CEA clearance pattern as a predictor of tumor response to neoadjuvant treatment in rectal cancer: a post-hoc analysis of FOWARC trial

Huabin Hu, Jin Huang, Ping Lan, Lei Wang, Meijin Huang, Jianping Wang, Yanhong Deng, Huabin Hu, Jin Huang, Ping Lan, Lei Wang, Meijin Huang, Jianping Wang, Yanhong Deng

Abstract

Background: The clinical factors that accurately predict the response to preoperative treatment in rectal cancer were yet unknown. The carcinoembryonic antigen (CEA) clearance pattern during neoadjuvant treatment has been developed and the predictive value explored in rectal cancer patients with elevated CEA levels (> 5 ng/mL).

Methods: The training cohort was derived from the FOWARC prospective phase III trial, and 71/483 eligible patients were included. The validation cohort consisted of 75/587 consecutive rectal cancer patients from Xiangya Hospital between 2014 and 2015. The kinetic changes in serum CEA were measured at different time points during the neoadjuvant treatment. An exponential trend line was drawn using the CEA values. The patients were categorized into two groups based on the R2 value of the trend line, which indicates the correlation coefficient between the exponential graph and measured CEA values: exponential decrease group (0.9 < R2 ≤ 1.0) and non-exponential decrease group (R2 ≤ 0.9).

Results: In multivariate analysis, the patients in the CEA exponential decrease group had significantly high adequate rate of downstaging (ypT0-2N0M0), and pathologic complete response (pCR) rates after neoadjuvant treatment in the training cohort. The predictive values of the CEA clearance pattern for tumor downstaging and pCR were further confirmed in an independent validation cohort.

Conclusions: The CEA clearance pattern was an independent predictor of tumor response to neoadjuvant treatment in patients with rectal cancer. It might serve as an adjunct in the assessment of complete clinical response and guide individualized treatment strategies.

Trial registration: NCT01211210.

Keywords: Carcinoembryonic antigen; Neoadjuvant treatment; Pathologic complete response; Rectal cancer.

Conflict of interest statement

Ethics approval and consent to participate

The institutional review board (IRB) of The Sixth Affiliated Hospital of Sun Yat-Sen University approved the present study (Approval number: 06-08-2010) and all documented consent from all patients who participated in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
An exponential trend line (blue line) was drawn using each CEA value (baseline, 2nd, 4th, 6th, 8th, and 14th week from the start of preoperative treatment). The function of the exponential curve (yellow line) was drawn. R2 values were calculated as the deviation between the calculated curves and the measured CEA value
Fig. 2
Fig. 2
Predictive ability of the CEA clearance pattern for TRG (a), tumor downstaging (b), and pCR (c) were compared to the other clinical parameters by AUC curves in the training cohort
Fig. 3
Fig. 3
Predictive ability of the CEA clearance pattern for TRG (a), tumor downstaging (b), and pCR (c) were compared to the other clinical parameters by AUC curves in the validation cohort

