Long Term Consequences

Perioperative management implications for cancer patients

90s periOp B blockers reduce all cause 1 year ( Swedish study with Atenolol) NA studies had more aggressive end pts and there was a significant increase in PeriOp strokes Spinals/epidurals (pelvic,urologic,major ortho) blood loss, DVTs, chronic incisional pain and PONCD

Terri Monk – BIS monitor observational study reported a 3 fold increase in one year mortality in elderly patients with deep anesthesia. This has now spawned the B Aware trials. She also noted; More pronounced effects of anesthetic agents in patients with carcinoma and commented on; Significant adverse long term consequence to GA esp at the extremes of age Learning & behavioural issues 2 years ( possibly age three in most recent studies ) Neurocognitive decline - elderly

We must investigate the mechanisms by which patients with cancer respond to standard anesthetic doses with more pronounced cortical electrical depression and how pharmacokinectics and dynamics are altered in pre existing disease states

IARS Smart Tots® research initiatives on pediatric inhalational anesthesia - (neuroplasicity, agent toxicity vs stress) i.e. This is more than separation anxiety! Ketamine ( nmda receptor inhibitors) Illicit substances ( Ecstasy, Amphetamines, Cocaine, crystal meth......) Etomidate

Surgical manipulation – tumor cell release into lymphatics and blood stream Micro metastases already present prior to surgery This MINIMAL RESIDUAL DISEASE can result in clinical mets when there is a balance shift between the patients immune status and the tumors ability to seed,proliferate and attract new blood vessels

Tumor cells released into circulation cell mediated immunity ( T cell and NK cell function) Increased Vascular Endothelial and other growth factors ( Normally promote wound healing but are pre empted by malignant cells)

Dose/patient specific dependent depression of neutrophil, macrophage, dendritic cell, T cell and NK cell immune functions

Morphine, and to a lesser degree synthetic narcotics, decrease cellular and humoral immune function. Systemic administration has been associated with a proangiogenic action promoting tumor growth. By contrast most non opiod analgesia preserves NK cell function and, in rodents, reduces metastatic tumor spread.

Red – single nucleotide polymorphisms

MOR – u opiod receptor VEGF – vasc endo growth factor Various mammallian tumor cell lines result in enhanced specificity of the mediators of angiogenisis

Genotype stratification was correlated to breast cancer specific mortality One further observation re European American vs Afro American breast cancer survival data

Prevent Neuroendocrine Stress by; 1. Blocking afferent neural traffic 2. Blocking descending efferent activation of the sympathetic nervous system Note: narcotic doses required to generate a stress free surgical anesthetic are impractical in most instances.

If pre incision functioning block then Neuroendocrine stress volatile anesthetic requirements post op opiods endogenous opiods (endorphins) Caveat: adequate perfusion pressure

Paravertable blocks; 4 fold in recurrence or mets in breast Ca Primary melanoma excision; if GA vs local or regional anesthesia: -ve predictive value 1.46 for survival Epidural anesthesia for Radical Prostatectomy, colonic cancer surgery and Ovarian Serous Adenocarcinoma – variable but survival or cancer free period

Blood transfusion Glucose control Fluid management Inhalational anesthetic toxicity – newborns Persistent incisional pain Beta blockers central agonists – clonidine NSAIDS NMDA receptor blockers

A subset of the CSP #345 ; the effect of Epidural Anesthesia/analgesia on perioperative outcome Prospective, randomized Aortic,gastric,biliary and colonic surgery Mar 92 to August 94 – followup to Dec 2002 Epidural.5% bupivacaine, Epi 1:200,000 : T6 block prior to GA End pts;,MI,CHF,HB, BP,PE,Resp failure,cerebral insults,ARF : were all NS at 30 days Post op pain, ambulation, LOS

247 pts with complete followup of 177 also of note: 70 not in study had similar survival experience 92 GA, 85 EGA IV post op opiods or 48+ hours epidural analgesia GA: Isoforane, N2O,Vecuronium,fentanyl

