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Abstract
Cancer causes considerable suffering and 80% of advanced cancer patients experience moderate to severe pain. Surgical tumor excision remains a cornerstone of primary cancer treatment, but is also recognized as one of the greatest risk factors for metastatic spread. The perioperative period, characterized by the surgical stress response, pharmacologic-induced angiogenesis, and immunomodulation results in a physiologic environment that supports tumor spread and distant reimplantation.In the perioperative period, anesthesiologists may have a brief and uniquewindow of opportunity to modulate the unwanted consequences of the stressresponse on the immune system and minimize residual disease. This reviewdiscusses the current research on analgesic therapies and their impact ondisease progression, followed by an evidence-based evaluation of perioperativepain interventions and medications.
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Introduction
In 2018, there were an estimated 18.1 million cases of cancer diagnosed around the world and 9.6 million cancer-related deaths.1 These numbers are expected to increase to about 21.7 million newly diagnosed cancer cases and 13.0 million cancer-related deaths due to population growth and aging.2 Cancer causes considerable suffering, and 80% of patients with advanced cancer experience moderate to severe pain.3 A meta-analysis of more than 44 studies revealed that more than 50% of patients with cancer in the USA experience pain, and pain is most prevalent among patients with advanced disease. Consequently, ongoing efforts to minimize cancer recurrence and spread are justified to prolong a patient’s survival time and to minimize suffering.
Surgical tumor excision is a cornerstone of primary cancer treatment, but is also recognized as one of the greatest risk factors for metastatic spread.4 Minimum residual disease, defined as clinically undetectable cancer cells that remain after macroscopic tumor removal, can be systemically dispersed as microemboli through a variety of mechanisms.5 The perioperative period, characterized by the surgical stress response and pharmacologic-induced angiogenesis and immunomodulation, results in a physiologic environment that supports tumor spread and distant reimplantation.6
In the perioperative period, anesthesiologists may have a brief and unique window of opportunity to modulate the unwanted consequences of the stress response on the immune system and minimize residual disease. The purpose of this review is to discuss the current evidence regarding which analgesic therapies may modify disease progression. Specifically, we reviewed the impact of surgery, pain, stress response, and perioperative analgesic choices on cancer recurrence, followed by an evidence-based evaluation of perioperative pain interventions and medications.
Methods
The Board of Directors of both the American Society of Regional Anesthesia and Pain Medicine and the European Society of Regional Anaesthesia and Pain Therapy (ASRA and ESRA, respectively) approved the creation of a workgroup charged with producing this document, citing a lack of systematic, evidence-based reviews for the management of perioperative pain during primary cancer surgery. Panelists were selected to participate in the workgroup on the basis of their clinical experience, published research, and ongoing investigations in the field of anesthesia, perioperative pain management, and cancer recurrence. Fourteen researchers were selected from an international pool of candidates. These panelists neither received compensation nor declared any relevant conflicts of interest.
The initial framework, organization, and objectives of the workgroup were discussed and edited by the invited coauthors prior to the review of existing research. Once finalized, the panel conducted a search of the existing literature using Medline/PubMed, Google Scholar, Medical Subject Headings, and Cochrane Review. Specific search terms included “cancer,” “anesthesia,” “pain,” “cancer recurrence,” “immunomodulation,” “surgical stress response,” “perioperative,” and “metastasis.” Terms were combined to execute multiple queries, and searches were conducted by each panelist independently. Search results were subsequently compiled to create a single reference list for further evaluation by the workgroup.
A total of 197 articles were identified during the initial query. Based on this compilation, panelists were asked to perform reviews of the literature, summarize, and present their findings at the 2016 ASRA fall meeting. During the conference, panelists discussed issues related to perioperative pain management, analgesic techniques, and postoperative cancer recurrence in a closed forum format. Recommendations presented at this encounter were reviewed and approved by members of the workgroup. Rating systems for scientific evidence were identified and evaluated in terms of their applicability to the creation of practice advisories or consensus statements. Based on this analysis, the group adopted the GRADE process (Grading of Recommendations Assessment, Development and Evaluation) to rate the quality of scientific evidence in systematic reviews and to develop recommendations that are as evidence-based as possible.7 The authors identified several advantages to the GRADE rating system over other published methodologies. The recognized benefit of the GRADE process is that it provides specifications for framing research questions, and it evaluates outcomes of interest and available evidence while accounting for bias risk, imprecision (broad CIs), result inconsistency between studies, and indirectness (using evidence from a representative population).7 The GRADE process creates a distinction between the quality of the evidence and the strength of a recommendation. The processes for rating the quality of evidence are separate from the process of grading the strength of the recommendation. Therefore, low-quality evidence can still be associated with a strong recommendation.
All articles were reviewed by at least three panelists, who assessed the quality of evidence using the GRADE rating system. First, studies were assigned an a priori point ranking of “2” (randomized controlled trials), “1” (observational studies), or “0” (all others) points. This score was subsequently upgraded or downgraded based on the identification of positive and/or negative elements (figure 1). Strength of association, dose–response relationships, and accountability of confounders yielded higher adjusted scores. Risk of bias, contradictory data, uncertainty, and imprecision reduced the adjusted scores. The initial ranking, therefore, could yield an adjusted range of +6 to −7 points.
GRADE system initial study ranking. GRADE, Grading of Recommendations Assessment, Development and Evaluation. RR: Relative Risk
The following step involved an evaluation of the benefit:risk ratio for each study outcome (online supplementary appendix A/Supplementary Digital Content 1). A range of +2 to −1 points were assessed to the initial ranking depending on whether the spectrum of benefit was devoid or outweighed by risk (figure 2).
Supplemental material
GRADE system: benefit:risk ratio point assignment. GRADE, Grading of Recommendations Assessment, Development and Evaluation.
The third step of the GRADE system involved an evaluation of “evidence directness,” which accounts for study populations and interventions and whether they are truly representative of those which the resulting recommendations address. Positive “directness” would yield an additional 2 points to the raw rating score. The final step involved an assessment of study “relative importance.” The GRADE system requires that only important outcomes be included in evidence profiles, and these are ranked as critical or important to a decision, yielding 1–3 additional points to the overall ranking. Final GRADE recommendations were categorized according to table 1.
GRADE system: final recommendations for human studies
Because the GRADE system only applies to human clinical trials, the workgroup adopted two additional grading scales for animal and cell studies. For animal research, study quality was rated as “strong,” “average,” or “weak” in terms of its ability to be extrapolated to human disease (table 2).
