Regional Anesthesia and Breast Cancer Recurrence

June 3, 2020 updated by: d sessler, The Cleveland Clinic
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

2108

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Vienna, Austria
        • Medical University of Vienna
  • China
      • Beijing, China
        • Peking Union Medical College Hospital
  • Germany
      • Düsseldorf, Germany, 40225
        • University of Düsseldorf
  • Ireland
      • Dublin, Ireland, 7
        • Mater Misericordiae Hospital
  • Singapore
      • Singapore, Singapore
        • Tan Tock Seng Hospital
  • United States
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Foundation

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: General anesthesia and opioid
General anesthesia followed by opioid administration
Drug: General anesthesia and opioids
General anesthesia, usually with sevoflurane, and opioid analgesia
Other Names:
  • General anesthesia
Active Comparator: Regional analgesia and propofol
Regional anesthesia and analgesia (either epidural or paravertebral) combined with propofol
Drug: Regional analgesia and propofol
Regional anesthesia and analgesia (either epidural or paravertebral), combined with deep sedation or general anesthesia
Other Names:
  • Regional analgesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Who Had Breast Cancer Recurrence After Breast Cancer Surgery
Time Frame: up to 10 years
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
Time Frame: 6 months and 1 year
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
Time Frame: 6 month and 1 year
neuropathic pain is a binary outcome: any pain vs. no pain
6 month and 1 year
SF-12 PCS Score
Time Frame: 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.
6 month and 1 year
SF-12 MCS Score
Time Frame: 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.
6 month and 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Cleveland Clinic

Investigators

  • Principal Investigator: Daniel I Sessler, MD, The Cleveland Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2007

Primary Completion (Actual)

February 1, 2018

Study Completion (Actual)

December 1, 2019

Study Registration Dates

First Submitted

January 3, 2007

First Submitted That Met QC Criteria

January 3, 2007

First Posted (Estimate)

January 4, 2007

Study Record Updates

Last Update Posted (Actual)

June 16, 2020

Last Update Submitted That Met QC Criteria

June 3, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 06-692

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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