cycles. 1

Standard Dosing Regimen

Primary Dosing Schedule

• Cisplatin: 60-80 mg/m² intravenously on day 1 of each 3-week cycle 1
• Etoposide: 100-120 mg/m² intravenously on days 1,2, and 3 of each 3-week cycle 1
• Number of cycles: 4 cycles is standard, though 4-6 cycles may be used if once-daily radiotherapy is employed 1

Alternative Split-Dose Cisplatin Schedule

• Cisplatin: 25 mg/m² on days 1-3 (split dosing) 1
• Etoposide: 100 mg/m² on days 1-3 1
• This split-dose approach is better tolerated and reduces the need for hydration 1

FDA-Approved Dosing Range

The FDA label for etoposide specifies that in small cell lung cancer, the dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m²/day for 4 days to 50 mg/m²/day for 5 days, with chemotherapy courses repeated at 3- to 4-week intervals after adequate recovery from toxicity 2

Critical Dosing Principles

Dose Intensity Maintenance

• Avoid dose reductions, particularly during the first two cycles, as maintaining dose intensity is crucial for optimal outcomes 1
• Standard dosing should be used consistently throughout treatment 1

Growth Factor Support

• G-CSF or GM-CSF can be administered safely when indicated, based on data from the CONVERT trial 1
• Earlier concerns about growth factor use during concurrent chemoradiotherapy have been addressed by more recent evidence 1

Timing of Radiotherapy Initiation

Preferred Timing

• Thoracic radiotherapy should be initiated as early as possible, beginning with the first or second cycle of chemotherapy 1
• Starting chest radiotherapy within 30 days after the beginning of chemotherapy is preferred 1
• Improved 5-year survival rates are seen when the time between the first day of chemotherapy and the last day of radiotherapy is <30 days 1

Alternative Timing

• When the patient's general condition does not allow immediate concurrent treatment or lung constraints preclude the target radiotherapy dose, chest irradiation may be postponed until the start of the third cycle of chemotherapy 1
• One Asian trial showed no survival difference when radiotherapy was administered with the third versus first cycle, with less toxicity in the late arm, though this contradicts Western meta-analyses 1

Radiotherapy Schedules

Standard of Care: Twice-Daily Radiotherapy

• 45 Gy in 30 fractions over 3 weeks (1.5 Gy twice daily) remains the standard of care 1
• This regimen demonstrated superiority over once-daily radiotherapy in the original landmark trial 1
• The CONVERT trial showed no significant difference in overall survival between twice-daily and once-daily schedules, but was not powered to show equivalence 1

Alternative: Once-Daily Radiotherapy

• 66 Gy in 33 fractions over 6-6.5 weeks (once daily) is an acceptable alternative when twice-daily radiotherapy is not logistically feasible 1
• The CONVERT trial showed 2-year overall survival of 56% with twice-daily versus 51% with once-daily, and 5-year survival of 34% versus 31% 1
• Toxicity was similar between schedules: grade 3-4 esophagitis 19% in both groups, grade 3-4 pneumonitis 3% versus 2% 1

Alternative Regimen for Cisplatin-Intolerant Patients

Carboplatin Substitution

• Carboplatin plus etoposide may be offered as an alternative for patients with contraindications to cisplatin 1, 3
• This substitution shows similar or slightly worse outcomes in small comparative studies 1
• Evidence quality is low, but the recommendation is strong given clinical necessity 1, 3

Important Caveat

• Single-agent carboplatin as a radiosensitizer should be avoided due to insufficient evidence of benefit 3
• The radiosensitizing benefit of carboplatin appears dependent on combination with etoposide rather than as monotherapy 3
• Carboplatin-etoposide regimens result in more myelosuppression compared to cisplatin-based therapy 3

Administration Guidelines

Etoposide Preparation and Administration

• Etoposide must be diluted prior to use with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection to give a final concentration of 0.2 to 0.4 mg/mL 2
• If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur 2
• The etoposide solution should be administered over a 30- to 60-minute period to avoid hypotension following rapid intravenous administration 2
• Etoposide should not be given by rapid intravenous injection 2

Safety Precautions

• Gloves are recommended when handling etoposide 2
• If etoposide solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water 2

Common Pitfalls and Caveats

Toxicity Management

• Grade 3-4 neutropenia occurs in approximately 55% of patients during chemotherapy and 57% with chemoradiotherapy 4
• Grade 3-4 esophagitis occurs in 19% of patients with modern radiotherapy techniques, significantly lower than historical rates 1
• Radiation pneumonitis (grade 3-4) occurs in only 2-3% of patients with modern techniques 1

Duration of Treatment

• Extending chemotherapy beyond 4-6 cycles is not recommended, as it does not substantially improve survival but increases toxicity 5
• Only small series have compared four with six cycles in localized SCLC 1

Consolidation Immunotherapy

• Consolidation treatment with nivolumab-ipilimumab after chemoradiotherapy showed no improvement in progression-free survival or overall survival in the STIMULI trial 1
• Multiple trials addressing immunotherapy in this setting are ongoing 1