Trial watch: local anesthetics in cancer therapy

ABSTRACT

Preclinical evidence indicates potent antitumor properties of local anesthetics. Numerous underlying mechanisms explaining such anticancer effects have been identified, suggesting direct cytotoxic as well as indirect immunemediated effects that together reduce the proliferative, invasive and migratory potential of malignant cells. Although some retrospective and correlative studies support these findings, prospective randomized controlled trials have not yet fully confirmed the antineoplastic activity of local anesthetics, likely due to the intricate methodology required for mitigating confounding factors. This trial watch aims at compiling all published preclinical and clinical research, along with completed and ongoing trials, that explore the potential antitumor effects of local anesthetics.

KEYWORDS:

• Cancer
• immunity
• local anesthetics
• stress

Introduction

Several retrospective clinical trials noted a significantly improved overall survival (OS) in cancer patients following the administration of local anesthetics (LAs) during the perioperative period and the surgical removal of primary tumors.^1–3 This observation prompted extensive preclinical studies aiming to investigate the underlying molecular mechanisms, altogether leading to the initiation of prospective clinical trials. The objective of this review is to provide an overview of crucial findings from both fundamental and clinical research, including ongoing prospective trials in this domain. In the first part of this work, we focus on preclinical studies investigating the intrinsic antitumor properties of LAs in vitro and in vivo. In the second part, we comprehensively summarized published clinical trials studying the potential impact of LAs employed during cancer surgery on postoperative outcome. Finally, we discuss ongoing clinical trials and hypothetical future updates in oncoanesthesia.

1. Preclinical investigation

1.1. Local anesthetics: anti-migrative and anti-mitotic effects

1.1.1. Anti-migrative property

Certain anesthetics that are currently employed in clinical practice for their analgesic properties have been shown to improve disease outcome in cancer patients following local application during oncosurgery. In line with this, LAs including lidocaine, tetracaine, and procaine were found to inhibit the adherence, migration and proliferation of various types of cancer cells in vitro.^4–8 Local as well as systemic injections of lidocaine (at concentrations used in surgery) minimized the occurrence of pulmonary metastases in mouse osteosarcoma⁹ and breast cancer models in vivo.^10–12 Some of these effects might be explained by the fact that LAs act on voltage-gated sodium and calcium channels (thus blocking pain conduction in neurons) which are also highly expressed in invasive tumors.¹³ By inhibiting calcium channels, LAs impinge on intracellular Ca²⁺ levels, which can affect (among other things) actin polymerization and induce cytoskeletal rearrangements.¹⁴ Moreover, LAs have the capacity to modulate the expression of vimentin and E-cadherin, which are both involved in cell adhesion via the formation of dynamic microtubule protrusions and tubulin microtentacles, respectively.¹⁵ Furthermore, the LA-mediated modulation of intracellular Ca²⁺, limits the shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF), which is a key driver of invasiveness and metastasis in many human cancers.⁹ Altogether, LAs can limit the aggregation and attachment of malignant cells.¹⁶

Furthermore, lidocaine was shown to inhibit the CXCL12-CXCR4 axis and to block transient receptor potential melastatin 7 (TRPM7) in human glioma and breast cancer cells, resulting in proliferative arrest and the inhibition of cell migration.^17–19 Lidocaine was also found to inhibit the WNT/beta-catenin pathway, thus blocking epithelial-mesenchymal transition and impairing the progression of ovarian cancer.²⁰ Bupivacaine reportedly interferes with gastric cell migration by blocking the RHO-A/RHO-associated protein kinase (ROCK)/myosin light chain (MLC) pathway, and ropivacaine reduces the migration of esophageal and thyroid cancer cells by inhibiting the RAS-related C3 botulinum toxin substrate 1/c-JUN N-terminal kinase/paxillin/focal adhesion kinase (RAC1/JNK/paxillin/FAK) pathway and integrin-alpha-2 expression, respectively.^21–23 Moreover, ropivacaine may interact with integrin-beta1, which is involved in tumorigenesis, ultimately inducing apoptosis.²⁴ Additionally, LAs may impact on matrix metalloproteinases (MMPs), retarding the dissemination of tumor cells through the extracellular space and thus decreasing the invasion of distant organs.^11,23,25,26

Collectively, these findings indicate that LAs can impair malignant cell migration, block epithelial-mesenchymal transition and reduce the metastatic potential through different mechanisms, including the inhibition of cytoskeletal remodeling, the inhibition of HB-EGF shedding and a limitation of MMP activity.

1.1.2. Anti-mitotic property

LAs also exhibit short-term cytostatic and long-term cytotoxic properties.²⁷ Interestingly, the chemical structure (ester or amide) does not seem to dictate cytotoxicity activity, whereas it is worth noting that chloroprocaine and prilocaine, which possess a short duration of action, induce fewer effects on cancer cells than agents with an extended time of efficacy.²⁸ Among the tested LAs, bupivacaine appears to be the most cytotoxic, while procaine is the least.

A number of mechanisms have been described for the cytostatic and cytotoxic effects induced by LAs. Thus lidocaine was shown to inhibit epidermal growth factor receptor (EGFR) activity^29,30 and to upregulate cytoplasmic polyadenylation element-binding protein 3 (CPEB3) in hepatocellular carcinoma.³¹ Moreover, lidocaine exerts anti-proliferative effects in bladder cancer cells by inhibiting isoprenylcysteine carboxylmethyltransferase, which coordinates posttranslational prenylation, thus affecting RAS and RHO-A-dependent signaling pathways.^32,33 Both lidocaine and ropivacaine also halt the proliferation of melanoma and gastric cancer cells by inhibiting extracellular signal-regulated kinases 1/2 (ERK1/2).^34,35 Certain LAs have may promote DNA damage and modulate the Phosphatidylinositol-3-kinase/Protein kinase B/mammalian target of rapamycin complex (PI3K/AKT/mTORC) axis, thus inhibiting cyclins and cyclin-dependent kinases (CDK) and inducing cell cycle arrest (or delay) at either the G0/1-S phase or at the S/G2/M transition.^{7,23,26,34,36–47} Enduring cytostatic stress can lead to the activation of apoptotic cell death pathways such as the p38 mitogen-activated protein kinase (MAPK) pathway, which results in the oligomerization of pro-apoptotic BAX and BAK, mitochondrial membrane permeabilization, the subsequent release of cytochrome c (CYTC) along with the formation of the apoptosome and the activation of effector caspases, resulting in the cleavage of substrates including poly ADP-ribose polymerase (PARP), in both solid tumors and hematopoietic malignancies.^{5,23,36,39,41,42,48–65} Further to the induction of apoptosis some articles also suggested that LAs may promote additional cell death modalities such as necrosis and ferroptosis.^46,66–71

