Japanese Journal of Clinical Oncology 32:54-58 (2002)
© 2002 Foundation for Promotion of Cancer Research
Usefulness of Analytical CEA Doubling Time and Half-life Time for Overlooked Synchronous Metastases in Colorectal Carcinoma
Department of Surgery II, School of Medicine, Nagoya University, Nagoya, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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Background: Measurement of carcinoembryonic antigen (CEA) has been widely applied to detect recurrence, especially of colorectal carcinoma. The validity however, is still controversial. We investigated serial changes in CEA values to calculate whether the CEA doubling time and half-life time could predict metastatic progression or prognosis in colorectal carcinoma.
Methods: Pre- and post-operative serial serum CEA contents were determined in 22 cases of colorectal cancer with or without metastasis. CEA values were determined by enzyme immunoassay (EIA). Patients were assigned depending upon survival time (within vs more than 18 months after primary resection) for assessment of CEA doubling time. From the gradient of the semi-logarithmic CEA graph, the preoperative doubling time was calculated and the postoperative half-life time was estimated according to the diagnosis of metastases within 2 years after primary resection [metastasis (+) or (–)].
Results: In spite of the effect of curative re-operation of metastatic lesions or of postoperative adjuvant chemotherapy, the CEA doubling time of the groups showed a relation with prognosis (p = 0.045, Student’s t-test) when the patients were divided into >18 and 
18 months survival time. The CEA half-life time of the groups without overlooked metastases was statistically longer than those with (mean ± SD 8.01 ± 2.07 and 4.33 ± 1.11, respectively, p < 0.01, one-factor ANOVA test). Clearance (k) showed a significant difference between the groups (p < 0.001, Student’s t-test).
Conclusion: The CEA doubling time appeared to be a less independent prognostic factor, whereas prolongation of the CEA half-life time might potentially suggest the existence of overlooked synchronous metastases from colorectal carcinoma.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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Many carcinoma patients are at high risk of persistent metastases after primary resection of lesions, which should be detected earlier than ever for the improvement of quality of life and also prognosis even during the maintenance phase of chemotherapy.
Considering the intraoperative risk of metastases, which appears to be one of the major cause of metastases, tumor cells may spill out into the blood stream during curative surgery and the circulating malignant cells could feasibly amplify carcinoembryonic antigen (CEA) messenger RNA (mRNA) in peripheral blood (1). The mechanism of metastases from colorectal cancers has been investigated in relation especially to liver metastasis but is still controversial (2–4), including the question of whether there is a cause–effect relationship between elevated blood levels of CEA and the development of liver metastasis (5,6). Moreover, potential overlooked metastases and micrometastases (7,8) that were already established before resection may still exist as a persistent problem at the time of diagnosis of primary carcinoma even when using accurate high-technology developments such as computed tomography (CT) and magnetic resonance imaging (MRI).
Serum and tissue tumor marker research has provided various tests for detecting cancer in early stages. Univariate and multivariate analyses using CA 19-9, for instance, have been reported to reveal that CA 19-9 concentration could be a prognostic variable for relapse and metastasis in colorectal carcinoma patients (9–11). CEA, of which the levels are routinely used, has been investigated to ascertain the correlation between CEA and anti-CEA in colorectal cancer patients (12) and the difference in validity between serum and tissue content of CEA in those patients (13) or in breast cancers (14).
On the other hand, newer molecular diagnostic techniques using the reverse transcriptase polymerase chain reaction (RT-PCR) or real-time fluorescence polymerase chain reaction of mRNA for CEA have been assessed in order to increase the detection of micrometastases from patients with esophageal cancer (15), gastrointestinal cancer or breast cancer (16–18). Some literature reports concluded that the molecular detection of CEA mRNA would be useful especially for lymph node metastases with higher sensitivity than histopathological examination (15,16). These improved results would compensate for the time and cost expended on the procedures involved with these techniques.
