Research ArticleClinical Studies

Prognostic Value of Carcinoembryonic Antigen (CEA), AFP, CA19-9 and CA125 for Patients with Colorectal Cancer with Peritoneal Carcinomatosis Treated by Cytoreductive Surgery and Intraperitoneal Chemotherapy

YA RUTH HUO, YEQIAN HUANG, WINSTON LIAUW, JING ZHAO and DAVID L. MORRIS
Anticancer Research March 2016, 36 (3) 1041-1049;

Abstract

Background: This study aimed to clarify the prognostic significance of tumour markers on long-term survival in colorectal peritoneal carcinomatosis (CRPC) following cytoreductive surgery and intraperitoneal chemotherapy. Patients and Methods: Preoperative serum tumour markers of 164 patients with CRPC were analyzed. Peritoneal cancer index (PCI) was measured and relationship to survival calculated. Results: Carcinoembryonic antigen (CEA) >6.5 mg/l and cancer antigen 125 (CA125) >16 U/ml remained independent predictors of survival after adjusting for PCI [adjusted hazard ratio (aHR)=2.46, 95% confidence interval (CI)=1.3-4.5, p<0.01 and aHR=2.23, 95% CI=1.21-4.09, p<0.01, respectively]. Patients with high CEA and low CA125 or vice versa had an approximately triple risk of death (HR=3.34, 95% CI=1.21 9.25, p=0.02 and HR=2.76, 95% CI=1.01 7.77, p=0.04, respectively). High CEA with high CA125 produced an additive effect, reflecting a six-fold increase in death (HR=6.57, 95% CI=2.62 13.69, p<0.001, median survival: not reached vs. 22 months). Conclusion: Serum CEA and CA125 in patients with CRPC treated with cytoreductive surgery and intraperitoneal chemotherapy convey a negative prognostic effect independently of PCI.

Tumour markers have been found to have a strong prognostic value for certain tumour types (1-5), there is controversy for the reason behind this. An elevated tumour marker may reflect a higher tumour load or may reflect tumour biology (2). Carcinoembryonic antigen (CEA) has both immunosuppressive and tumour cell-adhesion properties, which help mediate metastasis and invasion (6-10). However, poorly differentiated aggressive tumours may not secrete tumour markers (11). The Peritoneal Cancer Index (PCI) is a scale that reflects total intra-abdominal tumour load (12). Prior to cytoreductive surgery (CRS), extensive imaging is performed to ensure there is no disease outside of the abdomen. Therefore, with all the disease confined intra-abdominally, PCI in these patients reflects the total-body tumour load.

The aim of this study was to clarify the role of four serum tumour markers, namely CEA, cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9) and alpha-fetoprotein (AFP), as prognostic indicators of overall long-term survival in patients with colorectal peritoneal carcinomatosis (CRPC) treated with CRS and intraperitoneal chemotherapy (IPC).

Patients and Methods

Patient selection. From 1996 until October 2015, patients with CRPC were treated with CRS and IPC. Before CRS, patients underwent contrast-enhanced computed tomography (CT) chest/abdomen, fluorodeoxyglucose positron-emission tomography, either CT portography or primovist magnetic resonance imaging. In the early part of our series, a PCI cut-off limit of 20 was used. This was lowered to 15 in 2012.

CRS and IPC. A laparotomy was performed and assessment of the volume and extent of tumour deposits were recorded prospectively using PCI, as described by Jacquet and Sugarbaker (12). CRS was performed by the same surgical team according to Sugarbaker's techniques (13). Residual disease after CRS was recorded using the Completeness of Cytoreduction (CC) score (12). For CRPC, only complete cytoreduction (i.e. CC0) was included in this study. Our protocols for perioperative IPC have been described previously (14).

Data extraction. A specifically designed database recorded clinicopathological, treatment-related, and follow-up data. We followed-up all patients, including measurement of tumour markers and CT scans. Four serum tumour markers (CA19.9, CEA, CA125 or AFP) were taken as standard preoperative protocol (<1 month) prior to a peritonectomy. The markers were determined by the local pathology Unit for all patients. The majority of patients had all four tumour marker values recorded.

