Second Cancer Incidence and Cause-Specific Mortality in Primary Gastrointestinal Non-Hodgkin Lymphoma Survivors: A Population-Based Cohort Study.
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BACKGROUND: Therapeutic advances in primary gastrointestinal non-Hodgkin lymphoma (PGI-NHL) have improved patient prognosis but also raised concerns regarding long-term health outcomes. This study assesses patterns of second primary cancers (SPCs) and cause-specific mortality in PGI-NHL survivors. METHODS: A total of 7556 six-month survivors of PGI-NHL diagnosed between 1975 and 2015 were identified from the SEER database. SPC risks were evaluated using overall and site-specific standardized incidence ratios (SIRs) and absolute excess risks (AERs) relative to the US general population. Cause-specific mortality was assessed through proportional death distribution, the Fine-Gray competing risk regression model, standardized mortality ratios (SMRs), and AERs. RESULTS: During 75,914 person-years of follow-up, 1245 patients developed 1412 SPCs (SIR = 1.20, 95% CI = 1.14-1.27). Significantly elevated SIRs were observed for solid tumors (SIR = 1.16, 95% CI = 1.10-1.23) and hematolymphoid malignancies (SIR = 1.82, 95% CI = 1.49-2.19). Survivors with over 20 years of follow-up faced increased risks of oral cavity and pharyngeal cancers (SIR = 2.76, 95% CI = 1.11-5.69), gastric cancer (SIR = 3.12, 95% CI = 1.15-6.80), pancreatic cancer (SIR = 2.40, 95% CI = 1.10-4.55), and leukemia (SIR = 2.57, 95% CI = 1.17-4.87). The risk of developing SPCs decreased with increasing age at PGI-NHL diagnosis. Patients receiving combined chemoradiotherapy exhibited the highest overall SPC risk (SIR = 1.32, 95% CI = 1.09-1.58), particularly for gastric cancer (SIR = 8.20, 95% CI = 4.59-13.53) and pancreatic cancer (SIR = 3.15, 95% CI = 1.44-5.98). A total of 4949 deaths occurred (SMR = 1.80, 95% CI = 1.75-1.85), with excess mortality persisting beyond two decades. The cumulative incidence of all-cause mortality was 28.9% at 5 years, 45.8% at 10 years, and 69.1% at 20 years post-diagnosis. Non-cancer causes posed a significant risk, with higher mortality from infections (SMR = 2.48, 95% CI = 2.22-2.76), chronic liver diseases (SMR = 1.72, 95% CI = 1.20-2.38), and benign/in situ neoplasms (SMR = 1.62, 95% CI = 1.05-2.38). CONCLUSIONS: PGI-NHL survivors face elevated long-term SPC risk, particularly after chemoradiotherapy and in younger patients. Excess risks for both SPCs and mortality persist beyond two decades, necessitating lifelong, risk-adapted survivorship care that includes cancer surveillance, infection prevention, and chronic comorbidity management.