Clinical Study | Open Access
Yutaka J. Kawamura, Aika Tokumitsu, Junichi Sasaki, Shingo Tsujinaka, Takafumi Maeda, Ken Mizogami, Fumio Konishi, "Colorectal Carcinoma with Extremely Low CA19-9", Gastroenterology Research and Practice, vol. 2009, Article ID 780263, 4 pages, 2009. https://doi.org/10.1155/2009/780263
Colorectal Carcinoma with Extremely Low CA19-9
Aim. The aim of this study is to determine the significance of postoperative sequential measurements of serum CA19-9 in patients with extremely low serum level. Patients and Methods. Serum level of CA19-9 of 1096 patients who underwent surgery was measured preoperatively and every three months after surgery for 5 years. Patients with CA19-9 level of less than 2 U/mL at the time of diagnosis were defined as Extremely Low CA19-9 (ELCA). Results. One hundred and seven patients (9.8%) were ELCA. Of these, 86 underwent surgery with curative intent. Serum levels of CA19-9 in patients who did not undergo curative resection () and who developed recurrence () were less than 2.0 U/mL in all occasions during followup. In all patients without recurrence, serum level of CA19-9 also remained less than 2.0 U/mL. Conclusion. In patients with extremely low CA19-9, who consist of 9.8% of colorectal carcinoma cases, postoperative sequential measurement of serum level of CA19-9 contributed neither to assessment of curability of surgical resection nor to detection of recurrence.
For patients with colorectal carcinoma, assessment of curability of the surgery as well as that of recurrence is a very important issue. In fact, the close follow up program aiming at early detection of the recurrence after potentially curative surgery has been reported to improve survival rate [1–6]. Although the “best” program for detection of the recurrence and for the treatment failure is not yet determined, the combination of two modalities such as imaging studies and tumor markers is generally used.
Among tumor markers used in the field of gastroenterology, carcinoembryonic antigen (CEA) has been recommended in several guidelines and widely used for postoperative follow up as well as for the assessment of efficacy of the treatment [7–9]. CA19-9 has also been used as a tumor marker for colorectal carcinoma [10–13], usually accompanied with CEA [14–17].
CA19-9 is an antibody to carbohydrate chain sialyl Lewis a () which is synthesized by gylcosyltransferases , and it is well known that in certain group of patients serum level of CA19-9 is very low [19, 20]. However, little is known about the serum level of CA19-9 in these patients with special regards to progression and recurrence of colorectal carcinoma. The aim of this study is to clarify the changes of serum level of CA19-9 in these patients and elucidate its clinical significance.
2. Materials and Methods
Patients with colorectal carcinoma who were treated from 2000 to 2005 in our department were studied. Serum level of CA19-9 was measured preoperatively and every three month for 5 years postoperatively. If postoperative serum CA19-9 was elevated above the normal limit, the measurement was done after one month. And if elevation continued, imaging study was performed. In this study, the recurrence was diagnosed by the imaging studies, not solely by the elevation of tumor marker. Serum CA19-9 was measured by chemiluminescence enzyme immunoassay method. The upper limit of normal range was 37 U/mL, and the lowest measuring limit was 2 U/mL. Patients with CA19-9 level of less than 2 U/mL at the time of diagnosis of colorectal carcinoma were clinically defined as Extremely Low CA19-9 (ELCA). The change of serum CA19-9 level in these patients was analyzed with special regards to recurrence of colorectal carcinoma.
This study was approved by the Institutional Review Board. Informed consent from each patient was exempted by the Institutional Review Board of Jichi Medical University due to retrospective nature of this study.
From 2000 to 2007, 1096 patients with colorectal carcinoma were treated. Of these patients, 107 (9.8%) were ELCA. There were 65 males and 42 females with mean age of 64.0 (range, 29–86). Mean follow up period was 3.8 years (range: 1.0 to 5.3 years), and serum CA19-9 was measured 1626 times for these 107 patients. Numbers of patients with carcinoma in the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum were 8, 19, 5, 2, 31, and 42, respectively. Numbers of patients with clinical stages I, II, III, and IV were 31, 32, 27, and 17, respectively (Table 1).
