Exposing a Tumor to Air
abstract & commentary
Synopsis: Patients often express concern regarding tumor dissemination from surgical procedures. In this report, Yamaguchi and colleagues show that the detection of colorectal cancer cells in the mesenteric venous blood is associated with a worse survival. Detection of tumor cells in the peripheral blood after surgical manipulation is discussed.
Source: Yamaguchi K, et al. Ann Surg 2000;232:58-65.
Yamaguchi and colleagues report on the use of reverse transcriptase polymerase chain reaction (RT-PCR) technology to detect circulating tumor cells in blood from colorectal cancer patients. The patients in this study were operated on in 1997 at Yamaguchi et al’s institution in Japan. There were 38 operations for colon cancer and 14 for rectal cancer. RT-PCR was performed using cDNA primers specific for CEA and cytokeratin. Only the detection of mRNA for both CEA and cytokeratin was considered positive because of the potential for false-positive results with CEA alone. Samples collected included a pre- and postoperative specimen from the peripheral blood as well as a pre-resection intraoperative specimen obtained from the mesenteric venous blood.
Evidence for malignant cells in the mesenteric venous blood specimens was found in 16 (31%) of the patients as defined by a positive RT-PCR for both CEA and cytokeratin. There was a statistically significant relationship between PCR-positivity and stage. Importantly, the PCR-negative group survived significantly longer than the PCR-positive group. The PCR result was an independent prognostic factor based on a multivariate analysis. These data suggest that the demonstration of tumor cells being shed into the mesenteric venous blood provides important prognostic information.
Did surgical manipulation of the tumor cause any patients to become PCR positive? Considering the 49 peripheral blood samples that were PCR negative preoperatively, only five became PCR positive postoperatively. The relevance of this is unclear as two of the three peripheral blood samples that were PCR positive preoperatively became negative postoperatively. Yamaguchi et al suggest that intermittent shedding and sampling errors can account for some false results.
COMMENT by Kenneth w. Kotz, MD
How many times has a patient expressed concern that exposing a tumor to air will cause it to spread? Does surgical manipulation allow dissemination of malignant cells? Unfortunately, this study titled "Significant Detection of Circulating Cancer Cells in the Blood by RT-PCR During Colorectal Cancer Resection" was not able to answer these questions. Of those 49 patients who were considered negative preoperatively, 44 remained negative and five became positive. Conversion of peripheral blood from a negative to a positive result was not clearly associated with an adverse outcome. In the same issue of the Annals of Surgery, another study did show significantly more tumor cell detection in the blood during resection of liver metastases from colorectal cancer compared with before or after surgery.1 Other studies that have used PCR technology have also been able to show conversion from negative to positive PCR as a result of surgical manipulation of colorectal tumors.
Whether these findings will have any clinical benefit is unclear. Approaches to compensate for potential dissemination of tumor cells could include changing the surgical technique or starting the chemotherapy intraoperatively. A randomized clinical trial of the "no-touch technique" to address the role of surgery has been published.2 The no-touch technique, involving the ligation of the lymphovascular pedicle before mobilization of the tumor, did not result in a statistically significant improved outcome.2
Early postoperative chemotherapy was shown to have a survival advantage for premenopausal women with estrogen receptor negative breast cancer,3 a concept discussed by Dr. Ershler in the March 2000 issue of Clinical Oncology Alert.4 Whether immediate postoperative initiation of standard chemotherapy administered peripherally would be more effective than the same chemotherapy started 3-4 weeks postoperatively has not been tested in colorectal cancer.
The use of a fluorouracil infusion into the portal vein, which is started on the day of surgery, has been tested.5 Although only compared to no adjuvant therapy, the National Surgical Adjuvant Breast Project has shown that immediate postoperative portal vein infusions can be associated with a disease-free survival advantage and a trend toward overall survival.5 Whether this technique is time-dependent or could have additive effects when combined with standard peripherally-infused chemotherapy is unproven.
Yamaguchi et al have shown evidence that circulating colorectal cancer cells can be detected in mesenteric venous blood samples. In a multivariate analysis, only the detection of mRNA in mesenteric venous blood for both CEA and cytokeratin was significantly associated with survival. For example, at one year, those patients who were positive for both CEA and cytokeratin had a survival rate of nearly 60%, whereas if either the CEA or cytokeratin (or both) were negative, the one-year survival rate was more than 90%. The clinical usefulness of this information remains to be proven.
References
1. Weitz J, et al. Ann Surg 2000;232:66-72.
2. Wiggers T, et al. Br J Surg 1988;75:409-415.
3. Colleoni M, et al. J Clin Oncol 2000;18:584-590.
4. Ershler W. Clinical Oncology Alert 2000;15:20-21.
5. Wolmark N, et al. J Clin Oncol 1990;8:1466-1475.
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