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

## TL;DR

Survivors of gastrointestinal non-Hodgkin lymphoma face higher risks of second cancers and long-term mortality, especially after chemoradiotherapy and in younger patients.

## Contribution

This study identifies elevated long-term risks of second cancers and mortality in gastrointestinal non-Hodgkin lymphoma survivors, emphasizing the need for ongoing care.

## Key findings

- PGI-NHL survivors had a 20% higher risk of second cancers compared to the general population.
- Chemoradiotherapy was linked to significantly higher risks of gastric and pancreatic cancers as second cancers.
- Excess mortality from non-cancer causes like infections and chronic liver disease was observed in survivors.

## Abstract

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.

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.

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).

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.