Clinical course of these patients was represented in Figure 1. Of 17 patients with stage IV disease, five patients did not undergo surgery, and seven patients underwent resection with noncurative intent. These 12 patients remained to be clinically CA19-9 negative during follow up.
All patients with stages I, II, and III and five patients with stage IV disease underwent potentially curative surgery, and 15 patients developed recurrence. Serum levels of CA19-9 were less than 2.0 U/mL during follow up in patients both with and without recurrence.
Early detection of the recurrence after potentially curative surgery is an important issue in management of the patients with colorectal carcinoma [1–6]. Several studies revealed improved survival by intensive postoperative follow up program. Although there are differences in follow up programs among the studies, the imaging study and the measurement of serum tumor marker are included in postoperative follow up.
, which is recognized by CA19-9, is a carbohydrate chain which is expressed on tumor cells and is known to play a role in adhesion between tumor cells and endothelial cells . is secreted into the serum and is used as a tumor marker for pancreatic, hepatobiliary, gynecological, and colorectal carcinoma [9, 23–25]. Several studies revealed the usefulness of the measurement of serum CA19-9 [10–15, 26–29]; however, some studies failed to show its usefulness [30–34], and measurement of CA19-9 has not been recommended in guidelines [7–9]. Main focus of the previous studies was its accuracy in terms of predicting prognosis and its relevance to recurrence, though, only a few studies paid attention for patients with low serum CA19-9 value [19, 20].
In this study, we analyzed the serum level of CA19-9 in patients with colorectal carcinoma in order to clarify the changing pattern in serum CA19-9 and to determine the clinical role of its measurement. CA19-9 is an antigen which recognizes carbohydrate chain and the value of CA19-9 means the amount of the carbohydrate chains in sera, which is called secreted type . The amount of secreted type is determined by phenotype of both the Lewis (Le) and secretor (Se) genes. Narimatsu studied the correlation between phenotype of these two genes and the amount of serum and found that there is no secretion of in patients with phenotype of le/le and se/se. However, there are only a few studies concerning patients with low serum CA19-9 level. In this study, we defined ELCA as having lower than measuring limit and studied the relation of clinical course and serum level of CA19-9 [19, 20].
Although the synthesis of CA19-9 increases in a certain group of patients with colorectal carcinoma, particularly those with advanced disease, this study demonstrated that serum level of CA19-9 remains lower than the measurable limit in all ELCA cases irrespective of the stage at the time of diagnosis, progression, and recurrence. Our clinical definition of ELCA may include not only genetic Lewis negative cases but also the case with very weak expression of CA19-9; however, with our broad definition of Lewis negativity, our study showed no benefit of serial measurement of serum CA19-9 in patients with colorectal carcinoma whose serum level of CA19-9 was lower than measurable limit at the initial assessment.
Further investigation is necessary to elucidate the significance of CA19-9 in entire patients with colorectal carcinoma; however, we found that our criterion of ELCA is practically useful to determine the group of patients for whom serial measurement of serum CA19-9 is not contributory for clinical management. Additionally, because the previous studies focusing on the clinical significance of CA19-9 included patients who do not secrete CA19-9, who consisted of 9.8% of the patients with colorectal carcinoma, the exclusion of these patients may provide more precise information concerning the clinical significance of serum CA19-9.
We conclude that the measurement of serum CA19-9 should be omitted irrespective of clinical setting if the result of the first measurement of serum CA19-9 was less than lower limit. Because CA19-9 was used in variety of adenocaricnoma, we believe that further investigation concerning the clinical significance of CA19-9 in patients with other organ malignancies with less than measuring limit may facilitate the saving of medical cost.
The Authors thank Dr. Wendy Gray for her assistance in preparation of this manuscript.
- B. J. Kjeldsen, O. Kronborg, C. Fenger, and O. D. Jorgensen, “A prospective randomized study of follow-up after radical surgery for colorectal cancer,” British Journal of Surgery, vol. 84, no. 5, pp. 666–669, 1997.
- G. B. Secco, R. Fardelli, D. Gianquinto et al., “Efficacy and cost of risk-adapted follow-up in patients after colorectal cancer surgery: a prospective, randomized and controlled trial,” European Journal of Surgical Oncology, vol. 28, no. 4, pp. 418–423, 2002.
