Current Surveillance After Treatment is Not Sufficient for Patients With Rectal Cancer With Negative Baseline CEA

Authors: Dingcheng Shen MD1,2, Xiaolin Wang PhD1, Heng Wang MSc1, Gaopo Xu MSc1, Yumo Xie MD1,2, Zhuokai Zhuang MD1,2, Ziying Huang MD3, Juan Li MD, PhD2, Jinxin Lin MD, PhD2, Puning Wang MD, PhD2, Meijin Huang MD, PhD1,2, Yanxin Luo MD, PhD1,2, and Huichuan Yu MD, PhD1,2
View More View Less
  • 1 Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, and
  • | 2 Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University; and
  • | 3 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Background: Serum CEA has been widely used to screen for potential recurrent disease after resection in rectal cancer. However, the influence of baseline CEA on the performance of CEA in recurrence surveillance needs to be investigated. Patients and Methods: This longitudinal cohort study included 484 patients with nonmetastatic rectal cancer from 18,013 patients in a prospectively enrolled institutional database program of colorectal disease. Baseline CEA levels were determined before treatment, and CEA-based follow-up tests and examinations were applied in the surveillance after treatment. Results: A total of 62.6% (62/99) overall, 53.5% (23/43) local, and 64.9% (50/77) distant recurrences were seen in patients who had similar CEA levels with their baseline statuses. The sensitivity of elevated CEA levels during surveillance for overall recurrence was significantly lower in patients with negative baseline CEA than in those with elevated baseline CEA levels (41.3% vs 69.4%; P =.007). Moreover, similar results were observed in the surveillance for local (50% vs 61.5%; P =.048) and distant (39.6% vs 72.4%; P =.005) recurrences between these 2 patient groups. However, CEA had comparable and excellent specificity during surveillance for recurrent disease in these groups. The addition of CA19-9 to the CEA assay significantly improved the sensitivity in recurrence surveillance for patients with negative baseline CEA (49.2% vs 41.3%; P =.037). Finally, we identified a subgroup of CEA-turn recurrences characterized by negative CEA at baseline, elevated CEA at recurrence, and worse survival outcomes after recurrence (hazard ratio, 1.88; 95% CI, 1.07–3.30; P =.026). Conclusions: In patients with rectal cancer with negative baseline CEA, serum CEA had insufficient sensitivity in recurrence surveillance after treatment, and additional surveillance may improve oncologic outcomes. Baseline CEA should be considered before CEA-based surveillance can be applied in the follow-up trials.

Submitted August 22, 2021; final revision received October 8, 2021; accepted for publication October 11, 2021. Published online March 1, 2022.

Author contributions: Study concept and design: Yu. Supervision: Yu. Data collection: Shen, X. Wang, H. Wang, Xu, Xie, Zhuang, Z. Huang, JL, P. Wang, Yu. Data analysis and interpretation: Shen, Yu. Provision of study materials and patients: X. Wang, JL, P. Wang, M. Huang, Luo. Financial support: M. Huang, Luo, Yu. Writing – original draft: Shen. Writing – revision: Yu. Dr. Yu had full access to all data for this study and takes responsibility for the integrity and accuracy of the data.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This study was supported by the National Natural Science Foundation of China (number 81972245, Y. Luo; number 81902877, H. Yu), the Natural Science Foundation of Guangdong Province (number 2018A0303130303, H. Yu; number 2021A1515010134, M. Huang), the Sun Yat-sen University Clinical Research 5010 Program (number 2018026, Y. Luo), the “Five Five” Talent Team Construction Project of The Sixth Affiliated Hospital of Sun Yat-sen University (number P20150227202010251, Y. Luo), the Excellent Talent Training Project of The Sixth Affiliated Hospital of Sun Yat-sen University (number R2021217202512965, Y. Luo), The Sixth Affiliated Hospital of Sun Yat-sen University Clinical Research-“1010” Program (M. Huang), the Program of Introducing Talents of Discipline to Universities, and the National Key Clinical Discipline (2012).

Correspondence: Huichuan Yu, MD, PhD, 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, Guangdong, 510655, China. Email: yuhch5@mail.sysu.edu.cn

Supplementary Materials

    • Supplemental Materials (PDF 592 KB)
  • 1.

