Anesthesia and cancer recurrence

INTRODUCTION — The possibility that anesthetic drugs and techniques may influence the risk of cancer recurrence is of widespread importance to patients and the clinicians who care for them. The number of cancer cases increased by >25 percent globally between 2008 and 2018 [1,2], and nearly two-thirds of patients diagnosed with cancer will undergo anesthesia and surgery for intended cure or palliation as first-line treatment [3]. Thus, effects of anesthesia on cancer recurrence could have wide-ranging impact on population health.

This topic will discuss the effects of anesthetic drugs and techniques that have been reported in laboratory, animal, and human studies, the proposed mechanisms for such effects, the limitations of existing literature, and implications for anesthetic practice.

MECHANISMS OF METASTASIS — While surgery is often performed with curative intent, tumor resection is a risk factor for metastasis. The spread of tumor cells into the circulation can occur before, during, or after the procedure, allowing for distant organ metastasis [4]; minimal residual disease may remain and flourish even with clear resected surgical margins [5,6]; localized spread of disease can occur within a body cavity; and tumor emboli can spread via the lymphatic system.

Metastasis occurs when cancer cells are able to evade the immune system, proliferate, and invade tissues. The surgical period creates a tumorigenic physiologic environment, with potential for both direct and indirect effects on tumor cell survival. Multiple perioperative factors combine to create a state of relative immunosuppression, including the surgical stress response, the inflammatory response to surgery, and direct effects of anesthetics, opioids, and other perioperative medications. Hypothermia and blood transfusion can also suppress immune function. (See "Perioperative temperature management", section on 'Infection'.)

●The physiologic stress response to surgery causes relative immunosuppression through the release of hormonal mediators (eg, catecholamines, prostaglandins, and growth factors) [7]. Prostaglandins and catecholamines can cause activation of receptors that may increase the metastatic ability of cancer cells (eg, B2-adrenergic [8] and cyclooxygenase-2 receptors [9]).

●Inflammation associated with tissue trauma causes the release of cytokines (eg, interleukin-6 and prostaglandins such as prostaglandin E2) that can cause inhibition of activity of natural killer (NK) cells [10]. NK cells are essential in the perioperative phase as they are responsible for detecting and destroying circulating tumor cells [11].

Overcoming tissue hypoxia is central to growth of solid organ tumors, and cancer cells have adapted several pathways to ensure survival [12]. Tissue hypoxia causes an upregulated expression of the transcription factor hypoxia-inducible factor 1-alpha (HIF1A), which is important in the promotion of cellular pathways for angiogenesis, cell proliferation, and metastasis [13]. HIF1A causes downstream expression of vascular endothelial growth factor (VEGF) [14], which in turn stimulates angiogenesis-promoting tumor growth [15] and can promote remodeling of lymphatic pathways, allowing cell metastasis [16]. High levels of HIF1A have been associated with poorer prognosis in a number of solid tumors [11].

The effects of anesthetics and anesthetic techniques on the mechanisms of metastasis are discussed in relevant sections below.

EFFECTS OF ANESTHESIA

State of the literature — Some laboratory and animal studies suggest an association between anesthetic drugs and techniques and the activity and survival of cancer cells, through changes in the immune response, modulation of the neuroendocrine stress response to surgery, or through effects on cancer cell signaling. However, high quality clinical outcome studies are few. Most existing clinical studies are retrospective; most prospective trials were initially designed to study outcomes other than cancer recurrence. However, several randomized trials have now been published [17-20].

Clinical trials of the effects of anesthetics on cancer are difficult to perform, as patients require a combination of anesthetic agents. In order to anaesthetize patients and provide analgesia, they are often managed with either inhalation agents and opioids, or propofol as the anesthetic agent and regional anesthesia as the analgesic agent. It would be difficult ethically to perform surgery without providing perioperative pain relief, or to perform surgery solely under regional anesthesia to separate out specific anesthetic modalities to study their effects.

Randomized trials — Several randomized trials have not found a beneficial effect of regional anesthesia techniques on cancer recurrence.  

