Gastric cancer is a major health problem

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1 Original Article Access this article online Quick Response Code: Website: DOI: / Prognostic significance of carcinoembryonic antigen, carbohydrate antigen 19 9, alpha fetoprotein, and beta human chorionic gonadotropin in gastric cancer patients treated with surgery and chemotherapy regimen Bhawna Bagaria, S. K. Vardey 1, Rameshwaram Sharma 2, Ashish Bagaria 3 Abstract: Objective: The objective was to evaluate the potential usefulness of tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19 9 (CA19 9), alpha fetoprotein (AFP), and beta human chorionic gonadotropin (β HCG) in predicting tumor response in gastric cancer patients after treatment (surgery, chemo, or radiotherapy). Materials and Methods: Fifty patients suffering from gastric cancer and 50 normal healthy subjects were included in the study. CEA, AFP, and β HCG were estimated using commercial IMMULITE 2000 a solid phase, two site sequential chemiluminescent immunometric assay, and CA19 9 using commercial calbiotech CA19 9 enzyme linked immunosorbent assay (ELISA) kit, based on solid phase ELISA. Statistical analysis was done using SPSS Software version 10.0 (SPSS Inc., USA) and MedCalc to estimate the significance of observed differences. Results: Mean serum value of CEA, CA19 9, AFP, and β HCG were significantly higher as compared to healthy control subjects before therapy. After therapy the mean serum level of CEA, CA19 9, AFP, and β HCG were significantly higher in progressive disease an insignificant difference was seen in stable condition, and significantly lower results were seen in improved condition as compared to levels before therapy. Conclusion: The measurement of CEA, CA19 9, AFP, and β HCG blood levels during the course of gastric cancer treatment has valuable clinical significance for the efficacy of treatment. Key words: Alpha fetoprotein, beta human chorionic gonadotropin, carcinoembryonic antigen, carbohydrate antigen 19 9 Department of Biochemistry, S.D.M. Hospital, Departments of 1 Biochemistry, 2 Radiotherapy and Oncology and 3 Pathology, S.M.S. Medical College and Hospital, Jaipur, Rajasthan, India Address for correspondence: Dr. Bhawna Bagaria, Department of Biochemistry, S.D.M. Hospital, Jaipur, Rajasthan, India. E mail: bhawna_bagaria@ yahoo.com Submission: Accepted: Introduction Gastric cancer is a major health problem worldwide remaining one of the most common digestive tract cancers. Even when surgical resection is possible, long term survival is observed only in a minority of patients, with overall 5 years survival <30% following gastrectomy. [1] Surgery alone can cure only a minority of gastric cancer patients, the development of symptomatic metastatic disease from unresected microscopical tumor remnants being the main cause of death. [2] As chemotherapy alone has not shown benefit, treatment with a combination of chemo and radio therapy is advocated. Trials assessing the efficacy of neo adjuvant chemoradiation therapy are currently in progress. [3] Serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19 9 (CA19 9) measurements have been shown to be useful aids in detection of recurrence in patients following surgery, increasing level of tumor markers are inversely related to postoperative survival. [4] Additional markers that have been studied in relation to prognosis include Alpha fetoprotein (AFP), cytokeratins, and free beta subunit of human chorionic gonadotropin (hcg β), which appears to be pan marker for tumor activity. [5] Monitoring response to therapy is an important tool which can spare nonresponding patients potentially from serious side effects of chemo (radiation) therapy. While the investigations are limited, results suggest that tumor markers correlate well with responses measured by conventional imaging techniques. [6] The prevalence of positive tumor markers among gastric cancer patients selected for treatment is low, and when positive, they have been considered to provide little in the way of prognostic value. Oncobiology and Targets - Vol 2 Issue 1 Jan-Feb

