MacDonald study - INT0116 (SWOG 9008)

Background

Phase III RCT included 556 patients with completely resected (R0), adenocarcinoma of the stomach or gastroesophageal junction (approximately 20%); only 10% underwent D2 dissection. Adjuvant setting.

Interventions and follow up

Arm A: Surgery alone, no adjuvant treatment
Arm B: Adjuvant chemoradiation — 5-FU 425 mg/m²/d + leucovorin 20 mg/m²/d x5d, then 4500 cGy radiation (180 cGy/d) with concurrent 5-FU/LV, followed by 2 cycles 5-FU/LV
Primary endpoint: OS
mFollow up: ≥5 years

Results

mOS: 36 vs 27 mo, arm B vs A (HR for death 1.35; 95% CI 1.09-1.66; P=.005)
mRelapse-free survival: 30 vs 19 mo, arm B vs A (HR for relapse 1.52; 95% CI 1.23-1.86; P<.001)
3-yr OS: 50% vs 41%, arm B vs A

Adverse events

Hematologic: grade ≥3 toxicity 54%
Gastrointestinal: grade ≥3 toxicity 33%
Treatment-related deaths: 3 (pulmonary fibrosis, cardiac event, sepsis from myelosuppression)

Conclusions

Postoperative chemoradiation improved overall and relapse-free survival versus surgery alone in resected gastric/GEJ adenocarcinoma, establishing adjuvant chemoradiation as a standard.

Key Limitations

Suboptimal surgery (only 10% D2; 54% D0 resections) may have inflated benefit by compensating for inadequate lymphadenectomy. Substantial toxicity. Modern perioperative chemotherapy (FLOT, MAGIC) has largely supplanted this approach in many regions.

Clinical Context

Long-term update (Smalley et al, JCO, 2012, PMID: 22585691) confirmed durable survival benefit. ESMO supports perioperative or adjuvant therapy for resected gastric cancer; perioperative chemotherapy (e.g., FLOT) is preferred where adequate D2 surgery is performed.

References

MacDonald et al, NEJM, 2001, PMID: 1154774
Smalley et al, JCO, 2012, PMID: 22585691 (long-term update)