Grading system for animal studies
Cell studies were also graded as “strong,” “average,” or “weak” on the basis of study design, use of human cell lines, similar dosing and exposure time to human applications, significant dose–response findings, and consistency of effect (table 3). This grading system was based on the recommendations from the National Academies of Sciences, Engineering, and Medicine and the Occupational Safety and Health Administration (OSHA) guidelines for the evaluation of experimental studies in vitro.5 6 8
Grading system for in vitro studies
Summary of findings and recommendations for future research
These results were subsequently presented to the entire workgroup for internal peer review and an open format public discussion at the 2017 ASRA spring meeting and the 2017 ESRA and ASRA fall meetings. The recommendations presented herein were approved by the workgroup, taking into consideration these internal and external reviews. As stated in the Second ASRA Practice Advisory on Neurologic Complications,9 “recommendations that rely on limited clinical and animal data and, as such, the synthesis and interpretation of data by one group of experts, may differ from conclusions by another set of equally qualified experts.” The content of this document was approved by the ASRA and ESRA Board of Directors, as well as the ASRA Guidelines and Advocacy Regulatory Committee. “The recommendations contained herein do not define standard of care nor are they to be interpreted as guidelines. They are not intended to replace clinical judgment as applied to a specific patient scenario.”9
Incidence of postoperative cancer recurrence
Global cancer burden is expected to increase by 50% by the year 2030. It is estimated that 21 million patients will hear the words “you have cancer,” and 13 million will die from malignancies in 2030.10 11 Furthermore, cancer is the second leading cause of death worldwide.12 13 The prevalence of cancer increases with age, with the highest incidence in patients 75 years of age or older (21.8%).12 In 2016, the “Lancet Oncology Commission” called surgery “one of the major pillars of cancer care and control,” and considering that surgical procedures are performed to diagnose, initiate treatment, or palliate cancer, it is expected that millions of subjects worldwide will potentially suffer from planned and unplanned perioperative events related to oncologic surgery and the pharmacologic effects of anesthetics and analgesics.14 The number of cancer survivors will dramatically increase from 15.5 million in 2016 to 20.3 million in 2026, some of which will also require surgery for non-cancer procedures.14
The most common cancer among women is breast cancer. The majority of women with stages I–III disease undergo either breast conserving surgery or mastectomy. Overall, the 5-year relative survival rate is 89% and decreases to below 80% at 15 years.14 Lung cancer remains the most common cause of death among men and women. More than two-thirds of those with stages I–II non-small cell lung cancer are treated with surgery, while only a small percentage of those with stages III–IV or small cell histology receive surgical therapy.14 Approximately half of the patients with early lung cancer are alive at 5 years after treatment.4 Surgery is still the mainstay of treatment strategies (>75%) in patients with stages I–III colorectal cancer. The 5-year survival rate of patients with colorectal malignancies is 65%, but in those with localized disease it is estimated that survival improves to 90%.14 Surgery remains the most common therapeutic option for young patients (65 years old) with localized prostate cancer.4 Almost all patients with localized prostate cancer are alive at 5 years after treatment, but the 5-year survival rate falls to less than a third in those with advanced cancer.14
The most common cause of death in patients with solid cancers, either after curative therapies or palliative interventions, is disease progression. Lung cancer is by far the leading cause of cancer death among men (27%), followed by colorectal (9%) and prostate (8%) cancers. Among women, lung (25%), breast (14%), and colorectal (8%) cancers are the leading causes of cancer death. The rate of recurrence has significantly decreased in some cancers, thereby improving survival (ie, breast cancer in women and bladder cancer in men), but remains dismal for others such as pancreatic malignancies, ovarian cancers, and bladder cancer in women.14 15 The rate and median time for cancer progression depend on several factors related to tumor biology, host factors (ie, age, gender), comorbidity or physiologic reserve, or access to effective anticancer therapies (ie, access to surgery after neoadjuvant therapy or resumption of oncologic therapies after surgery). Other causes of early recurrence or death are related to the adverse events of oncologic therapies (ie, cardiomyopathy) or infectious postoperative complications.
Surgery, pain, stress response, and cancer recurrence
Anatomically, cancer is represented by tumor cells nested in the center of an amalgamation of fibroblasts, mesenchymal cells, and blood vessels; immune cells, signaling molecules, and extracellular matrix serve as the tumor base commonly known as the tumor microenvironment. Based on recent hierarchical theory of cancer genesis, tumor progression appears to be linked to a subset of tumor cells known as “cancer stem cells” residing in a specific environment within the tumor microenvironment called the cancer stem cell niche.16 These cells have the capacity for self-renewal, tumor initiation potential, and long-term tumor reinitiating function. The niche plays a major role in maintaining cancer stem cell activity, protects the cell from the host defense mechanisms, and facilitates metastasis. More importantly, within the niche, non-cancer stem cells can convert to cancer stem cells to maintain tumor cell equilibrium or tumor cells “stemness.”17 18
Postoperative cancer recurrence can be classified as local, regional, or distant. Local recurrences are commonly the result of minimal residual disease present at the tumor bed, also known as positive surgical margins. Although “positive margin resections” can be considered as a technical failure, there are numerous reasons why “clear margins” on the resected specimen cannot be achieved. Regional (typically lymph node metastasis) and distant metastases can be formed from “dormant” or “latent” tumors already present at the time of surgery or from the seeding of systemic or lymphatic circulating tumor cells (CTCs). There is a correlation between the number of CTCs in the peripheral circulation and survival in patients with breast, prostate, and colorectal cancers. Importantly, certain genetic (eg, mutation for drug resistance) and biological (eg, signaling pathways during treatment) characteristics of the CTCs could be predictive of treatment responses.19 20 To result in distant metastasis, CTCs need to migrate through the endothelial cells to reach the extracellular environment. CTCs are then required to lodge, survive, and proliferate in the tumor microenvironment to be effective in promoting distant metastasis.
Stress response
There is some evidence that the sympathetic nervous system’s actions may play a role in tumor progression and metastasis. For example, catecholamines promote angiogenesis via vascular endothelial growth factor (VEGF) and increased interleukin-6 (IL-6) levels.21
Gunduz et al 22 transferred large and small doses of mammary adenocarcinoma cells into the left and right legs of mice, respectively. After resection of the left leg (days 14, 21, or 28), an accelerated rate of growth of the contralateral tumor was observed. This suggests that postsurgical systemic factors may have promoted tumor progression. However, it is difficult to differentiate the effects of the surgical trauma from the hormonal and metabolic effects which the larger tumor may have exerted on the contralateral tumor.
Murthy et al 23 studied the influence of surgical trauma following hepatic wedge resection and partial nephrectomy on experimental metastasis using the transplantable murine mammary carcinoma cell line, TA3Ha, into syngeneic strain A mice. They demonstrated that surgical trauma induced by both laser and electrocautery equally renders the animal susceptible to experimental metastasis formation. Tumor cell injection 1, 7, and 10 days posthepatic surgery resulted in 36%, 20%, and 0% tumor formation, respectively, indicating that the events closer to the acute trauma and earlier events in wound healing support tumor implantation and/or growth better than those later on.
Role of inflammation in tumorigenesis and tumor promotion, and immunosurveillance
Cancer immunity is considered a systematic response of various immune cells directed against cancer cell neoantigens with the specific goal of cell destruction. The mechanism of eradication of cancer cell by the immune system is now known as immunoediting.24 In this model, three successive phases are commonly described: “elimination,” “equilibrium,” and “escape.” In the elimination phase, the immune system recognizes tumor cells as non-self and destroys them. The equilibrium phase represents a period of quiescence whereby a balance between tumor cells and antitumor cell activity is maintained. In this phase, the immune system cannot completely destroy the tumor but instead keeps the tumor in a dormant state. Finally, in the escape phase, the immune system can no longer maintain the balance between tumor cells and antitumor activity and tumor cells proliferate. The consequential effects of immunosuppression on cancer recurrence and survival have been shown in patients with various types of cancer.25 26 Moreover, the magnitude of surgery correlates with the degree of immunosuppression.27 More invasive surgeries lead to extensive tissue damage and severe pain and profound immunosuppression. Postoperative cancer recurrence can be classified as local, regional, or distant.
