Abstract
Purpose
Tumour growth and the formation of metastases are essential elements in the progression of cancer. The centre of treatment is the surgical resection of primary solid tumours. But even if the tumour can be removed without microscopic residual cells, local recurrences and distant metastases occur and determine the patient’s fate. During the operation, tumour cells are shed from the primary tumour and released into the circulation. These circulating tumour cells might play an important role in the formation of new tumour sites. Therefore, a functional innate and adaptive immune system is essential, especially in this perioperative period. Anaesthesia influences consciousness and pain perception and interacts directly with the immune system and tumour cells.
Methods
Review of the current literature concerning intra- and postoperative anaesthetic decisions and tumour progression.
Results
There are beneficial aspects for patient survival associated with total intravenous anaesthesia, the use of regional anaesthetics and the avoidance of allogeneic red blood cell transfusions. Alternatives such as irradiated intraoperative blood salvage and preoperative iron supplementation may be advantageous in cases where transfusions are limited or not wanted. The immunosuppressive properties of opioids are theoretical, but strong evidence to avoid them does not exist. The application of nonsteroidal anti-inflammatory drugs and postoperative nausea and vomiting prophylaxis do not impair the patient’s survival and may even have a positive effect on tumour regression.
Conclusion
Anaesthesia does play an important part in the perioperative period in order to improve the cancer-related outcome. Further research is necessary to make more concrete recommendations.
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Anaesthesia as a part of perioperative medicine
The focus of modern medicine is to see the whole, individual patient. It is an interdisciplinary discussion, not only about the disease, but also about the health, physical abilities und social integrity of patients altogether. The numerous disciplines of medicine and the areas of current research interact on a daily basis to gain new insights for curative treatments, recovery plans, prevention and palliative care. The elements of anaesthesia, including narcosis, analgesia and generally perioperative care, are necessary to make many of these aims possible.
After centuries of developments and improvements in medical procedures, hygiene, infrastructure and technologies, cancer is now one of the biggest health challenges. For almost any type of solid tumour, the only curable treatment option is surgery. But chemotherapy, radiation, immunotherapy and other new strategies help to improve survival rates, recovery outcomes and quality of life. The operation of a tumour is probably the most critical part of this equation. The role of modern anaesthesia is not only to make these surgeries possible for almost everyone of all ages and general health conditions but also to influence the course of cancer outcome itself. Current research highlights the effects of anaesthesia on tumour cells, their microenvironment and the immune system. Therefore, a general influence of the anaesthetic technique, including the choice of narcotics, pain management, patient blood management, oxygen saturation and postoperative nausea and vomiting (PONV) prophylaxis, may be important to understand and probably alter the interaction between the tumour cells and the patient’s organism, thereby improving the outcome of treatment.
Choice of narcotics
In the past decades, scientists searched for new narcotics with increased potential and reduced side effects. Today, there are numerous substances to induce and maintain narcosis. The two most commonly used drugs are propofol and sevoflurane. Propofol is used for intravenous induction and maintenance of short procedures or to prevent severe cases of nausea and vomiting (total intravenous anaesthesia [TIVA]). Sevoflurane as an inhalational agent is a potent and cheap way to maintain narcosis, with additional benefits for patients with cardiovascular health issues or for children as an inhalational induction. If the procedure or the condition of the patient does not dictate the choice of narcotics, the anaesthesiologist decides based on his preferences. Today, the decision for either a total intravenous or a balanced anaesthesia in cancer surgery is in question in terms of the possible impact on outcome.
In vitro experiments with different types of cancer cells can detect direct and indirect antitumour effects of propofol. Some of the direct effects include inhibition of proliferation, migration and invasion and induction of apoptosis based on micro-RNA alterations (e.g. induction of miR-125a-5p, miRNA-133a, etc.) and an influence on signalling pathways such as the inhibition of mitogen-activated protein kinase (MAPK), nuclear factor ‘kappa-light-chain-enhancer’ of activated B cells (NF-κB) and hypoxia-inducible factor-1 alpha (HIF-1α) [1,2,3]. Contrarily, propofol was also found to activate nuclear factor erythroid 2-related factor 2 (Nrf2) in gallbladder cancer, which leads to an inhibition of apoptosis [1]. Indirectly, propofol interferes with tumour progress due to increasing chemosensitivity and maintaining immunological function. Increased chemosensitivity was found for trastuzumab in breast cancer [4], paclitaxel and cisplatin in ovarian cancer [5, 6] and gemcitabine in pancreatic cancer [7]. Propofol preserves the immunological function compared to sevoflurane, which suppressed functional T1-lymphocytes in human colorectal and cervical cancer [8, 9] (Fig. 1).
These findings could be supported by in vivo data showing, for example, a reduced rate of lung metastasis of breast cancer cells after a single treatment with propofol in mice [10]. However, another in vivo study showed a depletion of tumour-associated macrophages from the tumour microenvironment and an upregulation of the immune checkpoint programmed death ligand-1 (PD-L1) by sevoflurane in melanomas, indicating a possible positive effect of sevoflurane in combination with the checkpoint inhibitor programmed death-1(PD-1) [11].
Clinical data are required to prove that these hypotheses are valid in humans. There are many retrospective analyses that indicate a beneficial effect of propofol versus inhalational agents. A meta-analysis by Jin et al. in 2019 summarized twelve studies with a pooled hazard ratio for all-cause mortality of 0.73 [95% CI 0.60, 0.89] for TIVA. But divided in subgroups of cancer types, only a statistical analysis of breast and colorectal cancer could be conducted, showing a positive trend for TIVA in colorectal but not in breast cancer. The limitations of this data are numerous: for instance, a retrospective study design, lack of statistical power and no clear control of confounding factors [12]. However, a large cohort study (166 966 inhalational, 29 337 TIVA) in Japan found no difference in overall survival in terms of any digestive cancer surgery, but a slight improvement in recurrence-free survival for TIVA when instrumental variable analyses were performed (HR 0.92, 95% CI 0.87, 0.98 p = 0.01) [13].
Prospective studies to compare the outcome of cancer surgery are rare. One of the few completed studies showed a significant reduction of vascular endothelial growth factor (VEGF) release in breast cancer surgery for TIVA with a positive trend, but no significant difference in short-term survival [14] (Fig. 1). Another study measured a preserved natural killer cell cytotoxicity also in breast cancer surgery, which supports the hypothesis of an immunoprotective effect of propofol [15]. A follow-up of survival data needs to be awaited. A third prospective study compared a TIVA in combination with a paravertebral nerve block with sevoflurane both in addition to remifentanil intraoperatively and a sufentanil pump postoperatively in radical lung resection for non-small cell lung cancer (NSCLC). Using a TIVA in combination with a paravertebral nerve block could reduce the release of VEGF and transformation growth factor-β (TGF-β) and improve the analgesic coverage for patients. Again, the follow-up regarding mortality rates is not yet ready [16]. A large (n = 2108) randomized controlled multicentre trial compared recurrence rates (7-year follow-up) after curative resection of breast cancer and found no difference between a paravertebral block in combination with propofol and general anaesthesia with sevoflurane and opioids [17] (Table 1).
The existing evidence is conflicting. On the one hand, experimental and many retrospective studies favour a propofol-based total intravenous anaesthesia to improve the outcome of surgery on certain cancer types such as colorectal cancer. On the other hand, for cancer types such as breast cancer, the choice of narcotics seems irrelevant. On this basis, no concrete recommendations can be made and prospective studies with a sufficient number of cases and long-term follow-up for other cancer types must be conducted.
