CALGB 9781

Background

Phase II/III RCT (CALGB 9781). 56 patients with resectable esophageal or gastroesophageal junction cancer enrolled (planned N=500; closed early due to poor accrual) comparing trimodality therapy (neoadjuvant chemoradiotherapy followed by surgery) vs definitive chemoradiotherapy alone. Included both squamous cell carcinoma and adenocarcinoma histologies.

Interventions and follow up

Arm A: Concurrent CRT (cisplatin 100 mg/m² day 1 + 5-FU 1000 mg/m²/day × 4 days, with 50.4 Gy in 28 fx) followed by esophagectomy
Arm B: Same CRT regimen (no surgery) — definitive chemoradiotherapy
Primary endpoint: Overall survival
mFollow up: Median 6 year

Results

5-year OS: 39% (trimodality) vs 16% (definitive CRT), P=.02
Median OS: 4.48 years (trimodality) vs 1.79 years (definitive CRT)
R0 resection rate: 73% (trimodality arm)

Adverse events

Main adverse events: Trimodality arm: significant surgical morbidity and mortality. Definitive CRT arm: esophageal stricture requiring dilation in some patients. Grade 3–4 toxicities expected with concurrent cisplatin/5-FU and radiation.

Conclusions

Trimodality therapy (neoadjuvant CRT followed by esophagectomy) showed significantly improved 5-year OS (39% vs 16%) compared to definitive CRT alone. However, the trial was underpowered (56 of 500 planned patients enrolled), limiting definitive conclusions. Results are directionally consistent with the hypothesis that surgery adds benefit after neoadjuvant CRT in resectable disease.

Key Limitations

Key Limitations: Critically underpowered — enrolled only 56 of the 500 planned patients. Poor accrual creates significant selection bias risk. The survival advantage for trimodality therapy (39% vs 16% at 5 years) may reflect both surgical benefit and favorable patient selection in those deemed fit for surgery. Published more than 10 years after the trial started. The concurrent CRT regimen (cisplatin/5-FU + 50.4 Gy) is different from the CROSS regimen that subsequently became standard for adenocarcinoma.

Clinical Context

CALGB 9781 provided early RCT evidence for trimodality therapy in esophageal cancer, predating the CROSS trial. The CROSS trial (carboplatin/paclitaxel + 41.4 Gy → surgery) subsequently became the definitive evidence base for neoadjuvant CRT in resectable esophageal cancer. CALGB 9781 remains relevant as historical context but is largely superseded by CROSS for decision-making.

References

References: Tepper J et al, J Clin Oncol 2008 (CALGB 9781)