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Carcinoembryonic Antigen Surge in Metastatic Colorectal Cancer Patients Responding to Oxaliplatin Combination Chemotherapy: Implications for Tumor Marker Monitoring and Guidelines

Department of Oncology and Section of Oncology, Institute of Medicine, Haukeland University Hospital, Bergen, Norway

To the Editor: In general, a rise in carcinoembryonic antigen (CEA) level in patients with metastatic colorectal cancer means tumor progression. We have, however, observed in four patients a transient increase in CEA level despite objective response among patients receiving oxaliplatin combination chemotherapy for metastatic colorectal cancer. Such a surge phenomenon has not previously been described for patients with metastatic colorectal disease and has implications for tumor marker monitoring and guidelines.

A series of 27 patients received a standardized chemotherapy as first-line treatment of metastatic disease from adenocarcinomas of the colon and rectum. Patients received oxaliplatin 85 mg/m² as a 2-hour infusion day 1 followed by a 3-minute bolus infusion with fluorouracil (FU) 500 mg/m² and 30 minutes later a bolus infusion with folinic acid (FA) 60 mg/m² every second week. FU and FA were also given day 2. Measurable lesions were reassessed by abdominal computed tomography scan and chest x-ray after every fourth cycle, and response graded after WHO criteria. The regimen was very active, in that we recorded a confirmed response rate of 63%. CEA level was analyzed in all patients at baseline and before each therapy by a microparticle enzyme immunoassay on an IMx (Abbott Laboratories, Abbott Park, IL, USA). Normal reference interval is < 3.0 µg/L. In a pilot patient treated outside this series, we observed a rise in CEA level despite a radiologic verified tumor response. We therefore re-examined the laboratory data for all 27 consecutive patients included in the study, in search of a possible surge response. We chose to define a CEA surge as a > 20% increase from a pathologically baseline value followed by a subsequent drop below 20% of the initial baseline value. Additional criteria were no progression of tumor lesions documented by radiological examination during the surge of CEA and baseline CEA value taken less than 2 weeks before start of therapy. Four patients (15%; 95% CI, 5% to 31%) met the criteria of therapy-induced CEA surge. Baseline CEA was taken 1 day before first treatment in all four surge patients (range, 78 to 1,800 µg/L). The time to reach maximum CEA level (range, 252 to 3,440 µg/L) varied from 13 to 56 days. Median rise in CEA from baseline was 263% (range, 24% to 632%). The immediate rise in CEA was not related to tumor progression, given that 3 patients had a partial response and one had stable disease (a slight regression). The lowest CEA measurement after the CEA peak was in the range 6 to 89 µg/L. The four patients did not show any sign of liver toxicity, but rather a normalization of liver enzymes. The initial patient who stimulated this report did not meet the criteria—baseline CEA level was taken 4 weeks before the start of therapy—and is not included in this series.

In this study we found a clinically relevant CEA surge in four of 27 patients on therapy. We believe this new observation may be due to the introduction of a more effective chemotherapy regimen for metastatic colorectal cancer. Oxaliplatin based chemotherapy is more effective giving a doubling of response rate compared with FU regimens alone.¹ A transient increase in tumor markers after chemotherapy has previously been seen in responding patients with nonseminomatous testicular cancer and breast cancer.^2–3 In six of the breast cancer patients, the initial CEA surge was incorrectly interpreted as evidence of disease progression, and inappropriate therapy changes were made.³ The most common pattern of tumor marker response after initiation of chemotherapy in responding patients is regression towards normal levels. A consistent rise in CEA is generally thought to be indicative of disease progression. An early rise in tumor markers after treatment start should, however, be serially followed to differentiate a true from a transient rise.

The 2000 update of the American Society for Clinical Oncology (ASCO) recommendations for the use of CEA level in monitoring therapy in patients with advanced colorectal cancer state that the present data is insufficient to recommend routine use of serum CEA alone for monitoring response to treatment.⁴ However, they recommend CEA measurements at the start of treatment for metastatic disease and every 2 to 3 months during active treatment. Two values above baseline are considered adequate to document progressive disease even in the absence of corroborating radiographs. CEA was regarded by the ASCO panel as the marker of choice for monitoring colorectal cancer. The National Academy of Clinical Biochemistry in the United States and the European Group on Tumor Markers also recommend the use of CEA for monitoring therapeutic response in metastatic colorectal cancer.^5–6 Our findings support the ASCO statement that response assessment should not be based on CEA level alone.⁴ It does, however, raise concern about the ASCO recommendation that two CEA values above baseline are adequate to document progressive disease even in the absence of corroborating radiographs. If we had followed this ASCO guideline of measurement of CEA level every second month, one of the surge patients would have been incorrectly interpreted as having experienced treatment failure, and therapy would have stopped. The patient would have been incorrectly removed from the treatment, giving her a time to progression of 11.2 months and 27.3-month survival. To avoid inappropriate therapy changes based on clinical misinterpretation of a CEA surge as an impending disease progression, we suggest that future ASCO guidelines should mention the possibility of CEA surge. Furthermore, we suggest that no therapy changes should be based on CEA levels alone at all during the first 6 months of therapy.

An initial rise in CEA level during effective chemotherapy in colorectal cancer patients may not always indicate progression of disease but may be a transient CEA surge in patients responding to chemotherapy. In monitoring tumor responses and in future guidelines for the use of tumor markers, the possibility of a surge phenomenon should be taken into account. This will especially be important if a new, more effective treatment with high response rates or rapid tumor destruction is introduced.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

1. Levi F, Zidani R, Misset JL: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350:681–686, 1997[CrossRef][Medline]

2. Horwich A, and Peckham MJ: Transient tumor marker elevation following chemotherapy for germ cell tumors of the testis. Cancer Treat Rep 70:1329–1331, 1986[Medline]

3. Loprinzi CL, Tormey DC, Rasmussen P, et al: Prospective evaluation of carcinoembryonic antigen levels and alternating chemotherapeutic regimens in metastatic breast cancer. J Clin Oncol 4:46–56, 1986[Abstract]

4. Bast RC, Ravdin P, Hayes DF, et al: 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1865–1878, 2001[Abstract/Free Full Text]

5. Fleisher M, Dnistrian AM, Sturgeon CM, et al: Practice guidelines and recommendations for use of tumor markers in the clinic, in Diamandis EP, Fritsche H, Schwartz MK, Chan DW (eds): Tumor Markers: Physiology, pathobiology, technology and clinical applications. Chicago, IL, AACC Press, 2002, pp 33–63

6. European Group on Tumor markers (EGTM): Tumour markers in gastrointestinal cancers—EGTM recommendations. Anticancer Res 19:2811–2815, 1999[Medline]

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