Pain management
Analgesia is an important factor in maintaining narcosis during a surgical procedure. But in cancer patients, pain is not only caused by wound healing but derives from the cancer itself. Therefore, pain treatment is also an issue before and after the surgery. Pain not only affects the physical and mental state of the patient but also alters the inflammatory and immunological responses of the body. According to the World Health Organization (WHO) cancer pain ladder, cancer pain treatment begins with nonopioids, followed by mild and severe opioids until the patient is pain free. There are numerous drugs within these categories with different potential to alleviate pain but also different effects towards tumour progression. For the perioperative period, modern anaesthesia also provides regional anaesthetic techniques such as an epidural catheter or nerve blocks with the potential not only to eliminate pain but also to improve cancer outcome.
NSAIDs
Although nonopioids, such as nonsteroidal anti-inflammatory drugs (NSAIDs), have a relatively low potential for pain relief caused by cancer or surgical incisions [18], there could be favourable side effects regarding cancer progression. A state of chronic inflammation can, on the one hand, contribute to the development of the tumour and, on the other hand, can be caused by the tumour and its micromilieu to create an environment that stimulates immunosuppression and evasion, as well as the proliferation of cancer cells [19]. NSAIDs, especially aspirin, have been shown to be a preventive factor in the development of various cancer entities [20]. A cyclooxygenase (COX) inhibition leads to anti-inflammatory effects, an enhancement in the immune response [21] and a platelet aggregation inhibition, which is important for the mechanism of forming metastases [22].
A phase II randomized controlled trial (RCT) showed an improvement in metastatic biomarkers of breast cancer after the implementation of propranolol and etodolac as a COX-2 inhibitor for 11 days perioperatively [23]. Another randomized study measured the apoptotic rate in squamous cell carcinoma cells of the oesophagus in patients who either received the COX-2 inhibitor meloxicam 2 weeks prior to surgery or not. They found a significant increase in apoptotic cells in the resected tumour tissue of patients receiving meloxicam (6.2% vs. 1.2%, p = 0.0005) [24]. In further randomized controlled trials, celecoxib was effective in preventing colorectal adenoma recurrence [25] and rofecoxib inhibited angiogenesis in colorectal cancer liver metastasis [26].
There is one prospective, randomized controlled trial evaluating the postoperative recurrence rate 45 months after rectal cancer surgery. Celecoxib was compared to a placebo and reduced postoperative inflammation, but did not affect recurrence [27] (Table 1).
The possible anticancer benefits of a perioperative NSAID use are theoretical so far. There is no evidence yet to improve survival or recurrence rates, so the use of NSAIDs should be limited to pain therapy at this time.
Opioids
Opioid receptors are not only expressed in the central nervous system to regulate pain perception but also occur on immune [28] and tumour cells [29]. Therefore, the effects of opioids on immune and tumour cells were investigated. It has been shown that different opioids alter the natural killer cell cytotoxicity (NKCC) in different manners. For example, it was reduced by morphine and fentanyl, increased by tramadol and buprenorphine did not affect it. This was shown in vivo and in patients undergoing surgery [30]. Other immune functions affected by opioids include T cell proliferation, cytokine and antibody production and phagocytosis [31] (Fig. 1). On the tumour cells themselves, a μ-receptor activation leads to a phosphorylation of the epidermal growth factor receptor, resulting in an induced proliferation and invasion [32]. In line with this, naltrexone, as a μ-receptor inhibitor, was able to suppress DNA synthesis and reduce the number of tumour cells and angiogenesis in vivo [33]. A special interest aroused for methadone, which was found to increase apoptosis and chemosensitivity of leukaemia and glioblastoma cells in vitro and in vivo via a cyclic adenosine monophosphate (cAMP) reduction, which leads to a caspase activation [34, 35]. However, these preclinical findings have not been translated into well-designed clinical studies yet, and the adverse effects of methadone, especially in patients without pain, should be considered with caution [36].
The clinical data to assess the effects of opioids themselves on cancer progression are limited. Especially intraoperatively, multiple factors influence each other, the immune response and the tumour cells themselves. A comparison between local anaesthesia and opioids may provide clues as to which technique is beneficial, but it does not determine whether it is a reduction in negative side effects by avoiding opioids or a positive influence of local anaesthetics.
Interestingly, one study on the intraoperative dose of opioids showed significantly improved overall and recurrence-free survival in patients receiving a high dose (> 710 μg fentanyl equivalent) during the resection of squamous carcinoma of the oesophagus [37]. In other cancer types, such as oral or colorectal cancer, the intraoperatively administered opioid dose was not significantly associated with the overall or recurrence-free survival [38] or the reviewed amount of data was inconclusive [39].
The analyses of postoperatively administered opioids have fewer confounding factors, but the subject is not feasible for a prospective design. A retrospective analysis found no correlation between the total amount of consumed opioids after curative lung cancer resection and long-term survival or recurrence rates [40]. Similar results were found in two large cohort studies on postoperative chronic opiate use after breast cancer surgery [41, 42]. However, a further retrospective study of a single centre showed a significant reduction in overall survival. They compared no opioid use at all after lung cancer resection with any kind of usage [43].
Although the experimental evidence on cancer-promoting effects of opioids exists, the definite clinical verification is still lacking. Data on both intraoperative and postoperative opioid administration are inconclusive. Randomized controlled trials on whether opioids should be obtained intraoperatively or not are not practicable. Therefore, large cohort studies are the best evidence so far that the dose and choice of opioids does not worsen the cancer-related outcome of surgery.
Local anaesthesia
Regional anaesthetic techniques are used either to avoid general anaesthesia (e.g. spinal anaesthesia, brachial plexus, distal ischiatic or femoral nerve block) or to complement perioperative pain therapy (e.g. epidural pain catheter, paravertebral block, nerve catheters or intraoperative intravenous lidocaine infusion). On the one hand, an opioid sparing effect could positively affect tumour progression; on the other hand, the anti-inflammatory and anti-adrenergic effects of local anaesthetics could play a relevant role. The most frequently discussed is the use of an epidural pain catheter in that matter.
Epidural anaesthesia
An immunoprotective effect of epidural anaesthesia in comparison to general anaesthesia was first described in 1980 [44]. The first retrospective studies evaluating the potential benefits for overall survival appeared more than 20 years later [45, 46] and aroused an increased interest in the subject. A meta-analysis in 2013 included fourteen studies, both retrospective and prospective, and found no association between cancer recurrence and epidural anaesthesia, but an advantage in overall survival, especially in colorectal cancer [47]. Focusing on colorectal cancer, a retrospective single-centre study showed an improved 5-year survival from 54 to 62% (p = 0.001) in patients with an additional epidural catheter [48]. A systematic meta-analysis with five studies concerning colorectal cancer without metastasis confirmed a positive association: HR 0.81 (95% CI 0.68–0.96, p = 0.055) [49]. Another study described the same benefits for prostate cancer, but not for colorectal or other cancer types [50]. Although there are many studies, including meta-analysis and systematic reviews, the results are conflicting, and a variety of limitations and bias apply.
