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

Results

Between March 10, 2014, and April 10, 2018, 586 patients were assessed for eligibility (Figure 1). Of 217 enrolled participants, seven patients withdrew consent after randomization. We eventually included 210 patients in the intention-to-treat analysis (sevoflurane group: n = 107, propofol group: n = 103).

Figure 1.

Flow diagram.

Baseline characteristics are presented in Table 1. Demographic and clinical data were balanced between treatment groups. Most participants were middle-aged, modestly morbid patients with an early-stage tumor. Baseline circulating tumor cell counts and positivity (using a cutoff value of at least 1 and at least 5 circulating tumor cells/7.5 ml blood) were similar in both allocation groups. Table 2 depicts the intra- and postoperative characteristics, which were well balanced between groups.

The evolution of circulating tumor cell counts over time is illustrated in Figure 2, Table 3, and Supplemental Digital Content figure 1, which depicts predicted tumor cell counts using the estimates from the Poisson model, including a linear time variable and baseline circulating tumor cell counts (http://links.lww.com/ALN/C415). Administrating sevoflurane versus propofol did not affect the primary outcome of circulating tumor cell counts over time (rate ratio, 1.27 [95% CI, 0.95 to 1.71]; P = 0.103). This was the case, regardless of whether time was considered as a linear or a factor variable, or whether an interaction term between time and anesthesia was introduced. However, when we explored the effect of anesthetics on the maximal circulating tumor cells value at any time point after surgery, administrating inhalational anesthesia (i.e., sevoflurane) led to a significant increase in maximal circulating tumor cell counts postoperatively (sevoflurane vs. propofol: rate ratio, 1.36 [95% CI, 1.18 to 1.56]; P < 0.0001; i.e., the maximum number of circulating tumor cells increased by a factor of 1.36 (or 36%) when sevoflurane was used compared with propofol).

Figure 2.

Evolution of circulating tumor cell counts over time.

When circulating tumor cells were analyzed as a binary outcome over time, the type of anesthesia did not have any effect on circulating tumor cell positivity, regardless of the cutoff value considered (cutoff value of at least 1 circulating tumor cell/7.5 ml blood: sevoflurane vs. propofol odds ratio, 1.21 [95% CI, 0.84 to 1.74]; P = 0.309; cutoff value of at least 5 circulating tumor cells/7.5 ml blood: sevoflurane vs. propofol odds ratio, 1.59 [95% CI, 0.86 to 3.01]; P = 0.139). Similar results were obtained when time was considered as a factor variable, and there was no evidence for an interaction between treatment and time.

We performed predefined analyses to explore whether tumor-related and perioperative factors modified the effect of anesthetics on circulating tumor cell counts. Models adjusted for tumor type (DCIS, luminal A, luminal B, triple negative, HER2 positive, other) and tumor size (Tis, T1, T2, T3, T4) did not reveal any relevant effect modification on circulating tumor cell counts over time or positivity (regardless of the cutoff value considered). Similarly, adjusting for opioid consumption did not yield any effect modification. In the exploratory models, however, the effect of inhalational anesthesia on maximal postoperative circulating tumor cells values remained robust (sevoflurane vs. propofol rate ratio, 1.26 [95% CI, 1.09 to 1.47]; P = 0.002; adjustment for tumor type, size, and opioid consumption).

Exploratory in vitro analyses were conducted in a subgroup of 60 patients randomly selected from the study data set (30 in the sevoflurane group and 30 in the propofol group). Similar natural killer cell-induced apoptosis rates were found in both treatment groups (mean apoptosis rate, for sevoflurane group, 34.7%; for propofol group, 35.7%). Overall, the necrosis rate of K562 tumor cells was less than 1%. Linear regression yielded no evidence for an association between apoptosis rates and maximal circulating tumor cell counts (regression coefficient, -0.077; 95% CI, -0.33 to 0.17; Figure 3). This was the case, regardless of treatment group assignment or whether an interaction term between anesthesia type and natural killer cell activity was introduced.

Figure 3.

Scatter plot of natural killer cell activity and maximal circulating tumor cell counts, by treatment.

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