Long Term Consequences. Perioperative management implications for cancer patients.

Anesthetic Choice/Management

Long Term Consequences

GoalsPerioperative management implications for cancer patients

PeriOperative Morbidity & Mortality

1980’s Anesth mortality was 1:10,000 now this is closer to 1:100,000

Δ Mandated SpO2, ETCO2, NIBP,ECG and AAM technology

10% all cause mortality (age 65+) in the year after surgery is 10,000 X more common than preventable anesthetic deaths but ......

Increasing evidence suggests PeriOp management may have long term consequences – PO Neuro Cognitive , Surg Site Infection and Cancer Recurrance

“Recent” Anesthetic Management History

90’s periOp B blockers reduce all cause mortality @ 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

More History

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

One of Monk’s conclusions

“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”

Pharmacologic Implications – foranother time

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

Are Anesth & Surg during infancy associated with altered academic performance during childhood?*

Ca Surgery : Generalizations from the lab

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 patient’s immune status and the tumors’ ability to seed,proliferate and attract new blood vessels

PeriOp balance shift * Surgery per se

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)

PeriOp balance Shift* Volatile inhalational anesthetics

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

PeriOp Balance Shift* Opiods

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.

MOR – Opiod Receptor

Red – single nucleotide polymorphisms

Neoplastic Variability

MOR – u opiod receptor

VEGF – vasc endo growth factor

Various mammallian tumor cell lines result in enhanced specificity of the mediators of angiogenisis

Opiod Receptor Gene A118G polymorphism predicts survival in patients with breast cancerBortstov AV et al Anesthesiology April 2012 896-902

Genotype stratification was correlated to breast cancer specific mortality

One further observation re European American vs Afro American breast cancer survival data

Regional Anesthesia;Spinals & Epidurals

Prevent Neuroendocrine Stress by;1. Blocking afferent neural traffic2. 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.

? Regional – General Combo

If pre incision functioning block then Neuroendocrine stress

volatile anesthetic requirements post op opiods endogenous opiods (endorphins)

Caveat: adequate perfusion pressure

“Random”, but associated studies

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

Other PeriOp decisions

Blood transfusionGlucose controlFluid managementInhalational anesthetic toxicity –

newbornsPersistent incisional painBeta blockerscentral ᾄ agonists – clonidineNSAIDS NMDA receptor blockers

Long term survival after colon cancer surgery:A variation associated with the choice of anesthesia Christopherson R et al Anesth Analg 2008:107;325-32

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

#345 (n=1021) Colonic Ca sub group

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 analgesiaGA: Isoforane,

N2O,Vecuronium,fentanyl

Long term survival Colonic CaChristopherson R et al Anesth Analg 2008Median survival: mets 2 yrs, no mets 6.1 yrs

Long Term Survival colonic CaChristopherson R et al Anesth Analg 2008

Epidural vs Traditional Pain Mgmt – Survival & Ca recurrance after Colectomy . Cummings KC etal Anesthesiology April 2012: 797- 805N=42151 with 23% epidural during

resection1996-2005, > 65 years with 4 year

follow up minimum> 1 year increase all cause survival

in epidural groupNo change in cancer reccurance rate

Anesthetic Technique for Radical Prostatectomy Surgery Affects Cancer Recurrance – Retrospective Analysis Biki B et al Anesthesiology 2008: 109; 180-7

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 75-100 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

Anesthetic Technique for Radical Prostatectomy Surgery Affects Cancer Recurrance – Retrospective Analysis Biki B et al Anesthesiology 2008: 109; 180-7 ......cont

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

Radical Prostate, lymph node dissection

Potential Influence of the Anesthetic Technique used during Open Radical Prostatectomy on Prostate Cancer related Outcome Wuethrich PY et al Anesth 2010:113;570-6

retrospective study Jan94-June97 n=103 GA+TEA, 45 not

incl re inadequate TEA July97-Dec2000 n=158 GA+

Morphine/Ketoloric Primary OutcomesBiochemical recurrence free survivalClinical progression free survivalCancer specific survivalOver all survival

Potential Influence Rad ProstateWuethrich et al Anesthiology 2010

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 2ug/cc @ 8-15 cc/hr X 48 hrs

Limitations TEA group – higher ASA, 2X infusion rate and less fentanyl (confounding variables)

Potential Influence Rad ProstateWuethrich et al Anesthiology 2010

Potential Influence Rad ProstateWuethrich et al Anesthiology 2010 Disscussion

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)

Do Intraoperative Analgesics Influence Breast Cancer Recurrence after Mastectomy? A retrospective analysisAnesth Analg 2010: 110; 1630-5

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

Breast Ca recurrance / Ketalorac

The Effects of Anesthetic Technique on Cancer Recurence ---RFA Small Hepatocellular CarcinomaLai A et all A&A 2012; 114: 290-6

Retrospective review Aug 1999 – Dec 2009 ; 179 consecutive pts with < 3cm hepatic tumors

End points - overall and recurrence free survival

Epidural (T8-10 1.5% lidocaine) vs GA (Fentanyl, Propofol TIVA)

Study limitation – adequate epidural anesthesia was not defined

Study results ???

????

RFA Hepatocellular Ca ......Hazard ratios:

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 = 1.26Epidural anesthesia for this procedure can be

associated with referred pain requiring add’n opiods. This could also limit current intensity or duration of therapy. Epi patients did not have any opiod sparing in the post op period.

SpA vs GA for lower limb MMBR J Anaesth June 15 2012

Mortality during a 10 yr Obs study52 SpA vs 221 GATrend toward better Cumulative

survival rates in patients who received spinal anesthesia:

SpA 96 months (CI 81-111)GA 69 months (CI 50-88)

SummaryWhat do we know about surgical stress response and Cancer?

A mine field – Periop period Opiods – analogs

of morphine – u3 Cox inhibiters Alpha adrenergic

antagonists Beta blockers Inhalational

anesthetics Regional

anesthesia

TRIM ( transfusion related immunomodulation)

Hypothermia Sepsis Statins Etomidate

Are GA’s always bad for Ca recurrance?The answer is : IT DEPENDENDS

Volatile Anesthetics Reduce Invasion of Colorectal Cancer cells thru down regulation of matrix metalloproteinase -9Muller Edenborn et al Anesthesiology 2012 117: 293-301

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

Conclusion

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.