A meta-analysis of only randomized controlled trials (RCTs) with mortality as the primary or secondary endpoint (n = 2201) showed an improvement in mortality rates from 4.9 to 3.1%. Further benefits for postoperative morbidities such as PONV, respiratory or cardiac complications have been shown [51]. In contrast, one of the recent randomized controlled trials showed an improvement in cellular immunity (cluster of differentiation (CD)3+, CD4+, CD4+/8+ T cells), but no difference in 3-year overall survival in gallbladder cancer [52] (Table 1).
Regarding cellular mechanisms, a prospective randomized analysis of tumour-infiltrating lymphocytes in adenocarcinoma of the lung showed an increased CD8+ lymphocyte subset and a decrease in regulatory T cells in the histology of resected tumours in patients with a combined anaesthesia (general + epidural) in comparison to general anaesthesia alone [53] (Fig. 1). Accordingly, a combined anaesthesia seems to reduce the body’s inflammatory response [interleukin (IL)-1, interleukin-8, c-reactive protein (CRP), tumour necrosis factor (TNF)α] following surgery and has a trend towards an improved recurrence-free survival in NSCLC (15 vs. 23 months, p = 0.08) [54] (Table 1). Similar results are shown in gastric cancer. Epidural anaesthesia preserves CD3+ cells, limits the release of IL-4 and IL-6 and increases the release of interferon (INF)-γ [55]. Two RCTs evaluate the effect of an epidural anaesthesia in combination with a TIVA for oesophagectomy vs. TIVA and intravenous opioids. Both revealed a reduced stress response with the use of an epidural anaesthesia [55, 56]. In detail, a reduction of IL-6, norepinephrine, cortisol, and adrenocorticotropic hormone (ACTH) was shown in combination with a higher secretion of IL-10, 3 h after surgery [57]. These results could not be confirmed in colorectal cancer [58].
In the past, many studies have been conducted with contradictory results. If we give more weight to the prospective randomized controlled trials, the evidence supports the use of epidural anaesthesia to increase overall survival. New studies show a preserved immune function during the critical perioperative period, which is approaching an explanation for the beneficial effects of epidural anaesthesia in some cancer types.
Intravenous lidocaine
Local anaesthetics, if administered epidurally, are partially absorbed into the blood. In this, they reach concentrations of 1–10 μM. As a substitute for epidural anaesthesia, the continuous application of intravenous lidocaine was therefore perioperatively investigated [59]. It has been shown that this can reduce opioid consumption and also positively influences PONV and the restoration of intestinal peristalsis after major abdominal, urological or gynaecological interventions.
This concentration of local anaesthetics is delivered into the blood flow of the tumour as well. In vitro data showed a dose-dependent antiproliferative effect of local anaesthetics on various cancer types. For example, an inhibition of migration, invasion and progression of colorectal cancer cells in vitro for lidocaine (10 μM), ropivacaine (10 μM) [60] and bupivacaine (1 mM) [61] was found. Similar results have been found in gastric cancer. Low concentrations of bupivacaine (10 μM) reduced the migration of gastric cancer cells, while high concentrations (1 mM) also increased apoptosis [62].
In vivo lidocaine (1.5 mg/kg bolus + 2 mg/kg/h) in combination with a sevoflurane narcosis significantly reduced lung metastasis of breast cancer in mice. This effect did not appear in combination with a ketamine-xylazine narcosis [63].
A retrospective analysis of intraoperative intravenous lidocaine infusion in pancreatic surgery (n = 915 in each group) revealed an improvement in overall survival after 1 (68% vs 62.6%, p < 0.001) and 3 years (34.1 vs 27.2%, p = 0.011) [64]. A prospective RCT identified a reduction of myeloperoxidase, histone H3 and matrix metalloproteinase MMP3 via intraoperative intravenous lidocaine infusion during breast cancer surgery. These findings support the hypothesis of an anti-metastatic effect of lidocaine [65].
The current evidence supports the use of intraoperative intravenous lidocaine infusions as a supplement in pain therapy when epidural anaesthesia is not possible or wanted. In addition, the hypothesis of an anticancer effect of lidocaine has been formulated but benefits in terms of survival and recurrence rates have yet to be demonstrated in prospective randomized controlled trials.
Patient blood management
Cancer is a consuming disease that often results in a state of cachexia, malnutrition and anaemia. Some of the curative operations cause high blood loss, which urges the anaesthesiologist to replace the losses with red blood cell transfusions to maintain a functioning cardiovascular system. It is well known that allogeneic red blood cell transfusions are negatively associated with the tumour outcome, with the need to investigate the alternatives. Especially in orthopaedic surgery, it is well established to optimize haemoglobin levels through preoperative iron supplementation and the intraoperative use of cell saving systems. In cancer surgery, the fear occurs to enhance tumour growth via iron supplementation [66] or erythropoietin and re-transfuse circulating tumour cells via cell salvage [67]. The actual evidence for these concerns is limited and therefore needs to be reassessed as tumour patients could benefit from these alternatives to avoid allogeneic transfusions.
Transfusions
There are meta-analyses (mostly retrospective data) concerning the impact of allogeneic blood transfusions on cancer outcome for almost all main tumour entities. To name a few, the odds ratio for all-cause mortality in gastric cancer is 2.17 [95% CI 1.72, 2.74, p < 0.001] when allogeneic blood transfusions were received [68]. For hepatocellular carcinoma, the risk ratio for mortality decreases continually from 0.9 [95% CI 0.87, 0.93, p < 0.05] after 1 year to 0.62 [95% CI 0.48, 0.8, p < 0.05] after 10 years if no blood transfusions were given [69]. Similar results in prostate cancer, where a hazard ratio of 1.43 [95% CI 1.24, 1.64, p < 0.01] for overall survival and even 1.74 [95% CI 1.18, 2.56, p = 0.005] for cancer specific survival was evaluated [70].
It has also been shown that the amount of transfusions is relevant for the prognosis of cancer outcome. A meta-analysis of ampullary cancer, operated as a pancreaticoduodenectomy, identified a threshold of ≥ 3 units of blood to be associated with a worse outcome than < 3 units or no transfusion [71]. A similar threshold of 800 ml was found in the above-mentioned study on gastric cancer [68].
The safety of blood salvage in cancer patients has been under review for over a decade now. There are experimental and small clinical studies that indicate that no increased recurrence or mortality rates occur from cell salvage when a leuco-reduction filter is used [72]. A meta-analysis comparing intraoperative blood salvage and allogeneic blood transfusion in malignant diseases in general revealed no difference regarding overall survival or recurrence rate [73] (Table 1). The German cross-sectional guidelines for hemotherapy recommend an autotransfusion of saved wound blood for tumour patients after a radiation with 50 Gray [74].
In conclusion, allogeneic blood transfusions should be avoided or limited as much as possible. There is currently no evidence that intraoperative blood salvage should be preferred over transfusions in cancer surgery, but it has been proven to be a safe alternative if allogeneic transfusions are either rejected by the patient or limited in their availability due to rare blood types or transfusion-related antibodies.