Almost all tumors have evidence of inflammatory infiltration.20 The survival of the postoperative minimal residual disease depends on several factors of which inflammation plays an important role. Interestingly, the mechanisms that lead to inflammation, pain, and cancer growth share common pathways, such as the activation of nuclear transcription factors (NF-κB).28–30 Among the mediators released during the inflammatory process, IL-6, interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), angiogenic factors such as VEGF and endothelial growth factor, reactive oxygen species, hypoxic inducible factors (HIF1-α and HIF2-α), and NF-kB pathways are directly or indirectly implicated in cancer cell survival.30 31 In response to inflammation, IL-6, cyclooxygenase 2 (COX-2), and matrix metalloproteinase (MMP-9) proto-oncogene c (Src) tumor-promoting gene are activated. Src gene activation is known to play a key role in the development of metastasis by upregulating the intercellular adhesion molecule (ICAM-1).30 32 This promotes transformation of epithelial cells to mesenchymal cells, aiding in the extravasation of tumor cells.33 34 Iliopoulos et al 35 found IL-6 modulates the conversion of non-cancer stem cells to cancer stem cells in breast cancer cells. Recently, it was shown that the postoperative pharmacologic inhibition of IL-6 significantly decreased tumorigenesis following partial hepatectomy in a knockout mice model of liver cancer.18
Fever is a component of the postoperative inflammatory response. Postoperative fever has been independently associated with increased recurrence (Relative Risk 1.89, 95% CI 1.02 to 3.52).36 A possible mechanism is that fever-related host inflammatory response reduces eradication of neoplastic cells. Postoperative wound complications can perpetuate the inflammatory response. Wound complications were strongly associated with increased systemic recurrence after multivariate analysis in a study of 1065 patients undergoing surgery for primary breast cancer, with an HR of 2.52 (95% CI 1.69 to 3.77, p<0.0001).37
Natural killer (NK) cells are cytotoxic lymphocytes (CLS) and are a key effector of the innate immune system in responding to neoplastic and virally infected cells. Circulating cancer cells can be eliminated from the circulation by the direct tumoricidal effects of NK cells. NK cells are also an important primer of other immune cells, recruiting them through interferon-gamma.33 The role of NK cells in immune surveillance is demonstrated in a number of experimental and clinical studies, showing that NK cell activity protects against cancer progression, while a decrease in NK cell function is associated with cancer progression.34 38–46
The perioperative period is characterized by both quantitative and qualitative changes in NK cells. Animal studies have suggested that surgery may adversely affect NK cell function and contribute to the formation of metastasis. Tai et al 42 examined the role of NK cells in preventing metastases in a murine surgical stress model.42 In NK cell intact mice, surgery led to a significant increase in pulmonary metastasis from B16lacZ melanoma cells on day 3. Infiltration by memory T cells is strongly associated with better oncologic prognosis.20 It is likely that tumor-associated macrophages and myeloid-derived suppressive cells with their associated cytokines IL-6, TNF, IL-1β and IL-23 drive tumor progression.43
Summary: Surgical stress response and cancer recurrence
Recommendation of existing evidence
There is strong laboratory evidence in live animal models that the extent of primary cancer surgery increases the risk of metastasis. Clinically, laparoscopic surgery results in less recurrence compared with open surgery for colorectal cancer. Thus there is strong evidence that the surgical stress response increases the risk of cancer recurrence in this tumor type. Although all tumors are different biological entities, it is plausible that other solid tumors may also be influenced to spread, based on the extent of surgery (strong recommendation, strong evidence).
Future research
Further randomized controlled trials (RCTs) evaluating the effect of laparoscopic versus open surgery on the rate of metastasis after other tumors, for example, lung, pancreatic, and esophageal, are not within the remit or control of our specialty to undertake. They may also be ethically difficult to deliver because surgical practice now favors the near routine use of laparoscopic procedures because of proven benefits other than possible reduction in metastatic recurrence.
Effects of perioperative pain on immune function
Perioperative pain is secondary to tissue injury following surgical trauma. Additionally, the perioperative period is associated with a host of influential factors such as inflammation, hypothalamic-pituitary axis activation, and sympathetic system over-reactivity, directly or indirectly contributing to initiation and maintenance of pain. These factors, acting either separately or in combination, promote postoperative immunosuppression, and this is evidenced by the decrease in NK cell activity in both humans and animals following surgery.44–47 Painful stimuli have been shown to reduce NK lymphocytes and NK cytotoxic activity.46 48–50 A recent study found decreased T lymphocytes and NK cell levels in postoperative patients. PD-1 (programmed cell death protein 1) is a cell surface receptor expressed on T cells and pro-B cells. PD-1 binds to ligands PD-L1 and PD-L2 on the cells which express these ligands and promotes self-tolerance of these cells by suppressing T cell inflammatory activity. In the cancer disease states, the interaction of PD-L1 on the tumor cells with PD-1 on a T cell reduces T cell functional signals to prevent the immune system from attacking the tumor cells. Increased PD-1 and programmed cell death ligand-1 (PD-L1) expression was observed and correlated with surgical trauma.51 Lastly, leukocyte cellular adhesion molecules (CD11), known to play a role in inflammation and cancer, are activated by pain.52 A recent meta-analysis of animal cancer models showed the efficacy of analgesics in attenuating the metastatic process.53
Can analgesic techniques influence immunomodulation and immune cell function?
