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10.1245/ASO.2005.03.565
Annals of Surgical Oncology 12:988-994 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Detection of Carcinoembryonic Antigen Messenger RNA–Expressing Cells in Portal and Peripheral Blood During Surgery Does Not Influence Relapse in Colorectal Cancer

Sotaro Sadahiro, MD1, Toshiyuki Suzuki, MD1, Kenji Ishikawa, MD1, Takeshi Saguchi, MD1, Yuji Maeda, MD1, Seiei Yasuda, MD1, Hiroyasu Makuuchi, MD1, Satoshi Yurimoto, PhmB1 and Chieko Murayama, PhD2

1 Department of Surgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
2 Department of Radiology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan

Correspondence: Address correspondence and reprint requests to: Sotaro Sadahiro, MD; E-mail: sadahiro{at}is.icc.u-tokai.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: No consensus has been reached on whether cancer cells detected in blood during colorectal cancer (CRC) surgery may serve as a prognostic indicator.

Methods: One hundred patients with CRC who underwent curative surgery were the subjects. Portal and peripheral blood were collected immediately after celiotomy and examined for carcinoembryonic antigen (CEA) messenger RNA (mRNA) by using competitive seminested reverse transcriptase-polymerase chain reaction. The median follow-up period was 59 months (range, 49–74 months).

Results: Until now, recurrence has been confirmed in 13 patients (13%). The 4-year recurrence rate was 6.7% (3 of 45) in patients with CEA mRNA–positive portal blood and 20.8% (10 of 48) in patients with CEA mRNA–negative portal blood (P = .09); it was 5.6% (2 of 36) and 19.3% (11 of 57) in patients with CEA mRNA– positive peripheral blood and CEA mRNA– negative blood, respectively (P = .12). There was no difference in disease-free survival between the CEA mRNA– positive and – negative groups. The multivariate analysis showed that the presence of tumor cells in portal or peripheral blood was a factor that reduced recurrence. The relative risks were .17 (P = .01) for the portal vein and .24 (P = .07) for the peripheral vein.

Conclusions: The detection of cancer cells in blood taken during surgery is not considered to be a poor-prognostic factor in CRC.

Key Words: Colorectal cancer • Carcinoembryonic antigen • Circulating cancer cells • Reverse transcriptase-polymerase chain reaction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Despite advances in surgical and adjuvant therapies, approximately 33% to 44% of patients with radically resected colorectal cancer will have tumor relapses.1–3 The main prognostic indicators used for colorectal cancer are the degree of tumor penetration in the bowel wall and lymph node involvement. Therefore, the current staging method, which has been widely used in the world—the International Union Against Cancer tumor-node-metastasis staging system—consists mainly of depth of tumor penetration and lymph node involvement.4 This staging system is not accurate enough to predict an individual’s risk of disease recurrence. There is a need for more sensitive methods to detect small-volume disease.

Reverse transcriptase-polymerase chain reaction (RT-PCR) has been developed to detect a very small number of disseminated tumor cells. The most common routes of metastasis from colorectal cancer are lymphatic spread to the regional lymph nodes and bloodborne metastasis to distant organs such as the liver and lung. Many authors have investigated the relationship between micrometastases in lymph nodes or bone marrow and prognosis.5–9 Although most of these studies showed that detection of micrometastases leads to poor prognosis, one article10 denying this relationship was recently published.

The significance of the detection of circulating cancer cells in portal and peripheral blood remains controversial.11–19 In a previous study, we examined the presence of circulating cancer cells in the portal and peripheral blood from 123 patients with colorectal cancer at the beginning of surgery by using RT-PCR targeting carcinoembryonic antigen (CEA) messenger RNA (mRNA).20 CEA mRNA expression was observed in portal blood in 51% of patients and in peripheral blood in 42%. The positive rate for CEA mRNA was significantly higher in patients with stage III and IV disease than in those with stage I and II disease. However, the positive rate was 38% in T1 (submucosal layer) patients; it was thus quite high even in early-stage disease. The positive rate was also not different between patients with liver metastasis (47%) and those without (52%). In this study, we investigated the association between the detection of cancer cells in blood during surgery and the recurrence, disease-free survival, and overall survival in patients who underwent curative surgery.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This study was performed on 100 patients with colorectal cancer who underwent surgery at the Department of Surgery, Tokai University, between April 1998 and March 2000. These 100 patients underwent curative resection and were selected from 123 patients examined for the presence of circulating cancer cells in portal and peripheral blood at the beginning of surgery by using the RT-PCR technique, which we reported previously.20 Because the aim of this study was to evaluate the significance of detection of circulating cancer cells for the cohort of patients with curative resection, we selected patients with curatively resected disease from the original cohort, which included patients with non–curatively resected disease. They all gave informed consent. According to the tumor-node-metastasis classification, 20 patients had stage I, 47 patients had stage II, and 32 patients had stage III disease. The T stage of one patient was unknown because of complete remission after preoperative chemoradiotherapy. Of these patients, 65 patients had colon cancer, and 35 patients had rectal cancer. None of the patients was lost to follow-up, with a median of 59 months (range, 49–74 months).

