Can regional analgesia reduce the risk of recurrence after breast cancer?: Methodology of a multicenter randomized trial

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Abstract

Surgery is the primary and most effective treatment of breast cancer, but minimal residual disease is probably unavoidable. Whether residual disease results in clinical metastases depends on numerous factors, including anti-tumor cell mediated immunity and angiogenic and growth signals in sites of residual disease. At least three perioperative factors adversely affect these: 1) the neuroendocrine stress response to surgery, 2) volatile anesthetics, and 3) opioids. Animal studies indicate that regional anesthesia and optimum postoperative analgesia independently reduce the metastatic burden in animals inoculated with breast adenocarcinoma cells following surgery. Retrospective studies in humans also suggest that regional analgesia may reduce recurrence risk after cancer surgery. We will test the hypothesis that local or metastatic recurrence after breast cancer surgery is lower in patients randomized to paravertebral or high-thoracic epidural analgesia combined with sedation or light anesthesia than in patients given intraoperative volatile anesthesia and postoperative opioid analgesia. In a Phase III, multi-center trial, Stage 1–3 patients having mastectomies for cancer will be randomly assigned to thoracic epidural or paravertebral anesthesia/analgesia, or to sevoflurane anesthesia and morphine analgesia. The primary outcome will be cancer recurrence. Enrolling 1100 patients over 5 years will provide 85% power for detecting a 30% treatment effect at an alpha of 0.05. We plan four equally spaced interim analyses, each evaluating efficacy and futility. 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 ultimately lethal.

Introduction

Breast cancer is the most common major malignancy in women and the second leading cause of cancer death. Treatment hinges on effective surgical removal of the primary tumor, but recurrence occurs in a significant portion of patients. Even with the best technique, tumor surgery is usually associated with release of tumor cells into the lymphatic and blood streams and a large fraction of patients already harbor micrometastases and scattered tumor cells at the time of surgery [1], [2], [3].

Whether this minimal residual disease results in clinical metastases depends largely on the balance between anti-metastatic immune activity and the tumor's ability to seed, proliferate, and attract new blood vessels [4], [5], [6]. In practice, the immune system and other host defenses frequently fail to neutralize minimal residual disease; consequently, local and metastatic disease remains common after breast cancer surgery. At least three perioperative factors shift the balance toward progression of minimal residual disease:

  • The first is surgery per se, which possibly releases tumor cells into the circulation [1], [2], [3], depresses cell-mediated immunity including cytotoxic T cell and natural killer (NK) cell functions [7], [8], [9], [10], reduces circulating concentrations of tumor-related anti-angiogenic factors (e.g., angiostatin and endostatin) [11], [12], [13], [14], increases concentrations of pro-angiogenic factors such as VEGF [15], [16], [17], [18], and releases growth factors that promote local and distant growth of malignant tissue [5].

  • The second factor is anesthesia per se, which impairs numerous immune components, including neutrophil, macrophage, dendritic cell, T-cell, and NK-cell functions [19], [20], [21], [22], [23].

  • The third is opioids, which are given to control surgical pain. Opioids inhibit both cellular and humoral immune function in humans [19], [24], [25]. Furthermore, morphine is pro-angiogenic and promotes breast tumor growth in rodents [26]. Consequently, non-opioid analgesia helps preserve natural killer cell function in animals and humans, and reduces metastatic spread of cancer in rodents [8].

Regional anesthesia and analgesia attenuate or prevent each of these adverse effects. For example, regional anesthesia moderates the neuroendocrine stress response to surgery by blocking afferent neural transmission from reaching the central nervous system and activating the stress response, and by blocking descending efferent activation of the sympathetic nervous system [27], [28], [29]. As might thus be expected, surgical stress is attenuated better by regional than by general anesthesia. Consequently, NK cell function is better preserved and metastatic load to the lungs is reduced with spinal analgesia in a rat model of breast cancer metastasis [7].

When regional and general anesthesia are combined, the amount of general anesthetic required is much reduced — as is, presumably, immune suppression. Furthermore, regional analgesia provides superb pain relief, usually obviating the need for postoperative opioids, and their consequent adverse effects on immune function and promotion of tumor growth [19], [25], [29]. Regional analgesia also reduces release of endogenous opioids [30].

Available data thus suggest that regional anesthesia and analgesia help preserve effective defenses against tumor progression by attenuating the surgical stress response, by reducing general anesthesia requirements, and by sparing postoperative opioids. Animal studies are consistent with this theory, showing that regional anesthesia and optimum postoperative analgesia independently reduce the metastatic burden in animals inoculated with breast adenocarcinoma cells [7], [9], [31].

Preliminary data in cancer patients also support our theory: paravertebral anesthesia and analgesia for breast cancer surgery were associated with an approximately four-fold reduced risk of recurrence or metastasis during a 2.5 to 4-year follow-up period, with the 95% CI of the hazard ratio being 0.06–0.71 [32]. Furthermore, patients who had epidural analgesia for open radical prostate surgery were significantly less likely to suffer recurrence (unpublished data). Consistent with these observations, retrospective analysis suggest that use of general anesthesia augments recurrence of melanoma [33].

We will thus conduct a multi-national clinical trial to compare recurrence rates in patients with primary breast cancer who will be randomly assigned to: 1) paravertebral or high-thoracic epidural analgesia combined with sedation or light anesthesia, or 2) sevoflurane anesthesia and postoperative opioid analgesia. Specifically, we will test the following hypotheses:

Primary Hypothesis

Recurrence of local and metastatic cancer after primary breast cancer surgery is reduced when patients are given regional analgesia combined with sedation or light anesthesia rather than sevoflurane anesthesia and postoperative opioid analgesia.

Secondary Hypothesis

All-cause mortality is reduced when patients are given regional analgesia rather than general anesthesia and opioid analgesia.

In this report, we outline our approach and study protocol. Our purpose is to establish an a priori record of our principal methods and primary endpoints.

Section snippets

Setting and population

The study is a multi-center clinical trial coordinated by the Department of OUTCOMES RESEARCH at the Cleveland Clinic; it is registered at ClinicalTrials.gov (#NCT00418457). The protocol has been approved by the Institutional Review Boards at the Cleveland Clinic, the University of Louisville, the Medical University of Vienna, and Mater Misericordia Hospital of the University of Dublin; applications have been submitted by other participating centers.

We will recruit patients with primary breast

Discussion

Our preliminary retrospective studies suggest that regional analgesia reduces the risk of cancer recurrence; for example, the cancer recurrence rate was found to be reduced by a factor-of-four (P = 0.01) in women with breast cancer who were given paravertebral analgesia rather than morphine for postoperative analgesia [32]. However only a large outcomes study such as the one we describe here can adequately test our hypothesis.

Confirming our hypothesis that regional analgesia for breast cancer

Acknowledgement

Nancy Alsip, Ph.D., of the OUTCOMES RESEARCH Institute (University of Louisville) edited the manuscript.

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    Received from the Department of OUTCOMES RESEARCH, Center for Anesthesia Research, and Department of Quantitative Health Sciences, The Cleveland Clinic, Cleveland, Ohio; Department of Psychology, Tel Aviv University, Tel Aviv, Israel; and Department of Anaesthesia, Mater Misericordiae University Hospital, Dublin, Ireland.

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