Prognostic Factor Associated with Pre- and Postneoadjuvant Carcinoembryonic Antigen in Patients with Middle and Low Rectal Adenocarcinoma and its Correlation with Pathological Findings

Abstract

Introduction

Colorectal cancer (CRC) ranks among the top three most common cancers in Brazil, and the carcinoembryonic antigen (CEA) is one of the most used and established methods for prognostic evaluation and recurrence monitoring in CRC patients.

Objective

To analyze the pre- and postneoadjuvant levels of CEA in patients with middle or low rectal adenocarcinoma who underwent elective retossigmoidectomy with total mesorectal excision or abdominoperineal amputation of the rectum and to correlate the differences in pre- and postneoadjuvant CEA levels with the pathological staging.

Materials and Methods

Retrospective analysis of patients over 18 years old who underwent elective retossigmoidectomy with total mesorectal excision or abdominoperineal resection of the rectum. Data regarding age, sex, type of surgery, absolute CEA values, and differences in pre- and postneoadjuvant CEA levels were evaluated.

Results

The electronic medical records of 77 patients diagnosed with middle or low rectal adenocarcinoma who underwent surgery were analyzed. The mean pre- and postneoadjuvant levels of CEA were of 15.21(± 26.41) ng/mL and 7.17(± 15.6) ng/mL respectively, indicating a statistically significant decrease (p = 0.00058). The cutoff value for the analysis of neoplastic invasion depth (T) was determined to be 4.9 ng/mL, with a sensitivity of 73%, specificity of 63%, positive predictive value of 81%, and accuracy of 66.7%. For disease stage N, a cutoff value of 16.5 ng/mL was used. In this sample, the CEA test showed that the sensitivity and specificity for identifying patients with positive N disease were 41% and 89%, respectively, with a positive predictive value of 70% and an accuracy of 59.7%.

Conclusion

Carcinoembryonic antigen levels significantly decreased after neoadjuvant therapy in patients with middle and low rectal cancer. Pretreatment CEA levels were primarily associated with tumor invasion depth.

Keywords

colorectal cancer - carcinoembryonic antigen - prognostic

Introduction

Colorectal cancer (CRC) ranks among the top three most common cancers in Brazil, with the highest incidence rates for both men and women in the Southeastern region.[1]. It is the most frequent neoplasm in the gastrointestinal tract and the third leading cause of cancer-related deaths worldwide.[2] In 2022, there were 20,245 deaths from colon and rectal cancer, accounting for 956 deaths per 100 thousand inhabitants.[1]

The carcinoembryonic antigen (CEA) is one of the most used and established methods for prognostic evaluation and recurrence monitoring in CRC patients.[3] [4] [5] Carcinoembryonic antigen is a glycoprotein located on the apical surface of mature enterocytes, closely associated with cell adhesion, proliferation, and migration functions. The antigen is located on the endoluminal surface of the cell membrane and is believed to be responsible for inhibiting cellular apoptosis.[6]

Ozawa et al.[7] retrospectively evaluated 150 patients with stages II and III colorectal cancer who underwent surgical or chemotherapeutic treatment, assessing recurrence rates through CEA. Consistent with other studies, they observed that elevated levels of this marker were associated with tumor progression, whereas its decline was related to treatment efficacy.[7] [8] [9]

In colorectal cancer, CEA levels typically normalize approximately six weeks after tumor resection. Persistently elevated levels after this period may indicate residual tumor, partial resection, or local or distant recurrence. The sensitivity and specificity of CEA measurement in detecting recurrence are ∼ 80% and 70%, respectively.[10] However, its effectiveness as a diagnostic tool for colorectal cancer is limited, with sensitivity ranging from 20 to 40%.[11] [12]

Objectives

• a) To analyze the pre- and postneoadjuvant levels of CEA in patients with middle or low rectal adenocarcinoma who underwent elective retossigmoidectomy with total mesorectal excision or abdominoperineal amputation of the rectum.

• b) To correlate the differences in pre- and postneoadjuvant CEA levels with the pathological staging.

Materials and Methods

The present retrospective study analyzed the electronic medical records of patients over 18 years old who underwent elective colorectal surgery, specifically retossigmoidectomy with total mesorectal excision or abdominoperineal resection of the rectum, between January 2014 and December 2022. The surgeries were performed by the Coloproctology Service of the General Surgery Department at Hospital Santa Marcelina in São Paulo, Brazil.