Blood Sampling
Blood was collected immediately after celiotomy and before cancer-bearing bowel was touched. Blood samples from the portal vein were obtained through a catheter inserted into the umbilical vein or into the inferior mesenteric vein. To prevent contamination with epithelial cells, peripheral blood samples were obtained through a catheter inserted into the peripheral vessel. The first 20 mL was discarded to prevent contamination with epithelial cells.

Competitive Seminested RT-PCR Technique
Because our technical procedure was reported in detail previously, we describe it briefly below.20 RNA isolation and reverse transcription were performed according to our previous article. In our seminested competitive PCR, a CEA competitor template was designed as follows. A 12–base pair (bp) fragment was inserted between nucleotides 2246 and 2247 of plasmid pCEA-WT containing 343 bp of CEA (nucleotides 1966–2308). PCR of the expanded clone yielded a band of 144 bp, compared with a band of 132 bp when wild-type CEA was used as a template.

CEA-specific oligonucleotide primers were synthesized as follows: primer A, 5'-TCTGGAACTTCTCC TGGTCTCTCAGCTGG-3'; primer B, 5'-TGTAGC TGTTGCAAATGCTTTAAGGAAGAAGC-3'; and primer C, 5'-fluorescein isothiocyanate-GGGCCAC TGTCGGCATCATGATTGG-3'. The first PCR was performed by using primers A and B with amplification of 30 cycles, and then this PCR product was applied for seminested PCR by using primers B and C with amplification of 30 cycles.

The integrity and amount of RNA for preparation of all complementary DNAs were analyzed by using the performance of the ß-actin competitive PCR as an internal control. A ß-actin competitor template was designed as described previously. PCR was performed by using oligonucleotide-specific primers for ßß-actin: 5'-CTTCTACAATGAGCTGCGTG-3' for the sense primer and 5'-TCATGAGGTAGTCAGT CAGG-3' for the antisense primer. Amplification was performed with 35 cycles. Each PCR procedure was performed under the same conditions as in our previous article.

Amplification products were electrophoresed on an 8% polyacrylamide gel and quantified with an FMBIO Fluorescence Image Analyzer (Hitachi Software Engineering, Yokohama, Japan). The CEA mRNA/ß-actin mRNA ratio was used to determine the relative CEA expression level. This technique can detect one CEA mRNA–expressing cancer cell in 1 x 105 normal lymphocytes.

Patient Follow-Up
Patients visited an outpatient department every 3 months or more frequently for the initial 2 years, every 4 to 6 months for the next 2 years, and every 6 to 12 months thereafter. Evaluation consisted of medical history, physical examination, and laboratory studies, including blood cell count, liver function tests, and serum CEA. Abdominal computed tomography or ultrasonography and chest radiography were performed every 6 months. Barium enema or colonoscopy was performed 1 year after surgery and every 2 to 3 years thereafter. Examinations were performed at any time when patients were symptomatic.

Statistical Analysis
The primary end point was to evaluate whether circulating cancer cells influenced patients’ disease-free survival. Categorical variables were compared by the {chi}2 test, with the Yates correction if needed. Probability curves were calculated by using the Kaplan-Meier method, and the log-rank test was used to compare the two groups.