- F. Rodríguez-Moranta, J. Saló, À. Arcusa et al., “Postoperative surveillance in patients with colorectal cancer who have undergone curative resection: a prospective, multicenter, randomized, controlled trial,” Journal of Clinical Oncology, vol. 24, no. 3, pp. 386–393, 2006.
- A. Figueredo, R. B. Rumble, J. Maroun et al., “Follow-up of patients with curatively resected colorectal cancer: a practice guideline,” BMC Cancer, vol. 3, article 26, 2003.
- G. M. Jeffery, B. E. Hickey, and P. Hider, “Follow-up strategies for patients treated for non-metastatic colorectal cancer,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD002200, 2002.
- A. G. Renehan, M. Egger, M. P. Saunders, and S. T. O'Dwyer, “Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials,” British Medical Journal, vol. 324, no. 7341, pp. 813–816, 2002.
- C. E. Desch, A. B. Benson III, M. R. Somerfield et al., “Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline,” Journal of Clinical Oncology, vol. 23, no. 33, pp. 8512–8519, 2005.
- C. Fucini, S. M. Tommasi, S. Rosi et al., “Follow-up of colorectal cancer resected for cure: an experience with CEA, TPA, Ca 19-9 analysis and second-look surgery,” Diseases of the Colon and Rectum, vol. 30, no. 4, pp. 273–277, 1987.
- G. Y. Locker, S. Hamilton, J. Harris et al., “ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer,” Journal of Clinical Oncology, vol. 24, no. 33, pp. 5313–5327, 2006.
- H. Katoh, K. Yamashita, Y. Kokuba et al., “Surgical resection of stage IV colorectal cancer and prognosis,” World Journal of Surgery, vol. 32, no. 6, pp. 1130–1137, 2008.
- V. Liska, L. Holubec Jr., V. Treska et al., “Dynamics of serum levels of tumour markers and prognosis of recurrence and survival after liver surgery for colorectal liver metastases,” Anticancer Research, vol. 27, no. 4C, pp. 2861–2864, 2007.
- T. C. Mineo, V. Ambrogi, G. Tonini et al., “Longterm results after resection of simultaneous and sequential lung and liver metastases from colorectal carcinoma,” Journal of the American College of Surgeons, vol. 197, no. 3, pp. 386–391, 2003.
- W.-S. Wang, J.-K. Lin, T.-J. Chiou et al., “CA 19-9 as the most significant prognostic indicator of metastatic colorectal cancer,” Hepato-Gastroenterology, vol. 49, no. 43, pp. 160–164, 2002.
- W. Reiter, P. Stieber, C. Reuter, D. Nagel, U. Lau-Werner, and R. Lamerz, “Multivariate analysis of the prognostic value of CEA and CA 19-9 serum levels in colorectal cancer,” Anticancer Research, vol. 20, no. 6D, pp. 5195–5198, 2000.
- T. Sato, G. Nishimura, A. Nonomura, K. Miwa, and I. Miyazaki, “Serological studies on CEA, CA 19-9, STn and SLX in colorectal cancer,” Hepato-Gastroenterology, vol. 46, no. 26, pp. 914–919, 1999.
- T. Nozoe, T. Rikimaru, E. Mori, T. Okuyama, and I. Takahashi, “Increase in both CEA and CA19-9 in sera is an independent prognostic indicator in colorectal carcinoma,” Journal of Surgical Oncology, vol. 94, no. 2, pp. 132–137, 2006.
- C.-C. Chen, S.-H. Yang, J.-K. Lin et al., “Is it reasonable to add preoperative serum level of CEA and CA19-9 to staging for colorectal cancer?” Journal of Surgical Research, vol. 124, no. 2, pp. 169–174, 2005.
- M. K. Gupta, R. Arciaga, L. Bocci, R. Tubbs, R. Bukowski, and S. D. Deodhar, “Measurement of a monoclonal-antibody-defined antigen (CA19-9) in the sera of patients with malignant and nonmalignant diseases. Comparison with carcinoembryonic antigen,” Cancer, vol. 56, no. 2, pp. 277–283, 1985.
- H. Narimatsu, H. Iwasaki, F. Nakayama et al., “Lewis and secretor gene dosages affect CA19-9 and DU-PAN-2 serum levels in normal individuals and colorectal cancer patients,” Cancer Research, vol. 58, no. 3, pp. 512–518, 1998.
