Abstract
Purpose
The introduction of new drugs and multimodal treatments for the management of patients with metastatic colorectal cancer (mCRC) has reduced the importance of time-to-event endpoints and reported the attention on the response-related endpoints. Furthermore, the prognostic role of the surgical scores before the resection of metastases has not been confirmed for multimodal treatments. The purpose of this research is to perform a meta-analysis of the studies that evaluated the relationship between carcinoembryonic antigen (CEA) response and outcome in patients with mCRC receiving systemic chemotherapy.
Methods
A systematic review of the literature on two databases and a selection of studies that evaluated the relationship between CEA response and outcome were performed according to predefined criteria. After, three meta-analyses were carried out on the selected studies, each for each outcome variable.
Results
Nineteen studies have been selected. Fourteen studies (1475 patients) have documented a close association between radiological response and CEA response (odds ratio (OR), 9.03; confidence intervals (CIs), 5.14–15.87; I2 statistic (I2), 72%). Four studies have reported a longer progression-free survival for patients with a CEA response (hazard ratio (HR), 0.73; CIs, 0.64–0.83; I2, 23%). Finally, 10 studies (13 study cohorts) have shown a strong relationship between CEA response and overall survival (OS) (HR, 0. 62; CIs, 0.55–0.70; I2, 35%).
Conclusions
CEA response merits further investigation as a surrogate endpoint of clinical trials of first-line medical therapy of patients with mCRC, and should be studied as a prognostic factor for those patients who are candidates for multimodal treatment strategies.
Similar content being viewed by others
References
Malvezzi M, Carioli G, Bertuccio P, Boffetta P, Levi F, La Vecchia C, Negri E (2017) European cancer mortality prediction for the year 2017, with focus on lung cancer. Ann Oncol 28:1117–1123
Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D’Angelica M (2007) Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 25:4575–4580
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T (2013) Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol 14:1208–1215
Schreckenbach T, Malkomes P, Bechstein WO, Woeste G, Schnitzbauer AA, Ulrich F (2015) The clinical relevance of the Fong and the Nordlinger scores in the era of effective neoadjuvant chemotherapy for colorectal liver metastases. Surg Today 45:1527–1534
Colloca G, Venturino A, Guarneri D (2016) Analysis of clinical end points of randomised trials including bevacizumab and chemotherapy versus chemotherapy as first-line treatment of metastatic colorectal cancer. Clin Oncol 28:e155–e164
Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, Tejpar S (2013) Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 31:3764–3775
Hammarstrom S (1999) The carcynoembrionic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 9:67–81
Tabuchi Y, Deguchi H, Imanishi K, Saitoh Y (1987) Comparison of carcynoembrionic antigen levels between portal and peripheral blood in patients with cororectal cancer. Cancer 59:1283–1288
Tiernan JP, Perry SL, Verghese ET, West NP, Yeluri S, Jayne DG, Hughes TA (2013) Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting. Brit J Cancer 108:662–667
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16
Mayer RJ, Garnick MB, Steele GD, Zamcheck N (1978) Carcinoembryonic antigen (CEA) as a monitor of chemotherapy in disseminated colorectal cancer. Cancer 42:1428–1433
Shani A, O’Connell MJ, Moertel CG, Schutt AJ, Silvers A, Go VLW (1978) Serial plasma carcynoembrionic antigen measurements in the management of metastatic colorectal carcinoma. Ann Intern Med 88:627–630
Al-Sarraf M, Baker L, Talley RW, Kithier K, Vaitkevicius VK (1979) The value of serial carcinoembryonic antigen (CEA) in predicting response rate and survival of patients with gastrointestinal cancer treated with chemotherapy. Cancer 44:1222–1225
Allen-Mersch TG, Kemeny N, Niedzwiecki D, Shurgot B, Daly JM (1987) Significance of a fall in serum CEA concentration in patients treated with cytotoxic chemotherapy for disseminated colorectal cancer. Gut 28:1625–1629
