Research ArticleClinical Studies

Prognostic Role of Carcinoembryonic Antigen and Carbohydrate Antigen 19-9 in Stage IV Colorectal Cancer

HIDETAKA KAWAMURA, MICHITAKA HONDA, YOSHINAO TAKANO, SHUNJI KINUTA, TAKAHIRO KAMIGA, SHIGEHIRA SAJI and KOJI KONO
Anticancer Research August 2022, 42 (8) 3921-3928; DOI: https://doi.org/10.21873/anticanres.15886

Abstract

Background/Aim: We investigated the association of the levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) with prognosis in patients with stage IV colorectal cancer at diagnosis. Patients and Methods: In this multicenter retrospective cohort study, patients with serum CEA and CA19-9 measured at diagnosis of stage IV colorectal cancer were included. The cutoff values were 5 ng/ml for CEA and 37 U/ml for CA19-9. Patients were categorized into four groups: those with normal levels for both CEA and CA19-9; those with only an elevated CEA level; those with only an elevated CA19-9 level; and those with elevated levels of both. Results: A total of 825 patients were included. Among them, 132 (16.0%) had normal levels for both markers, 258 (31.3%) had an elevated CEA level only, 33 (4.0%) had an elevated CA19-9 level only, and 402 (48.7%) had elevated levels of both CEA and CA19-9. Compared with patients with normal levels for both CEA and CA19-9, the multivariate hazard ratio for overall survival was 1.24 (95% confidence interval=0.95-1.62, p=0.12) for those with elevated CEA only, 2.04 (95% confidence interval=1.31-3.17, p=0.002) for those with elevated CA19-9 only, and 1.82 (95% confidence interval=1.41-2.32, p<0.001) in those with elevation of both CEA and CA19-9. Conclusion: Elevation of CEA alone was not prognostic. Elevation of only CA19-9 at diagnosis was associated with a worse prognosis in patients with stage IV colorectal cancer. The combined measurement of CEA and CA19-9 can be helpful as a predictive tool for the prognosis of stage IV colorectal cancer.

Key Words:

Colorectal cancer (CRC) is one of the most common cancer types worldwide (1). Approximately 20% of patients have stage IV CRC at diagnosis, and already have metastatic lesions (2). The prognosis of stage IV CRC is improving due to recent advances in multidisciplinary therapy (3). However, stage IV CRC is a heterogeneous disease. Therefore, it is challenging for clinicians to select the appropriate treatment for patients with stage IV CRC, considering their general condition and requests for treatment.

Identification of prognostic factors may help to personalize the treatment of stage IV CRC. The traditional and representative prognostic factors of stage IV CRC are the number of organs with metastasis, metastatic pattern, tumor location, and tumor differentiation (4-6). Additionally, it has recently been clarified that tumor genetic status is associated with prognosis and prediction of therapeutic effects in stage IV CRC, which is applied in clinical practice (7-9). Tissue biopsy with colonoscopy or surgery is the standard technique for assessing tumor genetic status. However, these techniques are invasive and not available for patients with stage IV CRC who are in poor general condition.

Therefore, we focused on two tumor markers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), which are noninvasive and commonly used for CRC in clinical practice (10). Approximately 80% and 60% of patients with stage IV CRC are found to have increased CEA and CA19-9, respectively, at diagnosis (11, 12). Some studies have shown that elevated serum levels of CEA and CA19-9 are associated with inferior prognosis in patients with stage IV CRC (13-16). Herein, we hypothesized that measurement of both CEA and CA19-9 at diagnosis may be helpful for predicting the prognosis of patients with Union for International Cancer Control stage IV CRC (17). We tested this hypothesis using a multicenter retrospective cohort study, focusing on patients with stage IV CRC.

Patients and Methods

Study design and cohort development. All nine designated cancer hospitals across Fukushima Prefecture participated in this multicenter retrospective cohort study. Firstly, we extracted data on patients with stage IV CRC, using topographical codes C18.0, C18.2-C18.9, C19.9, C20.9, defined according to the International Classification of Diseases for Oncology, Third Edition (ICD-O3) (18), from each institution’s hospital-based cancer registry. Secondly, we extracted the following data on patient clinical and demographic characteristics, including tumor markers, from medical records and administrative data: CEA and CA19-9 levels; Charlson comorbidity index (CCI); clinical symptoms from the primary tumor site; clinical tumor-node-metastases (cTNM) stage; Barthel index (as a measure of activities of daily life); and treatment type. Two gastrointestinal surgeons (MH and HK) who were blinded to the survival outcomes reviewed the patients’ medical records and computed tomography images before initial treatment in this cohort, and determined the depth of tumor invasion (T-stage) and regional lymph node metastasis (N-stage) (based on the TNM classification system (version 7) of the American Joint Committee on Cancer) (4); metastatic pattern (organs with metastases and number of sites of metastasis); and clinical symptoms from the primary tumor. Anonymized datasets acquired from individual hospitals were merged into a single dataset.