    Xie Y, Shi L, He X, et al. Gastrointestinal cancers in China, the USA, and Europe. Gastroenterol Rep (Oxf) 2021;9:91104.

  • 2.

    Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020;70:145164.

  • 3.

    Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 2019;16:713732.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Primrose JN, Perera R, Gray A, et al. Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial. JAMA 2014;311:263270.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 2019;9:CD002200.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Habr-Gama A, Gama-Rodrigues J, São Julião GP, et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys 2014;88:822828.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 2.2021. Accessed October 8, 2021. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 8.

    Eftekhar E, Naghibalhossaini F. Carcinoembryonic antigen expression level as a predictive factor for response to 5-fluorouracil in colorectal cancer. Mol Biol Rep 2014;41:459466.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Han JS, Nair PP. Flow cytometric identification of cell surface markers on cultured human colonic cell lines using monoclonal antibodies. Cancer 1995;76:195200.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Ramphal W, Boeding JRE, van Iwaarden M, et al. Serum carcinoembryonic antigen to predict recurrence in the follow-up of patients with colorectal cancer. Int J Biol Markers 2019;34:6068.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Huang SH, Tsai WS, You JF, et al. Preoperative carcinoembryonic antigen as a poor prognostic factor in stage I-III colorectal cancer after curative-intent resection: a propensity score matching analysis. Ann Surg Oncol 2019;26:16851694.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Saito G, Sadahiro S, Kamata H, et al. Monitoring of serum carcinoembryonic antigen levels after curative resection of colon cancer: cutoff values determined according to preoperative levels enhance the diagnostic accuracy for recurrence. Oncology 2017;92:276282.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Huh JW, Kim CH, Lim SW, et al. Factors predicting long-term survival in colorectal cancer patients with a normal preoperative serum level of carcinoembryonic antigen. J Cancer Res Clin Oncol 2013;139:14491455.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Chen Z, Huang Z, Luo Y, et al. Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer. J Transl Med 2021;19:73.

  • 15.

    Yu HC, Luo YX, Peng H, et al. Avoiding perioperative dexamethasone may improve the outcome of patients with rectal cancer. Eur J Surg Oncol 2015;41:667673.

  • 16.

    Huang Z, Wang X, Zou Q, et al. High platelet-to-lymphocyte ratio predicts improved survival outcome for perioperative NSAID use in patients with rectal cancer. Int J Colorectal Dis 2020;35:695704.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Jin M, Ye D, Li Y, et al. Association of a novel genetic variant in RP11-650L12.2 with risk of colorectal cancer in Han Chinese population. Gene 2017;624:2125.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Liu WB, Cao GW. Theory of cancer evolution-development and its significance for research of colorectal carcinoma [in Chinese]. Zhonghua Yu Fang Yi Xue Za Zhi 2018;52:226230.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Ye D, Hu Y, Jing F, et al. A novel SNP in promoter region of RP11-3N2.1 is associated with reduced risk of colorectal cancer. J Hum Genet 2018;63:4754.

  • 20.

    Jiang D, Jin M, Ye D, et al. Polymorphisms of a novel long non-coding RNA RP11-108K3.2 with colorectal cancer susceptibility and their effects on its expression. Int J Biol Markers 2020;35:39.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Ye D, Jiang D, Gu S, et al. Evaluating the predictive value of genetic risk score in colorectal cancer among Chinese Han population. J Hum Genet 2020;65:271279.

  • 22.

    Liao Y, Li S, Chen C, et al. Screening for colorectal cancer in Tianhe, Guangzhou: results of combining fecal immunochemical tests and risk factors for selecting patients requiring colonoscopy. Gastroenterol Rep (Oxf) 2018;6:132136.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Wu X, Zhang Y, Hu T, et al. A novel cell-free DNA methylation-based model improves the early detection of colorectal cancer. Mol Oncol 2021;15:27022714.

  • 24.

