Second Cancer Incidence and Cause-Specific Mortality in Primary Gastrointestinal Non-Hodgkin Lymphoma Survivors: A Population-Based Cohort Study

Abstract

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.