Iron supplementation
The exact prevalence of a total or functional iron deficiency causing anaemia varies between the different tumour types but concerns on average 36% and is a constant distress towards the physical abilities and quality of life of cancer patients [75]. In mild cases of anaemia, oral supplementation can be considered whereas in moderate or severe cases, the intestinal uptake of iron is so impaired that intravenous supplementation is necessary [76]. Although the haemoglobin levels and consequently the quality of life and fitness of different cancer patients could be improved especially by intravenous iron supplementation, the usage is small [77]. A systemic review in 2015 evaluated seven studies concerning the efficiency of preoperative iron supplementation to treat cancer specific anaemia. They found a reduction of allogeneic blood transfusions in all studies [78]. After that, studies with both conclusions were conducted but only concerning colorectal surgery. Mostly retrospective studies found a reduction of transfusions [79, 80], whereas a randomized controlled trial could not find any difference in the transfusion rate after oral or intravenous iron supplementation [81]. A prospective multicentre observational trial included all kinds of surgical patients and screened them for anaemia and iron deficiency. Iron supplementation was given intravenously in iron deficiency, with or without anaemia, 1, 2 or more than 2 weeks prior to surgery. Red blood cell transfusions could be reduced postoperatively in all patients, but only intraoperatively in those patients who received the infusion more than a week before surgery [82].
Experimental studies proved the important role of iron in the cell cycle, angiogenesis and formation of metastasis founding the hypothesis of a pro-oncotic effect of iron [67]. Contrarily, a high iron load in the tumour environment of non-small cell lung cancer tissue was associated with an increased M1 polarization of tumour-associated macrophages (TAM). TAMs are either polarized towards a pro-inflammatory type M1, or a type M2 associated with suppressing immune activity and promoting proliferation and angiogenesis [83]. Therefore, an increase in M1 macrophages leads to an increased pro-inflammatory environment and thus a survival benefit in patients with high iron levels in adenocarcinomas: HR 0.298 (95% CI 0.112; 0.790 p = 0.015) [84].
Epidemiological studies show conflicting results regarding a correlation between iron levels and carcinogenesis. An observational study on multiple myeloma identifies an iron overload as well as an iron deficiency as a factor for a worsened overall and recurrence-free survival [85]. There is one retrospective cohort study showing no decrease of the 5-year overall survival or progression-free survival by a preoperative intravenous iron supplementation of 1000–2000 mg in colorectal cancer patients undergoing radical resection [86].
In summary, the experimental and clinical data about the relevance of a preoperative iron substitution to treat anaemia is conflicting. Although a cancer-promoting effect of iron exists in some experimental studies, there are also data supporting a beneficial effect of a positive iron status at least for pulmonary adenocarcinoma. There is still no clinical evidence that a preoperative iron supplementation negatively affects survival or progression of cancer. However, since there is mixed evidence about the ability of iron supplementation to reduce allogeneic blood transfusions, it cannot be recommended to expend the preoperative substitution of iron in general. But this alternative could again be relevant for people who refuse blood transfusions or cannot receive them for other reasons.
Intraoperative oxygen application
There are numerous studies evaluating the intraoperative fraction of inspired oxygen (FiO2) regarding surgical site infections, wound healing and anastomotic insufficiencies or respiratory complications. But the data on an association towards tumour progression is limited. On the one hand, tumours are faced with hypoxia due to a poor vascularization. The tumour cells and their microenvironment are adapted to this niche with an enhanced production of growth mediators. On the other hand, high oxygen levels are associated with angiogenesis, erythropoietin production and oxidative stress, all factors also in favour of the tumour.
Experimental studies implied a tumour-suppressive effect of hyperbaric oxygen [87] and, also, normobaric hyperoxia via increased apoptosis rate of tumour cells in vitro and in vivo [88].
One clinical study, the PROXI trial, compared a FiO2 of 80% vs. 30% intraoperatively and 2 h postoperatively for abdominal surgery and originally evaluated that there is no difference in surgical site infections, but a higher 30-day mortality with 80% FiO2. There is a follow-up regarding the mortality rate after a medium of 2.3 years, showing a higher mortality for 80% FiO2 (23.2% vs. 18.3%), only significant in cancer patients (HR 1.45, p = 0.009) [89].
In summary, there are contradictory results from experimental and clinical studies that suggest that an elevated intraoperative oxygen fraction should be used with caution until further research has been carried out. Until then, a FiO2 around 30% should be preferred.
PONV prophylaxis
Postoperative nausea and vomiting (PONV) occur with an incidence of 20–40% after general anaesthesia and cause a high level of distress in many patients [90]. There are standard protocols to prevent or limit the severity of PONV, including an intraoperative application of 0.1 mg/(kg bodyweight) dexamethasone and 10 μg/(kg bodyweight) granisetron. It is known that glucocorticoids such as dexamethasone inhibit the immune system, raise blood glucose levels and have anti-inflammatory effects, thus promoting further tumour growth.
There are three retrospective studies that evaluate whether there is any correlation between a single dose of dexamethasone intraoperatively and a worsened tumour outcome. These studies included breast, colorectal and pancreatic cancer, and none could find a negative impact of a single dose of dexamethasone on mortality or recurrence. On the contrary, positive effects like a reduced rate of infectious complications and systemic inflammatory reactions were described in colorectal and pancreatic surgery [91,92,93].
In respect of these results, the standard PONV prophylaxis should be used on cancer patients at increased risk of developing nausea and vomiting.
Conclusion
The operation of a malignant tumour is a critical part to determine the long-term outcome of cancer patients. Besides the resection of the primary tumour, any alterations in the immunological abilities of the body to destroy remaining local and circulating tumour cells as well as direct influences of anaesthetics on these cells should be considered. Perioperative choices in anaesthesia include inhalational vs. intravenous narcotics, the application of different opioids and peripheral analgesics like NSAIDs, the addition of regional anaesthesia during surgery, patient blood management, the intraoperative oxygen application and the supplementation of dexamethasone to prevent nausea and vomiting.
The choice of narcotics might play a role in certain types of cancer. Propofol has direct antiproliferative effects on the tumour cells and preserves the immunological function and enhances chemosensitivity in vitro and in vivo as indirect effects on cancer progression. In patients undergoing surgery, a reduction of VEGF and TGF-β was found as possible mechanisms to diminish tumour growth. Propofol with its anti-inflammatory abilities might be superior to inhalational agents regarding the survival of, e.g. colorectal or lung cancer patients. It does not show these beneficial effects in breast cancer. More prospective randomized trials are ongoing. Hopefully, their results can lead to more definite recommendations in this topic.
Concerning cancer pain management, NSAIDs have anti-inflammatory and anti-thrombogenic properties which proved to be an advantage in the primary prevention of tumours, especially colorectal. Their role in the perioperative period and therefore in the secondary prevention of recurrence is understudied and needs further investigation. Opioids as the next step in pain therapy interact with the patient’s immune system. Opioids like fentanyl and morphine inhibit the natural killer cell cytotoxicity, whereas tramadol improves it. A direct induction of proliferative signalling pathways via the μ-receptor might influence tumour growth and survival. But clinical studies cannot prove a negative impact of intraoperative or postoperative opioid doses on the survival. Therefore, opioids remain the substantial foundation of cancer pain therapy.
Epidurally and intravenously administered local anaesthetics have favourable effects on overall survival of cancer patients. They have been shown to induce tumour-infiltrating cytotoxic (CD8+) lymphocytes and inhibit tumour-promoting regulatory T cells. Also, the immune components in the blood are changed towards an enhanced activation of the adapted immune system (CD3+, CD4+, CD8+) and a reduced systemic inflammatory reaction (reduction of Il-1, Il-4, Il-6, Il-8, TNFα, CRP; increased release of Il-10, INFγ) and stress response (reduced cortisol and norepinephrine levels). Procedures with a high amount of postoperative pain like open pancreatic or liver surgery should be covered with additional epidural pain catheters, whereas patients with shorter and less painful procedures can profit from intravenous lidocaine infusion as an alternative.