Statistical analysis. The data collected were analyzed by SPSS for Macintosh, version 23.0 (SPSS, Munich, Germany). Patient characteristics are reported using frequency and descriptive analyses. Differences between dichotomous groups were tested with a Chi-square test, whilst continuous groups were tested with the independent t-test. The median survival was defined as the time in which 50% of patients had died. Follow-up was calculated from the date of the first CRS to the date of the last follow-up. The median value of tumour markers of this study's cohort was set as the cut-off for high and low tumour-marker groups. Further analysis using the upper limit of the laboratory specified reference range was used (high CEA: >5 mg/l; high CA125 >35 U/ml; high CA19.9 >37 U/ml; high AFP >10 IU/l) (15). Kaplan–Meier method was used to develop survival curves. Cox regression was used to identify prognostic variables for survival in univariate and multivariate analyses. Sub-group analysis of survival was performed using quartiles of tumour markers. Clinically significant variables were included in the multivariate analysis. Linear regression was used to determine which tumour markers were correlated with PCI. A p-value of less than 0.05 was considered to statistically significant.

Results

A total of 164 patients were included in the study. The mean age was 55.2 years, 59.1% males. The median follow-up was 17 months (range=1-112 months). The median overall survival was 32 months. The mean pre-CRS values were: 37.0 mg/l for CEA, 2.8 IU/l for AFP, 77.3 U/ml for CA19-9 and 46.8 U/ml for CA125. The elevated tumour marker group were those with levels higher than the median for each tumour marker: high CEA >6.5 mg/l; high AFP >2 IU/l; high CA19-9 >17 U/ml; high CA125 >16 U/ml. The upper limit of the laboratory specified reference range for each tumour marker was also evaluated as stated above.

CEA. Serum CEA levels were measured preoperatively in 99.4% (163/164) of patients. Elevated CEA correlated with an elevated CA19-9 and a higher PCI score (Table I). In the univariate analysis, elevated CEA correlated with poor survival at both the laboratory cut off [>5 mg/l: 35 months vs. not reached; p<0.01], the median cut-off for this study (>6.5 mg/l: 23 months vs. NR; hazard ratio (HR)=3.2, 95% confidence interval (CI)=1.7-5.4, p<0.001) (Figure 1, Tables II and III). Multivariate analysis demonstrated elevated CEA (at both cut-offs) was an independent prognostic factor (CEA 0-6.5 mg/l vs. >6.5 mg/l: adjusted HR=2.46, 95% CI=1.3-4.5 p<0.01) (Figure 1, Tables II and III).

Sub-group analysis with CEA quartiles demonstrated a stepwise increase in the HR with each increasing CEA quartile compared to the first (lowest) quartile (HR=1.1 → 2.53 → 3.84) (Table IV). In univariate analysis, this HR was statistically significant for the fourth (highest) quartile (>18.5 mg/l) and third quartile (>6.7-18.5 mg/l) compared to the first quartile (0-2 mg/l) (HR=3.84, 95% CI 1.76-8.24, p=0.001 and HR=2.53, 95% CI=1.13-5.64, p=0.02, respectively). In multivariate analysis when adjusted for PCI, only the highest quartile was significantly different compared to the first quartile (adjusted HR=3.08, 95% CI=1.41-6.74, p=0.005) (Table IV).

CA125. Serum CA125 levels were measured preoperatively in 90.9% (149/164) patients. Elevated CA125 correlated with a younger age, a shorter interval between the primary CRC and CRS and a higher PCI (Table I). In the univariate analysis, an elevated CA125 correlated with a poor survival at both the clinical cut-off (>35 U/ml: 19 months vs. 56 months) and the median cut-off (>16 U/ml: 32 months vs. 61 months, HR = 2.67 (95% CI=1.46-4.86), p<0.001) (Figure 2, Table II and III). Multivariate analysis of CA125 at the two cut-offs was an independent prognostic factor (0-16 U/ml vs. >16 U/ml adjusted HR=2.23, 95% CI = 1.2-4.09, p<0.01) (Figure 2, Tables II and III).