The current study excluded patients who did not have pre- and postneoadjuvant CEA measurements, those with distant metastases, those with incomplete medical records, those with tumors not classified as middle or low rectal adenocarcinoma, and those who underwent surgical treatment without prior neoadjuvant therapy.

Data regarding age, sex, type of surgery, absolute CEA values, and differences in pre- and postneoadjuvant CEA levels were evaluated. The analyses were conducted using Spearman's correlation.

Results

The electronic medical records of 77 patients diagnosed with middle or low rectal adenocarcinoma who underwent surgery were analyzed. The surgeries included retossigmoidectomy with total mesorectal excision or abdominoperineal amputation following neoadjuvant treatment with radiotherapy and chemotherapy and without distant metastases. The mean age of the patients was of 61.87(± 11.78) years, with 50.64% of the cases being male. The mean height of the lesion from the anal verge was of 4.55 (± 2.96) cm, and 43 patients had retossigmoidectomy (55.84%).

The mean pre- and postneoadjuvant levels of CEA were of 15.21(± 26.41) ng/mL and 7.17(± 15.6) ng/mL respectively, indicating a statistically significant decrease (p = 0.00058). The mean Delta CEA, which represents the difference between pre- and postneoadjuvant CEA levels, was of 8.04(SD ± 17.81) ng/mL, as shown in [Table 1].

Table 1 Mean, median, and standard deviation for age, tumor distance from anal verge, and carcinoembryonic antigen (CEA) values

	Mean	Standard deviation	Median
Age (years)	61.87	± 11.78	65
Height (cm)	4.55	± 2.96	5
Pre-CEA (ng/mL)	15.21	± 26.41	6.10
Post-CEA (ng/mL)	7.17	± 15.60	2.70
Delta CEA	8.04	± 17.81	-2.6

When correlating pre- and postneoadjuvant CEA levels with patient age, no statistical significance was observed, nor with the height of the lesion from the anal verge.

On the other hand, when correlating preneoadjuvant CEA levels with local staging (T), a weak but statistically significant association was found (p = 0.026). A similar observation was made between postneoadjuvant CEA levels and lymph node staging (N) (p = 0.012), as shown in [Table 2]. Additionally, [Table 2] indicates that the difference between pre- and postneoadjuvant CEA levels did not demonstrate a statistically significant association with local or lymph node staging.

Table 2 Correlation between pre- and postneoadjuvant carcinoembryonic antigen levels and local and lymph node staging

	T	N
Pre-CEA	0.264;	0.155;
	p = 0.026	p = 0.189
Post-CEA	0.202;	0.277;
	p = 0.09	p = 0.012
Delta CEA	0.227;	0.052;
	p = 0.057	p = 0.663

Abbreviations: CEA, carcinoembryonic antigen; N, lymph node staging; T, local staging.

Using the receiver operating characteristic (ROC) curve, a cutoff value for the analysis of local staging (T) was determined to be 4.9 ng/mL, with a sensitivity of 73%, specificity of 63%, positive predictive value of 81%, and accuracy of 66.7% ([Fig. 1]).

Fig. 1 Receiver operating characteristic curve (preneoadjuvant carcinoembryonic antigen).

A statistical analysis of preneoadjuvant CEA levels was also conducted using the ROC curve in relation to disease stage N, with a cutoff value of 16.5 ng/mL. In this sample, the CEA test showed that the sensitivity and specificity for identifying patients with positive N disease were 41% and 89%, respectively, with a positive predictive value of 70% and an accuracy of 59.7% ([Fig. 2]).

Fig. 2 Receiver operating characteristic curve (preneoadjuvant carcinoembryonic antigen).

Discussion

The staging and, consequently, the prognosis of CRC can be inferred through clinical and laboratory data, radiological findings, surgical outcomes, and histopathological analysis, the latter being the most effective. However, despite its efficacy, histopathological staging demonstrates an accuracy of ∼ 65 to 70% in predicting prognosis. The primary limitation lies within clinical stages II and III.[13] [14] [15]

Carcinoembryonic antigen is a laboratory test used to estimate prognosis in CRC patients and to assess tumor recurrence during oncological follow-up. For example, it is known that after surgical tumor resection, CEA levels take ∼ 6 weeks to normalize.[10] However, its use as an independent prognostic factor is still debated, as 14 to 56% of CRC patients may have normal CEA levels.[16]

Lyu et al.[17] highlighted the importance of CEA in diagnosing lymph node metastases in CRC patients, providing significant clinical guidance. The study supports the use of pre- and postneoadjuvant CEA values in predicting tumor response, local invasion, and lymph node involvement in patients with middle and low rectal adenocarcinoma.

