In 2006, Exadaktylos et al.1 published a retrospective review of 129 patients undergoing surgery for breast cancer under general anesthesia. Pain management was accomplished with opioids in 79 patients and with paravertebral blocks in the remaining 50 patients, the choice depending on anesthesiologist and patient preference. The authors showed that after 36 months of follow-up, 94% of patients receiving regional anesthesia were still cancer free, compared with only 77% of those receiving opioids. This article started a strong and sustained interest in the possibility that perioperative anesthetic management might influence outcome after cancer surgery.
For a noncurative specialty of medicine such as operative anesthesiology, the concept that appropriate anesthetic management might improve cancer cure rates is, understandably, very exciting. Others quickly followed with more retrospective reviews of anesthetic management and its effect on recurrence. In the area of breast cancer surgery, Forget et al.2 published in this journal results from a group of 327 patients, showing that intraoperative administration of 20 mg ketorolac was associated with longer recurrence-free survival. This dataset was subsequently expanded and correlated with neutrophil:lymphocyte ratios.3 Other investigators have studied the effects of epidural local anesthetics and other interventions on prostate and colon cancer recurrence, with conflicting results.4 A large trial by Myles et al.5 retrospectively analyzed 500 patients who underwent abdominal surgery for various types of cancer. This study had a stronger design, as the cohort consisted of a subgroup of patients enrolled in a previous trial6 where subjects were prospectively randomized to receive epidural analgesia or not (in contrast to the nonrandom allocation in the other studies mentioned above). The authors found no differences in recurrence rates. Thus, the clinical data without exception have major design limitations and are very nonconclusive.
Meanwhile, other groups have attempted to identify potential mechanisms by which anesthetic management might affect recurrence rates. One common factor across clinical series is that they all studied some form of analgesia that would be likely to reduce postoperative opioid requirements: epidural analgesia, other nerve blocks, or non-opioid analgesics. Unfortunately, postoperative opioid use was not reported in the trials. But it might just be possible that, if opioids were to promote tumor recurrence, any approach that reduced opioid intra- and postoperative use would decrease recurrence rates.
A wealth of in vitro and animal data demonstrates that opioids promote tumor growth and metastasis, largely by inducing mitogenesis and angiogenesis. Endogenous opioids do the same, as demonstrated in μ-opiate receptor knockout mice, which show greatly reduced tumor growth after inoculation with malignant cells.7 Naloxone treatment reduces tumor outgrowth in rats8 but of course would not be useful in the clinical setting. However, peripherally acting opioid antagonists such as methylnaltrexone can be used clinically and show much promise.7
Cyclooxygenase inhibitors may prevent some of the opioid-induced effects on tumor growth. For example, celecoxib blocks morphine-induced tumor angiogenesis, resulting in greatly reduced tumor outgrowth in animal models,9 and rofecoxib decreases colonic polyp growth in humans.10 This might help explain the observed benefit of intraoperative ketorolac.
But most of the retrospective trials used some form of regional anesthesia, and therefore, one additional option to be considered is that local anesthetics themselves play a beneficial role. The article by Chang et al.11 in this issue of the journal addresses this possibility. They hypothesized that local anesthetics might induce apoptosis in tumor cells but not in normal tissue. This hypothesis was tested by exposing breast cancer cells and mammary epithelial cells (as a control) to lidocaine and bupivacaine. A number of methodologies were then used to determine apoptosis rates. After 4-hour treatment, lidocaine (7.4 mM) and bupivacaine (2.6 mM) induced apoptosis in 74% and 81% of tumor cells. In contrast, in noncancerous controls, apoptosis occurred in 8% and 19% of the cells. These findings were confirmed in a xenograft tumor model.
How relevant are these findings to our patients? The local anesthetic concentrations used were high and likely to be observed during tissue infiltration only. Concentrations in blood during epidural analgesia or nerve blockade are orders of magnitude lower. However, one need not kill 80% of the tumor cells to have a clinically relevant effect. Even a minor decrease in cell viability, which clinical blood concentrations might be able to induce, could lessen the likelihood of a successful metastasis implant, resulting in decreased recurrence rates. So it is conceivable that the observations made by Chang et al. suggest an important mechanism of action in the clinical setting: another small step forward in the big puzzle of anesthesia and cancer recurrence.
Several points must be considered by the clinician taking care of a patient with cancer. First, retrospective analyses suffer from enormous confounding and selection problems. Even if this were not the case, the available data are too conflicting to draw clinically meaningful conclusions. We will need the results of prospective, blinded, randomized trials. Several of these are in progress, including studies on anesthetic management of breast cancer. Because the answer requires long-term follow-up, it will be several years before we have conclusive results.
Second, we should not change clinical practice based on bench studies alone. As important as these are in understanding the pharmacology of our drugs, bench research and animal studies cannot substitute for properly performed clinical trials.
That’s the bad news. The good news is that if one adheres to best practices in anesthesiology, one, by and large, already uses a potentially optimal approach to the cancer patient. Decreasing postoperative opioid requirements by regional techniques, and by adopting a multimodal analgesic approach making maximum use of non-opioid adjuvants, including cyclooxygenase inhibitors, has many benefits apart from a putative role in preventing cancer recurrence. These approaches also limit volatile anesthetic requirements and reduce the surgical stress response, 2 factors implicated in recurrence. And our best practice already mitigates several other perioperative factors that have been suggested as relevant, including hypothermia, hypotension, anemia, and transfusion.
Until high-quality clinical trials tell us otherwise, doing the right thing for the surgical patient is also the right thing to reduce the likelihood of cancer recurrence.
Dr. Marcel Durieux is the Section Editor for Anesthetic Preclinical Pharmacology for the journal. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Durieux was not involved in anyway with the editorial process or decision.
Name: Marcel E. Durieux, MD, PhD.
Contribution: The author wrote the manuscript.
Attestation: The author approved the final manuscript.
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