Is it possible that particulars of perioperative anesthetic management (eg, using epidural local anesthetics during general anesthesia) might influence long-term recurrence risk after cancer surgery? Not too long ago, this would have been considered an impossibility, and at first glance, it does seem an unlikely proposition. How could a change in management during a procedure that lasts at most several hours lead to effects on cancer outcome years later? Yet, suggestive (though far from conclusive) retrospective clinical data indicate that there might be an effect, and even a significant one. Use of paravertebral blocks1 or the addition of ketorolac2 in breast cancer, or the addition of epidural anesthesia in prostate3 or colon cancer4 might reduce risk of recurrence. The story is far from clear, however, as other studies5,6 do not indicate benefit. Prospective randomized trials are in progress, but it will be many years before the results of these will be known.
Much more data are available at the basic science level, and in this chapter we therefore will focus on some of this evidence, discussing, where possible, animal rather than cellular data. Before reviewing the effects of specific perioperative interventions, however, it is necessary to discuss briefly the mechanisms by which metastasis occurs in the perioperative period. Then we will describe the main effects of anesthetic drugs on these mechanisms. Although outside the domain of pharmacology, we will also briefly touch on potential effects on cancer recurrence of some other perioperative events, such as hypovolemia, anemia, transfusion, and hypothermia.
METASTASIS IN THE PERIOPERATIVE PERIOD
Why does cancer recurrence happen at all, after what was supposed to be curative surgery? This is a highly complex issue, and here we can provide only a brief and admittedly simplified description of the process.
Two main mechanisms explain why recurrence happens. The first mechanism is that cancer cells are released into the circulation during surgery. This is well documented,7 unavoidable, and takes place even if a “no touch” technique is used for surgical resection. Pressure on the tumor will result in malignant cells being disseminated through the body. Tumor cell release into the circulation happens also in the absence of surgery, but the body has effective defense mechanisms that prevent (almost) all of these cells from surviving. Critical here are natural killer (NK) cells, which have the ability to recognize tumor cells and eliminate them.8 It follows that decreases in the number or activity of NK cells induced by perioperative interventions might increase the number of cancer cells surviving in the body. Indeed, it has been shown for a variety of tumor types that low levels of NK cell activity predict worse outcome after cancer surgery. For example, NK cell activity levels less than 20% correlate with poor survival after “curative” colon cancer surgery.9