The inclusion criteria were as follows: consecutive adult patients (≥18 years old) with histologically confirmed colorectal adenocarcinoma who had been clinically or intraoperatively diagnosed with stage IV CRC between 2008 and 2015 and whose CEA and CA19-9 levels were measured at diagnosis. Patients were excluded when there were insufficient data on their course of treatment.

Ethics approval and consent to participate. The study was conducted in accordance with the Declaration of Helsinki, as well as the relevant local laws and regulations, and the protocol was approved by the Institutional Review Boards of all participating hospitals (UMIN000033718). Informed consent from individual patients was waived in accordance with the Japanese government’s Ethical Guidelines for Medical and Health Research Involving Human Subjects, which allow an opt-out approach.

Measurement of tumor markers. We used the tumor marker values obtained within 1 month prior to the histological diagnosis of CRC. Serum CEA and CA19-9 levels were measured by enzyme-linked immunosorbent assay. The cutoff values were 5 ng/ml for CEA (15) and 37 U/ml for CA19-9 (19). Patients were categorized into four groups: Normal CEA and CA19-9 (normal CEA and CA19-9 levels); elevated CEA, (high level of CEA only); elevated CA19-9 (high CA19-9 level only); and both CEA and CA19-9 elevated (high levels for both tumor markers).

Outcomes. The primary endpoint for each group was overall survival (OS), calculated as the number of days from the date of diagnosis of stage IV CRC until death, loss to follow-up, or alive on December 31, 2017. Patients who had not experienced any events of interest were censored at the last follow-up date. The secondary outcome was metastatic pattern. Based on the metastatic organ and number of metastatic sites we described metastatic pattern as follows; liver metastases (presence or absence), pulmonary metastases (presence or absence), peritoneal dissemination (presence or absence), non-regional lymph node metastasis (presence or absence), other organ metastasis (bone, brain, ovary, and other [presence or absence]), number of metastatic organs (1 or ≥2), and severity of metastases (M-stage; M1a, M1b, and M1c) (17).

Covariates. Several demographic and clinical variables were included in the analysis, such as sex, age at diagnosis (<75 and ≥75 years), period of diagnosis (2008-2012 or 2013-2015), symptoms from primary tumor (absence or presence), primary site (right colon cancer [tumor located in the cecum, ascending colon, hepatic flexure, or transverse colon], left colon cancer [tumor located within the splenic flexure, descending colon, sigmoidal colon, or rectosigmoidal junction], or rectal cancer), and degree of tumor differentiation (highly or moderately differentiated, poorly differentiated). CCI was used to measure the patients’ comorbidities at first admission for CRC-related hospitalization; the results were classified as a binary variable based on the CCI score (0-2 and ≥3) (20). The Barthel index was used to measure the patients’ activities of daily life at both admission and discharge in their first hospitalization. This index uses a scale of 0 to 100 points; the scores were categorized as a binary variable (0-60 and 61-100) for analysis (21). T-Stage was classified as a binary variable (T1-3 and T4), as was N-stage (absence and presence). M-Stage was classified as a triple variable (M1a, M1b, and M1c).

Statistical analyses. Patient characteristics are reported as descriptive statistics, with continuous variables expressed as the median and range or interquartile range (IQR), and categorical variables expressed as counts and percentages. Univariate analyses were used to compare patient characteristics among the four groups categorized by CEA and CA19-9. Binary and categorical variables were compared using the Fisher exact test. Continuous variables were compared using the Kruskal–Wallis test.

We described the missing values and applied multiple imputation by a chained equation, which created 20 multiple imputed datasets. The estimates were based on combined results from multiple imputed datasets using Rubin’s rule to compensate for missing values (22).

Survival analysis was performed using the Kaplan–Meier method, and survival estimates were compared using the log-rank test. The association between the combination of tumor markers and OS was analyzed using Cox proportional hazards regression models for all-cause mortality, adjusted for sex, period of diagnosis, symptoms from primary tumor, primary site, degree of tumor differentiation, CCI, Barthel index, T-stage, N-stage, and M-stage. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. All significance tests were two-sided, and p-values of less than 0.05 were considered statistically significant. Statistical analyses were performed using STATA version 16.0 software (STATA Corporation, College Station, TX, USA).