●The first large randomized trial in this field compared two different anesthetic regimens for breast cancer surgery and was published in 2019 [18]. Approximately 2100 patients who underwent mastectomy or wide local excision with axillary dissection were randomly assigned to receive regional anesthesia/analgesia (paravertebral block with propofol sedation) or general anesthesia (sevoflurane with opioid analgesia). Cancer recurrence was similar between patients who received regional anesthesia versus general anesthesia (hazard ratio 0.97, 95% CI 0.74-1.28), occurring in 10 percent of patients in each group over a median follow-up of 36 months. Whether these results can be applied to patients who undergo other cancer surgeries, particularly more extensive or painful procedures, is unclear.

●In a follow-up analysis of data from a trial including over 1700 patients who underwent major abdominal or thoracic surgery and who were randomly assigned to epidural-general anesthesia versus general anesthesia alone with postoperative opioid analgesia, overall and recurrence free survival were similar in the two groups at over five year follow-up [19].  

●In a randomized trial including 400 patients who underwent video-assisted thoracoscopic surgery for lung cancer, recurrence free and overall survival were similar in patients who had general anesthesia with postoperative opioid analgesia, versus epidural-general anesthesia with postoperative epidural analgesia [20].

General anesthesia

Inhalation agents

●Volatile anesthetics — Laboratory studies have suggested some potential mechanisms whereby volatile anesthetics could enhance metastasis, including direct survival enhancing effects of volatile agents on cancer cells, and suppression of immune cell function and tumor cell killing [21-24]. However, the molecular mechanisms for such effects are incompletely understood, and there is conflicting evidence among the inhaled agents and among different cancer cell lines.

Volatile anesthetic agents (ie, isoflurane, sevoflurane, desflurane, halothane) also have proinflammatory effects [25].

Volatile agents may upregulate hypoxia-inducible factors, which may confer a cytoprotective effect for cancer cells perioperatively [11]. Isoflurane has been shown to upregulate hypoxia-inducible factor 1-alpha (HIF1A) and its downstream effectors in a prostate cell cancer line (PC3) in a dose-dependent manner [13]. Similarly, renal cell carcinoma (RCC4) cells exposed to isoflurane demonstrated upregulated levels of HIF1A and vascular endothelial growth factor (VEGF) [21]. In vitro studies of ovarian cancer cells found that exposure to isoflurane increased angiogenesis, cell proliferation, and migration associated with increased levels of insulin-like growth factor 1 and VEGF [26]. Other studies of ovarian cancer cell lines have demonstrated increased expression of genes related to metastasis after exposure to sevoflurane, desflurane, and isoflurane [27].

In contrast, some studies have suggested a protective effect of the volatile agents and variable results in different cancers. In one study, sevoflurane produced chemoresistance to cisplatin (a chemotherapeutic agent) in renal cell carcinoma cells; however, the opposite effect was seen in non-small cell lung cancer (NSCLC) cells [28]. In another study, sevoflurane suppressed proliferation of breast cancer cells through cell cycle arrest at the G1 phase [29].

A 2016 systematic review of a number of animal studies suggested a link between volatile anesthesia and the number and incidence of metastases in experimental models [30].

●Nitrous oxide — There are very little data on the effects of nitrous oxide on cancer recurrence. In a secondary analysis of a trial that compared outcomes in patients who received nitrous oxide or nitrogen during isoflurane/remifentanil anesthesia for colon resection, approximately 400 patients who had surgery for cancer were followed for four to eight years postoperatively [31]. There was no significant difference in cancer recurrence or mortality between groups.

Intravenous agents

Propofol — Propofol is the most commonly used intravenous induction agent and is often used for maintenance of anesthesia as well. Some preclinical evidence suggests that propofol may have antitumor effects. In laboratory studies, propofol exhibits antitumor effects by directly regulating key ribonucleic acid pathways and signaling in cancer cells [32]. Propofol also has antiinflammatory and antioxidative effects [33-38], which may protect against perioperative immune suppression.

In vitro studies have demonstrated a variety of antitumor effects of propofol in different cancer cell lines:

●In gastric cancer cell lines propofol has been found to inhibit cell proliferation, invasion, and migration [39].