De Gramont A, Krulik M, Cady J, Lagadec B, Maisani JE, Loiseau JP, Grange JD, Gonzalez-Canali G, Demuynck B, Louvet C, Seroka J, Dray C, Debray J (1988) High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer. Eur J Cancer Clin Oncol 24:1499–1503
Hamm CM, Cripps C (1998) Carcinoembryonic antigen in metastatic colorectal cancer. Clin Invest Med 21:186–191
Rothenberg ML, Cox JV, DeVore RF, Hainsworth JD, Pazdur R, Rivkin SE, Macdonald JS, Geyer CE, Sandbach J, Wolf DL, Mohrland JS, Elfring GL, Miller LL, Von Hoff DD (1999) A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786–795
Wang WS, Lin JK, Lin TC, Chiou TJ, Liu JH, Fan FS, Yen CC, Chen WS, Jiang JK, Yang SH (2001) Carcinoembryonic antigen in monitoring of response to systemic chemotherapy in patients with metastatic colorectal cancer. Int J Color Dis 16:96–101
Berglund A, Molin D, Larsson A, Einarsson R, Glimelius B (2002) Tumour markers as early predictors of response to chemotherapy in advanced colorectal carcinoma. Ann Oncol 13:1430–1437
Wang WS, Lin JK, Lin TC, Chiou TJ, Liu JH, Yen CC, Chen WS, Jiang JK, Yang SH, Wang HS, Chen PM (2002) Tumor marker CEA in monitoring of response to tegafur-uracil and folinic acid in patients with metastatic colorectal cancer. Hepatogastroenterol 49:388–392
Trillet-Lenoir V, Chapuis F, Touzet S, Barbier JY, Freyer G, Gaudin JL, Lombard-Bohas C, Valette PJ, Lledo G, Gouttebel MC, Boyer JD, Chassignol L, Hamon H, Claudel-Bonvoisin S, Leprince E, Amoyal P, Glehen O, Darnand P, Heilmann MO, Bleuse JP (2004) Any clinical benefit from the use of oncofoetal markers in the management of chemotherapy for patients with metastatic colorectal carcinomas? Clin Oncol 16:196–203
de Haas RJ, Wicherts DA, Flores E, Ducreux M, Levi F, Paule B, Azoulay D, Castaing D, Lemoine A, Adam R (2010) Tumor marker evolution: comparison with imaging for assessment of response to chemotherapy in patients with colorectal liver metastases. Ann Surg Oncol 17:1010–1023
Ghiringhelli F, Vincent J, Guiu B, Chauffert B, Ladoire S (2012) Bevacizumab plus FOLFIRI-3 in chemotherapy-refractory patients with metastatic colorectal cancer in the era of biotherapies. Investig New Drugs 30:758–764
Ng SL, Burns WI, Snyder RD, Newnham GM, McLachlan SA, Liew D, Dowling AJ (2012) A retrospective cohort study of metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy, with an exploratory analysis of changing serum carcinoembryonic antigen levels. Asia Pac J Clin Oncol 8:172–179
Petrioli R, Licchetta A, Roviello G, Pascucci A, Francini E, Bargagli G, Conca R, Miano ST, Marzocca G, Francini G (2012) CEA and CA 19.9 as early predictors of progression on advanced/metastatic colorectal cancer patients receiving oxaliplatin-based chemotherapy and bevacizumab. Cancer Investig 30:65–71
Kim G, Jung EJ, Ryu CG, Hwang DY (2013) Usefulness of carcinoembryonic antigen for monitoring tumor progression during palliative chemotherapy in metastatic colorectal cancer. Yonsei Med J 54:116–122
Huang SC, Lin JK, Lin TC, Chen WS, Yang SH, Wang HS, Lan YT, Lin CC, Jiang JK, Chang SC (2015) Concordance of carcinoembryonic antigen ratio and response evaluation criteria in solid tumors as prognostic surrogate indicators of metastatic colorectal cancer patients treated with chemotherapy. Ann Surg Oncol 22:2262–2268
Stremitzer S, Stift J, Graf A, Singh J, Starlinger P, Gruenberger B, Tamandl D, Gruenberger T (2015) CEA change after neoadjuvant chemotherapy including bevacizumab and clinical outcome in patients undergoing liver resection for colorectal liver metastases. Ann Surg Oncol 22:1315–1323
Michl M, Stintzing S, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmueller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Mueller S, Lerch MM, Modest DP, Kirchner T, Jung A, Heinemann V (2016) CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial). Ann Oncol 27:1565–1572
Thyrunavukarasu P, Talati C, Munjal S, Attwood K, Edge SB, Francescutti V (2015) Effect of incorporation of pretreatment serum carcinoembryonic antigen levels into AJCC staging for colon cancer on 5-year survival. JAMA Surg 150:747–755
Matias M, Casa-Nova M, Faria M, Pires R, Tato-Costa J, Ribeiro L, Costa L (2015) Prognostic factors after liver resection for colorectal liver metastasis. Acta Medica Port 28:357–369