2 Therefore, our study was planned to evaluate the potential usefulness of tumor markers CEA, CA19 9, AFP, and beta human chorionic gonadotropin (β HCG) in predicting tumor recurrence, that is, progressive disease, stable and improved condition after therapy for histologically confirmed gastric cancer cases. Materials and Methods This study was conducted after approval from the Institutional Research Committee S.M.S. Medical College and Hospital, (Rajasthan University of Health Sciences) Jaipur, Rajasthan, India. Ref. no. RS/278. Informed consent was obtained from all the patients enrolled in the study. We used SPSS Software version 10.0 (SPSS Inc. USA) and MedCalc to estimate the significance of the observed difference and calculate the percentage. Fifty patients freshly diagnosed from gastric cancer were selected for the study they later underwent surgery or chemotherapy according to disease status and clinician advice. Each patient was strictly examined first by brief clinical history related to diet, lifestyle, initial symptoms or any treatment received before. The patients were studied before and after receiving therapy. 50 healthy subjects were taken as normal control group. The study was conducted from July 2011 to December 2012 in S.M.S. Medical College and Hospital, Jaipur, India. The patients and healthy subjects were categorized into: Group 1: 50 patients suffering from gastric cancer Group 2: 50 normal healthy subjects. Inclusion criteria Group 1: Included histologically confirmed gastric cancer patients, initially diagnosed and not received any treatment before, for after therapy study same patients were taken as follow up after 6 months of treatment (surgery/radiotherapy/ chemotherapy regimen: Cisplatin, 5 FU, oxaliplatin, and leucovorin). Group 2: Included healthy subject who were not suffering from any physical ailment, acute illness, without hospitalization for any disease during previous 2 years and were not having any addiction to smoking, tobacco, or alcohol consumption. Females who were not pregnant were included in the study group. Exclusion criteria Cancer patients who have received surgery or chemotherapy (those who started the treatment recently or are old patients receiving treatment from several months back) were excluded Healthy subjects with any sort of gastrointestinal infections or disease, suffering from acute illness or hospitalized recently, people who were addicted to smoking, alcohol or tobacco consumption, female who were pregnant were excluded. Physical examination was performed by a combination of clinical and radiological means including biopsy, chest X rays, ultrasonography, computerized axial tomography, selective hepatic arteriography, peritoneoscopy, gastroscopy, colonoscopy, fiber optic esophagoscopy, bone scan, biochemical, and hematological assays as indicated. The chemo radiotherapeutic effect was evaluated on the basis of comparison of initial pretreatment and posttreatment imaging findings. The patients were accordingly classified in categories of progressive, stable or improved condition. Sample collection The blood samples were collected two times, that is, before treatment and 6 months after treatment, and as a part of the routine investigation in healthy subjects. Samples were taken in plain vial and allowed to clot. Serum was separated by centrifuging at 3000 rpm for 10 min and stored at 20 C till further assay was performed. CEA, AFP, and β HCG estimation was carried out using commercial IMMULITE 2000 a solid phase, two site sequential chemiluminescent immunometric assay (IMMULITE 2000 Systems, Siemens health care diagnostics product Ltd. Llanberis, Gwynedd, UK). CA19 9 estimation was carried out using commercial calbiotech CA19 9 enzyme linked immunosorbent assay (ELISA) Kit, based on solid phase ELISA (CA19 9 ELISA kit 96 T CalBiotech, USA). The tests were performed strictly according to the manufacturer s instruction stated in the literature. Due to frequent false positive outcomes caused by benign GI disorders and smoking, the generally adherent threshold value of CEA in GI cancers according to the kit used was: Male smokers: 6.2 ng/ml Male nonsmokers: 3.4 ng/ml Female smoker: 4.9 ng/ml Female nonsmokers: 2.5 ng/ml. For CA19 9, healthy men and women were expected to have values below 35 U/ml For AFP (IU/ml) normal range was IU/ml For β HCG (miu/ml) normal range for male was <2.5 miu/ml, and for female it was <5.3 miu/ml. Statistical analysis The aim of the study