To evaluate whether circulating cancer cells influenced disease-free survival, the Cox proportional hazard model (multivariate analysis) was used.21 We expected a low rate of recurrence because this study’s subjects had curatively resected disease. Therefore, we selected the PCR status in the portal or peripheral blood and the tumor-node-metastasis classification, which were considered to be the most influential factors for recurrence, and input these variables into the multivariate analysis model. All data were analyzed by using the SPSS II software package for Windows (release 11.0; SPSS Japan Inc., Tokyo, Japan), with the level of significance set at <.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Detection of CEA mRNA in Blood and Clinicopathologic Findings
Table 1Go shows the detection rate of CEA mRNA in the portal and peripheral blood taken at the beginning of surgery before manipulation of the tumor. Statistical differences in the detection rate were not found in any clinicopathologic finding. The detection rate of CEA mRNA was as high as 38% in portal blood and 25% in peripheral blood even in T1 patients with tumor penetration limited to the submucosa. Patients without lymph node metastasis showed high detection rates of 59% and 44% in portal and peripheral blood, respectively; however, there were no statistical differences between patients with and without lymph node involvement. Twenty of 35 patients with rectal cancer received preoperative chemoradiotherapy. There were no statistical differences in detection rates between patients treated with and without chemoradiotherapy.


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  		TABLE 1. Incidence of CEA mRNA–positive reaction
 
Recurrence
During the follow-up period, with a median of 59 months (range, 49–74 months), tumor recurrences were confirmed in 13 (13%) of 100 patients. Twelve of 13 relapsing patients died, and 1 is alive with cancer. Six patients died of other causes (pneumonia in four, cerebral infarction in one, and another cancer in one).

Table 2Go shows the relationship of the 4-year recurrence rate to clinicopathologic indices and to detection of CEA mRNA in blood. The recurrence rate was calculated by excluding seven patients (six patients experienced death as a result of other disease before the 4-year follow-up; one patient had disease of unknown stage). The patients with deep tumor penetration relapsed significantly more frequently (P < .01). In 13 relapsing patients, 3 were positive for CEA mRNA in the portal blood, and 2 were positive in the peripheral blood. However, there were no statistical differences between the recurrence rate and PCR status in portal or peripheral blood. The CEA mRNA expression level in one out of three relapsing and positive patients was extremely high (portal blood, 148 x 10)8/ß-actin; peripheral blood, 348 x 10)8/ß-actin), but levels in the remaining two patients were existing within the mean ± SD (portal blood, 22.9 ± 35.1 x 10)8/ß-actin; peripheral blood, 19.9 ± 40.0 x 10)8/ß-actin). The first site of recurrence was the lung in four patients, peritonea in three, liver in two, and lymph node in one. Three patients had local recurrence. In four patients who were positive for detection of cancer cells in circulating blood, the first site of recurrence was lung in three and local in one.


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  		TABLE 2. Relationship of the 4-year recurrence rate to clinicopathologic findings and to the status of CEA mRNA in blood
 
Disease-Free and Overall Survival
Disease-free and overall survival according to the presence or absence of CEA mRNA in the blood are shown in Figures 1Go and 2Go, respectively. There was no difference in disease-free survival between patients who were positive for CEA mRNA in portal or peripheral blood and those who were negative (P = .27 and P = .24, respectively). Overall survival was not different between these two patient groups (P = .23 and P = .13, respectively).


Figure 1
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  		FIG. 1. Disease-free survival curves according to the presence or absence of circulating tumor cells in the portal vein. Solid line, polymerase chain reaction (PCR) positive; broken line, PCR negative. X axis, years; Y axis, disease free survival (%).

 

Figure 2
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  		FIG. 2. Overall survival curves according to the presence or absence of circulating tumor cells in the portal vein. Solid line, polymerase chain reaction (PCR) positive; broken line, PCR negative. X axis, years; Y axis, overall survival (%).

 
Multivariate Analysis
The results of the multivariate analysis are shown in Table 3Go: the presence of cancer cells in portal or peripheral blood was found to be a factor that reduced recurrence. The relative risks were .17 (P = .01) for the portal vein and .24 (P = .07) for the peripheral vein. Stage III was a risk factor that increased recurrence, with relative risks of 13.95 (P = .02) for the portal vein and 7.76 (P = .06) for the peripheral vein.


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  		TABLE 3. Risks influencing disease recurrence by multivariate analysis
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The expression of CEA mRNA was measured quantitatively by seminested competitive PCR, assuming that its expression level was associated with recurrence. We reasoned that the quantitative measurement could find the threshold level of recurrence and predict the recurrence accurately. However, because the recurrence rate was as low as 13% in this series and because most relapsing patients were negative for CEA mRNA, it was difficult to analyze the correlation between the CEA mRNA expression level and recurrence. Out of three relapsing patients who were positive for CEA mRNA, one had an extremely high expression level (portal blood, 148 x 10)8/ß-actin; peripheral blood, 348 x 10)8/ß-actin), but others’ were within the mean ± SD (portal blood, 22.9 ± 35.1 x 10)8/ß-actin; peripheral blood, 19.9 ± 40.0 x 10)8/ß-actin).

