It has been suggested that inhalation agents, for the most part, have a tumorigenic effect since they both inhibit tumor cell apoptosis and stimulate tumor cell proliferation and migration. More specifically, in advanced breast cancer, elevated caveolin-1 concentrations have been associated with lower survival. This protein has been linked to higher resistance to apoptosis, migration and elevated invasivity in breast cancer cells. Ecimovic et al. [25] analyzed, in vitro, the ability of sevoflurane to stimulate tumor cell proliferation, migration and invasion in patients with positive (ER+) and negative (ER-) estrogen receptor breast cancer (with the latter not having invasive capacity).

However, Kawaraguchi et al. [26] documented that isoflurane confers a protective effect on tumor cells in colon cancer against TNF-mediated apoptosis (TRAIL or TNF-related apoptosis-inducing ligand) by interacting with caveolin-1.

Sevoflurane reduces NK activity, thereby reducing immunosurveillance and favoring progression of micrometastases. In contrast, a range of studies have been conducted to compare immunosuppression induced by halogenated anaesthetics vs. general intravenous anaesthesia, with inconsistent results [27,28,29,30,31,32]. Enlund et al. [27] found no significant differences in 1-year and 5-year survival in a sample of 1837 breast cancer patients. Kim et al. [29] compared propofol with a variety of halogenated agents (sevoflurane, desflurane, isoflurane and enflurane), without significant differences. Recent retrospective studies [30,31,32] provide cumulative evidence of the absence of significant differences between intravenous and inhalation anaesthetics in terms of recurrence or survival.

Opioids have an immunosuppressive effect that influences cellular and humoral immunity, as they reduce NK lymphocyte activity and proliferation, citokine production, phagocytic activity, and antibody release [33]. The type and degree of immunosuppression depends on the type, dose and time of exposure to the opioid. All synthetic opioids reduce NK activity [34,35].

Morphine inhibits T and NK lymphocyte activity, promotes lymphocyte apoptosis, reduces toll-like 4 factor in macrophages [36] and has angiogenic activity [37]. In addition, the tumorigenic activity of morphine is mediated by two independent mechanisms, namely: by direct stimulation of mu receptors in tumor cells, the overexpression of which has been associated with poor prognosis, and indirectly by promoting neo-angiogenesis through metabolic signaling pathways similar to those used by VEGF factor [38,39].

In breast tumor cells, fentanyl exhibits an antitumoral effect by reducing levels of proteins involved in cell apoptosis and differentiation mechanisms (Bax, Bcl2, Oct4, Sox2, and Nanog) [40]. Although tramadol is a µ-receptor agonist, its analgesic effect is prevailingly mediated by the inhibition of noradrenaline and serotonin reuptake. Sacerdote et al. [41] assessed the relationship between tramadol and immune response in patients with uterine carcinoma. The authors found that tramadol not only inhibits but also stimulates NK lymphocyte activity. Thereupon, Xia et al. [42] demonstrated, in vitro, in breast tumor cells that tramadol reduces tumor cell proliferation, migration and invasion by up to 28 days through the inhibition of the α2-adrenergic receptor. In a retrospective study, Kim et al. [43] observed lower rates of mortality and tumor recurrence in the group of breast cancer patients treated surgically who received tramadol. This effect is conferred by the inhibition of tumor cell proliferation, induction of apoptosis, and action on serotonergic receptors and transient receptor potential channel V1 or TRPV1.

There is a variety of locoregional anaesthesia techniques in breast cancer surgery that have good analgesic outcomes. Paravertebral block (PVB) is the most widely used technique, although it is associated with a higher risk of severe complications. New techniques have been developed, with pectoral block type II having shown good effectiveness, and having been employed in a similar context as PVB [44]. Several studies have been published comparing general anaesthesia and combined anaesthesia: five retrospective studies, two prospective studies and a systematic review. These studies provide evidence of the beneficial effects of not using opioids and/or local anaesthetics per se [45,46,47,48,49,50,51,52].

Exadaktylos et al. [45] published the first retrospective study assessing the outcomes of 129 patients with breast cancer treated surgically, of whom 50 received combined anaesthesia (PVB+Propofol) and 79 balanced general anaesthesia. The rate of recurrence was lower in the group that received combined anaesthesia. In contrast, a recent systematic review conducted by Pérez-González et al. [52] did not show statistically significant differences between combined and general anaesthesia.

Local anaesthetics block afferent and efferent nerve response and effectively suppress sympathic stimulation through the inhibition of hypothalamic–pituitary–adrenal (HPA) stimulation induced by surgical stress, thereby reducing HPA activity [52].

Lidocaine has been proven to exert beneficial effects in vivo and in vitro, and it is associated with a reduction in tumor cell proliferation, migration and invasion in breast, liver and lung cancer [53,54,55]. Lidocaine inhibits the proto-oncogen that releases Src, an intracellular non- tyrosine kinase protein that is involved in cell proliferation and migration processes through ICAM-1 phosphorylation, which enables neutrophils to cross the endothelium and increase immune response [55]. It has been reported to have effects on other signaling pathways such as TRPV-6 inhibition [56] or DNA demethylation in breast cancer cells [57]. Chang et al. [58] demonstrated in vitro that both lidocaine and bupivacaine induce breast cancer cell apopotosis through the activation of caspases 7, 8 and 9. In the same line, D’Agositino et al. showed that lidocaine inhibits cytoskeletal modification in breast cancer cells [59].

Evidence has been provided that lidocaine infiltration in the peritumoral region inhibits tumor growth by binding EGFR [60]. As for the immune system, lidocaine, at clinically relevant concentrations, stimulates the cytotoxic effect of NK lymphocytes [61]. A prospective, randomized trial conducted by Galoș et al. revealed that lidocaine reduced neutrophil extracellular traps, a phenomenon that has been associated with tumor recurrence [62].

The enzyme cyclooxygenase (COX-2) causes an increase in prostaglandins, which are involved in immune system control and angiogenesis. Ketorolac is the most extensively studied NSAID in relation to cancer. It is a COX-1 and COX-2 inhibitor that is commonly used in the perioperative period. Evidence from retrospective studies demonstrates that perioperative administration of ketorolac reduces breast cancer recurrence by diminishing the production of prostaglandins and VEGF. Forget et al. attempted to replicate these results in patients with breast cancer at high risk of recurrence (triple negative, neutrophil/lymphocyte ratio ≥ 4) [63] in a prospective study [64] of 203 patients, without differences having been found between treatment groups.