Sub-group analysis with CA125 quartiles demonstrated patients in the highest quartile (>30 U/ml), had a significantly poorer survival than patients in the lowest quartile (first quartile: 0-11 U/ml) in univariate and multivariate analysis (HR=2.98, 95% CI=1.39-6.39, p=0.005 and adjusted HR=2.21 95% CI=1.02-4.78, p=0.045, respectively). There were no statistically significant differences in overall survival between the first quartile with the second and third quartile. This may be due to the small patient number in each quartile (range=31-46 patients) (Table IV).

Combined hazardous effect of CEA and CA125 on survival. The combined effect of CEA and CA125 on survival is visualized in Figure 3 and summarized in Table IV. Compared to patients with low CEA with low CA125, patients with low CEA with high CA125 had an approximately triple risk of death (HR=2.76, 95% CI=1.01-7.77, p=0.04). Vice versa, a similar significant association was seen for patients with high CEA with low CA125 (HR=3.34, 95% CI=1.21-9.25, p=0.02). Patients with high CEA with high CA125 were six times more likely to die than those with low CEA with low CA125 (HR=6.57, 95% CI=2.62-13.69, p<0.001). This combined hazardous effect between CEA and CA125 persisted in multivariate analysis (Table V). Further analysis based on combined CEA and CA125 quartile groups are summarised in Table VI.

CA19-9 and AFP. After adjusting for PCI, the prognostic value of CA19-9 at the clinical cut-off became statistically non-significant (Tables II and III). This study's median cut-off value for CA19-9 (>17 U/ml) was not correlated with overall survival on univariate analysis (HR=1.53, 95% CI=0.87-2.70, p>0.05, median survival 42 months vs. 61 months) (Figure 4). Serum AFP was also not a useful prognostic factor (Figure 4, Tables II and III).

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Table I.

Baseline characteristics for low and high tumour marker groups.

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Table II.

Survival of patients divided into low and high groups at the median value for tumour markers.

Correlation between PCI with CA19-9, CEA, CA125 and AFP. Linear regression demonstrated that the intra-operative PCI score was positively significantly correlated with CA19-9 (standardized coefficient beta=0.41, R square: 0.17, p<0.001) and CA125 (Standardized beta coefficient: 0.29, R square=0.033, p=0.015). PCI was not significantly correlated with serum CEA (standardized beta coefficient=−0.02, R square: 0.033, p=0.84) or AFP (standardized beta coefficient=−0.15, R square: 0.012, p=0.14).

Discussion

Tumour markers are used to help detect, diagnose and manage certain types of cancer. They also have a functional role in cancer invasion and disease progression. Several studies have suggested that CA125 and CEA have immunosuppressive and cell-adhesion properties, advancing tumourigenesis and tumour proliferation through immune system evasion (7, 16, 17). Thus, CA125 and CEA have become targets for immunotherapy in recent years (6, 18-20).

The results from this study clearly demonstrate the adverse prognostic effect of CEA and CA125 for patients with CRPC is independent of PCI. Patients with an elevated level of CEA or CA125 were approximately three times more likely to die. Although the cut-offs for high groups were determined by the median derived from this study's cohort, similar findings were found using standardised, clinical laboratory reference values (Table I).

What is perhaps more interesting is the combined effect of CEA and CA125 on overall survival. Patients with a high CEA and high CA125 were almost six-fold more likely to die than patients with low CEA and low CA125. This suggests that these two mediate tumourigenesis and cancer progression via different, albeit complementary, mechanisms and would not be expected if they were simply markers of tumour volume.

