Do TIVA and regional anaesthesia reduce breast cancer recurrence?

Recurrence of breast cancer after regional or general anaesthesia: a randomised control trial. Sessler et al. The Lancet, 2019.394(10211): p1807-1815

Background

  • Breast cancer is the most common cancer in women and second leading cause of cancer death (Holly et al, 2017). Mortality usually due to distant organ metastasis despite surgical resection with curative intent.
  • Surgery is the primary treatment but residual disease is usually unavoidable (Hiller et al, 2018). Whether minimal residual disease results in clinical metastasis depends on balance between host defence and tumour survival.
  • Mechanistic and animal evidence, and observational analyses described perioperative factors impairing host defence against recurrence: surgical stress; volatile anaesthetics; and opioid analgesics.
  • In contrast, regional analgesia and propofol may reduce surgical stress and have anti-inflammatory effects.

Aims

  • Primary outcome: To ascertain whether regional anaesthesia-analgesia with paravertebral blocks and propofol sedation reduces breast cancer recurrence compared with general anaesthesia with sevoflurane and opioid analgesia
  • Secondary outcome: persistent incisional pain is common – regional anaesthesia might attenuate the development of persistent pain

Methods

  • The study was a multi centre randomised control trial across 13 hospitals in 8 countries.
  • Inclusion criteria were women <85years with breast cancer without known extension beyond breast and axillary nodes having potentially curative breast cancer resections.
  • Computer-generated randomisation was in a 1:1 ratio stratified by study site with random blocking. Follow-up investigators were blinded to intraoperative management.
  • 2132 patients were enrolled and randomly assigned to either:
    • Regional anaesthesia-analgesia with paravertebral blocks and propofol sedation +/- propofol-based GA
    • Volatile anaesthesia with sevoflurane, fentanyl and morphine
  • Groups were well-matched for demographics; intra-operative drugs, fluids and physiology; tumour characteristics; and treatment with radiotherapy and chemotherapy
  • Recurrence was assessed by contacting patients and/or healthcare providers 6-monthly until recurrence reported, 5-6 years elapsed, or study enrolment ended

Results

  • The study was stopped early after crossing a pre-planned futility boundary
  • Median follow-up was 36 (24-49) months
  • Primary outcome: no statistically significant difference in recurrence (adjusted HR 0.97, 95% CI 0.74-1.28):
    • Recurrence in regional analgesia-anaesthesia group 102/1043 (10%) vs volatile anaesthesia group 111/1065 (10%)
  • Secondary outcome: no statistically significant difference in persistent incisional or neuropathic pain

Discussion

Strengths

  • Multicentre study across 13 hospitals in 8 countries – recruited over an 11 year period
  • The study involved implementing paravertebral nerve blocks across many anaesthesia providers
  • This is the largest trial examining this issue to date – 2132 patients enrolled, only 24 excluded
  • There were few crossovers between groups (n = 6, 0.3%) – 5 block failures; 1 patient receiving volatile anaesthesia also received paravertebral block
  • High proportion of patients followed up (97%) – few lost to follow-up (n = 67, 3%)
  • The study was conducted in a population generalisable to our local practice
  • The design was pragmatic and consistent with usual clinical practice

Limitations

  • Treatment and outcomes for breast cancer improved over the 12 year study period – patients with early localised disease may not undergo resection in current practice, and may have extremely low risk of recurrence regardless of anaesthetic technique
  • Genetic/other characteristics that could affect recurrence were not recorded – these were not known about or not routine practice at the start of the trial. However, genetics do not generally affect decisions regarding primary surgical resection
  • The consort diagram did not present the number of patients screened for eligibility or approached for enrolment to the study
  • 60% study participants were from one hospital in China
  • The study was seeking to demonstrate a 30% relative risk reduction in cancer recurrence in the regional group – this was ambitious but may be in keeping with previously available (albeit lower-quality) evidence
  • The impact of sevoflurane on cancer may be dose-dependent but the average duration of surgery in both groups was only 1.3 hours: there was relatively short exposure to sevoflurane and low amounts of opioids

Conclusion

This randomised control trial demonstrated no statistically significant difference in breast cancer recurrence between patients receiving either regional or volatile anaesthesia.

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