{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:51:34Z","timestamp":1791193894586,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Advances in gastrointestinal (GI) cancer care have produced a growing population of long-term survivors at risk of second primary malignancies (SPMs). SPM definitions vary across studies, and SPMs remain underrepresented in cancer forecasting and prediction tools for GI cancer survivors. We conducted a narrative review across major GI cancer subtypes, summarizing site-specific SPM risk, key etiological pathways, and available prediction tools. Approximately one in ten colorectal cancer (CRC) survivors develops an SPM at ten years (pooled SIR ~1.15), a figure specific to CRC that does not generalize to other GI sites. Gastric cancer survivors carry excess risk of thyroid (O\/E 2.00), esophageal, small intestinal, and pancreatic (O\/E 1.60) malignancy, amplified by radiotherapy. Esophageal squamous cell carcinoma survivors show markedly elevated risk of upper aerodigestive tract tumors, consistent with field cancerization. Lynch syndrome (~16% second CRC risk at 10 years) and familial adenomatous polyposis (near-100% lifetime CRC risk without colectomy) confer some of the highest lifetime risks of metachronous GI malignancy reported to date. Most forecasting frameworks treat cancer incidence as a single event and do not adequately capture survivor-specific transitions, competing mortality, or germline susceptibility. GI cancer survivors form a distinct group whose risk is often overlooked. Harmonizing SPM definitions, extending multistate and competing-risk modeling, and integrating hereditary-risk stratification are near-term priorities for individualized surveillance.<\/jats:p>","DOI":"10.3390\/cancers18193195","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:57:18Z","timestamp":1791190638000},"page":"3195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Second Primary Malignancies in Gastrointestinal Cancer Survivors: Epidemiology, Risk Factors, and Future Prediction Models"],"prefix":"10.3390","volume":"18","author":[{"given":"Jyoti","family":"Yadav","sequence":"first","affiliation":[{"name":"The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Balizzakiwa","sequence":"additional","affiliation":[{"name":"The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemant","family":"Goyal","sequence":"additional","affiliation":[{"name":"Borland Groover, Baptist Medical Center-Downtown, Jacksonville, FL 32207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"ref_1","first-page":"308","article-title":"Cancer treatment and survivorship statistics, 2025","volume":"75","author":"Wagle","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1177\/2050640620977129","article-title":"Increased risk of second primary tumours in patients with oesophageal squamous cell carcinoma: A nationwide study in a Western population","volume":"9","author":"Falger","year":"2021","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s00405-005-0922-5","article-title":"Metachronous second primary tumours in the aerodigestive tract in patients with early stage head and neck squamous cell carcinomas","volume":"262","author":"Venegas","year":"2005","journal-title":"Eur. Arch. Oto-Rhino-Laryngol. Head Neck"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1055\/s-0031-1283939","article-title":"Das zweite Prim\u00e4rmalignom beim Krebspatienten\u2014Epidemiologie, Prognose und klinische Relevanz","volume":"137","author":"Grundmann","year":"2012","journal-title":"Zentralblatt Fur Chir."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1001\/jama.2020.23130","article-title":"Association of First Primary Cancer with Risk of Subsequent Primary Cancer Among Survivors of Adult-Onset Cancers in the United States","volume":"324","author":"Sung","year":"2020","journal-title":"J. Am. Med. Assoc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1002\/cncr.30164","article-title":"Risk of second primary malignancies among cancer survivors in the United States, 1992 through 2008","volume":"122","author":"Donin","year":"2016","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"(2005). Working Group Report International rules for multiple primary cancers (ICD-0 third edition). Eur. J. Cancer Prev., 14, 307\u2013308.","DOI":"10.1097\/00008469-200508000-00002"},{"key":"ref_8","unstructured":"Curtis, R.E., Freedman, D.M., Ron, E., Ries, L.A.G., Hacker, D.G., Edwards, B.K., Tucker, M.A., and Fraumeni, J.F. (2006). New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973\u20132000, National Cancer Institute. NIH Publ. No. 05-5302."