The aim of this study, however, was to examine two factors in the measurement of tumor marker CEA, the analytical CEA doubling time and the half-life time, with regard to their appropriateness, ease and effectiveness by simply following the serial changes in the results.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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Enrollment of Patients
Twenty-two patients with histologically proven colorectal carcinoma with or without synchronous metastasis, diagnosed to be curative at Nagoya University Hospital, were entered to assess pre/postoperative serial CEA alterations from 1987 to 1990. The median age was 58.5 ± 11.5 years (10 males, 12 females) and with a minimum follow-up of 3 years or until death. Informed consent was obtained from all the patients and/or their guardians. The research protocol was approved by the Ethics Committee of Nagoya University.
Measurement of Serum CEA
The serum CEA content was measured at intervals of 1–2 weeks (preoperatively) and every other day (postoperatively) at least four times, by enzyme immunoassay (EIA), using Olydas-120, Glaozyme New CEA (Wako Pure Chemical Industries, Osaka, Japan). CEA values <5 ng/ml were assessed as normal. Patients whose increased preoperative CEA values were under the cut-off point were also included to assess the CEA doubling time.
Statistical Analysis of CEA Doubling Time
From the serial preoperative CEA values, the associated doubling time of CEA was calculated individually based on the equation C(t) = C(t0)ekt (t = time; k = clearance), which was applied as representing the monoexponential decline curve of a drug that confers one-compartment characteristics on the body (19), and log(CEA) was determined by the equation logeC(t) = kt + logeC(t0).
Statistical Analysis of CEA Half-life Time
The serial CEA data obtained on postoperative days 1, 3, 5 and 7 were calculated individually based on the equation C(t) = C(t0)e–kt, which was used for the same reason as for the CEA doubling time. Log(CEA) was determined by the equation logeC(t) = –kt + logeC(t0), and was compared between those patients with and without any metastases or recurrences diagnosed within 2 years after the primary resection of colorectal carcinoma. The cut-off value of the CEA half-life time was estimated from these two groups.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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Preoperative Doubling Time vs Prognosis
The doubling times of serum CEA in all the eligible patients (total 11) are listed in Table 1. These curatively resected colorectal carcinoma patients with or without synchronous metastasis were randomly selected from among those who were supposed to have a clear increase in serum CEA level with r >0.9 before surgery. To investigate the correlation between survival time and preoperative CEA doubling time, the 11 patients included those who were diagnosed as developing metastasis including recurrent metastasis during postoperative follow-up. At the re-operation, for those patients who developed and had diagnosed metastasis, the metastatic lesion was curatively resected. The median doubling time of all the patients was 68.0 ± 57.4 days with a range of 15.4–162.1 days. When classified according to survival time at the postoperative 18th month, the groups ‘survival longer than 18 months’ and ‘dead within 18 months’ showed median doubling times of 90.3 ± 62.3 and 29.2 ± 8.9 days, respectively (p = 0.045, Student’s t-test).
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Postoperative Half-life Time and Metastases/Recurrence
Table 2 gives the half-life time of CEA in 14 patients (including three patients who were also assessed for the doubling time) assigned according to the development and diagnosis of metastases after curative surgery for colorectal carcinoma. Of nine patients with one or more metastases, the categories were five in liver, two in lung, two in lymph node and one in right adrenal. A statistically significant difference was observed between the two groups in the half-life times [median ± SD, 4.33 ± 1.11; metastasis/recurrence (–) group, 8.01 ± 2.07; (+) group, p < 0.01, one-factor ANOVA test]. Fig. 1 shows the comparison of the descending gradient of log(CEA) for the two groups. Considering the gradient of clearance (k), there is a statistically significant difference between metastasis/recurrence (–) and (+) (median ± SD, 0.167 ± 0.034 and 0.091 ± 0.022, respectively, p < 0.001, Student’s t-test).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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CEA assay has been considered to be a valuable adjunct to clinical examination in both preoperative and postoperative monitoring of patients with colorectal carcinoma with or without metastases since it was first described in 1965 by Gold and Freedman (20).
