Tumor markers in finding recurrent disease in colorectal cancer: a diagnostic review

Charlotte Verberne, Helma de Jong, Irene Grossmann, Geertruida de Bock, Theo Wiggers, Ido Kema, Anneke Muller Kobold


Aim: In the search for evidence-based follow-up of patients after resection for colorectal cancer, numerous tumor markers have been proposed. This review has evaluated these markers and comments on the diagnostic accuracy in finding recurrent disease in relation to Carcino-Embryonic Antigen (CEA).

Methods: A comprehensive literature review (1985-2010) was performed by two independent reviewers. Sensitivity and specificity of markers mentioned in the articles were checked by recalculation. A validated quality score system was used to estimate study quality.

Results: Seventeen studies focusing on eight different markers were included. Three markers were shown to have comparable or better accuracy than CEA: TPA, CA 242 and CA 72-4 in at least one study. These three markers, from four independent studies, showed a tumor marker sensitivity of > 60% in combination with an outperformance of CEA in follow-up. These results were not confirmed by six other studies investigating the same markers.

Conclusion: This review revealed three tumor markers other than CEA that have been shown to adequately indicate recurrences in colorectal cancer. However, comparability of studies was difficult. Therefore a prospective study of these markers seems necessary to investigate their real value, and to overcome design and inclusion biases.


tumor marker; CEA; clinical biochemistry; colorectal cancer


Barillari P, Bolognese A, Chirletti P, Cardi M, Sammartino P & Stipa V 1992 Role of CEA, TPA, and Ca 19-9 in the early detection of localized and diffuse recurrent rectal cancer. Dis Colon Rectum 35 471-476.

Barillari P, Sammartino P, Cardi M, Ricci M, Gozzo P, Cesareo S & Cerasi A 1991 Gastrointestinal cancer follow-up: the effectiveness of sequential CEA, TPA and Ca 19-9 evaluation in the early diagnosis of recurrences. Aust N Z J Surg. 61 675-80.

Bruinvels DJ, Stiggelbout AM, Kievit J, van Houwelingen HC, Habbema JD & van de Velde CJ. Follow-up of patients with colorectal cancer 1994 A meta-analysis. Ann Surg 219 174-182.

Carpelan-Holmstrom M, Louhimo J, Stenman UH, Alfthan H, Jarvinen H & Haglund C 2004 CEA, CA 242, CA 19-9, CA 72-4 and hCGbeta in the diagnosis of recurrent colorectal cancer. Tumour Biol 25 228-234.

Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, Lamerz R, Peltomaki P, Sturgeon C & Topolcan O 2007 Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer 43 1348-1360.

Eche N, Pichon MF, Quillien V, Gory-Delabaere G, Riedinger JM, Basuyau JP, Daver A, Buecher B, Conroy T, Dieu L, Bidart JM, Deneux L & Groupe de travail Nicole Eche (coordonnateur), oncobiologiste 2001 Standards, options and recommendations for tumor markers in colorectal cancer. Bull Cancer 88 1177-1206.

El-Awady S, Lithy R, Morshed M, Khafagy W, Abd Monem H, Waleed O, Badr S, Fekry A, El Nakeeb A, Ghazy H, El Yamany M, Metwally T, El-Arman M & Farid M 2009 Utility of serum preoperative carcinoemberyonic antigen in colorectal cancer patients. Hepatogastroenterology 56 361-366.

Engaras B 2003 Individual cutoff levels of carcinoembryonic antigen and CA 242 indicate recurrence of colorectal cancer with high sensitivity. Dis Colon Rectum 46 313-321.

Fernandes LC, Kim SB, Saad SS & Matos D 2006 Value of carcinoembryonic antigen and cytokeratins for the detection of recurrent disease following curative resection of colorectal cancer. World J Gastroenterol 28 3891-3894.