Xu et al.[18] analyzed 9,620 patients with locally advanced CRC and demonstrated higher CEA levels in those with tumor deposits in the mesorectum or mesenteric adipose tissue (p < 0.001). Engineer et al.[19] found that CEA levels greater or less than 5 ng/mL do not correlate with oncological resection standards (p = 0.701). However, in univariate analysis, elevated preneoadjuvant CEA levels were associated with lower disease-free survival and overall survival.

In the present study, the correlation and analysis of sensitivity, specificity, accuracy, and positive predictive value of preneoadjuvant CEA levels with pathological staging were conducted. Liu et al.[20] compared this marker and radiological staging with pathological results, finding a sensitivity of 64.7% and 41.1%, specificity of 97.5% and 98.6%, accuracy of 55% and 58.3%, and negative predictive value of 98.3% and 97.3%, respectively.

Zhou et al.[21] identified factors related to the complete pathological response of middle and distal rectal cancer in a univariate analysis. These factors included the number of consolidation chemotherapy cycles (p = 0.035), pretreatment CEA value (p = 0.030), tumor length on magnetic resonance imaging (MRI) (p = 0.027), and the presence of extramural invasion (p = 0.014). Using the ROC curve, the correlation between CEA values and complete pathological response revealed an accuracy of 74.1%, sensitivity of 63.16%, and specificity of 90.48%, with an optimal cutoff value of 3.1 ng/mL. In our study, an optimal cutoff value of 4.9 ng/mL for locoregional involvement was obtained.

Regarding costs, although the superiority of pelvic MRI for local staging and thoracic and abdominal computed tomography (CT) scans for distant studies is well known, the average cost for CEA testing ranges from R$ 34 to R$ 47. In contrast, the cost for MRI and CT scans is no less than R$ 1,500 for all 3 exams, with 1 study indicating a cost of $509 for these tests.[20]

Finally, the current study also observed a similar prevalence of CRC between males and females, with an average age in the 60s, consistent with most of the global literature.

A limitation of the present study is the retrospective data collection and the measurement of only the correlation between CEA levels and pathological data, without imaging data analysis through pelvic MRI. Nonetheless, this study highlights the importance of correlating a widely available test with local and lymph node pathological staging. Additionally, there was a trend toward statistical significance between delta CEA and locoregional staging.

Conclusion

The levels of CEA significantly decreased after neoadjuvant therapy in patients with middle and low rectal cancer. Pretreatment CEA levels were primarily associated with tumor invasion depth, underscoring the importance of this marker in predicting prognosis and treatment response in rectal adenocarcinoma patients.

Conflict of Interests

The authors have no conflict of interests to declare.

Authors' Contributions

Isaac José Felippe Corrêa Neto was responsible for drafting the article and conducting an analysis of the literature. Matheus Iguera Cirqueira, Gabriela Portal Monteiro, and Yasmin Gois de Mello contributed to the identification of study patients and the analysis of electronic medical records, ensuring the precision and organization of clinical data. Gabriel Fiorot Cruz Sperandio carried out the bibliographic review and the initial revision of the manuscript. Victor Keniti Gomes Nishiyama played a role in statistical analysis, ensuring methodological rigor in the results. Rodrigo Ambar Pinto collaborated on the initial revision and provided a critical analysis of the literature, strengthening the theoretical foundation of the article. Laercio Robles was responsible for the final revision and approval of the manuscript, ensuring its quality before completion.

