1. Describe perioperative concerns in patients with metastatic cancer and associated pain

Patients with metastatic cancer present with unique perioperative challenges. Before proceeding with surgery, one should consider the patient’s functional status, nutritional status, neo-adjuvant therapies, and pain state. All of these factors can lead to loss of functional abilities secondary to deconditioning [1]. As shown in colorectal patients, recreational activity and avoidance of sedentary lifestyle have been shown to increase survival and improve quality of life [2].

Intraoperatively, positioning may need special attention. Many primary cancers metastasize to the bone, increasing the risk of pathologic fractures. Therefore, proper positioning and padding are crucial to prevent unintended injury.

However, one of the greatest challenges in patients with metastatic disease is controlling postoperative pain. Pain upregulates the hypothalamic–pituitary axis, triggering cortisol and glucocorticoid production and consequent immunosuppression [3]. Therefore uncontrolled pain can promote tumor spread and lead to cancer recurrence and metastasis [4]. Patients with pain secondary to metastases often require a high-dose opioid therapy to alleviate baseline pain. Any additional acute pain can be difficult to control secondary to tolerance and utilization of multimodal analgesics is important.

2. Review the options available for controlling this patient’s postoperative pain

The options for controlling cancer patients’ postoperative pain include regional anesthesia, pure opioids, mixed-mechanism opioids, and non-opioid analgesics. The ideal regimen is multimodal, combining RA and diverse analgesics.

Regional anesthesia is particularly helpful for opioid-tolerant chronic pain patients undergoing major surgery. A meta-analysis comparing continuous peripheral nerve blockade (CPNB) and opioid regimens found CPNB to provide superior postoperative analgesia, reduce opioid consumption, reduce opioid-related side effects, and improve patient satisfaction [5]. Furthermore, CPNB possibly reduce intraoperative bleeding and transfusion, reduce postoperative joint inflammation, improve postoperative sleep and function, hasten readiness for discharge, and prevent chronic postsurgical pain (CPSP) [6–7]. Thus, unless contraindicated or refused, CPNB should be favored over intravenous opioid patient-controlled analgesia (PCA).

Unlike pure opioids, mixed-mechanism opioids, such as tramadol and methadone, have the added benefit of targeting neuropathic components of pain via serontonin-norepinephrine reuptake inhibition or N-methyl-D-aspartate (NMDA) receptor antagonism, respectively. Notably, adding tramadol to PCA morphine improves postoperative analgesia and reduces morphine requirements [8]. In a comparison of methadone PCA to morphine PCA for total hip arthroplasty analgesia, methadone was superior in analgesic potency while similar in side effects [9]. Multiple studies and consensus guidelines support intravenous methadone for postoperative analgesia in palliative care patients with cancer pain and/or opioid tolerance [10].

Non-opioid analgesic should also be employed. The addition of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen after major surgery results in a small but significant reduction in opioid consumption [11]. The combination of NSAIDs and acetaminophen results in better postoperative analgesia than either NSAIDs or acetaminophen alone [12]. Both gabapentin and pregabalin reduce acute postoperative pain, decrease opioid consumption, and facilitate prevention of CPSP [13–14]. Additionally, gabapentin may prevent postoperative delirium and pregabalin may prevent postoperative nausea and vomiting (PONV) [15–16]. Finally, either boluses or infusions of subanesthetic doses of ketamine, an NMDA receptor antagonist, may reduce postoperative opioid requirements and CPSP while preserving respiratory drive and reducing PONV without causing other significant adverse effects [17–18].

3. List intraoperative factors that may promote tumor metastasis and discuss prevention

Ironically surgical resection may in fact cause spread of cancer cells. In breast cancer patients, surgical excision showed four-fold increase in cancer spread to sentinel nodes [22]. Similarly, hematogenous dissemination of prostatic epithelial cells has been evident after radical prostatectomy [23]. While surgery is often the curative treatment, the possibility of cancer cell spread through vascular or lymphatic channels must be considered.

Immunomodulation plays a key role in maintaining quiescence of cancer cells. Natural killer (NK), T helper 1 (Th1), and cytotoxic T lymphocytes (CTL), along with the presence of cytokines such as interferon gamma (IFN-g) and tumor necrosis factor-α (TNF-α), aid in tumor suppression. Conversely, T helper 2 cells (Th2) and tumor-associated macrophages, under the influence of multiple interleukins, promote cancer growth [24]. During the perioperative period, naïve T helper 0 (Th0) cells can preferentially differentiate to Th2 cells, which inhibit NK and CTL cells. Increased production of prostaglandin E2 via upregulation of the cyclo-oxygenase (COX) enzyme increases metastasis through the lymphatic system [24]. Also, catecholamine triggered activation of beta 1 and 2 receptors on tumor cells is associated with increased tumor aggression [25].

