Effects of Anesthesia and Anesthetic Techniques on Metastasis of Lung Cancers: A Narrative Review

Figures & data

Table 1 Effects of Propofol on Lung Metastasis of Tumor Cells

Title	Author	Year	Type	Significant Result
Effects of propofol on pulmonary metastasis of intravenous injected tumor cells and expressions of MTA1 and Wnt1 in rats.^Citation19	Zhang Yet al	2014	In vivo study	Propofol could inhibit pulmonary metastasis of intravenous tumor cells in a dose-dependent manner and down-regulate the expression of MTA1 and Wnt1 in metastatic tumor tissues.
Effects of propofol on pulmonary metastasis of intravenously injected MADB106 tumor cells and expression of E-cadherin and β-catenin in rats.^Citation18	Wang W et al	2015	In vivo study	Propofol can down-regulate the expression of E-cadherin and β-catenin in metastatic tumor tissues by inhibiting Wnt/ β-catenin pathway, and inhibit lung metastasis of intravenous MADB106 tumor cells in a dose-dependent manner.
Distinct effects of general anesthetics on lung metastasis mediated by IL‐6/JAK/STAT3 pathway in mouse models.^Citation17	Li R et al	2020	In vivo study	In syngeneic mouse 4T1 and human MDA-MB231 breast cancer xenograft model, surgical resection of primary tumor in mice under sevoflurane anesthesia resulted in more lung metastasis than propofol.
Suppression of cell invasion and migration by propofol are involved in down-regulatin matrix metalloproteinase-2 and p38 MAPK signaling in A549 human lung adenocarcinoma epithelial Cells.^Citation22	Wu KC et al	2012	In vitro study	Propofol has a variety of anti-metastatic activities in A549 cells and can inhibit the migration and invasion of A549 cells. The possible signal pathway may be that it inhibits MMP-2 and MMP-9 and stimulates TIMP1 and TIMP2 by blocking the expression of MMP-2 and-9mRNA.
Propofol Inhibits Lung Cancer A549 Cell Growth and Epithelial-Mesenchymal Transition Process by Upregulation of MicroRNA-1284.^Citation24	Liu WZ et al	2018	In vitro study	Propofol could inhibit cell viability, migration, invasion, and the EMT process in lung cancer cells by regulation of miR-1284.
Propofol suppresses growth, migration and invasion of A549 cells by down-regulation of miR-372.^Citation25	Sun H et al	2018	In vitro study	Propofol inhibits the growth, migration and invasion of lung cancer A549 cells by down-regulating miR372 and inactivating Wnt/ β-catenin and mTOR pathways.
Propofol induces apoptosis of non‐small cell lung cancer cells via ERK1/2‐dependent upregulation of PUMA.^Citation26	Xing SG et al	2018	In vitro study	Propofol inhibits the survival and induces apoptosis of A549 cells in a dose-dependent manner in vitro. The mechanism may be that propofol inhibits cell survival and induces apoptosis through ERK1/2-dependent PUMA signaling pathway.
Propofol suppresses invasion of human lung cancer A549 cells by down-regulating aquaporin-3 and matrix metalloproteinase-9.^Citation20	Ye HJ et al	2016	In vitro study	Treatment with 50 and 100 µmol/L propofol for 24h significantly inhibits the number of invading cells by down-regulating the expression of AQP-3 and MMP-9 in A549 cells.
Propofol inhibits lung cancer cell viability and induces cell apoptosis by upregulating microRNA‐486 expression.^Citation30	Yang N et al	2017	In vitro study	Propofol increased the level of miR-486 in H1299 and H1792 cells in a dose-dependent manner. Propofol decreased the cell survival rate, but increased the percentage of apoptotic cells and the protein expression of FOXO1, FOXO3, Bim, pre-caspases and activated caspases.
Propofol suppresses LPS‐induced nuclear accumulation of HIF‐1alpha and tumor aggressiveness in non‐small cell lung cancer.^Citation23	Yang N et al	2017	In vitro study	Inflammation stimulated by endotoxin enhances the function of HIF-1α by increasing the expression level, protein stability and nuclear localization of NSCLC cells, which leads to the increase of markers and mediators of migration and invasion. Propofol inhibited all these effects by inhibiting hypoxia inducible factor-1α.
Propofol induces endoplasmic reticulum (ER) stress and apoptosis in lung cancer cell H460.^Citation21	Cui WY et al	2014	In vitro and in vivo	Propofol inhibits proliferation and induces apoptosis in H460 cells and inhibits tumor growth in vivo. propofol acts as a positive regulator in ER stress and JNK signaling pathway.
Impact of anesthetic agents on overall and recurrence-free survival in patients undergoing esophageal cancer surgery.^Citation31	Jun I.J et al	2017	Clinical study	Intravenous anesthesia with propofol (TIVA)was associated with better postoperative survival rates.