●In NSCLC, propofol was found to disrupt upregulation of HIF1A, thereby reducing the migration and invasion of the cancer cells [40].

●In studies of breast cancer cell lines, propofol reduced the expression of neuroepithelial cell transforming gene 1 (which is associated with promoting migration of adenocarcinoma in vitro [41]), and increased cell apoptosis via the miR-24/p27 pathway [42].

●In endometrial and esophageal squamous cell carcinoma cells, propofol reduced expression of the sex-determining region Y-box (SOX4) gene [43,44], which is associated with poorer prognosis of some cancers [45].

In a study of the effects of anesthetics on natural killer (NK) cell activity and metastasis in a rat model of breast cancer, propofol did not suppress NK cell activity or increase metastasis, whereas halothane, ketamine, and thiopental did [46].

Perhaps a better live animal study used a murine allogenic model of breast cancer. This means that mouse breast cancer cells were cultured and inoculated into the breast tissue of another mouse to enable tumor to develop. These tumors were resected under the anaesthetic technique of interest. This “4T1” model involves injecting tumor cells from the same species, instead of injecting human breast cancer cells into a mouse or another animal, thereby avoiding the effect of a confounding immune response to non-species tissue. In this model, propofol reduced lung metastasis compared with sevoflurane and similarly to lidocaine [47]. (See 'Lidocaine' below.)

Other intravenous agents — Ketamine and thiopental both demonstrate immune altering abilities. Both agents have been found to suppress NK cell activity [48,49]. In a rat model, ketamine was found to induce tumour metastasis more effectively than other intravenous agents. The same study demonstrated an increase in metastasis while using thiopental, while propofol was protective [46]. Ketamine tested on a human breast cancer cell line was found to upregulate levels of an anti-apoptosis protein, potentially increasing the ability of cells to invade and proliferate [50].

Intravenous versus inhalation anesthetics — Clinical studies (mostly retrospective) comparing intravenous and inhalation agents have reported mixed results, with some showing a beneficial effect of total intravenous anesthesia (TIVA) and others showing no effect compared with inhaled anesthetics [51-60]. Proving a causal relationship between anesthetic technique and long-term oncologic outcomes requires large, prospective, randomized international trials, which are just starting to be done. (See 'State of the literature' above.)

●Survival – A 2019 meta-analysis of six studies (five retrospective, one small randomized controlled trial) including over 7800 patients who underwent surgery for breast cancer, esophageal cancer, or NSCLC found that the use of TIVA was associated with improved recurrence–free survival, compared with volatile anesthesia (pooled hazard ratio [HR] 0.78, 95% CI 0.65-0.94) [61]. However, interpretation of these results is limited by heterogeneity with respect to the extent of surgery, types of cancers, and patient characteristics, as well as other limitations associated with the retrospective nature of most of the studies. A subsequent retrospective Danish database analysis of over 8600 propensity matched patients undergoing surgery for colorectal cancer found an association between volatile anesthetic use and a small increase in cancer recurrence compared with TIVA with propofol (hazard ratio 1.12, 95% CI 1.02-1.13) [62]. There was no difference in overall survival.

●Circulating tumor cells – A randomized trial of 210 women who underwent breast cancer surgery reported similar circulating postoperative tumor cell counts in patients who received sevoflurane versus propofol anesthesia [63].

●Immune cells – In a randomized trial of 153 patients who underwent surgery for resection of colorectal cancer, the fractions of postoperative circulating natural killer cells, helper T cells, and cytotoxic T cells were similar in patients who had sevoflurane versus propofol for anesthesia propofol or sevoflurane anesthesia. [64].

●Cancer regulatory factors – In vivo studies of the effects of intravenous versus inhalation agents on cancer regulatory factors have reported conflicting results. A small study of pro-oncogenic gene expression in patients who underwent resection for head and neck cancer found that those who received volatile agents had significant increases in expression of HIF1A [65]. In contrast, another study of patients who underwent surgery for breast cancer reported no difference in expression of regulatory T cell enzymes that promote cancer recurrence in patients who received volatile versus intravenous anesthesia [66].