Allogeneic blood transfusions should be avoided or used as little as possible as transfusions were shown to significantly worsen the overall survival of cancer patients throughout the different types of cancer. Additionally, to no transfusions at all, a threshold of 3 units or 800 ml of transfusions was identified as a prognostic marker for the outcome. Preoperative iron supplementation or irradiated intraoperative cell salvage is an alternative in specific cases.
Intraoperative oxygen application should be limited to assure a normal partial pressure of oxygen in arterial blood (PaO2) and oxygen saturation (SpO2). Contradictory to experimental results, a higher oxygen fraction (e.g. 80%) was associated with an increased 30-day and long-term mortality in cancer surgery.
Dexamethasone as an intraoperative single shot is considered a safe method to prevent postoperative nausea and vomiting.
Considering the numerous effects and interactions from anaesthetic agents with the tumour environment and the immunological function, anaesthesia is an important influence in tumour progression. Further research is necessary to formulate recommendations specific for the different tumour entities.
Data availability
The data that support the findings of this study are openly available in MEDLINE® at https://pubmed.ncbi.nlm.nih.gov/
References
Jiang S, Liu Y, Huang L, Zhang F, Kang R (2018) Effects of propofol on cancer development and chemotherapy: potential mechanisms. Eur J Pharmacol 831:46–51. https://doi.org/10.1016/j.ejphar.2018.04.009
Zeng J, Li YK, Quan FF, Zeng X, Chen CY, Zeng T, Zou J, Tong WJ (2020) Propofol-induced miR-125a-5p inhibits the proliferation and metastasis of ovarian cancer by suppressing LIN28B. Mol Med Rep 22(2):1507–1517. https://doi.org/10.3892/mmr.2020.11223
Xu Y, Pan S, Jiang W, Xue F, Zhu X (2020) Effects of propofol on the development of cancer in humans. Cell Prolif 53(8):e12867. https://doi.org/10.1111/cpr.12867
Tian D, Tian M, Ma ZM, Zhang LL, Cui YF, Li JL (2020) Anesthetic propofol epigenetically regulates breast cancer trastuzumab resistance through IL-6/miR-149-5p axis. Sci Rep 10(1):8858. https://doi.org/10.1038/s41598-020-65649-y
Wang P, Chen J, Mu LH, Du QH, Niu XH, Zhang MY (2013) Propofol inhibits invasion and enhances paclitaxel- induced apoptosis in ovarian cancer cells through the suppression of the transcription factor slug. Eur Rev Med Pharmacol Sci 17(13):1722–1729
Sun Y, Peng YB, Ye LL, Ma LX, Zou MY, Cheng ZG (2020) Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA-374a/forkhead box O1 signaling axis. Mol Med Rep 21(3):1471–1480. https://doi.org/10.3892/mmr.2020.10943
Du QH, Xu YB, Zhang MY, Yun P, He CY (2013) Propofol induces apoptosis and increases gemcitabine sensitivity in pancreatic cancer cells in vitro by inhibition of nuclear factor-κB activity. World J Gastroenterol 19(33):5485–5492. https://doi.org/10.3748/wjg.v19.i33.5485
Yu J, Han M, Geng J (2019) Influence of propofol intravenous anesthesia on hemorheology, haemodynamics and immune function of colorectal carcinoma patients undergoing radical resection. Pak J Med Sci 35(3):780–785. https://doi.org/10.12669/pjms.35.3.590
Liu S, Gu X, Zhu L, Wu G, Zhou H, Song Y, Wu C (2016) Effects of propofol and sevoflurane on perioperative immune response in patients undergoing laparoscopic radical hysterectomy for cervical cancer. Medicine (Baltimore) 95(49):e5479. https://doi.org/10.1097/md.0000000000005479
Freeman J, Crowley PD, Foley AG, Gallagher HC, Iwasaki M, Ma D, Buggy DJ (2019) Effect of perioperative lidocaine, propofol and steroids on pulmonary metastasis in a murine model of breast cancer surgery. Cancers (Basel) 11(5). https://doi.org/10.3390/cancers11050613
Sztwiertnia I, Schenz J, Bomans K, Schaack D, Ohnesorge J, Tamulyte S, Weigand MA, Uhle F (2020) Sevoflurane depletes macrophages from the melanoma microenvironment. PLoS One 15(5):e0233789. https://doi.org/10.1371/journal.pone.0233789
Jin Z, Li R, Liu J, Lin J (2019) Long-term prognosis after cancer surgery with inhalational anesthesia and total intravenous anesthesia: a systematic review and meta-analysis. Int J Physiol Pathophysiol Pharmacol 11(3):83–94
Makito K, Matsui H, Fushimi K, Yasunaga H (2020) Volatile versus total intravenous anesthesia for cancer prognosis in patients having digestive cancer surgery. Anesthesiology 133(4):764–773. https://doi.org/10.1097/aln.0000000000003440
Yan T, Zhang GH, Wang BN, Sun L, Zheng H (2018) Effects of propofol/remifentanil-based total intravenous anesthesia versus sevoflurane-based inhalational anesthesia on the release of VEGF-C and TGF-β and prognosis after breast cancer surgery: a prospective, randomized and controlled study. BMC Anesthesiol 18(1):131. https://doi.org/10.1186/s12871-018-0588-3
Cho JS, Lee MH, Kim SI, Park S, Park HS, Oh E, Lee JH, Koo BN (2017) The effects of perioperative anesthesia and analgesia on immune function in patients undergoing breast cancer resection: a prospective randomized study. Int J Med Sci 14(10):970–976. https://doi.org/10.7150/ijms.20064
Sen Y, Xiyang H, Yu H (2019) Effect of thoracic paraspinal block-propofol intravenous general anesthesia on VEGF and TGF-β in patients receiving radical resection of lung cancer. Medicine (Baltimore) 98(47):e18088. https://doi.org/10.1097/md.0000000000018088
Sessler DI, Pei L, Huang Y, Fleischmann E, Marhofer P, Kurz A, Mayers DB, Meyer-Treschan TA, Grady M, Tan EY, Ayad S, Mascha EJ, Buggy DJ (2019) Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial. Lancet 394(10211):1807–1815. https://doi.org/10.1016/s0140-6736(19)32313-x
van Helmond N, Steegers MA, Filippini-de Moor GP, Vissers KC, Wilder-Smith OH (2016) Hyperalgesia and persistent pain after breast cancer surgery: a prospective randomized controlled trial with perioperative COX-2 inhibition. PLoS One 11(12):e0166601. https://doi.org/10.1371/journal.pone.0166601
Todoric J, Antonucci L, Karin M (2016) Targeting inflammation in cancer prevention and therapy. Cancer Prev Res (Phila) 9(12):895–905. https://doi.org/10.1158/1940-6207.Capr-16-0209
Crusz SM, Balkwill FR (2015) Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol 12(10):584–596. https://doi.org/10.1038/nrclinonc.2015.105
