Regional Anesthesia and Breast Cancer Recurrence

Phase 3

Completed

Conditions: Breast Neoplasms

Interventions: Drug: General anesthesia and opioids
Drug: Regional analgesia and propofol

Registration Number: NCT00418457

Lead Sponsor: The Cleveland Clinic

Brief Summary: 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: 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 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.

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 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 2108

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
General anesthesia and opioid	General anesthesia and opioids	General anesthesia followed by opioid administration
Regional analgesia and propofol	Regional analgesia and propofol	Regional anesthesia and analgesia (either epidural or paravertebral) combined with propofol

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Had Breast Cancer Recurrence After Breast Cancer Surgery	up to 10 years	time to breast cancer recurrence from the end of surgery.

Secondary Outcome Measures

Name	Time	Method
Number of Participants That Experienced Post-Surgical Pain	6 months and 1 year	Brief Pain Inventory is used to evaluate with values of any pain vs. no pain (binary)
Number of Participants That Experienced Neuropathic Pain After Surgery	6 month and 1 year	neuropathic pain is a binary outcome: any pain vs. no pain
SF-12 PCS Score	6 month and 1 year	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.
SF-12 MCS Score	6 month and 1 year	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.

Trial Locations

Locations (6): Peking Union Medical College Hospital
🇨🇳
Beijing, China
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
University of Düsseldorf
🇩🇪
Düsseldorf, Germany
Mater Misericordiae Hospital
🇮🇪
Dublin, Ireland
Tan Tock Seng Hospital
🇸🇬
Singapore, Singapore
Medical University of Vienna
🇦🇹
Vienna, Austria