The validity of serum CEA measurement is, however, still controversial (21) with regard to the accurate detection of disease progression at an earlier stage compared with symptoms or signs of primary or recurrent carcinoma. In our previous study, we observed a proportional increase between preoperative CEA content and postoperative recurrence in curatively resected colorectal carcinoma patients; additionally, the continuous elevation of CEA and tumor progression showed a close relation, in agreement with other literature reports (22,23). Concerning early diagnosis, Rockall and McDonald (21) reported that 23 of 31 (74%) patients had symptoms or signs of recurrent disease prior to or simultaneously with an observed rise in CEA; moreover, we confirmed a markedly earlier start of CEA elevation than the clinical confirmation of recurrence (days after curative resection of colorectal carcinoma: 216.3 ± 145.1 and 400.6 ± 205.6, respectively).
However, Tuxen et al. (24) assessed the biological variation and analytical imprecision of CEA compared with other tumor markers in ovarian cancer and concluded that the biological variation should be individually included in the criteria for serum tumor marker assessment during monitoring. Considering the productivity of CEA in the target tumor, the serial change assessment would be potentially useful for serum CEA measurement. Serial CEA assays have been reported to help the detection of early tumor recurrence, especially when the assays are done frequently (25–29). Staab et al. (28) investigated the slope of CEA, which was indicated by the increase in 10 days, and concluded that the slope of CEA increase tended to be steeper in liver metastases than in localized tumor recurrences. Wood et al. (29) concluded that the differential pattern of two CEA rising curves (described as ‘fast’ and ‘slow’ rise) might be of help in predicting the site of a recurrent tumor: a ‘fast’ rise implied metastatic spread whereas a ‘slow’ rise suggested local recurrence alone.
Subsequently, a more accurate assessment for serial CEA content was introduced, namely the concept of doubling time. Yamada et al. (30) confirmed the correlation between CEA doubling time and survival time in colorectal carcinoma patients with synchronous metastases in liver or lung and also the significant difference in doubling time between liver and lung metastasis. The discrimination or characteristics of serum CEA would allow qualified selection of therapeutic treatments, and thus would assess the efficacy of various treatments (31).
When considering the result that we could not clearly confirm a significant correlation between CEA doubling time and prognosis, the assessment of preoperative CEA doubling time had limited validity, which was strongly affected mainly by postoperative adjuvant chemotherapy and re-resection after development of relapse or metastases. On the other hand, the CEA doubling time might potentially be estimated even in the patients whose CEA values are under the cut-off point, and it might become possible to detect malignant carcinoma among these patients. Further, the time of tumor genesis might be obtained by following reversely the gradient of the semi-logarithmic CEA graph.
We tried to analyze the postoperative serial regression of CEA and calculate its half-life time as an entirely novel strategy never reported in the literature on early diagnosis for overlooked metastases. The preoperative or postoperative CEA rise has been emphasized for the assessment of prognoses and recurrences thus far; the evaluation of the gradient of postoperative CEA regression might lead to rigorous and earlier diagnosis of tumor progression than that of postoperative CEA rise following prolonged CEA regression. Provided that the cut-off of the CEA half-life time is set at 5.5 days after curative resection, the cut-off point would clearly divide patients into two groups, metastases (+) and (–), without exception. Considering the duration of the postoperative measurement and follow-up, the prolongation of the half-life time might suggest especially the existence of overlooked synchronous metastases. The change in the gradient of the CEA regression curve during adjuvant therapy such as chemotherapy might potentially be an indicator of its sensitivity. Furthermore, the gradient analysis might distinguish those patients in the course of complete response or partial response, even for those whose regression curve shows a considerable excess from the associated cut-off point. To establish the precision, more aspects of the CEA half-life time (including sensitivity, specificity, accuracy and cut-off point) should be investigated on a larger scale in a subsequent study.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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The CEA doubling time did not show a distinct relation with prognosis in patients with colorectal carcinoma, whereas the assessment of the CEA half-life time and its regression curve might help in detecting overlooked synchronous metastases.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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We thank Ms Tomomi Murase and Ms Atsuko Tanaka for the analysis of the data and assistance with the preparation of the manuscript.
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FOOTNOTES |
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+ For reprints and all correspondence: Katsuki Ito, Department of Surgery II, School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: katsuki@tsuru.med.nagoya-u.ac.jp
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONAcknowledgmentsREFERENCES |
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Received July 18, 2001; accepted November 5, 2001.
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