A number of studies have assessed the response of different cancer cell lines when exposed to serum from patients who have undergone either volatile anesthesia or combined regional and propofol anesthesia. In one such study, LoVo colon cancer cells were exposed to serum from 40 patients who underwent colon cancer resection with either a thoracic epidural/propofol technique or sevoflurane/opioid analgesia technique [67]. Serum from those receiving the regional and propofol technique inhibited the proliferation and invasion of incubated cancer cells and showed higher rates of cell apoptosis than those receiving volatile and opioid analgesia [67]. In another study, serum from women who underwent breast cancer resection using either propofol/paravertebral block anesthesia or sevoflurane/opioid anesthesia demonstrated a preservation of NK cell activity and increased cancer cell apoptosis in those who had propofol/paravertebral block [22,34].

Regional anesthesia/analgesia — The effects of regional anesthesia or analgesia on cancer recurrence seem to be equivalent to general anesthesia [17]. (See 'Randomized trials' above.)

Regional anesthesia/analgesia could reduce cancer recurrence via several mechanisms: by reducing the stress response to surgery (via pain control or sympathetic block) [68,69], by reducing the need for opioids or volatile agents, or via direct effects of absorbed local anesthetics (see 'Lidocaine' below). However, there is no high-quality evidence in humans that confirms a beneficial effect of regional anesthesia on cancer recurrence. The first large international randomized trial of regional anesthesia/propofol versus general anesthesia with sevoflurane/opioids found similar rates of recurrence after breast cancer surgery [18] and two other studies found a similar effect of epidural regional anesthesia compared with IV opioid [19,20](see 'State of the literature' above). Most other existing studies are retrospective or small, and meta-analyses include heterogeneous cancers, surgical technique, patient populations, and follow-up.

A 2014 meta-analysis with data from over 3000 patients found no associated difference in cancer recurrence or survival in patients who received general-epidural anesthesia versus general anesthesia alone [70]. Similarly, a 2017 meta-analysis of 28 studies (retrospective, observational, and randomized) including over 67,000 patients who underwent surgery for a variety of cancers found similar recurrence-free survival, overall survival, and biochemical recurrence-free survival in patients who had regional anesthesia with or without general anesthesia and those who had general anesthesia alone [71]. A meta-analysis of 10 retrospective studies including approximately 13,760 patients who underwent radical prostatectomy for cancer found that regional anesthesia with or without general anesthesia was associated with improved overall survival, but similar cancer recurrence, compared with general anesthesia alone [72]. A further meta-analysis has suggested that neuraxial anesthesia may be associated with improved overall survival, particularly in patients with colorectal cancer, as well as reduced risk of cancer recurrence [73].

As discussed in an earlier section, serum from patients undergoing surgery for breast cancer using either propofol and paravertebral regional technique or opioid and volatile technique was examined in a number of studies in terms of immune effect. Those receiving a combined regional and intravenous agent technique demonstrated increased levels of immune cell infiltration into breast cancer tissue, increased levels of cancer cell apoptosis, and preserved NK cell cytotoxicity [22,23,34].

EFFECTS OF ADJUVANT DRUGS ADMINISTERED DURING ANESTHESIA

Opioids — Laboratory studies suggest several mechanisms by which opioids might influence metastasis or tumor growth. However, the evidence is conflicting and inconsistent across opioids, and the limited clinical data on the effects of perioperative opioids are inconclusive. Examples of relevant studies and concepts are discussed here.

Preclinical evidence

●Preclinical studies have found that some but not all opioids have immunosuppressive properties, including reduced natural killer (NK) cell cytotoxicity and impairment of neutrophil chemotaxis [74,75]. Opioids may act directly on cells of the immune system (eg, lymphocytes and mononuclear phagocytes) through opioid receptors or via nonopioid receptors (eg, toll-like receptor 4) [76]. In a murine model of breast cancer, morphine stimulated mast cell activation, which may accelerate cancer progression, via increased concentrations of substance P and cytokines [77].