References

    1. Arbman G, Nilsson E, Hallbook O, Sjodahl R. Local recurrence following total mesorectal excision for rectal cancer. Br J Surg. 1996;83(3):375–379. doi: 10.1002/bjs.1800830326.
    1. Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. LANCET. 1986;1(8496):1479–1482. doi: 10.1016/S0140-6736(86)91510-2.
    1. Roh MS, Colangelo LH, O'Connell MJ, Yothers G, Deutsch M, Allegra CJ, Kahlenberg MS, Baez-Diaz L, Ursiny CS, Petrelli NJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;27(31):5124–5130. doi: 10.1200/JCO.2009.22.0467.
    1. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–1740. doi: 10.1056/NEJMoa040694.
    1. Park IJ, You YN, Agarwal A, Skibber JM, Rodriguez-Bigas MA, Eng C, Feig BW, Das P, Krishnan S, Crane CH, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012;30(15):1770–1776. doi: 10.1200/JCO.2011.39.7901.
    1. Martin ST, Heneghan HM, Winter DC. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012;99(7):918–928. doi: 10.1002/bjs.8702.
    1. Das P, Skibber JM, Rodriguez-Bigas MA, Feig BW, Chang GJ, Wolff RA, Eng C, Krishnan S, Janjan NA, Crane CH. Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. CANCER-AM CANCER SOC. 2007;109(9):1750–1755.
    1. van Stiphout RG, Lammering G, Buijsen J, Janssen MH, Gambacorta MA, Slagmolen P, Lambrecht M, Rubello D, Gava M, Giordano A, et al. Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging. Radiother Oncol. 2011;98(1):126–133. doi: 10.1016/j.radonc.2010.12.002.
    1. Huh JW, Kim HR, Kim YJ. Clinical prediction of pathological complete response after preoperative chemoradiotherapy for rectal cancer. Dis Colon Rectum. 2013;56(6):698–703. doi: 10.1097/DCR.0b013e3182837e5b.
    1. Zhang J, Cai Y, Hu H, Lan P, Wang L, Huang M, Kang L, Wu X, Wang H, Ling J, et al. Nomogram basing pre-treatment parameters predicting early response for locally advanced rectal cancer with neoadjuvant chemotherapy alone: a subgroup efficacy analysis of FOWARC study. ONCOTARGET. 2016;7(4):5053–5062.
    1. Jayanand SB, Seshadri RA, Tapkire R. Signet ring cell histology and non-circumferential tumors predict pathological complete response following neoadjuvant chemoradiation in rectal cancers. Int J Color Dis. 2011;26(1):23–27. doi: 10.1007/s00384-010-1082-7.
    1. Kalady MF, de Campos-Lobato LF, Stocchi L, Geisler DP, Dietz D, Lavery IC, Fazio VW. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg. 2009;250(4):582–589.
    1. GOLD P. Freedman so: demonstration of tumor-specific antigens in human colonic CARCINOMATA by immunological tolerance and absorption techniques. J Exp Med. 1965;121:439–462. doi: 10.1084/jem.121.3.439.
    1. Perez RO, Sao JG, Habr-Gama A, Kiss D, Proscurshim I, Campos FG, Gama-Rodrigues JJ, Cecconello I. The role of carcinoembriogenic antigen in predicting response and survival to neoadjuvant chemoradiotherapy for distal rectal cancer. Dis Colon Rectum. 2009;52(6):1137–1143. doi: 10.1007/DCR.0b013e31819ef76b.
    1. Kleiman A, Al-Khamis A, Farsi A, Kezouh A, Vuong T, Gordon PH, Vasilevsky CA, Morin N, Faria J, Ghitulescu G, et al. Normalization of CEA levels post-neoadjuvant therapy is a strong predictor of pathologic complete response in rectal Cancer. J Gastrointest Surg. 2015;19(6):1106–1112. doi: 10.1007/s11605-015-2814-3.
    1. Yang KL, Yang SH, Liang WY, Kuo YJ, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Chang SC, et al. Carcinoembryonic antigen (CEA) level, CEA ratio, and treatment outcome of rectal cancer patients receiving pre-operative chemoradiation and surgery. Radiat Oncol. 2013;8:43. doi: 10.1186/1748-717X-8-43.
    1. Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, et al. Modified FOLFOX6 with or without radiation versus fluorouracil and Leucovorin with radiation in neoadjuvant treatment of locally advanced rectal Cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol. 2016;34(27):3300–3307. doi: 10.1200/JCO.2016.66.6198.
    1. Ryan R, Gibbons D, Hyland JM, Treanor D, White A, Mulcahy HE, O'Donoghue DP, Moriarty M, Fennelly D, Sheahan K. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. HISTOPATHOLOGY. 2005;47(2):141–146. doi: 10.1111/j.1365-2559.2005.02176.x.
    1. D'Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst. 2003;95(18):1376–1383. doi: 10.1093/jnci/djg043.
    1. Spiess PE, Lee AK, Leibovici D, Wang X, Do KA, Pisters LL. Presalvage prostate-specific antigen (PSA) and PSA doubling time as predictors of biochemical failure of salvage cryotherapy in patients with locally recurrent prostate cancer after radiotherapy. CANCER-AM CANCER SOC. 2006;107(2):275–280.
    1. Yoshimasu T, Maebeya S, Suzuma T, Bessho T, Tanino H, Arimoto J, Sakurai T, Naito Y. Disappearance curves for tumor markers after resection of intrathoracic malignancies. Int J Biol Markers. 1999;14(2):99–105. doi: 10.1177/172460089901400207.
    1. Kim JY, Kim NK, Sohn SK, Kim YW, Kim KJ, Hur H, Min BS, Cho CH. Prognostic value of postoperative CEA clearance in rectal cancer patients with high preoperative CEA levels. Ann Surg Oncol. 2009;16(10):2771–2778. doi: 10.1245/s10434-009-0651-x.
    1. Choi JS, Min JS. Significance of postoperative serum level of carcinoembryonic antigen (CEA) and actual half life of CEA in colorectal cancer patients. Yonsei Med J. 1997;38(1):1–7. doi: 10.3349/ymj.1997.38.1.1.
    1. Arnaud JP, Koehl C, Adloff M. Carcinoembryonic antigen (CEA) in diagnosis and prognosis of colorectal carcinoma. Dis Colon Rectum. 1980;23(3):141–144. doi: 10.1007/BF02587615.
    1. Harrison LE, Guillem JG, Paty P, Cohen AM. Preoperative carcinoembryonic antigen predicts outcomes in node-negative colon cancer patients: a multivariate analysis of 572 patients. J Am Coll Surg. 1997;185(1):55–59. doi: 10.1016/S1072-7515(97)00012-4.
    1. Park YA, Lee KY, Kim NK, Baik SH, Sohn SK, Cho CW. Prognostic effect of perioperative change of serum carcinoembryonic antigen level: a useful tool for detection of systemic recurrence in rectal cancer. Ann Surg Oncol. 2006;13(5):645–650. doi: 10.1245/ASO.2006.03.090.
    1. Wolmark N, Fisher B, Wieand HS, Henry RS, Lerner H, Legault-Poisson S, Deckers PJ, Dimitrov N, Gordon PH, Jochimsen P, et al. The prognostic significance of preoperative carcinoembryonic antigen levels in colorectal cancer. Results from NSABP (National Surgical Adjuvant Breast and bowel project) clinical trials. Ann Surg. 1984;199(4):375–382. doi: 10.1097/00000658-198404000-00001.
    1. Wallin U, Rothenberger D, Lowry A, Luepker R, Mellgren A. CEA - a predictor for pathologic complete response after neoadjuvant therapy for rectal cancer. Dis Colon Rectum. 2013;56(7):859–868. doi: 10.1097/DCR.0b013e31828e5a72.
    1. Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, van Dam RM, Jansen RL, Sosef M, Leijtens JW, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011;29(35):4633–4640. doi: 10.1200/JCO.2011.37.7176.
    1. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro UJ, Silva ESAJ, Campos FG, Kiss DR, Gama-Rodrigues J. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240(4):711–717.
    1. Probst CP, Becerra AZ, Aquina CT, Tejani MA, Hensley BJ, Gonzalez MG, Noyes K, Monson JR, Fleming FJ. Watch and wait?--elevated pretreatment CEA is associated with decreased pathological complete response in rectal Cancer. J Gastrointest Surg. 2016;20(1):43–52, 52. doi: 10.1007/s11605-015-2987-9.

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