Pennock ND, Martinson HA, Guo Q, Betts CB, Jindal S, Tsujikawa T, Coussens LM, Borges VF, Schedin P (2018) Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer. J Immunother Cancer 6(1):98. https://doi.org/10.1186/s40425-018-0406-y
Patrignani P, Patrono C (2018) Aspirin, platelet inhibition and cancer prevention. Platelets 29(8):779–785. https://doi.org/10.1080/09537104.2018.1492105
Shaashua L, Shabat-Simon M, Haldar R, Matzner P, Zmora O, Shabtai M, Sharon E, Allweis T, Barshack I, Hayman L, Arevalo J, Ma J, Horowitz M, Cole S, Ben-Eliyahu S (2017) Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin Cancer Res 23(16):4651–4661. https://doi.org/10.1158/1078-0432.Ccr-17-0152
Liu JF, Zhang SW, Jamieson GG, Zhu GJ, Wu TC, Zhu TN, Shan BE, Drew PA (2008) The effects of a COX-2 inhibitor meloxicam on squamous cell carcinoma of the esophagus in vivo. Int J Cancer 122(7):1639–1644. https://doi.org/10.1002/ijc.23288
Thompson PA, Ashbeck EL, Roe DJ, Fales L, Buckmeier J, Wang F, Bhattacharyya A, Hsu CH, Chow SH, Ahnen DJ, Boland CR, Heigh RI, Fay DE, Hamilton SR, Jacobs ET, Martinez EM, Alberts DS, Lance P (2016) Celecoxib for the prevention of colorectal adenomas: results of a suspended randomized controlled trial. J Natl Cancer Inst 108(12). https://doi.org/10.1093/jnci/djw151
Fenwick SW, Toogood GJ, Lodge JP, Hull MA (2003) The effect of the selective cyclooxygenase-2 inhibitor rofecoxib on human colorectal cancer liver metastases. Gastroenterology 125(3):716–729. https://doi.org/10.1016/s0016-5085(03)01061-8
Gan ZM, Wang XD, Lv DH, Liu D, Li L (2015) Perioperative immunomodulatory therapy does not decrease postoperative recurrence rate of rectal cancer. Nan Fang Yi Ke Da Xue Xue Bao 35(4):562–566
Chuang TK, Killam KF Jr, Chuang LF, Kung HF, Sheng WS, Chao CC, Yu L, Chuang RY (1995) Mu opioid receptor gene expression in immune cells. Biochem Biophys Res Commun 216(3):922–930. https://doi.org/10.1006/bbrc.1995.2709
Fichna J, Janecka A (2004) Opioid peptides in cancer. Cancer Metastasis Rev 23(3):351–366. https://doi.org/10.1023/B:CANC.0000031773.46458.63
Boland JW, Pockley AG (2018) Influence of opioids on immune function in patients with cancer pain: from bench to bedside. Br J Pharmacol 175(14):2726–2736. https://doi.org/10.1111/bph.13903
Odunayo A, Dodam JR, Kerl ME, DeClue AE (2010) Immunomodulatory effects of opioids. J Vet Emerg Crit Care (San Antonio) 20(4):376–385. https://doi.org/10.1111/j.1476-4431.2010.00561.x
Fujioka N, Nguyen J, Chen C, Li Y, Pasrija T, Niehans G, Johnson KN, Gupta V, Kratzke RA, Gupta K (2011) Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer. Anesth Analg 113(6):1353–1364. https://doi.org/10.1213/ANE.0b013e318232b35a
Li Z, You Y, Griffin N, Feng J, Shan F (2018) Low-dose naltrexone (LDN): a promising treatment in immune-related diseases and cancer therapy. Int Immunopharmacol 61:178–184. https://doi.org/10.1016/j.intimp.2018.05.020
Friesen C, Roscher M, Hormann I, Fichtner I, Alt A, Hilger RA, Debatin KM, Miltner E (2013) Cell death sensitization of leukemia cells by opioid receptor activation. Oncotarget 4(5):677–690. https://doi.org/10.18632/oncotarget.952
Friesen C, Hormann I, Roscher M, Fichtner I, Alt A, Hilger R, Debatin KM, Miltner E (2014) Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. Cell Cycle 13(10):1560–1570. https://doi.org/10.4161/cc.28493
Kreye G, Masel E, Hackner K, Stich B, Nauck F (2018) Methadone as anticancer treatment: hype, hope, or hazard?: a series of case reports and a short review of the current literature and recommendations of the societies. Wien Med Wochenschr 168:159–167. https://doi.org/10.1007/s10354-018-0623-5
Du KN, Feng L, Newhouse A, Mehta J, Lasala J, Mena GE, Hofstetter WL, Cata JP (2018) Effects of intraoperative opioid use on recurrence-free and overall survival in patients with esophageal adenocarcinoma and squamous cell carcinoma. Anesth Analg 127(1):210–216. https://doi.org/10.1213/ane.0000000000003428
Patino MA, Ramirez RE, Perez CA, Feng L, Kataria P, Myers J, Cata JP (2017) The impact of intraoperative opioid use on survival after oral cancer surgery. Oral Oncol 74:1–7. https://doi.org/10.1016/j.oraloncology.2017.09.006
Diaz-Cambronero O, Mazzinari G, Cata JP (2018) Perioperative opioids and colorectal cancer recurrence: a systematic review of the literature. Pain Manag 8(5):353–361. https://doi.org/10.2217/pmt-2018-0029
Oh TK, Jeon JH, Lee JM, Kim MS, Kim JH, Cho H, Kim SE, Eom W (2017) Investigation of opioid use and long-term oncologic outcomes for non-small cell lung cancer patients treated with surgery. PLoS One 12(7):e0181672. https://doi.org/10.1371/journal.pone.0181672
Boudreau DM, Chen L, Yu O, Bowles EJA, Chubak J (2019) Risk of second breast cancer events with chronic opioid use in breast cancer survivors. Pharmacoepidemiol Drug Saf 28(5):740–753. https://doi.org/10.1002/pds.4779
Cronin-Fenton DP, Heide-Jørgensen U, Ahern TP, Lash TL, Christiansen PM, Ejlertsen B, Sjøgren P, Kehlet H, Sørensen HT (2015) Opioids and breast cancer recurrence: a Danish population-based cohort study. Cancer 121(19):3507–3514. https://doi.org/10.1002/cncr.29532
Wang K, Qu X, Wang Y, Shen H, Liu Q, Du J (2015) Effect of mu agonists on long-term survival and recurrence in non-small cell lung cancer patients. Medicine (Baltimore) 94(33):e1333. https://doi.org/10.1097/md.0000000000001333
Rem J, Brandt MR, Kehlet H (1980) Prevention of postoperative lymphopenia and granulocytosis by epidural analgesia. Lancet 1(8163):283–284. https://doi.org/10.1016/s0140-6736(80)90780-1
Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ (2008) Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 109(2):180–187. https://doi.org/10.1097/ALN.0b013e31817f5b73
Tsui BC, Rashiq S, Schopflocher D, Murtha A, Broemling S, Pillay J, Finucane BT (2010) Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can J Anaesth 57(2):107–112. https://doi.org/10.1007/s12630-009-9214-7
Chen WK, Miao CH (2013) The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. PLoS One 8(2):e56540. https://doi.org/10.1371/journal.pone.0056540
Holler JP, Ahlbrandt J, Burkhardt E, Gruss M, Röhrig R, Knapheide J, Hecker A, Padberg W, Weigand MA (2013) Peridural analgesia may affect long-term survival in patients with colorectal cancer after surgery (PACO-RAS-Study): an analysis of a cancer registry. Ann Surg 258(6):989–993. https://doi.org/10.1097/SLA.0b013e3182915f61