Filella X, Molina R, Piqué JM, Garcia-Valdecasas JC, Grau JJ, Novell F, Astudillo E, de Lacy A, Daniels M & Ballesta AM 1994 Use of CA 19-9 in the early detection of recurrences in colorectal cancer: comparison with CEA. Tumour Biol 15 1-6.

Fucini C, Tommasi SM, Rosi S, Malatantis G, Cardona G, Panichi S & Bettini U 1987 Follow-up of colorectal cancer resected for cure. An experience with CEA, TPA, Ca 19-9 analysis and second-look surgery. Dis Colon Rectum 30 273-277.

Goebel G, Zitt M, Zitt M & Muller HM 2005 Circulating nucleic acids in plasma or serum (CNAPS) as prognostic and predictive markers in patients with solid neoplasias. Dis Markers 21 105-120.

Golovkov DA 2009 Key enzymes of the extracellular matrix in colorectal cancer. Bull Exp Biol Med. 147 :353-6.

Gomez D, Sangha VK, Morris-Stiff G, Malik HZ, Guthrie AJ, Toogood GJ, Lodge JP & Prasad KR 2010 Outcomes of intensive surveillance after resection of hepatic colorectal metastases. Br J Surg 97 1552-1560.

Gomez D, Sangha VK, Morris-Stiff G, Malik HZ, Guthrie AJ, Toogood GJ, Lodge JP & Prasad KR 2009 Modest effect of p53, EGFR and HER-2/neu on prognosis in epithelial ovarian cancer: a meta-analysis. Br J Cancer 101 149-159.

Griesenberg D, Nürnberg R, Bahlo M & Klapdor R 1999 CEA, TPS, CA 19-9 and CA 72-4 and the fecal occult blood test in the preoperative diagnosis and follow-up after resective surgery of colorectal cancer. Anticancer Res 19 2443-50.

Grossmann I, de Bock GH, Meershoek-Klein Kranenbarg WM, van de Velde CJ & Wiggers T 2007 Carcinoembryonic antigen (CEA) measurement during follow-up for rectal carcinoma is useful even if normal levels exist before surgery. A retrospective study of CEA values in the TME trial. Eur J Surg Oncol 33 183-7.

Grossmann I, Verberne CJ , De Bock GH, Havenga K, Kema IP , Klaase J , Renehan A & Wiggers T 2011 The Role of High Frequency Dynamic Threshold (HiDT) Serum Carcinoembryonic Antigen (CEA) Measurements in Colorectal Cancer Surveillance: A (Revisited) Hypothesis Paper. Cancers 3, 2302-2315.

Guadagni F, Roselli M, Cosimelli M, Mannella E, Tedesco M, Cavaliere F, Grassi A, Abbolito MR, Greiner JW & Schlom J 1993 TAG-72 (CA 72-4 assay) as a complementary serum tumor antigen to carcinoembryonic antigen in monitoring patients with colorectal cancer. Cancer 72 2098-2106.

Hall NR, Finan PJ, Stephenson BM, Purves DA & Cooper EH 1994 The role of CA-242 and CEA in surveillance following curative resection for colorectal cancer. Br J Cancer 70 549-553.

Herbst A, Wallner M, Rahmig K, Stieber P, Crispin A, Lamerz R & Kolligs FT 2009 Methylation of helicase-like transcription factor in serum of patients with colorectal cancer is an independent predictor of disease recurrence. Eur J Gastroenterol Hepatol 21 565-569.

Holubec L Jr, Topolcan O, Pikner R, Pecen L, Vaclavickova J, Wirthova M, Molacek J, Stieber P, Holdenrieder S, Sen LH & Finek J 2000 The significance of CEA, CA19-9 and CA72-4 in the detection of colorectal carcinoma recurrence. Anticancer Res 20 5237-5244.

Jeffery M, Hickey BE & Hider PN 2007 Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev 1 CD002200.

