Summary Surgery is an important treatment modality for the majority of solid organ cancers. Unfortunately, cancer recurrence following surgery of curative intent is common, and typically results in refractory disease and patient death. Surgery and other perioperative interventions induce a biological state conducive to the survival and growth of residual cancer cells released from the primary tumour intraoperatively, which may influence the risk of a subsequent metastatic disease. Evidence is accumulating that anaesthetic and analgesic interventions could affect many of these pathophysiological processes, influencing risk of cancer recurrence in either a beneficial or detrimental way. Much of this evidence is from experimental in vitro and in vivo models, with clinical evidence largely limited to retrospective observational studies or post hoc analysis of RCTs originally designed to evaluate non-cancer outcomes. This narrative review summarises the current state of evidence regarding the potential effect of perioperative anaesthetic and analgesic interventions on cancer biology and clinical outcomes. Proving a causal link will require data from prospective RCTs with oncological outcomes as primary endpoints, a number of which will report in the coming years. Until then, there is insufficient evidence to recommend any particular anaesthetic or analgesic technique for patients undergoing tumour resection surgery on the basis that it might alter the risk of recurrence or metastasis.

Influence of perioperative anaesthetic and analgesic interventions on oncological outcomes: a narrative review.

Background Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC. Methods Consecutive patients with stage I–III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data. Results A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88–0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89–1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells. Conclusions We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.

Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer

Understanding the intersection of the biology of pain, opioid therapy, and disease progression and survival is complicated and potentially of great importance in cancer care. Pain occurs in twothirds of patients with advanced malignancy and continues to impact a third of patients with cancer even after completion of curative treatment. Pain and other symptoms affect quality of life (QoL) during and after treatment. In addition, pain itself has been associated with shorter survival in diverse malignancies. As long as the benefits clearly outweigh risks, and opioids are safe and effective for cancer-related pain, this therapy is an important option. Like all medical drugs, however, opioids have unavoidable adverse effects. These include constipation, nausea, sedation, cardiovascular instability, respiratory depression, central nervous system toxicity, hyperalgesia, tolerance, and opioid use disorder. Such risks are well understood and typically discussed with patients. On the other hand, there is less awareness about the potential adverse effects of pain and opioids on the growth of certain cancers. Here, we review the evidence regarding opioid therapy, disease progression, and survival to raise awareness and stimulate greater dialogue regarding these issues among stakeholders in the cancer and pain communities. By doing so, our goal is that patients with cancer will be better positioned to address their coexisting priorities of pain relief and survival. The analgesic activity of opioids is mediated through mu-opioid receptors (MORs) in the central nervous system. Mu-opioid receptors are also present on endothelial cells and in human tumors (peripheral MORs), including prostate and lung cancer. Preclinical studies show that opioids promote angiogenesis by stimulating endothelial proliferation and migration and by activating survivaland growth-promoting signaling through protein kinase B (Akt) and mitogen-activated protein kinase pathways, respectively, in the endothelium (Fig. 1). In addition to promoting tumor angiogenesis, chronic morphine treatment also stimulates lymphangiogenesis, activates mast cells, promotes tumor growth and metastasis, impairs survival in mouse models of breast cancer, and is immunosuppressive. Furthermore, MORs and receptor tyrosine kinases are expressed and colocalized in advanced lung cancer, which may play a role in cancer growth and spread. Preclinical studies provide strong evidence that in animal models of several different malignancies, activation of peripheral MORs (on endothelial cells and tumors) by clinically used opioid medications promotes tumor progression through several different mechanisms. These involve signal transducers and activators of transcription 3 (STAT3), mitogen-activated protein kinase/extracellular signal–regulated kinase and Akt signaling pathways, nitric oxide synthesis, cyclooxygenase (COX)-2 activation, prostaglandin E2 production, cross-activation of epidermal growth factor receptor and vascular endothelial growth factor receptor 2 (VEGFR2), release of substance P, and mast cell activation. Our recent findings on morphineinduced retinal neovascularization in mice with sickle cell disease further validate the role of morphine in promoting angiogenesis through coactivation of VEGFR2 and the contribution of inflammatory cytokines and the STAT3 pathway in stimulating expression of endothelialMOR.Heightened inflammation aswell as activation of VEGFR2 and STAT3 signaling are the rule, not the exception, in most cancers. Importantly, opioids through MORs contribute to epithelial mesenchymal transformation in lung cancer, a process critical for progression of this cancer. Recent clinical studies raise the possibility that thesemechanismsmay play a role in both cancer progression andnociception in patients. Thesemechanistic insights also provide targets for intervention to ameliorate the inadvertent effect of opioids on cancer progression and QoL (Fig. 1). Pain also increases circulating endogenous opioid (eg, endorphin) levels and causes significant immunosuppression. Therefore, it is possible that even in patients who are not receiving opioid medications, elevated levels of endogenous opioids may activate peripheral MORs and cross-activate signaling pathways that influence tumor progression. Patients with inadequate pain control after major surgery also develop significant immunosuppression. These mechanisms may contribute to the known adverse prognostic effect of pain in malignancies. Several lines of evidence suggest that pain, systemic opioid exposure, and opioid receptor activity may be associated with adverse cancer outcomes in humans. In early-stage cancers (primarily those treated with potentially curative surgery), some retrospective studies reported that exposure to systemic opioids during anesthesia for cancer surgerywas associatedwith a higher incidence of recurrence and metastases, but other studies noted no such association. Opioid reduction strategies with multimodal analgesia have been investigated as a potential Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Pain, opioid therapy, and survival: a needed discussion