Of note, LAs can trigger the release of danger-associated molecular patterns (DAMPs) linked to immunogenic cell death (ICD), such as ATP and high mobility group box 1 (HMGB1), yet fail to promote the exposure of calreticulin at the plasma membrane.^28,72 ICD is accompanied by pre-mortem cellular stress responses, namely autophagy and endoplasmic reticulum (ER) stress that often precede and trigger the activation of various modalities of cell death. At clinically relevant concentrations, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, ropivacaine and prilocaine induce the formation of autophagosomes, as indicated by the lipidation of autophagy-related protein light-chain 3B (LC3B), and activate the three arms of ER stress: i) the protein kinase RNA-like endoplasmic reticulum kinase (PERK) catalyzing the phosphorylation of eukaryotic initiation factor 2 alpha (EIF2A), which then favors the translation of activating transcription factor 4 (ATF4); ii) the inositol-requiring enzyme 1 (IRE1), which leads to the alternative splicing of X-box binding protein 1 (XBP1) mRNA; and iii) the cleavage of activating transcription factor 6 (ATF6) in the Golgi apparatus. Once activated, these transcription factors (ATF4, ATF6, XBP1) translocate into the nucleus where they turn on the expression of pro-apoptotic genes such as the C/EBP homologous protein (CHOP).^{28,61,63–65,73}

1.2. Epigenetic effect

LAs can induce epigenetic changes that impact cell migration and viability. At clinically relevant concentrations, LAs reduce global methylation in cancer cells by inhibiting DNA methyltransferases (DNMTs), which in turn leads to the demethylation of CpG islands, thus restoring activity at epigenetically silenced loci including the expression of tumor suppressor genes.^{40,53,74–77} Procaine has been shown to enhance the expression of Wnt inhibitory factor-1 (WIF-1) gene, which is silenced due to promoter hypermethylation in lung cancers.⁷⁸ Furthermore, lidocaine decreases the expression of EGFR by up-regulating miR-520a-3p and miR-539, thus inhibiting proliferation and promoting apoptosis in colorectal, retinoblastoma and lung cancer cells.^51,79,80 Lidocaine, ropivacaine and bupivacaine inactivate cellular signaling including the MEK-ERK, PI3K/AKT/MTORC and nuclear factor-kappa B (NF-kB) pathways, by up-regulating miR-145 and miR-520a-3p, thus attenuating malignant growth and inhibiting migration in different model of cancer.^15,81–84 Lidocaine and bupivacaine can downregulate DANCR long noncoding RNA (lncRNA) by the induction of miR-187-5p and then suppress the proliferation of MCF-7 breast cancer cells.⁸⁵ Similarly in cervical cancer cells, lidocaine inhibits proliferation and promotes apoptosis through the increased expression of the lncRNA of maternally expressed gene 3 (MEG3).⁸⁶ Lidocaine also interferes with the regulation of circular RNA (circRNA), microRNA (miRNA) and messenger RNA (mRNA) species affecting cellular development and progression at all levels.^87–91 Ropivacaine induces cell cycle arrest in cervical cancer cells by inhibiting miR-96-mediated the maternally expressed gene 2/signal transducer and activator of transcription 3 (MEG2/pSTAT3) signaling,⁹² triggers apoptosis in glioma cells by impacting on the miR-424-5p/SNHG16 axis,⁹³ retards invasion and migration of choriocarcinoma by modulating the opioid growth factor receptor pseudogene 1 (OGFRP1) lncRNA and the miR-4731-5p/hypoxia-inducible factor 3A (HIF3A) axis,⁹⁴ suppresses the proliferation of glioblastoma via an impact on the miR-21-5p/lysine acetyltransferase 8 (KAT8) axis⁹⁵ and represses the progression of breast cancer by regulating miR-27b-3p/Yes-associated protein 1 (YAP).⁹⁶ Moreover, lidocaine upregulates microRNA-493 and miR-30c and thus sensitizes melanoma and cutaneous carcinoma to 5-fluorouracil and cisplatin, respectively.^97,98 Moreover, down-regulation of miR-21 and miR-10b by lidocaine reportedly overcomes cisplatin resistance in lung cancer cells.^99,100

In summary, these findings suggest that LAs exhibit potent epigenetic anticancer effects by reactivating epigenetically silenced genes and by modulating the expression of a set of miRNAs, lncRNAs and circRNAs, altogether impacting malignant progression.

1.3. Immune effects

LAs exert a broad impact on various immune effectors including the activity and proliferation of lymphocytes and natural killer (NK) cells. In vitro, in ovarian and pancreatic cancer as well as in lymphoblastic and acute leukemia cells, lidocaine increases the expression of NKG2D receptor, thus stimulating the cytolytic activity of NK cells.^101,102 Furthermore, in the randomized controlled trial reported by Wei et al., 62 patients with breast tumor resection were randomly assigned to intravenous lidocaine treatment or placebo. In this trial, a significant decrease in CD3⁺, CD4⁺ T cells and CD4⁺/CD8⁺ ratio was noticed in the control group, but lidocaine stabilized the level of immune effectors during postoperative period. Moreover, in patients treated with lidocaine the number of circulating NK cells decreased less rapidly in the postoperative period than in the control group.¹⁰³ In the study of Yardeni et al. 65 women undergoing hysterectomy were allocated to receive either intravenous lidocaine or placebo. Serum analysis revealed higher proliferation of lymphocytes and lower serum level of IL-6 in lidocaine treated patients as compared to the placebo group.¹⁰⁴ Similarly, Wang et al. observed that infusion of lidocaine during cancer uterine surgery preserves the balance Th1/Th2, improves the secretion of the antitumor IFN-γ, and attenuates apoptotic demise of lymphocytes.¹⁰⁵ Epidural injection of LAs also increased the serum concentration of IFN-γ, enhanced NK cell cytotoxicity, preserves Th1/Th2 ratio, and decreased pro-inflammatory cytokines such as IL1-β and IL-8, suggesting that the immune effects of LAs do not depend on the mode of administration but rather on their intrinsic properties.^106,107

Simultaneously, LAs reduce the function of immunosuppressive effectors such as regulatory T cells (Tregs) and T helper 17 cells (Th17) in vitro.^{28,102,105–107} Moreover, lidocaine and ropivacaine possess the ability to induce the maturation of dendritic cells into antigen-presenting cells while stimulating phagocytosis, thus facilitating tumor antigen presentation and allowing for the onset of antitumor responses and the development of immune memory. Furthermore, when injected intratumorally, LAs induce abscopal effects in tumors established in immunocompetent mice and sensitize cancers to immunotherapy with immune checkpoint inhibitors.^28,108 In essence, LAs play a crucial role in modulating the tumor microenvironment, rendering tumors more responsive to immunotherapy.^109,110

1.4. Metabolic effects

1.4.1. Mitochondrial dysfunction

LAs have been shown to mediate time – and dose-dependent effects on mitochondrial fusion and to induce dysfunction in energy-intensive cells such as cardiomyocytes, neurons, and cancer cells.²⁸ Following LA treatment, all complexes of the respiratory chain are inhibited, disrupting the primary source of energy production by halting oxidative phosphorylation. Additionally, the levels of two glycolytic enzymes, glucose 1,6-bisphosphate, and fructose 1,6-bisphosphate, are decreased. Mitochondrial disturbance is further manifested by the breakdown of the mitochondrial transmembrane potential and the production of reactive oxygen species.^{28,41,43,48,49,52,60,111,112} As a result, mitochondrial dysfunction leads to the release of pro-apoptotic molecules, such as cytochrome c, triggering caspase activation and inducing the cell death of malignant cells.^41,49,60

