What is the role of the CAV (cyclophosphamide, doxorubicin, and vincristine) regimen in the treatment of a patient with Small Cell Lung Cancer (SCLC)?

CAV Regimen in Small Cell Lung Cancer

The CAV (cyclophosphamide, doxorubicin, and vincristine) regimen is no longer recommended as standard therapy for SCLC in any treatment setting—it has been replaced by platinum-etoposide combinations for first-line therapy and by single-agent topotecan for second-line therapy. 1

Historical Context and Current Role

First-Line Treatment

• CAV was historically used as first-line therapy for SCLC alongside platinum-etoposide regimens, with response rates of 60-90% in limited-stage disease 1
• Current guidelines universally recommend platinum-etoposide (EP) as the standard first-line regimen rather than CAV 1
• Multiple studies demonstrated that CAV produces similar response rates to EP but is no longer preferred due to the established superiority of platinum-based regimens in modern practice 1

Second-Line Treatment: Where CAV Was Definitively Replaced

The pivotal von Pawel trial directly compared CAV to single-agent topotecan in 211 patients with relapsed SCLC (>60 days after initial therapy) and found:

• No difference in response rates (18% vs 24%, P=0.29) 1
• No difference in time to progression (12 weeks vs 13 weeks, P=0.55) 1
• No difference in overall survival (25 weeks for both arms, P=0.79) 1
• Significantly greater hematologic toxicity with CAV compared to topotecan 1

Based on this evidence, the American College of Chest Physicians explicitly recommends single-agent chemotherapy (Grade 1B recommendation) over combination regimens like CAV for second-line SCLC treatment 1

Current Evidence-Based Recommendations

For Relapsed/Recurrent SCLC

• Single-agent topotecan (oral or IV) is the FDA-approved standard second-line therapy 1, 2, 3
• Topotecan demonstrated survival benefit over best supportive care (26 weeks vs 14 weeks, P=0.01) 1, 4
• CAV may be considered as an alternative option only when topotecan is contraindicated or unavailable 1

For Platinum-Sensitive Disease (Relapse >6 Months)

• Rechallenge with first-line platinum-etoposide regimen is preferred over CAV 1, 3, 4
• A phase III trial showed comparable outcomes between topotecan and carboplatin-etoposide rechallenge in sensitive relapse 1

For Platinum-Resistant Disease (Relapse <3 Months)

• Single-agent topotecan or lurbinectedin are preferred 4
• Response rates with any regimen including CAV are poor (≤10%) in this population 3

Key Toxicity Considerations

CAV causes significantly more hematologic toxicity than modern alternatives:

• Grade 4 thrombocytopenia and grade 3/4 anemia occur more frequently with CAV than topotecan 1
• Granulocyte nadirs <500/μL occurred in 79-81% of patients receiving high-dose CAV 5, 6
• Life-threatening infections were more common with CAV (15% vs 4% with conventional dosing) 6

Common Pitfalls to Avoid

• Do not use combination chemotherapy (including CAV) in the second-line setting—it increases toxicity without improving survival compared to single-agent therapy 1, 3
• Do not attempt dose intensification of CAV—multiple randomized trials showed no survival benefit with high-dose CAV despite increased complete response rates, but substantially increased toxicity 5, 6
• Do not use CAV after platinum-etoposide failure in refractory disease—it has limited activity (28% response rate) with poor median survival of only 15 weeks 7

Bottom Line Algorithm

For any patient with SCLC requiring systemic therapy:

1. First-line: Use platinum-etoposide, not CAV 1
2. Second-line (sensitive relapse >6 months): Rechallenge with platinum-etoposide OR single-agent topotecan 1, 3, 4
3. Second-line (resistant relapse <6 months): Single-agent topotecan or lurbinectedin 4
4. CAV should only be considered if topotecan and other preferred agents are contraindicated or unavailable 1