Background Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied. Methods Surgical patients (N=740) with pathological stage I–III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database. Results On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24–0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02–1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways. Conclusions Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.

Intraoperative opioid exposure, tumour genomic alterations, and survival differences in people with lung adenocarcinoma.

BACKGROUND Opioid-induced hyperalgesia is a state of nociceptive sensitisation secondary to opioid administration. The objective of this meta-analysis was to test the hypothesis that high-dose intraoperative opioids contribute to increased post-operative pain and hyperalgesia when compared with a low-dose regimen in patients under general anaesthesia. METHODS We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and rated the certainty of evidence with the Grading of Recommendations, Assessment, Development and Evaluation system. Only trials investigating pain outcomes and comparing two different dosages of the same intraoperative opioid in patients under general anaesthesia were included. The primary outcome was pain score (analogue scale, 0-10) at 24 post-operative hours. Secondary outcomes included pain score and cumulative intravenous morphine equivalents (mg) consumed at 2 post-operative hours, together with mechanical pain threshold (g·mm-2 ). RESULTS Twenty-seven randomised controlled trials, including 1630 patients, were identified. Pain score at rest at 24 post-operative hours was increased in the high-dose group (mean difference [95% CI]: -0.2 [-0.4, -0.1]; trial sequential analysis-adjusted CI: -0.4, -0.02; low certainty of evidence). Similarly, at 2 post-operative hours, both pain score (mean difference [95% CI]: -0.4 [-0.6, -0.2]; low certainty of evidence) and cumulative intravenous morphine equivalents consumed (mean difference [95% CI]: -1.6 mg [-2.6, -0.7]; low certainty of evidence) were significantly higher in the high-dose group. Finally, the threshold for mechanical pain was significantly lower in the high-dose group (mean difference to pressure [95% CI]: 3.8 g·mm-2 [1.8, 5.8]; low certainty of evidence). CONCLUSIONS There is low certainty of evidence that high-dose intraoperative opioid administration increases pain scores in the post-operative period, when compared with a low-dose regimen.

Low- versus high-dose intraoperative opioids: A systematic review with meta-analyses and trial sequential analyses.

BACKGROUND Perioperative opioid use is associated with poor survival in patients with esophageal squamous cell carcinoma. The most common histological type of esophageal cancer in western countries is adenocarcinoma. The objective of this study was to evaluate the association between intraoperative opioid consumption and survival in patients with adenocarcinoma and squamous cell carcinoma of the esophagus. METHODS Records of patients who had undergone esophageal cancer surgery between January 2000 and January 2017 were reviewed. Comparisons were made between patients who received high versus low intraoperative doses of opioids. Groups were divided using the recursive partitioning method. Multicovariate Cox proportional hazards models were fitted to evaluate the impact of intraoperative opioid use on recurrence-free survival (RFS) and overall survival (OS). RESULTS For patients with esophageal squamous cell carcinoma, the univariable analysis indicated that lower opioid dosages (<710 μg fentanyl equivalents) were significantly associated with worse RFS (P = .009) and OS (P = .002). With the adjustment of age, stage, and adjuvant chemotherapy, multivariable analysis confirmed significant associations between higher dosages of intraoperative fentanyl equivalents and better RFS (P = .002; hazard ratio [HR], 0.376; 95% confidence interval [CI], 0.201~0.704). Likewise, higher intraoperative fentanyl equivalents administered was associated with improved OS (P = .002; HR, 0.346; 95% CI, 0.177~0.676). In the adenocarcinoma population, the association between intraoperative opioid dosage and RFS (P = .15) or OS (P = .36) was not significant from univariable analysis. With the adjustment of age, body mass index, tumor staging, neoadjuvant chemotherapy, and adjuvant chemotherapy, multivariable analysis demonstrated marginal significant association between intraoperative fentanyl equivalents and RFS (P = .0866; HR, 0.806; 95% CI, 0.629~1.032). The association between intraoperative fentanyl equivalents and OS was not significant (P = .51). CONCLUSIONS The results of this study indicate that the amounts of intraoperative opioids used are associated with recurrence and OS in patients with esophageal squamous cell carcinoma. The association between the dose of intraoperative opioids used and RFS was marginally significant in patients with adenocarcinoma. Until confirmation on our findings by future studies, opioids should continue to be a key component of balanced anesthesia in patients with esophageal cancer.