1.4.2. Neuroendocrine effect

Surgical procedures induce both local and systemic inflammatory pain, activating the corticotropic axis. The released cortisol and catecholamines negatively impact various immune effectors involved in immunosurveillance and the antitumor immune response. This results in suppressed leukocyte chemotaxis, impairment of the lytic activity of NK cells and T lymphocytes, decreased synthesis of immunoglobulins by plasma cells, and inhibition of the release of cytolytic interferon-γ (IFN-γ).¹¹³ Pro-inflammatory and pro-tumor cytokines such as IL-6, IL-10, and TNF-α are also generated, stimulating the production of MMP-9 and vascular endothelium growth factor (VEGF), thus contributing to carcinogenesis and angiogenesis.^114–117

Due to their substantial anti-inflammatory and analgesic properties, LAs effectively mitigate surgical pain and glucocorticoid stress, thus supporting the immune system.^118,119 In a rat model of surgical pain, the addition of spinal block to general anesthesia significantly reduced surgery-induced lung metastases.¹¹³ Furthermore, through their anti-inflammatory properties, lidocaine, ropivacaine, and chloroprocaine impede Src protein tyrosine kinase (Src)-dependent inflammatory signaling, reducing MMP-9 secretion and phosphorylation of cell-cell adhesion molecule-1. This contributes to the anti-invasiveness and metastatic effects.^25,120

1.4.3. Metabolite modulation

Lidocaine induces changes in intracellular metabolite levels by downregulating several pathways related to glutaminolysis, as well as choline, phosphocholine and total choline syntheses. This impact on the metabolomic profile contributes to the antiproliferative and anti-invasive activities of LAs.¹²¹

1.5. Synergistic effects

Surprisingly, several preclinical studies have observed remarkable synergistic effects when conventional anticancer therapies such as anthracyclines, taxanes, or platinum salts were combined with LAs, resulting in significantly potentiated antitumor activity in vitro and prolonged survival of cancer bearing mice in vivo.^{6,21,33,42,76,111,122–128} Combination of LAs with chemotherapy or immunotherapy, such as anti-programmed cell death protein 1 (PD-1) antibodies, significantly decreases tumor growth and improves OS in various mouse models of fibrosarcoma, breast tumors, and colon adenocarcinoma.^28,129–132 Thus, lidocaine enhanced the cytotoxicity of the CDK 4/6 inhibitor palbociclib in triple-negative breast cancer cells.¹³³ Lidocaine also sensitized human breast cancer cells to cisplatin induced cell death and potentiated its metastasis-inhibiting action.^124,125 Interestingly, in some cases, the combination of LAs with anticancer-therapy was shown to mitigate side effects, such as cisplatin-induced nephrotoxicity, thus offering the possibility of enhancing the chemotherapy dose.¹²⁶ In sum, each of the aforementioned local anesthetics can interfere with properties acquired by malignant cells, thus impeding their ability to survive, resist to cell death, proliferate, evade growth suppressors, induce angiogenesis, alter the immune system, promote inflammation and genome instability, deregulate cellular energetics or activate local invasion (Figure 1).

Figure 1. Anti-tumor properties of local anesthetics according to the hallmarks of cancer determined by Hanahan and Weinberg. Cancer cells acquire distinct hallmarks that allow them to survive, resist to cell death mechanisms and possess immortality, evade growth suppressors, proliferate, induce angiogenesis, alter the immune system, promote an inflammatory environment, create genome instability, deregulate cellular energetics, and activate invasion and migration processes. Each anti-tumor property of local anesthetics can target one of these acquired hallmarks of cancer cells and hence interfere with the oncogenesis process. EGFR, epithelial growth factor receptor; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinases; ICD, immunogenic cell death; MMP, matrix metalloproteinase; PI3K/Akt/mTOR, Phosphatidylinositol-3-kinase/Protein kinase B/mammalian target of rapamycin; TGF-β, transforming growth factor β; TRPM7, transient receptor potential melastatin 7; VEGF, vascular endothelial growth factor.

2. Clinical investigation

2.1. Retrospective studies and meta-analyses

Among 51 retrospective observational trials, 24 studies reported beneficial effect following the administration of LA during the removal of primary solid tumors. Importantly, positive outcome was not influenced by the mode of administration and occurred both with injections close to the tumor site (regional block, local injection, infusion through a catheter) and at a distance (spinal anesthesia, epidural, intravenous injection).^{1–3,134−145} For instance, intravenous lidocaine administered during cystectomy, ovariectomy or pancreatectomy increased OS and disease-free survival (DFS), emerging as an independent factor for better prognosis.^136,146,147 Local injection of lidocaine during hepatectomy decreased the incidence of recurrence and the rate of death.¹³⁷ Levobupivacaine, administered through paravertebral block to optimally control pain after mastectomy, was associated with increased recurrence-free survival (RFS) in breast cancer patients.² Epidural administration of LAs during the peri – and postoperative period of major surgical procedures was linked to better OS and DFS, lower recurrence rates and reduced postoperative complications such as pneumonia and anastomotic leakage. No LA appeared to be superior to another^{1,3,134,135,138–144,148−154} (Table 1).

Table 1. Retrospective studies investigating the oncological impact of local anesthetics.