Results

We identified 825 patients diagnosed with stage IV CRC between 2008 and 2015 with both CEA and CA19-9 levels measured at diagnosis (Figure 1). Among them, 132 (16.0%) had normal CEA and CA19-9 levels, 258 (31.3%) had elevated CEA, 33 (4.0%) had elevated CA19-9, and 402 (48.7%) had elevated CEA and CA19-9. The median follow-up time was 18.5 (IQR=6.7-33.5) months, and 609 (73.8%) patients died during the study period. Figure 2 shows the distribution of serum CEA and CA19-9 levels. The median CEA and CA19-9 values were 23.9 ng/ml (IQR, 6.5-160.1 ng/ml) and 45.4 U/ml (IQR=11.2-364.7 U/ml), respectively.

Figure 1.
Figure 1.

Overview of patient selection. CA19-9: Carbohydrate antigen 19-9; CEA: carcinoembryonic antigen.

Figure 2.
Figure 2.

Histograms of serum level of carcinoembryonic antigen (CEA) (median=23.9 ng/ml, interquartile range=6.5-160.1 ng/ml) (A) and carbohydrate antigen 19-9 (CA 19-9) (median=45.4 U/ml, interquartile range=11.2-364.7 U/ml) (B).

The patient demographics and clinical characteristics are summarized in Table I. In the group with elevated CA19-9, a higher proportion of patients had right colon cancer as their primary tumor and poorly differentiated adenocarcinoma. Regarding treatment for primary tumor and organs with metastasis, in the group with elevated CA19-9, a higher percentage of patients than in the other groups did not receive treatment.

View this table:
Table I.

Patients’ characteristics.

Metastatic pattern. Table II shows the number of organs with metastasis and their sites. Marker levels were significantly different among groups with and without liver metastasis (p<0.001), lung metastasis (p=0.022), and peritoneal dissemination (p=0.018). In the group with elevated CA19-9, a higher proportion of patients had peritoneal dissemination and did not have liver and lung metastasis. Regarding the number of organs with metastasis, a higher percentage of patients in the normal CEA and CA19-9 group had only one organ affected by metastasis (p<0.001). These results contributed to a significant difference in M-stage; the percentage of patients with M1a was higher in the normal CEA and CA19-9 group, and the percentage of patients with M1c was higher in the group with elevated CA19-9.

View this table:
Table II.

Metastatic pattern.

Adjusted HRs and OS curves. OS analysis for all patients was performed using the Kaplan–Meier method (Figure 3). The 1-year survival rates for those with normal CEA and CA19-9, elevated CEA, elevated CA19-9, and both CEA and CA19-9 elevated were 76.3% (95% CI=67.8-82.8%), 74.5% (95% CI=68.7-79.5%), 37.7% (95% CI=21.4-53.9%), and 58.5% (95% CI=53.4-63.3%) months, respectively (p<0.001). An analysis of OS by each treatment for each group was similarly performed (Figure 3B-D). Survival of patients treated with systemic chemotherapy followed a pattern similar to that for patients overall (p<0.001), although there were no statistically significant differences in those treated with metastasectomy (p=0.65) or without treatment (p=0.085).

Figure 3.
Figure 3.

Overall survival according to the main treatment for patients with stage IV colorectal cancer. A: All patients; B: systemic chemotherapy; C: metastasectomy; D: best supportive care. CA19-9: Carbohydrate antigen 19-9; CEA: carcinoembryonic antigen.

Compared with the normal CEA and CA19-9 group, the adjusted HRs for OS were 1.24 (95% CI=0.95-1.62, p=0.12) for the group with elevated CEA, 2.04 (95% CI=1.31-3.17, p=0.002) for the group with elevated CA19-9, and 1.82 (95% CI=1.41-2.34, p<0.001) for the group with elevated CEA and CA19-9, indicating a significantly poorer OS for the groups with elevated CA19-9, and elevation for both markers (Table III).

View this table:
Table III.

Hazard ratios for all-cause mortality using Cox proportional hazards regression models with multiple imputation method.

Discussion

This multicenter retrospective cohort study evaluated the clinical impact of the combination of CEA and CA19-9 at the diagnosis of stage IV CRC. Elevation of CA19-9 only was significantly associated with right colon cancer, poorly differentiated adenocarcinoma, and peritoneal dissemination. Thus, elevation of CA19-9 alone is associated with a worse prognosis in stage IV CRC. Additionally, elevation of CA19-9 alone was an independent factor for poor prognosis when data were adjusted for confounding factors, primary tumor site, degree of differentiation, and M-stage. These results indicate that it may be useful to measure both CEA and CA19-9 at diagnosis of stage IV CRC as a predictive tool, which can help in the personalization of treatment.

