INT-0096

Background

Phase 3 RCT (INT-0096). 417 patients with limited-stage SCLC (disease confined to one hemithorax, ipsilateral nodes, and supraclavicular fossa). Enrolled 1985–1992 at North American cooperative group institutions. All patients received cisplatin 60 mg/m² day 1 + etoposide 120 mg/m² days 1–3 × 4 cycles (21-day cycles). RT started with cycle 1.

Interventions and follow up

Arm A: Concurrent thoracic RT 45 Gy in 30 fractions of 1.5 Gy twice daily (BID) over 3 weeks + cisplatin/etoposide × 4 cycle
Arm B: Concurrent thoracic RT 45 Gy in 25 fractions of 1.8 Gy once daily (QD) over 5 weeks + cisplatin/etoposide × 4 cycle
Primary endpoint: OS
mFollow up: Median approximately 8 year

Results

Median OS: 23 months (BID) vs 19 months (QD), P=.04
2-yr OS: 47% (BID) vs 41% (QD)
5-yr OS: 26% (BID) vs 16% (QD)
Grade ≥3 esophagitis: 27% (BID) vs 11% (QD), P<.001

Adverse events

Main adverse events: Grade ≥3 esophagitis significantly higher with BID (27% vs 11%, p<0.001). Hematologic toxicity comparable between arms. No significant difference in other grade ≥3 toxicities. BID RT required patients to attend twice daily for 3 weeks, creating logistical burden.

Conclusions

Twice-daily accelerated (hyperfractionated) RT (45 Gy/30 fx BID) significantly improved median OS (23 vs 19 months) and 5-year OS (26% vs 16%) compared to once-daily RT in limited SCLC. Established BID CRT as the standard approach for limited SCLC in North America, accepting higher esophagitis rates for improved survival.

Key Limitations

Key Limitations: BID schedule requires twice-daily attendance over 3 weeks, creating substantial logistical burden that limits widespread adoption. Both arms received the same total dose (45 Gy) — the trial tests fractionation schedule, not total dose. CONVERT (Faivre-Finn, Lancet Oncol 2017) subsequently randomized BID 45 Gy vs QD 66 Gy and found no significant OS difference, suggesting higher QD doses may achieve comparable outcomes. Grade ≥3 esophagitis rate of 27% with BID is clinically significant. Long-term enrolling period (1985–1992) predates modern RT planning techniques.

Clinical Context

INT-0096 is the foundational trial establishing BID RT as standard for limited SCLC. Concurrent cisplatin/etoposide + 45 Gy BID starting with cycle 1 remains widely used. However, CONVERT showed 66 Gy QD (with modern planning) has comparable OS and similar esophagitis rates (~19% each), making QD acceptable when BID scheduling is impractical. PCI after completing CRT with CR/PR adds additional survival benefit (Auperin NEJM 1999).

References

References: Turrisi AT et al, N Engl J Med 1999 (INT-0096)