Zhang ZY, Gao W, Luo QF, Yin XW, Basnet S, Dai ZL, Ge HY (2016) A nomogram improves AJCC stages for colorectal cancers by introducing CEA, modified lymph node ratio and negative lymph node count. Sci Rep 6:39028
Kirat HT, Ozturk E, Lavery IC, Kiran RP (2012) The predictive value of preoperative carcinoembryonic antigen level in the prognosis of colon cancer. Am J Surg 204:447–452
Huh JW, Oh BR, Kim HR, Kim YJ (2010) Preoperative carcinoembryonic antigen level as an independent prognostic factor in potentially curative colon cancer. J Surg Oncol 101:396–400
Amri R, Bordeianou LG, Sylla P, Berger DL (2013) Preoperative carcinoembryonic antigen as an outcome predictor in colon cancer. J Surg Oncol 108:14–18
Lou Z, Meng RG, Zhang W, Yu ED, Fu CG (2013) Preoperative carcinoembryonic antibody is predictive of distant metastasis in pathologically T1 colorectal cancer after radical surgery. W J Gastroenterol 19:389–393
Selculbiricik F, Bilici A, Tural D, Erdamar S, Ozlem S, Buyukunal E, Demirelli F, Serdengecti S (2013) Are high initial CEA and CA 19-9 levels associated with the presence of K-ras mutation in patients with metastatic colorectal cancer? Tumour Biol 34:2233–2239
Tampellini M, Ottone A, Alabiso I, Barattelli C, Forti L, Berruti A, Aroasio E, Scagliotti GV (2015) The prognostic role of baseline CEA and CA 19-9 values and their time-dependent variations in advanced colorectal cancer patients submitted to first-line therapy. Tumor Biol 36:1519–1527
Strimpakos AS, Cunningham D, Mikropoulos PI, Barbachano Y, Chau I (2010) The impact of carcinoembryonic antigen flare in patients with advanced colorectal cancer receiving first-line chemotherapy. Ann Oncol 21:1013–1019
Garcia M, Seigner C, Bastid C, Choux R, Payan MJ, Reggio H (1991) Carcinoembryonic antigen has a different molecular weight in normal colon and in cancer cells due to N-glycosilation differences. Cancer Res 51:5679–5686
Rao US, Hoerster NS, Thirumala S, Rao PS (2013) The influence of metastatic site on the expression of CEA and cellular localization of β-catenin in colorectal cancer. J Gastroenterol Hepatol 28:505–512
Cho M, Akiba C, Lau C, Smith D, Telatar M, Afkhami M, Sentovich S, Melstrom K, Fakih M (2016) Impact of RAS e BRAF mutations on carcinoembryonic antigen production and pattern of colorectal metastases. World J Gastrointest Oncol 8:128–135
Das A, Kunkel M, Joudeh J, Dicker DT, Scicchitano A, Allen JE, Sarwani N, Yang Z, Kaifi J, Zhu J, Liao J, El-Deiry WS (2015) Clinico-pathological correlation of serial measurement of circulating tumor cells in 24 metastatic colorectal cancer patients receiving chemotherapy reveals interpatient heterogeneity correlated with CEA levels but independent of KRAS and BRAF mutation. Cancer Biol Ther 16:709–713
Bystrom P, Berglund A, Nygren P, Wernroth L, Johansson B, Larsson A, Glimelius B (2012) Evaluation of predictive markers for patients with advanced colorectal cancer. Acta Oncol 51:849–859
Shinkins B, Nicholson BD, James TJ, Primrose JN, Mant D (2014) Carcinoembryonic antigen monitoring to detect recurrence of colorectal cancer: how should we interpret the test results? Clin Chem 60:1572–1574
Lee JH, Kim SH, Jang HS, Chung HJ, Oh ST, Lee DS, Kim JG (2013) Preoperative elevation of carcinoembryonic antigen predicts poor tumor response and frequent distant recurrence for patients with rectal cancer who receive preoperative chemoradiotherapy and total mesorectal excision: a multi-institutional analysis in an Asian population. Int J Color Dis 28:511–517
Bajenova O, Gorbunova A, Evsyukov I, Rayko M, Gapon S, Bozhokina E, Shishkin A, O’Brien SJ (2016) The genome-wide analysis of carcinoembryonic antigen signaling by colorectal cancer cells using RNA sequencing. PLoS One 11:e0161256
Chiaravalloti A, Fiorentini A, Palombo E, Rinino D, Lacanfora A, Danieli R, Di Russo C, Di Biagio D, Squillaci E, Schillaci O (2016) Evaluation of recurrent disease in the re-staging of colorectal cancer by 18F-FDG PET/TC: use of CEA and CA 19-9 in patient selection. Oncol Lett 12:4209–4213