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e651","DOI":"10.1634\/theoncologist.2019-0266","article-title":"Second Primary Malignancies in Patients with Colorectal Cancer: A Population-Based Analysis","volume":"25","author":"Jia","year":"2020","journal-title":"Oncologist"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1097\/CEJ.0000000000000731","article-title":"The incidence of second primary cancer in male and female patients with initial colorectal cancer: A SEER population-based study","volume":"31","author":"Chen","year":"2022","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6756","DOI":"10.18632\/aging.204250","article-title":"The risk of developing second primary malignancies among colorectal cancer patients","volume":"14","author":"Du","year":"2022","journal-title":"Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1002\/cam4.1437","article-title":"Excessive risk of second primary cancers in young-onset colorectal cancer survivors","volume":"7","author":"He","year":"2018","journal-title":"Cancer Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"728","DOI":"10.5009\/gnl16526","article-title":"Assessment of the Risk of Colorectal Cancer Survivors Developing a Second Primary Pancreatic Cancer","volume":"11","author":"Chung","year":"2017","journal-title":"Gut Liver"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1245\/s10434-019-07326-7","article-title":"Sidedness of Colorectal Cancer Impacts Risk of Second Primary Gastrointestinal Malignancy","volume":"26","author":"Broman","year":"2019","journal-title":"Ann. Surg. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/jgh.16792","article-title":"Prognosis and clinicopathological features of patients with early-onset and late-onset colorectal cancer with second primary malignancies","volume":"40","author":"Chen","year":"2024","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"zrae092","DOI":"10.1093\/bjsopen\/zrae092","article-title":"Risk of metachronous neoplasia in early-onset colorectal cancer: Meta-analysis","volume":"8","author":"Pellino","year":"2024","journal-title":"BJS Open"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Shah, B.K., Khanal, A., and Hewett, Y. (2016). Second Primary Malignancies in Adults with Gastric Cancer\u2014A US Population-Based Study. Front. Oncol., 6.","DOI":"10.3389\/fonc.2016.00082"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/s10238-025-01706-y","article-title":"The persistent risk of secondary malignancies in gastric neuroendocrine tumor survivors: A population-based analysis","volume":"25","author":"Ding","year":"2025","journal-title":"Clin. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hussein, M., Mueller, L., Issa, P.P., Haidari, M., Trinh, L., Toraih, E., and Kandil, E. (2022). Latency Trend Analysis as a Guide to Screening Malignancy Survivors for Second Primary Thyroid Cancer. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081984"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100167","DOI":"10.1016\/j.esmogo.2025.100167","article-title":"Screening for second primary tumors in the aerodigestive tract in non-Asian populations with head and neck cancer\u2014Systematic review and meta-analysis","volume":"8","author":"Maan","year":"2025","journal-title":"ESMO Gastrointest. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q","article-title":"Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin","volume":"6","author":"Slaughter","year":"1953","journal-title":"Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"srep41785","DOI":"10.1038\/srep41785","article-title":"Treatment Outcomes of Patients with Locally Advanced Synchronous Esophageal and Head\/Neck Squamous Cell Carcinoma Receiving Curative Concurrent Chemoradiotherapy","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1055\/a-2111-5935","article-title":"Endoscopic screening of the upper gastrointestinal tract for second primary tumors in patients with head and neck cancer in a Western country","volume":"55","author":"Spaander","year":"2023","journal-title":"Endoscopy"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chen, Y.-H., Wang, Y.-K., Chuang, Y.-S., Hsu, W.-H., Kuo, C.-H., Wu, C.-W., Chan, L.-P., Wu, M.-T., and Wu, I.-C. (2020). Endoscopic Surveillance for Metachronous Esophageal Squamous Cell Neoplasms among Head and Neck Cancer Patients. Cancers, 12.","DOI":"10.3390\/cancers12123832"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1916-0216-42-36","article-title":"HPV Status and second primary tumours in Oropharyngeal Squamous Cell Carcinoma","volume":"42","author":"Xu","year":"2013","journal-title":"J. Otolaryngol. Head Neck Surg."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kong, J., Yu, G., Si, W., Li, G., Chai, J., Liu, Y., and Liu, J. (2021). Second Primary Malignancies in Patients with Hepatocellular Carcinoma: A Population-Based Analysis. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.713637"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"497","DOI":"10.3390\/genes5030497","article-title":"Lynch Syndrome: An Updated Review","volume":"5","author":"Sehgal","year":"2014","journal-title":"Genes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"v78","DOI":"10.1093\/annonc\/mdq169","article-title":"Familial colorectal cancer risk: ESMO Clinical Practice Guidelines","volume":"21","author":"Castells","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103755","DOI":"10.1016\/j.eclinm.2026.103755","article-title":"Pancreatic cancer risk and survival in patients with Lynch syndrome: A nationwide Dutch cohort study","volume":"91","author":"Bogdanski","year":"2026","journal-title":"eClinicalMedicine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1007\/s44197-023-00171-8","article-title":"Surveillance Compliance and Quality of Life Assessment Among Surgical Patients with Familial Adenomatous Polyposis Syndrome","volume":"14","author":"Alhassan","year":"2024","journal-title":"J. Epidemiol. Glob. Health"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1750-1172-4-22","article-title":"Familial adenomatous polyposis","volume":"4","author":"Half","year":"2009","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/S1470-2045(11)70061-4","article-title":"Proportion of second cancers attributable to radiotherapy treatment in adults: A cohort study in the US SEER cancer registries","volume":"12","author":"Curtis","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yang, R., Guan, X., Liu, E., Wei, R., Zhao, Z., Chen, H., Liu, Z., Yang, M., Jiang, Z., and Wang, X. (2020). Risk and Prognosis of Secondary Rectal Cancer After Radiation Therapy for Pelvic Cancer. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.584072"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ye, X., Tan, Y., Ma, R., Lou, P., and Yuan, Y. (2023). Radiation Therapy Changed the Second Malignancy Pattern in Rectal Cancer Survivors. Medicina, 59.","DOI":"10.3390\/medicina59081463"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1088\/0031-9155\/60\/3\/1237","article-title":"Radiation-induced second primary cancer risks from modern external beam radiotherapy for early prostate cancer: Impact of stereotactic ablative radiotherapy (SABR), volumetric modulated arc therapy (VMAT) and flattening filter free (FFF) radiotherapy","volume":"60","author":"Murray","year":"2015","journal-title":"Phys. Med. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.3390\/genes2041033","article-title":"Modeling the Risk of Secondary Malignancies after Radiotherapy","volume":"2","author":"Schneider","year":"2011","journal-title":"Genes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0360-3016(03)00073-7","article-title":"Radiation-induced second cancers: The impact of 3D-CRT and IMRT","volume":"56","author":"Hall","year":"2003","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3560","DOI":"10.1002\/cncr.32938","article-title":"Second cancer risk after primary cancer treatment with three-dimensional conformal, intensity-modulated, or proton beam radiation therapy","volume":"126","author":"Xiang","year":"2020","journal-title":"Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1136\/gut.2010.228056","article-title":"Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: The advantage of more extensive colon surgery","volume":"60","author":"Parry","year":"2010","journal-title":"Gut"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A Proportional Hazards Model for the Subdistribution of a Competing Risk","volume":"94","author":"Fine","year":"1999","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19628","DOI":"10.18632\/aging.103939","article-title":"Risk factors and prediction of second primary cancer in primary female non-metastatic breast cancer survivors","volume":"12","author":"Qian","year":"2020","journal-title":"Aging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e47400","DOI":"10.1097\/MD.0000000000047400","article-title":"Construction and validation of a competing risk model for specific survival of patients with second primary malignancies after prostate cancer","volume":"105","author":"Bao","year":"2026","journal-title":"Medicine"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Xu, J., Huang, C., Wu, Z., Xu, H., Li, J., Chen, Y., Wang, C., Zhu, J., Qin, G., and Zheng, X. (2022). Risk Prediction of Second Primary Malignancies in Primary Early-Stage Ovarian Cancer Survivors: A SEER-Based National Population-Based Cohort Study. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.875489"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12703","DOI":"10.1007\/s00432-023-05046-w","article-title":"Risk prediction of second primary malignancies after gynecological malignant neoplasms resection with and without radiation therapy: A population-based surveillance, epidemiology, and end results (SEER) analysis","volume":"149","author":"Wang","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1214\/25-AOAS2083","article-title":"Personalized risk prediction for cancer survivors: A generalized Bayesian semiparametric model of recurrent events with competing outcomes","volume":"19","author":"Nguyen","year":"2025","journal-title":"Ann. Appl. Stat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"439","DOI":"10.21037\/atm.2019.09.01","article-title":"Risk of second primary malignancy after non-small cell lung cancer: A competing risk nomogram based on the SEER database","volume":"7","author":"Zhou","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1001\/jama.2017.12126","article-title":"Discrimination and Calibration of Clinical Prediction Models","volume":"318","author":"Alba","year":"2017","journal-title":"J. Am. Med. Assoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1016\/S0140-6736(20)30366-4","article-title":"Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: A double-blind, randomised, placebo-controlled trial","volume":"395","author":"Burn","year":"2020","journal-title":"Lancet"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:57:58Z","timestamp":1791190678000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,3]]},"references-count":48,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193195"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193195","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,3]]}}}