NK cells may also be affected by morphine. In a study of 80 patients who underwent resection of rectal cancer, administration of either morphine or oxycodone was associated with reduced serum counts of NK cells and T lymphocytes for 6 to 12 hours after opioid injection [78]. A small study of NK cell activity in the serum of women undergoing breast cancer surgery found reduced in vitro NK cell cytotoxicity in patients who received sevoflurane/opioid anesthesia, compared with those who received propofol with regional anesthesia [22]. In another study of the same patient cohort, patients who were randomly assigned to receive sevoflurane/opioid anesthesia had a higher postoperative neurophil-lymphocyte ratio (a marker of increased risk of recurrence and poor outcome) than patients who received propofol with regional anesthesia [79]. Similar to a number of other clinical trials, the effects of individual anesthetic agents cannot be determined (eg, sevoflurane versus opioids).

●Opioids can also interact with inflammatory cytokines (interleukin [IL] 1, IL-4, IL-6, and tumor necrosis factor), which control gene expression at the mu-opioid receptor (MOR) [80]. In pathologic samples of excised breast cancer tissue, those receiving a propofol and paravertebral anesthesia technique had more infiltration of NK cells and T helper cells than those who received a general anesthetic with opioid analgesia, suggesting that the opioid techniques may suppress immune activation [23].

●Opioids may directly influence cancer cell growth via their action on MOR [76,81,82], which are overexpressed on the surface of certain cancer cell lines [83-85]. In a study of biopsy specimens from 34 patients with lung cancer, MOR expression was increased twofold in patients with metastatic disease, compared with those without metastasis [84]. Overexpression of MOR has been associated with reduced overall survival and reduced progression-free survival in prostate cancer patients [86]. In a study of patients with breast cancer, those with a MOR gene polymorphism had decreased cancer-related mortality over 10 years [87].

Consistent with the role of the MOR in cancer progression, methylnaltrexone, a MOR antagonist, may have beneficial effects in halting cancer progression and metastasis. In a post hoc analysis of two randomized trials, patients with end stage cancer treated with methylnaltrexone for opioid induced constipation had improved overall survival, compared with patients who did not receive methylnaltrexone [88]. In a laboratory study of non-small cell lung cancer (NSCLC) cell lines, treatment with methylnaltrexone inhibited invasion of cancer cells [89].

●The effects of opioids on cancer cell biology are variable and conflicting among various opioids, and in some cases have been shown to be protective. In mouse models, morphine has been shown to have anti-tumor or antimetastatic effects in breast cancer [90-92]. Antitumor effects of D,L methadone have been reported in glioblastoma [93] and leukemia models [94].

Clinical studies: complex link between perioperative opioids and oncologic outcomes — Available evidence on the effect of intraoperative opioid use and long-term oncologic outcome is complex, conflicting, and limited to laboratory or observational studies. There is at present no justification for any change in perioperative opioid prescribing practice on the basis that it might affect cancer recurrence.

Clinical studies of the effects of intraoperative or postoperative opioids on cancer recurrence have reported conflicting results. Until recently, the prevailing trend in experimental and observational studies was that opioid use during cancer resection surgery was associated with negative oncologic outcomes. However, several retrospective database studies from the same institution suggest a potentially differential effect of opioids in cancer subtypes, which may also be applicable to other tumors [95,96]. In one of these studies, characteristics of resected breast cancer tissue were analyzed for over 1100 women with triple negative breast cancer (TNBC), which is notoriously difficult to treat if it recurs [95]. The investigators identified opioid receptor expression in the TNBC tumors and correlated it with clinical anesthesia management and oncologic outcomes. Higher intraoperative opioid dose was associated with improved recurrence free survival (hazard ratio [HR] 0.93, 95% CI 0.88-0.99, per 10 morphine milligram equivalent [MME] increase), but this was not significantly associated with improved overall survival.

Examples of other relevant studies include the following.

