Retrospective Cohort Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2019; 25(33): 4945-4958
Published online Sep 7, 2019. doi: 10.3748/wjg.v25.i33.4945
Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer
Du Cai, Zeng-Hong Huang, Hui-Chuan Yu, Xiao-Lin Wang, Liang-Liang Bai, Guan-Nan Tang, Shao-Yong Peng, Ying-Jie Li, Mei-Jin Huang, Guang-Wen Cao, Jian-Ping Wang, Yan-Xin Luo
Du Cai, Zeng-Hong Huang, Hui-Chuan Yu, Xiao-Lin Wang, Liang-Liang Bai, Guan-Nan Tang, Shao-Yong Peng, Ying-Jie Li, Jian-Ping Wang, Yan-Xin Luo, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease (Supported by National Key Clinical Discipline), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
Du Cai, Zeng-Hong Huang, Shao-Yong Peng, Mei-Jin Huang, Jian-Ping Wang, Yan-Xin Luo, Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
Zeng-Hong Huang, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States
Guang-Wen Cao, Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
Author contributions: Cai D and Huang ZH contributed equally to this paper. Luo YX, Wang JP, Cao GW, and Huang MJ designed the research; Cai D and Huang ZH analyzed the data and drafted the article; Yu HC and Luo YX revised the article; Bai LL, Tang GN, Peng SY, and Li YJ collected and collated the data.
Supported by the National Basic Research Program of China (973 Program) (No. 2015CB554001, JW), the National Natural Science Foundation of China (No. 81972245, YL; No. 81902877, HY), the Natural Science Fund for Distinguished Young Scholars of Guangdong Province (No. 2016A030306002, YL), the Tip-top Scientific and Technical Innovative Youth Talents of Guangdong special support program (No. 2015TQ01R454, YL), the Project 5010 of Clinical Medical Research of Sun Yat-sen University-5010 Cultivation Foundation (No. 2018026, YL), the Natural Science Foundation of Guangdong Province (No. 2016A030310222, HY; No. 2018A0303130303, HY), the Program of Introducing Talents of Discipline to Universities, and National Key Clinical Discipline (2012).
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Sixth Affiliated Hospital, Sun Yat-sen University.
Informed consent statement: Patients were not required to provide informed consent for the study because the analysis used anonymous clinical data.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
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:
Corresponding author: Yan-Xin Luo, MA, MD, PhD, Associate Professor, Chief Doctor, Doctor, Surgical Oncologist, Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou 510655, Guangdong Province, China.
Telephone: +86-13826190263 Fax: +86-20-38254221
Received: March 12, 2019
Peer-review started: March 12, 2019
First decision: March 27, 2019
Revised: April 4, 2019
Accepted: May 18, 2019
Article in press: May 18, 2019
Published online: September 7, 2019
Research background

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy and one of the leading causes of cancer-related mortality worldwide. Therapy options for CRC have been developed rapidly in the past decade, but selecting optimal treatments for individuals remains a great challenge for clinicians due to the lack of effective markers.

Research motivation

Controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone, which is a widely used biomarker in rectal cancer. Recent studies have found that local CEA may play a more important role in the prognosis of CRC than overall serum CEA. Some studies have tried to add another factor like tumor size to improve the prognostic value of biomarker, such as prostate specific antigen density and tumor-infiltrating CD8+ T-cell density. Here, we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level, which may better reflect the malignancy of rectal cancer and improve the risk stratification system.

Research objectives

We aimed to investigate the prognostic impact of the preoperative CEA/tumor size in patients with rectal cancer, which may influence the decision-making process for a specific treatment regimen and patient counselling.

Research methods

We retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012. These patients were randomly divided into two cohorts for cross-validation: Training cohort and validation cohort. The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model. Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size. The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively.

Research results

In all, 556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into a training cohort (2/3 of 556, n = 371) and a validation cohort (1/3 of 556, n = 185). The cutoff was 2.429 ng/mL per cm. Comparison of the baseline data showed that high CEA/tumor size was correlated with older age, high TNM stage, presence of perineural invasion, high CEA, and high carbohydrate antigen 19-9 (CA 19-9). Kaplan-Meier curves showed a manifest reduction in 5-year OS (training cohort: 56.7% vs 81.1%, P < 0.001; validation cohort: 58.8% vs 85.6%, P <0.001) and DFS (training cohort: 52.5% vs 71.9%, P = 0.02; validation cohort: 50.3% vs 79.3%, P = 0.002) in the high CEA/tumor size group compared with the low CEA/tumor size group. Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS (training cohort: hazard ratio (HR) = 2.18 95% confidence interval (CI): 1.28-3.73, P = 0.004; validation cohort: HR = 4.83, 95%CI: 2.21-10.52, P < 0.001) as well as DFS (training cohort: HR = 1.47, 95% CI: 0.93-2.33, P = 0.096; validation cohort: HR: 2.61, 95%CI = 1.38-4.95, P = 0.003).

Research conclusions

This is the first study to evaluate the prognostic value of CEA/tumor size for stage I to III rectal cancer. We found that patients with high CEA/tumor size tended to have a worse outcome. Adjusting the confounding effect of tumor size can improve the prognostic value of CEA. Compared with CEA, another great advantage of CEA/tumor size is the ability to figure out those patients with higher CEA but relatively small tumor size. The results of our study suggest that these easily neglected tumors may represent higher malignancy and worse outcome, which may challenge the conventional risk stratification system. Since both CEA level and tumor size are routinely measured before surgery, the data of CEA/tumor size can be obtained by simple calculation. Therefore, CEA/tumor size can be easily applied in clinical practice.

Research perspectives

As a retrospective study, we were not able to obtain high-level clinical evidence, but the current retrospective study will provide an important basis for us to carry out a prospective study. A large-scale prospective study and longer follow-up time are needed in future study.