Holler JP, Ahlbrandt J, Gruß M, Hecker A, Weigand MA, Padberg W, Röhrig R (2015) The effect of peridural analgesia on long-term survival after surgery in patients with colorectal cancer: a systematic meta-analysis. Chirurg 86(7):655–661. https://doi.org/10.1007/s00104-014-2891-y
Pei L, Tan G, Wang L, Guo W, Xiao B, Gao X, Wang L, Li H, Xu Z, Zhang X, Zhao J, Yi J, Huang Y (2014) Comparison of combined general-epidural anesthesia with general anesthesia effects on survival and cancer recurrence: a meta-analysis of retrospective and prospective studies. PLoS One 9(12):e114667. https://doi.org/10.1371/journal.pone.0114667
Pöpping DM, Elia N, Van Aken HK, Marret E, Schug SA, Kranke P, Wenk M, Tramèr MR (2014) Impact of epidural analgesia on mortality and morbidity after surgery: systematic review and meta-analysis of randomized controlled trials. Ann Surg 259(6):1056–1067. https://doi.org/10.1097/sla.0000000000000237
Zhu J, Zhang XR, Yang H (2017) Effects of combined epidural and general anesthesia on intraoperative hemodynamic responses, postoperative cellular immunity, and prognosis in patients with gallbladder cancer: a randomized controlled trial. Medicine (Baltimore) 96(10):e6137. https://doi.org/10.1097/md.0000000000006137
Li MH, Xu ZZ, Huang SM, Li T, Li XY, Wang DX (2018) Effect of combined epidural anaesthesia on tumor-infiltrating lymphocytes in lung adenocarcinoma: a prospective exploratory sub-analysis. Acta Anaesthesiol Scand 62(5):687–700. https://doi.org/10.1111/aas.13068
Pi J, Sun Y, Zhang Z, Wan C (2019) Combined anesthesia shows better curative effect and less perioperative neuroendocrine disorder than general anesthesia in early stage NSCLC patients. J Int Med Res 47(10):4743–4752. https://doi.org/10.1177/0300060519862102
Wang L, Liang S, Chen H, Xu Y, Wang Y (2019) The effects of epidural anaesthesia and analgesia on T lymphocytes differentiation markers and cytokines in patients after gastric cancer resection. BMC Anesthesiol 19(1):102. https://doi.org/10.1186/s12871-019-0778-7
Li Y, Dong H, Tan S, Qian Y, Jin W (2019) Effects of thoracic epidural anesthesia/analgesia on the stress response, pain relief, hospital stay, and treatment costs of patients with esophageal carcinoma undergoing thoracic surgery: a single-center, randomized controlled trial. Medicine (Baltimore) 98(7):e14362. https://doi.org/10.1097/md.0000000000014362
Wang J, Yin Y, Zhu Y, Xu P, Sun Z, Miao C, Zhong J (2019) Thoracic epidural anaesthesia and analgesia ameliorates surgery-induced stress response and postoperative pain in patients undergoing radical oesophagectomy. J Int Med Res 47(12):6160–6170. https://doi.org/10.1177/0300060519866943
Siekmann W, Eintrei C, Magnuson A, Sjölander A, Matthiessen P, Myrelid P, Gupta A (2017) Surgical and not analgesic technique affects postoperative inflammation following colorectal cancer surgery: a prospective, randomized study. Color Dis 19(6):O186–o195. https://doi.org/10.1111/codi.13643
Picardi S, Lirk P, Boeckh R, Hollmann MW (2015) Adjuvants in modern anesthesia - lidocaine. Anasthesiol Intensivmed Notfallmed Schmerzther 50(5):322–327. https://doi.org/10.1055/s-0041-102213
Baptista-Hon DT, Robertson FM, Robertson GB, Owen SJ, Rogers GW, Lydon EL, Lee NH, Hales TG (2014) Potent inhibition by ropivacaine of metastatic colon cancer SW620 cell invasion and NaV1.5 channel function. Br J Anaesth 113(Suppl 1):i39–i48. https://doi.org/10.1093/bja/aeu104
Li T, Chen L, Zhao H, Wu L, Masters J, Han C, Hirota K, Ma D (2019) Both bupivacaine and levobupivacaine inhibit colon cancer cell growth but not melanoma cells in vitro. J Anesth 33(1):17–25. https://doi.org/10.1007/s00540-018-2577-6
Dan J, Gong X, Li D, Zhu G, Wang L, Li F (2018) Inhibition of gastric cancer by local anesthetic bupivacaine through multiple mechanisms independent of sodium channel blockade. Biomed Pharmacother 103:823–828. https://doi.org/10.1016/j.biopha.2018.04.106
Johnson MZ, Crowley PD, Foley AG, Xue C, Connolly C, Gallagher HC, Buggy DJ (2018) Effect of perioperative lidocaine on metastasis after sevoflurane or ketamine-xylazine anaesthesia for breast tumour resection in a murine model. Br J Anaesth 121(1):76–85. https://doi.org/10.1016/j.bja.2017.12.043
Zhang H, Yang L, Zhu X, Zhu M, Sun Z, Cata JP, Chen W, Miao C (2020) Association between intraoperative intravenous lidocaine infusion and survival in patients undergoing pancreatectomy for pancreatic cancer: a retrospective study. Br J Anaesth 125(2):141–148. https://doi.org/10.1016/j.bja.2020.03.034
Galoș EV, Tat TF, Popa R, Efrimescu CI, Finnerty D, Buggy DJ, Ionescu DC, Mihu CM (2020) Neutrophil extracellular trapping and angiogenesis biomarkers after intravenous or inhalation anaesthesia with or without intravenous lidocaine for breast cancer surgery: a prospective, randomised trial. Br J Anaesth 125:712–721. https://doi.org/10.1016/j.bja.2020.05.003
Pfeifhofer-Obermair C, Tymoszuk P, Petzer V, Weiss G, Nairz M (2018) Iron in the tumor microenvironment-connecting the dots. Front Oncol 8:549. https://doi.org/10.3389/fonc.2018.00549
Fischer D, Neb H, Choorapoikayil S, Zacharowski K, Meybohm P (2019) Red blood cell transfusion and its alternatives in oncologic surgery-a critical evaluation. Crit Rev Oncol Hematol 134:1–9. https://doi.org/10.1016/j.critrevonc.2018.11.011
Sun C, Wang Y, Yao HS, Hu ZQ (2015) Allogeneic blood transfusion and the prognosis of gastric cancer patients: systematic review and meta-analysis. Int J Surg 13:102–110. https://doi.org/10.1016/j.ijsu.2014.11.044
Xun Y, Tian H, Hu L, Yan P, Yang K, Guo T (2018) The impact of perioperative allogeneic blood transfusion on prognosis of hepatocellular carcinoma after radical hepatectomy: a systematic review and meta-analysis of cohort studies. Medicine (Baltimore) 97(43):e12911. https://doi.org/10.1097/md.0000000000012911
Li SL, Ye Y, Yuan XH (2017) Association between allogeneic or autologous blood transfusion and survival in patients after radical prostatectomy: a systematic review and meta-analysis. PLoS One 12(1):e0171081. https://doi.org/10.1371/journal.pone.0171081