●Another retrospective study involving approximately 900 patients who underwent surgery for NSCLC found that higher intraoperative fentanyl doses were associated with reduced overall survival (OS) for patients with early stage cancer, but not for patients with more advanced cancer [97]. Yet another retrospective study including approximately 2800 patients who underwent surgery for renal cell carcinoma, higher intraoperative opioid administration was associated with reduced recurrence free survival (HR 1.06 per 10 MME, 95% CI 1.03-1.09), and reduced OS (HR 1.05 per 10 MME, 95% CI 1.02-1.09) [98].

●In contrast, in a retrospective study including approximately 1680 patients who underwent resection of colorectal cancer, the intraoperative dose of fentanyl was not associated with the risk of recurrence or overall survival [99]. Similarly, a retrospective study of postoperative opioid administration in 1000 patients who underwent surgery for NSCLC found that increasing opioid dose was not associated with an increase in the risk of recurrence or death [100].

●A 2018 systematic review of the literature regarding perioperative opioids and colorectal cancer recurrence included 13 studies, with inconclusive results [101]. Meta-analysis was not possible due to low quality data.

Lidocaine — Intravenous lidocaine is commonly administered during anesthesia as a component of multimodal analgesia. There is strong in vitro evidence of a protective effect of systemic lidocaine on cancer recurrence, though there are limited relevant clinical data.

Laboratory and human studies have demonstrated that local anesthetics have antiinflammatory properties [102]. Lidocaine has been shown to reduce levels of the inflammatory markers IL-1, tumor necrosis factor-alpha, and IL-8, in addition to direct effects on cancer cells via blockade of voltage-gated sodium channels on tumor cells or other mechanisms [103,104]. Lidocaine reduces cancer cell viability and migration in laboratory studies, and improved survival in the 4T1 allogeneic mouse model of breast cancer [105]. In these studies, intravenous lidocaine reduced the volume of lung metastasis when combined with volatile anesthesia [106], potentially mitigating the effects of volatile anesthesia. In another study using the same murine model, the addition of lidocaine to the chemotherapeutic agent cisplatin resulted in a reduction in metastatic lung colony counts compared with control or cisplatin alone [107].

Retrospective clinical studies suggest an association between intraoperative IV lidocaine and improved outcomes after cancer surgery, though conclusions are limited by their retrospective design and unknown surgical variables. (See 'State of the literature' above.)

Examples include the following:

●In a retrospective study of approximately 2000 patients who underwent surgery for pancreatic cancer, disease-free survival after surgery was similar in patients who received intraoperative lidocaine (bolus 1.5 mg/kg IV at induction, followed by infusion at 2 mg/kg/hour IV) and those who received no lidocaine [108]. Lidocaine infusion was associated with a modest increase in overall survival at one and three years (overall survival at one year, 68 versus 63 percent, overall survival at three years 34 versus 27 percent).

●In another retrospective study of 144 patients who underwent radical cystectomy for bladder cancer, intraoperative IV lidocaine was associated with reduced overall mortality (adjusted hazard ratio 0.36, 95% CI 0.12-0.83) and reduced incidence of cancer recurrence (30 versus 47 percent) within two years, compared with patients who did not receive lidocaine [109]. Lidocaine was administered as a bolus of 1 mg/kg IV followed by infusion at 1.5 mg/kg/hour IV, stopped one hour prior to the end of surgery.

The VAPOR-C trial is a large, international, randomized controlled trial which commenced in 2021 after promising pilot-feasibility studies [110]. This trial is comparing propofol versus sevoflurane general anesthesia, with or without IV lidocaine, in a 2x2 factorial design.

Nonsteroidal antiinflammatory drugs — Several retrospective studies suggest that intraoperative administration of nonsteroidal antiinflammatory drugs (NSAIDs) during cancer surgery may reduce recurrence and improve survival. A retrospective single institution study of 720 women who underwent breast lumpectomy with or without axillary node dissection for cancer found an association between intraoperative administration of ketorolac or diclofenac and longer disease-free and overall survival [111]. Similarly, a retrospective study of 327 women who underwent mastectomy with axillary lymph node dissection reported lower cancer recurrence rates in patients who received intraoperative ketorolac compared with those who received sufentanil, ketamine, or clonidine [112].