Table 2 Effects of Different Anesthetic Methods on Tumor Metastasis and Recurrence

Title	Study Authors	Year	Type	Techniques Compared	Significant Results
Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro.^Citation91	Xu YJ et al	2016	In vitro study	GA+ epidural (n = 20); INHA +opioid (n = 20)	Inhibited the proliferation and invasion of LoVo cells and induced apoptosis in GA+ epidural group
Effects of neuraxial block and general anesthesia on tumor metastasis in rats^Citation100	Zheng Wei et al	2008	In vivo study	Ketamine, propofol, neuraxial block.	Compared with those in group neuraxial block, CD3(+), CD4(+), CD8(+), CD161a (+) lymphocytes the activity of circulating NK cells were significantly reduced in ketamine and Propofol; the lung metastases of MADB106 increased significantly in groups K and P (P<0.05 or 0.01).
Long-term Survival for Patients Undergoing Volatile versus IV Anesthesia for Cancer Surgery:A Retrospective Analysis.^Citation94	Wigmore J et al	2016	Clinical research	INHA (n =3316); TIVA (n = 3714)	INHA was associated with a hazard ratio of 1.59 (1.30 to 1.95) for death on univariate analysis and 1.46 (1.29 to 1.66) after multivariable analysis in TIVA
Impact of anesthetic agents on overall and recurrence-free survival in patients undergoing esophageal cancer surgery:A retrospective observational study^Citation31	Jun I.J et al	2017	Clinical research	INHA (n = 191); TIVA (n = 731)	INHA was independently associated with worse OR (HR 1.58); and RFS (HR 1.42); after multivariable analysis adjustment. in PSM cohorts, INHA was associated with worse OR (HR 1.45) and RFS (HR 1.44).
Long-Term Oncologic Outcomes for Patients Undergoing Volatile Versus Intravenous Anesthesia for Non-Small Cell Lung Cancer Surgery: A Retrospective Propensity Matching Analysis.^Citation97	Oh et al	2018	Clinical research	INHA (n = 194); TIVA (n = 749)	No difference in (HR) for recurrence between the TIVA and INHA groups (P =0.233); No difference in (HR) for death (P = 0.551).
A comparison of regional and general anesthesia effects on 5 year survival and cancer recurrence after transurethral resection of the bladder tumor:a retrospective analysis.^Citation99	Jang D et al	2016	Clinical research	GA (n=24); regional(spinal or epidural) (n=137)	Five-year survival was 87.5% for GA and 96.3% for regional (P = 0.099). Regional anesthesia showed higher 5-year survival (coefficient = −0.167,) more than GA through the partial correlation analysis.
Paravertebral block does not reduce cancer recurrence, but is related to higher overall survival in lung cancer surger: a retrospective cohort study^Citation101	Lee EK et al	2017	Clinical research	PCA (n = 574), TEA (n = 619), PVB (n = 536).	Analgesic method was associated with OS (P=0.0015); HR against TEA [95% confidence intervals]: PCA 0.58 PVB0.60. After PSM, PVB showed higher OR. No significant in RFS
Combined anesthesia shows better curative effect and less perioperative neuroendocrine disorder than general anesthesia in early stage NSCLC patients^Citation102	Pi et al	2019	Clinical research	GA (n = 76) GA+ epidural (n = 74)	Lower specific adverse events and improved OR, PFS were in GA+ epidural group; Lower MAP and levels of IL-1, IL-8, hs-CRP, TNF-α, MDA in GA group
Effects of combined general-epidural anesthesia and total intravenous anesthesia on cellular immunity and prognosis in patients with non-small cell lung cancer: A comparative study.^Citation103	Xu Q et al	2017	Clinical research	GA+ epidural (n =60) TIVA (n =60)	At 24 and 48 h after surgery, higher CD3+, CD4+, CD4+/CD8+ and CD56+ in group GA+ epidural, after 72h surgery, higherCD3+, CD4+, CD4+/CD8+ in group GA+ epidural.
Effects of epidural analgesia on cancer recurrence and long-term mortality in patients after non-small-cell lung cancer resection^Citation108	Wu et al	2019	Clinical research.	Epidural (n =1799); intravenous analgesia (n = 392)	3 year RF 69.8% and OR 92.4% in epidural group;3-year RF 67.4% and OR 89.6%in intravenous analgesia group; no significant difference in recurrence or mortality between groups, similar to the results after matching (HR: 0.97 to 1.31).
Effect of thoracic paraspinal block-propofol intravenous general anesthesia on VEGF and TGF-beta in patients receiving radical resection of lung cance^Citation107	Sen Y et al	2019	Clinical research	PPA(n=41); INHA(n=41)	Lower VEGF and TGFβ concentration in PPA group (P < 0.05)
A study on cellular immune function of patients treated with radical resection of pulmonary carcinoma with two different methods of anesthesia and analgesia^Citation104	Chen et al	2017	Clinical research	TIVA(n=17); TIVA+epidural+PCEA (n=17)	CD8+ increased and CD3+, CD4+, CD4+/CD8+ ratio and NK cells decreased in two groups;(p<0.05).