Tumor surgery	Local anesthetic	Design	Results	Ref.
Abdominal	Bupivacaine (epidural)	One hundred and thirty-two patients included (69 with epidural)	No association with RFS	157
Bladder	LA (epidural)	Four hundred and thirty-nine patients involved (215 with epidural).	Do not decrease risk of recurrence (p = .05). Epidural was a predictor of worse RFS (p = .009) and cancer-specific survival (p = .03)	155
Bladder	Lidocaine (intravenous)	One hundred and forty-four patients included.	Higher survival (p = .009). Less recurrence (p = .0023). Independent good prognosis factor (HR = 0.36, 95%CI[0.15–0.90]; p = .029).	146
Bladder	LA (epidural)	One thousand six hundred and twenty-eight patients included (887 epidural)	No benefit in improved short-term outcomes, cancer-specific survival (p = .804) or OS (p = .136)	158
Breast	Levobupivacaine (paravertebral)	One hundred and twenty-nine patients included (50 with paravertebral block)	Association between paravertebral block and RFS (p = .012)	2
Breast	LA (paravertebral)	Seven hundred ninety-two women involved (188 paravertebral)	No benefit in RFS (p = .172)	159
Cervix	LA (neuraxial)	One hundred and thirty-two patients treated with brachytherapy under neuraxial (n = 63) or GA (n = 69).	No benefit in recurrence (p = .863), in long-term mortality from recurrence (p = .265), or in all-cause mortality (p = .209)	160
Colon	LA (peridural)	Eight hundred and seventy-six patients involved (208 peridural)	Do not improve OS (p = .175), cancer-specific survival (p = .111) or DFS (p = .43)	161
Colon	Bupivacaine (epidural)	Two thousand seven hundred and forty-eight patients included (449 epidural)	No association between epidural and recurrence or death	162
Colon	LA (epidural)	Forty-two thousand one hundred and fifty-one patients included (9,670 epidural)	Association between epidural and improved survival (HR = 0.91, 95%CI[0.87–0.94]; p < .001)	138
Colo-rectal	LA (epidural)	Five hundred and eighty-eight patients involved (399 epidural).	Better five-year survival (p = .01)	3
Colo-rectal	LA (epidural)	Five hundred and nine patients enrolled (256 epidural).	Less recurrence in the subgroup of older patients (p = .01).	141
Colo-rectal	LA (epidural)	Six hundred and fifty-five patients included in two groups: epidural (n = 562) vs PCA (n = 93)	Reduction in all-cause mortality after rectal cancer surgery (p = .049).	142
Colo-rectal	LA (peridural)	Patients included into two groups (442 GA+peridural/307 GA alone)	Better 5-year survival (p = .02). HR for death decreased by 27%. In ASA 3–4 patients, significant greater survival (p < .009)	134
Colo-rectal	Bupivacaine (epidural)	Five hundred and ten patients involved (390 epidural)	Better 5-year RFS (HR = 0.74, 95%CI[0.56–0.95]; p = .036)	139
Colo-rectal	LA (epidural)	Two thousand nine hundred and eighty patients in each group after matching.	No benefit for mortality and recurrence.	163
Colo-rectal	Bupivacaine (epidural or spinal)	Four hundred and twenty-four patients included (107 epidural, 144 spinal, 173 PCA)	No difference in OS (p = .622) or DFS (p = .49) at 5 years	164
Colo-rectal	Bupivacaine (epidural)	Nine hundred and ninety-nine patients included (165 epidural)	No association between epidural and RFS or OS	165
Colo-rectal	Ropivacaine (epidural)	Two hundred and twenty-five patients included (92 epidural)	GA was associated with better outcomes	145
ENT	LA (epidural)	One hundred and seventy-one patients involved (111 epidural)	Increase DFS (HR = 0.49, 95%CI[0.25–0.96]; p = .04). Increase OS (p = .03)	143
Esophagus	Ropivacaine (epidural)	One hundred and fifty-three patients included (118 epidural)	No benefit in recurrence, 1-year mortality, or 5-year survival	166
Esophagus	LA (epidural)	One thousand nine hundred and twenty-one patients included (1,169 epidural)	Epidural improved 5-year survival (p = .012)	148
Esophagus	Ropivacaine (epidural)	Three hundred and fifty-six patients included (178 epidural)	Epidural decreased the incidence of pneumonia (p = .008), anastomotic leakage (p = .029), CRP level (p = .044). No benefits in recurrence (p = .47) or OS (p = .46)	149
Gastric	LA (epidural)	Two thousand seven hundred and forty-five patients (766 epidural)	No benefits in recurrence or survival	167
Gastric	Ropivacaine (epidural)	Three thousand seven hundred and ninety-nine patients included (3,425 epidural)	No benefits in recurrence (p = .471) or mortality (p = .138)	181
Gastric	Ropivacaine or levobupivacaine (epidural)	Two hundred and seventy-three patients included (157 epidural)	Greater long-term survival among younger patients<64 years-old (p = .042)	150
Gastric	LA (epidural)	One hundred and ninety-four patients included (97 epidural)	No benefit in survival (p = .147)	168
Gastro-esophageal	Bupivacaine (epidural)	One hundred and forty patients involved with epidural (n = 97) or not (n = 43).	Less recurrence (p = .01). Increased time to recurrence (HR = 0.33, 95%CI[0.17–0.63]; p < .0001). Better OS (HR = 0.42; 95%CI[0.16–0.75]; p = .005). Improved median time to death (p = .029)	140
Liver	Lidocaine (local injection)	Four hundred and eighty-nine patients involved (245 local injection).	Less recurrence (p = .0022). Less mortality (p = .036)	137
Liver	Bupivacaine (epidural)	Seven hundred and forty-four patients included (435 epidural)	No association between epidural and recurrence or mortality	169
Liver	Ropivacaine (epidural)	Eight hundred and nineteen patients included (451 epidural)	More recurrence (p = .036) and more death (p = .003) with epidural. No impact on RFS (p = .509)	156
Lung	Bupivacaine or ropivacaine (epidural)	Four hundred and forty-five patients involved (343 epidural /23 PCA/79 epidural + PCA)	No benefit in 2-year or 5-year RFS or OS	170
Lung	Bupivacaine (epidural)	Two thousand one hundred and ninety-one patients included (1,799 epidural)	No benefit in long-term mortality or OS	171
Melanoma	Bupivacaine (spinal anesthesia)	Two hundred and seventy-five patients included (52 spinal anesthesia + GA)	No benefit in survival (p = .087)	172
Ovary	LA (epidural)	One hundred eighty-two patients included (55 epidural).	Increased time to recurrence after surgery.	151
Ovary	Bupivacaine (neuraxial)	Eighty patients involved (37 epidural).	No benefit in OS or recurrence	173
Ovary	Lidocaine (intravenous)	Six hundred and four patients included after matching (302 lidocaine intravenous vs 302 without lidocaine)	Improved DFS (p = .015) and OS (p = .042)	147
Ovary	Bupivacaine or ropivacaine (epidural)	One hundred and forty-three patients included (106 epidural)	Better 3 – and 5-year OS (HR = 1.214; p = .043)	135
Ovary	LA (epidural)	One hundred and ninety-four patients included (60 epidural)	Less recurrence (p = .028). Longer DFS was associated with more than 48 h of epidural	152
Ovary	LA (epidural)	Six hundred and forty-eight patients included (435 epidural)	Better PFS (p = .021) and OS (p < .001). Epidural is independently associated with a decreased risk of progression (HR = 1.327, 95%CI[1.066–1.653]) and death (HR = 1.588, 95%CI[1.224–2.06])	153
Ovary	Ropivacaine (epidural)	One hundred and four patients included (51 epidural)	No benefits in DFS or OS	174
Pancreas	Lidocaine (intravenous)	Two thousand two hundred and thirty-nine patients involved. After propensity score: lidocaine (n = 915) or not (n = 915)	Benefit in 1-year OS (p < .001) and 3-year OS (p = .011). Lidocaine was associated with prolonged OS (HR = 0.616; 95%CI[0.29–0.783]; p = .013)	136
Pancreas	Ropivacaine (epidural)	Two hundred and fifteen patients included. 11 patients with high concentration of LA (0.375–0.5%) and 96 patients with low concentration (0.15–0.25%)	High concentration of ropivacaine improved OS (p = .04) and was an independent good prognostic factor (HR = 0.65, 95%CI[0.44–0.94]; p = .03)	154
Pancreas	Bupivacaine (epidural)	Two hundred and fifty-two patients included (n = 88 epidural; n = 164 without epidural)	No association with greater recurrence (p = .87) or all-cause mortality (p = .85).	175
Pancreas	Ropivacaine (peridural)	Ninety-eight patients included (70 peridural)	No benefits in recurrence or OS	176
Prostate	Bupivacaine (epidural)	One hundred and forty-eight patients involved (67 epidural)	Do not reduce the risk of progression. Do not improve survival.	177
Prostate	LA (epidural)	Two hundred and twenty-five patients included (102 epidural)	Lower risk of recurrence (p = .012)	1
Prostate	Bupivacaine (epidural)	Two hundred and sixty-one patients included (103 epidural)	Benefit in PFS (HR = 0.45; p = .002)	144
Prostate	LA (epidural)	One thousand one hundred and eleven patients included (578 epidural)	No benefit	178
Prostate	LA (epidural)	Ninety-nine patients included (49 epidural)	No benefit in recurrence (HR = 1.33, 95%CI[0.64–2.77]; p = .44)	179
Rectum	Bupivacaine (epidural)	One thousand two hundred and eighty-two patients included (237 epidural)	No association with RFS (p = .491) or OS (p = .984) or cancer-specific survival (p = .482)	180

Abbreviations: ASA, American society of anesthesiologists (physical status score); CI, confidence interval; CRP, C-reactive protein; DFS, disease-free survival; GA, general anesthesia; HR, hazard ratio; LA, local anesthetics; PCA, patient-controlled analgesia; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival

However, two articles concluded that LAs injected in epidural could be predictors of worse RFS and might increase mortality after cystectomy or hepatectomy.^155,156 Finally, 25 trials observed no association between LAs and outcome.^157–181 These results were combined in four meta-analyses, the conclusions of which confirmed the benefit of LAs injected through neuro-axial procedures during the perioperative period (Table 2). This benefit includes a decrease in the incidence of relapses and an improvement in both OS and DFS.^182–185

Table 2. Meta-analyses investigating the oncological impact of local anesthetics.

