Synchronous Versus Metachronous Multiple Malignant Tumors Involving the Digestive Tract: Predictors of Survival from a Single-Center Retrospective Study

<i>Background</i>: Multiple primary malignant tumors (MPMTs) involving the digestive tract pose diagnostic and therapeutic challenges, with survival differences between synchronous and metachronous forms not well defined. This study assessed predictors of overall survival (OS) in patients in whom at least one tumor originated in the digestive tract or accessory organs. <i>Methods</i>: We retrospectively reviewed 1920 oncology cases (January 2020-June 2023) from St. Nicholas Hospital, Romania. Of 118 patients with MPMTs, 45 had ≥1 digestive tract tumor. They were classified as synchronous (<2 months) or metachronous (>2 months) as per the SEER rules. Clinical, pathological, treatment, and follow-up data were analyzed; OS was evaluated using Kaplan-Meier and Cox regression. <i>Results</i>: Fifteen patients (33%) had synchronous tumors and 30 (67%) had metachronous tumors. Overall, 17 of 45 patients (37.8%) died by the last follow-up. The restricted mean survival time (RMST) was 31.3 months for those with synchronous vs. 68.3 months for those with metachronous tumors (HR = 2.49, 95% CI 0.95-6.50, <i>p</i> = 0.062; log-rank <i>p</i> = 0.053). Curative treatment of the first tumor was associated with markedly improved survival (RMST 58.2 vs. 29.4 months; HR = 20.5, 95% CI 3.68-114, <i>p</i> < 0.001). In the multivariable Cox regression analysis, advanced primary nodal stage (N2-N3) remained independently associated with reduced survival (adjusted HR 3.86, 95% CI 1.04-14.3, <i>p</i> = 0.044). The adjusted effect of synchronous vs. metachronous classification was attenuated (adjusted HR 2.22, 95% CI 0.84-5.86, <i>p</i> = 0.10). <i>Conclusions</i>: In this single-center, hypothesis-generating cohort, synchronous digestive-tract MPMTs were associated with shorter unadjusted survival than metachronous tumors, but advanced nodal stage and limited feasibility of curative therapy were the dominant independent predictors of poor outcome. Given the small sample size and retrospective design, these findings should be interpreted as preliminary and warrant validation in larger, multicenter cohorts.