Regional Anesthesia and Breast Cancer Recurrence

Study Overview
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Brief Summary
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In this multi-center trial, Stage 1-3 patients having mastectomies or isolated lumpectomy with axillary node dissection will be randomly assigned to thoracic epidural or paravertebral anesthesia/analgesia, or to general anesthesia and morphine analgesia. Participants will be followed for up to 10 years to determine the rate of cancer recurrence or metastasis.

Detailed Description
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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: Surgery per se depresses cell-mediated 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. Anesthesia impairs numerous immune functions, including those of neutrophils, macrophages, dendritic cells, T-cell, and natural killer cells. 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 four-fold (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. The investigators will thus test the hypothesis that recurrence after breast cancer surgery is lower with regional anesthesia/analgesia than with general anesthesia and opioid analgesia. In this multi-center trial, Stage 1-3 patients having mastectomies will be randomly assigned to thoracic epidural or paravertebral anesthesia/analgesia, or to general anesthesia and opioid analgesia. As with all time-to-event trials, interim and final analyses are based on the number of outcome events (recurrences in this case) rather than enrollment. The number of patients required is just an estimate and varies based on actual recurrence rates which in turn depend on patients' stage and grade, and ancillary treatments. There will be three evenly spaced interim analyses and a final analysis at 351 recurrences. Confirming our hypothesis will indicate that a minor 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.

Official Title
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Regional Anesthesia and Breast Cancer Recurrence

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: General anesthesia and opioids
* Drug: Regional analgesia and propofol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary breast cancer without known extension beyond the breast and axillary nodes (i.e. believed to be Tumor Stage 1-3, Nodes 0-2) Scheduled for unilateral or bilateral mastectomy with or without implant (isolated lumpectomy will not qualify) Isolated lumpectomy with axillary node dissection (anticipated removal of at least five nodes) Written informed consent, including willingness to be randomized to morphine or regional analgesia Exclusion Criteria: Previous surgery for breast cancer (except diagnostic biopsies) Inflammatory breast cancer Age < 18 or > 85 years old Scheduled free flap reconstruction ASA Physical Status ≥ 4 Any contraindication to epidural or paravertebral anesthesia and analgesia (including coagulopathy, abnormal anatomy) Any contraindication to midazolam, propofol, sevoflurane, fentanyl, or morphine Other cancer not believed by the attending surgeon to be in long-term remission Systemic disease believed by the attending surgeon to present ≥ 25% two-year mortality

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: General anesthesia and opioid<br>General anesthesia followed by opioid administration | Drug: General anesthesia and opioids<br>* General anesthesia, usually with sevoflurane, and opioid analgesia<br>* Other names: General anesthesia;|
| Active Comparator: Regional analgesia and propofol<br>Regional anesthesia and analgesia (either epidural or paravertebral) combined with propofol | Drug: Regional analgesia and propofol<br>* Regional anesthesia and analgesia (either epidural or paravertebral), combined with deep sedation or general anesthesia<br>* Other names: Regional analgesia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had Breast Cancer Recurrence After Breast Cancer Surgery | time to breast cancer recurrence from the end of surgery. | up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experienced Post-Surgical Pain | Brief Pain Inventory is used to evaluate with values of any pain vs. no pain (binary) | 6 months and 1 year | 
| Number of Participants That Experienced Neuropathic Pain After Surgery | neuropathic pain is a binary outcome: any pain vs. no pain | 6 month and 1 year | 
| SF-12 PCS Score | Physical and Mental Health Composite Scores (PCS & MCS) are computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | 6 month and 1 year | 
| SF-12 MCS Score | Physical and Mental Health Composite Scores (PCS & MCS) are computed using the scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. | 6 month and 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Anesthesia; regional, cancer recurrence, Anesthesia; inhalational, Analgesia; opioid