Muscle index, weight loss, and tumor type predict adjuvant therapy failure in periampullary cancer

Periampullary cancers frequently induce malnutrition and sarcopenia, which impair treatment tolerance and survival. Current nutritional assessment tools evaluate host status in isolation, ignoring the modifying effect of tumor biology. We developed and validated a simple nutritional risk score integrating host and tumor domains to identify high-risk patients and quantify the extent to which the association between preoperative risk and poor outcomes is mediated through a sequential pathway.

This dual-center retrospective cohort study included 533 patients who underwent pancreaticoduodenectomy. Using a time-ordered split, patients were assigned to training (n = 261), internal validation (n = 112), and temporal validation (n = 160) sets. Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression selected predictors for disease-free survival (DFS). The final model was validated internally and temporally, with head-to-head comparisons against 12 established nutritional scores. Formal sequential mediation analysis quantified the pathway from preoperative nutritional risk to postoperative complications, then to adjuvant therapy delay, and ultimately to reduced DFS.

The cohort had mean age 64.0 ± 9.8 years, 57.8% male. Median follow-up was 23 months. During follow-up, 261 recurrence or death events (49.0%) occurred; 1-year mortality was 55.7% (95%CI 51.5-59.9%). LASSO-Cox identified three independent predictors: total muscle index (TMI, mm²/m²), percent weight loss (>5% vs. ≤ 5%), and tumor type. The model showed good discrimination: C-index 0.783 (training), 0.718 (internal validation), and 0.702 (temporal validation). It significantly outperformed all 12 nutritional scores (all P < 0.001). High-risk patients had worse DFS (log-rank P < 0.0001) and a 3.29-fold higher risk of major complications (95% CI: 1.23-9.46). Complications led to a 22.27-fold higher risk of adjuvant therapy delay (95% CI: 6.70-90.28), which in turn reduced DFS (HR 2.66, 95% CI: 1.39-5.09). Mediation analysis showed that 20.9% (95% CI: 5.1-36.7%) of the total effect of high nutritional risk on DFS was mediated through this complication-to-delay pathway.

A simple three-variable score (muscle index, weight loss >5%, tumor type) enables preoperative identification of high-risk periampullary cancer patients. One-fifth of the excess recurrence risk may be mediated through a modifiable cascade of complications leading to adjuvant therapy delays, providing a clear rationale for targeted nutritional prehabilitation and perioperative interventions.