Until recently, opioid analgesia following cancer surgery has been emphasized, often neglecting multimodal approaches. Unfortunately, morphine has been shown to influence immunomodulation and immune cell function.54 55 Morphine has a negative dose-dependent action on NK cell cytotoxicity.51 56 Numerous studies have investigated the link between inflammatory mediators and morphine. Bonnet et al 57 demonstrated that morphine inhibited the production of proinflammatory cytokines, for example, TNF-α and IL-6 in monocytes. Upregulation of anti-inflammatory IL-4 mRNA, and its resulting modulation of the T helper cell balance, was demonstrated by Roy et al 58 Morphine also produces immunosuppression by inhibition of IL-2 transcription in activated T lymphocytes. CLS are important cells in tumor control. Morphine was shown to inhibit activation of CLS, mainly CD4+ and CD8+.59 60 Zhang et al 61 reported that morphine significantly reduced both immature and differentiated T cells, including cytotoxic CD8+ cells. This effect was in part mediated by a morphine-induced increase in corticosteroids. In vitro, morphine has been shown to increase CLS, modulating a potential anticancer effect.62 Human and animal data are conflicting, however. In patients following abdominal surgery, low-dose intrathecal morphine inhibited NK cell function.63 However, in chronic morphine abusers, the NK cell cytolytic activity was similar to opioid-naïve controls, whereas morphine was shown to increase cytolytic activity in NK cells in porcine models.64 65
Importantly, the synthetic opioids fentanyl, sufentanil, and alfentanil do not seem to mitigate immune system function as much as their natural counterpart, morphine. Sacerdote et al 66 found an enhanced NK cell activity after treatment with tramadol in patients undergoing uterine cancer surgery.66 The cytokine response to breast cancer surgery was evaluated in a randomized controlled fashion. In this study, several mediators of the immune system were analyzed from blood samples of patients randomized to regional paravertebral block and found that immune function was better preserved as compared with patients who did not receive paravertebral block. Tumorigenic cytokines (IL-1β and IL-8) were reduced, while antitumorigenic IL-10 was augmented.67
T helper cells that secrete cytokines which direct immune cells to attack target cells are known as Th1 cells. T helper cells which secrete cytokines that tend to oppose the activity of Th1 cells are known as Th2 cells. A higher or preserved Th1/Th2 is considered to be antitumor immunologic profile. Wada et al 68 showed a combination of general anesthesia (GA) and spinal anesthesia to preserve the Th1/Th2 cytokine balance and NK cell function, thus reducing the development of metastasis. An increase in antitumor T helper cells in the sera of patients who received GA with epidural anesthesia/analgesia for liver cancer resection was recently reported. In this report, in patients who received epidural block, Th1 frequency and Th1:Th2 ratio were slightly increased on postoperative day 2 and remarkably increased on postoperative day 7.69 Similar findings of immune preservation were described in patients with ovarian and cervical cancer.70 71 It is generally accepted that epidural analgesia and other neuraxial analgesic techniques have positive effects on immune system preservation. However, this may not be applicable to more peripheral blocks. For example, Purdy et al 72 studied the effect of rectus sheath block analgesia in patients undergoing cancer and benign surgery and could not find a difference in several biomarkers affecting immune response between patients randomized to rectus sheath block versus placebo.72 While the use of epidural anesthesia/analgesia has notable immunomodulatory effects, whether this effect is solely the result of sympathetic system blockade or secondary to systemic absorption of local anesthetics is not well delineated. In vitro studies found that therapeutic plasma concentrations of lidocaine enhance the function of NK cells.73 This confirms prior findings, citing a lesser reduction in immune function in patients receiving intravenous lidocaine compared with placebo.74 Similar findings of ameliorating postoperative immune function with ketamine and non-steroidal agents were reported.75 Observations of immunomodulation with a subset of analgesics are unequivocal and make them very appealing in the management of patients undergoing cancer surgery. There are no significant data exploring the effects of multimodal analgesia on immunomodulation. However, it is tempting to postulate that combining several analgesic agents with known immunomodulatory activity could lead to a more pronounced preservation of the immune system than any method used alone.
Summary: Analgesic techniques and influence on immunomodulation and immune cell function
Recommendation of existing evidence
There is strong evidence from human and animal data suggesting that epidural analgesia/anesthesia used alone or in combination with GA or sedation has positive effect on immune function and immunomodulation (strong recommendation for use, strong evidence).
There is also strong evidence from animal and human data that morphine has negative effects on immune function (strong recommendation for not using, average to strong recommendation). Nonetheless synthetic opioids do not seem to impact immune function (strong recommendation for use, weak to strong evidence).
Non-opioid analgesia in the form of intravenous lidocaine, non-steroidal agents, and ketamine have been found to preserve immune function (strong recommendation for use, weak to average evidence).
Multimodal analgesia is paramount in the perioperative period for several purposes (strong recommendation for use, weak evidence).
Areas of future research
RCTs of multimodal analgesia versus traditional management are needed to uncover the impact of the combination of various analgesics on immune cell function.
Perioperative analgesics
Role of morphine in cancer progression
A large amount of work has been dedicated to clarify whether morphine has a direct promoting effect on cancer progression or not. Direct effects include stimulation of tumor cell proliferation, invasion, and apoptosis. There is almost an equal number of publications reporting either a metastatic or an inhibitory effect in vitro.76–82 In animal studies, the contradictory results continue. In a rat model, for example, it was shown that intermittent injections of morphine decreased the growth of tumors of metastasizing colon cancer.83 Recently, however, it was shown that silencing the expression of the µ-opioid receptor (MOR) in Lewis lung cancer cells inhibited lung metastasis in wild-type mice by about 75%.84 Lastly, infusion of methylnaltrexone, a µ-opioid antagonist, significantly attenuated tumor growth in the same setting by up to 90%.84 Several studies have focused on the actions of MOR in the regulation of tumor growth and metastasis.85 The overexpression of MOR has been shown in both lung and prostate cancer. The theory that MOR is involved in metastasis is further supported by the diminished progression of lung carcinoma in MOR knockout mice treated with the opioid receptor antagonist naltrexone.84 Morphine does not influence the initiation of tumor development, but rather the progression of established breast tumor. This was recently demonstrated in a live animal, transgenic mouse study that found significantly decreased survival in a mouse model of breast adenocarcinoma.86 In the same study, it was found that morphine promoted lymphangiogenesis, mast cell activation and degranulation, and increased levels of inflammatory cytokines, tryptase and substance P. Morphine-treated mice had increased tumor burden and decreased length of survival.86 In an immunohistochemical study of the effect of MOR on metastasis, patients who had excision of non-small cell lung carcinoma were evaluated for their MOR status. There was a direct correlation between MOR expression and the extent of metastasis in these patients.84
The discrepancies in these results may be due to different models used, different doses of drug administered, and differing routes of administration. To extrapolate animal experimental data to human patients, a standardized protocol applicable and transferable to humans should be applied.87
Morphine and angiogenesis
Successful tumor growth depends on many factors, of which the most important are proliferation of tumor cells and angiogenesis, which are also necessary for metastasis.88 Degradation of the basement membrane, migration of endothelial cells in response to an angiogenic stimulus, and proliferation of these cells result in the rapid development of tumor vessels that are highly permeable to macromolecules and circulating inflammatory cells.89 The signal transduction cascade involved in this mechanism is known to include VEGF, PI3K-Akt (phosphoinositide 3-kinase) and eNOS (endothelial nitric oxide synthase) pathway, c-Src (proto-oncogene tyrosine-protein kinase Src), mitogen-activated protein kinase (MAPK), focal adhesion kinase, and adenosine monophosphate-activated kinase, among others. Few studies have investigated the effect of morphine on tumor cell-induced angiogenesis. Gupta et al demonstrated that, at clinically relevant concentrations, morphine stimulated human microvascular endothelial cell proliferation and angiogenesis in vitro.90 91 In vivo, these effects translated into enhanced tumor neovascularization in a breast cancer model. The same group showed that morphine promoted activation of the VEGF receptor, increased metastasis, and reduced survival in an animal model of hormone-dependent breast cancer, effects which were not blocked by naloxone. Other studies have demonstrated that morphine activates the VEGF receptors and promotes angiogenesis as well, but the effects could be blocked by methylnaltrexone.92 93 Studies have shown that chronic morphine treatment increased the levels of NOS, NO, and COX-2 in the murine kidney, mechanisms supposed to favor angiogenesis.94 Contradictory data have also been reported, however. Balasubramanian et al 95 demonstrated that morphine inhibited hypoxia-induced VEGF secretion in rat cardiomyocytes and human umbilical vein endothelial cells, and therefore reduced the potential of hypoxic tumor cells to favor angiogenesis. The same observation was made by Koodie et al 96 in a murine Lewis lung carcinoma model, but the effect of morphine was abolished by naltrexone, supporting the role of opioid receptors in this process.96 In this particular investigation, it was demonstrated that the inhibitory effect of morphine was mediated through the suppression of the hypoxia-induced mitochondrial p38 MAPK pathway.96 These contradictory results emphasize the need for standardized translational studies of morphine and cancer recurrence in patients.