This present study showed that the combination of elevated CA19-9 and normal CEA in patients with stage IV CRC is associated with right colon cancer, poorly differentiated adenocarcinoma and peritoneal dissemination. Similarly, a previous study demonstrated that patients with elevated CA19-9 levels have peritoneal dissemination or peritoneal recurrence after curative resection (23). Another previous report showed that half of the patients only with CA19-9 elevation had B-Raf proto-oncogene serine/threonine kinase (BRAF) mutations in metastatic CRC (24). BRAF mutations are detected in approximately 8-10% of metastatic CRC cases, and are associated with both right colon cancer and poorly differentiated adenocarcinoma (25-27). Together with the findings from the current study, these results support our conclusion that elevation of CA19-9 alone is associated with right colon cancer, poorly differentiated adenocarcinoma, and periodontal dissemination, all of which are associated with a poor prognosis.

One more reason for the differences in survival in patients with stage IV CRC with elevated CA19-9 and normal CEA levels may also be associated with BRAF mutations and microsatellite stable (MSS). According to a study by Thomsen et al, an elevated CA19-9 level is associated with poor prognosis (24). Additionally, Thomsen et al. reported that an elevated CA19-9 level was associated with short OS within a BRAF-mutant subgroup. On the other hand, according to a study by Kasi et al., patients with metastatic CRC with BRAF mutations and MSS had significantly elevated CA19-9 levels, while CEA levels were not significantly elevated (28). Patients with BRAF-mutant and MSS metastatic CRC have a worse prognosis than those with BRAF-mutant and microsatellite instability-high patients (25, 29). In the current study, patients with elevation only of CA19-9 may include patients with BRAF mutations and MSS.

To our knowledge, this is the first multicenter cohort study to report the clinical characteristics of stage IV CRC, including any treatment, and assess the impact of CEA and CA19-9 on prognosis, when adjusted for relevant covariates. Our results support the hypothesis that the measurement of CEA and CA19-9 can be helpful as a predictive tool for the prognosis of stage IV CRC, a heterogenous disease for which it is necessary for clinicians to incorporate a complicated treatment strategy. Tumor gene status with tissue biopsy is the recommended test to predict prognosis and response to systemic chemotherapy or immunotherapy in stage IV CRC (9). However, this technique and test are invasive and only available in some countries, because it is expensive and requires a high level of skill. Serum tumor markers have the advantage of being minimally invasive, technically easy and cost-effective. Therefore, our results may contribute to the spread of the clinical application of the use of the combination of serum CEA and CA19-9 levels to predict prognosis in patients with stage IV CRC in a simplified manner all over the world.

The present study has some limitations. Firstly, the study population may have included patients whose characteristics can increase or reduce levels of CEA and CA19-9, such as smoking, the presence of benign diseases, and Lewis blood type (15, 16). However, we did not collect data regarding these factors. Secondly, the patients were enrolled from 2008 to 2015, and the treatment strategies, including intensive chemotherapeutic regimens, immunotherapy, and molecular analysis (BRAF mutation and microsatellite instability), since then have changed significantly. Thus, our study may not be fully reflective of current medical practice. Thirdly, some data on the primary tumor site (1.9%), activities of daily life (10.5%), and degree of differentiation (7.2%) were missing. We described the missing values and applied multiple imputation methods to compensate for them. Finally, the sample size of this study may have been insufficient. Therefore, subgroup analysis for each treatment may not have had the strength to reveal a statistical difference between tumor locations in metastasectomy and no treatment.

In conclusion, elevation of serum CA19-9 alone was associated with a worse prognosis in stage IV CRC, right colon cancer, poorly differentiated adenocarcinoma, and peritoneal dissemination. These findings suggest that the measurement of both CEA and CA19-9 may be useful for predicting the prognosis of patients with stage IV CRC at diagnosis.

Acknowledgements

The Authors would like to express their gratitude to Seria Sato, Koji Uehara, Nobuko Kanno, Mika Yusa, Kazuhira Saito, Tomoko Oya, Yoshinobu Yamazaki, Yoko Endo, Chieko Tairako, Yumi Inaba, Shigeru Yamazaki, Atsushi Muto, Satoru Shiraso, and Naoyuki Yamashita for their contributions to the data collection.

Footnotes

  • Authors’ Contributions

    H.K. analyzed and interpreted the data and was a major contributor in writing the manuscript. M.H., Y.T., S.K., T.K., S.S., and K.K. obtained and interpreted the data. All Authors have read and approved the final article.

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest.

  • Received May 10, 2022.
  • Revision received June 15, 2022.
  • Accepted June 21, 2022.

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Prognostic Role of Carcinoembryonic Antigen and Carbohydrate Antigen 19-9 in Stage IV Colorectal Cancer
HIDETAKA KAWAMURA, MICHITAKA HONDA, YOSHINAO TAKANO, SHUNJI KINUTA, TAKAHIRO KAMIGA, SHIGEHIRA SAJI, KOJI KONO
Anticancer Research Aug 2022, 42 (8) 3921-3928; DOI: 10.21873/anticanres.15886
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