Our results based on qualitative detection indicated that patients whose CEA mRNA expression was positive in blood seemed to relapse less frequently. Tumor cells were detected in portal blood just after celiotomy and before mobilization in three out of four patients who had recurrence in the lung, but they were not detected in two patients with metastasis to the liver, which seems to be also hematogenous. According to our multivariate analysis, the absence of CEA mRNA in the blood was a factor that increased the risk of recurrence. However, this result is paradoxical, and we consider it incidental. In any case, our assumption that the detection of cancer cells in blood would increase the recurrence risk was discarded.

Taniguchi et al.12 reported that the 2-year disease-free survival rate was significantly poorer in patients positive for CEA mRNA expression in portal or peripheral blood during surgery compared with those negative for such expression. Yamaguchi et al.13 reported significantly poorer overall survival in patients with CEA mRNA and cytokeratin 20 mRNA detected in portal or peripheral blood during surgery. Fujita et al.16 and Ito et al.17 also reported poor disease-free survival in patients with tumor cells detected in the circulating blood. However, Bessa et al.15,18 reported no association between detection of tumor cells in preoperative and postoperative circulating blood and disease-free survival rate. Bessa et al.15,18 also reported no association between detection of tumor cells in preoperative and postoperative circulating blood and survival rate. Guller et al.11 investigated the association between CEA mRNA and cytokeratin 20 mRNA expression and recurrence in peritoneal lavage fluid and peripheral blood and reported that their association could not be identified by analyzing only peripheral blood. Vlems et al.19 also reported a negative view on the effect of minimal residual disease on recurrence. One of the reasons of controversial association between minimal residual disease and recurrence may be the timing of blood sampling (before, during, or after surgery). Blood samples were taken before tumor resection in most of the aforementioned reports, and we also took blood samples before tumor resection.

Patel et al.22 took blood samples before surgery and at selected time intervals for three postoperative months and reported that the positive rate for blood cancer cells in the Dukes’ A/B patients significantly decreased in 24 postoperative hours but did not decrease in the Dukes’ C patients and that the positive response after surgery was not random but consistent in the same patient. On the basis of these findings, they indicated the possibility that the evaluation of blood samples after curative section can be a predictive prognostic factor in Dukes’ A/B patients. Ito et al.17 reported a significantly poorer disease-free survival in patients positive for CEA mRNA in the peripheral blood after surgery. Guadagni et al.23 reported that some patients positive for CEA mRNA in the peripheral blood at more than one postoperative month had cancer recurrence.

Most cancer cells experimentally administered in the peripheral vein remain in the lung immediately after administration, but most perish after more than 8 hours, probably because of physical stress and so on.24 Cancer cells that tolerate this physical stress are likely to survive in the blood and metastasize. In experimental models, such cancer cells which aggregate each other are reported to be likely to metastasize.25 Therefore, minimal residual disease detected after curative resection of colorectal cancer may be closely associated with recurrence.

Bessa et al.18 investigated the CEA mRNA expression in peripheral blood taken 24 hours after surgery and reported a lack of association with disease-free survival or survival duration. However, because cancer cells experimentally administered into the peripheral vein are detected until 24 hours after administration,24 further studies are required to clarify the significance of minimal residual disease detected after curative resection of colorectal cancer.

Various factors, such as intravascular invasion from the primary lesion, expression of adhesion molecules, and host immunity, are involved in metastasis, and the existence of minimal residual disease is only one factor. However, the detection of cancer cells in blood means that some of the steps to metastasis have been already cleared. Although the false-positive rate of our method was 18%, we had previously reported that the positive rates of detection of circulating cancer cells in patients with T1 tumors and those with stage I disease were as high as 40% and 30%, respectively.20 Similar positive rates of cancer cells in the peripheral blood from Dukes’ A patients were reported elsewhere, and they were 33%,19,23 38%,26 and 71%.22 These figures indicate that, although tumor cells are surely shed into peripheral blood in early-stage colorectal cancer patients, this does not seem to be directly associated with metastasis. However, the clinical significance of minimal residual disease found after tumor resection is not clear, and future studies are required. At present, we are investigating the influence of minimal residual disease on prognosis by sampling peripheral blood more than 7 days after surgery.

Received for publication March 8, 2005. Accepted for publication July 20, 2005.


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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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