Summary: Perioperative opioids and cancer recurrence
Recommendation of existing evidence
There is average laboratory evidence, from cell culture studies, that opioids may have a detrimental effect on cancer, tending to promote cancer cell migration and invasion. There is average animal data which suggest that opioids facilitate tumor spread and reduce disease-free survival in animal models of cancer. Clinically, there is weak evidence that opioids may increase the risk of metastasis in some solid tumor cancers. This emanates from prospective observational analysis of MOR expression in excised non-small cell lung cancer tissue, which shows an association between increased MOR expression in cancer tissue and metastasis (strong recommendation against use, weak to average evidence).
There are, however, discrepancies that may be due to the variability in experimental conditions, different animal models used, different doses of drug administered, and differing routes of administration. To extrapolate animal experimental data to patients, a standardized protocol applicable and transferable to humans should be applied.
Future research priorities
It is warranted to undertake an RCT of the use of opioids versus none in any of the major solid tumors, especially lung cancer. The challenges include the need to provide adequate analgesia to patients with cancer, the gold standard of which is opioids. Therefore, although there is equipoise about the basic question of whether opioids influence cancer recurrence, particular challenges would be anticipated in delivering an RCT where opioids would be withheld from one patient group after cancer surgery. The alternative acute analgesic technique would require to be reliably effective. There is a need for standardized translational studies of morphine and cancer recurrence in patients.
Non-steroidal anti-inflammatory drugs
Prostaglandins are hormone-like lipid metabolites produced by the action of cyclooxygenase on fatty acids. Prostaglandins have many physiologic and pathophysiologic actions. There are three known forms of the cyclooxygenase enzymes which are coded for by different genes. COX-1 is constitutively expressed in cells while COX-2 is an inducible form and COX-3 is mainly expressed in the central nervous system. There is a significant body of evidence suggesting that COX-derived prostaglandins contribute to tumorigenesis, and in particular prostaglandin E2 (PGE2) is implicated.91 97
The role of COX-2 and prostaglandins in tumorigenesis and invasion was first suspected after an epidemiologic evidence demonstrated that regular intake of aspirin reduced the risk of colorectal cancer.98 A further study involving the use of the non-steroidal anti-inflammatory drug (NSAID), sulindac, demonstrated that patients with familial adenomatous polyposis had a marked reduction in polyp number and size after a year, a change that was reversed by discontinuation of the drug.99 100 It was then discovered that COX-2 is overexpressed in colorectal carcinomas.101 In 76 patients with colorectal carcinomas, COX-2 was overexpressed in both the tumor epithelial cells and also in the endothelium of the tumor vessels. These investigators correlated the COX-2 expression with Dukes staging, local tumor spread, and 5-year survival and found that higher COX-2 expression correlated well with more advanced Dukes staging and a reduced survival rate, but failed to show a correlation with local tumor spread.100 Rizzo et al 102 demonstrated that colorectal carcinoma cells with COX-2 overexpression tended to metastasize more frequently than those with a less pronounced expression. In contrast to these data, the phase III randomized trial of rofecoxib in the adjuvant setting of colorectal cancer failed to demonstrate a survival advantage in the group receiving the rofecoxib and failed to show a correlation with overall prognosis.103
Up to 40%–50% of invasive breast carcinomas overexpress COX-2. COX-2 expression is highest in ductal carcinomas in situ.104 A study examining 248 cases of breast cancer demonstrated a more dramatic increase in COX-2 expression in those cells that were hormone receptor-negative and human epidermal growth factor-positive and also correlated well with activation of the oncogene AKT (a key protein associated with cell proliferation, motility, and metabolism) and with a decreased survival.105 It would also appear that silencing the COX-2 in breast cancer cells resulted in a profound decrease in metastasis and tumor onset in vitro.106 The retrospective study of Retsky et al 107 supported these findings by demonstrating a fivefold reduction in relapses within the first 18 months in patients administered ketorolac, a widely used NSAID.
Lung cancer also appears to be tightly linked to COX-2 expression. Investigators have observed COX-2 overexpression in 70%–90% of lung adenocarcinomas.108 The significance of this COX-2 overexpression has been intensely debated, with a number of studies demonstrating a significant correlation between elevated COX-2 levels and poor prognosis and more aggressive disease in non-small cell lung cancer.109 110 Both non-selective and selective COX-2 inhibition have been associated with a reduced risk of developing NSCLC of between 36% and 63%.111–113 There seems to be an indication for RCTs evaluating the effect of NSAIDs especially COX-2 inhibitors in preventing cancer recurrence after primary excisional surgery.
Summary: Perioperative NSAIDs and cancer recurrence
Recommendations of existing evidence
There is average evidence that aspirin reduces metastasis in colorectal cancer. This emanates from follow-up analysis of RCTs designed to evaluate vascular events in patients with colorectal cancer. There is weak evidence that NSAIDs used during breast cancer surgery may reduce the risk of recurrence or metastasis (strong recommendation for use, weak to average evidence).
Future research priorities
It is warranted to undertake RCT of the use of NSAIDs versus none in patients with breast and colorectal cancer. The challenges to this are the fact that these are arduous, protracted, expensive studies: The size of the change likely to be present is a relative reduction of 20%, from an absolute recurrence rate of <10% in patients with breast cancer. Therefore, n>3000 patients may be needed, with a minimum 5-year follow-up. A further challenge is the clinical reality that NSAID use is almost routine analgesic care for perioperative acute cancer surgery patients, and it may be difficult to obtain support from colleagues and patients, internationally, to implement a protocol for an RCT where 50% of patients have NSAIDs withheld.
Ketamine
Ketamine is a non-competitive, high-affinity antagonist of the N-methyl-d-aspartate (NMDA) receptor that interacts with opioid, nicotinic, and muscarinic receptors and with voltage-sensitive calcium channels preventing excessive calcium influx and cellular damage.114 115 Ketamine has anti-inflammatory actions at sedative (subanesthetic) doses.116 Furthermore, it affects the immunoregulatory activities of macrophages, neutrophils, mast cells, and white blood cells.117–121 Ketamine also affects the immune system by activation of the innate immune mechanisms while it increases serum levels of TNF-α.122 123 Forget et al 124 showed that ketamine and clonidine administration prior to surgery significantly reduced the number of lung metastasis when compared with fentanyl with a less pronounced effect of ketamine on NK cell activity. Consistent with these results, Beilin et al 75 observed attenuation of secretion of the proinflammatory cytokines IL-6 and TNF-α, and preservation of IL-2 production after preinduction intravenous injection of ketamine at low dose (0.15 mg/kg).75 Despite the apparent beneficial effects of ketamine on the immune response, mammalian target of rapamycin (mTOR) inhibition and therefore antitumorigenic effects, and analgesic properties, the long-term effects of perioperative ketamine and the impact on tumor recurrence have not been evaluated.
Summary: Ketamine and cancer recurrence
Recommendation of existing evidence
There are currently very limited human data on the benefit of ketamine in human immune modulation in patients with cancer. There is weak evidence that ketamine reduced the number of lung metastasis versus fentanyl. Animal (murine and canine) studies that show strong evidence for the use of ketamine in animal cancer models may limit the extrapolation to humans. Finally, there is weak evidence from cell studies that ketamine suppresses proinflammatory cytokine production and immunoregulatory activity of mast cells, macrophages, and neutrophil in human whole blood.
