CEA Flare and Colorectal Cancer: A Good Prognostic Sign

By William B. Ershler, MD

Abstract & commentary

Synopsis: Within a large series of colorectal cancer patients receiving initial chemotherapy, a prompt rise and then drop in CEA level (flare) was observed in 11.6%. Compared with patients who had a continuous rise in CEA, those exhibiting a flare reaction had improved response to chemotherapy and progression-free and overall survival.

Source: Strimpakos AS, et al. The impact of carcinoembryonic antigen flare in patients with advanced colorectal cancer receiving first-line chemotherapy. Ann Oncol. 2010;21:1013-1019.

There is evidence from previously published small series of patients with advanced colorectal cancer that carcinoembryonic antigen (CEA) flare (a prompt rise in CEA titer after initial chemotherapy) may be an indication of favorable response to chemotherapy,1,2 but whether this translates to improved survival remains unknown. Strimpakos et al from the Royal Marsden Hospital (London) performed a retrospective review of 670 eligible patients with advanced colorectal cancer who received initial chemotherapy at their institution between January 2000 and February 2008. The study aimed to evaluate the incidence of CEA flare and its impact on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). For the study, a CEA flare was defined as a ≥ 15% rise from baseline (at least 4 ug/L), followed by a subsequent ≥ 15% decrease from baseline in CEA level within four to six weeks of initial treatment.

Patients with histologically proven advanced colorectal cancer undergoing first-line chemotherapy with three or more serial CEA measurements (one at baseline and two or more during treatment) were included. By analysis of serial CEA measurements, patients were considered in one of five categorical groups: 1) CEA flare; 2) decreasing CEA; 3) normal baseline CEA; 4) stable CEA; or, 5) increasing CEA.

Seventy-eight of 670 (11.6%) patients demonstrated the CEA flare phenomenon. The median baseline CEA value in the flare group was 74 ug/L (range 5–31 480 ug/L), and the median peak CEA value was 115 ug/L, reached in 21 days (range 4–61 days). The median duration of CEA flare (from date of baseline CEA to date of first CEA level below the baseline) was 49 days (range 16–117 days).

On multivariate analysis, compared with patients with increasing CEA (group 5), patients with CEA flare had a significantly better ORR (group 5 vs. group 1: 11% vs. 73%; risk ratio [RR]: 27.96; 95% CI: 9.55–81.88; p < 0.001), PFS (median 3.1 vs. 8.3 months; RR: 0.38; 95% CI: 0.26–0.56; p < 0.001) and OS (median 10.9 vs. 17.7 months; RR: 0.53; 95% CI: 0.34–0.82; p < 0.001).

In addition to the flare, this study also showed that a decreasing CEA pattern (group 2) and a normal baseline (group 3) were also associated with improved PFS and OS when compared to the increasing pattern (group 5). The number of patients in the "stable" CEA group (group 4) was insufficient to demonstrate a survival benefit.

Commentary

Thus, CEA flare was associated with a 62% relative reduction in the risk of progression and a nearly halving of the risk of death compared to an increasing CEA pattern. It is notable that patients with normal baseline CEA levels exhibited the best progression-free and overall survival. Nonetheless, this comprehensive analysis of a large series of colorectal cancer patients confirms and extends the favorable implications of CEA flare. In the previous reports, flare was associated with an improved response rate; in this report of a substantially larger series, not only was improved response rate observed, but also there was improved progression-free and overall survival compared with those whose with rising CEA levels in a pattern other than "flare."

Why this should be the case remains unknown. CEA is a glycoprotein normally found in embryonic tissue and various adenocarcinomas but not in healthy normal adult tissue.3 It remains unclear whether its presence has any significance with regard to local tumor growth, invasion, and metastases, or whether its level just signifies the overall burden of tumor cells. There are some experimental tumor models that would support the first hypothesis. For example, injection of exogenous CEA in a murine colorectal cancer model resulted in increased liver metastases.4 A mechanism accounting for a "flare" in CEA in a subset of treated patients also remains to be established. There is a current sense that CEA flares may be more prevalent in patients treated with oxaliplatin2,5 and, if so, we might expect to see more patients exhibiting a flare as more patients with advanced colorectal cancer are treated with this drug.

References

1. Ailawadhi S, et al. Chemotherapy-induced carcinoembryonic antigen surge in patients with metastatic colorectal cancer. Oncology. 2006;70:49-53.

2. Sorbye H, Dahl O. Transient CEA increase at start of oxaliplatin combination therapy for metastatic colorectal cancer. Acta Oncol. 2004;43:495-498.

3. Goldstein MJ, Mitchell EP. Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest. 2005;23:338-51.

4. Hostetter RB, et al. Carcinoembryonic antigen as a selective enhancer of colorectal cancer metastasis. J Natl Cancer Inst. 1990;82:380-385.

5. Prete SP, et al. Combined effects of 5-fluorouracil, folinic acid and oxaliplatin on the expression of carcinoembryonic antigen in human colon cancer cells: pharmacological basis to develop an active antitumor immunochemotherapy. J Exp Clin Cancer Res. 2008;27:5.