was to investigate the prognostic significance of four tumor markers CEA, CA19 9, AFP and β HCG in gastric cancer patients treated with surgery and chemoradiotherapy regimen. The test were performed before receiving therapy or before surgery and compared with levels of healthy control to evaluate any significant change. After 6 months of receiving treatment same tests were repeated and compared with pre therapy results to find out the change in levels of various markers and to analyze how they correlate with various clinical conditions (progressive, stable, improved) evaluated by imaging studies. Statistical analysis was performed using SPSS Software version 10.0 (SPSS Inc., USA) and MedCalc to estimate the significance of the observed differences. For the determination of significance, P < 0.05 was considered as statistically significant. determination of tumor markers was analyzed in different clinical status of disease. All the data were reported as mean ± standard deviation. Bar diagrams were constructed for statistical analysis. The differences between the measurements of each parameter were plotted against their means. Results Tables 1 and 2 shows general data of gastric cancer patients collected after taking clinical history. 14 Oncobiology and Targets - Vol 2 Issue 1 Jan-Feb 2015

3 Table 1 shows age and gender of gastric cancer patients and healthy control subjects as well as their comparison. Table 2 shows clinicopathologic characteristics and treatment modalities in gastric cancer patients. Table 3 and Figure 1 show mean serum values of tumor markers in gastric cancer patients and healthy control subjects. Table 4 and Figure 2 show mean serum value of tumor markers in gastric cancer patients after therapy in progressive, stable, and improved clinical condition. Table 1: Age and gender of gastric cancer patients compared with healthy control Variable Control Gastric cancer χ 2 (df) P Age < (1) Sex Male (1) Female The gastric cancer groups and healthy subject group were comparable (P>0.05). In the current study, majority of gastric cancer patients belonged to the age group below 60 years. Males had higher prevalence of gastric cancer when compared to females Table 2: Clinicopathologic characteristics and treatment modalities in gastric cancer patients Clinicopathologic characteristics Gastric cancer and treatment modalities Histopathology adenocarcinoma 42 Well differentiated 8 Moderately differentiated 22 Poorly differentiated 12 Signet ring cell 8 Mucinous - Metastasis 11 Lymph node metastasis 7 Liver metastasis 4 Treatment modalities Chemotherapy 11 Radiotherapy - Chemotherapy+radiotherapy 16 Surgery 2 Surgery+radiotherapy 3 Surgery+chemotherapy 14 Surgery+radiotherapy+chemotherapy 4 Adenocarcinoma predominates in gastric cancer. Lymph node metastasis is common the treatment modality is mainly chemotherapy either given alone or combined with surgery and radiotherapy Table 5 and Figure 3 show the positive and negative percentage of CEA, CA19 9, AFP, and β HCG in progressive, stable, and improved condition. Discussion In our study change in tumor marker levels after treatment (surgery or chemoradiotherapy) were compared with levels before treatment, a definite rise in tumor markers were seen in progressive disease, those in which tumor markers were not changed were relatively stable, those in which levels decreased were with a good response to treatment. Our results are according to the conclusions drawn by previous studies where a significant correlation was seen between the assessment of tumor marker response to serum level of tumor markers to successfully predict the prognosis of patients with advanced gastric cancer. [7] Our results were contradictory to studies given by Pectasides et al. that investigates the clinical utility of CEA, CA19 9, and CA 50 in the diagnosis, monitoring, and prognosis of 62 gastric carcinoma patients and estimated that only CA19 9 and CA 50 were useful for early detection of recurrence after curative surgery and adjuvant chemotherapy. [8] Tas et al. found CA19 9 was more sensitive than CEA for predicting relapse in patients with gastric cancer after radical surgery, the difference may be important in terms of clinical studies. [9] We found in our results that CEA along with CA19 9 was useful in predicting