In one small prospective trial, 38 patients were randomly assigned to receive propranolol and etodolac or placebo for five days before and after lumpectomy or mastectomy for breast cancer [113]. Markers of cellular and molecular pathways associated with cancer recurrence were reduced in patients who received the drug combination.

Long term use of aspirin and other NSAIDs is associated with reduced incidence of death from colorectal and possibly some other cancers. The mechanisms for these benefits and supporting evidence are discussed in detail separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Factors that modify breast cancer risk in women", section on 'Nonsteroidal anti-inflammatory drugs'.)

Alpha-2 adrenoceptor agonists — Alpha-2 adrenoreceptors may play a role in the development of breast cancer. Dexmedetomidine is a selective alpha-2 adrenoceptor agonist that is increasingly used in the perioperative period, particularly in low doses for sedation. Low dose clonidine, which is an older alpha-2 receptor agonist, is used as part of multimodal opioid-sparing analgesia. The literature regarding dexmedetomidine and/or clonidine and cancer recurrence is limited, and further study is required before drawing conclusions on their use.

A retrospective single center study of 250 patients who underwent surgery for NSCLC reported that duration of recurrent-free survival was similar in patients who received intraoperative dexmedetomidine and those who did not, though dexmedetomidine was associated with reduced overall survival [114].

A laboratory study of the effect of dexmedetomidine in rat models of lung, breast, and colon cancer found a dose-dependent increase on tumor cell retention and metastasis, which is thought to be mediated through stimulation of the alpha-2 adrenoceptors [115].

In a retrospective study of approximately 650 patients who underwent surgery for breast or lung cancer, recurrence-free survival and overall survival were similar in patients who received low dose clonidine intraoperatively and those who did not receive clonidine [116].

Beta blockers — The benefits of perioperative beta blockers on cancer recurrence have not been determined. Beta blockers may be administered during surgery to counteract catecholamine-mediated effects of the stress response to surgery. Laboratory studies have reported anti-tumor effects of beta blockers, including reduced proliferation of liver cancer cells [117] and preserved NK cell function when combined with NSAIDs [118]. In a study of patients who underwent breast cancer surgery, perioperative administration of propranolol attenuated the surgery-related increase in regulatory T cells (which suppress antitumor immunity) [119].

The clinical studies of the effects of beta blockers on cancer recurrence are inconclusive. A 2018 meta-analysis of 27 mostly retrospective studies (10 perioperative, the remainder epidemiologic) found that cancer recurrence was similar in patients who received beta blockers and those who did not [120]. Beneficial effects were possible in some tumor types, but the overall quality of the data was low.

In a 2015 meta-analysis of seven cohort studies in patients with breast cancer, the use of beta blockers was associated with reduced risk of breast cancer-related death (hazard ratio [HR] 0.50, 95% CI, 0.32-0.80), but similar risk of cancer recurrence and all-cause mortality, compared with patients who did not use beta blockers [121].

Dexamethasone — Glucocorticoids have antiinflammatory effects, which could be beneficial with respect to cancer recurrence, but also have immune modulating effects, which could reduce cancer cell killing. Dexamethasone is widely administered during anesthesia for prevention of postoperative nausea and vomiting and as an adjunct for analgesia. There is insufficient evidence to support a change in this practice based on concern for cancer recurrence.

The existing limited laboratory and clinical evidence is conflicting. In a preclinical study involving several different cancer cell lines, dexamethasone was associated with increase proliferation of some solid tumor cell lines, but not others [122].

In retrospective studies of women who underwent cytoreductive surgery for ovarian cancer [123], and surgery for endometrial cancer [124], cancer recurrence was similar in patients who did and did not receive intraoperative dexamethasone (4 to 10 mg intravenous [IV]) [123]. In a retrospective study of patients who underwent surgery for NSCLC, intraoperative dexamethasone was associated with longer survival after surgery [125]. In contrast, in a retrospective study of approximately 500 patients who underwent surgery for rectal cancer, intraoperative dexamethasone was associated with shorter disease-free survival [126].