Yao HS, Wang Q, Wang WJ, Hu ZQ (2008) Intraoperative allogeneic red blood cell transfusion in ampullary cancer outcome after curative pancreatoduodenectomy: a clinical study and meta-analysis. World J Surg 32(9):2038–2046. https://doi.org/10.1007/s00268-008-9675-9
Trudeau JD, Waters T, Chipperfield K (2012) Should intraoperative cell-salvaged blood be used in patients with suspected or known malignancy? Can J Anaesth 59(11):1058–1070. https://doi.org/10.1007/s12630-012-9781-x
Wu WW, Zhang WY, Zhang WH, Yang L, Deng XQ, Ou MC, Yang YX, Liu HB, Zhu T (2019) Survival analysis of intraoperative blood salvage for patients with malignancy disease: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 98(27):e16040. https://doi.org/10.1097/md.0000000000016040
Hansen E, Hofstädter F, Taeger K (1994) Autologous blood transfusion in tumor operations. Infusionsther Transfusionsmed 21(5):337–348
Muñoz M, Laso-Morales MJ, Gómez-Ramírez S, Cadellas M, Núñez-Matas MJ, García-Erce JA (2017) Pre-operative haemoglobin levels and iron status in a large multicentre cohort of patients undergoing major elective surgery. Anaesthesia 72(7):826–834. https://doi.org/10.1111/anae.13840
Ludwig H, Evstatiev R, Kornek G, Aapro M, Bauernhofer T, Buxhofer-Ausch V, Fridrik M, Geissler D, Geissler K, Gisslinger H, Koller E, Kopetzky G, Lang A, Rumpold H, Steurer M, Kamali H, Link H (2015) Iron metabolism and iron supplementation in cancer patients. Wien Klin Wochenschr 127(23-24):907–919. https://doi.org/10.1007/s00508-015-0842-3
Aapro MS, Beguin Y, Bokemeyer C, Glaspy JA, Hedenus M, Littlewood TJ, Ludwig H, Osterborg A, Rzychon B, Mitchell D (2011) Diagnosis, treatment, and use of intravenous iron for chemotherapy-induced anemia in Europe. J Clin Oncol 29(15_suppl):e19557-e19557. https://doi.org/10.1200/jco.2011.29.15_suppl.e19557
Borstlap WA, Stellingwerf ME, Moolla Z, Musters GD, Buskens CJ, Tanis PJ, Bemelman WA (2015) Iron therapy for the treatment of preoperative anaemia in patients with colorectal carcinoma: a systematic review. Color Dis 17(12):1044–1054. https://doi.org/10.1111/codi.13110
Kam PM, Chu CW, Chan EM, Liu OL, Kwok KH (2020) Use of intravenous iron therapy in colorectal cancer patient with iron deficiency anemia: a propensity-score matched study. Int J Color Dis 35(3):521–527. https://doi.org/10.1007/s00384-020-03508-y
Quinn EM, Meland E, McGinn S, Anderson JH (2017) Correction of iron-deficiency anaemia in colorectal surgery reduces perioperative transfusion rates: a before and after study. Int J Surg 38:1–8. https://doi.org/10.1016/j.ijsu.2016.12.029
Keeler BD, Simpson JA, Ng O, Padmanabhan H, Brookes MJ, Acheson AG (2017) Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer. Br J Surg 104(3):214–221. https://doi.org/10.1002/bjs.10328
Triphaus C, Judd L, Glaser P, Goehring MH, Schmitt E, Westphal S, Füllenbach C, Lindau S, Zacharowski K, Meybohm P, Choorapoikayil S (2019) Effectiveness of preoperative iron supplementation in major surgical patients with iron deficiency: a prospective observational study. Ann Surg Publish Ahead of Print. https://doi.org/10.1097/sla.0000000000003643
Kim J, Bae JS (2016) Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediat Inflamm 2016:6058147–6058111. https://doi.org/10.1155/2016/6058147
Thielmann CM, Costa da Silva M, Muley T, Meister M, Herpel E, Muckenthaler MU (2019) Iron accumulation in tumor-associated macrophages marks an improved overall survival in patients with lung adenocarcinoma. Sci Rep 9(1):11326. https://doi.org/10.1038/s41598-019-47833-x
Beguin Y, Aapro M, Ludwig H, Mizzen L, Osterborg A (2014) Epidemiological and nonclinical studies investigating effects of iron in carcinogenesis--a critical review. Crit Rev Oncol Hematol 89(1):1–15. https://doi.org/10.1016/j.critrevonc.2013.10.008
Wilson MJ, Dekker JWT, Buettner S, Harlaar JJ, Jeekel J, Schipperus M, Zwaginga JJ (2018) The effect of intravenous iron therapy on long-term survival in anaemic colorectal cancer patients: results from a matched cohort study. Surg Oncol 27(2):192–199. https://doi.org/10.1016/j.suronc.2018.03.005
Yttersian Sletta K, Tveitarås MK, Lu N, Engelsen AST, Reed RK, Garmann-Johnsen A, Stuhr L (2017) Oxygen-dependent regulation of tumor growth and metastasis in human breast cancer xenografts. PLoS One 12(8):e0183254. https://doi.org/10.1371/journal.pone.0183254
Kim SW, Kim IK, Ha JH, Yeo CD, Kang HH, Kim JW, Lee SH (2018) Normobaric hyperoxia inhibits the progression of lung cancer by inducing apoptosis. Exp Biol Med (Maywood) 243(9):739–748. https://doi.org/10.1177/1535370218774737
Meyhoff CS, Jorgensen LN, Wetterslev J, Christensen KB, Rasmussen LS (2012) Increased long-term mortality after a high perioperative inspiratory oxygen fraction during abdominal surgery: follow-up of a randomized clinical trial. Anesth Analg 115(4):849–854. https://doi.org/10.1213/ANE.0b013e3182652a51
Cao X, White PF, Ma H (2017) An update on the management of postoperative nausea and vomiting. J Anesth 31(4):617–626. https://doi.org/10.1007/s00540-017-2363-x
McSorley ST, Dolan RD, Roxburgh CS, Horgan PG, MacKay GJ, McMillan DC (2019) Possible dose dependent effect of perioperative dexamethasone and laparoscopic surgery on the postoperative systemic inflammatory response and complications following surgery for colon cancer. Eur J Surg Oncol 45(9):1613–1618. https://doi.org/10.1016/j.ejso.2019.05.020
Sandini M, Ruscic KJ, Ferrone CR, Warshaw AL, Qadan M, Eikermann M, Lillemoe KD, Fernández-Del Castillo C (2018) Intraoperative dexamethasone decreases infectious complications after pancreaticoduodenectomy and is associated with long-term survival in pancreatic cancer. Ann Surg Oncol 25(13):4020–4026. https://doi.org/10.1245/s10434-018-6827-5
Kim MH, Kim DW, Park S, Kim JH, Lee KY, Hwang J, Yoo YC (2019) Single dose of dexamethasone is not associated with postoperative recurrence and mortality in breast cancer patients: a propensity-matched cohort study. BMC Cancer 19(1):251. https://doi.org/10.1186/s12885-019-5451-5
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Plücker, J., Wirsik, N.M., Ritter, A.S. et al. Anaesthesia as an influence in tumour progression. Langenbecks Arch Surg 406, 1283–1294 (2021). https://doi.org/10.1007/s00423-021-02078-z
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DOI: https://doi.org/10.1007/s00423-021-02078-z