- H. Narimatsu, H. Iwasaki, S. Nishihara et al., “Genetic evidence for the Lewis enzyme, which synthesizes type-1 Lewis antigens in colon tissue, and intracellular localization of the enzyme,” Cancer Research, vol. 56, no. 2, pp. 330–338, 1996.
- Y. Munemoto, Y. Iida, J. Abe et al., “Significance of postoperative adjuvant immunochemotherapy after curative resection of colorectal cancers: association between host or tumor factors and survival,” International Journal of Oncology, vol. 20, no. 2, pp. 403–411, 2002.
- V. Trillet-Lenoir, F. Chapuis, S. Touzet et al., “Any clinical benefit from the use of oncofoetal markers in the management of chemotherapy for patients with metastatic colorectal carcinomas?” Clinical Oncology, vol. 16, no. 3, pp. 196–203, 2004.
- O. Uygur-Bayramiçli, R. Debak, E. Orbay et al., “Type 2 diabetes mellitus and CA 19-9 levels,” World Journal of Gastroenterology, vol. 13, no. 40, pp. 5357–5359, 2007.
- M. Carpelan-Holmström, J. Louhimo, U.-H. Stenman, H. Alfthan, and C. Haglund, “CEA, CA 19-9 and CA 72-4 improve the diagnostic accurary in gastrointestinal cancers,” Anticancer Research, vol. 22, no. 4, pp. 2311–2316, 2002.
- F. Safi, T. Kuhns, and H. G. Beger, “Comparison of CA 72-4, CA 19-9 and CEA in the diagnosis and monitoring of gastric cancer,” International Journal of Biological Markers, vol. 10, no. 2, pp. 100–106, 1995.
- T. Nakagoe, T. Sawai, T. Tsuji et al., “Preoperative serum level of CA19-9 predicts recurrence after curative surgery in node-negative colorectal cancer patients,” Hepato-Gastroenterology, vol. 50, no. 51, pp. 696–699, 2003.
- N. M. Forones and M. Tanaka, “CEA and CA 19-9 as prognostic indexes in colorectal cancer,” Hepato-Gastroenterology, vol. 46, no. 26, pp. 905–908, 1999.
- T. Nakayama, M. Watanabe, T. Teramoto, and M. Kitajima, “CA19-9 as a predictor of recurrence in patients with colorectal cancer,” Journal of Surgical Oncology, vol. 66, no. 4, pp. 238–243, 1997.
- M. Diez, F. J. Cerdán, M. Pollán et al., “Prognostic significance of preoperative serum CA 19.9 assay in patients with colorectal carcinoma,” Anticancer Research, vol. 14, no. 6B, pp. 2819–2825, 1994.
- M. Gasser, C. Gerstlauer, M. Grimm et al., “Comparative analysis of predictive biomarkers for therapeutical strategies in colorectal cancer,” Annals of Surgical Oncology, vol. 14, no. 4, pp. 1272–1284, 2007.
- S. Morita, T. Nomura, Y. Fukushima, T. Morimoto, N. Hiraoka, and N. Shibata, “Does serum CA19-9 play a practical role in the management of patients with colorectal cancer?” Diseases of the Colon and Rectum, vol. 47, no. 2, pp. 227–232, 2004.
- A. Takeda, H. Shimada, K. Nakajima et al., “Serum p53 antibody as a useful marker for monitoring of treatment of superficial colorectal adenocarcinoma after endoscopic resection,” International Journal of Clinical Oncology, vol. 6, no. 1, pp. 45–49, 2001.
- A. Webb, P. Scott-Mackie, L. D. Cunningham et al., “The prognostic value of CEA, HCG, AFP, CA125, CA19-9 and c-erb b-2, HCG immunohistochemistry in advanced colorectal cancer,” Annals of Oncology, vol. 6, no. 6, pp. 581–587, 1995.
- W. M. Thomas, J. F. R. Robertson, M. R. Price, and J. D. Hardcastle, “Failure of CA19-9 to detect asymptomatic colorectal carcinoma,” British Journal of Cancer, vol. 63, no. 6, pp. 975–976, 1991.
Copyright © 2009 Yutaka J. Kawamura et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.