    Niu F, Wen J, Fu X, et al. Stool DNA test of methylated syndecan-2 for the early detection of colorectal neoplasia. Cancer Epidemiol Biomarkers Prev 2017;26:14111419.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Wang J, Liu S, Wang H, et al. Robust performance of a novel stool DNA test of methylated SDC2 for colorectal cancer detection: a multicenter clinical study. Clin Epigenetics 2020;12:162.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th Edition of the AJCC Cancer Staging Manual and the future of TNM. Ann Surg Oncol 2010;17:14711474.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    National Health Commission of the People’s Republic of China. Chinese protocol of diagnosis and treatment of colorectal cancer (2020 edition) [in Chinese]. Zhonghua Wai Ke Za Zhi 2020;58:561585.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    National Cancer Center, China, Expert Group of the Development of China Guideline for the Screening, Early Detection and Early Treatment of Colorectal Cancer. China guideline for the screening, early detection and early treatment of colorectal cancer (2020, Beijing) [in Chinese]. Zhonghua Zhong Liu Za Zhi 2021;43:1638.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Yu H, Luo Y, Wang X, et al. Time to lowest postoperative carcinoembryonic antigen level is predictive on survival outcome in rectal cancer. Sci Rep 2016;6:34131.

  • 30.

    Hu H, Huang J, Lan P, et al. CEA clearance pattern as a predictor of tumor response to neoadjuvant treatment in rectal cancer: a post-hoc analysis of FOWARC trial. BMC Cancer 2018;18:1145.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Deng Y, Chi P, Lan P, et al. Neoadjuvant modified FOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: final results of the Chinese FOWARC trial. J Clin Oncol 2019;37:32233233.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Xie Y, Lin J, Wang X, et al. The addition of preoperative radiation is insufficient for lateral pelvic control in a subgroup of patients with low locally advanced rectal cancer: a post hoc study of a randomized controlled trial. Dis Colon Rectum 2021;64:13211330.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med 1965;122:467481.

  • 34.

    Sonoda H, Yamada T, Matsuda A, et al. Elevated serum carcinoembryonic antigen level after curative surgery is a prognostic biomarker of stage II-III colorectal cancer. Eur J Surg Oncol 2021;47:28802887.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Ozawa T, Matsuda K, Ishihara S, et al. The robust performance of carcinoembryonic antigen levels after adjuvant chemotherapy for the recurrence risk stratification in patients with colorectal cancer. J Surg Oncol 2021;124:97105.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Verberne CJ, Zhan Z, van den Heuvel E, et al. Intensified follow-up in colorectal cancer patients using frequent carcino-embryonic antigen (CEA) measurements and CEA-triggered imaging: results of the randomized “CEAwatch” trial. Eur J Surg Oncol 2015;41:11881196.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Wille-Jørgensen P, Syk I, Smedh K, et al. Effect of more vs less frequent follow-up testing on overall and colorectal cancer-specific mortality in patients with stage II or III colorectal cancer: the COLOFOL randomized clinical trial. JAMA 2018;319:20952103.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Yu H, Luo Y. Decentered crowdfunded clinical studies—open a new era of medical research. JAMA Oncol 2019;5:910.

  • 39.

    Huang R, Meng T, Zha Q, et al. The predicting roles of carcinoembryonic antigen and its underlying mechanism in the progression of coronavirus disease 2019. Crit Care 2021;25:234.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Yang C, Wang J, Liu J, et al. Elevated carcinoembryonic antigen in patients with COVID-19 pneumonia. J Cancer Res Clin Oncol 2020;146:33853388.

  • 41.

    Luo G, Jin K, Deng S, et al. Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter. Biochim Biophys Acta Rev Cancer 2021;1875:188409.

  • 42.

    Lin PC, Lin JK, Lin CC, et al. Carbohydrate antigen 19-9 is a valuable prognostic factor in colorectal cancer patients with normal levels of carcinoembryonic antigen and may help predict lung metastasis. Int J Colorectal Dis 2012;27:13331338.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Stiksma J, Grootendorst DC, van der Linden PW. CA 19-9 as a marker in addition to CEA to monitor colorectal cancer. Clin Colorectal Cancer 2014;13:239244.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Dong H, Tang J, Li LH, et al. Serum carbohydrate antigen 19-9 as an indicator of liver metastasis in colorectal carcinoma cases. Asian Pac J Cancer Prev 2013;14:909913.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 366 366 366
PDF Downloads 191 191 191
EPUB Downloads 0 0 0