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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2015; 21(21): 6434-6443
Published online Jun 7, 2015. doi: 10.3748/wjg.v21.i21.6434
Short-term and long-term risk factors in gastric cancer
Giuseppe Verlato, Daniele Marrelli, Simone Accordini, Maria Bencivenga, Alberto Di Leo, Alberto Marchet, Roberto Petrioli, Giacomo Zoppini, Michele Muggeo, Franco Roviello, Giovanni de Manzoni
Giuseppe Verlato, Simone Accordini, Unit of Epidemiology and Medical Statistics, Department of Public Health and Community Medicine, University of Verona, 37134 Verona, Italy
Daniele Marrelli, Franco Roviello, Department of Medicine, Surgery and Neurosciences, Section of General Surgery and Surgical Oncology, Translational Research Laboratory, University of Siena, 53100 Siena, Italy
Maria Bencivenga, Giovanni de Manzoni, Upper Gastrointestinal Surgery, University of Verona, 37126 Verona, Italy
Alberto Di Leo, General Surgery, Hospital “Santa Maria del Carmine”, 38068 Rovereto, Italy
Alberto Marchet, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35121 Padua, Italy
Roberto Petrioli, Department of Medicine, Surgery and Neurosciences, Medical Oncology Unit, University of Siena, 53100 Siena, Italy
Giacomo Zoppini, Michele Muggeo, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata, University of Verona, 37126 Verona, Italy
Author contributions: Verlato G devised the study and prepared the draft of the manuscript; Verlato G did the statistical analysis; Marrelli D, Di Leo A, Roviello F and de Manzoni G founded the GIRCG with other colleagues and contributed to the GIRCG database; Bencivenga M, Marchet A and Petrioli R contributed to the GIRCG database; Muggeo M organized and coordinated the Verona Diabetes Study, with the help of Zoppini G; all the authors contributed to the interpretation of results and to the revision of the manuscript; all the authors read and approved the final manuscript.
Conflict-of-interest: Giuseppe Verlato has received financial support from BioMed Central to participate to the 2014 Congress of the ERS (European Respiratory Society). The other Authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Giuseppe Verlato, MD, PhD, Unit of Epidemiology and Medical Statistics, Department of Public Health and Community Medicine, University of Verona, Sezione di Epidemiologia e Statistica Medica, Istituti Biologici 2 B, Strada Le Grazie 8, 37134 Verona, Italy. giuseppe.verlato@univr.it
Telephone: +39-45-8027628 Fax: +39-45-8027154
Received: December 15, 2014
Peer-review started: December 16, 2014
First decision: January 22, 2015
Revised: February 28, 2015
Accepted: March 31, 2015
Article in press: March 31, 2015
Published online: June 7, 2015
Processing time: 178 Days and 1.3 Hours
Abstract

While in chronic diseases, such as diabetes, mortality rates slowly increases with age, in oncological series mortality usually changes dramatically during the follow-up, often in an unpredictable pattern. For instance, in gastric cancer mortality peaks in the first two years of follow-up and declines thereafter. Also several risk factors, such as TNM stage, largely affect mortality in the first years after surgery, while afterward their effect tends to fade. Temporal trends in mortality were compared between a gastric cancer series and a cohort of type 2 diabetic patients. For this purpose, 937 patients, undergoing curative gastrectomy with D1/D2/D3 lymphadenectomy for gastric cancer in three GIRCG (Gruppo Italiano Ricerca Cancro Gastrico = Italian Research Group for Gastric Cancer) centers, were compared with 7148 type 2 diabetic patients from the Verona Diabetes Study. In the early/advanced gastric cancer series, mortality from recurrence peaked to 200 deaths per 1000 person-years 1 year after gastrectomy and then declined, becoming lower than 40 deaths per 1000 person-years after 5 years and lower than 20 deaths after 8 years. Mortality peak occurred earlier in more advanced T and N tiers. At variance, in the Verona diabetic cohort overall mortality slowly increased during a 10-year follow-up, with ageing of the type 2 diabetic patients. Seasonal oscillations were also recorded, mortality being higher during winter than during summer. Also the most important prognostic factors presented a different temporal pattern in the two diseases: while the prognostic significance of T and N stage markedly decrease over time, differences in survival among patients treated with diet, oral hypoglycemic drugs or insulin were consistent throughout the follow-up. Time variations in prognostic significance of main risk factors, their impact on survival analysis and possible solutions were evaluated in another GIRCG series of 568 patients with advanced gastric cancer, undergoing curative gastrectomy with D2/D3 lymphadenectomy. Survival curves in the two different histotypes (intestinal and mixed/diffuse) were superimposed in the first three years of follow-up and diverged thereafter. Likewise, survival curves as a function of site (fundus vs body/antrum) started to diverge after the first year. On the contrary, survival curves differed among age classes from the very beginning, due to different post-operative mortality, which increased from 0.5% in patients aged 65-74 years to 9.9% in patients aged 75-91 years; this discrepancy later disappeared. Accordingly, the proportional hazards assumption of the Cox model was violated, as regards age, site and histology. To cope with this problem, multivariable survival analysis was performed by separately considering either the first two years of follow-up or subsequent years. Histology and site were significant predictors only after two years, while T and N, although significant both in the short-term and in the long-term, became less important in the second part of follow-up. Increasing age was associated with higher mortality in the first two years, but not thereafter. Splitting survival time when performing survival analysis allows to distinguish between short-term and long-term risk factors. Alternative statistical solutions could be to exclude post-operative mortality, to introduce in the model time-dependent covariates or to stratify on variables violating proportionality assumption.

Keywords: Gastric cancer; Type 2 diabetes; Mortality; Short-term risk factors; Long-term risk factors; Survival analysis; Cox model; Proportional hazards assumption

Core tip: In gastric cancer patients mortality from recurrence peaked in the first two years after curative gastrectomy and then declined. The prognostic significance of risk factors was not stable, as the effect of T and N decreased with time, while the effect of histology became apparent after two years. Advancing age was associated with increased post-operative mortality. Hence, the proportional hazards assumption of the Cox model was violated. A possible solution was to split survival analysis in the first two years of follow-up and subsequent years. By comparison, overall mortality and prognostic significance of risk factors was rather stable in a cohort of type 2 diabetic patients.