• References

• 1 Ministério da Saúde Instituto Nacional de Câncer José Alencar Gomes da Silva Ministério da Saúde Instituto Nacional de Câncer. Estimativa 2023 Incidência de câncer no Brasil. 2023.
• 2 Pucci MD, Dasenbrock A, Tanzawa CK, dos Santos MB. Perfil Clínico-Epidemiológico do Câncer Colorretal na Região Oeste do Paraná, Brasil, 2016–2018. Rev Bras Cancerol 2023; 69 (01) e113143
• 3 Yan C, Hu Y, Zhang B. et al. The CEA-/lo colorectal cancer cell population harbors cancer stem cells and metastatic cells. Oncotarget 2016; 7 (49) 80700-80715
• 4 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71 (03) 209-249
• 5 Konishi T, Shimada Y, Hsu M. et al. Association of Preoperative and Postoperative Serum Carcinoembryonic Antigen and Colon Cancer Outcome. JAMA Oncol 2018; 4 (03) 309-315
• 6 Zi-Yang Y, Kaixun Z, Dongling L. et al. Carcinoembryonic antigen levels are increased with pulmonary output in pulmonary hypertension due to congenital heart disease. J Int Med Res 2020; 48 (11) 300060520964378
• 7 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 (01) 97-105
• 8 Gao Y, Wang J, Zhou Y, Sheng S, Qian SY, Huo X. Evaluation of Serum CEA, CA19-9, CA72-4, CA125 and Ferritin as Diagnostic Markers and Factors of Clinical Parameters for Colorectal Cancer. Sci Rep 2018; 8 (01) 2732
• 9 Campos-da-Paz M, Dórea JG, Galdino AS, Lacava ZGM, de Fatima Menezes Almeida Santos M. Carcinoembryonic Antigen (CEA) and Hepatic Metastasis in Colorectal Cancer: Update on Biomarker for Clinical and Biotechnological Approaches. Recent Pat Biotechnol 2018; 12 (04) 269-279
• 10 Duffy MJ. Carcinoembryonic antigen as a marker for colorectal cancer: is it clinically useful?. Clin Chem 2001; 47 (04) 624-630
• 11 Fernandes LC, Matos D. Marcadores tumorais no câncer colorretal. Rev Col Bras Cir 2002; 29 (02) 106-111
• 12 Moura RM, Matos D, Galvão Filho MM, D'Ippólito G, Sjzenfeld J, Giuliano LM. Value of CEA level determination in gallbladder bile in the diagnosis of liver metastases secondary to colorectal adenocarcinoma. Sao Paulo Med J 2001; 119 (03) 110-113
• 13 Compton CC. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 2003; 16 (04) 376-388
• 14 Solimene ACC, Carneiro CRW, Melati I, Lopes JD. Functional differences between two morphologically distinct cell subpopulations within a human colorectal carcinoma cell line. Braz J Med Biol Res 2001; 34 (05) 653-661
• 15 Reiter W, Stieber P, Reuter C, Nagel D, Lau-Werner U, Lamerz R. Multivariate analysis of the prognostic value of CEA and CA 19-9 serum levels in colorectal cancer. Anticancer Res 2000; 20 (6D): 5195-5198
• 16 Priolli DG, Cardinalli IA, Piovesan H, Margarido NF, Martinez CAR. Proposta para estadiamento do câncer colorretal baseada em critérios morfofuncionais: correlação com níveis séricos do antígeno carcinoembrionário. Rev Bras Coloproctol 2007; 27 (04) 374-383
• 17 Liu Y, Chen J. Expression Levels and Clinical Significance of Serum miR-497, CEA, CA24-2, and HBsAg in Patients with Colorectal Cancer. BioMed Res Int 2022; 2022: 3541403
• 18 Xu T, Yu Z, Zhang Q, Liu B, Li Y, Wang F. Prognostic and staging value of tumor deposits in patients with rectal cancer after neoadjuvant chemoradiotherapy. Transl Cancer Res 2021; 10 (12) 5028-5039
• 19 Engineer R, Basu T, Chopra S. et al. Factors influencing response to neoadjuvant chemoradiation and outcomes in rectal cancer patients: tertiary Indian cancer hospital experience. J Gastrointest Oncol 2015; 6 (02) 155-164
• 20 Liu GC, Zhang X, Xie E. et al. The Value of Restaging With Chest and Abdominal CT/MRI Scan After Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer. Medicine (Baltimore) 2015; 94 (47) e2074
• 21 Zhou C, Wang K, Zhang X. et al. Assessing the predictive value of clinical factors to pathological complete response for locally advanced rectal cancer: An analysis of 124 patients. Front Oncol 2023; 13: 1125470

Publication History

Received: 04 October 2024

Accepted: 29 October 2024

Article published online:
29 December 2025