Tumor surgery	Local anesthetic	Design	Results	Ref.
Solid tumors	LA (epidural)	Ten studies (=3,254 patients) included.	Subgroups with prostate cancer or follow-up less than or equal to two years (OR = 0.66, 95%CI[0.46–0.95], p = .027; OR = 0.70, 95%CI[0.51–0.98], p = .035; respectively) for recurrence and metastasis rate	183
Solid tumors	LA (regional anesthesia)	Twenty studies	Improve OS (HR = 0.84; 95%CI[0.75–0.94; I^2 = 41%] No reduction in recurrence (HR = 0.91, 95%CI[0.70–1.18; I^2 = 83%]	184
Solid tumors	LA (neuraxial)	Twenty-one studies involved (15,160 patients with neuraxial anesthesia and 36,460 with GA)	Improved OS (HR = 0.853, 95%CI[0.741–0.981]; p = .026) Improve RFS (HR = 0.846, 95%CI[0.718–0.998]; p = .047)	185
Solid tumors	LA (epidural)	Fourteen studies (47,000 patients) included	Improved OS (p = .013)	182

Abbreviations: CI, confidence interval; GA, general anesthesia; HR, hazard ratio; LA, local anesthetics; OR, odds ratio; OS, overall survival; RFS, recurrence-free survival

2.2. Prospective studies

Twenty-eight prospective randomized controlled trials have investigated whether the use of LAs improves oncological outcomes (Table 3). Thirteen of these studies did not show significant differences between the treatment groups.^{179,186–197} However, 50% of the published trials reported positive benefits in various solid tumors.

Table 3. Prospective randomized controlled trials investigating the oncological outcomes of local anesthetics.

Tumor surgery	Local anesthetic	Design	Results	Ref.
Bladder	Ropivacaine + lidocaine (epidural)	One hundred patients included (50 with epidural)	Longer DFS (p = .02)	198
Breast	Levobupivacaine (paravertebral)	Twenty-two patients randomized to receive propofol/paravertebral or sevoflurane/opioid	The serum of patients from the group paravertebral inhibits the proliferation of ER-MDA-MB-231 breast cancer cells in vitro.	204
Breast	Bupivacaine (paravertebral)	Forty patients randomized to receive paravertebral block or not.	Less increase in IL-6. Higher level in IFN-γ.	115
Breast	Ropivacaine (paravertebral)	One hundred and eighty patients randomized to receive paravertebral block or not.	Do not decrease recurrence or mortality	187
Breast	Ropivacaine (paravertebral)	Sixty patients involved to receive paravertebral block or not.	Do not decrease recurrence	188
Breast	Ropivacaine+ lidocaine (local injection)	Fifty-six patients randomized to receive local anesthesia or GA	Higher total lymphocytes number in GA group (p = .04)	205
Breast	Lidocaine (peritumoral)	One thousand five hundred and eighty-three patients randomized to receive lidocaine (n = 796) or not (n = 804)	Better 5-year DFS (HR = 0.74, 95%CI[0.58–0.95]; p = .017) and OS (HR = 0.71, 95%CI[0.53–0.94]; p = .019)	203
Breast	LA (paravertebral)	Two thousand one hundred and eight patients included (1,043 with paravertebral block)	No difference between groups	189
Cervix	Lidocaine (bolus and continuous intravenous infusion)	Thirty women randomized to receive lidocaine iv or normal saline.	Increase in the proliferation of lymphocytes. Decrease in apoptosis of lymphocytes. Better level of INF-γ	105
Colon	Bupivacaine (epidural)	One hundred and seventy-seven patients randomized to receive epidural or not.	Epidural improved survival before 1.46 years (p = .012)	199
Colon	Ropivacaine (epidural)	Forty patients randomized to receive epidural or not.	Decreased in VEGF (p = .001), TGF-β (p = .027) and IL-6 (p = .007). Increased in IL-10 (p = .001).	206
Colon	Ropivacaine (intraperitoneal catheter)	Thirty-seven patients randomized to receive LA through intraperitoneal catheter (n = 19) or not (n = 18).	No benefit in OS or all-cause mortality. Higher rate of cancer-specific mortality (p < .046)	190
Colo-rectal	Ropivacaine (intraperitoneal catheter)	Sixty patients included (30 with infiltration)	No effect on NK cytotoxicity, recurrence or metastases	191
Colo-rectal	LA (epidural)	One hundred and eighty patients randomized to receive epidural (n = 89) or PCA (n = 91).	No significant difference for DFS at 5 years	192
Colo-rectal	Lidocaine (intravenous)	Eighty-two patients randomized to receive lidocaine or not with or without ketamine.	No influence on inflammatory markers.	197
Colo-rectal	Lidocaine (intravenous)	One hundred and fifty patients randomized to receive lidocaine (n = 77) or not (n = 73).	Decreased rate of recurrence (p = .03) but no impact on 1-year survival (p = .22)	200
ENT	Ropivacaine (epidural)	Thirty patients randomized to receive epidural or not.	Reduction in blood glucose (p = .0153) and cortisol (p = .0074)	118
Gastric	Ropivacaine (epidural)	Fifty patients randomized to receive epidural or not.	Increased in IFN-γ. Less increase in IL-6.	207
Liver	Ropivacaine (bolus+ infiltration)	Sixty patients included (20 with tramadol, 20 with ropivacaine, 20 with fentanyl)	Ropivacaine increased survival (p = .029)	201
Lung	Ropivacaine (paravertebral)	Forty patients involved to receive paravertebral/propofol vs sevoflurane	Lower VEGF and TGF-β concentration (p < .05)	208
Lung	Ropivacaine (paravertebral)	One hundred and fifty-nine patients randomized to receive ropivacaine (10 mg or 25 mg or 50 mg)	No influence on OS	193
Lung	Ropivacaine (epidural)	Four hundred patients included (200 with epidural)	No benefits in RFS or OS	194
Ovary	Ropivacaine (intraperitoneal catheter)	Forty patients randomized to have intraperitoneal catheter of LA or not	Serum cortisol was lower in LA group (p = .023)	209
Ovary	Ropivacaine (intraperitoneal catheter)	Forty women involved to receive intraperitoneal catheter or not.	Reduction of time to initiate chemotherapy after surgery (p = .021)	202
Pancreas	Lidocaine (intravenous)	Five hundred and sixty-three patients randomized to receive lidocaine intravenous (n = 283) or not (n = 280)	No association with better OS (p = .79) or DFS (p = .44)	195
Prostate	Ropivacaine (epidural)	Ninety-nine patients randomized to receive epidural/GA or GA alone.	No difference in DFS.	179
Solid tumors	Bupivacaine or Ropivacaine (epidural)	Four hundred and forty-six patients included (230 with epidural)	No benefits in DFS	186
Solid tumors	Ropivacaine (epidural)	One thousand seven hundred and twelve patients included (853 with epidural)	No benefits in OS	196