Gade M, Kubik M, Fisker RV, Thorlacius-Ussing O, Petersen LJ (2015) Diagnostic value of 18F-FDG-PET/TC as first choice in the detection of recurrent colorectal cancer due to rising CEA. Cancer Imaging 15:11
Zhang Y, Feng B, Zhang GL, Hu M, Fu Z, Zhao F, Zhang XL, Kong L, Yu JM (2014) Value of 18F-FDG PET-TC in surveillance of post-operative colorectal cancer patients with various carcinoembryonic antigen concentrations. World J Gastoenterol 20:6608–6614
Bramswig KH, Poettler M, Unseld M, Wrba F, Uhrin P, Zimmermann W, Zielinski CC, Prager GW (2013) Soluble carcinoembryonic antigen activates endothelial cells and tumor angiogenesis. Cancer Res 73:6584–6596
Ordonez C, Zhai AB, Camacho-Leal P, Demarte L, Fan MMY, Stanners CP (2007) GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin α5β1-fibronectin interaction. J Cell Physiol 210:757–765
Chan CHF, Camacho-Leal P, Stanners CP (2007) Colorectal hyperplasia and dysplasia due to human carcinoembryonic antigen (CEA) family member expression in transgenic mice. PLoS One 12:e1353
Samara RN, Laguinge LM, Jessup JM (2007) Carcinoembryonic antigen inhibits anoikis in colorectal carcinoma cells by interfering with trail-R2 (DR5) signaling. Cancer Res 67:4774–4782
Blumenthal RD, Hansen HJ, Goldenberg DM (2005) Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (carcinoembryonic antigen). Cancer Res 65:8809–8817
Gemei M, Mirabelli P, Di Noto R, Corbo C, Iaccarino A, Zamboli A, Troncone G, Galizia G, Lieto E, Del Vecchio L, Salvatore F (2013) CD66c is a novel marker for colorectal cancer stem cell isolation, and its silencing halts tumor growth in vivo. Cancer 119:729–738
Scurr MJ, Brown CM, Costa Bento DF, Betts GJ, Rees BI, Hills RK, Gallimore A, Godkin A (2015) Assessing the prognostic value of preoperative carcinoembryonic antigen-specific T-cell responses in colorectal cancer. J Natl Cancer Inst 107:djv001
An X, Ding PR, Xiang XJ, Wang ZQ, Wang FH, Feng F, Jiang WQ, He YJ, Xu RH, Li YH (2010) Carcinoembryonic antigen surge in metastatic colorectal cancer patients responding to irinotecan combination chemotherapy. Biomarkers 15:243–248
Aquino A, Formica V, Prete SP, Correale PP, Massara MC, Turriziani M, De Vecchis L, Bonmassar E (2004) Drug-induced increase of carcinoembryonic antigen expression in cancer cells. Pharmacol Res 49:383–396
Eftekhar E, Naghibalhossaini F (2014) Carcinoembryonic antigen expression level as a predictive factor for response to 5-fluorouracil in colorectal cancer. Mol Biol Rep 41:459–466
Prager GW, Braemswig KH, Martel A, Unseld M, Heinze G, Brodowicz T, Scheithauer W, Kornek G, Zielinski C (2014) Baseline carcinoembryonic antigen (CEA) serum levels predict bevacizumab-based treatment response in metastatic colorectal cancer. Cancer Sci 105:996–1001
Yoshino T, Obermannovà R, Bodoky G, Garcia-Carbnero R, Ciuleanu T, Portnoy DC, Kim TW, Hsu Y, Ferry D, Nasroulah F, Taberbero J (2017) Baseline carcinoembryonic antigen as a predictive factor of ramucirumab efficacy in RAISE, a second-line metastatic colorectal carcinoma phase III trial. Eur J Cancer 78:61–69
Seyal AR, Parekh K, Arslanoglu A, Gonzalez-Guindalini FD, Tochetto SM, Velichko YS, Yaghmai V (2015) Performance of tumor growth kinetics as an imaging biomarker for response assessment in colorectal liver metastases: correlation with FDG PET. Abdom Imaging 40:3043–3051
Shindoh J, Loyer EM, Kopetz S, Boonsirikamchai P, Maru DP, Chun YS, Zimmitti G, Curley SA, Charnsangavej C, Aloia TA, Vauthey JN (2012) Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol 30:4566–4572
Iwanicki-Caron I, Di Fiore F, Roque I, Astruc E, Stetiu M, Duclos A, Tougeron D, Saillard S, Thureau S, Benichou J, Paillot B, Basuyau JP, Michel P (2008) Usefulness of the serum carcinoembryonic antigen kinetic for chemotherapy monitoring in patients with unresectable metastasis of colorectal cancer. J Clin Oncol 26:3681–3686
Author information
Authors and Affiliations
Contributions
All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Colloca, G.A., Venturino, A. & Guarneri, D. Carcinoembryonic antigen reduction after medical treatment in patients with metastatic colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis 34, 657–666 (2019). https://doi.org/10.1007/s00384-018-03230-w
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-018-03230-w