Current research efforts are focused on ways to minimize these deleterious effects of systemic inflammatory reaction. Using anti-inflammatory agents, such as indomethacin, aspirin, and celecoxib, has shown some antimetastatic effects [4]. Statin drugs also show promise with beneficial anti-inflammatory and immunomodulation effects, while also decreasing certain cholesterol end products required by dividing cancer cells.

Controversy surrounds the use of blood transfusion regarding its effect on tumor metastasis. Although allogeneic blood transfusions have been shown to decrease recipient’s immune response and promote tumor growth, currently no such conclusion can be made based on the available literature. In patients with colorectal cancer undergoing resection, no relationship between the amount of blood transfusion and cancer recurrence was found [26]. Transfusion of intraoperative salvaged blood does not seem to be correlated with poorer outcomes. In a recent meta-analysis, the transfusion of blood salvaged during the surgery was associated with similar outcomes as when allogenic blood was given [27]. Some advocate the use of a leukoreduction filter or irradiation; however, the absolute necessity of these has not been proven [28].

Volatile agents have been shown to cause suppression of all aspects of the immune system. This, along with surgically mediated immune suppression, has been hypothesized to be a cause of metastatic progression of cancer cells [29]. Factors that are affected by anesthetics play a key role in prevention of tumor progression. NK cells, TNF-α, hypoxia-inducible factor 1-alpha (HIF1-α), as well as matrix metalloproteinase (MMP) are some of the main factors influenced by anesthetics [29, 30]. NK cells as well as TNF-α are known to aid in detection and destruction of tumor cells. Various studies have shown that halogenated agents suppress these specific factors that aid in tumor destruction [29]. Conversely, MMP, known to facilitate tumor invasion and migration, has been found to be downregulated by sevoflurane [31]. As it seems, the exact role of volatile anesthetics in tumor progression has yet to be determined. Although tumor-promoting factors appear to be affected by volatile anesthetics, a definitive correlation has not been made.

One of the most commonly used intravenous anesthetic agents, propofol, is now being researched as possibly having an antitumor effect. Propofol suppresses HIF 1-α synthesis of proteins involved in tumor progression [32–33]. HIF1-α plays a role in regulating the GTPase RhoA, which is another factor modulated by propofol. MMP-2 and MMP-9 are inhibited by propofol, preventing migration of tumor cells via the decrease in expression of the extracelluar matrix (ECM) protein [30]. Cytotoxic T lymphocyte activity is promoted with propofol use, thereby inhibiting growth of tumor cells [33]. Ketamine has been shown to be profoundly immunosuppressive. In one study, ketamine was shown to significantly depress the activity and number of NK cells, making it the most potent immunosuppressant IV anesthetic researched [32].

Along with central nervous system (CNS) and peripheral tissue receptor location, the Mu opioid receptor (MOR) has also been found in vascular endothelial cells and is upregulated in cancer cells [34]. The most widely researched opioid with regards to tumor metastasis is morphine. Morphine was found to promote angiogenesis in breast cancer cells in animal models, leading to increased size and neovascularization of these tumors. Along with angiogenesis, morphine directly acts to upregulate Neuroepithelial cell transforming gene1, which mediates cytoskeleton organization and tumor cell migration in breast cancer cells [35]. Morphine’s direct action on the immune system via MOR on immune cells leads to a decrease in NK cell cytotoxicity, production of antibodies and cytokines, and decreased phagocytic activity of these cells [1]. In contrast to centrally and peripherally acting opioids, intrathecal opioids may not have the same immunosuppressive effects. Systemic morphine was shown to suppress lymphocyte proliferation; conversely, intrathecal morphine did not alter the function of these cells [36].

The known mechanism of action of local anesthetics is to block voltage-gated sodium channels (VGSC). These channels are found to be overexpressed in many types of cancer cells including breast, prostate, colon, non-small cell and small-cell lung cancer [37]. Inhibition of VGSC by non-local anesthetic blockers affects tumor metastasis; although, evidence to support local anesthetic inhibition is limited [38]. However, non-VGSC mediated mechanisms of LA antitumorigenic effects have been shown. Piegeler et al. looked into the antimetastatic potential of local anesthetics and found that amide LAs were able to inhibit lung cancer cell migration by inhibition of TNF- α and intercellular adhesion molecule-1 phosphorylation [39]. This is the first evidence of a molecular mechanism that appears to be independent of local anesthetics’ known role as sodium-channel blockers.