Anesthesia and Circulating Tumor Cells in Primary Breast Cancer Patients

A Randomized Controlled Trial

Frédérique Hovaguimian, M.D.; Julia Braun, Ph.D.; Birgit Roth Z'graggen, Ph.D.; Martin Schläpfer, M.D.; Claudia Dumrese, Ph.D.; Christina Ewald, Ph.D.; Konstantin J. Dedes, M.D.; Daniel Fink, M.D.; Urs Rölli, M.Sc.; Manfred Seeberger, M.D.; Christoph Tausch, M.D.; Bärbel Papassotiropoulos, M.D.; Milo A. Puhan, Ph.D.; Beatrice Beck-Schimmer, M.D.

Disclosures

Anesthesiology. 2020;133(3):548-558. 

In This Article

Discussion

In this randomized controlled trial including 210 participants undergoing surgery for primary breast cancer, the type of anesthesia did not seem to affect circulating tumor cell counts over time or circulating tumor cell positivity. In one secondary analysis, there was a 36% increase in the maximal number of postoperative circulating tumor cells in patients receiving inhalational anesthesia. Additional in vitro analyses in a random selection of 60 patients did not reveal any evidence for an association between natural killer cell-induced apoptosis rates and maximal circulating tumor cell counts.

This trial investigated the effect of anesthesia on perioperative circulating tumor cell counts, an independent prognostic factor for breast cancer. In contrast to previously published randomized trials,[15–17] our study was larger and had an adequate control group, and the issue of long follow-up periods was mitigated by using a prognostic factor.

In our trial, circulating tumor cell counts at baseline were higher than those reported in previous studies. Several reasons may account for this discrepancy. First, all of our patients underwent sentinel lymph node localization 18 to 24 h before baseline circulating tumor cell assessment, and we cannot formally exclude that an injection in the vicinity of the tumor would not lead to any circulating tumor cells release. Second, approximately 30% of our patients had wire-guided localization of the tumor, which implies direct manipulation of the tumor shortly before circulating tumor cell assessment.

Because the identification of circulating tumor cells with the CellSearch assay may imply some degree of subjectivity (i.e., images of potential tumor cell candidates are displayed to trained laboratory technicians and assessed following predefined criteria), we verified all samples with at least 5 tumor cells/7.5 ml blood using the automated software ACCEPT (Supplemental Digital Content Figure 2, illustrating the flow chart of the validation analysis;http://links.lww.com/ALN/C415).[30] Overall, the comparison showed a good correlation (Supplemental Digital Content Figure 3 illustrates the correlation between these two methods;http://links.lww.com/ALN/C415). Compared to the ACCEPT software, there was an overestimation of circulating tumor cell counts by 1.66 units with human assessment (Supplemental Digital Content Figure 4 illustrates the agreement between these two methods;http://links.lww.com/ALN/C415). However, in this validation analysis, only samples with high tumor cell counts were considered. This may bias the results toward an overestimation of the difference in means. In other words, if all samples, i.e., including those with 0 to 4 tumor cells/7.5 ml blood, had been included, the difference in means of 1.66 units would have likely been smaller. Second, the overestimation of 1.66 units was nondifferential, i.e., applied to both groups, regardless of treatment assignment.

Apart from one secondary analysis, our findings contrast with numerous previously published studies suggesting better outcomes with the use of intravenous anesthesia. The potential reasons for this disparity are two-fold. First, clinical studies reporting on cancer outcomes were based on retrospective data analyses,[7–14] which are prone to bias and confounding. Second, evidence of a protective effect associated with propofol was partly driven by in vitro studies,[31–35] which may not reflect the delicate interplay between immune and tumor cells observed in vivo. Our findings, however, are consistent with a recently published, large, randomized controlled trial addressing the effect of regional versus general anesthesia on breast cancer recurrence.[36] Although this trial was not specifically designed to compare inhalational with intravenous anesthesia, most patients allocated to general anesthesia received sevoflurane, whereas those allocated to regional anesthesia received propofol. In line with our study, this trial failed to show any difference in cancer outcomes.

Our results, however, need to be interpreted with caution. First, we assumed circulating tumor cell counts would be an appropriate prognostic factor to measure the impact of anesthesia on the risk of tumor recurrence, but we did not perform a long-term outcome analysis to confirm this assumption. Although many oncological markers seem to be ideally placed in the causal pathway leading to distant disease, several other factors will eventually be needed to result in metastatic spread, and uncertainty regarding the ability of these prognostic factors to predict "hard endpoints" must be acknowledged.[37] A second concern is that the exact meaning of circulating tumor cell changes in the perioperative period remains unclear. In studies investigating the predictive validity of circulating tumor cells changes in primary and metastatic breast cancer, patients converting from "positive" to "negative" status were found to have longer progression-free survival and overall survival than those with a persisting "positive" status.[23,38–42] However, circulating tumor cell detection was performed over many weeks or months, and there is no firm evidence that these findings also apply to the immediate and rather short perioperative period.

Other limitations are inherent to the CellSearch assay itself. Although the pattern EpCAM+/CK+/DAPI+/CD45- is a widely accepted molecular circulating tumor cell signature, other combinations may also occur: it has been argued, for instance, that 7.8 to 10.3% of breast cancers might lack EpCAM expression.[43,44] Further skepticism has been partly related to the fact that for a given tumor, a variety of circulating tumor cells phenotypes seems to exist.[45] Thus, in some patients included in our study, the ability to detect circulating tumor cells might have been hampered by the technique used. Finally, the in vitro analysis was performed in a sample of 60 patients only, thereby limiting our ability to fully assess the association between natural killer cell-induced apoptosis rates and circulating tumor cell counts. The risk of other sources of bias (such as selection, performance, attrition, and detection bias) was deemed low.

In this randomized controlled trial, we investigated the effect of anesthesia on an independent prognostic factor in primary breast cancer patients. There was no difference in circulating tumor cell counts over time or circulating tumor cell positivity between patients receiving sevoflurane and patients receiving propofol. One secondary analysis suggested a favorable effect of propofol on maximal postoperative circulating tumor cell values. Trials collecting long-term outcomes (NCT02786329, NCT03034096, NCT01975064, and NCT02660411) will bring further evidence regarding the possible effects of anesthesia during cancer surgery.

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