Kievit J 2000 Colorectal cancer follow-up: a reassessment of empirical evidence on effectiveness. Eur J Surg Oncol 26 322-328.

van Larebeke N, Husson B, De Coen W & Pluygers E 2003 Immunologic and other biological parameters as a function of smoking status and of residence in areas differing in terms of air pollution. Int J Environ Health Res 13 55-69.

Lecomte T, Berger A, Zinzindohoué F, Micard S, Landi B, Blons H, Beaune P, Cugnenc PH & Laurent-Puig P 2002 Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis. Int J Cancer 100 542-548.

Moher D, Liberati A, Tetzlaff J, Altman DG & The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6 e1000097.

Morita S, Nomura T, Fukushima Y, Morimoto T, Hiraoka N & Shibata N 2004 Does serum CA19-9 play a practical role in the management of patients with colorectal cancer? Dis Colon Rectum 47 227-232.

Nicolini A, Ferrari P, Duffy MJ, Antonelli A, Rossi G, Metelli MR, Fulceri F, Anselmi L, Conte M, Berti P & Miccoli P 2010 Intensive risk-adjusted follow-up with the CEA, TPA, CA19.9, and CA72.4 tumor marker panel and abdominal ultrasonography to diagnose operable colorectal cancer recurrences: effect on survival. Arch Surg 145 1177-1183.

Nicolini A, Caciagli M, Zampieri F, Ciampalini G, Carpi A, Spisni R & Colizzi C 1995 Usefulness of CEA, TPA, GICA, CA 72.4, and CA 195 in the Diagnosis of primary colorectal cancer and at its relapse. Cancer Detect Prev 19 183-195.

Park IJ, Choi GS & Jun SH 2009 Prognostic value of serum tumor antigen CA19-9 after curative resection of colorectal cancer. Anticancer Res 29 4303-4308.

Plebani M, Basso D, Roveroni G, De Paoli M, Galeotti F & Corsini A 1997 N-terminal peptide of type III procollagen: a possible predictor of colorectal carcinoma recurrence. Cancer 79 1299-1303.

Renehan AG, Egger M, Saunders MP & O'Dwyer ST 2002 Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. BMJ 324 813.

Schwarzenbach H, Hoon DS & Pantel K 2011 Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 11 426-437.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM & Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics 2005 REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93 387-391.

Spila A, Ferroni P, Cosimelli M, D'Alessandro R, Abbolito MR, Mariotti S, Aloe S, Carone MD, Graziano F, Tedesco M, Martini F, Mancini R, Stigliano V, Roselli M & Guadagni F 2001 Comparative analysis of CA 242 and CA 19-9 serum tumor markers in colorectal cancer patients. A longitudinal evaluation. Anticancer Res 21 1263-1270.

Tjandra JJ & Chan MK 2007 Follow-up after curative resection of colorectal cancer: a meta-analysis. Dis Colon Rectum 50 1783-1799.

Wiratkapun S, Kraemer M, Seow-Choen F, Ho YH & Eu KW 2001 High preoperative serum carcinoembryonic antigen predicts metastatic recurrence in potentially curative colonic cancer: results of a five-year study. Dis Colon Rectum 44 231-235.

Wood WG 2008. Immunoassays & co.: past, present, future? A review and outlook from personal experience and involvement over the past 35 years Clin Lab 54 423-438.

Yakabe T, Nakafusa Y, Sumi K, Miyoshi A, Kitajima Y, Sato S, Noshiro H & Miyazaki K 2010 Clinical significance of CEA and CA19-9 in postoperative follow-up of colorectal cancer. Ann Surg Oncol 17 2349-2356.

Zeng Z, Cohen AM & Urmacher C 1993 Usefulness of carcinoembryonic antigen monitoring despite normal preoperative values in nodepositive colon cancer patients. Dis Colon Rectum 36 1063-1086.

Full Text: PDF


  • There are currently no refbacks.

Copyright © 2017 Lorem Ipsum Press