N=42151 with 23% epidural during resection , > 65 years with 4 year follow up minimum > 1 year increase all cause survival in epidural group No change in cancer reccurance rate

Patients for RP Jan 94- Dec 03 f/u to Oct 06 GA; fentanyl 1-2 ug/kg, propofol 1- 2mg/kg,.5mg/kg atracurium N2O/O2, Diclofenac bid T11-12 epidural Rx prior to surgery vs post op IV PCA If Epidural patients required post op IV morphine they were included in the GA group n=6

GA/PCA =123, Epidural/GA =102 : #s in each group determined by preferences, relative contraindications etc was NS but ASA score,complications & surg time in epidural group Primary outcome biochemical recurrence ie PSA from post op nadir possible Rad Rx, endocrine or chemo Rx

retrospective study Jan94-June97 n=103 GA+TEA, 45 not incl re inadequate TEA July97-Dec2000 n=158 GA+ Morphine/Ketoloric Primary Outcomes Biochemical recurrence free survival Clinical progression free survival Cancer specific survival Over all survival

Standardized GA incl fentanyl 2 ug/kg, N2O,forane T10-12 TEA.25% bupivacaine 8-10 cc/hr, No COX inhib PostOp.1% bupivacaine/fentanyl cc/hr X 48 hrs Limitations TEA group – higher ASA, 2X infusion rate and less fentanyl (confounding variables)

Excess prostaglandin release and endogenous cortisol immunosuppression NSAIDS inhibit prostaglandin synthesis Cyclooxyngenase 2 is induced in tumor promoters – prostaglandin synthesis increase prostate cell lines while COX2 inhibitors induce apoptosis (cell death)

327 mastectomy/Axillary dissection chart reviews – 1 surgeon, 1 Oncologist, 2 anesthetists ( Feb 03- Sept 08) 8 excluded re pulm mets, incomplete op etc. Pre incision: Clonidine or Ketamine or Ketoloric, all received postOp diclofenac & acetaminophen GA sufentanil, STP or propofol, Sevo or Des plus Air/Oxygen

Retrospective review Aug 1999 – Dec 2009 ; 179 consecutive pts with < 3cm hepatic tumors End points - overall and recurrence free survival Epidural (T % lidocaine) vs GA (Fentanyl, Propofol TIVA) Study limitation – adequate epidural anesthesia was not defined Study results ???

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Recurrance free survival; Epi vs GA (3.66), Tumor # (2.28), GGT ( 1.39) Overall survival; Liver function (2.30), Tumor # (2.36) GA no benefit in overall survival Inverse probability weighted Epi vs GA = 1.26 Epidural anesthesia for this procedure can be associated with referred pain requiring addn opiods. This could also limit current intensity or duration of therapy. Epi patients did not have any opiod sparing in the post op period.

Mortality during a 10 yr Obs study 52 SpA vs 221 GA Trend toward better Cumulative survival rates in patients who received spinal anesthesia: SpA 96 months (CI ) GA 69 months (CI 50-88)

What do we know about surgical stress response and Cancer?

Opiods – analogs of morphine – u3 Cox inhibiters Alpha adrenergic antagonists Beta blockers Inhalational anesthetics Regional anesthesia TRIM ( transfusion related immunomodulation) Hypothermia Sepsis Statins Etomidate

The answer is : IT DEPENDENDS

Malignant tumors invade extracellular matrix Surgical clamping triggers a reperfusion injury by upregulation of MMP9 (neutrophils,a rich source of MMP9, accumulate because of IL 8) Complex in vitro study demonstrated volatile anesthetics reduce reperfusion injury – this is not new But indices of colorectal matrix invasion were reduced

Data suggests;the possibility that anesthetic conduct may contribute to the recurrence of cancer ( liberal opiod Rx or inadequate analgesia) Equally worrying is the possibility that anesthesia, or the stress response to surgery could activate dormant cancer cells in an individual undergoing non cancer surgery.