Regional Anesthesia and Breast Cancer Recurrence

NCT ID: NCT00418457

Last Updated: 2020-06-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 2108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2019-12-31

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.

Conditions

Breast Neoplasms

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

General anesthesia and opioid

General anesthesia followed by opioid administration

Group Type: ACTIVE_COMPARATOR

General anesthesia and opioids

Intervention Type: DRUG

General anesthesia, usually with sevoflurane, and opioid analgesia

Regional analgesia and propofol

Regional anesthesia and analgesia (either epidural or paravertebral) combined with propofol

Group Type: ACTIVE_COMPARATOR

Regional analgesia and propofol

Intervention Type: DRUG

Regional anesthesia and analgesia (either epidural or paravertebral), combined with deep sedation or general anesthesia

Interventions

General anesthesia and opioids

General anesthesia, usually with sevoflurane, and opioid analgesia

Intervention Type: DRUG

Regional analgesia and propofol

Regional anesthesia and analgesia (either epidural or paravertebral), combined with deep sedation or general anesthesia

Intervention Type: DRUG

Other Intervention Names

General anesthesia; Regional analgesia

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

d sessler

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniel I Sessler, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Medical University of Vienna

Vienna, , Austria

Peking Union Medical College Hospital

Beijing, , China

University of Düsseldorf

Düsseldorf, , Germany

Mater Misericordiae Hospital

Dublin, , Ireland

Tan Tock Seng Hospital

Singapore, , Singapore

Countries

United States; Austria; China; Germany; Ireland; Singapore

References

Li M, Zhang Y, Pei L, Zhang Z, Tan G, Huang Y. Potential Influence of Anesthetic Interventions on Breast Cancer Early Recurrence According to Estrogen Receptor Expression: A Sub-Study of a Randomized Trial. Front Oncol. 2022 Feb 10;12:837959. doi: 10.3389/fonc.2022.837959. eCollection 2022.

Reference Type: DERIVED

PMID: 35223519 (View on PubMed)

Aghamelu O, Buggy P, Smith G, Inzitari R, Wall T, Buggy DJ. Serum NETosis expression and recurrence risk after regional or volatile anaesthesia during breast cancer surgery: A pilot, prospective, randomised single-blind clinical trial. Acta Anaesthesiol Scand. 2021 Mar;65(3):313-319. doi: 10.1111/aas.13745. Epub 2020 Nov 29.

Reference Type: DERIVED

PMID: 33187020 (View on PubMed)

Sessler DI, Pei L, Huang Y, Fleischmann E, Marhofer P, Kurz A, Mayers DB, Meyer-Treschan TA, Grady M, Tan EY, Ayad S, Mascha EJ, Buggy DJ; Breast Cancer Recurrence Collaboration. Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial. Lancet. 2019 Nov 16;394(10211):1807-1815. doi: 10.1016/S0140-6736(19)32313-X. Epub 2019 Oct 20.

Reference Type: DERIVED

PMID: 31645288 (View on PubMed)

Levins KJ, Prendeville S, Conlon S, Buggy DJ. The effect of anesthetic technique on micro-opioid receptor expression and immune cell infiltration in breast cancer. J Anesth. 2018 Dec;32(6):792-796. doi: 10.1007/s00540-018-2554-0. Epub 2018 Sep 18.

Reference Type: DERIVED

PMID: 30229370 (View on PubMed)

Kim R. Anesthetic technique and cancer recurrence in oncologic surgery: unraveling the puzzle. Cancer Metastasis Rev. 2017 Mar;36(1):159-177. doi: 10.1007/s10555-016-9647-8.

Reference Type: DERIVED

PMID: 27866303 (View on PubMed)

Pei L, Zhou Y, Tan G, Mao F, Yang D, Guan J, Lin Y, Wang X, Zhang Y, Zhang X, Shen S, Xu Z, Sun Q, Huang Y; Outcomes Research Consortium. Ultrasound-Assisted Thoracic Paravertebral Block Reduces Intraoperative Opioid Requirement and Improves Analgesia after Breast Cancer Surgery: A Randomized, Controlled, Single-Center Trial. PLoS One. 2015 Nov 20;10(11):e0142249. doi: 10.1371/journal.pone.0142249. eCollection 2015.

Reference Type: DERIVED

PMID: 26588217 (View on PubMed)

Wu J, Buggy D, Fleischmann E, Parra-Sanchez I, Treschan T, Kurz A, Mascha EJ, Sessler DI. Thoracic paravertebral regional anesthesia improves analgesia after breast cancer surgery: a randomized controlled multicentre clinical trial. Can J Anaesth. 2015 Mar;62(3):241-51. doi: 10.1007/s12630-014-0285-8. Epub 2014 Dec 6.

Reference Type: DERIVED

PMID: 25480319 (View on PubMed)

Jaura AI, Flood G, Gallagher HC, Buggy DJ. Differential effects of serum from patients administered distinct anaesthetic techniques on apoptosis in breast cancer cells in vitro: a pilot study. Br J Anaesth. 2014 Jul;113 Suppl 1:i63-7. doi: 10.1093/bja/aet581. Epub 2014 Jul 9.

Reference Type: DERIVED

PMID: 25009197 (View on PubMed)

Buckley A, McQuaid S, Johnson P, Buggy DJ. Effect of anaesthetic technique on the natural killer cell anti-tumour activity of serum from women undergoing breast cancer surgery: a pilot study. Br J Anaesth. 2014 Jul;113 Suppl 1:i56-62. doi: 10.1093/bja/aeu200. Epub 2014 Jul 9.

Reference Type: DERIVED

PMID: 25009196 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

06-692

Identifier Type: -

Identifier Source: org_study_id