Areas of future research
There are no studies addressing the use of ketamine in the perioperative period, as an analgesic, and its impact on immunosuppression and cancer recurrence. Future research should look beyond acute molecular changes and focus on large population studies that determine the actual recurrence of cancer in patients managed perioperatively with a multimodal analgesic.
Local anesthetics
Effect of intravenous lidocaine in postoperative pain control
It is well established that lidocaine exhibits analgesic and antihyperalgesic properties.125 Numerous studies have demonstrated the beneficial effect of perioperative administration of intravenous lidocaine infusions on postoperative analgesia. For example, Rimback et al 126 demonstrated the benefits of lidocaine in treating paralytic ileus in 1990, and Ness127 reported that lidocaine has a beneficial role specifically in the treatment of visceral pain.127
The mechanisms of the analgesic and antihyperalgesic properties of lidocaine have been described in vitro and in vivo.125 128 These involve the inhibition of ion channels such as the voltage-gated sodium channels (VGSC), K+, and Ca2+, the glycinergic system, Gαq-coupled protein receptors, and the NMDA receptors. It is well known that local anesthetics, distinct from sodium channel blockade, have potent anti-inflammatory properties.129 130 Local anesthetic agents may also have anti-inflammatory actions via a non-VGSC mechanism.131 It has been shown that lidocaine and other amide local anesthetics attenuate in vivo and in vitro leukocyte adherence and transmigration, as well as priming (contact of T or B cells with an antigen) and phagocytosis.132–139 Furthermore, lidocaine reduces the levels of IL-1β, IL-6, and IL-8, and the expression of intercellular adhesion molecule-1 (ICAM-1) in activated human endothelial cells, and inhibits the release of prostanoids, thromboxanes, leukotrienes, and histamine by mastocytes.140–143 The anti-inflammatory effects of intravenous lidocaine have also been demonstrated in humans in a double-blind, randomized, placebo-controlled trial in patients undergoing colorectal surgery.144 In another randomized, placebo-controlled trial in patients undergoing abdominal hysterectomy, patients in the lidocaine group demonstrated reduced postoperative pain as well as a decrease in the plasma concentrations of IL-6 and IL-1Ra.74 Additionally, the response of lymphocyte proliferation to phytohemagglutinin-M was improved, indicating that lidocaine attenuates surgery-induced immunosuppression. While Kaba et al 145 reported that concentrations of C reactive protein (CRP) were similar in both lidocaine and control groups in patients undergoing laparoscopic colectomies, Ahn et al 146 found that in the lidocaine group the plasma concentrations of CRP were decreased in patients undergoing the same procedure within the first two postoperative days.146
It has been demonstrated that the amides (lidocaine and ropivacaine) but not the ester local anesthetic chloroprocaine inhibit human lung adenocarcinoma cell migration and proliferation. These phenomena are associated with the inhibition of the Src kinase and the intracellular adhesion molecule phosphorylation and are independent of sodium channel blockade.32 147 148 It is not completely understood whether local anesthetics downregulate VGSC accounting for their antiproliferative effects.149–151 Strongly metastatic cells (high metastatic potential) have hyperexcitable membranes, which confer their metastatic capability.152 This phenomenon was not observed in tumor cells with weak metastatic potential.153 154 In vitro studies of various types of cancer cells have demonstrated increased VGSC expression of different subtypes especially the Nav 1.5 (preferentially blocked by lidocaine) and Nav 1.7 α subunits.155–157 This, coupled with a downregulation of voltage-gated potassium channels, makes the cells more excitable, as sodium can enter with greater ease while potassium cannot efflux.
Transient receptor potential cation channel subfamily V member 6 (TRPV6), responsible for transcellular calcium absorption, is another channel whose inactivation has been implicated in inhibiting human breast cancer cell migration and invasion in vitro.158 Calcium is essential for cell migration, and some cancers (breast, ovarian, colon, and prostate) have overexpression of TRPV6.159 Jiang et al 160 recently showed that lidocaine inhibits TRPV6-expressing cancer cells by reducing calcium influx, therefore limiting their capacity for invasion and migration.
DNA methylation is an epigenetic alteration that may be responsible for the reported increase in patient survival. Numerous studies have demonstrated that DNA methylation is responsible for suppression of tumor activity and the silencing tumor-suppressor genes in specific types of cancer.161 Procaine, an ester local anesthetic, has been shown to inhibit proliferation and DNA methylation in vitro (human hepatoma cells).162 In vitro experimentation on breast cancer cells, both estrogen positive and negative cell lines, has demonstrated demethylation of DNA at clinically relevant concentrations of lidocaine and ropivacaine.152 163 Hence, both ester and amide local anesthetics may be beneficial for cancers in which DNA demethylation is enhanced, although it appears that the potency of lidocaine is far greater than that of other local anesthetic agents. The proposed mechanism by which this demethylation occurs appears to involve inhibition of DNA methyl transferase and the subsequent disinhibition of tumor suppressor genes.164
Apoptosis (cell death) plays an important role in both carcinogenesis and cancer treatment. The apoptosis rate in cancer is reduced, resulting in malignant cell survival. Voltage-gated potassium channels have been linked to increased apoptosis and growth.165 The apoptotic effect of amide local anesthetics (lidocaine and ropivacaine) has been demonstrated in vitro in human non-small cell lung cancer cells (NSCLC), as well as human thyroid cancer cells.166 167 Both of these studies implicated the involvement of the MAPK pathway as a main player in this process. A recent study in a mouse model of hepatocellular carcinoma suggested that lidocaine may have a beneficial role by enhancing caspase-dependent cancer cell apoptosis via the MAPK pathway, a signaling mechanism that can lead to uncontrolled growth for many tumors.168
Lidocaine is the only local anesthetic used systemically for the treatment of postoperative pain. Apart from the analgesic effects, protection of the immune system, and reduction in opioid requirement, preclinical or clinical studies are required to demonstrate the beneficial role of using local anesthetics systemically (eg, intravenous lidocaine infusions) in cancer surgery.
Summary: Effect of intravenous lidocaine and cancer recurrence
Recommendation of existing evidence
There is currently strong evidence from in vitro studies suggesting the protective effect of local anesthetics on cancer recurrence. With the exception of sparse animal studies, there is a lack of preclinical or clinical investigations indicating their beneficial role in cancer surgery. There is no existing evidence to support any clinical recommendations. Given the relatively low risk and promising animal data, however, a weak recommendation may be supported.
Areas of future research
There is currently a need to conduct human prospective randomized controlled studies (RCTs), specifically with intravenous lidocaine infusions, in order to make any clinical recommendations. More importantly, proof-of-concept, smaller pilot studies demonstrate that intravenous lidocaine infusions may alter cancer cell biology and thus reduce recurrence.
