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Regional Anesthesia and Breast Cancer Recurrence

Phase 3
18 Years
85 Years
Open (Enrolling)
Breast Neoplasms

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Trial Information

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 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

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. Enrolling 1,100 patients over 5 years will provide an 85% power for
detecting a 30% treatment effect at an alpha of 0.05 with a total of four potential stopping
points. 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.

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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Outcome Measure:

Cancer recurrence rate

Outcome Time Frame:

up to 10 years

Safety Issue:


Principal Investigator

Daniel I Sessler, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Cleveland Clinic


United States: Institutional Review Board

Study ID:




Start Date:

January 2007

Completion Date:

March 2015

Related Keywords:

  • Breast Neoplasms
  • Breast Cancer
  • Anesthesia; regional
  • cancer recurrence
  • Anesthesia; inhalational
  • Analgesia; opioid
  • Breast Neoplasms
  • Neoplasms
  • Recurrence



Cleveland Clinic Foundation Cleveland, Ohio  44195