the clinical response in gastric cancer patients. The overexpression of CEA on the basolateral surface of cancer cells is believed to contribute to the disruption of normal intercellular and cell collagen bonds, thus precipitating a disordered histological architecture and facilitating cellular emigration. When free in circulation, CEA acts as an aggregant which facilitates entrapment of circulating tumor cells within the microvasculature of the liver. Figure 1: Mean serum values of tumor markers in gastric cancer patients and healthy control subjects Table 3: Statistical evaluation of serum tumor markers in healthy control subjects and gastric cancer patients before therapy Group CEA CA 19-9 AFP Beta-HCG Control group 2.23±0.82 ( ) 17.18±8.49 ( ) 2.12±1.02 ( ) 2.35±1.48 ( ) Gastric cancer 6.23±7.73**** (1-30) 28.11±18.14**** ( ) 3.95±3.92*** ( ) 4.93±5.84*** ( ) *No significant difference (P>0.05), **Mild significant difference (P<0.05), ***Highly significant difference (P<0.01), ****Very high significant difference (P<0.001). Mean serum value of CEA, CA 19-9, AFP and β-hcg was significantly higher as compared to healthy control subjects. CEA: Carcinoembryonic antigen, CA 19-9: Carbohydrate antigen 19-9, AFP: Alpha fetoprotein, β-hcg: Beta human chorionic gonadotropin Oncobiology and Targets - Vol 2 Issue 1 Jan-Feb

4 Table 4: Statistical evaluation of tumor markers after therapy (progressive/stable/improved) condition versus tumor markers levels before therapy Clinical status CEA CA 19-9 AFP β-hcg Pre-therapy 6.23±7.73 ( ) 28.11±18.14 ( ) 3.95±3.92 ( ) 4.93±5.84 ( ) Progressive (n=21) 10.68±8.62** ( ) 36.79±13.13** ( ) 5.80±3.07** ( ) 8.42±6.52** ( ) Stable (n=18) 4.04±1.87* ( ) 21.74±9.04* ( ) 3.01±1.60* ( ) 3.22±1.81* ( ) Improved (n=11) 1.96±1.11**** ( ) 16.46±7.10*** ( ) 1.77±0.55**** ( ) 2.2±1.27*** ( ) *No significant difference (P>0.05), **Mild significant difference (P<0.05), ***Highly significant difference (P<0.01), ****Very high significant difference (P<0.001). Mean serum values of tumor markers CEA, CA 19-9, AFP, and β-hcg were significantly higher in progressive disease, in stable condition the difference was insignificant and in improved condition mean serum level of tumor markers were significantly lower as compared to levels before therapy. CEA: Carcinoembryonic antigen, CA 19-9: Carbohydrate antigen 19-9, AFP: Alpha fetoprotein, β-hcg: Beta human chorionic gonadotropin Table 5: Tumor markers (CEA, CA 19-9, AFP, β-hcg) in percentage versus clinical status (progressive, stable, and improved condition) Clinical status CEA CA 19-9 AFP β-hcg of CEA (+) of CEA ( ) of CA 19-9 (+) of CA 19-9 ( ) of AFP (+) of AFP ( ) of β-hcg (+) of β-hcg ( ) Progressive (42%) Stable (36%) Improved (22%) The percentage of positive CEA, CA 19-9, AFP and β-hcg was higher in progressive disease, as compared to levels in stable condition. The percentage of positive CEA, CA 19-9, AFP, and β-hcg were very low in improved condition. CEA: Carcinoembryonic antigen, CA 19-9: Carbohydrate antigen 19-9, AFP: Alpha fetoprotein, β-hcg: Beta human chorionic gonadotropin Figure 2: Mean serum value of tumor markers in gastric cancer patients after therapy in progressive, stable and improved clinical condition. PT: Pre therapy, P: Progressive disease, S: Stable condition, I: Improved condition In experimental models, tumors which produce CEA have a higher rate of metastatic implantation within the liver, as opposed to other sites, than non CEA procedures. Due to its structural similarity to immunoglobulins CEA has some immunoregulatory function. It has been to found to inhibit T B cell cooperation, induce suppressor T cell activity, and inhibit natural killer cell cytolysis. For all these reasons, an elevated serum CEA level while reflecting a poor prognosis on the basis of an increased tumor load may be directly contributing to tumor metastatic potential. [10] Postoperative serum CA19 9 elevation was better related to peritoneal recurrence than to liver metastasis. The mechanism of peritoneal seeding is generally accepted as most of the free tumor cells are sloughed from the primary tumor, but some might have come from other sources, for example, lymph nodes, ovary, or liver, tumor invasion to peritoneal mesothelial cells might stimulate the expression of CA19 9 with