Alpha-2 agonists
The α2-receptors constitute a family of G-protein-coupled receptors with three pharmacologic subtypes, α2A, α2B, and α2C. Dexmedetomidine is also commonly used in the perioperative period and has a higher affinity for the α2 than α1 adrenoreceptor (1620:1). Dexmedetomidine improves short-term mortality in patients with sepsis.169 170 Potential explanations for those beneficial effects may be related to their anti-inflammatory effects. In vitro studies have shown a decrease in cytokine release in response to lipopolysaccharide from macrophages and glial cells exposed to dexmedetomidine.171–173 Likewise, animal models of acute lung injury reveal reduced TNF-α expression mediated by inhibition of MAPK.174 An RCT, comparing the anti-inflammatory effects of dexmedetomidine and midazolam, revealed lower systemic levels of TNF-α, IL-1β, and IL-6 in those patients with sepsis treated with dexmedetomidine.175
Despite all these potential benefits of α2 agonists on the modulation of the inflammatory response triggered by surgery, it is important to consider that several cancer cell lines, including pancreatic and breast cancer cells, express α2 adrenoreceptors.176 177 Additional in vitro and in vivo studies demonstrated increased proliferation, migration, and invasion of breast cancer cells exposed to dexmedetomidine, mediated by extracellular-signal-regulated kinase (ERK) signaling pathway.178
Summary: Alpha-2 agonists and cancer recurrence
Recommendations of existing evidence
Alpha-2 adrenoreceptors are expressed in human breast cancer cells and may play a critical role in the genesis of human breast cancer. As such, dexmedetomidine, an alpha-2 adrenergic agonist with sedative, analgesic, and hemodynamic effects, widely used in the perioperative period, seems like an obvious drug to evaluate immune modulation in the perioperative period. Unfortunately, no clinical human study has evaluated this option and there is no evidence whether the use of perioperative dexmedetomidine affects cancer recurrence.
Two in vitro studies in human cell lines show strong evidence that dexmedetomidine ameliorates the inflammatory response. Unfortunately, these studies did not evaluate any cancer-related conditions. Other in vitro studies used murine cell lines and the level of evidence is average. Some cell studies have demonstrated increased tumor cell activity with exposure to dexmedetomidine.
Areas of future research
Considering the wide use of this drug in the perioperative period and the known role of alpha-2 adrenoreceptors in breast cancer, a large RCT is warranted to determine the potential long-term effects of dexmedetomidine in cancer recurrence and development of metastasis.
Steroids
Dexamethasone
Steroids administered in the perioperative period have immune-modulating effects that include suppression of NK cells and enhanced resistance of the tumor cell to apoptosis.179 180 Dexamethasone is a frequently used antiemetic in the perioperative period. A recent study reporting the 5-year follow-up of patients who received dexamethasone or placebo before elective colectomy for colon cancer or non-small cell lung cancer found no difference in overall or disease-free survival. Patients who received a dose of 4–10 mg of dexamethasone had a significantly higher rate of distant recurrence but a non-significant trend toward higher cancer-specific mortality.181
Summary: Dexamethasone and cancer recurrence
Evidence of existing evidence
There is weak evidence that dexamethasone used as a prophylactic antiemetic during colorectal cancer surgery may produce an increased risk of cancer recurrence or metastasis but no change in cancer-specific mortality (conflicting weak recommendations for and against use, weak evidence).
Future research priorities
It is warranted to undertake RCTs on the use of dexamethasone versus placebo in patients with cancer. The primary challenge to such a study is the fact that this would be an arduous, protracted, expensive trial: The size of the impact likely to be present is a relative reduction of 20%, from an absolute recurrence rate of <20% in patients with colorectal cancer. Therefore, n>2000 patients may be needed, with minimum 5-year follow-up.
Perioperative pain interventions and cancer
To date, there is no level 1 evidence indicating that the use of any regional anesthesia technique during oncologic surgery has an impact on the progression or formation of new metastasis. There are a number of potential mechanisms by which regional anesthesia may affect the rate of recurrence, including reduction or abolition of the neuroendocrine component of the stress response, reduction in the requirement for opioids and volatile anesthetics, modulation of the immune system, the direct effect of local anesthetics, and a reduced secretion of proangiogenic factors such as VEGF.
Nerve blocks
Although there are ongoing multicenter prospective RCTs to evaluate the effects of paravertebral anesthesia on breast cancer (NCT00418457) and the effects of epidural anesthesia on colorectal cancer (NCT00684229), all current research on the long-term outcomes of regional anesthesia in cancer surgery comes from retrospective human and live animal studies.
There are early animal studies which clearly demonstrate an effect of regional anesthesia in rat cancer models.182 183 Two retrospective human trials looking at the effects of regional anesthesia on metastasis and survival have generated interest in this field. The first, a study by Exadaktylos and colleagues in 2006,184 compared patients undergoing breast cancer surgery under paravertebral nerve block and propofol total intravenous anesthesia (TIVA) with patients receiving a balanced volatile-based general anesthetic with opioid analgesia. Recurrence and metastasis-free survival was 94% and 77% (68%–87%) at 36 months in the paravertebral and GA patients, respectively (p=0.012). The same investigators compared patients receiving an epidural and general anesthetic with those who received a general anesthetic and postoperative patient controlled analgesia (PCA) for radical prostatectomy. They found that patients who received GA with epidural analgesia had a 57% lower risk of cancer recurrence than patients who had GA and postoperative opioids.184 In contrast to these results, there are other studies which did not find a difference in recurrence or metastasis when regional anesthesia was used. One such retrospective study compared recurrence rates of those patients who received an epidural with those who did not during surgical removal of late-stage ovarian malignancy.185 However, a retrospective study on the influence of epidural anesthesia for upper operative resection of gastroenterologic malignancies found that there were differing associations between epidural anesthesia and esophageal tumors versus gastric tumors, and that histologic tumor grade may determine the potential benefits of epidural anesthesia on cancer recurrence. Furthermore, this retrospective study suggested an association between longer duration of epidural exposure and lower cancer recurrence rates, suggesting a dose–response effect.186
Another retrospective study looking at the effects of regional anesthesia in surgery for colorectal carcinoma found that it did not reduce overall recurrence in patients younger than 64 years of age, but did find a small difference in those patients above this age.187 A long-term follow-up analysis of the Multicenter Australian Study of Epidural Anesthesia and Analgesia in Major Surgery (MASTER) trial, the first prospective clinical study in which patients undergoing laparotomy were randomized to receive GA with either epidural or opioid analgesia, found no difference in cancer-free survival rates between study groups. The median time to recurrence of cancer or death was 2.8 (95% CI 0.7 to 8.7) years in the control group and 2.6 (95% CI 0.7 to 8.7) years in the epidural group (p=0.61). Recurrence-free survival was similar in both epidural and control groups (HR 0.95, 95% CI 0.76 to 1.17, p=0.61).188 Possible confounding factors include an increased requirement for volatile anesthetic in the opioid analgesia group.
