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Carcinoembryonic Antigen, Biomarker Discovery, and Trial Design

Department of Surgery, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612

Correspondence: Address correspondence and reprint requests to: Timothy J. Yeatman, MD; E-mail: yeatman{at}moffitt.usf.edu.

Carcinoembryonic antigen (CEA) has long been known to provide potential benefit for predicting colorectal cancer patient outcomes. Park et al.¹ provide a careful new look at an old problem. They assessed serum CEA levels both before surgery and 7 days after surgery in 631 patients who underwent curative resection for stage II and III adenocarcinoma of the rectum. Their patients were divided into three groups: group A with normal CEA levels in both measurements, group B with increased preoperative levels and normal postoperative levels, and group C with increased levels in both measurements. The data demonstrated that the survival rate was significantly worse for group C, as might be expected: 35% for group C versus 64% and 54% for groups A and B, respectively. Local recurrences were not predicted by CEA levels, thus suggesting that significant fluctuations of CEA are primarily linked to meta-static disease.

As the authors point out, previous studies have clearly shown a relationship to increases in CEA before surgery, but studies of postoperative CEA levels have been limited by low sample sizes and variable approaches to the timing of CEA collections. The authors reportedly took the serum half-life of CEA into consideration in their design, selecting 7 days as the standard to avoid potential associations with postoperative chemotherapy or radiotherapy. In fact, the CEA serum half-life is relatively short, but when preoperative CEA levels are very high, they may not return to normal within 7 days, and this is one potential caveat to the interpretation of this study. For example, if the half-life of CEA is approximately 3 days, as has been reported in some studies, then a preoperative CEA level of 60 ng/mL would not likely be normal (<5 ng/mL) in 7 days. Thus, one would have to question whether a different result would have been achieved if the postoperative CEA levels were obtained at some time >7 days.

Despite the limitations of their study, the authors demonstrate the potential added benefit of tumor markers by using a properly designed and powered trial. This study demonstrates a potential prognostic utility in obtaining an early CEA level after surgery when the CEA level is increased before surgery. Patients without an early return to normal CEA levels may be suspected to have systemic disease until proven otherwise and may need to be monitored more closely.

In the process of performing this study, the authors have also developed a potentially significant resource for new biomarker discovery. They demonstrate the potential for additional new markers to be discovered with a similar trial design in which surgery is used to completely extirpate the offending lesion, and a dramatic change in a specific marker then occurs. In this case, CEA is the control biomarker for the serum set. It can also be used to identify cases in which CEA is not useful and in which additional new markers are required. The dramatic flux in serum levels is the key to potential new biomarker detection. With the new mass spectrometry–based proteomic technologies now available, the promise of discovering new markers is at hand, particularly if trial designs such as the one described by Park et al. are used.

Received for publication October 8, 2005. Accepted for publication October 26, 2005.

REFERENCES

1. Park Y-A, Lee KY, Kim NK, Baik SH, Sohn SK, Cho CW. Prognostic effect of perioperative change of serum carcino-embryonic antigen level: a useful tool for detection of systemic recurrence in rectal cancer. Ann Surg Oncol (in press).

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