Background
Phase 3, multicenter, randomized 2-step trial. N=354 patients with resected (curative-intent pancreaticoduodenectomy) adenocarcinoma of the pancreatic head who were progression-free after 5 cycles of adjuvant systemic chemotherapy. Tests whether adding fluoropyrimidine-sensitized chemoradiotherapy (CXRT) to adjuvant chemotherapy improves overall survival. (Step 1 tested gemcitabine ± erlotinib, previously reported; the step-2 radiotherapy randomization is reported here.)
Results
Interventions and follow up: Arm A: a 6th cycle of chemotherapy (gemcitabine or an oxaliplatin-based combination) followed by chemoradiotherapy — 50.4 Gy in 28 fractions with concurrent capecitabine or 5-FU (n=180).
Arm B: a 6th cycle of chemotherapy alone (n=174).
Primary endpoint: overall survival (OS).
mFollow up: 2.2 years (all); 7.4 years (living patients).
Results: OS (all): median 2.3 yr (CXRT) vs 2.6 yr (chemo); 5-yr 27.9% vs 23.1%; HR 0.96 (90% CI 0.79–1.18); P=.77 — primary endpoint not met.
DFS (all): HR 0.82 (95% CI 0.65–1.03); P=.089.
OS, node-negative: 5-yr 48.1% vs 28.6%; P=.0063.
DFS, node-negative: 5-yr 21.4% vs 15.2%; P=.014.
Arm B: a 6th cycle of chemotherapy alone (n=174).
Primary endpoint: overall survival (OS).
mFollow up: 2.2 years (all); 7.4 years (living patients).
Results: OS (all): median 2.3 yr (CXRT) vs 2.6 yr (chemo); 5-yr 27.9% vs 23.1%; HR 0.96 (90% CI 0.79–1.18); P=.77 — primary endpoint not met.
DFS (all): HR 0.82 (95% CI 0.65–1.03); P=.089.
OS, node-negative: 5-yr 48.1% vs 28.6%; P=.0063.
DFS, node-negative: 5-yr 21.4% vs 15.2%; P=.014.
Adverse events
Grade 3: 38% (CXRT) vs 19% (chemo); P<.001.
Grade 4/5: 6% vs 5% — no significant increase.
Grade 4/5: 6% vs 5% — no significant increase.
Conclusions
Adding adjuvant chemoradiotherapy to adjuvant chemotherapy did not improve overall survival or DFS, and did not raise grade 4/5 toxicity, in resected pancreatic head adenocarcinoma. A prespecified nodal-status interaction showed node-negative patients derived an OS and DFS benefit from CXRT, supporting risk-stratified consideration of adjuvant CXRT in that subgroup if confirmed with modern systemic therapy.
Key Limitations
Primary OS endpoint negative; the node-negative benefit is an interaction-based subgroup finding (hypothesis-generating). The gemcitabine-based systemic backbone is now outdated — mFOLFIRINOX is the preferred adjuvant standard (PRODIGE-24/PA.6) — so applicability to current practice is uncertain. Long accrual with protocol amendments (erlotinib arm dropped after LAP07; oxaliplatin combinations later permitted); only patients progression-free after 5 cycles were randomized (selection bias). Grade 3 toxicity doubled with CXRT.
Clinical Context
The role of adjuvant chemoradiotherapy in resected pancreatic cancer has been long debated (RTOG 9704, ESPAC-1, EORTC, LAP07). NCCN lists adjuvant chemoradiotherapy as an option chiefly for higher-risk features (e.g., positive margins), while ASCO and ESMO favor adjuvant chemotherapy (mFOLFIRINOX) alone. RTOG 0848 does not displace mFOLFIRINOX as the systemic standard but provides randomized evidence that sequential CXRT may benefit node-negative disease.