Experimental data from an inoculation model of breast cancer in live animal models suggest that regional anesthesia attenuates the perioperative immunosuppression, particularly by preserving NK cell function.189 Data from another animal model suggest that regional anesthesia modifies the circulating T lymphocyte population perioperatively, in a manner conducive to resisting hepatic tumor development.190 Serum drawn from women undergoing surgery for breast cancer, who were randomized to receive a paravertebral block and TIVA anesthetic technique, led to greater human donor NK cell cytotoxicity in vitro compared with serum from women who received GA. A further study by the same group found that the serum from patients randomized to receive the balanced general anesthetic had decreased apoptotic rates in estrogen receptor-negative breast cancer.180 Desmond and colleagues191 examined breast tissue excised from patients in the NCT00418457 trial, looking at the differential effect of paravertebral regional anesthesia with TIVA versus GA (with volatile) and morphine analgesia for breast cancer excision on metastasis. The tissue of 28 patients was stained for CD56 (NK cells), CD4 (T helper cells), CD8 (T suppressor cells), and CD68 (macrophages). Examination of the stained slides revealed a significantly lower NK cell population in the group that received the regional block and TIVA. There were no differences in CD68 or CD8 populations.179
There are a number of biological functions which are essential for cancer cells to survive, thrive, and metastasize. A number of studies have focused on the direct effect of regional anesthesia on angiogenesis. Angiogenesis is stimulated partly by synthesis and secretion of VEGF. There is some debate over whether or not regional anesthesia can reduce angiogenesis. There are three prominent prospective trials investigating the effect of regional anesthesia on the postoperative levels of factors promoting angiogenesis. The first of these studies compares the levels of VEGF and PGE2 in 30 patients undergoing breast cancer surgery.191–194 Patients were randomized into two groups: one group received a paravertebral block, while the other group was managed with morphine analgesia. Both groups received a general anesthetic with sevoflurane and nitrous oxide. Venous blood samples were taken preoperatively and at 4 and 24 hours postoperatively and tested for VEGF and PGE2. No difference was demonstrated between the groups.
In a study by the same investigators, 40 patients undergoing breast cancer surgery were randomized to get either a paravertebral nerve block and TIVA, while the second group received sevoflurane GA plus morphine analgesia as part of the international prospective RCT (NCT00418457). The results showed a mean postoperative change in VEGF concentrations among GA patients of 733 pg/mL vs 27 pg/mL for paravertebral and TIVA patients (difference, 706 (97.5% CI 280 to 1130) pg/mL, p=0.001). In contrast, the mean postoperative change in transforming growth factor β concentration among GA patients was −163 pg/mL vs 146 pg/mL for paravertebral and TIVA patients (difference, 309 (97.5% CI −474 to −143) pg/mL, p=0.005).195
The third prospective study investigating the effect of regional anesthesia on VEGF levels in cancer surgery looked at the effect of an epidural regional technique for colorectal cancer. This study involved randomization of 40 patients into two equal groups: the control group received a general anesthetic with volatile-based GA and morphine analgesia, while the other group received an epidural and TIVA with propofol. Significantly, patients who received an epidural and TIVA showed decreases in VEGF (526 (261) vs 834 (304) pg mL (−1), p=0.001) and TGF-β (p=0.027) 24 hours after surgery compared with patients subjected to GA.195
Summary: Perioperative regional anesthesia and cancer recurrence
Recommendation of existing evidence
There is weak evidence from multiple retrospective analyses in multiple tumor types that regional analgesia techniques might reduce metastasis. But these are only hypothesis-generating associations, and there are almost as many retrospective analyses refuting any such association (conflicting weak recommendations for and against use, weak evidence).
Future research priorities
Given the conflicting results of the review, no recommendation can be made at this time. A number of clinical trials, at least n=9, are registered evaluating various regional analgesia techniques, usually against opioid analgesia in various forms of cancer. The challenges are the fact that these are arduous, protracted, expensive studies: The size of the change likely to be present is a small relative reduction in recurrence, from a low absolute recurrence rate. Therefore, n>3000 patients may be needed, with a minimum 5-year follow-up.
Neuraxial blocks (human studies)
A meta-analysis published in 2012 found no significant impact of neuraxial anesthesia on NK cell function; more recent studies, however, suggest the opposite. Two RCTs compared the effects of epidural anesthesia on NK cell function and circulating cytokines in women who underwent ovarian or cervical cancer surgery. Both studies demonstrated that women treated with epidural anesthesia had significantly higher NK cell function and lower inflammatory profile (lower concentrations of IL-1 and higher concentrations of IL-10) than those treated with intravenous opioid analgesia.64 65 Another two RCTs conducted in patients with esophageal and gastric cancers also demonstrated that the use of thoracic epidural analgesia significantly decreased circulating proinflammatory markers and had protective effects on the function of NK cells.196 197 Contrary to these two previous studies, the use of epidural analgesia did not have a significant impact on proinflammatory cytokines in patients who had radical prostatectomy for prostate cancer. It is worth mentioning that those patients who received epidural analgesia showed lower circulating concentrations of IL-17 than those who did not.198 IL-17 has important implications in patients with cancer because it stimulates angiogenesis and inhibits apoptosis of cancer cells, and its receptor is highly expressed in cancer-associated fibroblasts of patients with prostate cancer.193 194
There are more than a dozen retrospective studies that investigated the association between the use of neuraxial anesthesia or analgesia and lower rates of cancer recurrence. Unfortunately, the results from these studies are controversial because of several factors, including the inherent bias of retrospective studies, lack of standardization of outcomes, and significant confounders such as tumor staging (early vs advanced), tumor mutation, timing of neuraxial analgesia (intraoperative vs postoperative vs perioperative), or use of different anesthetic maintenance (volatile vs propofol infusion).
In summary, RCTs show that neuraxial anesthesia/analgesia decreases the inflammatory response and has at least a partial protective effect in some of the immunologic derangements associated with surgery. However, there is an absence of published literature from RCTs assessing the impact on disease-free survival or tumor recurrence rates.
Summary: Neuraxial blocks and cancer recurrence
Recommendations of existing evidence
There are five RCTs demonstrating a small-to-moderate protective role of epidural anesthesia on the immune function and inflammatory response (strong evidence, weak for using).
Areas of future research
Future studies are needed to elucidate whether the magnitude of immune protection offered by neuraxial anesthesia translates into longer survival times after cancer surgery.
Conclusions
The number of cancer survivors will dramatically increase from 15.5 million in 2016 to 20.3 million in 2026. The incidence of tumor recurrence and metastatic disease after curative surgery is multifactorial, but there is significant evidence that perioperative events may play a significant role in these occurrences. Moreover, some of these patients will also require surgery for non-cancer conditions. Consequently, the therapeutic choices for preoperative, intraoperative, and postoperative care may play an important role in the survival rate. We have outlined the multiple conditions that may affect tumor progression and metastasis and summarized the recommendations of existing evidence and the potential for future research in each of these areas. These recommendations are particularly important in the area of postoperative pain and the role of opioids in tumor recurrence. Likewise, the potential benefit of NSAIDs, ketamine, alpha-2 agonists, and dexamethasone is outlined, although the evidence is weak at this point. It is noteworthy that in vitro studies with intravenous lidocaine infusion have shown promising results in altering tumor cell biology and could potentially affect tumor recurrence. The evidence on the use of regional anesthesia, including neuraxial blocks, as a tool to reduce tumor recurrence and metastasis, was evaluated. It was concluded that there is conflicting evidence for and against its use for this purpose.
Based on our analysis, RCTs are recommended to determine the role of different anesthetic and analgesic techniques, recognizing the major hurdles to complete the type of studies because of the number of patients to be randomized, the evaluation in a single type of cancer, and the long-term follow-up (table 4).
Acknowledgments
The authors would like to acknowledge Carlos Alejandro Marrero Benedetti.
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Footnotes
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required
Provenance and peer review Not commissioned; externally peer reviewed