CEA. Serum CEA is a highly glycosylated cell-surface glycoprotein that is linked to invasion and metastasis (7, 18), by targeting intercellular adherens junction complexes (8, 19) and promoting cellular aggregation (9). Moreover, CEA is immunosuppressive (10, 20, 21). We acknowledge that 15-20% of patients with metastatic disease do not have an elevated level of CEA, however, our study found 40% of our patients to have normal CEA levels (0-5 mg/l, 44.7%). This may be due to the eligibility criteria of patients, whereby only patients with small amounts of peritoneal metastases were eligible for CRS and IPC (PCI ~15). A few studies have found that patients with low to normal CEA levels are more likely to have poorly differentiated CRC, and there was a trend for patients with well-/moderately differentiated tumours to have elevated CEA compared to those with poorly differentiated tumours (15, 22).

Despite the lower proportion of poorly differentiated tumours in the group with elevated CEA, univariate analysis of prognostic factors demonstrated CEA >5 mg/l to be correlated with a worse prognosis (p<0.01). Similarly, one previous study demonstrated CEA to be a strong prognostic factor for patients with advanced CRC (15). A stepwise increase in mean CEA with Dukes' stage was reported in 945 patients with stage A, B, C and D (23). A raised CEA level was correlated with poorer survival for all four stages, supporting a relationship to tumour biology. The main limitation in previous studies was not being able to control for the confounding effect of tumour load in patients with advanced CRC.

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Table III.

Prognostic value of tumour markers and survival outcomes, divided according to clinical cut-offs.

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Table IV.

Survival and hazard ratios for patients by carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) quartiles (n=163).

A major strength of our study is the ability to control for tumour load (by using the PCI score). As patients in this study did not have any detectable extra-abdominal disease, PCI reflected the total tumour load. PCI is one of the strongest prognostic factors for overall survival for patients with CRPC as shown in previous studies, as well as in our study (24, 25). Nonetheless, even after controlling for PCI, an elevated CEA level (>5 mg/l and >6.5 mg/l cut-offs) remained a strong prognostic factor. It is important to highlight that the prognostic value of CEA did infact decrease after adjustment for tumour load (PCI) (i.e. HR changed from 3.20 to 2.46, remaining significant), potentially reflecting an association between CEA level and tumour burden. However, linear regression demonstrated that the association between CEA and PCI was not statistically significant. These findings suggest that the absolute serum CEA level reflects aggressive tumour biology, but not tumour burden in patients with CRPC. A second major strength is that the very active preoperative staging of our patients excluded all but tiny undetectable systemic disease, and this together with the complete CRS allows a measure of CEA controlled for PCI, which is likely to reflect the effect of biological behaviour on survival.

CA125. CA125 is mucin 16, a member of the mucin family of glycoproteins (17). CA125 has been shown to play a role in advancing tumourigenesis and tumour proliferation by immune system evasion, metastatic invasion, induced motility and mediating chemotherapy resistance (17, 26). There have been no studies to our knowledge to have examined the prognostic value of CA125 in CRPC. In CRC without peritoneal carcinomatosis, the proportion of patients with elevated CA125 ranges between 22.5% and 54% (15, 27-30). Using a similar cut-off as previous studies (>35 U/ml), this study identified 21.3% of patients had an elevated CA125 level. This is somewhat lower than expected for CRC with peritoneal spread considering that previous studies have found: (a) a higher proportion of elevated CA125 in advanced CRC (54%) (15, 28); (b) elevated CA125/MUC16 in peritoneal diseases such as peritoneal mesothelioma (31); and (c) CA125/MUC16 binding is a high-affinity, N-glycan-dependent interaction that facilitates peritoneal metastasis (32). Survival bias and selection bias for CRS may potentially account for this lower proportion of patients with CA125 >35 U/ml, whereby patients with CRC with elevated CA125 may rapidly develop peritoneal disease and quickly fall outside of the criteria for CRS with IPC (PCI <10-15). This is further supported by the significantly higher PCI for patients with CA125 >16 U/ml (PCI 7.2 vs. 10.3, p=0.002).

Figure 1.
Figure 1.

Kaplan–Meier survival curves for groups with low and high serum carcinoembryonic antigen (CEA) (0-6.5 and >6.5 mg/l, respectively). HR: Hazard ratio; CI: confidence interval; adjusted HR: HR adjusted for Peritoneal Cancer Index.