Abbreviations: DFS, disease-free survival; GA, general anesthesia; HR, hazard ratio; iv, intravenous; IFN, interferon; IL, interleukin; LA, local anesthetic; NK, natural killer cells; OS, overall survival; PCA, patient-controlled analgesia; RFS, recurrence-free survival; TGF, tumor growth factor; VEGF, vascular endothelial growth factor

For instance, Guerrero Orriach et al. demonstrated in their study that epidurally administered ropivacaine, in association with intravenous hypnotics and lidocaine, increased DFS in a group of 100 patients with bladder cancer undergoing surgical procedures, as compared with the control group anesthetized with volatile hypnotics and opioids.¹⁹⁸ Christopherson et al. observed similar results after comparing colectomy performed under general anesthesia with isoflurane and fentanyl, with or without epidural bupivacaine.¹⁹⁹ In the study by Alexa et al., a significant reduction in recurrences was observed after the intravenous injection of lidocaine during colectomy.²⁰⁰ After hepatectomy, the analgesic infusion of ropivacaine (bolus plus continuous injection through a local catheter) improved postoperative survival compared to the use of tramadol and fentanyl to control surgical pain.²⁰¹ The perfusion of ropivacaine through an intraperitoneal catheter minimized the time to initiate adjuvant chemotherapy after ovariectomy compared to the control group.²⁰² Finally, the recent multicenter randomized controlled trial by Badwe et al., including 1583 patients, showed significantly better OS and DFS, with or without recurrence, after the use of locally injected lidocaine in peritumoral tissue before the removal of breast tumors.²⁰³

Interestingly, indirect effects on the immune system were also observed. The serum of patients receiving LA during oncological surgery involved more active lymphocytes capable of inhibiting the proliferation of cancer cells in vitro.^105,204,205 Several ancillary studies reported a significant decrease in the pro-tumor inflammatory cytokines IL-6, while there was an increase in the anti-tumor IFN-γ.^{105,115,206,207} Lower levels of VEGF, tumor growth factor-β (TGF-β), and cortisol in plasma were also observed in cases of ropivacaine injection through epidural, intraperitoneal or paravertebral routes, suggesting both a local impact (perhaps by slowing down the secretion of growth factors by the surrounding tumor tissue) and a systemic impact (perhaps by decreasing glucocorticoid stress).^{118,206,208,209}

3. Future investigation

3.1. Completed trials

Numerous prospective randomized controlled trials have been initiated following the publication of the aforementioned preclinical studies, with the primary goal of confirming the data (Table 4). Most of the completed or terminated trials aim to evaluate whether the use of LAs with various modes of administration during the removal of primary breast, colorectal, liver, or lung cancer improves OS and/or DFS and hence decreases the incidence of recurrence (NCT01204242; NCT00418457; NCT03117894; NCT01231204; NCT01318161; NCT02801409; NCT01179308; NCT02256228; NCT02012244).

Table 4. Completed and terminated prospective trials investigating the oncological outcomes of local anesthetics.

Tumor surgery	Local anesthetic	Administration route	Oncological endpoints	Potential endpoints related to cancer outcome	Phase	Status	Ref.
Breast	Lidocaine	Intravenous	5-year recurrence	Chronic pain Opioid use	2	completed	NCT01204242
Breast	LA	Epidural or Regional (paravertebral)	10-year recurrence	Postsurgical pain Neuropathic pain	3	completed	NCT00418457
Breast	LA	Regional	Circulating tumor cells, level of cytokines, breast cancer antibodies, dendritic cells, T, B and NK cells		Obser-vational	completed	NCT01716065
Breast	Ropivacaine vs lidocaine	Regional (paravertebral)	Recurrence up to 12 months	Postoperative pain	NA	completed	NCT04390698
Breast	Ropivacaine	Regional	Mortality 3 – and 5-year recurrence	Opioid use, actual/chronic pain	NA	completed	NCT03117894
Breast	Ropivacaine	Regional (continuous infusion for 3 days)	3-year cancer recurrence	Opioid use Pain	4	completed	NCT01231204
Colo-rectal	Ropivacaine	Epidural	5-year mortality 7-year recurrence	Inflammation (perioperative cytokine concentration in blood), postoperative pain	3	terminated	NCT01318161
Colo-rectal	Ropivacaine	Infiltration	1-year recurrence, NK cell activity	Inflammatory responses, IL-2 level	NA	completed	NCT02012244
Liver	Lidocaine	Sub-cutaneous	Percentage change from post – to pre-operative values of HepG2 cells; Invasion, migration and proliferation of HepG2 cells cultured in patients’ serum	IL-1β, IL-6, TNF-α, IFN-γ and IL-2 level	NA	completed	NCT04510935
Liver	LA	Local	Cell proliferation Cell migration and metastasis		NA	completed	NCT03594188
Lung	LA	Epidural	4-year RFS, mortality, OS, number of CD8^+ and Treg in tumor, percentage of NK and T-cell in blood	Pain	NA	completed	NCT02801409
Lung	LA	Epidural	5-year disease-free survival, NK cell function, immune function markers,	Pain	NA	terminated	NCT01179308
Ovary	Ropivacaine	Intraperitoneal	PFS, morbidity	Inflammatory markers, opioid use, pain	3	completed	NCT02256228
Pancreas	Bupivacaine	Epidural	Immunoprofile (CD4^+, CD8^+, CD19^+, NK, DC, Treg), 1-year survival		NA	completed	NCT01929915
Prostate	Bupivacaine + ropivacaine	Epidural	NK activity	Release of IL-2, IL-6, TNF-α, cortisol	3	completed	NCT01367418

Abbreviations: DC, dendritic cell; IFN, interferon; IL, interleukin; LA, local anesthetics; NA, non-applicable; NK, natural killer; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; TNF, tumor necrosis factor; Treg, regulatory T cells

Many interventional trials were designed to investigate the control of acute/chronic postoperative pain by LA and explore a potential link with cancer outcomes (NCT01204242; NCT04390698; NCT03117894; NCT01231204; NCT01318161; NCT02012244; NCT02801406; NCT01179308). Several clinical trials include an ancillary study to evaluate the role of LA on the level and activity of immune cells collected from the blood of patients (NCT01716065, NCT04510935, NCT02801409, NCT01179308, NCT01367418, NCT01929915) or assess their impact on the proliferation and migration of cancer cells (NCT03594188; NCT04510935).

Five trials (NCT01318161; NCT02012244; NCT04510935; NCT02256228; NCT01367418) are investigating whether LA decreases the surgery-induced inflammatory response by assessing the levels of pro-inflammatory and pro-tumor cytokines (IL-2, IL-6, TNF-α).