Effects of Intraoperative Opioid Use on Recurrence-Free and Overall Survival in Patients With Esophageal Adenocarcinoma and Squamous Cell Carcinoma.

Background Recently, the concept of persistent postsurgical opioid use has been described for patients undergoing cancer surgery. Our hypothesis was based on the premise that patients with oral tongue cancer require high dosages of opioids before, during, and after surgery, and thus a large percentage of patients might develop persistent postsurgical opioid use. Methods After institutional review board approval, we conducted a retrospective study that included a cohort of patients with oral tongue cancers who underwent curative-intent surgery in our institution. Multivariable logistic regression models were fit to study the association of the characteristics of several patients with persistent (six months after surgery) and chronic (12 months after surgery) postoperative opioid use. Results A total of 362 patients with oral tongue malignancies were included in the study. The rate of persistent use of opioids after surgery was 31%. Multivariate analysis showed that patients taking opioids before surgery and those receiving adjuvant therapy were 2.9 and 1.78 times more likely to use opioids six months after surgery. Fifteen percent of the patients were taking opioids 12 months after surgery. After adjusting for clinically relevant covariates, patients complaining of moderate tongue pain before surgery and those taking opioids preoperatively had at least three times higher risk of still using these analgesics one year after surgery. Conclusions Patients with oral tongue cancers have a high risk of developing persistent and chronic postsurgical opioid use.

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

Supplemental Digital Content is Available in the Text. Squamouscell carcinoma cells promoted an inflammatory microenvironment and induced sensitization of both human and rat dorsal root ganglion neurons in patch clamp electrophysiology recordings. Abstract Introduction: Currently, cancer pain is viewed as a process orchestrated by the release of pronociceptive molecules and the invasion of neural structures, referred to as perineural invasion (PNI). Cancer pain resulting from PNI is well-documented, but the mechanisms leading to peripheral sensitization because of tumor growth are not fully known. Methods: A retrospective study was used to examine how the use of anti-inflammatory medications affected preoperative pain in patients with oral squamous cell carcinoma cancer. We then used an in vitro coculture model in which dorsal root ganglion (DRG) neurons were incubated together with Fadu human head and neck squamous cell carcinoma cancer cells to explore how cancer cells affect the electrical membrane properties of sensory neurons. Results: We found that inflammation contributes to preoperative pain in patients with oral squamous cell carcinoma. After coculture with Fadu human head and neck squamous cell carcinoma cancer cells, we identified markers of inflammation in coculture media and found evidence of neuronal sensitization, including spontaneous activity, reduced current thresholds, depolarized resting membrane potential, and enhanced responses to current stimulation in human and rat DRG neurons. In rats, these effects were influenced by sex and age: neurons from young adult female rats were resistant to changes in neuronal activity, in contrast to neurons from older adult female rats or male rats of either age group. Conclusions: Pro-inflammatory substances released in cancer cell–DRG coculture promoted neuronal hyperexcitability and may contribute to cancer pain after PNI, and these effects may differ across age groups and sexes.

Kim N. Du

Papers

Effects of Intraoperative Opioid Use on Recurrence-Free and Overall Survival in Patients With Esophageal Adenocarcinoma and Squamous Cell Carcinoma.

Persistent and Chronic Postoperative Opioid Use in a Cohort of Patients with Oral Tongue Squamous Cell Carcinoma.

Fadu head and neck squamous cell carcinoma induces hyperexcitability of primary sensory neurons in an in vitro coculture model