Figure 2.
Figure 2.

Kaplan–Meier survival curves for low and high cancer antigen 125 (CA125) groups (0-16 and >16 U/ml, respectively). HR: Hazard ratio; CI: confidence interval; adjusted HR: HR adjusted for Peritoneal Cancer Index.

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Table V.

Correlation of carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) with overall survival.

Although the prognostic value of CA125 is unclear for CRC without peritoneal carcinomatosis (27-29), this study demonstrated that elevated CA125 (>16 U/ml or >35 U/ml) is an independent prognostic factor for CRPC (0-16 U/ml vs. >16 U/ml: median survival 61 months vs. 32 months, p<0.001). Interestingly, linear regression demonstrated CA125 to have a positive association with PCI, suggesting that the CA125 level not only reflects aggressive tumour biology, but also a higher tumour load. Future prospective studies examining the correlation between CA125 and tumour load in CRPC are necessary.

Figure 3.
Figure 3.

Kaplan–Meier survival curves for low and high carcinoembryonic antigen (CEA; 0-6.5 and >6.5 mg/l, respectively) and cancer antigen 125 (CA125; 0-16 and >16 U/ml, respectively) groups. HR: Hazard ratio; CI: confidence interval;’ adjusted HR: HR adjusted for Peritoneal Cancer Index.

Limitations. There are several limitations to our study. Firstly, PCI is a somewhat arbitrary method to determine tumour load as it is determined by the surgeon and does not measure the actual cubic volume of tumour. Moreover, as any lesion 0.5 cm to 5 cm in diameter receives a score of 2, it does not allow differentiation between lesions 0.6 cm and 4.5 cm in size. However, PCI is currently the gold standard, internationally accepted method for calculating peritoneal tumour load, and remains one of the strongest prognostic factors for CRPC (24, 25). A second limitation in this study was that our tumour markers were performed by a variety of laboratories. Despite these limitations, a very strong relationship between serum CEA and CA125 levels and survival was seen independently of PCI. Future studies comparing patients whose postoperative levels normalized to those with elevated tumour markers would be interesting.

Figure 4.
Figure 4.

Kaplan–Meier survival curves for low and high cancer antigen 19-9 (CA19-9) groups (0-17 U/ml and >17 U/ml, respectively). HR: Hazard ratio; CI: confidence interval; adjusted HR: HR adjusted for Peritoneal Cancer Index.

Figure 5.
Figure 5.

Kaplan–Meier survival curves for low and high alpha-fetoprotein (AFP) groups (0-2 IU/ml and >2 IU/ml, respectively). HR: Hazard ratio; CI: confidence interval; adjusted HR: HR adjusted for Peritoneal Cancer Index.

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Table VI.

Correlation between carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) quartile groups on overall survival (148 patients with both CA125 and CEA values).

Conclusion

Elevated serum levels of CA125 and CEA are significantly correlated with a poor prognosis in CRPC. If the level of only one of these markers is raised, it approximately triples the risk of death. If both are elevated, there is a summative effect and the risk of death increases six-fold. AFP and CA19-9 had no prognostic role in this study. The identification of CA125 and CEA as prognostic factors independent of tumour load highlights the fact that that elevated values reflect aggressive tumour biology, and not just tumour burden. This gives hope that abrogating or reducing the biological effects of these molecules could improve outcome and could lead to development of a new class of anticancer agents.

Footnotes

  • Conflicts of Interest

    None.

  • Received December 5, 2015.
  • Revision received January 5, 2016.
  • Accepted February 5, 2016.

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Prognostic Value of Carcinoembryonic Antigen (CEA), AFP, CA19-9 and CA125 for Patients with Colorectal Cancer with Peritoneal Carcinomatosis Treated by Cytoreductive Surgery and Intraperitoneal Chemotherapy
YA RUTH HUO, YEQIAN HUANG, WINSTON LIAUW, JING ZHAO, DAVID L. MORRIS
Anticancer Research Mar 2016, 36 (3) 1041-1049;
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