another possibility being that tumor cells with expression of CA19 9 might have higher behavior ability of peritoneal metastasis pathway and may function as adhesion molecules, adhesion of tumor cells to the endothelial cell of blood vessels may be mediated by an interaction between Sialyl Lewis and E selectin and tumor cell induced % CEA (+) % CEA (-) % CA19-9 (+) % CA19-9 (-) % AFP (+) % AFP (-) % β-hcg (+) IMPROVED STABLE PROGRESSIVE % β-hcg (-) Figure 3: The positive and negative percentage of CEA, CA19-9, AFP and Beta- HCG in progressive, stable and improved condition platelet aggregation. [11] Thus, high pre CA19 9 might provide the important information needed to predict the subsequently possible peritoneal seeding of tumors not detected in radiologic examination and help the decision to treat patients. [12] One study confirmed that as the primary tumor size became larger the serum CEA positive cases become more abundant. The recurrence rate after curative surgery was significantly higher in the serum CEA positive group. [13] Researchers continue to evaluate the prognostic significance of CEA in patients with gastric cancer in order to individualize treatment approaches. Patients with higher CEA levels had a significantly higher rate of cancer recurrences within the peritoneal cavity than those with normal or lower CEA levels, also CEA levels within the peritoneal cavity are strongly associated with mortality among patients with early gastric cancer that has been surgically removed. [14] Although CEA as a marker for gastric cancer has a low sensitivity, when levels of this antigen are elevated, it may correlate with the stage of the cancer involved. The sensitivity of this marker can be improved in the detection of gastric cancer 16 Oncobiology and Targets - Vol 2 Issue 1 Jan-Feb 2015

5 by combining CEA results with outcomes of other markers such as sialylated Lewis antigens CA19 9 or CA50. [15] An earlier study from Thaker suggested serial measurements of CA19 9 may be useful during and following cancer treatment and may give the doctor important information whether treatment is working, whether all the cancer was removed successfully during surgery, and whether the cancer is recurring. [16] Ishigami et al. evaluated levels of CEA and CA19 9 preoperatively in all gastric cancer patients and analyzed correlations between CEA or CA19 9 and clinicopathologic features, and estimated the prognostic utility of these tumor markers. Serum CEA levels were significantly correlated with serum CA19 9 levels and influenced prognosis. [17] In our study, we found significant changes in AFP values in progressive, stable, and improved conditions of gastric cancer patients. In a study, it was seen there was a higher incidence of lymph node metastasis, a deeper invasion of gastric wall, a higher frequency of advanced stage, a more marked lymphatic invasion in the AFP(+) group than in the AFP ( ) group. AFP producing gastric cancers had aggressive behavior and their clinical or biological features were quite different from the AFP ( ) gastric cancers. [18] It has been reported that AFP producing gastric cancer has high proliferative activity, weak apoptotic activity, and rich neovascularization compared with AFP ( ) gastric cancer. It is likely that these biological observations reflect the aggressive clinical behavior of AFP producing gastric cancer. [19] Recent reports described that some factors associated with mitosis, cell movement, proliferative activity, and tumor progression such as Ki 67, hepatocyte growth factor, and its receptor, c Met, vascular endothelial growth factor (VEGF), and its isoform VEGF C, were found to be highly expressed in AFP producing gastric cancer and might contribute to the poor prognosis and drug resistance of this tumor. [20] Choi et al. found the potential usefulness of the tumor markers CEA, CA19 9, and AFP in predicting tumor recurrence after radial gastrectomy for histologically confirmed gastric adenocarcinoma, they suggested that a recurrence in peritoneum should be considered in patients whose AFP at the time of initial diagnosis is elevated and those in whom the CA19 9 increases during postoperative follow up. [21] Tomiyama et al. examined AFP producing gastric cancer is a rare condition with a high incidence of