Finally, the trial NCT00418457 has published results. In this multicenter randomized controlled trial, 2132 women undergoing breast cancer surgery were enrolled and allocated either to a general anesthesia group with volatiles and opioids or to a regional anesthesia-analgesia group, including paravertebral block plus intravenous hypnotic. Both groups were homogeneous for the characteristic baseline of patients, tumor, and surgical information. The regional administration of LA did not reduce the recurrence of cancer compared to the general group, and no association between baseline factors and the different types of anesthesia on recurrence was found.

3.2. Ongoing trials

Several randomized trials are currently investigating the effects of LAs administered through various routes on the activity of key antitumor immune effectors (Table 5). The study NCT02669186 aims to analyze the impact of bupivacaine on NK cytotoxicity. Here, bupivacaine is injected with or without fentanyl through epidural administration, which is distant from the tumor site and induces minimal serum concentrations of the LA. In the study NCT01841294, NK activity is measured after an intravenous lidocaine infusion, promoting 100% bioavailability of the LA and high tumor perfusion. Trials NCT01588847 and NCT05470166 are also focused on changes in the quantity of different immune cells (NK cells, T-cells, B-cells, activated thrombocytes) after the injection of bupivacaine alone through spinal anesthesia compared with general anesthesia involving a mix of intravenous and volatile hypnotics.

Table 5. Ongoing prospective trials investigating the oncological outcomes of local anesthetics.

Tumor surgery	Local anesthetic	Administration	Oncological endpoints	Other endpoints potentially related to cancer outcome	Phase	Status	Ref.
Abdominal tumor	Bupivacaine	Epidural	NK cytotoxicity		NA	enrolling by invitation	NCT02669186
Bladder	Bupivacaine	Spinal	2-year RFS 2-year PFS		NA	unknown	NCT03597087
Bladder	Bupivacaine	Regional (obturator nerve block)	Recurrent tumor at 3 months		NA	recruiting	NCT04638569
Breast	Lidocaine + bupivacaine	Tumor site	5-year DFS	Pain, opioid use	3	unknown	NCT00938171
Breast	Lidocaine	Peri-tumoral	5-year DFS 5-year OS		3	not yet recruiting	NCT01916317
Breast	Ropivacaine	Regional (erector spinae plane)	3-year PFS 3-year OS	Chronic pain, neuropathic pain	NA	not yet recruiting	NCT05494502
Breast	LA	Regional (paravertebral)	Genome expression by microarray, immune progenitors, 7-year RFS 7-year OS		NA	unknown	NCT03779685
Breast	Bupivacaine	Regional (paravertebral)	Change in level of PD-1 and PD-L1 on peripheral blood monocyte cells	Total analgesia (paracetamol)	NA	unknown	NCT04657237
Colo-rectal	Lidocaine	Intravenous	Antiproliferative and apoptotic effects of anesthetics, evaluation of patient serum on colon cancer cell culture (HCT116) 5-year survival	Lidocaine concentration	1	recruiting	NCT04162535
Colo-rectal	Lidocaine	Intravenous	5-year survival, 5-year recurrence	Pain, opioid use	Early 1	recruiting	NCT02786329
Colo-rectal	Lidocaine	Intravenous	NK activity	Pain, opioid use	4	unknown	NCT01841294
Glio-blastoma	LA	Local	Morbidity, resection percentage, progression-free survival, OS, residual tumor volume		Obser-vational	recruiting	NCT04708171
Liver	LA	Infiltration vs epidural	3 – and 5-year OS 5-year DFS		NA	unknown	NCT03813953
Liver	LA	Local	3-year recurrence		Obser-vational	unknown	NCT02474511
Lung	LA	Epidural	3-year DFS	Pain, opioid use	NA	not yet recruiting	NCT02840227
Melanoma	Bupivacaine	Spinal	OS, change of total amount of immune cells (T-, B-, NK-cells), changes in TGF-β, activation of thrombocytes, potential predictive biomarkers		NA	unknown	NCT01588847
Ovary	Ropivacaine	Intraperitoneal	Time to start of adjuvant chemotherapy after surgery, 3-5-year survival, morbidity		3	recruiting	NCT04065009
Pancreas	Lidocaine	Intravenous	NK level, lymphocytes level	Pain, analgesic consumption	NA	recruiting	NCT05470166
Pancreas	Lidocaine	Intravenous	Src tyrosine kinase activity in circulating tumor cells, cytokine/chemokine levels in serum, regulation of gene expression, circulating tumor cells		Early 1	recruiting	NCT04048278
Pancreas	Lidocaine vs ropivacaine	Intravenous vs Epidural	1 – and 3-year recurrence 1 – and 3-year survival after surgery	LA concentration	2	not yet recruiting	NCT04449289
Solid tumors	Ropivacaine + lidocaine	Regional	5-year recurrence, 5-year survival, percentage of immunocytes and cytokines	Intraoperative anesthetic level, pain	NA	not yet recruiting	NCT03134430

Abbreviations: DC, dendritic cell; DFS, disease-free survival; LA, local anesthetics; NA, non-applicable; NK, natural killer cells; OS, overall survival; PD(L)1, Programmed cell Death (Ligand) protein 1; PFS, progression-free survival; RFS, recurrence-free survival; TGF, tumor growth factor

The phase 1 trial NCT04162535 is evaluating whether the anesthetic agents used during colorectal tumor removal induce antiproliferative effects. Here, patient serum containing various concentrations of anesthetics and different levels of immune effectors is tested in vitro on HCT116 human colon carcinoma cells.

Three studies focus on immune and genome changes induced by LAs. The early phase 1 study NCT04048278 assesses whether intravenous lidocaine can modify the activity of the oncogenic kinase SRC involved in the proliferation and survival of circulating tumor cells and the regulation of gene expression. Trials NCT04657237 and NCT03779685 investigate whether paravertebral block, used to control surgical and postoperative pain during mastectomy, induces changes in the transcriptome, impacts immune progenitors, and specifically disturbs the expression of PD-1 and programmed cell death (ligand) protein 1(PD-L1) on blood monocyte cells.

Interestingly, many ongoing studies are exploring factors that might indirectly influence oncological outcomes. Three prospective trials (NCT04162535; NCT04449289; NCT03134430) plan to assess the serum concentration of anesthetics to find an association with cancer progression. Several studies are designed to measure pain and opioid consumption, which may encourage tumor growth and recurrence (NCT00938171; NCT05494502; NCT04657237; NCT02786329; NCT01841294; NCT02840227; NCT05470166; and NCT03134430). The phase 3 trial NCT04065009 is evaluating whether the use of LA influences the time to start adjuvant chemotherapy after surgery. Finally, most ongoing research is also examining the effect of LAs on RFS and OS (NCT03597087; NCT04638569; NCT00938171; NCT05494502; NCT03779685; NCT04162535; NCT02786329; NCT02474511; NCT03813953; NCT02474511; NCT02840227; NCT01588847; NCT04449289 and NCT03134430).

Discussion

The past two decades have witnessed a growing number of articles examining the role of LAs in oncological outcomes. Preclinical studies have consistently demonstrated the anti-tumor actions of both ester and amide type LAs across various tumor types. Notably, prilocaine and chloroprocaine, although acting quickly, are less investigated, possibly due to their short duration of action, which might render them less efficient on malignant cells.

