Regional Anesthesia and Breast Cancer Recurrence

Surgery is the primary and most effective treatment of breast cancer, but residual disease in the form of scattered micrometastases and tumor cells are usually unavoidable. Whether minimal residual disease results in clinical metastases is a function of host defense and tumor survival and growth. At least three perioperative factors shift the balance toward progression of minimal residual disease: (1) Surgery per se depresses cellmediated immunity, reduces concentrations of tumor-related anti-angiogenic factors (e.g., angiostatin and endostatin), increases concentrations of pro-angiogenic factors such as VEGF, and releases growth factors that promote local and distant growth of malignant tissue. (2) Anesthesia impairs numerous immune functions, including those of neutrophils, macrophages, dendritic cells, T-cell, and natural killer cells. (3) Opioid analgesics inhibit both cellular and humoral immune function in humans, increase angiogenesis, and promote breast tumor growth in rodents. However, regional analgesia attenuates or prevents each of these adverse effects by largely preventing the neuroendocrine surgical stress response, eliminating or reducing the need for general anesthesia, and minimizing opioid requirement. Animal studies indicate that regional anesthesia and optimum postoperative analgesia independently reduce the metastatic burden in animals inoculated with breast adenocarcinoma cells following surgery. Preliminary data in cancer patients are also consistent: paravertebral analgesia for breast cancer surgery reduced risk of recurrence or metastasis approximately fourfold (95% CI of estimated hazard ratio is 0.71 0.06) during a 2.5 to 4-year follow-up period compared to opioid analgesia. Similar results were observed with epidural analgesia for prostate surgery. We will thus test the hypothesis that recurrence after breast cancer surgery is lower in patients randomized to regional anesthesia & analgesia with propofol sedation than to sevoflurane general anesthesia and opioid analgesia. In a Phase III, multi-center trial, Stage 1-3 patients having mastectomies will be randomly assigned to paravertebral or thoracic epidural anesthesia/analgesia, or to general anesthesia and morphine analgesia. Enrolling 1,100 patients over 5 years will provide an 85% power for detecting a 30% treatment effect at an alpha of 0.05. Confirming our hypothesis will indicate that a small modification to anesthetic management, one that can be implemented with little risk or cost, will reduce the risk of cancer recurrence — a complication that is often