Glucocorticoids are also widely used for prevention of chemotherapy-induced nausea and vomiting and as adjuvant therapy for pain control in patients with known metastatic cancer, without concern for worsening disease. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Glucocorticoids'.)

Oxygen — The role of oxygen administration in postoperative cancer recurrence is unclear. Supplemental oxygen is routinely administered during anesthesia; the total amount of oxygen exposure during anesthesia should be limited, and fraction of inspired oxygen (FiO₂) of 0.3 to 0.4 should provide adequate oxygenation with a margin of safety for most patients. (See "Mechanical ventilation during anesthesia in adults", section on 'Fraction of inspired oxygen'.)

As discussed above, tissue hypoxia is involved in important mechanisms for angiogenesis and tumor progression (see 'Mechanisms of metastasis' above). However, hyperoxia may also facilitate proliferation of tumor cells via positive effects on angiogenesis [127] and the formation of reactive oxygen species that may damage DNA [128]. Such mechanisms are complex and have not been fully elucidated.

In vitro studies have reported that exposure to high concentration of oxygen can increase the migration and secretion of angiogenesis factors of breast cancer cells [129].

The effect of FiO₂ on the risk of new or recurrent cancer was investigated in a post hoc analysis of the PROXI trial, in which patients who underwent abdominal surgery (approximately one-half for cancer) were randomly assigned to receive 30 percent or 80 percent oxygen during and for two hours after surgery [130]. The overall frequency of new cancers was similar between groups. However, the time to diagnosis of a new cancer and cancer-free survival were shorter in patients who received 80 percent oxygen.

IMPLICATIONS FOR PRACTICE — There is evidence from laboratory, animal, and retrospective human studies that anesthetic agents may affect cancer recurrence. However, there is insufficient evidence to suggest a change in anesthetic practice or the use of specific agents for the purpose of reducing the risk of cancer recurrence in patients who undergo cancer surgery.

SUMMARY

●Whereas laboratory, animal, and retrospective human data suggest that anesthetic agents may affect cancer recurrence, there is insufficient evidence to suggest the use of specific anesthetic agents or techniques to reduce the risk of cancer recurrence in patients who undergo cancer surgery. (See 'Implications for practice' above.)

●The perioperative period is associated with multiple factors that may influence tumor cell survival, including the inflammatory and stress responses to surgery, relative immunosuppression, and possible direct effects of anesthetics, opioids, and other perioperative medications. (See 'Mechanisms of metastasis' above.)

●A body of laboratory and animal studies suggests an association between anesthetic drugs and techniques and the activity and survival of cancer cells. Most existing clinical studies are retrospective or were initially designed to study outcomes other than cancer recurrence, and are therefore inconclusive with respect to cancer recurrence. (See 'State of the literature' above.)

●Volatile anesthetics have proinflammatory effects, and may have direct and indirect effects on cancer cell survival, including immune suppression and upregulation of hypoxia-inducible factors (H1F1-A). However, the laboratory, animal, and human studies on cancer recurrence after the use of volatile agents are conflicting. (See 'Inhalation agents' above.)

●Propofol may have antiinflammatory and antioxidative effects that protect against immune suppression and may preserve natural killer (NK) cell activity. (See 'Propofol' above.)

●Clinical studies that have compared intravenous and inhalation anesthetic agents have shown mixed results regarding cancer recurrence. (See 'Intravenous versus inhalation anesthetics' above.)

●Regional anesthesia could reduce cancer recurrence by reducing the need for opioids or volatile anesthetics, or reducing the stress response to surgery. However, several randomized trials have not confirmed a beneficial effect. (See 'Randomized trials' above and 'Regional anesthesia/analgesia' above.)

●Laboratory studies suggest that opioids might influence metastasis or tumor growth. However, the evidence is conflicting and inconsistent across opioids, and the limited clinical data on the effects of perioperative opioids are inconclusive. (See 'Opioids' above.)

●There is strong in vitro evidence of a protective effect of systemic lidocaine on cancer recurrence, though there is limited relevant clinical data. (See 'Lidocaine' above.)