Although the direct anti-tumor action of LAs appears straightforward, understanding how LAs may exert anti-tumor effects after injection far from the tumor site is more complex. Indeed, locally injected LAs are close to the tumor bed, hence favoring the control of the residual malignant cells before migration. Through continuous intravenous injection, LAs can propagate through the systemic circulation, ensuring a stable diffusion throughout the entire tumor and the circulating tumor cells disseminated during the surgical intervention. The potential positive effects of spinal or epidural administration are intriguing, and one hypothesis suggests that epidural anesthesia reduces glucocorticoid stress during oncological surgery. This stress, triggered by local inflammatory pain, releases pro-inflammatory, pro-tumor cytokines, cortisol and catecholamines, promoting the proliferation, migration and invasiveness of cancer cells.^210–213

Controlled pain and inflammation, through optimal pain control, may enhance the capacity of the immune system to mount anticancer responses, as indicated by increased release of IFN-γ. Moreover, by inducing a partial ICD response, LA may stimulate cytotoxic T lymphocytes (CTLs) and generate immune memory to control residual circulating malignant cells and decrease recurrence incidence.^214–217 Preclinical results suggested that intratumoral lidocaine and ropivacaine influence the tumor microenvironment by increasing activated CD8⁺ T cells and decreasing immunosuppressive cells such as FOXP3⁺ Tregs, hence reenforcing immunosurveillance and preventing metastatic spread.^218,219 This may also sensitize to immunotherapy with PD-1 blocking antibodies.^220–222

While preclinical studies provide robust evidence for the anti-tumor effects of LAs, clinical studies face several challenges in translating these results. Many published trials lack power, with observational and retrospective designs often hampered by an imbalance in study groups.¹⁸¹ A number of confounding factors such as heterogeneity in disease stage, variations in (neo)-adjuvant immunomodulatory treatments, cancer aggressiveness and the concurrent use of pro-tumor agents, further complicate the interpretation of results. The mode of LA administration, with variations in injection duration and methods, is also debated. Additional confounding factors such as undernutrition, anemia, inflammation, pain, and stress are often not optimally controlled.

Despite these challenges, subgroup analyses suggest that specific patient groups or tumor types may be particularly susceptible to the beneficial actions of LAs. However, recent well-designed trials have provided contrasting results. Sessler et al.’s study found no reduction in breast cancer recurrence with paravertebral block compared to the control group, possibly due to the anti-tumor properties of the volatile hypnotic sevoflurane that was used in the control group.^223–225 In contrast, Badwe et al.’s trial showed a significant increase in DFS and OS in the lidocaine group, supporting a potential direct cytolytic effect of lidocaine on breast tumor cells.²⁰³ Of note, irrespective of the mode and duration of administration, LA did not induce side effects. Thus, further studies should focus on the safety and feasibility of different combination strategies such as LA plus chemotherapy and immunotherapy.²²⁶ Future clinical trials should also explore whether LA cotreatment would allow reducing the toxicity of conventional anticancer agents. Another focus should be to use LAs for potentiating the anti-tumor immune response by stimulating immune effectors, modulating the tumor microenvironment and in fine rendering the tumors more sensitive to antineoplastic treatments.

Conclusion

Attempts are underway to clinically translate promising preclinical data on the potential antitumor and immunomodulatory properties of local anesthetics (LAs). This endeavor meets challenges due to several factors, such as the relatively modest therapeutically effects of LAs and the presence of various confounding biases. As a result, there is an urgent need for significant efforts to ameliorate the design of future clinical trials by reducing selection bias, increasing the number of inclusions and targeting patient populations that might benefit from LA interventions such as early-stage patients. Future investigations should explore the impact of LAs when used in combination with conventional anti-tumor agents, peri-operative but also as alongside the treatment. This comprehensive approach is crucial for gaining a deeper understanding of the potential benefits of LAs in the context of anticancer treatments. By refining study design, controlling confounding factors, and identifying optimal patient populations, clinician scientists might contribute to clarifying the role of LAs in improving oncological outcomes.

Abbreviations

ATF4	=	activating transcription factor 4
ATF6	=	activating transcription factor 6
ATP	=	adenosine triphosphate
CDK	=	cyclin-dependent kinase
CHOP	=	C/EBP homologous protein
circRNA	=	circular RNA
CPEB3	=	cytoplasmic polyadenylation element-binding protein 3
CYTC	=	cytochrome C
DAMPs	=	danger associated molecular patterns
DC	=	dendritic cell
DFS	=	disease-free survival
DNMTs	=	DNA methyltransferases
EGFR	=	epithelial growth factor receptor
EIF2alpha	=	eukaryotic initiation factor 2 alpha
ER	=	endoplasmic reticulum
ERK	=	extracellular signal-regulated kinases
GA	=	general anesthesia
HB-EGF	=	heparin-binding epidermal growth factor-like growth factor
HIF	=	hypoxia-inducible factor
HMGB1	=	high mobility group box 1
ICD	=	immunogenic cell death
ICU	=	intensive care unit
IFN	=	interferon
IL	=	interleukin
IRE1	=	inositol-requiring enzyme 1
KAT8	=	lysine acetyltransferase 8
LA	=	local anesthetics
LC3B	=	lipidation of autophagy-related protein light-chain 3B
lncRNA	=	long non-coding RNA
MAPK	=	mitogen-activated protein kinase
MEG	=	maternally expressed gene
miRNA	=	microRNA
MMP	=	matrix metalloproteinase
NA	=	non-applicable
NK	=	natural killer
NF-kB	=	nuclear factor-kappa B
OGFRP1	=	opioid growth factor receptor pseudogene 1
OS	=	overall survival
PARP	=	poly ADP-ribose polymerase
PCS/MCS	=	Physical and Mental Health Composite Scores
PD(L)1	=	Programmed cell Death (Ligand) protein 1
PERK	=	protein kinase RNA-like endoplasmic reticulum kinase
PI3K/Akt/Mtorc	=	phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex
PONV	=	postoperative nausea and vomiting
RAC1/JNK/paxillin/FAK	=	RAS-related C3 botulinum toxin substrate 1/c-JUN N-terminal kinase/paxillin/focal adhesion kinase
RHO-A/ROCK/MLC	=	RHO-associated protein kinase/myosin light chain
RFS	=	recurrence-free survival
Src	=	Src protein tyrosine kinase
STAT3	=	Signal transducer and activator of transcription 3
Th	=	T helper cells
TGF	=	tumor growth factor
TIVA	=	total intravenous anesthesia
TNF	=	tumor necrosis factor
Treg	=	regulatory T cells
TRPM7	=	transient receptor potential melastatin 7
VEGF	=	vascular endothelium growth factor
WIF-1	=	Wnt inhibitory factor-1
YAP	=	Yes-associated protein 1
XBP1	=	X-box binding protein 1

Acknowledgments

KCLP receives funding from Agence Régionale en Santé (ARS) Ile de France Année-Recherche Pharmacie; OK receives funding from Institut National du Cancer (INCa) and Agence National de la Recherche (ANR); GK is supported by the Ligue contre le Cancer (équipe labellisée); ANR – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); European Research Council (ICD-Cancer), European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; INCa; Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. LB receives funding from the Societé Française d’Anesthésie-Réanimation (SFAR), the Ligue contre le cancer, the foundation Monahan.

Disclosure statement

OK and GK have been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. OK is a scientific co-founder of Samsara Therapeutics. GK is in the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. GK’wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results. The other authors declare no conflicts of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.