Abbreviations: BCR, biochemical recurrence; CSS, cancer specific survival; GA, general anaesthesia; HR, hazard ratio; OR, odds ratio; OS, overall survival; PCA, patient-controlled analgesia; PFS, progression-free survival; PVB, paravertebral block; RCT-PHA, RCT-post hoc analysis; PSM, the propensity score matched; RFS, recurrence-free survival; TURBT, transurethral resection of bladder tumour; PCEA, patient-controlled epidural analgesia; INH, volatile inhalational; TEA, thoracic epidural analgesia; PPA, paravertebral nerve block-propofol intravenous general anesthesia.

Table 3 Effect of Anesthesia or Anesthesia on Metastasis of Lung Cancer

Anesthetic Factors	In vivo Study	In vitro Study	In Clinical Studies	Predominant Effects
Intravenous drug
Propofol	Inhibition^Citation16,Citation18,Citation19	Inhibition^Citation17,Citation20^–^Citation26	Inhibition^Citation32	Beneficial
Etomidate		Inhibition^Citation33	Inhibition^Citation34	Beneficial
Opioids	Activation^Citation38,Citation40	Dose-dependent,^Citation43 depressed NK activity^Citation44	Increase recurrence^Citation47,Citation49	Inconclusive
Methylnaltrexone	Inhibition^Citation40,Citation42	Inhibition^Citation40,Citation41		Beneficial
Ketamine	Activation^Citation5,Citation12		Inhibition^Citation51,Citation52	Inconclusive
Tramadol	Inhibition^Citation54			Beneficial
Midazolam	Inhibition^Citation56	Inhibition^Citation56,Citation57		Beneficial
Dexmedetomidine	Activation^Citation56	Inhibition^Citation59	Activation^Citation60	Inconclusive
NSAIDs	Inhibition^Citation79			Beneficial
Muscle relaxant cisatracurium vecuronium		Inhibition^Citation61		Beneficial
Volatile agents
Sevoflurane	Inhibition^Citation62,Citation63	Activation 64, inhibition^Citation66,Citation69^–^Citation71 increase sensitivity to chemotherapy^Citation67,Citation68		Inconclusive
Isoflurane		Inhibition^Citation65 activation^Citation72		Inconclusive
Desflurane	Activation^Citation73			Harmful
Halothane	Activation^Citation74			Harmful
Local anesthetics
Lidocaine Ropivacaine Bupivacaine procaine	Inhibition^Citation16,Citation88	Inhibition^Citation81^–^Citation87		Beneficial
Anesthetic techniques
TIVA VS inhaled anesthetics			Longer survival rate with TIVA^Citation94 Not improve prognosis^Citation31,Citation97,Citation98	Inconclusive
PVB VS PCA VS TEA			Longer overall survival with PVB^Citation101	Benefit of PVB
Epidural combined general anesthesia VS general anesthesia			Improving long-term survival in Combined anesthesia^Citation10	Benefit of combined anesthesia
CGEA VS TIVA			Less interference with the immune system^Citation103,Citation104	Benefit of CGEA
Epidural analgesia			No difference in recurrence-free survival or overall survival^Citation108	Inconclusive

Abbreviations: NSAIDs, non-steroidal anti-inflammatory drugs; TIVA, total intravenous anesthesia; PVB, paravertebral block; TEA, thoracic epidural analgesia; PCA, patient-controlled analgesia; CGEA, combination of general-epidural anesthesia.

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