liver metastasis and a poor prognosis that accounts for only % of malignant gastric tumors. Serum AFP levels are generally understood to elevate in association with recurrence. Measures of serum AFP levels have therefore been used as markers during the postoperative follow up period. [22] Adachi et al. reported serum AFP is sometimes high in patients with primary gastric carcinoma. The survival was influenced by the serum AFP level, tumor size, serosal invasion, lymph node metastasis, and liver metastasis. [23] Significant changes in β HCG values in progressive, stable, and improved conditions of gastric cancer patients were seen in our study. The work of Acevedo and his colleagues has repeatedly shown that the presence of complete hcg β (i.e., hcg β with the carboxy terminal peptide), has a significant presence in the cell membranes of cultured fetal and cancer cell. Its expression in cancer defines the metastatic aggressiveness of the tumors in which it is found. HCG must now join with the above biomarkers as a key factor defining the metastatic phenotype. Cancer incidence, regardless of whether it is of viral, chemical, or radiation origin expresses hcg β, and this should not be surprising because sialoglycoproteins on the tumor cell surface have a long history of association with invasiveness and metastasis. [24] Louhimo et al. evaluated the prognostic significance of serum tumor markers CEA, CA19 9, CA 72 4, CA 242 and free hcg β in gastric cancer, (hcg β) has been reported to be expressed in various digestive tract malignancies, and have previously shown a sensitivity of 41% in serum of gastric cancer patients. [25] Lundin et al. suggested that hcg has an immunosuppressive effect by changing the cell mediated and humoral immune response to the stimulus of cancer antigens and that hcg on the tumor surface suppresses the action of T cells, thereby favoring highly proliferative activity and invasive capacity. Furthermore, hcg positive tumors have a multifaceted resemblance to trophoblastic tissue, which has been suggested to be a contributory factor to the more aggressive behavior. [26] Marked elevations of AFP or β hcg were associated with very few disease states. In patients with extragonadal disease or metastasis at the time of diagnosis, highly elevated AFP or β hcg values can be used in place of biopsy to establish a diagnosis of the nonseminomatous germ cell tumor. Following AFP and β hcg levels is imperative in monitoring response to treatment in patients who have nonseminomatous germ cell tumors. Patients with AFP and β hcg levels that do not decline as expected after treatment have a significantly worse prognosis, and changes in therapy should be considered. [27] Conclusion Our present study confirms the suggestion that the measurement of CEA, CA19 9, AFP, and β HCG blood levels before and during follow up of gastric cancer treatment has valuable clinical significance as an indicator for the efficacy of treatment. The response correlated well with patient s state of health (progressive, stable, and improved conditions as visualized by imaging). The procedures such as X ray, magnetic resonance imaging, scanner, etc., are not only expensive but have a greater risk for human health. By using the information that these markers can provide, patient specific treatment protocols can be developed, implemented, and monitored for improved patient outcomes. Acknowledgment We express our sincere thanks to the Cancer Radiotherapy Department, S.M.S. Medical College and Hospital, Jaipur, India for providing their help in the above study. References 1. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the different disease hypothesis. Cancer 2000;88: Sturgeon CM, Diamandis EP, editors. The National Academy Oncobiology and Targets - Vol 2 Issue 1 Jan-Feb

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J Clin Oncol 2001;19: How to cite this article: Bagaria B, Vardey SK, Sharma R, Bagaria A. Prognostic significance of carcinoembryonic antigen, carbohydrate antigen 19-9, alpha fetoprotein, and beta human chorionic gonadotropin in gastric cancer patients treated with surgery and chemotherapy regimen. Oncobiol Targets 2015;2:13-8. Source of Support: Nil, Conflict of Interest: None declared. 18 Oncobiology and Targets - Vol 2 Issue 1 Jan-Feb 2015