Clinical trial NCT00418457: Regional Anesthesia and Breast Cancer Recurrence
Official title: Regional Anesthesia and Breast Cancer Recurrence
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Neoplasms
Keywords: Breast Cancer
Anesthesia; regional
cancer recurrence
Anesthesia; inhalational
Analgesia; opioid
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
First posted: 2007-01-04
Enrollment: 2108
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Number of Participants Who Had Breast Cancer Recurrence After Breast Cancer Surgery
timeFrame: up to 10 years
Secondary outcomes:
measure: Number of Participants That Experienced Post-Surgical Pain
timeFrame: 6 months and 1 year
measure: Number of Participants That Experienced Neuropathic Pain After Surgery
timeFrame: 6 month and 1 year
measure: SF-12 PCS Score
timeFrame: 6 month and 1 year
measure: SF-12 MCS Score
timeFrame: 6 month and 1 year
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Düsseldorf
country: Germany
facility: University of Düsseldorf
city: Dublin
country: Ireland
facility: Mater Misericordiae Hospital
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
Study officials:
affiliation: The Cleveland Clinic
name: Daniel I Sessler, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.